Pharmaceutical composition, use and preparation method thereofThis application is a divisional application entitled "pharmaceutical composition" on day 2003, 21/4, application No. 03814236.8.
Technical Field
The present invention relates to a composition useful for the delivery of androgens. More particularly, the invention relates to a pharmaceutical composition comprising an androgen and an enhancer, i.e., a substance that increases the rate at which the androgen permeates through the membrane.
Background
Androgens include, for example, 17 β -hydroxyandrost-4-en-3-one, commonly referred to as testosterone, and Dihydrotestosterone (DHT), a metabolite of testosterone. Testosterone is a naturally occurring androgen that is secreted by men and, to a much lesser extent, by women. In males, testosterone and DHT are responsible for normal growth and development of the male sex organs and maintenance of secondary sex characteristics. In women, testosterone and DHT are believed to play an important role in normal growth, sexual desire and sexual function. In addition, androgens promote the retention of nitrogen, sodium, potassium and phosphorus, and reduce urinary excretion of calcium. Androgens have also been reported to increase protein anabolism, decrease protein catabolism, and stimulate red blood cell production.
In serum, testosterone exists predominantly in a form bound to a protein (usually albumin or sex hormone binding protein). Unbound testosterone is called "detached testosterone" (FT). The term "total testosterone" (T) refers to the total amount of testosterone in the serum, i.e., the sum of protein-bound testosterone and free testosterone. The typical half-life of testosterone in serum is from 10 to 100 minutes.
Androgens such as testosterone and DHT bind to androgen receptors on cells. The resulting androgen-receptor complex regulates gonadotropin secretion and spermatogenesis. The androgen-receptor complex is also responsible for external virilization and sexual maturity and adulthood and most androgen actions. DHT is a particularly potent androgen because it has a greater affinity for the androgen receptor than testosterone.
Testosterone production is stimulated by Luteinizing Hormone (LH). It is believed that Follicle Stimulating Hormone (FSH) also stimulates testosterone production. The concentration of testosterone in the serum is regulated, in part, by a negative feedback pathway in which testosterone inhibits the formation and/or secretion of luteinizing hormone-releasing hormone (LHRH). LHRH stimulates the secretion of LH by the pituitary gland. Testosterone also acts by regulating the sensitivity of the pituitary gland to LHRH.
Male hypogonadism is a disorder in males that is caused by or characterized by an abnormal reduction in sexual gland function. Male hypogonadism is manifested by lower than normal concentrations of testosterone in the serum. The U.S. Federal food and drug administration estimates that about 4 to 5 million Americans have male hypogonadism, with about 5 of every 1000 men affected by male hypogonadism. It is believed that in men over the age of 50, 1 in every 5 is affected by male hypogonadism. Primary male hypogonadism is caused by testicular degeneration, and secondary male hypogonadism is due to spontaneous gonadotropin, LHRH deficiency, or pituitary hypothalamic injury. Other various causes of male hypogonadism include, for example, a decrease in the number of leydig cells in the testes due to aging, and primary organ etiology. Symptoms associated with male hypogonadism include decreased libido with or without impotence, depression, decreased libido, fatigue and loss of energy, erectile dysfunction, depressed mood, osteoporosis, decreased lean body mass, decreased muscle mass, decreased bone density and regression of secondary characteristics.
Women with lower than average androgen concentrations in the serum also suffer from conditions associated with androgen deficiency. Causes of androgen deficiency in women include aging, ovariectomy, and ovarian failure. Symptoms associated with androgen deficiency in women include female sexual dysfunction, loss of libido, and muscle wasting.
The normal concentration of androgen in the serum can be achieved by administering exogenous androgen to the patient. There is a large body of literature reporting the maintenance or restoration of male secondary sexual characteristics, sexual behavior, energy, mood and muscle development, as well as a reduction in the percentage of fat in body composition and an improvement in bone density, with exogenous androgen administration.
Various methods of administering exogenous androgens have been established. Preferably, these methods should not only increase the concentration of androgen in the serum, but also, due to the short half-life of androgen, they should allow for the normalization of androgen release into the serum over a longer period of time, thereby maintaining an effective concentration of androgen in the serum for an appropriate period of time and avoiding adverse effects that may result from sudden increases and decreases in androgen concentration in the serum. In addition, it is desirable that these methods produce little or no deleterious effects, such as irritation, injury to the human body, and pain.
Oral delivery of exogenous androgens has been used to treat hypogonadism. However, androgen released orally is first absorbed from the gastrointestinal tract. This absorption is irregular and therefore often results in sudden increases and decreases in androgen concentration in the serum. In addition, androgens absorbed via the gastrointestinal tract enter the portal circulation and are rapidly degraded by the liver. Only a relatively small amount of androgen enters the systemic circulation. Androgens may also produce deleterious effects through the portal circulation system and the liver.
Exogenous androgens may also be released directly into the systemic circulation in an parenteral manner. This release allows androgen to enter the systemic circulation directly, avoiding the gastrointestinal tract and liver. However, the androgen released parenterally is rapidly absorbed into the serum by a syringe, thereby making it difficult to achieve a sustained release of androgen and causing a sudden increase in the concentration of androgen in the serum, followed by a gradual decrease. The use of esterified forms of androgens can slow the rate of androgen absorption. Esterified forms of androgens are more soluble than non-esterified forms in the fatty carrier liquids commonly used for parenteral delivery. However, this esterified form of androgen is rapidly de-esterified in serum, making it difficult to maintain a sustained release of androgen. Furthermore, the uptake of androgen from the syringe is irregular, resulting in sudden fluctuations in androgen concentration in the serum. Furthermore, parenteral delivery is uncomfortable, causing problems of patient compliance.
