ADMINISTRATION OF LEVODOPA AND CARBIDOPAFIELD OF THE INVENTIONThe invention relates to substances, compositions, dosage forms and methods comprising levodopa and / or carbidopa.
BACKGROUND OF THE INVENTIONParkinson's disease is a neurodegenerative, progressive disorder of the extrapyramidal nervous system that affects the mobility and control of the muscular skeletal system. Its characteristic aspects include tremor at rest, rigidity, and bradykinetic movements. The aureus pattern of the present therapy for Parkinson's Disease is the drug levodopa (also called L-dopa). Levodopa, an aromatic amino acid, is a white, crystalline compound with a molecular weight of 197.2. It is designated chemically as (-) - L- (alpha) -amino- (beta) - (3,4-dihydroxybenzene) propanoic acid. Its empirical formula is c9 H .. N04 and its structural formula is:Current evidence indicates that the symptoms of Parkinson's disease are related to the drastic reduction of dopamine in the striatum. The administration of dopamine is ineffective in the treatment of Parkinson's disease apparently because it does not cross the blood barrier of the brain. Levodopa, however, can cross the blood barrier of the brain through a large neutral amino acid carrier transport system. Presumably Levodopa becomes dopamine in the brain. It is believed that this is the mechanism through which Levodopa relieves the symptoms of Parkinson's disease. Usually Levodopa is combined with carbidopa.
Carbidopa, an aromatic amino acid decarboxylation inhibitor, is a white crystalline compound, slightly soluble in water, with a molecular weight of 244. 3. It is chemically designed as (-) - L - ((alpha) - acid monohydrate. hydrazino - ((alpha) -methyl- (beta) - (3,4-dihydrobenzene) propanoic Its empirical formula is C? oH14N2O4 • H2O, and its structural formula isWhen Levodopa is administered orally it is rapidly decarboxylated in the extracerebral tissues so that only a small portion of a given dose is transported without changes to the central nervous system. Carbidopa inhibits the decarboxylation of peripheral Levodopa,making Levodopa more available for brain transport. When co-administered with Levodopa, carbidopa increases the plasma levels of Levodopa and reduces the amount of Levodopa required to produce a given response of around 75%. Carbidopa prolongs the half-life of Levodopa plasma by 50 minutes to 1.5 hours and decreases plasma and urinary dopamine and its main metabolites, homovanillic acid. The above compounds have been incorporated into a variety of oral immediate release dosage forms, such as Sinemet ™ (carbidopa and Levodopa). Conventional controlled release versions of these oral dosage forms have also been developed, such as Sinemet ™ CR. One problem with these conventional oral dosage forms is that they do not provide particularly good control of Parkinson's disease compared to other therapies. For example, long-term studies of intraduodenal infusion of Levodopa / carbidopa solutions find that motor fluctuations in Parkinson's patients can be markedly reduced. These infusion techniques show a positive effect even after 4-7 years of duodenal infusion continues. D. Nilsson and golds, "Duodenal levodopa infusion in Parkinson's disease-long term experience", Acta Neurol Sean 104: 343-348 (2001). Said intraduodenal infusion has been shown to be superior to the oral dosage of Levodopa and carbidopa using dosage forms ofconventional oral controlled release. D. Nyholm et al., "Optimizing Levodopa Phannacokinetics: Intestinal Infusion Versus Oral Sustained- Release Tablets", Clin. Neuropharmacology 26 (3): 156-163, (2003). The average intraindividual coefficient of variation for Levodopa concentrations in the plasma was 34% and was significantly lower (14%, p <; 0.01) during infusion continues. The video evaluations per hour showed a significant increase in the ACTIVATED time (evidenced through a normal or close to normal ability to perform the specified motor tasks) during the infusion and a significant decrease in time OFF (severe Parkinson's disease) ) and dyskinesia. The peak effect of the dyskinesias is suppressed, resulting in the elimination of the peaks of the concentrations of Levodopa and central dopamine. With respect to the superior therapeutic functioning of such long-term infusion strategies, they remain difficult and inconvenient to increase, since they require the patient to be tied to a pump during all waking hours. Additionally, a malfunction of the pump can occur, resulting in severe problems for the patient with Parkinson's. Accordingly, substances, compositions, dosage forms and methods for conducting the aforementioned problems are necessary.
BRIEF DESCRIPTION OF THE INVENTIONIn one aspect, the invention relates to a substance comprising: a complex comprising Levodopa and a transport portion. In one aspect, the invention relates to a method comprising: providing an alkyl sulfate salt; converting the alkyl sulfate salt to an alkyl sulfate acid form; contacting levodopa with the acid form of the alkyl sulfate to form a complex of alkyl levodopa-sulfate; and isolate the complex. In one aspect, the invention relates to a substance comprising: a complex comprising carbidopa and a transport portion. In one aspect, the invention relates to a method comprising: providing an alkyl sulfate salt; converting the alkyl sulfate salt to an alkyl sulfate acid form; contacting carbidopa with the acid form of the alkyl sulfate to form a complex of alkyl levodopa-sulfate; and isolate the complex. In one aspect, the invention relates to an oral dosage form comprising: (i) an oral controlled distribution dosage structure comprising a structure that controllably distributes a substance comprising levodopa and a substance comprising carbidopa; where at least a portion of thea substance comprising levodopa and a portion of the substance comprising carbidopa are contained through the dosage structure of the controlled distribution; and wherein the structure of the controlled distribution dosage is adapted to distribute in a controlled manner the portion of the substance comprising levodopa and the portion of the substance comprising carbidopa contained by the controlled distribution dosage structure at rates that are effective for , after a single administration of dosage form to the patient: a. Provide a levodopa Cmax on a scale of about 236 around 988 ng / ml, b. Provide a levodopa AUC of around 3676 around 15808 h'ng / ml, and c. Maintain a drug concentration of the levodopa plasma that is at least 15% Cmax through a window of at least about 10 hours duration. d. Provide a Cmax of carbidopa at a scale of about 1 approximately 500 ng / ml μmoles / l, e. Provide an AUC of carbidopa from about 20,000 to about 200,000 h'ng / ml, and f. Maintain a plasma drug concentration of carbidopa that is at least 15% Cmax through a window of at least a duration of 10 hours.
In one aspect, the invention relates to a dosage form of oral controlled distribution comprising a dosage structure of oral controlled distribution comprising a structure that distributes in a controlled manner a substance comprising levodopa; wherein at least a portion of the substance comprising levodopa is contained through the controlled distribution dosage structure; and wherein the controlled distribution dosage structure is adapted to distribute in a controlled manner the portion of the substance comprising levodopa contained through the controlled distribution dosage structure at an upward rate of effective release for, after a single administration of a dosage form to a patient, provides a levodopa plasma profile in the order of substantially zero for a window of at least a duration of about six hours. In one aspect, the invention relates to a composition comprising: levodopa; an alkyl sulfate salt; and a pharmaceutically acceptable carrier.
BRIEF DESCRIPTION OF THE DRAWINGSThe following drawings are not drawn to scale, and are set forth to illustrate various embodiments of the invention. Figure 1 is a diagram of the epithelial cells of the tractgastrointestinal, which illustrate two routes of drug transport through the epithelium of the G.l. Figure 2 shows a diagram of an osmotic liquid dosage form. Figure 3 shows a diagram of an osmotic liquid dosage form. Figure 4 shows a diagram of an osmotic dosage form. Figure 5 shows a diagram of a three-layer osmotic dosage form. Figure 6 shows a diagram of a dosage form of elemental osmotic pump. Figures 7A-7C show diagrams of a controlled release dosage form. Figure 8 shows u? release profile of a dosage form according to the invention., Figure 9 shows a graph of the plasma concentration for levodopa and a levodopa complex according to the invention; Figure 10 shows a graph of the plasma concentration for levodopa and a levodopa complex according to the invention.
DETAILED DESCRIPTION OF THE INVENTIONDefinitions The present invention is best understood by reference to the following definitions, drawings and illustrative description provided herein. By "ascending release rate" means a rate of release wherein the amount of drug released as a function of time increases over a period of time, preferably continuously and gradually. Preferably, the rate of release of the drug as a function of time is increased in a stable manner (instead of in steps). More preferably, an upward release rate can be characterized as follows. The rate of release as a function of time for a dosage form is measured and plotted as the percentage of release of the drug against time or as milligrams of drug released / hour versus time. An ascending release rate is characterized by an average speed (expressed in mg of drug per hour) where the speed within a given two-hour period is greater as compared to the previous two-hour time period, during a period of time from about two hours to about 12 hours, preferably, about 2 hours to about 18 hours, more preferably about 4 hours to about 12 hours, even more preferably, from about 4 hours to about18 hours. Preferably, the increase in average speed is gradual so that at least about 30% of the dose is distributed during any two hour interval, more preferably, less than about 25% of the dose is distributed during any two hour interval. . Preferably, the rate of upward release is maintained until at least about 50%, more preferably up to at least about 75% of the drug the dosage form has been released. By "area under the curve" or "AUC" it means the total area under the concentration curve of the plasma drug (levodopa or carbidopa). It is calculated from the time of administration to the point of time of the last concentration of drug in the miscible plasma using a trapezoidal method plus an extrapolation to infinity according to the last proportion of the concentration of drug in the plasma miscible to the apparent inclination of the linear portion of the terminal (natural) record of the profile of the concentration of the drug in the plasma. By "C" it means the concentration of a drug in the blood plasma, or serum, of a subject, generally expressed as mass per unit volume, typically nanograms per milliliter. For convenience, this concentration can be referred to herein as "drug plasma concentration", "drug concentration in plasma", or "plasma concentration" which are intended to be intensive in the concentration of the drug measured in any fluid or tissue of the drug. proper body. The concentration ofplasma drug at any time after administration of the drug is referred to as Time, as in C9h or C24h, etc. By "composition" is meant a drug in combination with additional active pharmaceutical ingredients, and optionally in combination with inactive ingredients, such as carriers, excipients, suspending agents, surfactants, disintegrants, binders, diluents, lubricants, stabilizers, antioxidants, osmagents, plasticizers. , and similar. By "complex" it means a substance comprising a portion of the drug and an associated transport portion through an adjusted ion pair bond. A drug portion-transport portion complex can be distinguished from a pair of loose ions from the drug portion and the transport portion through a difference in octanol / water cleavage behavior, characterized by the following ratio :? LogD = Log D (complex) -Log D (pair of loose ions) > 0. 15 (Equation 1) where: D, the distribution coefficient (apparent partition coefficient), is the ratio of the equilibrium concentrations of all the species of the drug portion and the octanol transport portion for the same species in water (deionized water) at a fixed pH (typically around pH = 5.0 around pH = 7.0) at 25 ° C. Log D (complex)determine for a complex of the drug portion, the transport portion prepared in accordance with the teachings herein. Log D (loose ion pair) is determined for a physical mixture of the drug portion, the transport portion in deionized water. Log D can be determined experimentally or can be predicted for single ion pairs using commercially available software packages (eg ChemSilico, Inc., Advanced Chemistry Development Inc). For example, the apparent partition coefficient of octanol / water (D = C octane C water) of a putative complex (in deionized water at 25 ° C) can be determined and compared with a physical mixture of 1: 1 (mol / mol) ) of the transport portion and the drug portion in deionized water at 25 ° C. If the difference between Log D pairs putative complex (D + T-) and Log D for the physical mixture of 1: 1 (mol / mol), D + || T is determined to be greater than or equal to 0.15, the putative complex is confirmed as being a complex according to the invention. In preferred modalities,? Log D > 0.20, and more preferably? Log D > 0.25, even more preferably? Log D > 0.35. By "controlled distribution" or "controllable distribution" means a continuous or discontinuous release of a drug over a prolonged period of time, wherein drug is released at (a) a controlled rate during (b) a controlled period of time and in ( c) a form that provides the distribution for the Gl superior and G.l. Bottom, preferably the distribution for the G.I. tract, coupled with drug absorptionimproved as compared to the absorption of the drug in an immediate release dosage form. Controlled distribution technologies include technologies that improve the absorption of the upper GI tract and lower GI of levodopa and / or carbidopa, preferably the absorption of the lower GI tract of levodopa and / or carbidopa. Technologies that improve the absorption of the upper GI tract and the lower GI tract of levodopa and / or carbidopa, preferably the absorption of the lower GI tract, of levodopa and / or carbidopa include, but are not limited to, (i) complexing for the levodopa and / or carbidopa forms with transport portions and / or distribution of said complexes to the upper and lower GI tract, preferably to the lower GI tract; e (i) forming prodrugs of levodopa and / or carbidopa forms with improved upper and lower GI tract absorption and / or distribution, preferably to the lower GI tract, of said prodrugs to the upper and lower GI tract, preferably at lower GI tract. In a preferred embodiment, levodopa and carbidopa are distributed in a controlled manner through the formation of complexes of levodopa and carbidopa with alkyl sulfate salts coupled with the distribution of said complexes to the upper and lower GI tract. By "dosage forms" is meant a pharmaceutical composition in a medium, carrier, vehicle, or device suitable for administration to a patient in need thereof. By "drug" or "drug portion" means a drug,compound, or agent, or a residue of said drug, compound or agent, which provides some pharmacological effect when administered to a subject. For use in the formation of a complex, the drug comprises an acid, basic or zwitterionic residual structural element (s). In embodiments according to the invention, the drug portions comprising acidic structural elements or acidic residual structural elements are complexed with transport portions comprising basic structural elements or acidic residual structural elements that are complexed with transport portions comprising structural elements. basic or basic residual structural elements. In embodiments according to the invention, the drug portions comprising acidic structural elements or acidic residual structural elements are complexed with transport portions comprising basic structural elements or basic residual structural elements. In modalities according to invention, the drug portions comprising basic structural elements or basic residual structural elements are complexed with transport portions comprising acidic structural elements or acidic residual structural elements. In embodiments according to the invention, portions of drugs comprising zwitterionic structural elements or zwitterionic residual structural elements are complexed with transport portions either acidic or basic structural elements, or acidic or basic residual structural elements. In athe pKa mode of an acidic structural element or, an acidic residual structural element is less than about 7.0, preferably less than about 6.0. In one embodiment, the pKa of a basic structural element or a basic residual structural element is greater than about 7.0, preferably greater than about 8.0. The zwitterionic structural elements or zwitterionic residual structural elements were analyzed in terms of their individual basic structural element or basic residual structural element or their acid residual structural element or their acid structural element, depending on how the complex is to be formed with the transport portion . By "orifice" or "exit orifice" means suitable means for releasing the active agent from the dosage form. The term includes aperture, hole, gauge, pore, element, porous design, porous insert, hollow fiber, capillary tube, microporous insert, microporous design, and the like. By "fatty acids" is meant any of the group of organic acids of the general formula CH3 (CnHx) COOH wherein the hydrocarbon chain is either saturated (x = 2n, for example palmitic acid, CH3C? 4H2sCOOH) or unsaturated (for monounsaturated, x = 2n-2, for example oleic acid, CH 3 C 16 H 30 COOH). By "immediate release" means a dose of a drug that is substantially completely released from a dosage form within a period of time of about one hour or less and, preferably, about 30 minutes or less. Certain forms ofControlled dosage distribution may require a short period of time after the administration in which drug release is initiated. In embodiments, wherein the slight delay in the release of the initial drug is undesirable, an external immediate release layer can be applied to the surface of the controlled distribution dosage form. An immediate release dosage of the drug applied as a layer to the surface of the dosage form refers to a dose of the drug prepared in a pharmaceutically suitable carrier to form a coverage solution that will rapidly dissolve after administration while providing a dose of immediate release of the drug. As the art is known, said outer layers of the immediate release drug may contain the same or a different drug or drugs as contained within the underlying dosage form. By "intestine" or "gastrointestinal tract (GI)" means the portion of the digestive tract that extends from the inferior opening of the stomach to the anus, composed of the small intestine (duodenum, jejunum, and ileum) and the large intestine (ascending colon) , transverse colon, descending colon, sigmoid colon, and rectum). By "pair of loose ions" it means a pair of ions that, at a physiological pH and in an aqueous environment, are easily interchangeable with other free ions or in loose pairs that may be present in the environment of the pair of loose ions. The pairs of loose ions can be found experimentally through the exchange of records of a member of apair of loose ions with another ion, at a physiological pH and in an aqueous environment, using reverse phase HPLC. Loose ion pairs can also be referred to as "physical mixtures", and are formed through the physical mixing of the ion pair together in a medium. By "lower gastrointestinal tract" or "lower GI tract" means the large intestine. By "patient" is meant an animal, preferably a mammal, more preferably a human, in need of a therapeutic intervention "Pharmaceutically acceptable salt" means any salt of a free acid pharmaceutical agent with a low solubility rate and / or low dissolution whose cation does not contribute significantly to the toxicity or pharmacological activity of the salt, and, as such, are pharmacological equivalents of free acid pharmaceutical agents of a low solubility rate and / or low dissolution. Suitable pharmaceutically acceptable salts include base edition salts, alkali metal salts, for example sodium or potassium salts; alkaline earth metal salts, for example calcium or magnesium salts; and are formed to obtain two suitable organics, for example quaternary ammonium salts, which can be similarly prepared through the reaction of the drug compound with a suitable pharmaceutically acceptable base. By "pharmaceutical composition" is meant a composition suitable for administration to a patient in need thereof.
By "prolonged period of time" means a continuous period of time of more than 1 hour, preferably of more than 4 hours, more preferably of more than 8 hours, more preferably of more than 14 hours, preferably, greater than about 14 hours and up to 24 hours. As used here, unless otherwise indicated,"release rate" or "degree of release" of a drug refers to the amount of drug released from a dosage form per unit of time; for example, mg of the drug released per hour (mg / hour). Drug release rates for dosage forms are typically measured as an in vitro rate of drug release, i.e., an amount of the drug released from the dosage form per unit time measured under appropriate conditions and in a suitable fluid. The release rates referred to herein are determined through the placement of a dosage form to be tested in deionized water in metal coil or metal cage controller device samples affixed to a Type IV USP bath indexer to a bath of constant temperature water of 37 ° C. The aliquots of release rate solutions, collected at pre-set intervals, are then injected into a chromatographic system fitted with an ultraviolet or refractive index detector to quantitate the amounts of drug released during the test intervals. An alternate release velocity test method can be carried out using the Distek5100 (2-vane tester).
