Detailed description of the invention
The present invention overcomes the drawbacks inherent in known therapeutic/cyclodextrin physical mixtures by providing a formulation that is easy to manufacture and has a solubility, dissolution profile and/or bioavailability of the therapeutic agent that approximates the properties of a corresponding pharmaceutical formulation containing a therapeutic agent/cyclodextrin complex. In preparing various pharmaceutical formulations of the present invention, sulfoalkyl ether cyclodextrin (SAE-CD) derivatives are used in the present invention. The formulations of the present invention are useful for rapid, controlled, delayed, timed, pulsatile, and sustained release of a variety of therapeutic agents. The formulation may also include multiple dosage forms.
Sulfoalkyl ether cyclodextrin derivatives
The terms "alkylene" and "alkyl" as used herein (e.g., in-O- (C)2-C6Alkylene) SO3-groups or alkylamines) include linear, cyclic and branched, saturated and unsaturated (e.g. containing a double bond) divalent alkylene groups and monovalent alkyl groups, respectively. The term "alkanol" in the present specification includes linear, cyclic and branched, saturated and unsaturated alkyl moieties of alkanol groups, wherein the hydroxy group may be substituted at any position of the alkyl moiety. The term "cycloalkanol" includes unsubstituted or substituted (e.g. by methyl or ethyl) cycloalkanols.
The present invention provides compositions comprising a mixture of cyclodextrin derivatives having a structure as defined in formula (I), wherein the composition comprises on average at least 1 and up to 3n +6 alkyl sulfonic acid groups per cyclodextrin molecule. The invention also provides compositions comprising a single type of cyclodextrin derivative, or at least 50% of a single type of cyclodextrin derivative.
The cyclodextrin derivatives of the invention are substituted at least one of the primary hydroxyl groups (e.g. R)1-R3At least one of which is a substituent), or they are substituted at both the primary and 3-position hydroxyl groups (e.g., R)1-R3At least one and R4、R6And R8At least one of which is a substituent). According to the inventors' studies, substitution at the 2-position hydroxyl group does not theoretically occur in the product of the present invention as much as possible.
The cyclodextrin derivatives of the invention are obtained in pure composition, that is, the composition comprises at least 95% by weight of cyclodextrin derivatives substituted at least on the primary hydroxyl groups of the cyclodextrin molecule (e.g., R of formula (I))1、R2Or R3). In a preferred embodiment, the resulting pure composition comprises at least 98 wt% of the cyclodextrin derivative.
In some compositions of the invention, unreacted cyclodextrin has been substantially removed and residual impurities (e.g., less than 5% by weight of the composition) do not affect the performance of the composition comprising the cyclodextrin derivative.
The cyclodextrin derivatives used herein are generally prepared as described in U.S. patent No.5,134,127, the entire contents of which are incorporated herein by reference. The preparation method comprises dissolving cyclodextrin in aqueous base at a suitable temperature, such as 70-80 deg.C, in as high a concentration as possible. For example, to prepare the cyclodextrin derivatives of the present invention, the appropriate alkyl sultone is added in an amount corresponding to the molar amount of primary CD hydroxyl groups present, under vigorous stirring to ensure maximum contact of the phases.
Various SAE-CD derivatives evaluated include SBE
4β、SBE
7β、SBE
11Beta and SBE
4γ, which correspond to formula I wherein n ═ 5, and 6, m is 4, and which have 4, 7, 11, and 4 sulfoalkyl ether substituents. These SAE-CD derivatives were found to increase the solubility of poorly water soluble drugs to varying degrees. For example, the following table summarizes the binding constants and solubilities observed in several SAE-CD (0.1M, 25 ℃) and methylprednisolone.
| SAE-CD type | Binding constant | Solubility (mg/ml) |
| SBE4β | 700 | 5.62 |
| SBE7β | 710 | 5.95 |
| SBE11β | 960 | 6.73 |
| SBE4γ | 2600 | 14.74 |
In another embodiment, the present invention uses Dipyridamole (DP), a basic drug (pka ═ 6.28), poorly water soluble in the free base form (3.6 μ g/ml, 25 ℃), and has low and variable bioavailability. Discovery of SBE
7β -CD dramatically increases the solubility of DP. The following table summarizes the presence and absence of SBE
7Solubility of DP at different pH values for β -CD.
| pH | SBE7beta-CD concentration (M) | DP solubility (. mu.g/ml) |
| 7.0 | 0 | 3.56 |
| 7.0 | 0.1 | 504 |
| 4.0 | 0 | 1990 |
| 4.0 | 0.1 | 16000 |
Although the above embodiments illustrate some examples of the SAE-CD derivatives of the present invention, this should not be construed as limiting the scope of the invention.
Pharmaceutical formulations comprising sulfoalkyl ether cyclodextrins
To obtain cyclodextrin pharmaceutical formulations with acceptable solubility, dissolution and bioavailability characteristics, it is generally accepted in the art that prior to preparing a pharmaceutical formulation comprising cyclodextrin and therapeutic agent, a clathrate or inclusion complex of cyclodextrin and therapeutic agent, respectively, must be preformed. However, the inventors of the present invention found that a preformed SAE-CD: the therapeutic agent complex is not required.
The pharmaceutical formulations of the invention comprising SAE-CD comprise an SAE-CD derivative of formula (I) above, a pharmaceutical carrier, a therapeutic agent, and optionally other adjuvants and active ingredients, wherein a substantial portion of the therapeutic agent is not complexed with the SAE-CD derivative.
Because it is expected that the therapeutic agent contained in the formulation of the invention will be largely uncomplexed with SAE-CD, it is possible that some therapeutic agent/SAE-CD complex will be present. SAE-CD is present in the present invention: the therapeutic agent complex may or may not be intentional, i.e., the complex may be prepared separately and then included in the formulation according to the Stella et al patent, or the complex may be formed during the preparation of the formulation of the present invention.
"therapeutic agent/SAE-CD complex" generally refers to a clathrate or inclusion complex of the sulfoalkyl ether cyclodextrin derivative of formula (I) with a therapeutic agent. The therapeutic agent in the complex: the ratio of SAE-CD is variable, ranging from 1: 2 to 2: 1 on a molar basis, and preferably about 1: 1. In another embodiment of the dosage form of the invention, the therapeutic agent: the ratio of SAE-CD is in the range of 2: 1 to 1: 100, preferably about 1: 1 to 1: 20, and more preferably 2: 1 to 1: 10 on a molar basis. Accordingly, SAE-CD is typically, but not necessarily, present in excess of the therapeutic agent. The excess amount can be determined by the inherent solubility of the therapeutic agent, the desired dosage of the therapeutic agent, and the binding constant between the particular drug (therapeutic agent) and the particular SAE-CD comprising the complex.
By "complexed" is meant "becoming part of a clathrate or inclusion complex," that is, the complexed therapeutic agent is part of a clathrate or inclusion complex with the sulfoalkyl ether cyclodextrin derivative. By "substantial portion" is meant at least about 50% by weight of the therapeutic compound. Thus, greater than 50% by weight of the therapeutic agent contained in the formulation according to the invention is uncomplexed with SAE-CD. In various embodiments, preferably 60% by weight or more, more preferably 75% by weight or more, even more preferably 90% by weight or more, and most preferably 95% by weight or more of the therapeutic agent remains uncomplexed with SAE-CD in the pharmaceutical formulation.
"physical mixture" refers to a mixture of a drug and SAE-CD formed by physically mixing the drug and SAE-CD, wherein the physical mixing minimizes the formation of a drug/SAE-CD containing complex.
It is desirable that the therapeutic agent begin to complex with the SAE-CD when a formulation comprising a composition of the present invention is administered to a patient and the composition is contacted with bodily fluids. For example, when a capsule containing a therapeutic agent and SAE-CD powder is administered orally to a patient, the capsule will dissolve, thereby allowing the gastric fluid to contact the therapeutic agent and SAE-CD, and then form a therapeutic agent/SAE-CD complex. Suitable dosage forms will hydrate the physical mixture prior to release from the formulation to ensure proper complex formation.
Therapeutic agents in the formulation: the ratio of SAE-CD depends on a number of factors, such as the inherent solubility of the therapeutic agent, the desired dosage of the therapeutic agent, and the binding constant between the particular drug (therapeutic agent) and the particular SAE-CD at which the inclusion complex is formed. These factors together determine the amount of SAE-CD required in the formulation and thus the SAE-CD: ratio of therapeutic agents.
Most SAE-CD has a molecular weight of about 2000, most therapeutic agents have a molecular weight of 200-500, and most drugs form 1: 1 inclusion complexes with SAE-CD. Because of these molecular weight differences, SAE-CD is typically added in amounts of at least about 1-10 times the weight of the therapeutic agent, and may be even higher. This ensures that one mole of CD dissolves one mole of drug and that the binding constant between drug and CD is infinite. For most solid dosage forms for administration to humans, tablets having a total weight of less than 1 gram are preferred, and because additional excipients are required in the tablet, the tablet preferably contains less than 500mg of CD. Therefore, based on this simple assumption, the drug with which SAE-CD is formulated is usually less than 50 mg. Since most drugs do not have an infinitely high binding constant to SAE-CD, the total dose of drug that is usually formulated with SAE-CD is less than 50 mg.
More specifically, the therapeutic agent can form a weak to very strong inclusion complex with the SAE-CD. Very weak inclusion complexes with binding constants less than about 500M-1The weak complex is a binding constant of about 500-1000M-1The medium complex is 5000M with a binding constant of about 1000--1A strong complex having a binding constant of about 5000--1And very strong complexes with binding constants greater than about 20000M-1The complex of (1).
The relative increase in solubility of poorly soluble drugs in the presence of SAE-CD is a product of the binding constant and molar concentration of SAE-CD present. For very weakly bound drugs, 100: 1 SAE-CD and drug are required on a molar basis. In this case, the amount of drug in the formulation may be as low as 1 mg. A1: 1 ratio is permissible if the binding constant of SAE-CD to the therapeutic agent is very strong. In this case, up to 50mg of drug may be used, provided that the inherent solubility of the drug is appropriateDosage of the composition. Consider the binding constant as 10000M-1And the binding constant is realistic for many drugs. In the presence of 0.1M SAE-CD, the solubility of the drug will increase by about 1000-fold over the solubility in the absence of SAE-CD. If the intrinsic solubility of the drug is about 1ng/ml, a solubility of only about 1 μ g/ml is possible when 0.1M SAE-CD is present. However, if the intrinsic solubility of the drug is about 10. mu.g/ml, a solubility of about 10mg/ml is possible when about 0.1M SAE-CD is present.
The present invention includes pharmaceutical formulations comprising various therapeutic agent/SAE-CD physical mixtures: osmotic pump tablets, multi-layer tablets, coated pellets, powders for injection, capsules, coated granules, and hot melt extruded films.
The coated tablets, granules and pellets of the invention comprise an optional film coating and a solid core. The film coating includes a film forming agent and optionally a pore former. The film coating may also comprise multiple film forming agents and optionally pore formers, for example in some embodiments of the film coating a combination of multiple film forming agents is used.
The terms "film-forming agent" and "release-controlling agent" are used interchangeably herein and include polymeric compounds (of natural, synthetic, semi-synthetic or genetically engineered origin) that form a thin film coating around a solid core of a formulation and that control the release rate of the therapeutic agent or SAE-CD from the core.
FIG. 1, which will be described in detail in example 1, depicts the release profiles of two osmotic pump tablets containing Methylprednisolone (MP), which differ only in the complexation of SAE-CD with the therapeutic agent. Of the two compositions, the first comprises methylprednisolone/SBE7beta-CD physical mixture, and the second comprises methylprednisolone-SBE7beta-CD complexes, formulated as controlled release osmotic pump tablets according to example 1. MP and SBE7beta-CD (1: 7 molar ratio) was compressed with the drug carrier into a solid core that was spray coated with a mixture of ethylcellulose, PEG 3350, PEG 400 and ethanol to form a 140 μm thick film coating around the solid core. Using USP dissolution apparatus II (100rpm, 37)C) and for the HPLC analysis of Methylprednisolone (MP) to determine the dissolution profile. Fluorescence analysis using 2, 6-toluidinonaphthalenesulfonic acid (2, 6-TNS) was performed to quantify SAE-CD. The first formulation, represented by open circles in FIG. 1, contains a separately preformed MP-SBE7beta-CD lyophilized complexes. The second formulation, indicated by the filled circles, contains mostly uncomplexed MP, with SBE7beta-CD is in the form of a physical mixture. The third formulation, represented by a square, comprises a physical mixture of lactose, fructose and MP. The curves corresponding to the preformed complexes and the physical mixtures have similarities indicating that the latter have similar or substantially similar release characteristics to the former. It should be noted that for this particular formulation, MP and SBE7The beta-CD has substantially the same release profile. These results are for MP and SBE7beta-CD is depicted in FIGS. 2a and 2b, respectively.