Transdermal delivery of androgens avoids many of the disadvantages of oral and parenteral delivery. Such administration is relatively painless, allowing the androgen to enter the systemic circulation without having to first pass through the gastrointestinal tract and the liver.
One method of transdermally delivering androgen involves the use of a transdermal patch that is adhered to the skin of a patient and contains a reservoir of androgen that is absorbed by the skin. However, such patches are irritating to the skin, often painful to remove, and prone to dislocation. In addition, such patches are unsightly, are noticeable when left uncovered, are large and bulky, and may leave a discolored area of skin after removal. Furthermore, the compositions contained in such patches are often irritating to the skin.
Another method of transdermal androgen delivery involves applying an androgen-containing composition directly to the skin in the form of a gel. Such gels are referred to herein as "topical gels" to distinguish them from other compositions in the form of gels contained in articles applied to the skin (e.g., transdermal patches).
The present invention relates to the provision of an improved androgen-containing composition which can be applied directly to the skin for sustained delivery of androgen to an individual in need thereof.
Reported progress
Androgen-containing compositions have been developed in the form of topical gels for direct application to the skin, e.g., the back, shoulders, upper arms, abdomen or thighs. The use of such topical gels overcomes the adverse effects of the previously described patches and the previously described adverse pharmacokinetic effects of oral and parenteral androgen administration. In addition, because such topical gels generally contact a larger area of skin than patches, and the skin acts as an appropriate reservoir for the androgen released, sustained normalization of androgen release into serum can be achieved over a longer period of time.
The ability of an androgen gel to effectively release androgen often depends on whether and what enhancer, i.e., a substance that accelerates the rate at which androgen passes through the skin or other body membrane, is used. Examples of topical androgen gels include those described in U.S. Pat. No. 5,968,919 to Samour et al and U.S. Pat. No. 6,503,894 to Dudley et al. U.S. Pat. No. 5,968,919 describes a topical testosterone gel which also contains a dioxolane or dioxane compound which acts as an enhancer. Topical testosterone gel described in U.S. Pat. No. 6,503,894 (available as Solvay Pharmaceuticals, Inc., Marietta, Georgia, U.S. ASold) also contains an enhancer, i.e., isopropyl myristate.
Disadvantages of the topical androgen gels described above include, for example, variable gel and lack of emollient properties; their use results in dry skin and skin irritation. In addition, patent No. 6,503,894 is capable of delivering relatively small amounts of testosterone across the skin, while patent No. 5,968,919 contains an enhancer which can irritate the skin.
Disclosure of Invention
According to the present invention, there is provided a pharmaceutical composition comprising: (A) an androgen; (B) cyclic enhancers of the type described in U.S. Pat. No. 5,023,252 to Hsieh (assigned to the same assignee as the present invention); and (C) a thickener. The composition is in its preferred form in the form of a gel, containing a cyclic ester or ketone enhancer.
Another aspect of the present invention is a unit dose formulation capable of being administered into the blood stream of a male patientSupplying testosterone transdermally such that after one unit dose is administered to a patient, the amount of circulating testosterone (AUC) in the patient's serum is within a period of 24 hours after administration0-24) The amount of circulating testosterone (AUC) reached in the serum of the patient during the same 24-hour period as when the drug was not administered0-24) By contrast, about 100 ng.h/dL, the unit dose contains up to about 1% by weight testosterone, about 0.01 to 25% by weight of a cyclic enhancer of the type described in U.S. Pat. No. 5,023,252(Hsieh), and about 0.1 to 10% by weight thickening agent, the testosterone being present in the unit dose in an amount of about 1 to 300 mg.
Another aspect of the invention is a unit dose formulation capable of transdermally supplying testosterone to the blood of a female patient such that after one unit dose is administered to the patient, the amount of circulating testosterone (AUC) in the blood serum of the patient is within a period of 24 hours after administration0-24) The amount of circulating testosterone (AUC) reached in the serum of the patient during the same 24-hour period as when the drug was not administered0-24) By contrast, about 0.10 to about 11,700ng.h/dL, the unit dose containing up to about 1% by weight testosterone, about 0.01 to about 25% by weight of a cyclic enhancer of the type described in U.S. Pat. No. 5,023,252(Hsieh), and about 0.1 to about 10% by weight thickening agent, the testosterone being present in the unit dose in an amount of about 0.01 to about 100 mg.
Another aspect of the invention is a unit dose formulation capable of transdermally supplying dihydrotestosterone to the blood of a male patient such that after one unit dose is administered to the patient, the amount of circulating dihydrotestosterone (AUC) in the serum of the patient is within a period of 24 hours after administration0-24) The amount of circulating dihydrotestosterone (AUC) reached in the serum of the patient during the same 24-hour period as when the drug was not administered0-24) By contrast, about 11,625-465,000pg.h/mL, the unit dose contains up to about 1% by weight dihydrotestosterone, about 0.01-25% by weight of a cyclic enhancer of the type described in U.S. Pat. No. 5,023,252(Hsieh), and about 0.1-10% by weight of a thickening agent, the dihydrotestosterone being present in the unit dose in an amount of about 5-200 mg.