USP apparatus) in 900 ml of artificial gastric fluid (AGF, pH = 1.2). The temperature of the dissolution medium was maintained at 37 ° C and the speed of the blade between 100 rpm. The concentration of levodopa was measured with UV spectroscopy at 280 nm. As used herein, a rate of drug release obtained at a specific time refers to the rate of in vitro release obtained at a specified time after the implementation of the release rate test. The time in which a specified percentage of the drug within a dosage form has been released from said dosage form is referred to as the "Tx" value, where "x" is the percentage of the drug that has been released. For example, a reference measurement commonly used to evaluate the release of the drug from dosage forms is the time in which 70% of the drug within the dosage form has been released. This measurement is referred to as "T70" for the dosage form. Preferably, T70 is greater than or equal to about 8 hours, more preferably T70 is greater than or equal to about 12 hours, even more preferably, T70 is greater than or equal to 16 hours, preferably, T70 is greater than or equal to around 20 hours. In one embodiment, T70 is greater than or equal to about 12 hours, and less than about 24 hours. In another embodiment, T70 is greater than or equal to about 8 hours and less than about 16 hours. By "residual structural element" means a structural element that is modified through interaction or reaction with anothercompound, chemical group, ion, atom, or similar. For example, a carboxyl structural element (COOH) interacts with sodium to form a sodium carboxylate salt, COO- being a residual structural element. By "solvent (s)" means a substance in which several other substances may be completely or partially dissolved. In the present invention, preferred solvents include aqueous solvents, and solvents having a dielectric constant less than that of water. Preferred solvents have a dielectric constant lower than that of water. The dielectric constant is a measure of the polarity of a solvent and the dielectric constants for illustrative solvents are shown in Table 1.
TABLE 1 Characteristics of Illustrative SolventsThe solvents water, methanol, ethanol, 1-propanol, 1-butanol, and has been acetic are polar protic solvents having a hydrogen atom linked to an electronegative atom, typically oxygen. The solvents acetone, ethyl acetate, methyl ethyl ketone, and acetonitrile are dipolar aprotic solvents, and are in one embodiment, preferred for use in the formation of complexes of the invention. Bipolar aprotic solvents do not contain an OH bond but typically have a large bond dipole by virtue of a multiple bond between the carbon and any oxygen or nitrogen. Most bipolar aprotic solvents contain a double C-O bond. Solvents having a dielectric constant less than that of water are particularly useful in the formation of the complexes of the invention. The bipolar aprotic solvents mentioned in Table 1 have a dielectric constant of at least two times lower than that of water and a bipolar moment closure for or greater than water. By "structural element" it means a chemical group of (i) is part of a larger molecule and, (ii) has distinguishable chemical functionality. For example, an acidic group a basic group of a compound is a structural element. By "substance" means a chemical entity that has specific characteristics. By "pair of adjusted ions" means a pair of ions that are, even physiological pH and in an environment use not easily interchangeable with other free ions or in loose pairs that may be present is in the environmentof a pair of adjusted ions. A pair of adjusted ions can be experimentally detected by observing the absence of the exchange of a member of an ion pair adjusted with another ion, at a physiological pH and in an aqueous environment, using isotopic and NMR labeling or spectroscopy of dough. The pairs of adjusted ions can also be found experimentally observing the lack of ion pair separation, even physiological pH and in an aqueous environment, using reverse phase HPLC. By "therapeutically effective amount" means that the amount of a drug produces the biological or medicinal response in a tissue, animal or human system is being investigated by a researcher, veterinarian, doctor or other doctor, which includes alleviating the symptoms of the disease or disorder that is being treated. More specifically, a therapeutically effective amount of the substances of the invention preferably alleviates the symptoms, complications, or biochemical signs of diseases sensitive to levodopa or carbidopa therapy. The exact dose will be evaluated by the skilled artisan using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (Vols 1-3, 1992), Lloyd, 1999, The Art, Science, and Technology of Pharmaceutical Compounding; Pickar, 1999, Dosage Calculations). A therapeutically effective dose is also one in which any toxic or deleterious side effect is overcome in clinical terms by the therapeutically beneficial effects. In addition, it should be noted that for each particular subject, theSpecific dosages should evaluate whether to adjust over time according to the individual need and professional judgment of the person administering and supervising the administration of the compounds. By "transport portion" is meant a compound capable of forming, or a residue of that compound which has formed, a complex with a drug, wherein the transport portion serves to improve the transport of the drug through the epithelial tissue, compared with that of the drug not in complex. The transport portion comprises a hydrophobic portion and an acidic, basic or zwitterionic element, or an acid, basic or zwitterionic residual structural element. In a preferred embodiment, the hydrophobic portion comprises a hydrocarbon chain. In a modality, the pKa of a basic structural element or basic residual structural element is greater than about 7.0, preferably greater than about 8.0. The zwitterionic structural elements or zwitterionic residual structural elements were analyzed in terms of their individual basic structural element or basic residual structural element or acid residual structural element, depending on how the complex will be formed with the drug portion. In a more preferred embodiment, the transport moieties comprise pharmaceutically acceptable acids, including, but not limited to carboxylic acids, and salts thereof. In embodiments, the transport moieties comprise fatty acids or their salts, benzenesulfonic acid or its salts, benzoic acid or its salts, fumaric acid or itssalts, or salicylic acid and its salts. In preferred embodiments the fatty acids or their salts comprise from 6 to 18 carbon atom (C6-C18), more preferably from 8 to 16 carbon atom (C8-C16), even more preferably from 10 to 14 carbon atom ( C10-C14), and preferably 12 carbon atom (C12). In more preferred embodiments, the transport moieties include alkyl sulphates (either saturated or unsaturated) and salts thereof, such as potassium, magnesium, and sodium salts, including particularly sodium octal sulfate, sodium decyl sulfate, sodium lauryl sulfate, sodium, and sodium tetradecyl sulfate. In preferred embodiments the alkyl sulfate or its salts comprise 16 to 18 carbon atoms (C6-C18), more preferably 8 to 16 carbon atoms (C8-C16), even more preferably 10 to 14 carbon atoms (C10) -C14), and preferably 12 carbon atoms (C12). Other anionic surfactants are also suitable. In another more preferred embodiment, the transport moieties comprise pharmaceutically acceptable primary amines or salts thereof, particularly primary aliphatic amines (both saturated and unsaturated) and salts thereof, diethanolamine, ethylene diamine, procaine, choline, tromethamine, meglumine, hydroxides of magnesium, aluminum, calcium, zinc, alkyltrimethylammonium, alkyltrimethylammonium bromides, benzalkonium chloride, and benzethonium chloride. Also useful are other pharmaceutically acceptable compounds comprising tertiary or secondary amines, and their salts, and cationic surfactants.
By "upper GI tract" or "upper GI tract" means that portion of the gastrointestinal tract that includes the stomach and small intestine. By "window" means a period of time that has a defined duration. The windows preferably start at the time of administration of a dosage form to a patient, or any time thereafter. For example, in a modality a window can have a duration of around 12 hours. In preferred embodiments, the window may start at a variety of times. For example, in a preferred embodiment, the window may start about one hour after the administration of a dosage form, and have a duration of about 12 hours, which means that the window could be opened one hour after the administration of the dosage form and be saved at about 13 hours after the administration of the dosage form. By "velocity in the zero order of release" means a rate of release wherein the amount of drug released as a function of time is substantially constant. More particularly, the rate of release of the drug as a function of time should vary by at least about 30%, preferably, less than about 20%, more preferably, less than about 10%, more preferably, less than about 5%, where the measurement is taken during period of time where the cumulative release is betweenabout 25% and about 75%, preferably, between about 25% and about 90% by the total weight of the drug in the dosage form. By "plasma profile in the order of zero" means a substantially unchanging or substantially flat amount of a particular drug in a patient's plasma during a particular time interval. Generally, the plasma concentration of a drug exhibiting a plasma profile in the order of zero will vary by no more than about 30% and preferably no more than about 10% of a time interval for the subsequent time interval.
Controlled distribution, complex formation, and characterization The inventors have unexpectedly discovered that it is possible to solve the problems in the art explained above by using substances, compositions, dosage forms and methods that distributeLevodopa and / or carbidopa using controlled distribution methods as set forth herein. Said substances, compositions, dosage forms and methods are useful, inter alia for the treatment of the disease ofParkinson. In particular, the inventors observe that a conventional solution for the aforementioned problems could be application of conventional controlled release technologies. However, once a detailed extermination of the data is done, theinventors have discovered that these conventional controlled release technologies are insufficient to solve the aforementioned problems in the art. As a pharmacokinetic understanding, the inventors have recognized that levodopa and / or carbidopa are poorly absorbed in the lower GI tract and possibly even in portions of the G.l. higher. This is corroborated through the understanding in the art that levodopa is transported through the intestinal epithelium mainly through carriers for large neutral L-amino acids. D. Nilsson et al. "Absorption of L-DOPA from the proximal small intestine studied in the rhesus monkey by positron emission tomography", European J. of Pharm. Sci. 7: 185-189 (1999). It is known that these carriers are concentrated in portions close to the upper GI tract. Additionally, absorption studies have shown that virtually all levodopa absorption occurs within four hours after oral administration, indicating that almost all absorption occurs in the upper GI tract. The authors concluded that "These data suggest that the release of levodopa can not be sustained beyond that of a Sinemet CR without additional reduction in bioavailability and increases variability". I. R. Wilding et al., "Characterization of the In Vivo Behavior of a Controlled-Release Formulation of Levodopa (Sinemet CR)", Clin. Neuropharmacology 14 (4): 305-321 (1991). Since the data regarding the intestinal absorption of carbidopa are moderately scarce, the inventors have recognized thatthis absorption can also be concentrated in the upper GI tract, and its structure itself contributes to being transported by the transporters of the same amino acid as a hypothesis is made to transport levodopa. Therefore, fluctuating levels of carbidopa, due to poor absorption of carbidopa in portions of the GI tract, can lead to periods in which the plasma concentration of carbidopa is significantly reduced with concomitant periods of lower levodopa levels (due to the metabolism of levodopa). These fluctuations are undesirable, as observed anywhere here. The inventors have further recognized that the poor absorption of the lower GI tract (and portions of the upper distal Gl tract) implies that conventional controlled release (CR) techniques will not work in the development of an oral dosage form of levodopa and / or carbidopa exhibit reduced concentration fluctuations. In particular, said techniques are not used to develop plasma profiles substantially in the order of zero, preferably plasma profiles in the order of zero, such as those produced with intraduodenal infusion. Generally, a CR dosage form will move through the G tract I. superior to the lower GI tract within 8-10 hours or less. Once the dosage form including levodopa and / or carbidopa reaches the lower GI tract, the absorption of the compound will be significantly reduced. In fact, as noted above, absorption is essentially complete as rapidly as four hours after dosing. ByConsequently, the CR dosage forms will have to be dosed more frequently in the bid or qd to achieve an efficiency. This can be the source of undesirable concentration fluctuations and peak affects observed previously. Therefore, the inventors have surprisingly recognized that only a specific sub-class of controlled release technologies, referred to herein as controlled release technologies, could be sufficient to provide a bid or qd dosage of levodopa and / or carbidopa. These controlled distribution technologies comprise substances comprising levodopa and / or substances comprising carbidopa which demonstrate an improved lower GI tract absorption. Substances comprising levodopa and / or substances comprising carbidopa which demonstrate improved absorption of the lower GI tract include, but are not limited to, complexes of levodopa and / or carbidopa with alkyl sulfate salts; and prodrugs of levodopa and / or carbidopa having an improved lower I.I. absorption. In a preferred embodiment, levodopa and / or carbidopa in the form of a complex is patiently controlled a patient in need thereof. The controlled distribution of substances comprising levodopa and / or substances comprising carbidopa, according to the present invention, provides a mechanism through which plasma profiles can be achieved in the order of substantially zero, preferablyPlasma profiles in the order of zero, of levodopa and / or carbidopa. Said plasma profiles in the order of substantially zero, preferably plasma profiles in the order of zero, can alleviate the problems observed in the prior art with respect to the oral dosage forms (concentration balances and peak affects), while providing a a substantially improved convenient dosage is compared to infusion pumps. Various embodiments of controlled distribution technologies of the invention will now be explained in detail here. In certain embodiments, levodopa and / or carbidopa are modified to demonstrate absorption of the improved lower GI tract. Pharmaceutical development typically activates drug forms for absorption in the upper GI tract instead of the lower GI tract, because the upper GI tract has a much larger surface area for drug sanction than the lower GI tract . The lower GI tract lacks microvilli that are present in the upper GI tract. The presence of microvilli greatly increases the surface area for absorption of the drug, and the upper GI tract has 480 times the surface area of the G-shaped touch. The differences in the cellular characteristics of the upper and lower GI tracts also contribute to the poor absorption of the molecules in the G tract. lower. Figure 1 illustrating common routes for the transport of compounds through the epithelium of the G tract. I. epithelial cellsIndividuals, represented by 10a, 10b, 10c, form a cellular barrier along the small and large intestine. The individual cells are separated by water channels or tight junctions, such as the junctions 12a, 12b. Transport through the epithelium occurs through either or both of a transcellular path and a paracellular path. The transcellular trajectory for transport, indicated in Figure 1 through date 14, involves the movement of the compounds through the wall and body of the epithelial cell through passive diffusion or through carrier mediated transport. . The paracellular path for transport involves a movement of molecules through the just junctions between individual cells, as indicated by date 16. Paracellular transport is less specific but has a greater overall capacity, partly because it results in Through the length of the GI tract, however, the adjusted joints vary along the length of the GI tract, with an increase close to the distal gradient with an effective 'tension' of the fit adjusted. In this way, the duodenum in the upper GI tract is more "permeable" than the ileus in the upper GI tract that is more "permeable" than the colon, in the lower GI tract (Knauf, H. and others, Klin Wochenschr ., 60 (19): 1191-1200 (1982)). Since the typical residence time of a drug in the tractG. I superior is that approximately four to six hours, drugs that have poor absorption G.l. lower are absorbed through the body through a period of only four to six hours after theoral ingestion It is often medically desirable that the administered drug be present in the patient's bloodstream at a relatively constant concentration throughout the day. To achieve this with traditional drug formulations exhibit absorption in the lower minimum GI tract, patients would need to ingest the drugs three to four times per day. Practical experience with this inconvenience for patients suggests that this is not an optimal treatment protocol. The situation with levodopa and / or carbidopa is an example. To provide constant dosing treatments, conventional pharmaceutical development has suggested several controlled release drug systems. Such systems function through the release of their drug payload for an extended period of time after administration. Nevertheless, these conventional forms of controlled release systems are not effective in the case of drugs exhibit minimal economic absorption. Since the drugs are only absorbed in the upper GI tract and since the residence time of the drug in the upper GI tract is only four to six hours, the fact that a proposed controlled release dosage can release its payload after of residence period of the dosage form in the upper GI does not mean that the body will continue to absorb the controlled release drug after four to six hours of residence in the GI tract Rather, the drug released through a form of controlled release dosing after the dosage formhas entered the lower GI tract. It is usually not absorbed and is rather expelled from the body. It has surprisingly been found that many common drug portions with poor absorption characteristics, once they are complexed with certain transport moieties exhibit significantly improved absorption, particularly absorption in the lower Gl tract, although absorption in the GI tract can also be improved. It is further surprising that complexes, such as certain substances comprising levodopa and / or substances comprising carbidopa, according to the invention show an improved absorption compared with the pairs of loose ions (ie a non-complex form) that it comprises the same ions of the complexes of the invention. These unexpected results have been found to apply to many categories of drug portions, including drug portions comprising a basic structural element, a residual structural element. Unexpected results of the present invention can also be applied to drug portions comprising a zwitterionic structural element, a zwitterionic residual structural element. An example of said drug portion comprises levodopa and / or carbidopa. The unexpected results of the present Danish invention may apply to portions of drugs comprising an acidic structural element an acidic residual structural element.