When the therapeutic agent is testosterone (TST), SBE7Physical mixture formulations of beta-CD and TST exhibit the same dissolution characteristics as the corresponding lyophilized mixtures. (FIG. 8) the solid core of the tablet comprises a 1: 1 molar ratio of TST to SBE7beta-CD. The film coating of the tablet comprises sorbitol, PEG 400 and cellulose acetate. The release profile of the physical mixture and complex formulation is comparable to that of the baseline TST/fructose-lactose formulation.
When the thickness of the film coating or film surrounding the tablet core, which comprises MP and SBE, is increased to 200 μm7Physical mixtures of β -CD or lyophilized complexes, only slight differences in release characteristics of the physical mixtures and lyophilized complexes were noted; however, SBE7The release profile of beta-CD is substantially similar to that of MP. These results are for MP and SBE7beta-CD is depicted in FIGS. 3a and 3b, respectively. Other exemplary film-coated tablets having film thicknesses of 38, 89, 137, 198 and 234 μm were prepared and evaluated as described above. The results in FIGS. 4a and 4b show SBE in each dosage form7The release profile of beta-CD is essentially the same as MP. In the 234 μm membrane embodiment, the lyophilized complex appears to release SBE more rapidly than MP7beta-CD. However, the release rate figures for the physical mixture embodiments of FIGS. 4a and 4b are not to scaleWhen plotted against the reciprocal of film thickness, the results indicated SBE7The release profile of β -CD is substantially similar to that of MP (FIG. 5).
The film thickness does not necessarily have a significant effect on the release characteristics of a given dosage form. FIG. 10 depicts film thickness versus EUDRAGITTM-L/urea film coating and dipyridamole/SBE7The effect of a sustained release formulation of a solid core of a physical mixture of β -CD. For this embodiment, the results show that the release characteristics of DP are independent of membrane thickness, but dependent on solution pH.
Changing the composition of film coating into EUDRAGITTMS and urea, a sustained release formulation can be made that releases DP at a pH of about 7.2 instead of 6.8 (fig. 11). A more alkaline pH corresponds to a pH in the small or large intestine of the patient. Thus, sustained release formulations comprising a solid core and a film coating and releasing the therapeutic agent in the intestine or colorectal can be prepared. The solid core comprises the therapeutic agent and SAE-CD, while the film coating comprises a film-forming agent that is a polymer with pH-dependent solubility.
Membrane surrounding solid core to affect MP and SBE7Release of beta-CD. In embodiments of the invention in which there is no membrane surrounding the solid core, SBE is included7The core of the physical mixture of β -CD and MP has the same or substantially the same release characteristics as the core of the complex comprising the same substance. Fig. 6 depicts the release profile of MP from solid cores containing lyophilized complex (filled circles), physical mixture (open circles) and fructose-lactose-MP physical mixture (squares). In this example, the fructose-lactose mixture acts as an osmotic agent rather than a solubilizing agent. The physical mixture exhibits substantially the same release characteristics as the composite.
MP/SBE7The molar ratio of β -CD may affect the release profile of a given dosage form. FIGS. 7a-7d depict MP and SBE7Profile of beta-CD release from film-coated tablets containing MP and SBE in the form of a physical mixture (FIGS. 7a and 7c) and a lyophilized complex (FIGS. 7b and 7d)7beta-CD, wherein MP/SBE7The molar ratio of beta-CD was 1/10, 1/7 and 1/3 (w/w). These results are shown in the tableClear and low SBE7The relative amount of beta-CD may reduce the MP release profile. Thus, dosage forms with different release profiles may also be controlled by MP/SBE7beta-CD ratio. These results also indicate that the physical mixture and the lyophilized complex have substantially the same release characteristics.
The film coating used may comprise a polymer with pH dependent solubility. Fig. 9 depicts the release profile of a sustained release formulation comprising a tablet core and a film coating. The tablet core comprises SBE7A physical mixture of β -CD and Dipyridamole (DP). Film coating (150 μm) comprising EUDRAGIT with pH-dependent solubilityTM-L. SBE when the pH of the solution in which the tablet is immersed rises from 1.5 to 6.8 after 2 hours7beta-CD and DP exhibited essentially the same release profile. The two hour delay corresponds to the formulation releasing most of the DP in the ileum and jejunum of the patient.
The film coatings or films of the present invention comprise a combination of film forming agents. FIG. 12 depicts an embodiment of the invention wherein the film coating comprises a 1: 1 mixture of Cellulose Acetate (CA) and hydroxypropyl methyl cellulose phthalate (HPMCP) and the solid core comprises SBE7beta-CD and DP. The combination of film forming agents provides the formulation with a combination of delayed and controlled release of the therapeutic agent.
Changing the film thickness from 90 μm to 170 μm did not appear to substantially affect the release characteristics of DP due to the use of a film-forming agent with pH dependent solubility. Thus, in this embodiment, the present invention provides a delayed and controlled release pharmaceutical formulation with a release profile that is only slightly dependent on the film thickness (fig. 13).
Particular embodiments of the present invention have delayed release, combined delayed and controlled release and/or controlled release characteristics. In the embodiment of FIG. 14, DP/SBE is included7Tablet cores of beta-CD were coated with CA: HPMCP and film thickness at various ratios. The delayed release embodiment, represented by a block, comprises a 90 μm film coating comprising a 1: 1 mixture of CA: HPMCP. Combined delayed and controlled Release implementation represented by diamondsThe embodiment includes a 105 μm film coating comprising a 6: 4 mixture of CA: HPMCP. Thus, by varying the ratio of CA to HPMCP, the relative distribution of controlled and delayed release to total release profile in the formulation can also be controlled.
It should be noted that in the absence of SAE-CD according to the present invention, no suitable drug release profile can be obtained for the therapeutic agents exemplified herein. For example, no DP release was obtained for tablet cores comprising DP, citric acid and fructose-lactose surrounded by a 120 μm thick film consisting of CA: HPMCP (50: 50). In another example, EUDRAGIT is used for the same tablet coreTMIncomplete DP release was observed when surrounded by a 120 μm thick film of-L and urea (50: 50).
Accordingly, the present invention also provides a pharmaceutical formulation having delayed release, controlled release or a combination delayed release and controlled release properties comprising a tablet core comprising a physical mixture of a therapeutic agent and SAE-CD and a film coating surrounding the tablet core comprising a combination of film forming agents.
Additional osmotic pump tablets were prepared according to example 2 and their dissolution characteristics were evaluated. These tablets comprise a tablet core comprising DP/SAE-CD surrounded by a film coating comprising one or more of the following: cellulose acetate, ethyl cellulose, wax, EUDRAGITTM E100、EUDRAGITTMRS, and EUDRAGITTM RL、EUDRAGITTM L、EUDRAGITTMS, cellulose acetate phthalate, hydroxypropyl methyl phthalate and HPMC acetate succinate. Pore formers evaluated included poly (ethylene glycol) 3350(PEG 3350), sorbitol, sucrose, polyols, xylitol, mannitol, carbohydrates, sugar, lactose, maltose, glucose, water-soluble cyclodextrins, and urea. Other compounds suitable for use as film forming agents include cellulose acetate butyrate, cellulose acetate propionate, cellulose propionate, HPMC, carageenan, cellulose nitrate, hydrophilic cellulosic materials, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl cellulose, ethyl cellulose, polyethylenePolyacetate, and latex dispersions, polyacids, enteric polymers, polysaccharides, acacia gum, tragacanth gum, guar gum, gelatin, proteins, albumin, polylactic acid, biodegradable polymers, polyglutamic acid, and mixtures thereof.
As mentioned above, it is not necessary that the pharmaceutical formulation according to the invention comprises a coated core, wherein the coating comprises a film-forming agent and a pore-forming agent. In the example of fig. 14, the rate of release and total release of DP is controlled by film thickness and film composition, where increasing the amount of CA relative to HPMCP decreases the rate of release of DP overall and the total release of DP also decreases. However, in the embodiment of fig. 15, MP is released from the tablet including a coating consisting of a film forming agent, a plasticizer and an anti-sticking agent, but not including a pore forming agent. In the formulation, the coating comprises EUDRAGITTMRS and EUDRAGITTMRL in a 9: 1 weight ratio and the coating on the tablet core represents about 5% by weight of the total weight of the tablet. Accordingly, the present invention also provides a controlled release pharmaceutical formulation consisting essentially of a core surrounded by a coating comprising a film forming agent, wherein the coating controls the release rate of the drug even in the absence of a pore forming agent in the coating.
At least one aspect of the present invention provides a controlled release solid pharmaceutical formulation consisting essentially of an uncoated core, wherein the core comprises a controlled release matrix comprising a release rate modifier, a therapeutic agent, and a sulfoalkyl ether cyclodextrin. Unlike other embodiments of the present invention, this particular embodiment can provide controlled release of the poorly water soluble drug Prednisolone (PD) in the absence of a release rate modifying coating. In the example of fig. 16, the release rate modifier is Hydroxypropylmethylcellulose (HPMC). In the absence of cyclodextrin, only about 50 wt% of PD was released after 11 hours; however, the addition of SAE-CD resulted in the release of 90 wt% or more PD after about 6 hours and essentially complete drug release after 11 hours.
FIG. 17 shows the effect of varying the ratio of therapeutic agent to sulfoalkyl ether cyclodextrin, where the amount of prednisolone and HMPC in the uncoated core remains constant while varyingSBE7beta-CD and lactose monohydrate. Specifically, PD was constantly maintained at 5% by weight of the formulation, while HMPC was constantly maintained at 25% by weight of the formulation. The amounts of cyclodextrin and lactose were varied such that they were about 70% by weight of the formulation in the exemplary formulation of fig. 17. Generally, as the amount of SAE-CD in the formulation decreases and the amount of lactose increases, the release rate of PD and the total release of DP decreases, while the release rate of SAE-CD increases. In other words, when the ratio of PD/SAE-DC is increased, the release rate of the drug decreases, while the release rate of SAE-CD increases. Thus, one embodiment of a controlled release pharmaceutical formulation according to the present invention comprises an uncoated core comprising SAE-CD, a therapeutic agent, and a release rate modifier. Exemplary formulations include those wherein about 40%, preferably 60%, more preferably 80% of the drug is released within 4 hours after administration of the formulation, and 60%, preferably 80%, more preferably 90% of the drug is released within 8 hours after administration of the formulation.
In the controlled release formulation according to the present invention, the core is uncoated, and the ratio of the release rate modifier to one or both of the therapeutic agent or SAE-CD has an effect on the release rate of the drug and the total amount of released drug. Thus, fig. 18 depicts the release profiles of various formulations, where the amounts of drug and cyclodextrin in the formulation are held constant, while the amounts of release rate modifier (HPMC) and diluent (lactose) are varied. Generally, the release rate of the drug decreases as the ratio of the release rate modifier to the drug increases, and the release rate of the cyclodextrin decreases as the ratio of the release rate modifier to the cyclodextrin increases. In the embodiment of FIG. 18, when the release rate modifier to drug ratio is about 10: 1, about 40-50% of the drug is released within about 6 hours after administration and about 55-60% of the drug is released within about 12 hours after administration. When the ratio of release rate modifier to drug is about 5: 1, the formulation releases about 65-75% of the drug about 6 hours after administration and about 75-90% of the drug after 12 hours. PD was 5% by weight of the formulation, SAE-CD was 35% by weight of the formulation, and the amount of HPMC in the formulation was increased to vary between 25-50% by weight.
Embodiments of formulations according to the invention, which include an uncoated core and release drug at a controlled rate, are typically influenced by the molecular weight and/or viscosity of the release rate modifier contained in the core. It is generally accepted that an increase in polymer viscosity corresponds to an increase in polymer molecular weight, an increase in polymer branching or an increase in polymer substitution. For example, fig. 19 depicts an uncoated core formulation wherein the core comprises 5 wt.% PD, 70 wt.% SAE-CD, and 25 wt.% HPMC. HPMC includes HPMC K100M (viscosity of 100000cps) or HMPC K15M (viscosity of 15000 cps). The release rate of PD increases with increasing viscosity of the release rate modifier. The control sample including HPMC K100M but no cyclodextrin released about 30 wt% PD within 6 hours and about 50 wt% PD within 11 hours. Surprisingly, as the viscosity of HPMC increased from 15000 to 100000, the release rate of PD and thus the total release of PD increased; however, the release rate of cyclodextrin and the total amount of cyclodextrin released are reduced. This property is quite unexpected as one skilled in the art would generally appreciate that the release rate of a component in a controlled release formulation would decrease with increasing viscosity of the release rate modifier. Thus, this embodiment of the present invention provides a controlled release formulation wherein the release rate modifier is present in an amount sufficient to cause the release rate of the drug to be dependent upon the viscosity of the release rate modifier.