Another aspect of the present invention is a unit dose formulation capable of transdermally supplying dihydrotestosterone to the blood of a female patient such that the mean concentration of dihydrotestosterone (AUC) in the serum of the patient is achieved within a period of 24 hours after administration of one unit dose to the patient0-24) Mean dihydrotestosterone concentration (AUC) achieved in serum over the same 24-hour period as patients without drug administration0-24) By comparison, about 11.6 to 232,500pg.h/mL, and the unit dose contains up to about 1% by weight of dihydrotestosterone, about 0.01 to 25% by weight of a cyclic enhancer of the type described in U.S. Pat. No. 5,023,252(Hsieh), and about 0.1 to 10% by weight of a thickening agent, the dihydrotestosterone being present in the unit dose in an amount of about 0.005 to about 100 mg.
In a further aspect of the invention, there is provided a method of treating a condition in a patient comprising the step of delivering to the patient a composition comprising an androgen, a cyclic enhancer of the type described in U.S. Pat. No. 5,023,252(Hsieh), and a thickening agent.
In a further aspect of the invention there is provided a method for treating a condition in a patient, comprising the step of administering once daily to the shoulder or upper arm of the patient a unit dose formulation capable of supplying testosterone transdermally to the blood of the patient such that after one unit dose is administered to the patient the amount of circulating testosterone (AUC) in the patient's serum is reached over a period of 24 hours after administration0-24) The amount of circulating testosterone (AUC) reached in the serum of a patient within the same 24-hour period as that of the non-administered drug0-24) By contrast, about 100 ng.000 ng.h/dL, the unit dose contains up to about 1% by weight testosterone, about 0.01 to 25% by weight of a cyclic enhancer of the type described in U.S. Pat. No. 5,023,252, and about 0.1 to 10% by weight thickening agent, the testosterone being present in the unit dose in an amount of about 1 to 300 mg.
Another aspect of the invention is a method of preparing a composition for treating a condition in a patient, wherein the step comprises mixing an androgen, a cyclic enhancer of the type described in U.S. patent No. 5,023,252(Hsieh), and a thickening agent.
Detailed Description
The compositions of the present invention contain an androgen. The term "androgen" as used herein refers to: testosterone, Dihydrotestosterone (DHT), and precursors, analogs, salts, complexes and analogs of testosterone and DHT. Examples of precursors of testosterone and DHT include, for example, DHEA, pregnenolone, progesterone, 17-OH-progesterone, and androsterone. Analogues of testosterone and DHT include: testosterone esters comprising C with straight and branched bonds1-18Alkyl esters (referred to herein as "simple alkyl esters"), e.g., testosterone enanthate, testosterone propionate, testosterone undecanoate, and testosterone enanthate, and cycloaliphatic esters, e.g., testosterone cypionate, testosterone cyclopentyl alkyl ester, and testosterone cyclohexyl alkyl ester; and analogous esters of DHT.
The androgen is present in the composition at a pharmaceutically effective concentration. Generally, the androgen is applied in an amount of about 0.01 to about 15%, more typically about 0.01 to about 10%, and most typically about 0.1 to about 5% by weight of the composition for most applications.
The compositions of the invention also contain an enhancer, i.e., a compound that increases the rate at which an androgen can pass through body membranes (e.g., skin and mucous membranes). The enhancer of the invention is a compound of the formula:
wherein X and Y are oxygen, sulfur or of the structure
Or is an imino group of ═ N-R; provided that when Y is imino, X is imino, and when Y is sulfur, X is sulfur or imino; a is a group of the structure
Wherein X and Y are as defined above; m and n are integers from 1 to 20 and the sum of m + n is not more than 25; p is an integer of 0 or 1; q is an integer of 0 or 1; r is an integer of 0 or 1; each R, R1、R2、R3、R4、R5And R6Independently hydrogen or a linear or branched alkyl group having 1 to 6 carbon atoms, however, R1To R6Only one of which may be alkyl; provided that when p, q and r are 0 and Y is oxygen, then m + n is at least 11; with the further proviso that when x is imino, q is equal to 1, Y is oxygen, and p and r are 0, then m + n is at least 11.
Enhancers of the above formula are referred to herein as "Hsieh enhancers" and are described in the above-mentioned U.S. Pat. No. 5,023,252. These enhancers are lipophilic and "membrane compatible", meaning that they do not cause damage to the membrane to which the composition of the invention is applied (hereinafter referred to as the "target membrane"). These enhancers also produce no or only low levels of irritation to the target membrane and actually act as emollients.
Preferred Hsieh enhancers for use in the present invention are macrocyclic enhancers. As used herein, the term "macrocyclic" refers to cyclic compounds having at least 12 carbons in the ring. Examples of macrocyclic enhancers preferred for use in the present invention include: (A) macrocyclic ketones, for example, 3-methylcyclopentadecanone (muscone), 9-cyclopentadecen-1-one (civetone), cyclohexadecanone, and cyclopentadecanone (normuscone); and (B) macrocyclic esters, for example, pentadecanolides, such as oxacyclohexadecan-2-one (cyclopentadecanolide; omega-pentadecanolide).
Oxacyclohexadecan-2-one and cyclopentadecanolide are particularly preferred. In human clinical trials it was found that when the composition of the invention containing oxacyclohexadecan-2-one is applied to a target membrane, only 2-4% of patients develop problems (e.g. erythema) at the site of application.