Not wanting to be linked through an understandingSpecific to the mechanisms, the inventors reason as follows: When placing pairs of loose ions in a polar-only environment, it is assumed that the polar solvent molecules will insert themselves in the space occupied by an ionic bond, in this wayseparating the bound ions. A dissolution cartridge, comprising polar solvent molecules electrostatically bound to a free ion, can be formed from the free ion. This dissolution cartridge then prevents the free ion from forming an ionic bond in loose ion pairs with another free ion. In a situation where there are multiple types of counter-ions present in the polar solvent, any pairing of loose ions can be relatively susceptible to competition with the counter-ion. This effect is more pronounced according to the polarity, expressed as the dielectric constant of the solvent, it increases. Based on Coulomb's law, the force between two ions with charges (q1) and (q2) and separated by a distance (r) in a medium of dielectric constant (e) is:j _ - _ (Equation 2) 4pe "eWhere is that constant of permissiveness of space. TheThe equation shows the importance of the dielectric constant (s) on the stability of a pair of loose ions in solution. In aqueous solution that has a high dielectric constant (s = 80), the attractive forceElectrostatic is significant between reduced if the water molecules attack the ionic bond and separate the charged charged ions. Consequently, high dielectric constant solvent molecules, once they are present in the vicinity of the ionic bond, will attack the bond and eventually break it. The unbonded ions are then free to move around the solvent. These properties characterize a pair of loose ions. The pairs of adjusted ions are formed differently from the pairs of loose ions, and consequently have different properties of a pair of loose ions. The pairs of adjusted ions are formed through the reduction of the number of polar solvent molecules in the bond space between the two ions. This allows the ions to move tightly together, and results in a bond that is significantly stronger than a bond of loose ion pairs, but is still considered as an ionic bond. As described more fully here, the pairs of adjusted ions are obtained by using less polar solvent than water to reduce the arrest of the school solvent between the ions. For an additional explanation of the loose and adjusted ion pairs, see D. Quintanar-Guerrero et al. , "Applications of the Ion Pair Concept to Hydrophilic Sustances with Special Emphasis on Peptides," Pharm. Res. 14 (2): 119-127 (1997). The difference between loose and tight ion pairs can also be observed using chromatographic methods. When usingReversed phase chromatography, loose ion pairs can be easily separated under conditions that will not separate tight ion pairs. The bonds according to this invention can also be made stronger through the selection of the cation resistance and the anion correlation with one another. For example, in the case not of the solvent is water, the cation (base) and anion (acid) can be selected to attract each other more strongly. If a weaker link is desired, then a weaker attraction should be selected. The portions of biological membranes can be modeled to a first order of approximation as lipid bilayers for purposes of understanding the molecular transport through said membranes. Transport through the bilayer portions of lipid (as opposed to active carriers, etc.) is unfavorable for ions due to their unfavorable distribution. Several researchers have proposed that the naturalization of the charge of these ions can improve transport through the membrane. In the "ion pair" theory, the drug and ion portions are paired with counter-ions of transport portions to "bury" the charge and convert the resulting ion pair into more prone to move through a lipid bilayer. . This method has generated a fair amount of attention research, especially with respect to improving the absorption of orally administered drugs through the intestinal epithelium. Since the ion pairs have generated a lot of attentionresearch, have not always generated much success. For example, it was found that the ion pairs of two antiviral compounds do not result in an increase in absorption due to the effects of the ion pair on the transcellular transport, rather an effect on the monolayer integrity. The authors concluded that ion pair formation may not be very efficient as a strategy to improve transepithelial transport of charged hydrophilic compounds as a competition through other ions that are found in in vivo systems that can abolish the beneficial effect of contrasts. -iones J. Van Gelder et al., "Evaluation of the Potential of Ion Pair Formation to Improve the Oral Absorption of Two Potent Antiviral Compounds, AMD3100 and PMPA", Int. J. of Pharmaceutics 186: 127-136 (1999). Other authors have observed that the absorption experiments with ion pairs have not always pointed towards well-defined mechanisms D. Quintanar-Guerrero and others, Applications of the Ion Pair Concept to Hydrophilic Sustances with Special Emphasis on Peptides, Pharm. Res. 14 (2): 119-127 (1997). The inventors have unexpectedly discovered that a problem with these ion pair absorption experiments is that they were carried out using loose ion pairs, the place of tight ion pairs. Certainly, many ion pair absorption experiments described in the art do not even expressly distinguish between pairs of adjusted ions and loose ion pairs. An expert has to distinguish that loose ion pairs are actually described by checkingthe methods described for making ion pairs, and none of these methods described for manufacturing are directed to loose ion pairs or tight ion pairs. Loose ion pairs are relatively susceptible to competition with counter-ions, and for solvent-mediated cleavage (for example mediated by water) of the ironic bonds linking loose ion pairs. Accordingly, when the drug portion of the ion pair reaches the membrane wall of the intestinal epithelial cell, it may or may not be associated with the pair of loose ions with a transport portion. The events of the ion pair existing near the membrane wall may depend more on the local concentration of two individual ions than on an ion bond that holds the ions together. In the absence of two portions that are binding when they approach the wall of the intestinal epithelial cell membrane, the absorption rate of the non-complex drug portion could not be affected by the non-complex transport portion. Accordingly, loose ion pairs would have only a limited impact on absorption compared to administration of a single drug portion. In contrast, the complexes of the invention possess bonds that are more established in the presence of polar solvents such as water. Accordingly, the inventors reasoned that, through complex formation, the drug portion and the transport portion would likely be more associated as ion pairs at the time the portions were closer to the membrane wall. This associationit would increase the events in which the charges of the portions would be buried and would become the pair of ions resulting in more prone to move through the membrane of the cell. In one embodiment, the complex comprises a bond of ion pairs adjusted between the drug portion and the transport portion. As explained here, the adjusted ion pair bonds are more stable than the loose ion pair bonds, thus increasing the likelihood that the drug portion and the transport portion are associated as ion pairs at the time in which the portions are close to the wall of the membrane. This association will increase the events in which the charges of the portions will be buried and turned into a complex of bonding of pairs of adjusted ions more likely to move through the membrane of the cell. It should be noted that the inventive complexes can improve absorption relative to the non-complexed drug portion through the G.I. tract, as the complex is intended to improve transcellular transport generally, not only in the lower GI tract. For example, if the drug portion is its substrate for an active transporter found primarily in G.l. superior, the complex formed from the drug portion will still be a substrate for the transporter. Accordingly, the total transport may be a sum of the transport flux effected by the transporter plus the improved transcellular transport provided by the present invention. In one modality, the complexes of theThe invention provides improved absorption in the upper GI tract, the lower GI tract, and in both the upper GI tract and the lower GI tract. The complexes according to the invention can be made from a variety of drug and transport portions. Generally speaking, the transport portion is selected first, and then the appropriate transport portion is selected to form the complex of the invention. An expert may consider a number of factors in the selection of the transport portions, including, but not limited to, the toxicity and tolerability of the transport portion, the polarity of the structural element or the residue of the structural element of the drug portion. , by virtue of the structural element or the residue of the structural element of the transport portion, the possible therapeutic advantages of the transport portion. In certain preferred embodiments, the hydrophobic portions of the transport portion comprise a hydrophobic chain, more preferably an alkyl chain. This alkyl chain can aid in the promotion of the stability of the complex through the steric protection of the ionic bond of attacks through the molecules of the polar solvent. It should be noted that the complexes of the invention can improve absorption in relation to the non-complexed drug portion through the GI tract, not only the lower GI tract, according to the complex intended to improve transcellular transport generally, not only in the tract Lower GI. For example, if the drug portion is your substrate forAs an active transporter that is mainly found in the upper GI, the complex formed from the drug portion will still be a substrate for the transporter. Accordingly, the total transport may be a sum of the transport flux effected by the transporter plus the improved transcellular transport provided by the present invention. In one embodiment, the complexes of the invention provide improved absorption in the upper GI tract, the lower GI tract, and both in the upper GI tract and in the G tract. Lower. The complexes according to the invention can be formed from a variety of drug and transport portions. Generally speaking, the drug portion is selected first and then the appropriate transform portion is selected to form the complex of the invention. An expert could consider a number of factors in the selection of transport portions, including but not limited to the toxicity and tolerability of the transport portion, the polarity of the structural element or the residue of the structural element in the drug portion, the strength of the structural element or the residue of the structural element of the transport portion, the possible therapeutic advantages of the transport portion, and the steric barrier of the link between the drug portion and the transport portion that is provided through the transport portion. In preferred embodiments the transport moieties comprise alkyl sulfates or their salts, having from 6 to 18 carbon atoms (C6-C18), more preferably from 8 to 16 carbon atoms (C8-C16), still more preferably from 10 to 14 carbon atoms (C10-C14), and preferably 12 carbon atoms (C12). In other preferred embodiments, the transport moieties comprise fatty acids, or their salts, having from 6 to 18 carbon atoms (C6-C18), more preferably from 8 to 16 carbon atoms (C8-C16), even more preferably from 10 to 14 carbon atoms (C10-C14), and preferably 12 carbon atoms (C12). The methods for making them 3ANBPA compounds of the invention described herein, include the appended examples. An alternative way to improve the lower G.I absorption of levodopa and carbidopa is to produce prodrugs of the compounds which are substrates for active transporters expressed in the epithelial cells that cover the lumen of the human colon. U.S. Patent Application 20030158254 to Zerangue et al., Filed August 21, 2003, entitled "Engineering absorption of therapeutic compounds via colonic transporters" ("Zerangue"), are hereby incorporated by reference in their entirety for all purposes , describes the modified drugs to be said substrates, includes compounds suitable for use in prolonged-release oral dosage forms, particularly those that release the drug for periods of more than about 2-4 hours after administration. Zerangue describes a variety of carriers useful in the practice of this invention, comprising the sodium-dependent multivitamin transporter (SMVT), and monocarboxylate transporters 1 and 4(MCT 1 and MCT 4). Zerangue also describes methods for identifying agents or portions of conjugate that are substrates of a carrier, and agents, conjugates and portions of conjugate that can be classified. In particular, Zerangue describes compounds to be classified as variants of known carrier substrates. Such compounds comprise salts or acids of bile, steroids, ecosanoids, or natural toxins an analogue thereof, as described by Smith, Am. J. Physiol. 2230, 974-978 (1987); Smith, Am. J. Physiol. 252.G479-G484 (1993); Boyer, Proc. Nati Acad. Sci. USA 90,435-438 (1993); Fricker, Biochem. J. 299,665-670 (1994); Ficker, Biochem J. 299,665-670 (1994); Ballatori, Am. J. Physiol. 278. Zerangue further discloses the binding of the agents to the conjugate portions, and various prodrugs, which comprise pivaloxymethylgabaptentin carbamate, acetoxyethylgabapentin carbamate, and alpha-aminopropylisobutyryl gabapentin. Levodopa and carbidopa are described in paragraph 92 of Zerangue. Prodrugs of levodopa and carbidopa which are substrates for active transporters expressed in epithelial cells that cover the human colon are specifically encompassed by the present invention. The prodrugs of levodopa and carbidopa can be distributed using controlled distribution technologies described herein.
Illustrative dosage forms and methods of use A variety of dosage forms are suitable for use with the drugs of interest. In embodiments, dosage forms are provided that allow dosing that maintains a drug concentration in the plasma that is at least 15% Cmax along a window of at least about 10 hours in duration. A dosage form can be configured and formulated according to any design that distributes a desired dose of levodopa or carbidopa. In certain embodiments, the dosage form is orally administrable and is sized and given the form of a tablet or capsule. Orally administered dosage forms can be manufactured according to one or several different methods. For example, the dosage form can be manufactured as a diffusion system, such as a reservoir device or matrix device, a dissolution system, such as the encapsulated dissolution systems (including, for example, "minute time pills" and beads) and matrix dissolving systems and combination of diffusion / dissolution systems and ion exchange resin systems, as described in Remington's Pharmaceutical Sciences, 18th ed., p. 1682-1685 (1990). An important consideration in the practice of this invention is the physical state of the drug substance that is to be distributed through the dosage form. In certain embodiments, the substances comprise levodopa and / or substances comprising carbidopa may be in apaste or liquid state, in which case the solid dosage forms may not be suitable for use in the practice of this invention. In such cases, dosage forms capable of distributing substances in a paste or liquid state should be used. For example, an inventive complex comprising levodopa and sodium lauryl sulfate can be in a paste-like state. In such a case, dosage forms capable of distributing substances in a paste or liquid state should be used to distribute the complex. Alternatively, in certain embodiments, a different transport portion may be used to raise the melting point of the substances, thereby making it more likely that the inventive complexes are present in a solid form. A specific example of a dosage form suitable for use with the present invention is an osmotic dosage form. The osmotic dosage forms, in general, use osmotic pressure to generate a driving force to inhibit the fluid within a compartment formed, at least in part, through a semipermeable wall that allows free diffusion of the fluid but not of the drug or osmotic agent (s), nap present. An advantage of the osmotic systems is that the overcoming is independent of the pH and, in this way, it continues at the osmotically determined speed over a prolonged period of time even when the dosage form transits the gastrointestinal tract and finds different micro-environments that have significantly different pH values. A review of these forms ofDosage is found in Santus and Baker, "Osmotic drug delivery: a review of the patent literature," Journal of Controlled Relay, 35: 1-21 (1995). The osmotic dosage forms are also described in detail in the following U.S. Patent Nos., Which are incorporated herein in their entirety: Nos. 3,845,770; 3,916,899; 3,995,631; 4,008,719; 4,111, 202; 4,160,020; 4,327,725; 4,519,801; 4,578,075; 4,681, 583; 5,019,397; and 5,156,850. The present invention provides a liquid formulation of controlled distribution of substances comprising levodopa and / or substances comprising carbidopa for use with oral osmotic devices. Oral osmotic devices for distributing liquid formulations and methods for using them are known in the art, for example, as described and claimed in the following U.S. Patents. owned jointly by ALZA Corporation: 6,419,952; 6,174,547; 6,551, 613; 5,324,280; 4,111, 201; and 6, 174, 547; each of which are hereby incorporated by reference in their entirety for all purposes. Methods for using oral osmotic devices to deliver therapeutic agents at an upward rate of release can be found in International Applications Nos. WO 98/06380, WO 98/23263, and WO 99/62496, each of which are incorporated herein by reference. by reference its totality for all purposes. Illustrative liquid carriers for the present invention include lipophilic solvents (e.g. oils and lipids), surfactants and hydrophilic solvents. Illustrative hydrophilic solvents, for example,include, but are not limited to, Capmul PG-8, Caprol MPGO, Capryol 90, Plurol Oleique CC 497, Capmul MCM, Labrafac PG, N-Decyl Alcohol, Caprol 10G100, Oleic Acid, Vitamin E, Maisine35-1, Gelucire 33 / 01, Gelucire 44/14, Lauryl Alcohol, Captex 355EP, Captex 500, Caplic / Caprylic Triglyceride, Peceol, Caprol ET, Labrafil M2125 CS, Labrafac CC, Labrafil M 1944 CS, Captex 8277, Myvacet 9-45, Isopropyl Nyristate, Caprol PGE 860, Olive Oil, Plurol Oleique, Peanut Oil, Captex 300 Low C6, and Capricho Acid. Exemplary surfactants, for example, include, but are not limited to, Vitamin E TPGS, Cremophor EL-P, Labrasol, Tween 20, Cremophor RH40, Pluronic L-121, Acconon S-35, Pluronic L-31, Pluronic L-35, Pluronic L-44, Tween 80, Pluronic L-64, Solutol HS-15, Span 20, Cremofor EL, Span 80, Pluronic L-43, and Tween 60. Hydrophilic solvents illustrative examples include, but are not limited to, Isosorbide, Dimethyl Ether, Polyethylene Glycol 400 (PEG-3000), Transcutol HP, Polyethylene Glycol 400 (PEG-4000), Polyethylene Glycol 400 (PEG-300), Polyethylene Glycol 400 (PEG-6000), Polyethylene Glycol 400 (PEG-400), Polyethylene Glycol 400 (PEG-8000), Polyethylene Glycol 400 (PEG-600), and Propylene Glycol (PG). In one embodiment, a liquid formulation comprises from about 10% to about 90% of substances comprising the levodopa complex, from 10% to about 30% of substances comprising carbidopa, and about 10% about 90% of one or more liquid carriers. For example, in some embodiments, the liquid formulation will comprise levodopa and / or hydrophilic solvent such asPG. In such embodiments, the liquid formulation may comprise from about 10% to about 90% of substances comprising the levodopa complex and about 10% about 90% of the hydrophilic solvent. In other embodiments, the liquid formulation may comprise about 40% of substances comprising the levodopa complex, 10% of substances comprising the carbidopa complex and about 50% of liquid carriers. In a preferred embodiment, the liquid carrier may comprise about 50% surfactant, such as Cremofor EL, solutol, or Tween 80, and about 50% of the hydrophilic solvent, such as PG. The skilled practitioner will understand that any formulation comprising a sufficient dosage of substances comprising levodopa and / or substances comprising carbidopa are solubilized in a liquid carrier suitable for administration to a subject and for use in an osmotic device can be used herein invention. In an exemplary embodiment of the present invention, the liquid carrier is PG, Solutol, Cremofor EL, a combination thereof. The liquid formulation according to the present invention may also comprise, for example, additional excipients such as an antioxidant, impregnation improver and the like. Antioxidants can provide deceleration or effectively stop the velocity of any self-oxidizable material present in the capsule. Representative antioxidants may comprise a selected numberfrom the ascorbic acid group; alpha tocopherol; ascorbyl palmitate; ascorbates; isoascorbates; butylated hydroxyanisole; butylated hydroxytoluene; non-dihydroguiaretic acid, esters of glic acid comprising at least three carbon atoms comprising a wind selected from the group consisting of propylgalate, octylgalate, decylgalate, decylgalate; 6-ethoxy-2,2,4-trimethyl-1,2-dihydro-guinoline; N-acetyl-2,6-di-t-butyl-p-aminophenol; butyl tyrosine; 3-tertiarbutyl-4-hydroxyanisole; 2-tertiary-butyl-4-hydroxyanisole; 4-chloro-2,6-di-tertiary butyl phenol; 2,6-ditertiary butyl p-methoxy phenol; 2,6-diterciary butyl-p-cresol: polymeric antioxidants; trihydroxybutyrophenone, physiologically acceptable salts of ascorbic acid, erythorbic acid, and ascorbyl acetate; calcium ascorbate; sodium ascorbate; sodium bisulfite; and