Figure 20 includes the release profile of an uncoated controlled release core formulation comprising 5 wt.% PD, 35 wt.% SAE-CD, 50 wt.% HPMC, and 10 wt.% lactose, wherein the viscosity of the HPMC increases from 15000 to 100000. In this particular example, which includes high concentrations of HPMC relative to cyclodextrin and drug, the release rates and total release of drug and SAE-CD appear to be substantially independent of HPMC viscosity. Thus, the controlled release uncoated core formulation according to the invention allows the release of the therapeutic agent as follows: about 60% of the therapeutic agent is released within about 4 hours, about 80% of the drug is released within about 10 hours, or about 80% of the formulation is released within about 4 hours and more than 90% of the formulation is released within about 10 hours. The present invention also provides a controlled release uncoated formulation wherein about 40% of the drug is released within 4 hours and about 50% of the drug is released within 8 hours. In other words, one embodiment of the formulation includes a release rate modifier in an amount sufficient to render the release rate of the drug substantially independent of the viscosity of the release rate modifier.
Figures 19 and 20 show that the release of drug from the formulation will be substantially independent of the viscosity of the release rate modifier when the concentration of the release rate modifier in the formulation is higher, whereas the release rate of drug from the core will be substantially dependent on the viscosity of the release rate modifier when the concentration of the release rate modifier in the core is lower. In other words, increasing the amount of release rate modifier in the core generally reduces the dependence of the drug release rate on the molecular weight or viscosity of the release rate modifier.
Another aspect of the invention provides a multi-layered controlled release solid pharmaceutical formulation or dosage form comprising at least one first layer comprising a physical mixture of a therapeutic agent and SAE-CD and at least one second layer comprising a release rate modifier. In this embodiment, as well as other embodiments of the invention, a substantial portion of the therapeutic agent is not complexed with SAE-CD. The components of the at least first and second layers cooperate to provide controlled release of the therapeutic agent. In this embodiment, the formulation may comprise two, three, four or more separate, simultaneous, sequential or otherwise compressed layers having the desired therapeutic agent release characteristics. In a preferred embodiment, the multi-layer formulation includes an intermediate first layer comprising the therapeutic agent and SAE-CD sandwiched between two second layers, each of which contains a release rate modifier. According to the present invention, the first and second layers may comprise other pharmaceutical excipients and components known to those skilled in the art.
While it is an object of the present invention to provide a controlled release solid pharmaceutical formulation comprising a combination of SAE-CD and a therapeutic agent, wherein the majority of the therapeutic agent is not complexed with SAE-CD, the formulations of the present invention may also include other compositions wherein the therapeutic agent is complexed with SAE-CD. For example, one embodiment of the invention can include a core comprising a first composition comprising a physical mixture of SAE-CD and a therapeutic agent, wherein a substantial portion of the therapeutic agent is not complexed with SAE-CD, and a second composition comprising a preformed complex of SAE-CD and the therapeutic agent.
Example 8 details a method of making an exemplary embodiment of a multilayer tablet according to the present invention comprising at least one fast-release layer adjacent to a controlled-release layer. FIG. 23a depicts a bilayer tablet (1) comprising a fast-release layer (3) comprising a major amount of drug together with SAE-CD in a physical mixture and a fast-release matrix and a controlled-release layer (2) comprising a major amount of a physical mixture of drug, SAE-CD and a release rate modifier. The fast release layer disintegrates and releases the drug to the environment immediately upon administration to a patient or upon addition of the tablet to a dissolution medium. Figure 23b depicts a trilayer tablet with the controlled release layer (6) made as described in example 8 sandwiched between two fast release layers (5a, 5b) made as described in example 8. It should be noted that the quick release layer of fig. 23b contains a preformed indomethacin/SAE-CD complex. The bilayer and trilayer tablets may be coated with a process, enteric or controlled release coating if desired.
In another embodiment, a multi-layered controlled release formulation includes at least first, second, and third layers, wherein the first layer comprises a first composition comprising a physical mixture of SAE-CD and a therapeutic agent, wherein a majority of the therapeutic agent is not complexed with SAE-CD, the second layer comprises a second composition comprising a preformed complex of SAE-CD and the therapeutic agent, and the third layer comprises a release rate modifier. In this particular embodiment, a third layer covers one or both of the first and second layers.
FIG. 24 depicts another embodiment of the controlled release formulation (7) of the present invention wherein the controlled release core (8) comprises a physical mixture of a drug and SAE-CD and is surrounded by a compression coating (9) comprising a preformed complex of the drug and SAE-CD.
The controlled release formulations of the present invention also include physical mixture particles or granular formulations wherein a first set of particles comprises a physical mixture of a first therapeutic agent, a first sulfoalkyl ether cyclodextrin, and a release rate modifier, and a second set of particles comprises an inclusion complex of the first therapeutic agent and a second sulfoalkyl ether cyclodextrin. The first set of particles preferably releases the first therapeutic agent in a controlled manner, while the second set of particles preferably releases the second therapeutic agent in a rapid manner. The first and second therapeutic agents may be the same or different. Likewise, the first and second sulfoalkyl ether cyclodextrins can also be the same or different. The granules preferably contain other pharmaceutically acceptable excipients. If delayed and controlled release of the second therapeutic agent is desired, the second set of particles may be coated with a delayed release coating. The delayed release may be pH, erosion, or solubility controlled. Delayed release coatings include those described in this specification and others known to those skilled in the art.
Osmotic pump formulations prepared according to the following examples generally include a semipermeable coating surrounding a core containing a physical mixture of the therapeutic agent, SAE-CD and a pharmaceutically acceptable carrier, wherein a substantial portion of the therapeutic agent is not complexed with SAE-CD and the membrane has channels therethrough that place the core in communication with the environment of use. The core may also comprise an osmotic agent and a pharmaceutically acceptable excipient. The semi-permeable membrane may include one or more pore-forming agents to render the membrane porous, thereby allowing the therapeutic agent to diffuse from the membrane and create a dual-function osmotic pump.
In the embodiments described in detail below, the formulation includes a film coating surrounding the core, and the film may also include channels therein to communicate the core with the environment of use. For example, the channels are formed in the thin film by laser drilling or by a drill tip. If the membrane is porous, i.e., allows diffusion of the drug therethrough, and also includes channels, the formulation will release the drug by a combination of osmotic and diffusive action. If the membrane is semipermeable, i.e., does not allow diffusion of the drug therethrough, and includes channels, the formulation will release the drug in an osmotic manner.
The term "osmotic agent" refers to a compound or group of compounds that, when contained in the core of an osmotic pump and in contact with water in the environment of use, creates an osmotic pressure across the membrane of the osmotic pump. Such osmotic agents include, for example, salts, water-soluble compounds, sugars, and other substances known to those skilled in the art. SAE-CD and other hydrophilic or ionizing compounds or polymers may also be used as penetrants.
Example 11 describes a method of making an osmotic pump that releases Testosterone (TS) into a use environment by a combination of diffusion and osmosis. FIG. 25 depicts TS, sugar, hydroxypropyl- β -cyclodextrin (HP- β -CD), and (SBE)7m-comparative curves of beta-CD release from various osmotic pump formulations. The first formulation comprises a physical mixture of ts (o) and a mixture of sugars (●, lactose and fructose, 1: 1); the second formulation comprises TS (□) and (SBE)7m- β -CD (■); while the third formulation contained TS (), and HP- β -CD (). The results show that the osmotic pumps comprising (SBE) are comparable to those comprising a mixture of sugars or HP-beta-CD7mOsmotic pumps of- β -CD release larger amounts of TS and more acceptable release rates.
The advantageous properties of the present formulations allow one to prepare drug delivery devices with combined and controlled diffusional and osmotic release of the drug. These devices can be made by varying the amount of pore former in the semipermeable membrane or the ratio of hydrophilic polymer to hydrophobic polymer or by varying the thickness of the semipermeable membrane in the device. In a preferred embodiment, the thickness of the membrane will be sufficient to allow a lower rate of release of the drug by diffusion than by osmosis, thereby allowing release of the therapeutic agent/SAE-CD inclusion complex formed in the core of the device primarily by osmosis.
In another preferred embodiment, the therapeutic agent is released mostly by diffusion across the sides of the membrane, and a small fraction by osmosis through channels in the membrane. This type of combination and controlled release device is prepared by decreasing the film thickness and increasing the porosity of the film, that is to say increasing the amount of pore former relative to film former.
In yet another preferred embodiment, the therapeutic agent is released mostly by osmosis through channels in the membrane and a small portion by diffusion across both sides of the membrane. This type of combination and controlled release device is prepared by increasing the thickness of the membrane and decreasing the porosity of the membrane, that is to say by reducing the amount of pore former in the membrane or eliminating it, and/or by increasing the diameter of the channels.
The layers, films or coatings in the various embodiments of the pharmaceutical compositions and formulations of the present invention are typically applied in the form of a film or by compression. The film is typically formed as follows: the solution, suspension or emulsion is applied to an existing core or solid and the liquid portion is then removed to form a substantially dry film. Compression coatings are typically prepared by compressing a second pharmaceutical composition over a first pharmaceutical composition.
The term "pore former" as used herein refers to a substance that helps to form pores in the film coating of the present invention or to increase the water permeability of the film. Such pore formers include, for example, sugars such as lactose, glucose, fructose, sucrose, mannose; alpha-hydroxy acids such as citric acid, tartaric acid, fumaric acid, succinic acid, glycolic acid, lactic acid, and mixtures thereof and salts thereof; halogen counterions such as bromine, fluorine, iodine and chloride; divalent metal cations such as magnesium and calcium; anionic species such as phosphate, sulfate, sulfonate, nitrate, bicarbonate, and mixtures thereof and salts thereof; cellulosic materials, such as HPC, HPMC, hydroxyethylcellulose, methylcellulose; poly (ethylene oxide); poly (vinyl pyrrolidone); gums and gelling agents, such as guar gum, xanthan gum, alginic acid, acacia gum, tragacanth gum, mixtures thereof and salts thereof; clays, such as montmorillonite, bentonite, Veegum, kaolin; other substances, e.g. diatomaceous earth, magnesium silicate, organo-bentonite, hectorite, PLURONICSTMA hydrophilic surfactant; polyols, such as sorbitol, mannitol, xylitol; proteins, such as albumin, collagen, gelatin; a water-soluble amino acid; disintegrants, such as starch, sodium starch glycolate, cross-linked cellulose; and a water-soluble organic compound; mixtures thereof. Water-permeable pore formers generally enhance the filmPermeability of (2).
The formulations of the present invention form an SAE-CD complex upon contact with bodily fluids. In a particular embodiment, the formulation of the invention hydrates the SAE-CD/therapeutic agent physical mixture prior to release of the therapeutic agent, aiding in complex formation.
Method for improving bioavailability and bioabsorption
For poorly water soluble, hydrophobic, and poorly bioavailable drugs, the present invention advantageously provides methods of enhancing water solubility and improving bioavailability and/or bioabsorption in a patient. For drugs that are water soluble, hydrophilic, and highly bioavailable, the present invention provides a method for improving the rate of bioabsorption in a patient.
As used herein, the terms "poorly water soluble" and "hydrophobic" refer to therapeutic agents having a solubility in neutral water of less than about 1mg/ml at 20 ℃. The terms "water soluble" and "hydrophilic" refer to therapeutic agents having a solubility in neutral water of greater than about 1mg/ml at 20 ℃.
In some embodiments, the methods of the present invention for improving the bioavailability or bioabsorption rate of a therapeutic agent comprise the steps of: providing a mixture of a therapeutic agent and a sulfoalkyl ether cyclodextrin derivative, and then administering the mixture to a patient. By "improving bioavailability and/or bioavailability" is meant that the bioavailability and/or bioavailability of a therapeutic agent when administered in combination with SAE-CD is different (or relatively improved) from the bioavailability and/or bioabsorption when administered alone.
In another embodiment, the method of the invention comprises the steps of: the sulfoalkyl ether cyclodextrin derivative is formulated with an uncomplexed therapeutic agent in a single pharmaceutically acceptable dosage form, which is then administered to a patient.
Without wishing to be bound by any theory, it is believed that SAE-CD improves the bioavailability and/or bioabsorption rate of a therapeutic agent by forming clathrates or comprising complexes upon contact with the body fluid of a patient. The therapeutic agent/SAE-CD combination can be formulated using a variety of methods described in detail below. It is only necessary to observe that the amount of SAE-CD should be sufficient to complex with the therapeutic agent in the patient receiving the formulation.
General theory of the invention
Therapeutic agents included in the present invention may have a wide range of water solubility, bioavailability, and hydrophilicity values. Thus, the present invention includes any therapeutic agent that can form a clathrate or comprise a complex with the SAE-CD derivative of formula (I). Therapeutic agents to which the present invention is particularly applicable include poorly water soluble, hydrophobic therapeutic agents, as well as water soluble, hydrophilic therapeutic agents. The formulations of the present invention are generally used in unit doses, including less than about 500mg, particularly less than about 150mg, more particularly less than about 50mg of the therapeutic agent. It will be appreciated by those skilled in the art that the therapeutic agents used in the formulations of the present invention are independently selected from the therapeutic agents disclosed in the present invention.