The enhancer is present in the composition at a concentration that enhances penetration of the membrane by the androgen to be delivered. Various factors should be considered in determining the amount of enhancing agent to be used. These factors include, for example, the flux to be achieved (rate of passage through the membrane) and the stability and compatibility of the components in the formulation. Generally, the amount of enhancer employed in most applications is from about 0.01% to about 25% by weight of the composition, more usually from about 0.1% to about 15% by weight of the composition, and most usually from about 0.5% to about 15%.
The compositions of the present invention also contain a thickening agent for increasing the viscosity of the composition. The increase in viscosity slows the flow of the composition, which can improve surface adhesion. The increase in viscosity also retards the movement of the particles dispersed in the composition, allowing the compound dispersed therein to remain suspended for an extended period of time. Generally, applications containing testosterone or a precursor, analog, salt, complex or analog thereof use gels having a viscosity of about 500-. Applications containing DHT or its analogs, salts, complexes or analogs employ gels having viscosities of about 1,000-.
Essentially any suitable thickener or mixture of thickeners can be used in the practice of the present invention. Preferred thickeners are characterized by at least one of the following properties: low or no irritation to the target membrane, bioadhesive, is listed in the National Formulary or the united states pharmacopeia. Preferred sources of thickeners are those that do not contain any residual components (e.g., benzene and toluene) that can damage the membrane. Furthermore, preferred thickeners are synthetic rather than derived from natural sources in order to reduce the risk of harmful impurities.
As mentioned above, preferred thickeners for use in the present invention include thickeners that are non-irritating or less irritating to the target membrane. Examples of such thickeners include: cellulose-based thickeners, such as cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and hydroxypropyl methyl cellulose; and an acrylic thickener. An example of a preferred acrylic thickener is carbomer, e.g., a non-linear polymer of acrylic acid crosslinked with a polyalkenyl polyether. Preferred examples of carbomers useful in the present invention include carboxypolymethylene, carboxyvinyl polymers and alkyl acrylates, such as acrylic acid/alkyl methacrylate copolymers. The above materials are all available from Noveon, with carboxypolymethylene as the CarbopolCommercially available carboxyvinyl polymers as CarbopolSold as Pemulen TR-And (5) selling. Additional information regarding the above carbomers is provided in the NO-veon publications TDS-57, 60, 61, 93, 94, 103, 114, 117, 118, 124, 164, 232-3, 237, 244 and TOX-001. In addition, in the absence of acrylic acid/alkyl methacrylate copolymer (Pemulen TR-) In the composition as the main thickener, it is preferably present as a co-thickener because the acrylic acid/alkyl methacrylate copolymer gives the composition a smoother feel than a composition without the acrylic acid/alkyl methacrylate copolymer and also acts as an emollient.
The thickener is present in the composition in a concentration that results in the composition having the desired viscosity value. In general, most applications employ the thickening agent in an amount of about 0.1 to about 10%, more usually about 1 to about 6% by weight of the composition.
The compositions of the present invention may also contain a carrier capable of solubilizing one or more of the components that make up the compositions of the present invention. Essentially any suitable carrier or mixture of carriers that is a suitable excipient for the compositions of the invention can be used in the practice of the invention. Preferred carriers are characterized by at least one of the following properties: no or low irritation to the target membrane; listed in the U.S. formulary or U.S. pharmacopeia; can improve the penetration of androgen to membrane; can perform other functions in the composition, such as functions as emollients, humectants, plasticizers, lubricants and/or protein stabilizers.
Essentially any solvent that dissolves at least one compound of the composition of the present invention can be used. Alcohols are the preferred primary solvents for use in the present invention because they are capable of dissolving the active compound and the thickener and act as swelling thickeners in compositions using carbomers as the thickener. It is believed that alcohols may also enhance the penetration of androgens through membranes. Examples of preferred alcohols are lower alkanols, such as ethanol and isopropanol, as they evaporate rapidly, thereby ensuring adequate permeation of the androgen through the target membrane.
Preferred co-solvents include glycerol, propylene glycol, polyethylene, polypropylene and polysiloxanes. In addition to functioning as a co-solvent, glycerin also functions as a humectant, emollient, plasticizer to plasticize the stratum corneum of the skin, and penetration enhancer, and propylene glycol functions as an emollient and penetration enhancer.
The carrier is present in the composition at a concentration such that it acts as a suitable excipient for the composition of the invention. Generally, the carrier is used in most applications in an amount of about 40-98% by weight of the composition, more usually about 50-98% by weight of the composition.
In a preferred form, the lower alkanol is used in the application in an amount of at least about 40% by weight of the composition, typically about 40-80%, more typically about 50-75% by weight of the composition, and most typically about 60-75% by weight of the composition.
Where a greater flux of a compound is desired, it may be designed such that a first fluid in the carrier which is miscible with or dissolves the compound of interest evaporates more rapidly than a second fluid which is immiscible or partially miscible with or does not dissolve the compound of interest. In this case, when the first fluid evaporates, the compound of interest remains in a supersaturated environment, which facilitates its entry into a less saturated environment, i.e. permeation through the membrane. For example, oxacyclohexadecan-2-one is miscible with ethanol, but only partially miscible with propylene glycol and immiscible with water. Thus, if it is desired to increase the flux of oxacyclohexadecan-2-one, the carrier may comprise ethanol and propylene glycol and/or water. As another example, testosterone is soluble in ethanol, but insoluble in water, and partially soluble in propylene glycol. Thus, if it is desired to increase testosterone flux, the carrier may comprise ethanol and water or ethanol and propylene glycol. In addition, water may be used to prevent "back-flow", or the flow of water from the membrane into the matrix of the composition.