similar. The amount of antioxidant used for the present purposes, for example, may be from about 0.001% to 25% of the total weight of the composition present in the lumen. Antioxidants are known in the prior art in the patents of E.U.A. Nos. 2,707,154; 3,573,936; 3,637,772; 4,038,434; 4,186,465 and 4,559,237, each of which is hereby incorporated by reference in its entirety for all purposes. The liquid formulation of the invention may comprise impregnation improvers that facilitate the absorption of the active agent in the environment of use. Such enhancers may, for example, open so-called "tight junctions" in the gastrointestinal tract or modify the effect of cellular components, such as a glycoprotein and the like. TheSuitable builders may include alkali metal salts of salicylic acid, such as sodium salicylate, caprylic acid or caprice, such as caprylate or sodium caprate and the like. Enhancers may include, for example, bile salts, such as sodium deoxycholate. Several p-glycoprotein modulators are described in the Patents of E.U.A. Nos. 5,112, 817 and 5,643,909, each of which is hereby incorporated by reference in its entirety for all purposes. Various other absorption enhancing compounds and materials are described in the U.S. Patent. No. 5,824, 638, which is also incorporated herein by reference in its entirety for all purposes. The improvers can be used either alone or as mixtures in combination with other enhancers. In certain modalities, the substances comprising levodopa and / or substances that they comprise are administered as a self-emulsifiable formulation. Like the other carriers, the functions of the surfactant to prevent aggregation, reduce the interfacial tension between constituents, improve the flow of free constituents, and decrease the incidence of constituent retention in the dosage form. The formulation of the therapeutic emulsion of this invention comprises a surfactant that imparts emulsification. Exemplary surfactants may also include, for example, in addition to the surfactants listed above, a member selected from the group consisting of polyoxyethylenated castor oil comprising 9 moles of ethylene oxide, polyoxyethylenated castor oil comprising 15 moles of ethylene oxide, polyoxyethylene castor oil thatit comprises 20 moles ethylene oxide, polyoxyethylenated castor oil comprising 25 moles ethylene oxide, polyoxyethylenated castor oil comprising 40 moles ethylene oxide, polyoxyethylenated castor oil comprising 52 moles ethylene oxide, polyoxyethylenated sorbitan monopalmitate comprising moles ethylene oxide, polyoxyethylenated sorbitan monostearate comprising 20 moles of ethylene oxide, polyoxyethylenated sorbitan monostearate comprising 4 moles of ethylene oxide, polyoxyethylenated sorbitan tristearate comprising 20 moles of ethylene oxide, polyoxyethylenated sorbitan monostearate comprising 20 moles of oxide ethylene, polyoxyethylenated sorbitan trioleate comprising 20 moles of ethylene oxide, polyoxyethylene lauyryl ether, polyoxyethylenated stearic acid comprising 40 moles of ethylene oxide, polyoxyethylenated stearic acid comprising 50 moles of ethylene oxide, polyoxyethylenated stearyl alcohol which it comprises 2 moles of ethylene oxide, and polyoxyethylenated oleyl alcohol comprising 2 moles of ethylene oxide. The surfactants are available from Atlas Chemical Industries. The emulsified drug formulations of the present invention may initially comprise an oil and a nonionic surfactant. The oil phase of the emulsion comprises any pharmaceutically acceptable oil that is not miscible with water. The oil may be an edible liquid such as a non-polar ester of an unsaturated fatty acid, derivatives of said esters, or mixtures of said esters. The oil can be vegetable, mineral, animal or marine in origin. Examples of non-toxic oilsthey may also include, for example, in addition to the surfactants listed above, a member selected from the surfactants listed above, a member selected from the group consisting of peanut oil, cottonseed oil, sesame oil, corn oil, oil of almond, mineral oil, castor oil, coconut oil, palm oil, cocoa butter, safflower, a mixture of mono and diglycerides of 16 to 18 carbon atoms, unsaturated fatty acids, fractionated triglycerides derived from chain fatty acids short of 10 to 15 carbon atoms, acetylated monoglycerides, acetylated diglycerides, acetylated triglycerides, oleic also known as glyceral triolate, palmitin also known as glyceryl tripalmitate, esterarían also known as glyceryl tristearate, laurel acid hexyl ester, oleic acid ester oleic, glycolylated ethoxylated glycerides of natural oils, fatty acids They are branched with 13 molecules of ethylene oxide, and decyl ester of oleic acid. The concentration of oil, or oil derivative in the emulsion formulation can be formed from about 1% by weight to about 40% by weight, with the% by weight of all constituents in the preparation of the emulsion equal to 100% by weight. weight. The oils are described in Pharmaceutical Sciences by Remington, 17th Ed., Pp. 403-405, (1985) published by Mark Publishing Co., in the Encyclopedia of Chemistry, Van Nostrand Reinhold, 4th Ed., Pp. 644-645, (1984) published by Van Nostrand Reinhold Co .; and in the U.S. Patent. No. 4,259,323, each of which is hereby incorporated by reference in its entirety and forall purposes The amount of substances comprising levodopa and / or substances comprising carbidopa in the dosage forms of the present invention are generally from about 10% to about 90% by weight of the composition depending on the therapeutic indication and the desired administration period, for example, every 12 hours, every 24 hours, and the like. Depending on the dose of the desired drug to be administered, one or more dosage forms may be administered. The osmotic dosage forms of the present invention may possess two distinct shapes, a soft capsule shape (shown in Figure 3) and a soft capsule shape (shown in Figure 2). The soft capsule, as used by the present invention, preferably in its final form comprises a piece. The one-piece capsule is a capsule-sealed construction of the drug formulation there. The capsule can be made through various methods including the plate method, the rotary die method, the oscillating die method and the continuous process. An example of the plate method is as follows. The plate method uses a group of moles. A hot sheet of a prepared capsule sheet forming material lies on the lower mold and the formulation is emptied thereon. A second sheet the foil forming material is placed on the formulation followed by the upper mold. The group of molds is placed under a pressand a pressure is applied, with or without heat, to form a unit capsule. The capsules are washed with a solvent to remove excess agent formulation from the exterior of the capsule, and the dried capsule an air is encapsulated with a semipermeable wall. The spinning die method uses two continuous films of capsule sheet forming material that are brought to convergence between a pair of revolving dice and a wedge of the injector. The procedure of whoever seals the capsule in double and coincident operations. In this process, the sheets of the capsule sheet forming material are fed onto the guide rollers, and then down between the wedge injector and the die rolls. The formulation of the agent to be encapsulated flows through gravity into a positive displacement pump. The pump measures the formulation of the agent through the wedge injector and inside the sheets between the rolls of the die. The lower part of the wedge contains small holes aligned with the dice cavities of the die rolls. The capsule is sealed more or less in half when the pressure of the formulation of the pumped agent forces the sheets into the dice cavities, where the capsules are simultaneously filled, shaped, hermetically sealed and cut from the capsules. sheets of foil forming materials. The sealing of the capsule is achieved by mechanical pressure on the rolls of the dice and by heating the sheets of the sheet-forming materials through the wedge. After fabrication, the capsules filled with the agent formulation dry the presence of forced air, and a semi-permeable sheetencapsulate there. The oscillating die method produces capsules by driving two films of capsule sheet forming material between a group of vertical dice. The dice when closed, open and close hold a forming row of the continuous vertical plate after the rows of the cavities through the film. The cavities are filled with the agent formulation, and the cavities are moved through the dice, sealed, shaped and cut from the moving film as filled capsules with the agent formulation. The continuous process is a manufacturing system that also uses rotating dies, with the added feature that the process can successfully fill the active agent in a dry powder form within a soft layer, in addition to encapsulating liquids. The capsule filled with the continuous process is encapsulated with a semipermeable polymeric material to produce the capsule. The processes for the manufacture of soft capsule are described in the Patents of E.U.A. Nos. 4,627,850 and 6,419, 952, each of which is hereby incorporated by reference in its entirety for all purposes. Dosage forms of the present invention can also be made from an injection moldable composition through an injection molding technique. The injection-moldable compositions provided for injection molding in the semipermeable wall comprise a thermoplastic polymer, or the compositions comprise a blend of thermoplastic polymers and injection molding ingredients.optional The thermoplastic polymer that can be used for the purposes of the present invention comprises polymers having a low softening point, for example, below 200 ° C, preferably within the range of 40 ° C to 180 ° C. The polymers are preferably synthetic resins, polymerized addition resins, such as polyamides, resins obtained from diepoxides and primary alkanolamines, glycerin resins and italic anhydrides, polymethane, polyvinyl resins, polymer resins with free terminal positions or carboxyl or carboxamide groups esterified, for example, acrylic acid, acrylic amide, or acrylic acid esters, polycaprolactone, and its copolymers with dilactide, diglycolide, valerolactone and decalactone, a resin composition comprising polycaprolactone, and polyalkylene oxide, and a resin composition comprising plicaprolactone, a polyalkylene oxide such as polyethylene oxide, poly (cellulose) ) such as poly (hydroxypropylmethylcellulose), poly (hydroxyethylmethylcellulose), and poly (hydroxypropylcellulose). The membrane forming composition may comprise optional membrane forming ingredients such as polyethylene glycol, talc, polyvinyl alcohol, lactose, or polyvinyl pyrrolidone. Compositions for forming an injection molding polymer composition may comprise 100% thermoplastic polymer. The composition in another embodiment comprises from 10% to 99% of a thermoplastic polymer and from 1% to 90% of a different polymer with the total equal to 100%. The invention also provides a thermoplastic polymer composition comprising from 1% to 98% of a first polymerthermoplastic, from 1% to 90% of a second polymer, different and from 1% to 90% of a third polymer, different with all polymers equal to 100%. Representative composition comprises from 20% to 90% of the thermoplastic polycaprolactone and 10% to 80% of poly (alkylene oxide); a composition comprising from 20% to 90% polycaprolactone and 10% to 60% poly (ethylene oxide) with ingredients equal to 100%; a composition comprising 10% 97% polycaprolactone, 10% to 97% poly (alkylene oxide), and 1% to 97% poly (ethylene glycol) with all ingredients equal to 100%; a composition comprising from 20% to 90% polycaprolactone and from 10% to 80% poly (hydroxypropylcellulose) against the ingredients equal to 100%; and a composition comprising from 1% to 90% polycaprolactone, from 1% to 90% poly (ethylene oxide), 1% to 90% poly (hydroxypropylcellulose) and 1% to 90% poly (ethylene glycol) with all ingredients equal to 100%. The percentage, expressed as a percentage by weight. In another embodiment of the invention, a composition for injection molding can be prepared to provide a membrane through the mixture of a composition comprising a polycaprolactone 63% by weight, polyethylene oxide 27% by weight, and polyethylene glycol 10% by weight in a conventional mixing machine such as a Moriiama mixer 65 ° C to 95 ° C, with the ingredients added to the mixer in the following addition sequence, polycaprolactone, polyethylene oxide and polyethylene glycol. In an example, all incidents are mixed during 135minutes at a rotor speed of 10 to 20 rpm. Next, the mixes are fed into the Baker Perkins Kneader extruder at 80 ° C to 90 ° C, at a pump speed of 10 rpm and a screw speed of 22 rpm, and then cooled from 10 ° C to 12 ° C, to reach a uniform temperature. Then the cooled extruded composition is fed into an Albe Pelletizer, converted into tablets at 250 ° C, and with a length of 5 mm. The tablets are then fed into an injection molding machine, an Arburg Allrounder ™ at 93 ° C to 177 ° C, heated to a molten polymer composition, and the liquid polymer composition is forced into a molding cavity at a time. high pressure and at a rate until the mold is filled and the composition comprises the polymers that solidify in a preselected form. The parameters for injection molding consist of a band temperature through zone 1 to zone five of the barrel from 91 ° C to 191 ° C, an injection molding pressure of 1818 bar, a speed of 55 cm3 / s , and a mold temperature of 75 ° C. Injection molding compositions and injection molding processes are described in the U.S. Patent. No. 5,614, 578, which is incorporated herein by reference in its entirety and for all purposes. Altervely, the capsule can conveniently be in two parts, with one part (the "cap") sliding and covering the other part (in "body") while the capsule is deformable under the forces exerted by the expandable layer and the seals to prevent fluid leakage, the formulation of theagent active between the portions in the shape of the body's telescope and the covers. The two parts completely surround and encapsulate the internal lumen that contains the liquid, the formulation of the active agent, which may contain the useful additives. The two parts can be adjusted together after the body is filled with a preselected formulation. The assembly can be done by sliding or gluing in the form of the telescope the section of the lid over the body section, and sealing the lid and body, while completely surrounding and encapsulating the formulation of the active agent. Soft capsules typically have a wall thickness that is greater than the wall thickness of the hard capsules. For example, soft capsules can, for example, have a wall thickness in the order of 10-40 mils, approximately 20 mils being typical, while hard capsules can, for example, have a wall thickness in the order of 2-6 mils, about 4 mils being typical. In one embodiment of the dosing system, a soft capsule may be a single individual construction and may be surrounded by the non-asymmetric hydro-activated layer, the expandable layer. The expandable layer will generally be non-asymmetric and have a thicker remote portion of the exit orifice. The presence of a non-asymmetric layer functions to ensure that the maximum dose of the agent is distributed from the dosage form, as the more section through that of the distant layer of the passage swells and moves towards the orifice. In yet another configuration, the expandable layer can be formedof different sections that do not entirely comprise a capsule covered with a barrier layer. The expandable layer may be an individual element that is formed to adjust the shape of the capsule in the contact area. The expandable layer can be conveniently fabricated through tablet-forming techniques to form the concave surface that is complementary to the outer surface of the barrier-coated capsule. Suitable tools such as a convex punch in a conventional tablet-forming press can provide the necessary complementary shape for the expandable layer. In this case, the expandable layer is granulated and compressed, the place formed as a cover. Methods for the formation of an expandable layer through tablet-forming techniques are well known, having been described, for example, in U.S. Pat. Nos. 4,915,949; 5,126,142; 5,660,861; 5,633,011; 5,190,765; 5,252,338; 5,620,705; 4,931, 285; 5,006,346; 5,024,842; and 5,160,743, each of which is incorporated herein by reference in its entirety for all purposes. In some embodiments, a barrier layer can first be covered in the capsule and then the expandable, tablet-like layer is attached to the barrier-coated capsule with a biologically active adhesive. Suitable killers include, for example, manure paste, aqueous gelatin solution, aqueous gelatin / glycine solution, acrylate vinyl acetate-based adhesives such as Duro-Tak adhesives (National Starch and Chemical Company), aqueous solutions of polymershydrophilic water soluble such as hydroxypropyl methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, and the like. The intermediate dosage form can then be coated with a semipermeable layer. The exit orifice is formed on one side or at the end of the capsule opposite the expandable layer section. Since the expandable layer absorbs liquid, it will swell. Since it is limited by the semipermeable layer, as the capsule coated with barrier and expressed and liquid is compressed, the formulation of the active agent inside the capsule in the environment of use. Hard capsules typically consist of two larger parts, a lid and a body, which are fitted together after the body is filled with a pre-selected appropriate formulation. This can be done by sliding or moving the telescope form the section of the layer over the body section, thus completely moving and encapsulating the formulation of the useful agent. Hard capsules can be made, for example, by immersing stainless steel molds in a bath containing a solution of a capsule sheet forming material to cover the mold with the material. Afterwards, the molds are taken out, cooled, and cited in a current of air. The capsule is removed from the mold and trimmed to produce a foil member with an internal lumen. The interconnected layer that in the form of a telescope covers the formulation received by the body is made in a similar way. Then, the closed and filled capsule can be encapsulated with a semi-permeable sheet. The semipermeable sheet can be applied to the parts of the capsule before or afterthat the parts come together in the final capsule. In another embodiment, the hard capsules can be made with each part having matching closure rings near its open end that allow the joining and closing together of the overlapped lid and the body after filling with the formulation. In this embodiment, a pair of matching closure rings are formed within the lid portion and the body portion, and these rings provide the closure means to securely hold the capsule together. The capsule can be manually filled with the formulation, or can be filled through a machine with the formulation. In the final manufacture, the hard capsule is encapsulated with a semipermeable sheet is permeable to the passage of the fluid and substantially impermeable to the passage of the useful agent. Methods for forming hard cap filtration formulations are described in the U.S. Patent. No. 6,174, 547, the U.S. Patent. Nos. 6,596,314, 6,419,952, and 6,174,547, each of which is hereby incorporated by reference in its entirety for all purposes. Hard and soft capsules may comprise, for example, gelatin; gelatin having a viscosity of 15 to 30 millipoises and a resistance to crystallization of 160 to 250; a composition comprising gelatin; glycerin, water and titanium dioxide; a composition comprising gelatin, erythrosine, iron oxide and titanium dioxide; a composition comprising gelatin, glycerin, sorbitol, potassium sorbate and titanium dioxide; a composition comprising gelatin, glycerin, potassium sorbate and titanium dioxide; a composition comprising gelatin, glycerinacacia, and water; and similar. Useful materials for forming the capsule wall are known from the U.S. Patent. Nos. 4,627,850; and at 4,663,148, each of which is hereby incorporated by reference in its entirety for all purposes. Alternatively, the capsules can be made from materials other than gelatin (see for example, products made by BioProgres foot). Capsules typically can be provided, for example, in sizes from about 3 to about 22 minims (1 minim being equal to 0.0616 ml) and in oval, oblong or other forms. They can be supplied in standard form and in several standard sizes, conventionally designed as (000), (00), (0), (1), (2), (3), (4), and (5). The largest number corresponds to the smallest size. Non-standard forms can also be used. In either case of the soft capsule, or thin capsule, non-conventional shapes and sizes may be provided if required for a particular application. The osmotic devices of the present invention comprise a semipermeable wall permeable to the passage of the biological fluid outside and substantially impermeable to the passage of the drug formulation. The selectively permeable composition used to form the wall is essentially non-erodible and is insoluble in biological fluids during the life of the osmotic system. The semipermeable wall comprises a composition that does not adversely affect the host, the drug formulation, an osmopolymer, osmotic agent and the like. The polymersRepresentative for forming the semipermeable wall comprises semipermeable homopolymers, semipermeable copolymers, and the like. In a presently preferred embodiment, the compositions may comprise cellulose esters, cellulose ethers, and cellulose ester-ethers. Cellulosic polymers typically have a degree of substitution, "D.S", in their anhydroglucose unit of more than 0 to 3 inclusive. By degree of substitution means the average number of hydroxyl groups originally present in the anhydroglucose unit that are