The amount of therapeutic compound to be added to the formulations of the present invention is selected according to known principles in pharmacy, clinical pharmacology and pharmacology. A therapeutically effective amount of a therapeutic compound is specifically included. By the term "therapeutically effective amount" it is understood to include a pharmaceutically effective amount with respect to, for example, pharmacology. A pharmaceutically effective amount refers to an amount of a drug or pharmaceutically active substance sufficient to induce a desired or intended therapeutic response, or in other words, an amount sufficient to induce a significant biological response when administered to a patient. The term "effective amount" with respect to vitamins or minerals means that the amount of a particular ingredient in a patient is at least 10% of the recommended Daily Allowance (RIDA) for the United states. For example, if the desired ingredient is vitamin C, an effective amount of vitamin C will include an amount of vitamin C sufficient to provide 10% or more of the RDA. Typically, if the tablet includes minerals or vitamins, it includes higher amounts, preferably 100% or more of the RDA that is suitable. The therapeutic compounds are typically used in finely divided form, such as powders or granules, to increase dissolution. It is preferred to use the therapeutic compound in the form of a fine powder to increase dissolution. More preferably, no less than 80%, preferably no less than 90%, of the therapeutic compound may pass through a 100 mesh (150 micron) screen. The therapeutic compound is added in an amount of usually 0.1 to 50%, preferably 1 to 25% by weight of the composition, and the ratio may be suitably changed depending on the therapeutic compound used.
Exemplary therapeutic agents include almost water-insoluble antibacterial agents of the picolinic acid type, such as benofloxacin, nalidixic acid, enoxacin, ofloxacin, aminofloxacin, flumequine, tosufloxacin, pyrrominic acid, pipemidic acid, milofloxacin, oxolinic acid, cinoxacin, norfloxacin, ciprofloxacin, pefloxacin, lomefloxacin, enrofloxacin, danofloxacin, binofloxacin, sarofloxacin, ebafloxacin, difloxacin, and salts thereof. Other therapeutic agents include penicillins, tetracyclines, cephalosporins and other antibiotics, bactericidal substances, antihistamines and decongestants, anti-inflammatory agents, antiparasitic agents, antiviral agents, local anesthetics, antifungal agents, amoebicidal agents, or trichomonacidal agents, analgesics, antiarthritics, anti-asthmatic agents, anticoagulants, anticonvulsants, antidepressants, antidiabetics, antineoplastics, antipsychotics, antihypertensives, and muscle relaxants. Representative biocidal materials are the biocidal combinations of beta-lactam antibiotics, tetracyclines, chloramphenicol, neomycin, gramicidin, bacitracin, sulfonamides, nitrofurazone, nalidixic acid and the like, and fluorodeuteroalanine/pentazidone. Representative antihistamines and decongestants are perilamine, chlorpheniramine maleate, tetrahydrozoline, and antazoline.
Representative anti-inflammatory agents are cortisone, hydrocortisone, betamethasone, dexamethasone, fluocortolone, prednisolone, triamcinolone, indomethacin, sulindac and its salts and corresponding sulfides. A representative antiparasitic agent is ivermectin.
Representative antiviral compounds are acyclovir and interferon. Representative analgesics are diflunisal, aspirin or acetaminophen. Representative anti-arthritic drugs are phenylbutazone, indomethacin, silindac, their salts and the corresponding sulfides, dexamethasone, ibuprofen, allopurinol, oxyphenbutazone or probenecid. Representative anti-asthmatics are theophylline, ephedrine, beclomethasone dipropionate and epinephrine. Representative anticoagulants are dihydroxycoumarin and warfarin. Representative anticonvulsants are diphenylhydantoin and diazepam. Representative antidepressants are amitriptyline, chlordiazepoxide, perphenazine, protriptyline, imipramine and doxepin. Representative antidiabetic agents are insulin, somatostatin and its analogs, tolbutamide, tolazamide, acetohexamide and chlorpropamide. Representative antineoplastic agents are doxorubicin, fluorouracil, methotrexate and asparaginase. Representative antipsychotics are prochlorperazine, thioridazine, molindone, fluphenazine, trifluoperazine, perphenazine, armitrityline and trifluoropropyline. Representative antihypertensive agents are spironolactone, methyldopa, hydralazine, clonidine, chlorothiazide, dessertpine, timolol, propranolol, metoprolol, prazosin hydrochloride and reserpine. Representative muscle relaxants are chlorosuccincholine, danbrolene, cyclobenzaprine, methocarbamol and diazepam.
Some other examples of therapeutic agents include, but are not limited to, aclofennin, amobarbital, aminobenzoic acid, amobarbital, ampicillin, anethole, aspirin, azopropazone, azulene barbituric acid, beclomethasone dipropionate, bencyclane, benzaldehyde, benzocaine, benzodiazepine, benzothiazide, betamethasone, 17-betamethasone valerate, bromobenzoic acid, bromoisoprenyl urea, butyl p-aminobenzoate, chloral hydrate, chlorambucil, chloramphenicol, chlorobenzoic acid, chlorpromazine, cinnamic acid, clofibrate, coenzyme A, cortisone acetate, cyclohexarbital, cyclohexyl anthranilate, deoxycholic acid, dexamethasone acetate, diazepam, digoxigenin, estradiol, flufenamic acid, fluocinolone, 5-fluorouracil, flurbiprofen, griseofulvin, and, Guaiazulene, hydrocortisone acetate, ibuprofen, indica, indomethacin, and,Iodine, ketoprofen, lankacidin antibiotics, mefenamic acid, menadione, tolmetin, methamphetal, methicillin, metronidazole, mitomycin, nitrazepam, nitroglycerin, nitrourea, paramethasone, penicillin, pentobarbital, phenobarbital, phenylbutyric acid, phenylpentanoic acid, phenytoin, prednisolone acetate, progesterone, propylhydroxybenzoate, onifolin, prostaglandin A series, prostaglandin B series, prostaglandin E series, prostaglandin F series, quinolone microbicides, reserpine, lactospira, sulfacetamide, sulfonamide, testosterone, thalidomide, vitamin B1 dilauryl sulfate, thiamphenicol palmitate, thiopental, triamcinolone, VIAGRATMVitamin a, vitamin D3, vitamin E, vitamin K3, and warfarin.
If desired, the therapeutic compound contained in the pharmaceutical preparation is formulated in the form of a pharmaceutically acceptable salt thereof. The term "pharmaceutically acceptable salts" as used herein refers to derivatives of the disclosed compounds wherein the therapeutic compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; alkali metal or organic salts of acidic groups such as carboxylic acids; and so on. Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed with non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those produced from the following acids: inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfonic acid, sulfamic acid, phosphoric acid, nitric acid, and the like; organic acids such as amino acids, acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid and the like.
The pharmaceutically acceptable salts of the present invention are synthesized by conventional chemical methods from the parent therapeutic activation containing a basic or acidic group. Typically, such salts are prepared, for example, by reacting the free acid or base forms of these compounds with a predetermined amount of the appropriate base or acid in water or an organic solvent or a mixture of the two. Generally, nonaqueous media are preferred. Examples of suitable salts are found in Remington's Pharmaceutical Sciences, 18 th edition, MackPublishing Company, Easton, PA, 1990, Chapter 40, the contents of which are incorporated herein by reference.
The term "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions, and/or formulations that do not produce excessive toxicity, irritation, allergic response, or other problem or complication when contacted with the tissues of human beings and animals, but that do not have a reasonable benefit/risk ratio, based on sound medical judgment.
The term "active ingredient" as used herein may also be defined as flavoring agents, sweetening agents, vitamins, minerals, and other such compounds in the pharmaceutical arts. The formulations of the present invention may also include adjuvants such as colorants, disintegrants, lubricants, bioadhesives, and other materials known to those skilled in the art.
Disintegrating agents include starch-based materials such as corn starch, potato starch, pregelatinized and modified starch, cellulose-based materials such as Ac-di-sol, montmorillonite, cross-linked PVP, sweetener, bentonite and VEEGUMTMMicrocrystalline cellulose, alginates, sodium starch glycolate, gums such as agar, guar gum, locust bean gum, pectin and tragacanth. In a specific embodiment, the tablet of the present invention does not dissolve rapidly to hydrate the SAE-CD/therapeutic agent physical mixture therein.
Protease inhibitors that may be included in the formulations of the present invention include, for example, antiproteases, leupeptins, chymostatin, amistatin, and puromycin.
Penetration enhancers that may be included in the formulations of the present invention include, for example, calcium chelators such as EDTA, methylated beta-cyclodextrin, and polycarboxylic acids; surfactants such as sodium lauryl sulfate, sodium lauryl sulfate,Carnitine, carnitine esters, and tween; bile salts such as sodium taurocholate; fatty acids such as oleic acid and linoleic acid; and non-surfactants such as AZONETMAnd dialkyl sulfoxides.
The flavoring agent which can be added to the composition can be selected from synthetic flavoring oils and flavoring aromatics and/or natural oils, extracts from plants, leaves, flowers, fruits, etc., and mixtures thereof. They may include cinnamon oil, oil of wintergreen, peppermint oil, clove oil, bay oil, anise oil, eucalyptus oil, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage, oil of bitter almonds, and oil of cassia oil. Vanilla, citrus oil, and fruit essential oil may also be used as flavoring agents, with citrus including lemon, orange, grape, lime, and grapefruit, and with fruit including apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot, and the like. Particularly useful flavoring agents include commercially available orange, grape, cherry, and bubble gum flavors and mixtures thereof. The amount of flavoring agent depends on a variety of factors, including the desired organoleptic effect. Particularly preferred flavorings are grape and cherry flavorings and citrus flavors such as orange flavoring.
Materials that may be incorporated in the formulations of the present invention may be pre-treated to form granules. This process is called "granulation". As generally defined, "granulation" is any process of increasing particle size in which small particles are agglomerated together to form larger, permanent agglomerates, resulting in a free-flowing composition of suitable consistency. Such granulated compositions may have a consistency similar to dry sand. Granulation may be accomplished by stirring in a mixing device or by compaction, extrusion or agglomeration.
The term "vitamin" as used herein refers to a trace amount of organic material required in the diet. For the purposes of the present invention, the term "vitamin" includes, but is not limited to, vitamin B1, vitamin B2, niacin, pantothenic acid, pyridoxine, biotin, folic acid, vitamin B12, lipoic acid, ascorbic acid, vitamin a, vitamin D, vitamin E, and vitamin K. The term "vitamins" also includes their coenzymes. Coenzymes are specific chemical forms of vitamins. Coenzymes include vitamin B pyrophosphate 1(TPP), flavin mononucleotide (FMM), Flavin Adenine Dinucleotide (FAD), Nicotinamide Adenine Dinucleotide (NAD), Nicotinamide Adenine Dinucleotide Phosphate (NADP), coenzyme A (CoA), pyridoxal phosphate, biocytin, tetrahydrofolic acid, coenzyme B12, lipoyl lysine, 11-cis-retinal, and 1, 25-dihydroxyvitamin D3. The term "vitamin" also includes choline, carnitine, and alpha, beta, and gamma carotenes.
The term "minerals" as used herein refers to inorganic substances, metals, etc., which are required in the human diet. The term "mineral" as used herein includes, but is not limited to, calcium, iron, zinc, selenium, copper, iodine, magnesium, phosphorus, chromium, and the like, and mixtures thereof.
The term "food additive" as used herein refers to a substance that has a considerable nutritional effect when used in small amounts. Food additives include, but are not limited to, the following: pollen, bran, malt, seaweed, cod liver oil, ginseng, and fish oil, amino acids, proteins, and mixtures thereof. It is understood that the food additive may include vitamins and minerals.
Bioadhesives may also be included in the formulations of the present invention. Bioadhesives are defined as substances that can adhere to biological surfaces such as mucous membranes or skin tissue. The bioadhesive can firmly confine the formulation to the mucosa. Preferred bioadhesives are fibrous or particulate, water swellable but water insoluble. A suitable ratio of bioadhesive to other ingredients can produce a strong clotting effect. Bioadhesive polymers useful in the present invention include, but are not limited to, hydrophilic and water dispersible polymers having free carboxylic acid groups and relatively high base binding capacity. These polymers and hydrophilic cellulosic materials are polycarboxylic vinyl polymers and polyacrylic acid polymers. Some hydrophilic polysaccharide gums, such as guar gum, locust bean gum, psyllium seed gum, and the like, may also be suitable for use in the formulations of the present invention. The weight ratio of bioadhesive to active ingredient can be quite broad. In practice, the weight ratio of bioadhesive to active ingredient is generally from about 1: 10 to 10: 1.