The compositions of the present invention may also contain a crystallization inhibitor which inhibits the crystallization of androgens. Essentially any suitable crystallization inhibitor or mixture of inhibitors can be used in the practice of the present invention. Preferred crystallization inhibitors work by lowering the crystallization temperature of the androgen. An example of such a crystallization inhibitor is polyethylene glycol 1000.
The crystallization inhibitor is present in the composition in a concentration effective to inhibit crystallization of the androgen. In general, it is believed that most applications containing a crystallization inhibitor will employ the crystallization inhibitor in an amount of from about 0.001% to about 5% by weight of the composition, more typically from about 0.01% to about 2% by weight of the composition, and most typically from about 0.1% to about 1% by weight of the composition.
The compositions of the present invention may also contain a preservative to prevent oxidation, microbial growth or contamination of the components of the composition. Essentially any suitable preservative or mixture of preservatives can be used in the present invention. Preferred preservatives include: food additive biocides, for example, quaternary ammonium salts, sorbic acid, acetic acid, and benzoic acid or salts thereof; and antioxidants, for example, vitamin C, vitamin E, Butylated Hydroxyanisole (BHA) and Butylated Hydroxytoluene (BHT). Examples of preferred antimicrobial preservatives include benzalkonium chloride and cetylpyridinium chloride.
The preservative is present in the composition at a concentration capable of inhibiting microbial growth, oxidation of a component of the composition, or contamination of the composition. In general, most applications containing a preservative will employ the preservative in an amount of from about 0.0001% to about 1.0% by weight of the composition, more typically from about 0.005% to about 0.1% by weight of the composition.
Neutralization may be required in compositions using thickeners in order to achieve the desired thickening of the composition, and a neutralizing agent may be included in the composition. Carbomers, which are acidic molecules, need to be neutralized to a pH between 3 and 9 to reach their maximum viscosity. Essentially any suitable neutralizing agent or mixture of neutralizing agents can be used in the practice of the present invention. Preferred neutralizing agents are characterized by having at least one of the following properties: a pKa of greater than about 9, with a pKa of greater than about 9.5 being particularly preferred; are pharmacopoeia documented and approved by governmental agencies for use in pharmaceutical formulations. Examples of the neutralizing agent showing the above two properties include triethanolamine, tromethamine, triethylamine, 2-amino-2-methyl-1-propanol, sodium hydroxide, ammonium hydroxide and potassium hydroxide.
The choice of neutralizing agent for use in the present application should be made taking into account the thickening agent used. When a solvent is used, the choice of neutralizing agent should take into account the primary solvent used in the composition and the concentration of the primary solvent in the composition. If an unsuitable neutralizing agent is used, the thickener may precipitate out of solution. Noveon publication TRS-237 provides a chart listing neutralizing agents suitable for compositions containing concentrations of alcoholic solvents.
The neutralizing agent is present in the composition in a concentration that results in the composition having the desired viscosity. Generally, most applications containing a neutralizing agent employ the neutralizing agent in an amount sufficient to provide a composition having a pH of about 3 to 9, more typically about 4 to 8.
The compositions of the present invention may also contain other optional technically recognized components in technically recognized amounts. For example, substances may be added that adjust rheological properties, feel, slip, stability, wettability, fragrance, and other physical properties that may be desired by a practitioner. Additionally, buffers may be added to maintain the composition at a certain pH.
The compositions of the present invention may be presented in various forms, for example, as a gel, cream, lotion, ointment, or thickened solution. Preferably in the form of a gel.
In a preferred form, the composition is in the form of a homogeneous gel that is capable of remaining in a homogeneous state for the duration of the drug's useful life.
The compositions of the present invention preferably have a good yield value. The yield value measures the resistance of the composition to rupture under stress, for example when rubbed on the skin. The composition should also preferably be capable of sustained normalized release of the androgen into the blood stream for an extended period of time. Other preferred properties of the composition include emolliency (no or low irritation to the target film), lubricity, and the ability to avoid sloughing.
The compositions of the invention, when used to deliver testosterone to a male patient, can be delivered in a unit dose formulation comprising an amount of testosterone such that after one administration of the unit dose to the patient, the amount of circulating testosterone (AUC) in the patient's serum is achieved within a period of 24 hours after administration0-24) Number of circulating testosterone in serum (AUC) reached in the same 24-hour period as in non-administered patients0-24) In contrast, the concentration is about 100-35,000ng.h/dL, preferably about 600-23,500ng.h/dL, and most preferably about 2900-11,700 ng.h/dL. Such a unit dose for male patients will use about 1-300mg testosterone, more typically about 5-200mg testosterone, and most typically about 25-100mg testosterone. In a preferred form, the unit dose contains up to about 1% testosterone by weight.