replaced by a substituent group, or converted to another group. The hydroglucose unit may be partially or completely substituted with groups such as acyl, alkanoyl, alkenoyl, aroyl, alkyl, alkoxy, halogen, carboalkyl, alkylcarbamate, alkylcarbonate, alkylsulfonate, alkylsulfamate, semipermeable polymer forming groups, and the like. The semipermeable compositions typically include a member selected from the group consisting of cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose acetate, cellulose diacetate, mono-, di-, and cellulose trialkanilate, mono -, di-, and trialkenylates, mono-, di-, and triaroylates, and the like. Exemplary polymers may include, for example, cellulose acetate having one of that D.S. of 1.8 to 2.3 and an acetyl content of 32 to 39.9%; cellulose diacetate having a D.S. of 1 to 2 and an acetyl content of 21 to 35%, cellulose triacetate having a D.S. of 2 to 3 and an acetyl content of 34 to 44.8%, and the like. The more specific cellulosic polymers include cellulose propionate having a D.S. of 1.8 anda propionyl content of 38.5%; cellulose acetate propionate has an acetyl content of 1.5 to 7% and an acetyl content of 39 to 42%; cellulose acetate propionate having an acetyl content of 2.5 to 3%, an average propionyl content of 39.2 to 45%, and a hydroxyl content of 2.8 to 5.4%; cellulose acetate butyrate having a D.S. of 1.8, an acetyl content of 13 to 15%, and a butyryl content of 34 to 39%; cellulose acetate butyrate having an acetyl content of 2 s 29%, a butyryl content of 17 to 53%, and a hydroxyl content of 0.5 to 4.7%; cellulose triacilates having a D.S. from 2.6 to 3 such as cellulose trivalerate, cellulose trilamate, cellulose tripalmitate, cellulose trioctanoate, and cellulose tripropionate; cellulose diesters having a D.S. from 2.2 to 2.6 such as cellulose disuccinate, cellulose dipalmitate, cellulose dioctanoate, cellulose dicaprylate, and the like; mixed cellulose esters such as cellulose acetate valerate, cellulose acetate succinate, cellulose propionate succinate, cellulose acetate octanoate, cellulose valerate palmitate, cellulose heptanoate acetate, and the like. Semipermeable polymers are known in the U.S. Patent. No. 4,077,407 and can be synthesized through procedures described in the Encyclopedia of Polymer Science and Technology, Vol. 3, pages 325 to 354, 1964, published by Interscience Publishers, Inc., New York; each of which is hereby incorporated by reference in its entirety for all purposes. Additional semipermeable polymers for formation of semi-permeable wallthey may comprise, for example, acetaldehyde dimethyl cellulose acetate; ethylcarbamate cellulose acetate; cellulose acetate methylcarbamate; cellulose dimethylaminoacetate; semipermeable polyamide; semipermeable polyurethanes; semipermeable sulfonate polystyrenes; selectively crosslinked semipermeable polymers formed through coprecipitation of a polyanion and a polycation as described in U.S. Patents. Nos. 3,173,876; 3,276,586; 3,541,005; 3,541, 006; and 3,546,142, each of which is hereby incorporated by reference in its entirety for all purposes; semipermeable polymers as described in the Patent of E.U.A. No. 3,133,132, which is hereby incorporated by reference in its entirety and for all purposes; semipermeable polystyrene derivatives; semi-permeable poly (sodium styrene sulfonate); semipermeable poly (vinylbenzyltrimethylammonium chloride); semipermeable polymers, which exhibit a fluid permeability of 10-5 to 10-2 (ce.mols / cm.hr atm) expressed as differences by atmosphere of hydrostatic or osmotic pressure through a semi-permeable wall. Polymers are known in the art in US Patents. Nos. 3,845,770; 3,916,899; and 4,160, 020; and in Handbook of Common Polymers, by Scott, J. R., and Roff, W. J., 1971, published by CRC Press, Cleveland. Ohio, each of which is hereby incorporated by reference in its entirety in its entirety for all purposes. The semipermeable wall may also comprise an agent for flow regulation. The agent for flow regulation is acompound added to aid in the regulation of fluid permeability or flow through the wall. The flow regulating agent may be a flow improver or a decreasing agent. The agent can be preselected to increase or decrease the liquid flow. Agents that produce a ma increase in permeability in fluids such as water, are generally essentially hydrophilic, while those that produce a ma decrease in fluids such as water are essentially hydrophobic. The amount of regulator in the wall when incorporated therein is generally from about 0.01% to 20% by weight or more. Flow regulating agents in a flow-increasing embodiment include, for example, polyhydric alcohols, polyalkylene glycols, polyalkylene diols, alkylene glycol polyesters, and the like. Typical flow improvers include polyethylene glycol 300, 400, 600, 1500, 4000, 6000, poly (ethylene glycol-co-propylene glycol), and the like; low molecular weight glycols such as polypropylene glycol, polybutylene glycol and polyamylene glycol: polyalkylene diols such as poly (1,3-propanediol), poly (1,4-butanediol), poly (1,6-hexanediol), and the like; aliphatic diols such 1,3-butylene glycol, 1,4-pentamethylene glycol, 1,4-hexamethylene glycol, and the like; alkylene triols such as glycerin, 1,3-butantriol, 1,4-hexanediol, 1,3,6-hexantriol and the like; esters such as ethylene glycol dipropionate, ethylene glycol butyrate, ethylene glycol dipropionate, glycerol acetate esters, and the like. Representative reducing agents include, for example, phthalates substituted with an alkyl or alkoxy group, or with both alkyl and alkoxy groupssuch as diethyl phthalate, dimethoxyethyl phthalate, dimethyl phthalate, and [di (2-ethylhexyl) phthalate], aryl phthalates such as triphenyl phthalate, and butyl phthalate benzyl; unsolvable salts such as calcium sulfate, barium sulfate, calcium phosphate and the like; nonsoluble oxides such as titanium oxide; polymers in the form of powder, granules or the like such as polystyrene, polymethylmethacrylate, polycarbonate, and polysulfone; esters such as citric acid esterified with long chain alkyl groups; waterproof fillers substantially of water; Resins compatible with cellulose-based wall-forming materials and the like. Other materials that can be used to form the semipermeable wall to impart flexibility and elongation properties to the wall, to make the wall from less to non-brittle and to convert the tensile strength to the rupture, include, for example, phthalate plasticizers such as dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, straight chain phthalates from six to eleven carbons, di-isononyl phthalate, diisodecyl phthalate, and the like. Plasticizers include non-phthalates such as triacetin, dioctyl azelate, epoxidized phthalate, tri-isoctyl trimelate, tri-isononyl trimethylthio, sucrose acetate isobutyrate, epoxidized soybean, and the like. The amount of plasticizer in the wall when incorporated there is about 0.01% to 20% by weight, or greater. The semipermeable wall surrounds and forms a compartment containing a plurality of layers, one of which is an expandable layer which in some embodiments may contain osmagents. The layerexpandable comprises in one embodiment a hydroactivated composition that swells in the presence of water, such as that present in gastric fluids. Conveniently, it may comprise an osmotic composition comprising an osmotic solute which exhibits an osmotic pressure gradient across the semipermeable layer against an external fluid present in the environment of use. In another embodiment, the hydroactivated layer comprises a hydrogel that imbibes and / or absorbs fluids in the layer through the outer semipermeable wall. The semipermeable wall is non-toxic. It maintains its physical and chemical integrity during the operation and is essentially free from interaction with the expandable layer. The expandable layer in a preferred embodiment comprises a hydroactive layer comprising a hydrophilic polymer, also known as an osmopolymer. The osmopolymers exhibit fluid inhibition properties. The osmopolymers can swell, the hydrophilic polymers, whose osmopolymers interact with water and biological aqueous fluids and swell or expand to a state of equilibrium. The osmopolymers exhibit the ability to swell in water and biological fluids and retain a significant portion of the fluid embedded within the polymer structure. Osmopolymers swell or expand to a very high degree, usually exhibiting 2- to 50-fold increase in volume. The osmopolymers may be intertwined or non-interlaced. The hydrophilic, swellable polymers are in a mode slightly interlaced, such interlaces being formed through covalent or ionic bonds or regionscrystalline residues after they swell. The osmopolymers may be a plant, animal or synthetic origin. Osmopolymers are hydrophilic polymers. Hydrophilic polymers suitable for the purpose of the present invention include poly (hydroxy-alkyl methacrylate) having a molecular weight of about 30,000 to 5,000,000; poii (vinylpyrrolidone) having a molecular weight of about 10,000 to 360,000; anionic and cationic hydrogels; polyelectrolyte complexes; polyvinyl alcohol having a low acetate residue, entangled with glyoxal, formaldehyde, or glutaraldehyde and having a degree of polymerization of about 200 to 30,000; a mixture of methyl cellulose, crosslinked agar and carboxymethyl cellulose; a mixture of hydroxypropyl methylcellulose and sodium carboxymethylcellulose; a mixture of hydroxypropyl ethyl cellulose and sodium carboxymethyl cellulose, a mixture of sodium carboxymethyl cellulose and methyl cellulose, sodium carboxymethyl cellulose; potassium carboxymethylcellulose; a water-swellable water-insoluble copolymer formed from a dispersion of the maleic anhydride copolymer with styrene, ethylene, propylene, butylene or finely divided isobutylene crosslinked with from about 0.001 to about 0.5 moles of agent per mole of maleic anhydride crosslinked by copolymer; water-swellable polymers of N-vinyl lactams; polyoxyethylene-polyoxypropylene gel; carob gum; polyacrylic gel; polyester gel; polyuria gel; polyether gel, polyamide gel; polyeleculose gel; polyoma gel; initially dry hydrogels that imbibe and absorb water that penetrates thecrystalline hydrogel and its vitreous temperature decreases; and similar. Representatives of other osmopolymers may comprise polymers that form hydrogels such as Carbopol ™, acid carboxypolymer, an acrylic polymer crosslinked-linked with a polyallyl sucrose, also known as carboxypolymethylene, and carboxyvinyl polymer having a molecular weight of 250,000 a 4,000,000; Cyaname ™ polyacrylamide; water-swellable indenmaleic anhydride polymers intertwined; Good-rite ™ polyacrylic acid having a molecular weight of 80,000 to 200,000; Poiyox ™ polyethylene oxide polymer that has a molecular weight of 100,000 to 5,000,000 and higher; starch graft copolymers; Aqua-Keeps ™ acrylate polymer polysaccharides composed of condensed glucose units such as polyglycan entangled with diester; and similar. Representative polymers that form hydrogels are known in the prior art in the U.S. Patent. No. 3,865,108; Patent of E.U.A. No. 4,002,173; Patent of E.U.A. No. 4,207,893; and in Handbook of Common Polymers, by Scott and Roff, published by Chemical Rubber Co., Cleveland, Ohio, each of which is incorporated herein by reference for all purposes. The amount of osmopolymer comprising a hydro-activated layer may be in the form of about 5% to 100%. The expandable layer in another manufacture may comprise an osmotically effective compound comprising organic and inorganic compounds that exhibit an osmotic pressure gradient across asemipermeable wall that against an external fluid. The osmotically effective compounds, as with the osmopolymers, imbibe fluid within the osmotic system, while making the fluid available to push it against the inner wall, i.e., in some embodiments, the barrier layer and / or the hard capsule wall or gentle to push the active agent of the dosage form. The osmotically effective compounds are also known as effective solutes, and also as osmagents. Osmotically effective solutes which may be used comprise magnesium sulfate, magnesium chloride, potassium sulfate, sodium sulfate, lithium sulfate, potassium acid phosphate, mannitol, urea, inositol, magnesium succinate, tartaric acid, carbohydrates such as raffinose, sucrose, glucose, lactose, sorbitan, and mixtures thereof. The amount of osmagent may be from about 5% to 100% of the weight of the layer. The expandable layer optionally comprises an osmopolymer and an osmagent with the total amount of osmopolymer and osmagent equal to 100%. Osmotically effective solutes are known in the prior art as described in US Pat. No. 4,783,337, hereby incorporated by reference in its entirety for all purposes. In certain embodiments, the dosage forms may further comprise a barrier layer. The barrier layer in certain embodiments is deformable under the pressure exerted by the expandable layer and will be impermeable (or less permeable) to fluids and materials that may be present in the expandable layer, the formulation and the environment of use,during the distribution of the active agent formulation. A certain degree of permeability of the barrier layer may be allowed if the rate of distribution of the active ingredient formulation is not detrimentally effected. However, it is preferred that the barrier layer does not completely transport fluids and materials therein in the dosage form and environment of use during the distribution period of the active agent. The barrier layer may be deformable under the forces applied through the expandable layer to enable compression of the capsule to force the formulation of the liquid active agent from the outlet orifice. In some embodiments, the barrier layer will be deformable to an extent that will create a seal between the expandable card and the semipermeable layer in the area where the exit orifice is formed. In that form, the barrier layer will form or flow to a limited extent to seal the initially exposed areas of the expandable layer and the semipermeable layer when the outlet orifice is being formed, such as by piercing or the like, during the initial stages. of the operation. When sealed, the only avenue for impregnation of the liquid within the expandable layer is through the semipermeable layer, and there is no return flow of the fluid within the expandable layer through the exit orifice. Suitable materials for forming the barrier layer may include, for example, polyethylene, polystyrene, with ethylene vinyl acetate polymers, polycaprolactone and Hytrel ™ polyester elastomers (Du Pont), cellulose acetate, cellulose acetate pseudolatex (such as It is describedin the U.S. Patent. No. 5,024,842), cellulose acetate propionate, cellulose acetate butyrate, ethyl cellulose, ethyl cellulose pseudolatex (such as Reléase as supplied by Colorcon, West Point, Pa. O Aquacoat ™ as supplied by the FMC Corporation, Philadelphia , Pa.), Nitrocellulose, polylactic acid, polyglycolic acid, with glycolic acid polymers, with polylactide glycolide polymers, collagen, polyvinyl alcohol, polyvinyl acetate, polyethylene vinylacetate, polyethylene terephthalate, polybutadiene styrene, polyisobutylene, polymer of polyisobutylene of isoprene, polyvinyl chloride, with polymers of polyvinylidene chloride-vinyl chloride, copolymers of esters of acrylic acid and methacrylic acid, with polymers of methyl methacrylate and ethylacrylate, latex of acrylate esters (such as Eudragit supplied by Rohm Pharma, Darmstaat, Germany), polypropylene, copolymers of propylene oxide and ethylene oxide, with block polymers of propylene oxide and ethylene oxide, copolymers of ethylene vinyl alcohol, copolymer of ethylene vinyl alcohol, polysulfone, poly-xylenes, entangled acrylics, silicones, or polyesters, acrylics normally interlaced , silicones, or polyesters, butadiene-styrene rubber, and mixtures of the foregoing. Preferred materials may include cellulose acetate, with esters of acrylic acid and methacrylic acid polymers, copolymers of methyl methacrylate and ethylacrylate, and acrylate ester latexes. Preferred copolymers can include poly (butylmethacrylate), (2-dimethylaminoethyl) methacrylate, methylmethacrylate) 1: 2: 1, 150,000, sold under the trademark EUDRAGITAND; poly (ethylacrylate, methylmethacrylate) 2: 1, 800,000, sold under the trademark EUDRAGIT NE 30 D; poly (methacrylic acid, methyl methacrylate) 1: 1, 135,000, sold under the trademark EUDRAGIT L; po! i (methacrylic acid, ethyl acrylate) 1: 1, 250,000, sold under the trademark EUDRAGIT L; poly (methacrylic acid, methyl methacrylate) 1: 2,135,000, sold under the trademark EUDRAGIT S; poly (ethyl acrylate, methyl methacrylate, trimethylammonium ethyl methacrylate chloride) 1: 2: 0.2, 150,000, sold under the trademark EUDRAGIT RL; poly (ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1: 2: 0.1, 150,000, sold as EUDRAGIT RS. In each case, the ratio x: y: z indicates the molar proportions of the monomer units and the last number is the average molecular weight of the polymer. Especially preferred is cellulose acetate which contains plasticizers such as acetyl tributyl citrate and ethylacrylate methyl methacrylate copolymers such as Eudragit NE. The above materials for use as the barrier layer can be formulated with plasticizers to make the barrier layer suitably deformable such that the force exerted by the expandable layer will collapse the compartment formed by the barrier layer to distribute the agent formulation active, liquid. Examples of typical plasticizers are as follows: polyhydric alcohols, triacetin, polyethylene glycol, giicerol, propylene glycol, acetate esters, glycerol triacetate, triethyl citrate, acetyl triethyl citrate, glycerides, acetylated monoglycerides, oils, mineral oil, castor, and the like. Plasticizers can bemix within material in amounts of 10-50% by weight based on the weight of the material. The various layers that form the barrier layer, the expandable layer and the semipermeable layer can be applied through conventional coating methods such as described in US Pat. No. 5,324,280, incorporated herein by reference in its entirety for all purposes. Since the barrier layer, the expandable layer, and the semipermeable wall have been illustrated and described for convenience as individual layers, each of these layers can be composed of several layers. For example, for particular applications it may be desirable to cover the steps with a first layer of material that facilitates the coating of a second layer having the permeability characteristics of the barrier layer. In this case, the first and second layers comprise the barrier layer. Similar considerations apply to the semipermeable layer and the expandable layer. The exit orifice can be formed through mechanical perforation, laser drilling, eroding an element that can be eroded, extracting, dissolving, exploding or quoting an anterior passage of the composite wall. The exit orifice may be a forum formed through the filtration of sorbitol, lactose or the like of a wall or layer as described in U.S. Pat. No. 4,200,098, incorporated herein by reference in its entirety for all purposes. This patent describes those of controlled size porosity formed through dissolution, extraction orfiltration of a material from a wall, such as sorbitol of cellulose acetate. A preferred form of laser drilling is the use of a pulse laser to want incremental form to remove material from the composite wall to the desired depth to form the exit orifice. Figure 4 is a schematic station of another illustrative osmotic dosage form. Dosage forms of this type are described in detail in the Patents of E.U.A. Nos .: 4,612,008; 5,082,668; and 5,091, 190, which are incorporated herein by reference. Briefly, the dosage form 40, shown in the cross-section, has a semi-permeable wall 42 defining an internal compartment 44. The inner compartment 44 contains a core compressed in two layers having a drug layer 46 and an expression layer. 48. As will be described later, the expression layer 48 is a displacement composition is placed within the dosage form such that when the ejection layer expands during use, the materials forming the drug layer are expelled from the dosage form to through one or more output ports, such as the outlet port 50. The ejection layer can be placed in contact with the stratified configuration with the drug layer, as illustrated in Figure 4, or it can have one or more layers interventoras that separates the expulsion layer and the drug layer. The drug layer 46 comprises substances comprising levodopa and / or substances comprising carbidopa in a mixture withSelected excipients, such as those explained above with reference to Figure 3 An illustrative dosage form can have a drug layer comprising a complex, a poly (ethylene oxide) as a carrier, sodium chloride as an osmagent, hydroxypropylmethylcellulose as a binder , and magnesium stearate as an inhabitant. The ejection layer 48 comprises the osmotically active component (s), such as one or more polymers that imbibe an aqueous or biological fluid and swell or expand to a high degree, typically exhibiting a 2-50 fold increase volume. The osmopolymer can be entangled or non-interlaced, and in a preferred embodiment the osmopolymer is at least slightly interlaced to create a polymer network that is so large and tangled that it easily exits the dosage form during use. Examples of polymers that can be used as an osmopolymer are provided in the references cited above which describe the osmotic dosage forms in detail. A typical osmopolymer is a poly (alkylene oxide), such as poly (ethylene oxide), and a poly (alkaline carboxymethylcellulose), wherein the alkali is sodium, potassium, or lithium. Additional excipients such as a binder, a lubricant, an antioxidant, and a colorant can also be included in the ejection layer. In use, when the fluid is imbibed through the semipermeable wall, the osmopolymer (s) swell and is expelled against the drug layer to cause release of the drug through the outlet port (s).