The SAE-CD containing pharmaceutical formulations of the present invention may require specific hydrophobic or hydrophilic binders to obtain a suitable product. Suitable hydrophobic binders include cellulose acetate butyrate, cellulose acetate propionate, high molecular weight (200000) cellulose propionate, medium molecular weight (75000) cellulose propionate, low molecular weight (25000) cellulose propionate, cellulose acetate, cellulose nitrate, ethyl cellulose, polyvinyl acetate, and the like. Suitable hydrophilic binders include polyvinylpyrrolidone, vinyl alcohol polymers, polyethylene oxide, water-soluble or water-swellable cellulose and starch derivatives, and others known to those skilled in the art.
Examples of other binders that may be added to the formulations of the present invention include, for example, acacia, tragacanth, gelatin, starch, cellulosic materials such as methylcellulose and sodium carboxymethylcellulose, alginic acid and salts thereof, polyethylene glycols, guar gum, polysaccharides, sugars, inert sugars, Poloxomers (PLURONIC)TMF68、PLURONICTMF127) Collagen, albumin, gelatin, cellulosic materials in a non-aqueous solvent, pregelatinized starch, starch paste, and mixtures thereof. Other binders include, for example, polypropylene glycol, polyoxyethylene-polypropylene copolymer, polyvinyl ester, polyethylene glycol, polyethylene sorbitan ester, polyethylene oxide, or mixtures thereof, as well as others known to those skilled in the art.
The melting and/or softening points of these binders generally increase with increasing molecular weight. Binders with melting or softening point temperatures in excess of 150 c may require the use of plasticizers during the preparation of the formulation to lower the melting or softening point temperature of the binder to below 150 c. The binder is typically in the form of a powder, granules, flakes, or a hot-melt liquid.
The term "release rate modifying agent" as used herein refers to a substance that modifies the release rate of a therapeutic agent from a pharmaceutical formulation according to the present invention. The release rate modifier facilitates controlled release of the therapeutic agent and may cooperate with other components of the formulation to delay, sustain, time, pH-dependent, target, or control release of the therapeutic agent. It will be appreciated that some of the above-described binders may also be used as release rate modifiers.
The term "plasticizer" as used herein includes all compounds capable of plasticizing the binder used in the present invention. The plasticizer should be capable of lowering the melting point temperature or glass transition point temperature (softening point temperature) of the adhesive. Plasticizers such as low molecular weight PEG generally allow the average molecular weight of the adhesive to be broader, thereby lowering its glass transition temperature or softening point. Plasticizers also generally reduce the viscosity of the polymer. Plasticizers may also impart particularly advantageous physical properties to the formulations of the present invention.
Plasticizers that may be used in the present invention include, by way of example and not limitation, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols having aliphatic hydroxyl groups, ester-type plasticizers, glycol ethers, poly (propylene glycol), multi-block polymers, mono-block polymers, low molecular weight poly (ethylene glycol), citrates, triacetin, propylene glycol phthalate, phosphate esters, sebacates, glycol derivatives, fatty acid esters, and glycerin.
The plasticizer may also be ethylene glycol, 1, 2-butanediol, 2, 3-butanediol, styrene glycol, diethylene glycol, dipropylene glycol, triethylene glycol, tetraethylene glycol and other poly (ethylene glycol) compounds, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, dimethyl sebacate, di (2-ethylhexyl) sebacate, trimethylol phosphate, triethyl phosphate, triphenyl phosphate, acetylated monoglyceride, mineral oil, castor oil, triacetin, butyl stearate, glycerol monostearate, butoxyethyl stearate, stearyl alcohol, cyclohexylethyl phthalate, cyclohexylmethyl dibutyl phthalate, ethylene glycol monoethyl phosphate, propylene glycol monoethyl ether, sorbitol, ethyl lactate, butyl lactate, dibutyl sebacate, dimethyl sebacate, di (2-ethylhexyl) sebacate, triethyl phosphate, triphenyl phosphate, acetylated monoglyceride, mineral oil, castor oil, glycerol triacetate, butyl, Diethyl phthalate, dibutyl phthalate, diisopropyl phthalate, dimethyl phthalate, dioctyl phthalate, acetyl tributyl citrate, triethyl citrate, acetyl triethyl citrate, tributyl citrate, and allyl glycolate. All of the above plasticizers are commercially available, for example, Aldrich or Sigma chemical Co or Morflex, Inc. The present invention also includes the use of a combination of plasticizers in the formulation.
The formulations of the present invention generally comprise a solid core comprising the sulfoalkyl ether cyclodextrin of formula (I) above, a pharmaceutically acceptable carrier, and a therapeutically effective amount of a therapeutic agent, a majority of which is not complexed with the sulfoalkyl ether cyclodextrin. The solid core is surrounded by a film coating. Such formulations may include solid dosage forms such as, but not limited to, chewable sticks, capsules, fibers, films, gels, granules, chewing gums, implants, suppositories, pellets, powders, averages, tapes, lozenges, pills, sticks, strips, and wafers.
Routes of administration include oral, buccal, nasal, implant, rectal, vaginal, sublingual, otic and urethral. The formulations of the present invention are generally administered with a pharmaceutically acceptable carrier or diluent, the proportion or nature of which can be determined by the solubility and chemical nature of the selected therapeutic agent, the selected dosage form, and standard pharmaceutical practice. Solid oral dosage forms may contain conventional excipients such as lactose, sucrose, magnesium stearate, resins and similar materials, flavoring agents, coloring agents, buffering agents, preservatives, or stabilizers. These formulations may also contain a moisture absorbent, which can draw moisture out of the tablet core. The hygroscopic agent may include water-soluble electrolytes, small organic compounds, osmotic adjusting agents to increase osmotic pressure in the formulation and absorb moisture.
The term "patient" as used herein refers to a warm-blooded animal such as mammals, e.g., cats, dogs, mice, guinea pigs, horses, cattle, sheep and humans.
The term "unit dosage form" as used herein refers to a single or multiple dose dosage form containing an amount of active ingredient together with a diluent or carrier, said amount being one or more predetermined units normally required for a single therapeutic administration. In case of a multi-dose dosage form, such as a liquid or a scored tablet, the predetermined unit may be a portion, such as a half or a quarter, of a multi-dose scored tablet. It will be understood that the specific dose level for a patient will depend upon a variety of factors including the condition being treated, the therapeutic agent employed, the activity of the therapeutic agent, the severity of the condition, the health, age, sex, diet, and pharmacological response of the patient, the specific dosage form employed, and other like factors.
Various components or compounds may be used to aid in the preparation of suitable dosage forms of the invention. Such components or compounds include, but are not limited to, acidulants, alkalizing agents, adsorbents, fungicidal preservatives, antioxidants, buffering agents, colorants, encapsulating agents, flavorants, stiffening agents, suppository bases, sweeteners, tablet detackifiers, tablet binders, tablet and capsule diluents, tablet coatings, tablet direct compression excipients, tablet disintegrants, tablet glidants, tablet lubricants, tablet/capsule opacifiers, and tablet polishing agents.
The term "acidulant" as used herein refers to a compound that provides an acidic medium for product stability. Such compounds include, for example, but are not limited to, acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid, and the like.
The term "alkalizer" as used herein refers to a compound that provides an alkaline medium for the stability of the product. Such compounds include, for example, but are not limited to, aqueous ammonia, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, and trolamine, and the like.
The term "adsorbent" as used herein refers to a substance capable of retaining other molecules on its surface by physical or chemical (chemisorption) means. Such compounds include, for example, but are not limited to, powders and activated carbon, and the like.
The term "preservative" as used herein refers to a compound used to prevent the growth of microorganisms. Such compounds include, for example, but are not limited to, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetyl pyridinium chloride, chlorobutanol, phenol, phenethyl alcohol, phenylmercuric nitrate, thimerosal, and the like.
The term "antioxidant" as used herein refers to a substance that inhibits oxidation reactions and thus serves to prevent deterioration of the formulation due to oxidation processes. Such compounds include, for example, but are not limited to, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl perylate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, and the like.
The term "buffer" as used herein refers to a compound that acts to resist changes in pH upon dilution or addition of an acid or base. Such compounds include, for example, but are not limited to, potassium metaphosphate, potassium phosphate, sodium acetate, and anhydrous and sodium citrate dihydrate, among others.
The term "colorant" as used herein refers to compounds used to impart color to solid (e.g., tablets and capsules) pharmaceutical preparations. Such compounds include, for example, but are not limited to FD & C Red No.3, FD & C Red No.20, FD & C Yellow No.6, FD & C Blue No.2, D & C Green No.5, FD & C Orange No.5, D & C Red No.8, caramel, Red iron oxide, and the like. The colorant may also include titanium dioxide, natural colorants such as grape skin extract, beet red powder, beta carotene, annatto extract, carmine, turmeric, paprika, and the like.
The term "encapsulating agent" as used herein refers to a compound used to form a thin shell to enclose a drug or pharmaceutical formulation for convenient administration. Such compounds include, for example, but are not limited to, gelatin, nylon, biodegradable polyesters, D, L-poly (lactic acid), polylactide-co-10 glycolic acid, cellulose acetate phthalate, and the like.
The term "flavoring agent" as used herein refers to compounds used to impart a pleasant taste and odor to a pharmaceutical formulation. In addition to natural flavors, a number of synthetic flavors can also be used. Such compounds include, for example, but are not limited to, anise oil, cinnamon oil, cocoa, mint, orange oil, peppermint oil, vanilla, and the like.
The term "sweetener" as used herein refers to a compound used to impart sweetness to a formulation. Such compounds include, for example, but are not limited to, aspartame, dextrose, glycerin, mannitol, sodium saccharin, sorbitol, sucrose, and the like.
The term "tablet detackifier" as used herein refers to a substance used during the manufacturing process to prevent the sticking of tablet ingredients to the punches and dies of a tablet making machine. Such compounds include, for example, but are not limited to, magnesium stearate, corn starch, silica, talc, and the like.
The term "tablet binder" as used herein refers to a substance used to bind powder particles together during tablet granulation. Such compounds include, for example, but are not limited to, acacia gum, alginic acid, sodium carboxymethylcellulose, compressible sugars (e.g., NuTab), ethylcellulose, gelatin, liquid glucose, methylcellulose, povidone, pregelatinized starch, and the like.
The term "tablet and capsule diluent" as used herein refers to an inert substance used as a filler in the preparation of tablets and capsules to increase the desired volume, flow properties and compression characteristics. Such compounds include, for example, but are not limited to, dibasic calcium phosphate, kaolin, fructose, sucrose, glucose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol, calcium sulfate, starch, and the like.
The term "tablet coating agent" as used herein refers to a compound used to coat the formed tablet to protect the drug from decomposition by atmospheric oxygen or moisture, to mask the taste or odor of the drug, or for aesthetic purposes. The coating can be of various types, including sugar coating, film coating, or enteric coating. The sugar coating is water-based and forms a thick covering around the formed tablet. A film coating is a thin covering that surrounds the formed tablet or bead. If not enteric, the film coating will dissolve in the stomach. Enteric coated tablets or beads will pass through the stomach and disintegrate in the intestinal tract. Some water insoluble coatings (e.g., ethyl cellulose) may be used to coat the tablets and beads to slow the release of the drug as the tablets pass through the gastrointestinal tract. Such compounds for coating include, for example, but are not limited to, liquid glucose and sucrose (for sugar coating); hydroxyethyl cellulose, hydroxypropyl methylcellulose, methylcellulose (e.g., Methocel), and ethylcellulose (e.g., Ethocel) (for film coating); and cellulose acetate phthalate and shellac (35% alcohol solution, "drug glaze") (for enteric coating), and the like.
The term "tablet direct compression excipient" as used herein refers to a compound used to directly compress a tablet. Such compounds include, for example, but are not limited to, dicalcium phosphate (e.g., Ditab), phosphorus-, lactose spray dried or anhydrous, microcrystalline cellulose (AVICEL)TM) Dextran (EMDEX)TM) Sucrose (NUTAB)TM) And others known to those skilled in the art.
The term "tablet glidant" as used herein refers to substances used to reduce friction in tablets and capsules during tablet compression. Such compounds include, for example, but are not limited to, colloidal or fumed silica, magnesium stearate, corn starch, talc, and the like.
The term "tablet lubricant" as used herein refers to a substance used to reduce friction in tablets and capsules during tablet compression. Such compounds include, for example, but are not limited to, calcium stearate, magnesium stearate, mineral oil, stearic acid, hydrogenated vegetable oil, benzoic acid, poly (ethylene glycol), sodium chloride, PRUVTMAnd zinc stearate.
The term "tablet/capsule opacifier" as used herein refers to compounds used to make capsules or tablet coatings opaque to light. May be used alone or in combination with a colorant. Such compounds include, for example, but are not limited to, titanium dioxide and the like.
The term "tablet polishing agent" as used herein refers to a compound used to impart an attractive shine to a coated tablet. Such compounds include, for example, but are not limited to, carnauba wax, white wax, and the like.