The composition of the invention is inFor delivery of testosterone to a female patient, it may be delivered in the form of a unit dose formulation comprising an amount of testosterone such that after one administration of the unit dose to the patient, the amount of circulating testosterone (AUC) in the patient's serum is reached within 24 hours after administration0-24) The amount of circulating testosterone in serum (AUC) achieved in the same 24-hour period as in non-administered patients0-24) In contrast, it is about 0-10-11,700ng.h/dL, preferably about 100-8,800ng.h/dL, and most preferably about 600-6,000 ng.h/dL. Such unit doses for female patients use about 0.01-100mg testosterone, more typically about 1-75mg testosterone, and most typically about 5-50mg testosterone. In a preferred form, the unit dose contains up to 1% testosterone by weight.
The compositions of the invention, when used to deliver DHT to a male subject, can be delivered in a unit dose formulation containing an amount of DHT such that after one unit dose is administered to the subject, the serum of the subject achieves a circulating DHT (AUC) over a period of 24 hours after administration0-24) Is the same as the amount of circulating DHT in serum (AUC) achieved in an unsubjected patient over the same 24-hour period0-24) In contrast, it is about 11,625-465,000pg.h/mL, preferably about 23,250-232,500pg.h/mL, and most preferably about 46,500-116,250 pg.h/mL. Such unit doses for male patients use about 5-200mg DHT, more typically about 10-100mg, and most typically about 20-50mg DHT. In a preferred form, the unit dose contains up to 1% by weight of DHT.
When used to deliver DHT to a female patient, the compositions of the invention can be delivered in a unit dose formulation containing an amount of DHT such that after one unit dose is administered to the patient, the amount of circulating DHT (AUC) in the patient's serum is achieved over a period of 24 hours after administration0-24) Number of circulating DHT (AUC) achieved in serum over the same 24-hour period as when the patient was not administered0-24) In contrast, it is about 11.6-232,500ph.h/mL higher. Preferably about 116. ang. 116,250pg.h/ml, most preferably about 2.325-58,100 pg.h/ml. For womenThe unit dose is about 0.005 to about 100mg DHT, more typically about 0.05 to about 50mg DHT, and most typically about 1 to about 25mg DHT. In preferred forms, the unit dose contains up to about 1% by weight DHT.
The composition of the invention in gel form may be contained in a tube, sachet or metered pump. Such a tube or sachet may contain a unit dose of the composition. A metered pump can dispense a metered dose of the composition.
Conditions associated with a sub-normal androgen concentration in the blood serum of a patient may be treated by administering to the patient a composition of the present invention. The composition may be administered topically. If the composition is in the form of a gel, the composition may be rubbed onto a membrane, such as the skin, of the patient, preferably the intact, clean and dry skin of the shoulder or upper arm or upper body, and held there for a period of time sufficient to release the androgen into the patient's serum.
The dosage will depend on the condition being treated, the frequency of administration and the amount of androgen in the composition. For the treatment of male hypogonadism, a preferred once daily dosage of the 1% testosterone gel of the present invention comprises from about 0.1 to about 30g of the composition, more preferably from about 0.5 to about 20g of the composition, and most preferably from about 2.5 to about 10g of the composition. A preferred once daily dosage of the 1% DHT gel of the present invention for use in the treatment of male hypogonadism contains from about 0.5 to about 20 grams of the composition, more preferably from about 1 to about 10 grams of the composition, and most preferably from about 2 to about 5 grams of the composition. For the treatment of female testosterone deficiency, a preferred once daily dose of a 1% testosterone gel of the present invention comprises about 0.001 to 10g of the composition, more preferably about 0.1 to 7.5g of the composition, and most preferably about 0.5 to 5g of the composition. A preferred once daily dose of a 1% DHT gel of the invention for use in the treatment of testosterone deficiency in women comprises from about 0.0005 g to about 10g of the composition, more preferably from about 0.005 g to about 5g of the composition, and most preferably from about 0.1 g to about 2.5g of the composition. If after a period of time (e.g., about 7-14 days) following the initial administration of the composition, the desired clinical response is not achieved, or the measured androgen concentration in the patient's serum is found to remain below that of a normal adult, the number of administrations, frequency of administration, and/or number of administrations can be increased. Similarly, if the androgen concentration in the blood serum of a patient is found to be higher than the normal adult concentration after a period of time (e.g., about 7-14 days) has elapsed since the beginning of administration of the composition, the number of administrations, frequency of administration, and/or number of administrations can be reduced.
In the case of unit doses, one or more unit doses may be administered to the patient, depending on the condition being treated, the amount of androgen to be released and the frequency of administration. The number of unit doses can be increased or decreased as required, depending on whether the desired clinical effect has been achieved and the androgen concentration in the serum of the patient being treated, as described above.
The compositions of the present invention may be formulated by conventional means, for example, by mixing the components with stirring. Conventional equipment may be used. One of the advantages of the present invention is the ability to formulate the composition without having to resort to special means to achieve the desired result. A simple glassware or stainless steel mixing vessel may be used. The compositions can generally be formulated at room temperature or slightly elevated temperature and atmospheric pressure.
Examples
The following include examples of the compositions of the present invention and comparative compositions.
Example 1
The following example describes the preparation of a composition that can be used as a topical gel for the release of testosterone, which is exemplary of the composition of the present invention. The concentrations of the ingredients constituting the composition are expressed in weight percentages relative to the total weight of the composition.
The composition containing the above ingredients was formulated into one 1000g serving. All ingredients were weighed accurately to two decimal places and then added to the vessel. Oxacyclohexadecan-2-one, ethanol, propylene glycol and glycerol were weighed in a beaker. All mixing steps were carried out at about 22 ℃. Between each addition and during stirring, a teflon stopper was placed on top of the container to prevent evaporation.