The ejection layer may also include a component referred to as a binder, which is typically a cellulose, or vinyl polymer, such as aspolin-n-vinylamide, poly-n-vinylacetamide, poly (vinyl pyrrolidone), poly-n- vinylcaprolactone, poly-n-vinyl-5-methyl-2-pyrrolidone, and the like. The ejection layer may also include a lubricant, such as sodium stearate or magnesium stearate, and an antioxidant to inhibit oxidation of the ingredients. Representative antioxidants include, but are not limited to, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, a mixture of 2 and 3 tertiary-butyl-4-hydroxyanisole, and butylated hydroxyethylene. An osmagent can also be incorporated into the drug layer and / or the ejection layer of the osmotic dosage form. The presence of the osmoagent establishes a gradient of osmotic activity through the semipermeable wall. Illustrative agents include salts, such as sodium chloride, potassium chloride, lithium chloride, etc. and sugars, such as raffinose, sucrose, glucose, lactose and carbohydrates. With a continuous reference to Figure 4, the dosage form may optionally include an outer cover (as shown) to color code the dosage forms according to the doses or to provide an immediate release of the substances comprising levodopa and / or substances that comprise carbidopa or other drugs. In use, water flows through the wall and into the ejection layer and the drug layer. The expulsion layer imbibes fluid and begins to swell and, consequently, expelled drug layer 44causing material in the layer to be expelled through the exit orifice and into the gastrointestinal tract. The ejection layer 48 is designed to imbibe fluid and continue to swell, thereby continuously expelling the substances comprising levodopa and / or substances comprising carbidopa from the drug layer throughout the period during which the dosage form is in. the gastrointestinal tract. In this form, the dosage form provides a supply of substances comprising levodopa and / or substances comprising carbidopa to the gastrointestinal tract for a specified window. In one embodiment, the dosage forms of the investment comprise two or more forms of substances comprising levodopa and / or substances comprising carbidopa whereby a first form of substances comprising levodopa and / or substances comprising carbidopa are available for absorption by the tract G.l. superior and a second form is presented for the absorption in act G. I. inferior. This can facilitate optimal absorption in circumstances where different characteristics are needed to optimize the absorption through the G tract. I .. This modality is achieved by using an osmotic dosage form in three layers. A specific illustrative dosage form comprises a first and a second form of substances comprising levodopa as shown in Figure 5. The osmotic dosage form 60 has a three layer core 62 comprising a first layer 64 of a first formof substance comprising levodopa, a second layer 66 comprising a second form of a substance comprising levodopa, and a third preferred layer 68, the expulsion layer. The three layer dosage form is prepared to have a first layer of 85.0% by weight of the first form of a substance comprising levodopa, 10.0% by weight of polyethylene oxide of molecular weight of 00,000, 4.5% by weight of polyvinylpyrrolidone having a molecular weight of about 35,000 to 40,000, and 0.5% by weight of magnesium stearate. The second layer is comprised of 93% by weight of a second form of a substance comprising levodopa, 5.0% by weight of polyethylene oxide, with a molecular weight of 5,000,000, 1.0% by weight of polyvinylpyrrolidone having a molecular weight of about 35,000 to 40,000, and 1.0% by weight of magnesium stearate. The ejection layer consists of 63.67% by weight of polyethylene peroxide, 30.00% by weight and sodium chloride, 1.00% by weight of ferric oxide, 5.00% by weight of hydroxypropylmethylcellulose, 0.08% by weight of butylated hydroxytoluene and 0.25% by weight of magnesium stearate. The semipermeable wall is comprised of 80.0% by weight cellulose diacetate having an ethyl content of 39.8% and 20.0% by weight of polyoxyethylene-polyoxypropylene copolymer. The dissolution rates of the dosage forms, such, as those shown in Figures 2-5, can be determined according to a general procedure such as that set forth in Example 6. InIn general, the release of the drug formulation from the dosage form starts after contact with an aqueous environment. In the dosage form illustrated in Figure 2, the complex drug-transport portion portion, present in the adjacent layer of the exit orifice, is released after contact with an aqueous environment and continues for the life of the device. The dosage form illustrated in Figure 5 provides an initial release of the salt from the drug portion, present in the drug layer adjacent to the exit orifice, when the release of the complex from the drug portion-transport portion occurs subsequently. . It will be appreciated that this dosage form is designed to release the salt from the drug portion while in transit in the upper GI tract, corresponding approximately to the first eight hours of transit. The complex is released as the dosage form travels through the lower GI tract, approximately corresponding to such long periods with approximately eight hours after ingestion. The design has the advantage that it increases the absorption of the lower GI tract provided for the complex. An exemplary dosage form, preferred in the art as a dosage form of elemental osmotic, is shown in Figure 6. Dosage form 20, shown in a cropped view, is also referred to as an elementary osmotic pump, and is comprised of of one for the semipermeable 22 that surrounds and pigeonholes an internal compartment 24. The internal compartment contains a single layer of the referred componentHere, the drug layer 26, which comprises substances comprising levodopa and / or substances comprising carbidopa 28 in a mixture with the selected excipients. The excipients are adapted to provide a gradient of osmotic activity to attract fluid from an external environment through the wall 22 and to form the formulation of the distributable substances comprising levodopa and / or substances comprising carbidopa once the absorption of the fluid. The excipients may include a suitable suspending agent, also referred to herein, the drug carrier 30, a binder 32, a lubricant 34, and an osmotically active agent referred to as an osmagent 36. Illustrative materials for each of these components are provided to continuation. The semipermeable wall 22 of the osmotic dosage form is permeable to the passage of an external fluid, such as water and biological fluids, hero substantially impervious to the passage of components in the internal compartment. The materials useful for forming the wall are essentially non-erodible and are substantially insoluble in biological fluids during the life of the dosage form. Representative polymers for forming the semipermeable wall include homopolymers and copolymers, such as cellulose esters, cellulose ethers, and cellulose ether esters. The flow regulating agents can be mixed with wall-forming materials to modulate the permeability of the wall fluid. For example, agents that produce a marked increase in fluid permeability such as water from the general are essentiallyhydrophilic, while those that produce a marked decreased water permeability are essentially hydrophobic. Exemplary flow regulating agents include polyhydric alcohols, polyalkylene glycols, polyalkylene diols, polyesters of alkylene glycols and the like. In operation, the osmotic gradient across the wall 22 due to the presence of osmotically active agents to us gastric fluid is imbibed through the wall, swelling the drug layer, and the formation of a distributable formulation of substances comprising levodopa and / or substances comprising carbidopa (for example a solution, suspension, slurry, or other flowable composition) within the internal compartment. The distributable formulation is released through an outlet 38 according to the continuous fluid in both the internal compartment. Even when the 3ANBPA formulation is released from the dosage form, the fluid continues to be expelled into the internal compartment, while continuing release is conducted. In this form, the substances comprising levodopa and / or the substances comprising carbidopa are released in a sustained form over an extended period. Figures 7A-7C illustrate another illustrative dosage form, known in the art and described in the US Patents. Nos. 5,534,263; 5,667,804; and 6,020,000, which are specifically incorporated herein by reference. Briefly, a cross-sectional view of a dosage form 80 is shown before ingestion in the gastrointestinal tract in Figure 7A. the dosage form is comprised of a cylindrical matrix 82comprising substances comprising levodopa and / or substances comprising carbidopa. The ends 84, 86 of the matrix 82 are preferably rounded and connected in shape in order to ensure easy ingestion. Bands 88, ninety and 92 concentrically surround the cylindrical matrix and are formed of a material that is relatively insoluble in an aqueous environment. Suitable materials are set forth in the patents cited above and in Example 6 below. After ingestion of the dosage form 80, the matrix regions 82 between the bands 88, 90, 92 start erosion, as illustrated in Figure 7B. erosion of the matrix initiates the release of the substances comprising levodopa and / or the substances comprising carbidopa in the fluid environment of the GI tract while the dosage form continues transit through the GI tract, the matrix continues to erode, as Figure 7C is illustrated. Here, erosion of the matrix has advanced to an extension of the dosage form is divided into three pieces, 94, 96, 98. The erosion will continue until the portions of the matrix of each of the pieces have been completely eroded. The bands 94, 96, 98 will then be expelled from the GI tract. It will be appreciated that the dosage forms described in Figures 2 through 7C are merely illustrative of a variety of dosage forms designed for and capable of achieving the distribution of the complex of the drug. portion of the invention to the GI tract. Experts in the pharmaceutical arts can identify other dosage forms that could beadequate. It should be noted that, in some cases, a dosage form of uncontrolled release may be desirable. For example, levodopa and / or the levodopa and / or carbidopa complex and / or a carbidopa complex can be dosed using an immediate release dosage form if the controlled distribution to the lower GI tract is not necessary for a specific clinical situation. This can be the situation, for example if chemically an immediate change of action is desired. Due to the improved bioavailability, the complexes of the invention can be administered as an IR dosage form to achieve a plasma levodopa concentration higher than Sinemet at an equivalent dose. The apparent economic dose could lead to a delay induced by reduced levodopa in gastric emptying as suggested by DRC Robertson and others, "The influence of levodopa on gastric emptying in man." Br J Clin Pharmacol 29: 47-53 (1990). This can provide a dosage form and IR of the complexes of the invention with a faster initial effect of Sinemet® action. Typical doses of substances comprising levodopa and / or substances comprising carbidopa in the dosage forms of the invention may vary widely. The inventors observe the molecular weight of the substances comprising levodopa and / or substances comprising carbidopa can vary significantly depending on doses administered as a salt of loose ion pairs, a complex, astructural counterpart, etc. Accordingly, the strength of the dosage of the substances comprising levodopa and / or the substances comprising carbidopa need to be varied according to the form incorporated in the dosage form varies. The dose administered is generally adjusted according to the desired result for individual patients. Since the molecular weight is different for various forms of levodopa and / or carbidopa, it is confusing to report the dose to a form according to its equivalent weight. It is preferable to report how the equivalent weight of levodopa monohydrate or carbidopa is in the form currently available on the market and unknown to most physicians (for example, the forms available in Sinemet®). For example, the molecular weight of levodopa lauryl sulfate is 463.59, the molecular weight of levodopa is 197.9. To dose 200 mg of equivalent weight of levodopa, it would be necessary to dose 470 mg of levodopa lauryl sulfate. On these bases, certain embodiments according to the invention may comprise an equivalent weight of the form (s) of levodopa present in the dosage form ranging from about 10 mg to about 1000 mg, preferably from about 50 mg to about of 900 mg, and more preferably from about 100 mg to about 400 mg. the particular dosage forms may contain about 10mg, about 20mg, about 30mg, about 40mg, about 50mg, about 100mg, about 150mg, about 200mg, about 300mg, about of 400 mg, around 500 mg, aroundof 750 mg, or about 1000 mg equivalents by weight in a given dosage form. In addition, embodiments of the invention may comprise a weight equivalent of the form (s) of carbidopa present the dosage form from the scale of about 1 mg to about 300 mg, preferably from about 2.5 mg to about 250 mg, and more preferably from about 25 mg to about 100 mg. the particular dosage forms may contain about 1 mg, about 2 mg, about 2.5 mg, about 5 mg, about 10 mg, about 20 mg, about 40 mg, about 50 mg, about 60 mg , about 75 mg, about 100 mg, about 200 mg, or about 300 mg equivalents by weight in a given dosage form. Preferred dosage regimens comprise a dosing twice a day (eg, bid) or once a day (eg, qd). In one aspect, the invention provides a method for treating an indication, such as a disease or disorder, preferably a disease or disorder responsive to treatment through the administration of levodopa, in a patient by administration of a dosage form of distribution. controlled comprising substances comprising levodopa and / or substances comprising carbidopa. In one embodiment, a composition comprising substances comprising levodopa and / or substances comprising carbidopa and a pharmaceutically acceptable carrier is administered to the patient throughoral administration. The present invention is further directed to a method of treatment comprising the administration to a patient of the need thereof, of a dosage form of oral controlled distribution comprising substances comprising levodopa and / or substances comprising carbidopa wherein the substances comprise Levodopa and / or substances comprising carbidopa are released from the dosage form at a rate substantially in the order of zero, preferably a release rate in the order of zero. A variety of controlled dosage forms described herein are capable of providing a velocity substantially in the order of zero, preferably a velocity in the order of zero. Said dosage forms comprise elementary osmotic pumps, matrix and two-layer osmotic dosage forms, as well as others well known to one skilled in the art. It is clinically desirable to maintain a reasonably consistent inhibition of peripheral decarboxylase through a reasonably consistent concentration of plasma carbidopa. This leads to a reasonably constant concentration of levodopa in plasma that is desirable to keep patients under control. K J Black et al., "Rapid intravenous loading of levodopa for human research: clinical results." Journal of Neuroscience Methods 127: 19-23 (2003); R. Durso "Variable absorption of carbidopa, while peripheral and central levodopa metabolism". J Clin Pharmacol 40: 854-60 (2000).
By limiting the periods in which carbidopa or levodopa concentrations are at least about 15% of their respective Cmax may be useful to reduce potential side effects, and may provide economic effects of drug, which may be associated with of continuously high plasma (for example, continuous infusion) of levodopa. The continuously high levels of levodopa are down regulated, and the lower plasma levels are able to restore, the sensitivity of the dopamine receptors. This effect was reported for enteral infusion of levodopa in J. M. Cedarbaum et al., "Sustained enteral administration of levodopa increases and interrupted infusion decreases levodopa dose requirements." Neurobiology 40: 995-997 (June 1990), incorporated herein by reference. The inventors hypothesize that this method can be applied to the development of the dosage forms of the invention to provide controlled distribution oral therapies that have improved clinical results. An expert can optimize the time during which the drug concentrations in the plasma of carbidopa or levodopa are not at least about 15% of their respective Cmax to provide dosage forms that have an optimal performance for the patient. In certain embodiments, the period during which the plasma drug concentration of carbidopa is at least 15% Cmax, and the period during the drug concentration in levodopa plasma is at least about 15% Cmax It can not be the same.
For example, the plasma concentration of carbidopa may fall below about 15% Cmax before the levodopa concentration drops below about 15% Cmax, or vice versa. In preferred embodiments, the controlled distribution dosage structure is adapted to controllably distribute substances comprising levodopa and / or substances comprising carbidopa contained by the controlled distribution dosage structure at an upward rate of effective release for, after a single administration of the dosage form to a patient, provides a profile in the plasma substantially in the order of zero of levodopa and / or carbidopa throughout a window of at least about ten hours duration. These plasma profiles may be clinically advantageous because they provide for the distribution in the order of zero of substances comprising levodopa and / or substances comprising carbidopa during a period when the immediate release of levodopa is administered and / or the immediate release of carbidopa may not provide this profile in the order of zero. The lack of a profile in the order of zero can lead to the "on-off" problems and other problems noted above with respect to conventional dosage forms. The ascending release rate modes are particularly useful in circumstances where the uptake of G.l. it is even smaller than the absorption of G.l. higher. In such cases, the ascending release rate may partially compensate for the G.l. more lowreduced or even reduced absorption in areas of G.l. superior that do not possess high levels of active transporters that may be responsible for the primary transport of levodopa and carbidopa. In the up-release rate mode, the rate of release during the first approximately 3 hours after dosing an inventive dosage form is about 1 / F times that of the rate of release beyond about 3 hours after the dosage where F = X / Y and where X = bioavailability of levodopa or carbidopa when it is distributed in the Gl lower as a complex of the invention, and Y = bioavailability of levodopa or carbidopa when it is distributed to G.l. superior as a complex of the invention. Several ascending release velocity profiles can be obtained by one skilled in the art by optimizing the appropriate formulations. For example, one skilled in the art could adjust the dosage form shown in Figure 5 to vary the release rates and thus achieve an ascending release rate profile. Such adjustments are known to one skilled in the art. In one embodiment, the dosage forms of the invention can achieve an upward release rate through the provision of more than one drug layer. In osmotic devices with multiple layers of drug, a gradient of drug concentration betweenLayers facilitates the achievement of an ascending drug release rate over an extended period of time. For example, in one embodiment of the present invention, the osmotic dosage form comprises a first drug layer and a second drug layer, wherein the concentration of the drug contained within the first layer is greater than the concentration of the drug contained in the drug. second layer, and the expandable layer is contained within the third layer. In an outward order from the core of the dosage form is the expandable layer, the second drug layer, and the first drug layer. In operation through the cooperation of the components of the dosage form, the substances comprising levodopa and / or substances comprising carbidopa are successively released, in a sustained and controlled manner, from the second drug layer and after the first layer of the drug, such that an upward release rate is achieved during an extended period. The present invention is further directed to pharmaceutical compositions, as the term is defined herein, and to methods for administering pharmaceutical compositions to a patient in need thereof. Preferably the present invention is directed to methods for administering pharmaceutical compositions to a patient in need of therapeutically effective amounts. In one embodiment, the invention relates to a substance comprising: a complex comprising levodopa and a portion oftransport, preferably wherein the transport portion comprises an alkyl sulfate salt, more preferably wherein the alkyl sulfate salt comprises sodium lauryl sulfate. The invention also relates to a pharmaceutical composition comprising: the substance and a pharmaceutically acceptable carrier, and an oral dosage form comprising carbidopa, or a carbidopa complex. In other preferred embodiments, the oral dosage form further comprises carbidopa or a carbidopa complex. In other preferred embodiments, the oral dosage form comprises an oral dosage form of controlled distribution, preferably the oral dosage form comprises a dosage form of osmotically controlled oral distribution, more preferably the dosage form of osmotic oral controlled distribution comprises a solid osmotic oral controlled distribution dosage form. In other preferred embodiments, the solid osmotic oral controlled distribution dosage form further comprises carbidopa, or the solid osmotic oral controlled distribution dosage form further comprises a carbidopa complex. In certain preferred embodiments, the orally controlled osmotic distribution dosage form comprises a dosage form of oral osmotic liquid controlled distribution, which preferably comprises carbidopa or a carbidopa complex. The invention also relates to methods comprising the administration of any of the above oral dosage forms to a patient. The invention also relates to the oral dosage form wherein the form ofcontrolled distribution dosage distributes the substance in a distribution dose pattern of about 0 wt% to about 20 wt% in about 0 to about 4 hours, about 20 wt% to about 50 wt% in about 0 to about 8 hours, about 55% by weight to about 85% by weight in about 0 to about 14 hours, and about 80% by weight to about 100% by weight in about 0 to around 24 hours. The invention further relates to the oral dosage form wherein the controllable controlled dosage form distributes the substance in a distribution dose pattern of from about 0 wt% to about 20 wt% in about 0 to around 4 hours, about 20% by weight to about 50% by weight in about 0 to about 8 hours, about 55% by weight to about 85% by weight in about 0 to about 14 hours, and about 80% by weight to about 100% by weight in about 0 to about 20 hours. The invention further relates to the oral dosage form wherein the controllable controlled dosage form distributes the substance in a distribution dose pattern of from about 0 wt% to about 20 wt% in about 0 to about 2 hours, about 20% by weight to about 50% by weight in about 0 to about 4 hours, about 55% by weight to about 85% by weight in about 0 to about 7 hours, and about 80% by weight to about 100% by weight in about 0 to about 8 hours.