The formulations of the present invention comprising the therapeutic agent/SAE-CD physical compound are particularly suitable for the following therapeutic agents: cerivastatin, cryptophycin, jaspimide, chikusetron (ambrosin), busulfan, propranolol, etoposide, paclitaxel, brefeldin A prodrug (NSC # D656202), 9-amino-20 (S) -camptothecin, prednisolone acetate, prednisolone, pancreatin, rhizoxin, bryostatin 1, taxotere O6-benzylguanine, androstane, guanine, chloramphenicol, dapsone, sulfacone, benclomethasone dipropionate, menadione, tamoxifen citrate, cholesterol, estrone, verapamil hydrochloride, equilenin, warfarin, indomethacin, phenytoin, cinnarizine, amiodarone hydrochloride, naproxen, piroxicam, thiabendazole, papaverine, miconazole (free base), nifedipine, testosterone, progesterone, carbamazepine, methylprednisolone, dexamethasone, hydrocortisone and diclofenac.
The invention will be better understood by reference to the following examples which illustrate in detail some of the preparation steps of the formulations of the invention. All of these embodiments are intended to be illustrative. They should not be considered as limiting the scope and nature of the invention.
Example 1
Testosterone- (SBE)7-beta-CD sustained release formulations
This example demonstrates the use of the present invention in the preparation of a sustained release formulation in which the pharmacologically active agent is testosterone as an example.
Phase solubility study
Excess testosterone was added to 0.25ml (SBE)7-beta-CD solution, concentration range is 0.0-0.05 mmol/l. The dispersion was allowed to equilibrate in a shaking water bath (100rpm, 25 ℃) for at least 24 hours. Dispersion 1 was centrifuged at 2500rpmAt 0 min, 20 μ l of the supernatant was sampled with a gas tight 100 μ l syringe (Hamilton co., NV), diluted with mobile phase and the solution was analyzed for testosterone concentration by HPLC. For A with Higuchi and ConnorsLMethod for determining testosterone- (SBE)7-beta-CD binding constant K1∶1。
Preparation of tablet cores
With testosterone/(SBE) in a molar ratio of 1: 17-beta-CD to prepare tablet cores. The tablet core is made of testosterone- (SBE)7-beta-CD complex or a physical mixture of the two compounds. The compound is prepared by freeze-drying testosterone- (SBE)7-beta-CD solution (5-15%, in (SBE)7m-beta-CD). Also prepared without (SBE)7-tablets of beta-CD. They consisted of testosterone in a 1: 1 ratio with a 50: 50(w/w) mixture of fructose and lactose (Fischer Scientific, NJ). The mixture was ground in a mortar and then sieved through a 200 mesh (75 μm) screen under low humidity conditions. The mixture is stored in a desiccator when not in use. Approximately 120mg tablets were compressed in a tablet die at a pressure of 1 ton over a period of 1 minute using a Carver laboratory tablet press (Fred s. Carver inc., NJ).
Preparation of semipermeable membranes
A coating formulation was prepared by dissolving 1.0% sorbitol (Sigma, MO) in 3.7% double distilled water and 0.4% PEG 400(Sigma, MO). 2.0% cellulose acetate (CA-398-10, Eastman Chemical Co., TN) was suspended in the above solution, and then 55.7% methylene chloride and 37.2% methanol were added to the mixture. The dispersion was shaken and sonicated until the solid components were completely dissolved. The coating solution was air sprayed (airburst, Paasche) onto the stainless steel surface under a constant air flow (40 ℃). They were left at room temperature for 24 hours. The film was peeled from the surface, examined for cracks and defects with a microscope (x 70), and then measured for thickness with a micrometer (Ames, MA). The film was fixed on a dissolution tablet containing the tablet, with its surface sprayed on the steel in contact with the tablet surface.
In vitro Release Studies
The release study was performed as follows: the tablets were placed in a USP dissolution apparatus II (Vanderkamp 600, VanKel Industries Inc.) containing 900ml of water at 37 ℃ and rotating at 100 rpm. Samples were collected at each time point. The film was removed from the tablets and the drug was allowed to dissolve completely, from which 100% release was determined. Samples were analyzed by HPLC for testosterone concentration.
Testosterone HPLC detection
Testosterone was measured using a 15cm ODS Hypersil column followed by UV detection (Shimadzu scientific Instruments, Inc., Japan) at 238 nm. The mobile phase contained 60% acetonitrile and 40% double distilled water.
Example 2
Dipyridamole- (SBE)7-beta-CD delayed release formulations
Analysis program
Dipyridamole was analyzed using a 15cm ODS Hypersil column. The sample volume was 20. mu.l, and the UV detection wavelength was 285nm (Shimadzu 6A, Shimadzu, Japan). The mobile phase consisted of 70% methanol and 30% ammonium phosphate buffer (pH5.0) and was passed through the column at a flow rate of 1.5 ml/min. Detection by fluorescence analysis (SBE)7m- β -CD, 0.2ml of 1mM2, 6-toluidino-naphthalenesulfonic acid was added to 0.8ml of the sample. The solution was then excited at 325nm and the emitted fluorescence detected at 455nm using a Perkin 25 Elmer (Perkin-Elmer, CT) fluorescence detector.
Phase solubility test
Preparation (SBE) in different buffer solutions at pH 4.0-7.0 (citric acid for 4 and 5, phosphate for 6 and 7)7-beta-CD (0-0.1M) solution. Excess dipyridamole was added to 0.25ml of these solutions and equilibrated in a shaking 25 ℃ water bath for at least 24 hours (preliminary experiments showed that equilibrium solubility was reached within 24 hours). The solution was centrifuged at 2500rpm for 10 minutes. Injection with 100. mu.l airtightA 20 μ l aliquot of the supernatant was carefully sampled from the vessel (Hamilton co., NV), diluted with mobile phase and then analyzed by HPLC. The solubility data was then used to determine binding constants according to the method of Higuchi and Connors for AL-type phase characteristics.
Preparation of the physical mixture
Physical mixture dipyridamole (SIGMA, MO), (SBE)7beta-CD and citric acid (SIGMA, MO) (1: 9: 3), then ground by hand using a mortar and pestle. The milled physical mixture was sieved through a 200 mesh (75 μm) sieve. This step was repeated 2 times. The mixture is stored in a desiccator when not in use.
Description of the dissolution tablets and preparation of the tablet cores
The dissolution piece consisted of a cylindrical stainless steel center piece, a stainless steel platform, a stainless steel cover piece, two Teflon pieces (top and bottom) and a Teflon insert piece. The cylindrical central tablet has a hole (radius: 7.5mm) in the center, into which the tablet is pressed. The stainless steel cover sheet and the top Teflon sheet had the same hole in the center. The center piece is inverted and screwed to the platform. Pouring into the cylindrical hole about 120mg of a physical mixture comprising the drug, (SBE)7-beta-CD and citric acid, and then firmly placing a punch therein. The tablet cores were compressed using a Carver tablet press (Fred Carver inc., NJ) over a period of 1 minute at a pressure of 1 ton. The punch is carefully removed from the central sheet.
Film coating
Preparation of Polymer solutions
Mixing 5 wt% of EUDRAGITTMEUDRAGIT is prepared by dissolving R or S (Huls America, NJ), 5% urea (SIGMA, MO) or polyethylene glycol (PEG 3350, SIGMA, MO) and 0.75% triethyl citrate (TEC, SIGMA, MO) in 89.25% ethanolTMAnd (4) coating. The above steps were carried out until a clear solution was achieved. 5% of 5 polymers and 1% of TEC were dissolved in 94% of a solvent containing the same amounts of dichloromethane and formazanAlcohol, thereby preparing polymer solutions of cellulose acetate (CA-320S7 Eastman Chemical Co., TN) and hydroxypropylmethyl cellulose phthalate (HPMCP, Eastman Chemical Co., TN). The ratio of CA to HPMCP was varied from 50: 50 to 75: 25, but the total amount of polymer was kept at 5%. Dissolution proceeds until a clear solution is reached.
Tablet coating
The coating solution was air-sprayed directly onto the tablet surface under a constant air flow (about 70 ℃). The coated tablets were dried under the same air flow for an additional 15 minutes. The tablets were dried at room temperature for a further 16 hours. It is assumed that the thickness of the film after and before drying is different from the thickness of the tablet. The thread micrometer is caused to measure the thickness.
In vitro Release Studies
Using Eudragit L and CA: the release studies of HPMCP-coated tablets were performed as follows: the dissolution tablets were placed in a USP dissolution apparatus II (Vanderkamp 600, VanKel Industries Inc.) containing 450ml of hydrochloric acid (pH1.5, 37 ℃, 100 rpm). After 2 hours, the eluted piece was carefully removed and placed in 450ml of phosphate buffer (pH1.5, 37 ℃ C., 100rpm) to continue the elution test. Periodically, 1.5ml of sample was withdrawn and the same amount of dissolution medium was added to the dissolution vessel. For CA: HPMCP coated tablets, the film was removed from the dissolution tablets and the drug was completely dissolved, from which 100% release was determined. The release experiments for tablets coated with Eudragit were carried out analogously, first in 450ml of hydrochloric acid for 2 hours, then placed in phosphate buffer (ph6.4) for a further 5 hours, and then in phosphate buffer (ph 7.2).
0.5ml of the sample was diluted half in the mobile phase and the diluted sample was analyzed by HPLC to determine the drug concentration as described in the latter section. The remaining samples were filtered through PVDF membrane (Fischer scientific, NJ) and analyzed by fluorescence assay (SBE) as described below7-β-CD。
Examples3
Methylprednisolone- (SBE)7-beta-CD sustained release formulations
Phase solubility study
An excess of Methylprednisolone (MP) was added at 0.25ml (SBE)7-beta-CD solution, concentration range is 0.0-0.2 mol/l. The dispersion was allowed to equilibrate in a shaking water bath (100rpm, 25 ℃) for at least 24 hours. The dispersion was centrifuged at 2500rpm for 10 minutes, and 20. mu.l of the supernatant was sampled with a gas-tight 100. mu.l syringe (Hamilton Co., NV), diluted with the mobile phase, and then analyzed by HPLC for methylprednisolone concentration in the solution. For A with Higuchi and ConnorsLMethod for determining methylprednisolone- (SBE) by using type chart7-beta-CD binding constant K1∶1。
Preparation of tablet cores
methylprednisolone/(SBE) with a molar ratio of 1: 77-beta-CD to prepare tablet cores. The ratio is calculated by using a predetermined binding constant so that there is a sufficient amount of (SBE) in the tablet core7- β -CD solubilizes all methylprednisolone already present. Tablet cores were also prepared at 1: 3 and 1: 10 ratios to study methylprednisolone/(SBE)7The effect of the proportion of-CD on the release (cf. result 4). The tablet core is made of methylprednisolone- (SBE)7-beta-CD complex or a physical mixture of the two compounds. The composition is prepared by lyophilizing methylprednisolone- (SBE)7-beta-CD solution (5-15%, in (SBE)7m-beta-CD). Also prepared without (SBE)7-tablets of beta-CD. They consisted of methylprednisolone in a 1: 7 ratio with a 50: 50(w/w) mixture of fructose and lactose (Fischer Scientific, NJ). The mixture was ground in a mortar and then sieved through a 200 mesh (75 μm) screen under low humidity conditions. The mixture is stored in a desiccator when not in use. A tablet of about 150mg was compressed in a dissolution tablet using a Carver laboratory compression press (Fred s. Carver inc., NJ) at a pressure of 1 ton over a period of 1 minute.
Preparation of semipermeable membranes
A coating formulation was prepared by mixing 4.5% ethylcellulose (Ethocel Standard 10 Premium, dow chemicals, MI) and the same amount of poly (ethylene glycol) 3350(PEG 3350, Sigma, MO). To this mixture was added 0.9% PEG 400(Sigma, MO) and 90.1% absolute ethanol. The dispersion was shaken and sonicated until the solid components were completely dissolved. The coating solution was air sprayed (airburst, Paasche) onto the Teflon surface under a constant air flow (40 ℃). At the end of the spraying, the film was dried for 5 minutes at 40 ℃ under a stream of air. Then left at room temperature for 24 hours. The film was peeled from the Teflon surface, examined for cracks and defects with a microscope (X70), and then measured for thickness with a micrometer (Ames, MA). The film was fixed on a dissolution tablet containing a tablet, the surface of which sprayed on Teflon was in contact with the tablet surface.
In vitro Release Studies
The release study was performed as follows: the tablets were placed in a USP dissolution apparatus II (Vanderkamp 600, VanKel Industries Inc.) containing 350ml of water at 37 ℃ and rotating at 100 rpm. Samples were collected at each time point. The film was removed from the tablets and the drug was allowed to dissolve completely, from which 100% release was determined. Samples were analyzed by HPLC and fluorescence detection to determine methylprednisolone and (SBE), respectively7-concentration of β -CD.
Methylprednisolone HPLC detection
Methylprednisolone was measured with a 15cm ODS Hypersil column, followed by UV detection (LC-10AT, Shimadzu Scientific Instruments, Inc., Japan) AT 254 nm. The mobile phase contained 30% acetonitrile and 70% ph4.7 acetate buffer.