80g of oxacyclohexadecan-2-one in solid form are warmed to melt in a water bath at 40-50 ℃ and added to the vessel. 400g of ethanol are added to the vessel, and the beaker containing the oxacyclohexadecan-2-one is rinsed repeatedly in small portions during the addition. Then 50g of propylene glycol and 50g of glycerol are added in succession to the vessel and the mixture formed is gently stirred with an electromagnetic stirrer until the solid is free to move. 10g testosterone powder was then added to the vessel and the resulting mixture was stirred until testosterone was completely dissolved. Subsequently, 5g of polyethylene glycol was added and stirred until the polyethylene glycol was completely dissolved. 3g of an acrylic acid/alkyl methacrylate copolymer and 15g of carboxypolymethylene are added to a vessel in succession and stirred for approximately 1 hour and 20 minutes. 336g of ethanol was then added to the vessel and the previously used beaker was repeatedly rinsed in small portions with the ethanol added. While stirring the contents of the vessel, 50g of water and 1g of tromethamine crystals were combined and weighed into one beaker previously used, shaken until dissolved, and then slowly added dropwise to the center of the vessel near the vortex over 20 minutes with a disposable polyethylene dropper. The resulting mixture was stirred for an additional 18 hours. The order of addition above is not critical. A colorless, transparent to translucent gel was obtained with a viscosity of about 3,500 cps (measured under standard measuring conditions) and a musk-like fragrance. The gel can be extruded from a tube or sachet and can be dispensed from a metering pump.
Example 2
The following example describes the preparation of a composition that can be used as a topical gel for the release of Dihydrotestosterone (DHT), which is exemplary of the composition of the present invention. The concentrations of the ingredients constituting the composition are expressed in weight percentages relative to the total weight of the composition.
The composition containing the above ingredients was formulated into 400g portions. All ingredients were weighed accurately to two decimal places and then added to the vessel. Oxacyclohexadecan-2-one, ethanol, propylene glycol and glycerol were weighed in a beaker. All mixing steps were performed at room temperature. Between each addition step and during stirring, a teflon plug was placed on top of the vessel to prevent evaporation.
4g of oxacyclohexadecan-2-one solid was added to the vessel. Ethanol was then added and the beaker containing the oxacyclohexadecan-2-one was repeatedly rinsed in small portions as it was added. 20g of propylene glycol and 4g of glycerol are then added in succession and the mixture formed is stirred gently with an electromagnetic stirrer until the solid is free to move. 4g of DHT are then added to the vessel and the resulting mixture is stirred until the dihydrotestosterone is completely dissolved. 1g of polyethylene glycol is then added to the vessel and the resulting mixture is stirred until the polyethylene glycol is completely dissolved. Then 2g of acrylic acid/alkyl methacrylate copolymer and 4g of carboxypolymethylene are added in succession and the resulting mixture is stirred for approximately 1 hour and 20 minutes. The remaining ethanol (296 g of ethanol used to prepare the gel) was then added to the vessel and the previously used beaker was rinsed in small portions. While stirring the contents of the vessel, 64.68g of water and 0.32g of tromethamine crystals were weighed and mixed in a previously used beaker and shaken to dissolve. The order of addition is not critical.
Example 3
The following example describes the preparation of a composition that can be used as a topical gel for the release of Dihydrotestosterone (DHT), which is exemplary of the composition of the present invention. The concentrations of the ingredients constituting the composition are expressed in weight percentages relative to the total weight of the composition. This composition was similar to that described in example 2, except that slightly less ethanol was used, and slightly more base oil, polyethylene glycol 400 and water.
The composition containing the above ingredients was formulated into 400g one serving. All ingredients were weighed accurately to two decimal places and then added to the vessel. Oxacyclohexadecan-2-one, ethanol, propylene glycol and glycerol were weighed in a beaker. All mixing steps were performed at room temperature. Between the addition steps and during stirring, a teflon plug was placed on top of the vessel to prevent evaporation.
4g of oxacyclohexadecan-2-one in solid form was added to the vessel. Ethanol was then added to the vessel and the beaker containing the oxacyclohexadecan-2-one was repeatedly rinsed in small portions during the addition. Subsequently, 20g of propylene glycol and 20g of glycerol were added in succession to the vessel and the resulting mixture was stirred with stirring with an electromagnetic stirrer until the solids were free to move. 4g of DHT are then added to the vessel and the resulting mixture is stirred until the dihydrotestosterone is completely dissolved. 2g of polyethylene glycol are then added to the vessel and the resulting mixture is stirred until the polyethylene glycol is completely dissolved. 2g of acrylic acid/alkyl methacrylate copolymer and 4g of carboxypolymethylene are then added in succession and the resulting mixture is stirred for approximately 1 hour and 20 minutes. The remaining ethanol (278.4 g of ethanol was used in the preparation of this gel) was then added to the vessel and the beaker used previously was repeatedly rinsed in portions during the addition. While stirring the contents of the vessel, 65.28g of water and 0.32g of tromethamine crystals were weighed and combined in a beaker previously used and shaken until dissolved. The order of addition above is not critical.