The invention relates to a method comprising: providing an alkyl sulfate salt; converting the alkyl sulfate salt to an acid form of the alkyl sulfate; contacting levodopa with the acid form of the alkyl sulfate to form a complex of alkyl sulfate of levodopa; and isolating the alkyl sulfate complex; and isolate the complex. In other embodiments, the invention relates to the method wherein the alkyl sulfate salt comprises sodium lauryl sulfate. In other embodiments, the invention relates to the method wherein the conversion of the salt comprises sodium lauryl sulfate. In other embodiments, the invention relates to the method wherein the conversion of the alkyl sulfate salt to an acid form of the alkyl sulfate is carried out using an ion exchange process. The invention relates to a substance comprising: a carbidopa complex and a transport portion. In preferred embodiments of the substance, the transport portion comprises an alkyl sulfate salt, preferably wherein the alkyl sulfate salt comprises sodium lauryl sulfate. In other embodiments, the invention relates to a pharmaceutical composition comprising the substance and a pharmaceutically acceptable carrier. The invention also relates to an oral dosage form comprising the pharmaceutical composition, which preferably further comprises levodopa or a levodopa complex. In preferred embodiments, the oral dosage form comprises an oral dosage form of controlled distribution, preferably the oral dosage form comprises oral dosage form of distributionosmotic controlled, more preferably the oral dosage form of osmotic controlled distribution comprises oral dosage form of solid osmotic controlled distribution, even more preferably the oral dosage form of solid osmotic controlled distribution further comprising levodopa or a levodopa complex. In other embodiments, the oral dosage form of osmotic controlled distribution comprises oral dosage form of liquid osmotic controlled distribution, preferably wherein the liquid oral osmotic controlled distribution dosage form further comprises levodopa or a levodopa complex. The invention also relates to methods comprising the administration of oral dosage forms prior to a patient. The invention further relates to oral dosage forms, wherein the controllable controlled dosage form distributes the substance in a distribution dose pattern of from about 0 wt% to about 20 wt% in about 0 to about of 4 hours, about 20% by weight to about 50% by weight in about 0 to about 8 hours, about 55% by weight to about 85% by weight in about 0 to about 14 hours, and about 80% by weight to about 100% by weight in about 0 to about 24 hours. In another embodiment, the controlled distribution dosage form controllably distributes the substance in a distribution dose pattern of from about 0 wt% to about 20 wt% in about 0 to about 4 hours, about 20% in weightat about 50% by weight in about 0 to about 8 hours, about 55% by weight to about 85% by weight in about 0 to about 14 hours, and about 80% by weight about 100% by weight in about 0 to about 20 hours. In yet another embodiment, the controllable controlled dosage form distributes the substance in a distribution dose pattern of from about 0 wt% to about 20 wt% in about 0 to about 2 hours, about 20%. by weight to about 50% by weight in about 0 to about 4 hours, about 55% by weight to about 85% by weight in about 0 to about 7 hours, and about 80% by weight about 100% by weight in about 0 to about 8 hours. The invention relates to a method comprising providing an alkyl sulfate salt; converting the alkyl sulfate salt to an acid form of the alkyl sulfate; contacting carbidopa with the acid form of the alkyl sulfate to form a complex of alkyl levodopa-sulfate; and isolate the complex. In preferred embodiments, the alkyl sulfate salt comprises sodium lauryl sulfate. In preferred embodiments, converting the alkyl sulfate salt to an acid form of the alkyl sulfate is carried out using an ion exchange process. The invention relates to an oral dosage form comprising: (i) an orally distributed dosage structure comprising the structure that controllably distributes a substance comprising levodopa and a substance comprising carbidopa; inwherein at least a portion of the substance comprising levodopa and a portion of substance comprising carbidopa are contained by the controlled distribution dosage structure; and wherein the controlled distribution dosage structure is adapted to controllably distribute the portion of the substance comprising levodopa and the portion of the substance comprising carbidopa contained by the controlled distribution dosage structure at rates that are effective for, after a single administration of the dosage form to a patient: a. provide a levodopa Cmax on the scale of approximately 236 to around 988 ng / ml, b. provides an AUC of levodopa from about 3676 to about 15808 h'ng / ml, and I maintain the concentration of the drug in levodopa plasma which is at least about 15% of the C max of levodopa along a window of at least about ten hours long. d. provides a Cmax of carbidopa on the scale from about 1 to about 500 ng / ml μmol / l, e. provides an AUC of carbidopa from about 20,000 to about 200,000 h'ng / ml, and f. maintain a plasma drug concentration of carbidopa that is at least about 15% of the Cmax of carbidopa throughout a window of at least about ten hours duration.
In preferred embodiments, the substance comprising levodopa comprises: a levodopa complex or a prodrug of levodopa. In other preferred embodiments, the substance comprising carbidopa comprises: a carbidopa complex or a carbidopa prodrug. In preferred embodiments of the dosage form, the controlled distribution dosage structure is adapted to controllably distribute the portion of the substance comprising levodopa contained by the controlled distribution dosage structure at a rate that is effective for, after a single dose. administration of the dosage form to a patient, maintains the concentration of the drug in levodopa plasma which is at least about 15% of the levodopa Cmax along a window of at least about twelve hours in duration. In other preferred embodiments of the dosage form, the controlled distribution dosage structure is adapted to controllably distribute the portion of the substance comprising levodopa contained by the controlled distribution dosage structure at a rate that is effective for, after a administration alone of the dosage form to a patient, maintains the concentration of the drug in levodopa plasma which is at least about 15% of the C max of levodopa over a window of at least about sixteen hours in duration. In preferred embodiments of the dosage form, the controlled distribution dosage structure is adapted to controllably distribute the portion of the substance comprising levodopacontained by the controlled distribution dosage structure at a rate that is effective for, after a single administration of the dosage form to a patient, maintains the concentration of the drug in levodopa plasma which is at least about 15% of the Cmax of levodopa along a window of at least about eighteen hours long. In preferred embodiments of the dosage form, the controlled distribution dosage structure is adapted to controllably distribute the portion of the substance comprising levodopa contained by the controlled distribution dosage structure at a rate that is effective for, after a single dose. administration of the dosage form to a patient, maintains the concentration of the drug in levodopa plasma which is at least about 15% of the C max of levodopa along a window of at least about twenty hours duration. In preferred embodiments of the dosage form, the controlled distribution dosage structure is adapted to controllably distribute the portion of the substance comprising carbidopa contained by the controlled distribution dosage structure at a rate that is effective for, after a single administration of the dosage form to a patient, maintains the drug concentration in the plasma of carbidopa which is at least about 15% of the Cmax carbidopa along a window of at least about twelve hours duration. In preferred embodiments of the dosage form, the controlled distribution dosage structureIt is adapted to controllably distribute the portion of the substance comprising carbidopa contained by the controlled distribution dosage structure at a rate that is effective for, after a single administration of the dosage form to a patient, maintains a drug concentration. in plasma of carbidopa which is at least about 15% of the carbidopa Cmax along a window of at least about sixteen hours in duration. In preferred embodiments of the dosage form, the controlled distribution dosage structure is adapted to controllably distribute the portion of the substance comprising carbidopa contained by the controlled distribution dosage structure at a rate that is effective for, after a single dose. administering the dosage form to a patient maintains a drug concentration in the plasma that is at least about 15% of the Cmax carbidopa throughout a window of at least about eighteen hours duration. In preferred embodiments of the dosage form, the controlled distribution dosage structure is adapted to controllably distribute the portion of the substance comprising carbidopa contained by the controlled distribution dosage structure at a rate that is effective for, after a single dose. administration of the dosage form to a patient, maintains a concentration of drug in the plasma of carbidopa which is at least about 15% of the carbidopa Cmax along a window of at least about twenty hours duration.
The invention relates to a dosage form of oral controlled distribution comprising a dosage structure of oral controlled distribution comprising a structure that controllably distributes a substance comprising levodopa; wherein at least a portion of the substance comprising levodopa is contained by the controlled distribution dosage structure; and wherein the controlled distribution dosage structure is adapted to controllably distribute the portion of the substance comprising levodopa contained by the controlled distribution dosage structure at an effective upward release rate for, after a single administration of the form of dosage to a patient, provides a plasma profile of levodopa substantially in the order of zero for a window of at least about six hours duration. In preferred embodiments of the dosage form of the oral controlled distribution, the controlled distribution dosage structure is adapted to controllably distribute the portion of the substance comprising levodopa contained by the controlled distribution dosage structure at an effective upward release rate for, after a single administration of the dosage form to a patient, provides a levodopa plasma profile substantially in the order of zero for a window of at least about twelve hours in duration. In preferred embodiments of the oral controlled distribution dosage form, the controlled distribution dosage structure isadapted to controllably distribute the portion of the substance comprising levodopa contained by the controlled distribution dosage structure at an effective upward release rate for, after a single administration of the dosage form to a patient, provides a plasma profile of levodopa substantially in the order of zero for a window of at least about sixteen hours. In preferred embodiments of the oral controlled distribution dosage form, the substance comprising levodopa comprises: a levodopa complex or a prodrug of levodopa. Preferred embodiments of the oral controlled distribution dosage form further comprise: an orally distributed dosage structure comprising the structure that controllably distributes a substance comprising carbidopa; wherein at least a portion of the substance comprising carbidopa is contained by the controlled distribution dosage structure; and wherein the controlled distribution dosage structure is adapted to controllably distribute the portion of the substance comprising carbidopa contained by the controlled distribution dosage structure at an effective upward release rate for, after a single administration of the form of dosage to a patient, provides a plasma profile of carbidopa substantially in the order of zero for a window of at least about six hours duration. In preferred embodiments of the dosage form oforally controlled distribution, the controlled distribution dosage structure is adapted to controllably distribute the portion of the substance comprising carbidopa contained by the controlled distribution dosage structure at an effective upward release rate for, after a single administration of the form of dosing to a patient, provides a plasma profile of carbidopa substantially in the order of zero for a window of at least about twelve hours in duration. In preferred embodiments of the oral controlled distribution dosage form, the controlled distribution dosage structure is adapted to controllably distribute the portion of the substance comprising carbidopa contained by the controlled distribution dosage structure at an effective up-release rate for , after a single administration of the dosage form to a patient, provides a plasma profile of carbidopa substantially in the order of zero for a window of at least about sixteen hours in duration. In preferred embodiments of the dosage form of oral controlled distribution, the substance comprising carbidopa comprises: a carbidopa complex or a carbidopa prodrug. The invention relates to a composition comprising: levodopa; an alkyl sulfate salt; and a pharmaceutically acceptable carrier. Preferably, in the composition, the alkyl sulfate salt comprises sodium lauryl sulfate. The invention also relates to a formof oral dosage comprising the pharmaceutical composition, preferably wherein oral dosage form further comprises carbidopa. The invention relates to an oral dosage form comprising: (i) an oral controlled distribution dosage structure comprising the structure that controllably distributes a substance comprising levodopa; wherein at least a portion the substance comprising levodopa is contained by the controlled distribution dosage structure; and wherein the controlled distribution dosage structure is adapted to controllably distribute the portion of the substance comprising levodopa contained by the controlled distribution dosage structure at rates that are effective for, after a single administration of the dosage form a a patient: a. provide a Cmax of levodopa on the scale of from about 236 to about 988 ng / m, b. provides a levodopa AUC of about 3676 at about 15808 h 'ng / mL, and maintains the drug concentration in levodopa plasma which is at least about 15% of the levodopa Cmax along a window of at least about of ten hours. In preferred embodiments, the substance comprising levodopa comprises: a levodopa complex or a prodrug of levodopa. In preferred embodiments, the distribution dosage structurecontrolled is adapted to controllably distribute the portion of the substance comprising levodopa contained by the controlled distribution dosage structure at a rate that is effective for, after a single administration of the dosage form to a patient, maintains the concentration of the drug in levodopa plasma which is at least about 15% of the levodopa Cmax along a window of at least about twelve hours in duration. In preferred embodiments, the controlled distribution dosage structure is adapted to controllably distribute the portion of the substance comprising levodopa contained by the controlled distribution dosage structure at a rate that is effective for, after a single administration of the dosage form. dosage to a patient, maintains the concentration of the drug in levodopa plasma which is at least about 15% of the C max of levodopa along a window of at least about sixteen hours duration. In preferred modalities, the controlled distribution dosage structure is adapted to controllably distribute the portion of the substance comprising levodopa contained by the controlled distribution dosage structure at a rate that is effective for, after a single administration of the dosage form to a patient, maintains the drug concentration in levodopa plasma which is at least about 15% of the levodopa Cmax along a window of at least about eighteen hours duration. In preferred embodiments, the distribution dosage structurecontrolled is adapted to controllably distribute the portion of the substance comprising levodopa contained by the controlled distribution dosage structure at a rate that is effective for, after a single administration of the dosage form to a patient, maintains the concentration of the drug in levodopa plasma which is at least about 15% of the levodopa Cmax along a window of at least about twenty hours duration. The invention relates to an oral dosage form comprising: (i) an oral controlled distribution dosage structure comprising a structure that controllably distributes a substance comprising carbidopa; wherein at least a portion of the substance comprising carbidopa is contained by the controlled distribution dosage structure; and wherein the controlled distribution dosage structure is adapted to controllably distribute the portion of the substance comprising carbidopa contained by the controlled distribution dosage structure at rates that are effective for, after a single administration of the dosage form to a patient: a. provides a Cmax of carbidopa on the scale from about 1 to about 500 ng / ml pmol / l, b. provides an AUC of carbidopa from about 20,000 to about 200,000 h'ng / ml, and c. maintains a plasma drug concentration of carbidopa that is at least about 15% of Cmax carbidopalength of a window of at least about ten hours. In preferred embodiments, the substance comprising carbidopa comprises: a carbidopa complex or a carbidopa prodrug. In preferred embodiments, the controlled distribution dosage structure is adapted to controllably distribute the portion of the substance comprising carbidopa contained by the controlled distribution dosage structure at a rate that is effective for, after a single administration of the form of dosage to a patient, maintains a plasma drug concentration of carbidopa that is at least about 15% of the Cmax of carbidopa along a window of at least about twelve hours in duration. In preferred embodiments, the controlled distribution dosage structure is adapted to controllably distribute the portion of the substance comprising carbidopa contained by the controlled distribution dosage structure at a rate that is effective for, after a single administration of the form of dosage to a patient, maintains a plasma drug concentration of carbidopa which is at least about 15% of the Cmax carbidopa along a window of at least about sixteen hours duration. In preferred embodiments, the controlled distribution dosage structure is adapted to controllably distribute the portion of the substance comprising carbidopa contained by the controlled distribution dosage structure at a rate that is effective for, after asingle administration of the dosage form to a patient, maintains a plasma drug concentration of carbidopa which is at least about 15% of the Cmax of carbidopa along a window of at least about eighteen of duration. In preferred embodiments, the controlled distribution dosage structure is adapted to controllably distribute the portion of the substance comprising carbidopa contained by the controlled distribution dosage structure at a rate that is effective for, after a single administration of the form of dosage to a patient, maintains a plasma drug concentration of carbidopa that is at least about 15% of the Cmax carbidopa along a window of at least about twenty hours duration. Although the above invention has been described in detail by way of example for purposes of clarity of understanding, it will be apparent to those skilled in the art that certain changes and modifications are encompassed throughout the description and can be practiced without undue experimentation within the scope of the appended claims, which are presented by way of illustration and not limitation. The compositions of the invention are generally formulated as being substantially isotonic, sterile and completely in accordance with all the rules of the Practice of Manufacture of Goods (GMP) of the Food and Drug Administration of E.U.A. All publications and patent documents citedpreviously they are incorporated by reference in their entirety for all purposes to the same extent as if each were individually denoted. Each mentioned scale includes all the combinations and sub-combinations of scales, as well as specific numbers contained therein.
EXAMPLESThe following examples are illustrative of the present invention and should not be construed as limiting the scope of the invention in any way, as these examples and other equivalents thereof will be apparent to those skilled in the art in light of the present disclosure, drawings and appended claims.
EXAMPLE 1 Preparation of the complex of levodopa-lauryl sulfate1. The ion exchange column was packed with cationic resin DOWEX50WX8-100 and a net weight of 117 g was obtained. 2. The column was rinsed with 70 ml of deionized water (DI)(reverse circulation), taking care not to allow the column to dry. 3. 5,768 g of sodium lauryl sulfate were dissolved in 577 ml of DI water.4. 175 ml of DI water was passed through the column dropwise using a separatory funnel. Then the solution from step 3 was passed through the column dropwise using a separatory funnel and the eluate was collected. After the SDS solution was passed through the column, a total of 70 ml of DI water was used to rinse the column. The total of the spent sodium lauryl sulfate was calculated to be less than that point of equilibrium of the ion exchange resin (capacity). The first eluate of 91 ml was discarded, the second eluate of 486 ml was collected and used for complex formation. The third eluate of 70 ml was also discarded. 5. 3,323 g of levodopa base were added to the second eluate, the mixture was stirred to solubilize levodopa at room temperature. The water was removed in a vacuum oven at 40 ° C. After the sample was dried, 6.5 g of the product was collected. The product was in the form of a paste.
EXAMPLE 2 Preparation of the levodopa-tetradecyl sulfate complex ofThe following steps were performed to form the tetradecyl sulfate complex of levodopa. This complex is expected to have a higher melting point than the complex produced according to Example 1, and therefore have a greater utility in solid dosage forms. The ion exchange column was packed with the resincation, the Amberlyst 15 catalyst and a net weight of was focused to a net weight of 19.16 g. The column was rinsed with 20 ml of deionized water (DI) ((reverse circulation)), being careful not to allow the column to dry. 1,582 g of sodium tetradecyl sulfate were dissolved in 100 ml of DI water. The solution from step 3 was passed through the column dropwise using a separatory funnel and the eluate was collected. After the sodium tetradecyl sulfate was passed through the column, a total of 20 ml of DI water was used to rinse the column. The total of the past sodium tetradecyl sulfate was calculated to ensure that it is less than the equilibrium point of the ion exchange resin (capacity). to. Add 0.986 g of levodopa eluate from step 4, stir the mixture to solubilize the levodopa at room temperature. Stir the water in a vacuum oven at 40 ° C. After the mixture was dried, a theoretical yield of 2.141 g of the product can be collected.
EXAMPLE 3 Preparation of the carbidopa-lauryl sulfate complex1. The ion exchange column was packed with the cationic resin, DOWEX50WX8-100 and the net weight of 117 g was focused.