(SBE)7-beta-CD fluorescence detection
To 0.8ml of the sample was added 0.2ml of a 1E-3mol/l solution of 2, 6-10 toluylamino-naphthalenesulfonic acid to detect (SBE)7- β -CD. The solution was excited at 325nm and the fluorescence emitted was detected at 455nm (65040 fluorescence spectrometer, Perkin-Elmer, CT).
Example 4
The tablet comprises: (SBE)7-beta-CD and therapeutic agents
The tablets according to the invention are generally prepared as follows. Dry mix therapeutic agent and (SBE)7- β -CD for about 10 minutes. The remaining ingredients were added and the mixture was then dry mixed for about 10 minutes. The tablets were compressed to a hardness of about 8-10 Kg. The formulations according to the invention were prepared using the following exemplary formulations.
Indometacin preparation
| Composition (I) | Amount (mg) |
| 1: indometacin | 25 |
| 1：SBE7-βCD | 300 |
| 2：EMDEXTM | 160 |
| 2: polyoxy-0.4M (polyethylene oxide) | 20 |
| 2: sucrose | 55 |
| 3：PRUVTM(sodium stearyl fumarate) | 12 |
| 3: magnesium stearate | 3 |
| 3: corn starch | 25 |
| Total of | 600 |
The above ingredients were used to prepare 600mg of tablet cores having a rapid release profile. The numbers next to the ingredients indicate the order of addition. After addition of the ingredients, the mixture was dry mixed for 5-10 minutes. Addition of PRUV separately from other ingredients (step 3)TMMagnesium stearate and corn starch, and dry mixing for an additional 5 minutes in the overall procedure.
Dipyridamole formulations
| Composition (I) | Amount (mg) |
| Dipyridamole | 25 |
| 1：SBE7-βCD | 300 |
| 2: citric acid | 53 |
| 2：PEG 3350 | 25 |
| 2: glucose | 125 |
| 2：Cabosil M5P | 2 |
| 3：PRUVTM | 10 |
| 3: magnesium stearate | 5 |
| 3：Ac-Di-SolTM | 10 |
| Total of | 555 |
555mg of tablet cores having a rapid release profile were prepared using the above ingredients. The numbers next to the ingredients indicate the order of addition. After addition of the ingredients, the mixture was dry mixed for 5-10 minutes. Addition of PRUV separately from other ingredients (step 3)TMMagnesium stearate and Ac-Di-SolTMAnd dry mixing for an additional 5 minutes in the overall procedure.
Piroxicam preparation
| Composition (I) | Amount (mg) |
| 1: piroxicam | 10 |
| 1：SBE7-βCD | 77 |
| 2: sorbitol | 45 |
| 2: glucose | 50 |
| 2: citric acid | 10 |
| 2: xylitol, its preparation method and use | 47.5 |
| 2：PEG 3350 | 9 |
| 3: magnesium stearate | 1.5 |
| 3: fumed silica | 1.5 |
| 3: cross-linked sodium cellulose | 5.5 |
The above ingredients were used to prepare 500mg of tablet cores having a rapid release profile. The numbers next to the ingredients indicate the order of addition. After addition of the ingredients, the mixture was dry mixed for 5-10 minutes. Adding magnesium stearate, fumed silica (CABOSIL) separately from other ingredients (step 3)TMM5P) and croscarmellose sodium, and dry mixing for an additional 5 minutes in the overall procedure.
Diltiazem formulations
| Composition (I) | Amount (mg) |
| 1: diltiazem | 10 |
| 1：SBE7-βCD | 270 |
| 2: citric acid | 19 |
| 2：PEG 6000 | 5 |
| 2: glucose | 246 |
| 2: sorbitol | 40 |
| 3：PRUVTM | 5 |
| 3：CABOSILTM M5P | 3 |
| 3: starch glycolate | 2 |
| Total of | 600 |
The above ingredients were used to prepare 600mg of tablet cores having a rapid release profile. The numbers next to the ingredients indicate the order of addition. After addition of the ingredients, the mixture was dry mixed for 5-10 minutes. Addition of PRUV separately from other ingredients (step 3)TM、CABOSILTMM5P and sodium starch glycolate, and dry mixing for an additional 5 minutes in the overall procedure.
Warfarin formulations
| Composition (I) | Amount (mg) |
| 1: warfarin | 2 |
| 1：SBE7-βCD | 150 |
| 2：EMDEXTM | 138.5 |
| 2: sodium bicarbonate | 20 |
| 2: sodium lauryl sulfate | 2.0 |
| 3: magnesium stearate | 2.5 |
| Total of | 315 |
The above ingredients were used to prepare a tablet core having a fast release profile of 315 mg. The numbers next to the ingredients indicate the order of addition. After addition of the ingredients, the mixture was dry mixed for 5-10 minutes. Magnesium stearate was added separately from the other ingredients (step 3) and dry mixed for an additional 5 minutes in the overall procedure.
Methylprednisolone preparation: a. the
| Composition (I) | Amount (mg) |
| 1：MP | 10 |
| 1：SBE4-γCD | 200 |
| 2: xylitol, its preparation method and use | 151 |
| 2: pregelatinized starch | 150 |
| 2: sucrose | 33 |
| 3：CABOSILTM M5P | 4 |
| 3：PRUVTM | 12 |
| Total of | 560 |
The above ingredients were used to prepare 560mg of tablet cores having a fast release profile. The numbers next to the ingredients indicate the order of addition. After addition of the ingredients, the mixture was dry mixed for 5-10 minutes. Addition of PRUV separately from other ingredients (step 3)TMAnd CABOSILTMM5P, and dry mixing for an additional 5 minutes in the overall procedure.
Methylprednisolone preparation: b is
| Composition (I) | Amount (mg) |
| MP | 4 |
| Spray dried lactose monohydrate (SUPERTAB)TM，FMC Corp.) | 96 |
| Microcrystalline cellulose (CEOLUSTM, FMC Corp.) | 32 |
| Sodium stearyl fumarate (PRUV)TM，Mendell) | 2 |
| SBE7-βCD(CAPTISOLTM，Cydex，Inc.) | 116 |
| Total of | 250 |
The above formulation was prepared as follows. First, SBE reduction with mortar and pestle7- β CD particle size and then passing the powder through a 100 mesh screen. Sodium stearyl fumarate was also sieved through a 100 mesh screen prior to use. SBE7- β CD and MP were mixed together in a glass mortar. Then adding CEOLUS sequentiallyTM、SUPERTABTM、PRUVTMThe components are mixed simultaneously. Tablets each weighing 250mg were pressed by hand on a Stokes B2 press using a 7mm standard cup die. The tablets were compressed to a hardness of about 14 kp.
Indometacin tablet-gelatin capsule
| Composition (I) | Amount (mg) |
| 1: indometacin | 25 |
| 1：SBE7-βCD | 300 |
| 2：EMDEXTM | 155 |
| 2: polyoxy-0.4M (polyethylene oxide) | 20 |
| 2: sucrose | 55 |
| 3：PRUVTM(sodium stearyl fumarate) | 20 |
| 3: corn starch | 25 |
| Total of | 600 |
Using the above ingredients, 600mg hard gelatin capsules containing 3X 200mg film coated minitablets according to the invention were prepared. The uncoated mini-tablet cores have a fast release profile. The tablets were prepared as follows. The numbers next to the ingredients indicate the order of addition. After addition of the ingredients, the mixture was dry mixed for 5-10 minutes. Addition of PRUV separately from other ingredients (step 3)TMAnd corn starch, and was dry mixed for an additional 5 minutes in the overall procedure. The mixture was then divided into 3 equal parts and each part was compressed into small pieces. After coating the tablet cores with the film-forming agent according to the invention according to the following examples, the coated tablets are placedPlaced in hard gelatin capsules.
It should be noted that in several of the embodiments described above, such as the EMDENTMAnd the polyoxy-0.4M may be replaced by release controlling agents or release rate modifying agents such as HPMC, HPC, cellulose acetate butyrate, cellulose acetate propionate, cellulose propionate, carrageenan, cellulose acetate, nitrocellulose, methylcellulose, hydroxyethylcellulose, ethylcellulose, polyvinyl acetate, latex dispersions, acacia, tragacanth, guar gum, gelatin, and the like. Uncoated tablet cores having controlled or sustained release properties are thus prepared, which may optionally be further coated with a film-forming agent according to the invention to form tablets having a combination of delayed release and controlled or sustained release properties, that is to say that upon reaching a predetermined site in the gastrointestinal tract the film of the tablet becomes porous and allows the therapeutic agent to be released from the tablet cores in a controlled or sustained release manner. Sustained or controlled release tablet cores are suitable for tablets containing very water soluble film formers, very porous films, substantial amounts of osmotic or solubilizing agents, and other such conditions.
Alternative methods of preparing tablet cores include, for example, dry granulation, wet granulation, hot melt extrusion, and compression-grinding-recompression. Thus, dry granulation may involve preforming tablets or strips that contain all of the tablet ingredients in addition to the SAE-CD, grinding the preformed tablets or strips, mixing the ground material with the SAE-CD, and then recompressing the mixture to form the desired tablet.
Indometacin controlled or sustained release tablet core
| Composition (I) | Amount (mg) |
| 1: indometacin | 25 |
| 1：SBE7-βCD | 300 |
| 2：HPMC | 100 |
| 2: sucrose | 55 |
| 3：PRUVTM(sodium stearyl fumarate) | 20 |
| 3: corn starch | 25 |
| Total of | 525 |
Tablet cores of 525mg with controlled or sustained release properties were prepared using the above ingredients. The numbers next to the ingredients indicate the order of addition. After addition of the ingredients, the mixture was dry mixed for 5-10 minutes. Addition of PRUV separately from other ingredients (step 3)TMAnd corn starch, and was dry mixed for an additional 5 minutes in the overall procedure.
Prednisolone controlled release tablet core
| Composition (I) | Amount (mg) |
| Prednisolone | 15 |
| SBE7-βCD | 210 |
| HPMCK100M | 75 |
| Total of | 300 |
300mg of tablet cores having controlled release characteristics were prepared using the above ingredients. The ingredients were mixed by hand and then tablets were prepared on a Carver press under 1 ton pressure over a period of 7 seconds. Tablets were prepared using a standard cup die of 5/16 ". The release profile upon dissolution was determined according to USP method 2 at 37 ℃ in a water bath of 900ml at 100rpm (paddle). Prednisolone (PD) release was measured by HPLC and SBE was measured by TNS as described herein7-beta CD release.
Additional controlled release tablet cores are prepared according to the present invention, comprising the ingredients and corresponding amounts described below.
| Composition (I) | Amount (mg) |
| Prednisolone | 5-30 |
| SBE7-βCD | 50-210 |
| Lactose | 0-210 |
| HPMC K100M | 50-200 |
The uncoated core controlled release pharmaceutical formulation may comprise a therapeutic agent, SAE-CD, a release rate modifier, and optionally one or more other pharmaceutical excipients.
Example 5
Tablet cores prepared from the granules comprise: SBE7-beta CD and therapeutic agents
Tablets according to the invention may comprise granules and are prepared by wet granulation as follows. The percentages indicated correspond to weight percentages based on the weight of the final formulation. This example is based on 10mg of Methylprednisolone (MP). Dry mix therapeutic agent (20%) and SBE7- β CD to form a physical mixture. Lactose (40%) and glucose (8%) were wet granulated with PVP-water suspension (4%) until a 2 wt% increase was reached to form the desired granules. Sodium bicarbonate (3.5%), PRUVTM(4.5%), silicon dioxide (0.5%) and xylitol (2%) were mixed with the granulate and the physical mixture, and the final mixture was then compressed into tablets, with a hardness of about 8-10 Kg.
Example 6
Tablet film coating
The film coating of tablets according to the invention is generally prepared using the following ingredients and conditions. Film coatings are typically based on water, water/solvents and/or solvents such as alcohols. Typically, the film former is dissolved or suspended within one-half of the predetermined solution volume, and then the other ingredients are added. Further water or solvent is added as desired, thereby bringing the mixture to the final volume. The tablet cores prepared as above were coated with the resulting solution or suspension according to example 7. The coating compositions described in detail below are based on a volume of 100ml of the final solution or suspension.
EUDRAGIT
TMRS30D membrane
| Composition (I) | Quantity (g) |
| EUDRAGITTM RS 30D | 15 (dry weight) |
| Triethyl citrate (TEC) | 3 |
| Talc | 7.5 |
EUDRAGIT is obtained from the manufacturer in the form of a 30% by weight aqueous latex dispersionTMRS 30D. Mixing EUDRAGITTMRS30D (film former) was dispersed in water (50ml) while stirring, and then TEC, talc and HPMC (pore former) were added sequentially. Further water was added to bring the volume of the final solution to 100 ml. Other pore formers and film formers are commonly used.
EUDRAGIT
TMRL 100 film
| Composition (I) | Quantity (g) |
| EUDRAGITTM RL 100 | 15 (dry weight) |
| TEC | 3 |
| Talc | 7.5 |
| HPMC | 1.5 |
Mixing EUDRAGITTMRL 100 is formulated in Isopropanol (IPA). Mixing EUDRAGITTMRL 100 was dissolved in IPA (50ml) with stirring, then TEC, talc and HPC were added in that order. Further IPA was added to bring the volume of the final solution to 100 ml.
EUDRAGIT
TM RS 30D/EUDRAGIT
TMRL30D film
| Composition (I) | Quantity (g) |
| EUDRAGITTM RS 30D | 13.5 (dry weight) |
| EUDRAGITTM RL 30D | 1.5 (dry weight) |
| TEC | 3 |
| Talc | 7.5 |
| HPMC | 1.5 |
Diluting EUDRAGIT in WaterTMRL30D and EUDRAGITTMRS30D while stirring, then TEC, talc and HPC were added in order. Further water is added to adjust the final volume to the desired value. EUDRAGITTMRL30D functions to enhance EUDRAGITTMWater permeability of the film.
Cellulose ethyl film
| Composition (I) | Quantity (g) |
| Ethyl cellulose | 15 (dry weight) |
| Dibutyl sebacate | 4.5 |
| Talc | 8.0 |
| HPMC E5 | 1.5 |
Ethyl cellulose was dissolved in isopropanol while stirring, and then TEC, talc and HPMC E5 were added in order. Further isopropanol was added to adjust the final volume to the desired value. The same procedure was performed using HPC instead of HPMC E5.
Cellulose acetate membranes
| Composition (I) | Quantity (g) |
| Cellulose acetate | 12 (dry weight) |
| TEC | 5 |
| Talc | 7.5 |
| Lactose | 1.5 |
Cellulose acetate was placed in isopropanol while stirring, and then TEC, talc and lactose were added in order. Further solvent is added to adjust the final volume to the desired value. In using the film formulation, it may be necessary to run the Hi-Coater at a temperature of 45 ℃ or higher.
EUDRAGIT
TMRS30D and EUDRAGIT
TML100 film
| Composition (I) | Quantity (g) |
| EUDRAGITTM RS 30D | 15 (dry weight) |
| Micronized EUDRAGITTM L 100 | 1 (dry weight) |
| Triethyl citrate (TEC) | 3 |
| Talc | 7.5 |
Adding TEC and talc in EUDRAGITTMRS30D dispersion, with stirring. Adding micronized EUDRAGIT under stirringTML100, and then further water was added to adjust the volume of the dispersion to a desired value. Other film formers such as cellulose acetate and HPMCP may typically be used in these combined film formulations.
EUDRAGIT
TML100 film
| Composition (I) | Quantity (g) |
| EUDRAGITTM L 100 | 15 (dry weight) |
| Triethyl citrate (TEC) | 3 |
| Talc | 7.5 |
Mixing EUDRAGITTML100 was dissolved or suspended in isopropanol or water, respectively, while stirring, and then TEC and talc were added in order. Further solvent or water is added to adjust the final volume to the desired value. In some embodiments, the film may be used to form enteric-release tablets or to coat tablets that have been coated with other film coatings of the present invention. The resulting tablets allow the therapeutic agent to be released from the tablet core in a delayed controlled or sustained release manner.
EUDRA GIT
TMRS30D and EUDRAGIT
TMRL30D film
| Composition (I) | Quantity (g) |
| EUDRAGITTM RS 30D | 15.0 (dry weight) |
| EUDRAGITTM RL 30D | 1.67 (dry weight) |
| Plasticizer (triethyl citrate) | 2.8 |
| Antiblocking agents (glyceryl monostearate, Imwittor)TM 900) | 1.5 |
| Deionized water | q.s. |
Mixing water, triethyl citrate and Imwittor in a beakerTM900 to form a dispersion, the dispersion being made up of PowergenTMThe mixer was homogenized until the temperature was below 35 ℃. The dispersion was sieved through a 60 mesh screen, recovered and stirred until the temperature was below 30 ℃. Including EUDRAGITTMRS30D (30% by weight aqueous dispersion) and EUDRAGITTMEUDRAGIT OF RL30D (30% by weight aqueous Dispersion)TMThe dispersion was passed through a 60 mesh screen, then mixed with the first dispersion and equilibrated for 30 minutes before spraying the final dispersion on the tablet cores. This particular formulation provides a semipermeable membrane that does not contain a pore-forming agent.
EUDRAGIT
TMRS30D and EUDRAGIT
TMRL30D film
| Composition (I) | Amount (wt%) |
| EUDRAGITTM RS 30D | 40 |
| EUDRAGITTM RL 30D | 3 |
| Plasticizer (triethyl citrate) | 2.5 |
| Talc | 6 |
| Deionized water | Balance to 100 |
The film formulation does not contain a pore former, yet allows moisture to penetrate into the tablet core. The dispersion was plasticized with TEC for 1 hour before spraying on the tablet cores.
AQUACOAT
TMFilm formulations
| Composition (I) | Amount (wt%) |
| AQUACOATTM ECD | 50 |
| Dibutyl sebacate (DBS) | 3 |
| Water (W) | Balance to 100 |
These dispersions were plasticized with DBS for at least 8 hours prior to spraying on the tablet cores
Other ethylcellulose dispersions such as SURELEASETMThe product (Colorcon) is also a suitable film coating for controlled release.
Example 7
Coating tablet cores with film-forming agents
Film coated tablets are generally prepared as follows. Other identical conditions and equipment can generally be used to prepare the present formulations, as known to those skilled in the art.
Vector Hi-Coater (perforated tablet coating pan) was used under the following conditions:
inlet temperature: 45-75 deg.C
Outlet temperature: 28-38 deg.C
Injection speed: 2-3g/min
Loading tablets: 300g
Rotating speed: 20rpm
After preparation of the solution or suspension comprising the film former and the other ingredients (according to example 6), the tablet cores were placed in a Hi-Coater and then film-coated until a film thickness of 100-125 μm was achieved. The coated tablets were dried overnight at about 40 ℃. Tablet thickness and film composition were varied as needed. The process is generally applied to water or solvent based film coating compositions.
Example 8
Multilayer tablet
Bilayer and multilayer tablets containing drug and SBE in a sustained release matrix composition are prepared on a Stoke's D tablet press or similar equipment7-physical mixtures of β -CD and preformed complexes.
The method A comprises the following steps: bilayer tablet
Preparation of a pharmaceutical composition comprising indomethacin and SBE according to example 47-physical mixtures of β -CD and immediate release layers of complexes. Specifically, 240mg of granules containing 10mg of indomethacin were compressed in a Stoke's D tabletting machine to form an immediate release layer.
Mixing the following ingredients, thereby producing a controlled release layer, whereinIndomethacin and cyclodextrin are present in the form of a physical mixture:
| indometacin | 15mg |
| SBE7-β-CD | 180mg |
| HPMC K15M | 80mg |
| Spray-dried lactose | 85mg |
| MCC PH101 | 48mg |
| Magnesium stearate | 2mg |
Mixing indomethacin and SBE7- β -CD was mixed into a physical mixture and then added in HPMC, spray dried lactose and MCC and mixed in a double shell mixer for 15 minutes. Magnesium stearate was added to the powder and mixed for an additional 5 minutes. The mixture was pressed onto the immediate release layer described above. Tablets weighing about 650mg were compressed to a hardness of about 10 kg. The tablets are then coated with a readily water soluble polymer such as HPMC E5 or an enteric or controlled release coating.
The method B comprises the following steps: three-layer tablet
Made as described abovePreparing a first immediate release composition, but reacting indomethacin with SBE using known conditions7-beta-CD complexing to form a drug/SAE-CD complex, which is included in the immediate release composition instead of the corresponding physical mixture. The first immediate release composition is compressed into a first immediate release layer. The controlled release composition was prepared as described in method a and then pressed on one side of the first immediate release layer to form the controlled release layer. The second immediate release composition is prepared according to the method used to prepare the first immediate release composition. A second immediate release composition is then compressed onto the side of the controlled release layer opposite the first immediate release layer. In this exemplary embodiment, the indomethacin is distributed between the three layers of the formulation as follows: the amount in the first and second immediate release layers was 25 wt%, while the remaining 50 wt% of the drug was present in the controlled release layer. The tablets may then be coated with a readily water soluble polymer such as HPMC E5 or an enteric or controlled release coating.
Example 9
Tablet comprising a controlled release core and a compression coating
As described in the examples above, tablet cores comprising a physical mixture of indomethacin and cyclodextrin in the presence of HPMC K15M and other excipients can be compressed into sustained release matrix tablets. Immediate release granules comprising preformed complexes may be compressed onto the extended release core using a suitable tablet press known to those skilled in the art. The granules in the press coating disintegrate rapidly and the preformed complex is released into the dissolution medium or gastrointestinal fluids to rapidly dissolve the indomethacin. The tablet core coated with the physical mixture slowly erodes and hydrates, which promotes the formation of the drug-cyclodextrin complex and controls the release of the complex to the surrounding environment.
Example 10
Granules produced by melt technology
Granules comprising a physical mixture of drug, cyclodextrin, hydrophilic polymer, and other functional excipients can be prepared by melt granulation or hot melt granulation. A physical mixture was prepared from the following ingredients:
| diltiazem | 10mg |
| SBE7-β-CD | 270mg |
| Citric acid | 19mg |
| PEG 6000 | 42mg |
| HPMC K15M | 50mg |
| Total of | 400mg |
The material was melt granulated by passing through an extruder at 60 ℃ or at the same temperature to form granules having a particle size that passed through a #20 mesh screen, and then mixed with 75mg of MCC PH101, 10mg of magnesium stearate and 15mg of talc to produce tablets weighing 500 mg. These tablets containing the drug in physical admixture will hydrate in the dissolution medium or in the gastrointestinal tract to slowly release diltiazem by diffusion and erosion mechanisms.
Example 11
Osmotic pump for diffusively and osmotically controlled release of a drug
For the preparation of the cores, Carver was usedTMLaboratory press with 6.35mm flat punch at 1 ton/cm2Pressing TS and (SBE) within 60 seconds under pressure of (1)7m-beta-CD, HP-beta-CD or a physical mixture of sugars (1: 1 physical mixture of lactose and fructose). TS and (SBE) in physical mixture7mThe molar ratio of-beta-CD is 1: 1 to 1: 1.43, and the molar ratio of-beta-CD to HP-beta-CD in the physical mixture is 1: 1 to 1: 1.79. Physical mixtures of TS with β -CD derivatives or sugars were prepared using a mortar and pestle. The compressed tablet core is placed in a tablet die as described above.
A semipermeable membrane was prepared by mixing 59.3% cellulose acetate, 29.6% sorbitol, and 11.1% PEG or talc in methylene chloride/methanol/water (3/2/0.2 weight ratio). The final solids concentration in the solution was 3.34% w/w. The film was repeatedly produced by film coating using an air brush at a jet rate of 1.7g/min on the basis of an osmotic pump apparatus while drying with hot air blown from a dryer fixed at 30cm above the die. The membrane was peeled from the basal surface of the osmotic pump device and then placed on the release side of the device. TEFLON for the filmTMThe seal and stainless steel gasket are fixed in place.
Dissolution and release rates in TS from tablet cores (no membrane) or osmotic pump units (tablet cores covered with semi-permeable membrane) were measured according to the paddle (paddle) method using a USP apparatus. The dissolution medium is 900ml of distilled water or various potassium chloride solutions (37 ℃ C.), and the stirring speed of the paddle is 0-100 rpm. The device is placed in a container with the release side facing upwards. Bulk solution TS samples were analyzed by HPLC methods described in previous phase solubility studies.
The release of the osmotic pump agent was measured. Osmotic pumps (SBE)7mThe amounts of-CD, HP- β -CD and sugar released from OPT were calculated by the weight difference between the total and residual amounts released at each sampling time in the study. The weight of the remaining ingredients at each sampling time was testosterone quantified by HPLC, while the sorbitol and PEG contents were determined from those without osmotic agentOsmotic pumps were measured gravimetrically. The weight of released penetrant is the residual weight after evaporation at 60 ℃ and vacuum drying of 200ml solution samples for 12 hours. Because of the very high water solubility, it is assumed that sorbitol and PEG are released from the membrane of the osmotic pump immediately and completely upon entering the test solution.
The foregoing is a detailed description of specific embodiments of the invention. In light of the present disclosure, those skilled in the art will recognize that obvious modifications may be made to the embodiments disclosed herein without departing from the spirit and scope of the present invention. All of the embodiments disclosed and claimed herein can be made using appropriate experimentation in light of the present disclosure. The scope of the invention is defined by the following claims and their equivalents. Accordingly, the claims and specification should not be construed to unduly narrow the scope of the present invention.