The column was rinsed with 70 ml of deionized water (DI) ((reverse circulation)), being careful not to allow the column to dry. 5.768 g of sodium lauryl sulfate were dissolved in 577 ml of DI water. 175 ml DI water was passed through the column dropwise using a separatory funnel. Then the solution from step 3 was passed through the column dropwise using a separatory funnel and the eluate was collected. After the SDS solution was passed through the column, a total of 70 ml DI water was used to rinse the column. The total spent sodium lauryl sulfate was calculated to ensure that it is better than the resin equilibrium point of the ion exchange (capacity). The first 91 ml eluate was discarded; the second 486 ml eluate was collected and used to form the complex. The third eluate of 70 ml was also discarded. Add 4,116 g of carbidopa monohydrate to the second eluate, stir the mixture to solubilize the carbidopa at room temperature. Stir the water in a vacuum oven at 40 ° C. After the sample is dried, a theoretical maximum of 8.3 g of the product can be obtained.
EXAMPLE 4 Preparation of the carbidopa-tetradecyl sulfate complexThe following steps were carried out to form the carbidopa-tetradecyl sulfate complex. This complex is expected to have a pointof fusion higher than the complex produced according to Example 3 and therefore may have greater utility in the solid dosage forms. 1. The ion exchange column was packed with the cationic resin, DOWEX50WX8-100 and focused to a net weight of 117g. 2. The column was rinsed with 70 ml of deionized water (DI) ((reverse circulation)), being careful not to let the column dry. 3. 5,768 g of sodium tetradecyl sulfate were dissolved in 577 ml of DI water. 4. 175 ml DI water was passed through the column dropwise using a separatory funnel. Then the solution from step 3 was passed through the column dropwise using a separatory funnel and the eluate was collected. After the sodium tetradecyl sulfate solution was passed through the column, a total of 70 ml of DI water was used to rinse the column. The total of the past sodium tetradecyl sulfate was calculated to ensure that it is less than the equilibrium point of the ion exchange resin (capacity). The first 91 ml eluate was discarded; the second 486 ml eluate was collected and used to form the complex. The third eluate of 70 ml was also discarded. 5. Add 3,752 g of carbidopa monohydrate to the second eluate, stir the mixture to solubilize carbidopa at room temperature. Remove water in a vacuum oven at 40 ° C. After the sample is dried, a theoretical maximum of 7.94 g of the product can be obtained.
EXAMPLE 5 Liquid osmotic dosage formA hard-shell oral osmotic device system was manufactured to supply the complex of Example 1 in the GI tract. First, an osmotic ejection layer formation was granulated with a Glatt fluid bed granulator (FBG). The composition of the expelled granules is comprised of 63.67% by weight of polyethylene oxide of 7,000,000 molecular weight, 30.00% by weight of sodium chloride, 1.00% by weight of ferric oxide, 5.00% by weight of hydroxypropylmethylcellulose of 9,200 weight. molecular weight, 0.08% by weight of butylated hydroxytoluene and 0.25% by weight of magnesium stearate. Second, the granulation of the barrier layer was produced using FBG medium. The composition of the granules of the barrier layer was comprised of 55% by weight of Kollidon, 35% by weight of Magnesium Stearate and 10% by weight of EMM. Third, the granules of the osmotic ejection layer and the granules of the barrier layer were compressed into a two-layer tablet with a Korsch Multi-layer press. 350 mg of the granules of the osmotic ejection layer were added and rammed, then 100 mg of the granules of the barrier layer were added and finally compressed under a force of 4500 N in an osmotic / barrier two-layer tablet. . Fourth, 470 mg of the complex made according to Example 1were dissolved in 108 mg of propylene glycol (PG) using sonication at 45 ° C for 5.5 hours. Next, the gelatin capsules (size 0) were sub-coated with Sureleasem. This will inhibit impregnation with water within the liquid formulation encapsulated during the operation of the system. The subcoat is an ethylcellulose membrane applied in the form of an aqueous dispersion. The dispersion contained 25% by weight solids and was diluted to contain 15% by weight solids through the addition of purified water. The weight of the Surelease ™ membrane was 17 mg. Then, a covered gelatine capsule released was separated into two segments (body and lid). The drug layer composition (578 mg) was filled into the body of the capsule. Next, the osmotic tablet / barrier was placed in the body of the filled capsule. Before inserting the motors into the capsules, a layer of sealing solution was applied around the barrier layer of the gelatin-coated bilayer motors. After inserting the motor, a layer of band solution was applied around the diameter at the interface of the capsule and the motor. This sealing and band solution are the same, which are made of water / ethanol 50/50% by weight. Next, the membrane composition comprising 80% cellulose acetate 398-10 and 20% Pluronic F-68 was dissolved in acetone with a solids content of 5% in the coating solution. The solution was sprayed on the pre-covered assemblies in a HiCater LDCS at 30.48 cm.
After coating the membrane, the systems were dried in an oven at 45 ° C for 24 hours: the assemblies were coated with 131 mg of controlled speed membrane. Then, a 0.77 mm exit hole was drilled on the side of the drug layer using a mechanical drill. Each system comprises 470 mg of the complex of Example 1. By adjusting the weight of the membrane, the worship of the release of the systems can be controlled.
EXAMPLE 6 Profile for a liquid osmotic dosage formThe release rate for the dosage form made according to Example 5 was carried out in a Distek 5100 (USP apparatus with a two-vane tester) in 900 ml of artificial plastic fluid (AGF, pH = 1.2). The temperature of the dissolution medium was maintained at 37 ° C and the speed of the blade was 100 rpm. The concentration of Levodopa was measured with in-line UV spectroscopy at 280 nm. The systems were tested. The results showed a cumulative release, and Figure 8 is provided.
EXAMPLE 7 Liquid osmotic dosage formA hard shell oral osmotic device system for delivering the complexes of Example 1 and 3 in the GI tract can be prepared as follows: First, an osmotic ejection layer formation is granulated using a Glatt fluid bed granulator (FBG) . The composition of the expelled granules is comprised of 63.67% by weight of polyethylene oxide of 7,000,000 molecular weight, 30.00% by weight of sodium chloride, 1.00% by weight of ferric oxide, 5.00% by weight of hydroxypropylmethylcellulose of 9,200 weight. molecular weight, 0.08% by weight of butylated hydroxytoluene and 0.25% by weight of magnesium stearate. Second, the granulations of the barrier layer were produced using an FBG medium. The composition of the granules of the barrier layer is comprised of 55% by weight of Kollidon, 35% by weight of Magnesium Stearate and 10% by weight of EMM. Third, the granules of the osmotic ejection layer and the granules of the barrier layer are compressed into a bilayer tablet with a Korsch Multi-layer press. 350 mg of the granules of the osmotic ejection layer were added and rammed, then 100 mg of the granules of the barrier layer were added and finally compressed under a force of 4500 N in an osmotic / two-layer tablet. barrier.
Fourth, 235 mg of the Levodopa-lauryl sulfate complex (100 mg equivalent of Levodopa) was dissolved in accordance withExample 1, and 54 mg of the carbidopa-lauryl sulfate complex (25 mg equivalents of carbidopa) made in accordance with Example 3 in about 200 mg of propylene glycol (PG) using sonication at 45 ° C for six hours. Next, the gelatin capsules (size 0) were coated with Surelease. This will inhibit impregnation with water within the liquid formulation encapsulated during the operation of the system. The subcoat is an ethylcellulose membrane applied in the form of an aqueous dispersion. The dispersion contains 25% by weight solids and was diluted to contain 15% by weight solids through the addition of purified water. The weight of the release membrane this 17 mg. Next, a Surelease ™ coated gelatin capsule was separated into two segments (body and lid). The drug layer composition (500 mg) is filled into the body of the capsule. Next, the osmotic / barrier tablet was placed in the body of the filled capsule. Before inserting the motors into the capsules, a layer of sealing solution was applied around the barrier layer of the gelatin-coated bilayer motors. After the insertion of the motor, a layer of band solution was applied around the diameter at the interface of the capsule and the motor. This sealing solution and band are the same, which are made of water / ethanol 50/50% by weight. Next, the composition of the membrane comprising 80%of cellulose acetate 398-10 and 20% Pluronic F-68 was dissolved in acetone with a solids content of 5% in the coating solution. The solution was sprayed on the pre-assemblies, covered in a Hi-coater of 30.48 cm. After coating the membrane, the systems were dried in an oven at 45 ° C for 24 hours. The assemblies were coated with 131 mg of membrane with speed control. Next, a 0.77 mm hole was drilled in the side of the drug layer using a mechanical drill. By adjusting the weight of the membrane, the duration of the release of the systems can be controlled.
EXAMPLE 8 Preparation of a dosage form comprising a complex of levodopa-tetradecyl sulfate and the complex of carbidopa-tetradecyl sulfateA dosage form was prepared as follows: The layer of the Levodopa-tetradecyl sulfate complex in the dosage form was prepared as follows. First, 7.56 grams of levodopa-tetradecyl sulfate complex, prepared as described in Example 2, 1.74 grams of carbidopa-tetradecyl sulfate complex, prepared as described in Example 4, 0.50 g of polyethylene oxide of 5,000,000 weight Molecular, 0.10 g of polyvinylpyrrolidone having a molecular weight of about 38,000 was dry blended in a conventional mixer for 20 minutes to produce a homogeneous mixture. Then, denatured anhydrous ethanol was slowly added to the mixture with acontinuous agitation for five minutes. The mixed wet composition was passed through a 16 mesh filter and dried overnight at room temperature. Then, the dried granules were passed through a 16 mesh filter and 0.10 g of magnesium stearate was added and all the dry ingredients were mixed dry for five minutes. The composition is comprised of 75.6% by weight of levodopa-tetradecyl sulfate complex, 17.4% by weight of carbidopa-tetradecyl sulfate complex, 5.0% by weight of polyethylene oxide of 5,000,000 molecular weight, 1.0% by weight of polyvinylpyrrolidone having a molecular weight of about 35,000 to 40,000 and 1.0% by weight of magnesium stearate. An ejection layer comprised of an osmopolymer hydrogel composition was prepared as follows. First, 637.70 g of a pharmaceutically acceptable polyethylene oxide comprising 7,000,000 molecular weight, 300 g of sodium chloride and 10 g of ferric oxide were separately sorted through a 40 mesh filter. The classified ingredients were mixed with 50 g of hydroxypropylmethylcellulose of 9,200 molecular weight to produce a homogeneous mixture. Then, 150 ml of denatured anhydrous alcohol was slowly added to the mixture with continuous stirring for 5 minutes. After. 0.80 g of butylated hydroxytoluene was added followed by further mixing. The freshly prepared granulation was passed through a 20 mesh filter and allowed to dry for 20 hours at room temperature (room). The dry ingredients were passed through a 20 mesh filter and2.50 mg of magnesium stearate were added and all the ingredients were mixed for 5 minutes. The final composition is comprised of 63.67% by weight of polyethylene oxide, 30.00% by weight of sodium chloride, 1.00% by weight of ferric oxide, 5.00% by weight hydroxypropylmethylcellulose, 0.08% by weight of butylated hydroxytoluene and 0.25% by weight of magnesium stearate. The bilayer dosage form was prepared as follows. First, 654 mg of the composition of the drug layer was added to a punch and a group of dice and the two layers were compressed under a compression force of 1000 kg in a group of punch die with a diameter of 0.714 cm, forming an intimate two-layer core (tablet). A semipermeable wall forming composition was prepared comprising 80.0% by weight of cellulose acetate having 39.8% acetyl content and 20.0% polyoxyethylene-polyoxypropylene copolymer having a molecular weight of 7680-9510 through the dissolution of the ingredients in acetone in a composition of 80:20% by weight /% by weight to make a solid solution at 5.0% The placement of the container of the solution in a hot water bath during this step accelerates the dissolution of the components. The wall-forming composition was sprayed on and around the bilayer core to provide a semi-permeable wall with a thickness of 60 to 80 mg. Then, an exit hole of 1.02 mm was perforated with laser in the bilayer tablet surrounded by semi-permeable walls. to provide thecontact with the layer containing the drug with the outside of the distribution device. The dosage form was dried to remove any residual solvent and water. The release rate of the dosage form made according to Example 8 was performed with a Distek 5100 (two-blade USP tester apparatus) in 900 ml of artificial gastric fluid (AGF, pH = 1.2). The temperature of the dissolution medium was maintained at 37 ° C and the speed of the blade was 100 rpm. The concentration of levodopa was measured with in-line UV spectroscopy at 280 mm. Two systems were tested.
EXAMPLE 9 Modified matrix dosage formA matrix dosage form according to the present invention was prepared as follows. 247 grams of the levodopa-tetradecyl sulfate complex, prepared as described in Example 2, 57 grams of carbidopa-tetradecyl sulfate complex, prepared as described in Example 4, 25 grams of hydroxypropyl methylcellulose having an average molecular weight of 9,200 grams per mole, and 15 grams of hydroxypropyl methylcellulose having a molecular weight of 242,000 grams per mole, were passed through a screen having a mesh size of 40 cables per inch. The celluloses each have an average hydroxyl content of 8% and an average methoxyl content of 22% by weight. The powdersThe resulting dimensions were mixed in a whirlpool. Anhydrous ethyl alcohol was slowly added to the mixed powders with stirring until a dough consistency was produced. The wet mass was then extruded through a 20 mesh filter and air dried overnight. The resulting dry material was filtered again through a 20 mesh filter to form the final granules. Two grams of magnesium stearate pallet lubricant, which is sized through an 80 mesh filter, was then dropped onto the granules. 663 mg of the resulting granulation was placed in a side cavity having an inner diameter of 9/32 inches and compressed with a deep concave punch tool using a two ton pressure head. This forms a longitudinal core having a overall length, including the rounded ends, of 1.75 cm. The cylindrical body of the capsule, from the base of the tablet to the base of the tablet, is issued a distance of 12 millimeters. Each core contains a unit dose of the levodopa-tetradecyl sulfate complex of 495 mg (equivalent to 200 mg levodopa) and carbidopatetradecyl sulfate complex of 114 mg (equivalent to 50 mg carbidopa). Next, the polyethylene rings having an internal diameter of 0.71 cm, a wall thickness of 0.03 cm and a width of 2 mm were then manufactured. These rings, or bands, were inserted with pressure into the core to complete the dosage form.
EXAMPLE 10 Colonic absorption in vivo using a ligated colonic model rinsed in ratsAn animal model commonly known as the "linked intracolonic model" sense for test formulations. Surgical preparation of 0.3-0.5 kg anesthetized fasted male Sprague-Dawley rats continued as follows. A segment near the colon was isolated and the colon was rinsed from the fecal materials. The segment was added at both ends while a catheter was placed in the lumen exteriorized above the skin to distribute the test formulation. The colonic content was rinsed and the colon was returned to the abdomen of the animal. Depending on the experimental configuration, the test formulation was added after the segment was filled with 1 ml / kg of 20 mM sodium phosphate pH regulator, pH 7.4, to more accurately sift the current color environment into a clinical situation The rats were allowed to equilibrate for approximately one hour after the surgical preparation and before the final exposure test formulation. The test compounds were administered as an intracolonic bolus and distributed to 2 mg of levodopa / rat or 2 mg of levodopa lauryl sulfate / rat. Blood samples were obtained from the jugular catheter at 0, 15, 30, 60, 90, 120, 180 and 240 minutes after the administration of the test formulation and analyzed for the concentration of levodopa in the blood.
Another group of rats was treated with levodopa intravenously, at a dose of 0.4 mg / kg. the blood samples were extracted in the same times indicated above for the analysis of the levodopa concentration. The plasma concentration of levodopa for each test animal, and the average plasma concentration for the animals in each test group, is shown in Tables A-C. Figure 9 shows the average levodopa concentration in each test group, a function of time.
TABLE A Levodopa colonic: 2 mq of levodopa / rat, plasma level (nq / ml)Time (hour) Rat 1 Rat 2 Rat 3 0 0 0 0 0.25 8.9 9.42 6.09 0.5 10.8 17.7 9.18 1 8.59 12.8 17.2 1.5 10.4 9.32 26.5 2 17.6 12.9 24.9 3 18.8 13 14.5 4 32.5 13.1 9.61TABLE B Levodopa colonic lauryl sulfate: 2 mg of levodopa / rat lauryl sulfate. (0.85 mg levodopa equivalent / rat). Plasma level (ng / ml)Time (hour) Rat l Rat 2 Rat 3 0 0 0 0 0.25 92.3 182 187 0.5 48.8 137 130 1 15.9 29.3 47.1 1.5 0 17.8 28.6 2 0 11 19.1 3 8.15 13.6 7.2 4 5.82 7.49 7.28TABLE C Levodopa iv: 0.4 mq levo opa / kg. plasma level (ng / ml)Time (hour) Rat 1 Rat 2 Rat 3 0 0 0 0 0.033 336 247 690 0.167 53.2 53.6 110 0.5 16 11.4 41.6 1 7.34 11.5 18.2 1.5 6.51 0 13.8 2 0 5.82 8.23 3 0 0 5.53EXAMPLE 11 Duodenal Absorption in vivoNine rats were randomly assigned in three test groups (n = 3). Levodopa or levodopa-lauryl sulfate complex, prepared as described in Example 1, in a saline vehicle was intubated at the beginning of the duodenum of rats at dosages of 2 mg of levodopa / rat or 2 mg of levodopa lauryl sulfate / rat. The remaining test group was given 0.4mg / kg of levodopa intravenously. Blood samples were taken from each animal during aperiod of three or four hours and analyzed for levodopa content. The results are shown in Tables D-F and Figure 10.
TABLE D Levodopa iv: 0.4 mq of levodopa / kg, level in plasma (ng / ml) Time (hour) Rat 1 Rat 2 Rat 3 0 0 0 0 0.033 336 247 690 0.167 53.2 53.6 110 0.5 16 11.4 41.6 1 7.34 11.5 18.2 1.5 6.51 0 13.8 2 0 5.82 8.23 3 0 0 5.53TABLE E Levodopa iv: 0.4 mg levodopa / kg, plasma level (ng / ml)Time (hour) Rat 1 Rat 2 Rat 3 0 0 0 0 0.5 159 143 7.57 1 48.6 52.9 80.2 2 9.48 22.3 13 3 5.73 6.26 6.28 4 0 5.06 5.97TABLE F Duodenal Levodopa Lauryl Sulfate: 2 mg levodopa lauryl sulfate / rat (0.85 mg levodopa equivalent / rat), plasma level (nq / ml) Time (hour) Rat 1 Rat 2 Rat 3 0 9.42 8.7 8.55 0.5 210 113 65.6 1 57.3 51.3 43.7 2 21.3 22 9.24 3 12 11.6 24 4 8.07 7.45 19.6