Comparative example C-1
The following is AndroComposition, a topical 1% testosterone gel: testosterone USP (testosterone comprises 1% by weight of the composition), isopropyl myristate, carboxyvinyl polymer, sodium hydroxide, purified water and ethanol (ethanol comprises 67.0% by weight of the composition).
The following is AndroDescription of comparative use of the composition (hereinafter referred to as "C-1 composition") and the composition of the invention (hereinafter referred to as "No. 1 composition"). The formulation of the No.1 composition is as described in example 1, except that Tromethamine (Tris amino) is replaced by Tromethamine (Tromethamine) as neutralizing agent. Since the No.1 composition was prepared by mass production, the respective processes and equipment were appropriately changed. Such suitable variations are known to those skilled in the art and include variations in the order of addition of the components and the time of mixing. In addition, excess ethanol is added during manufacture to compensate for evaporation that occurs when larger equipment is used.
A total of 180 patients were screened in this study. 29 male patients with hypogonadism (25 caucasians, 2 asians, 1 black and 1 spanish) were selected for treatment. The average age of these patients was 61.2 (+ -8.9) years, the average height was 70.2 (+ -2.7) inches, and the average body mass index was 27.1 (+ -3.1). In 19 patients 0800h (+ -30 min) serum testosterone concentrations were below 250 ng/dL. 10 patients had 0900h (+ -30 min) serum testosterone concentrations of 250-300 ng/dL. In addition to male hypogonadism, patients generally demonstrated good health status through medical history, physical examination, clinical laboratory evaluations, and electrocardiogram 3 weeks prior to the start of study drug administration. This study was conducted at Orlando Clinical Research Center, Crlando, Florida USA.
The study was conducted in a randomized, label-public, two-way full crossover fashion. Each patient received a 5g dose of the No.1 composition and 15g dose of the C-1 composition, 7 days apart and placed in different positions (right/left shoulder). The composition is applied by the patient's hand to the intact, clean and dry shoulder skin and rubbed dry. Each dose contained 50mg testosterone. Approximately 10mL whole blood samples were collected before and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8,10, 12, 15, 18, 24 and 48 hours after dosing. Patients were housed and supervised during each administration period from about 12 hours prior to administration to after completion of 24 hours of blood collection. The next day a 48 hour blood sample was collected.
The blood samples were centrifuged at 1500 Xg for 10 minutes at 18 ℃ to separate the serum. The resulting serum was transferred to plastic tubes and immediately frozen and stored at-20 ℃ (± 3 ℃) until analysis. Analysis Total Testosterone (T) is Coat-a-Total testosterone test kit. Analysis of Free Testosterone (FT) by Coota-ion manufactured by Diagnostics Products CorporationFree testosterone test kit. Analysis of Dihydrotestosterone (DHT) Active manufactured by Diagnostics Systems LaboratoriesTMDihydrotestosterone test kit. All tests were performed by ICON laboratories, New York, USA.
Serum concentrations of T, FT and DHT were determined, as well as the highest concentrations (C) achieved over a 48 hour periodmax). Serum concentrations (not baseline adjusted) were plotted against time for T, FT and DHT. For T, FT and DHF, the area under the serum concentration-time curve from 0 to 24 hours (AUC) was determined using the linear trapezoidal rule0-24). The results of the baseline adjustment are summarized in tables 1 to 3 below.
TABLE 1
Baseline adjusted Total testosterone-mean (standard deviation) CmaxAnd AUC0-24
Composition comprising a metal oxide and a metal oxideCmax(ng/dL)AUC0-24(ng.h/dL)
No.1 480(±70.3) 5864.5(±77.9)
C-1 368(±60.9) 4499.1(±77.9)
TABLE 2
Baseline adjusted free testosterone-mean (standard deviation) CmaxAnd AUC0-24
Composition comprising a metal oxide and a metal oxideCmax(ng/dL)AUC0-24(ng.h/dL)
No.1 20.08(±77.8) 240.7(±75.4)
C-1 14.55(±69.8) 164.2(±90.0)
TABLE 3
Baseline-adjusted dihydrotestosterone-median (range) CmaxAnd AUC0-24**
Composition comprising a metal oxide and a metal oxideCmax(pg/dL)AUC0-24(pg.h/dL)*
No.1 321(23-964) 4891.0(257.5-15259.1)
C-1 313(16-1038) 4091.7(225.0-16034.5)
*One patient did not count AUC0-24Because the sample volume is notA second stage of analysis can be performed.
**The assumption of normal is not applicable to the ANOVA model. Non-parametric analysis was therefore performed.
The values in tables 1 to 3 above were estimated using WinNonlin pharmacokinetic software. C abovemaxAnd AUC0-24Values were adjusted via baseline, which is the pre-dose concentration. To CmaxIs to subtract the pre-dose concentration from the measured concentration. Several negative values are generated. These values are taken as zero input unless they occur at the last sampling time point, in which case they are ignored in view of pharmacokinetics. For AUC0-24The pre-administration concentration of testosterone in the patient's serum was subtracted from the measured concentration values at each sampling time over a 24 hour period (assuming that testosterone concentrations in hypogonadal subjects did not change much over a 24 hour period).
For T, mean C of adjusted baseline after application of No.1 compositionmaxAverage C over baseline adjustment after C-1 composition administrationmaxAbout 30% higher. For FT, mean C adjusted baseline after application of No.1 compositionmaxAverage C over baseline adjustment after C-1 composition administrationmaxAbout 38% higher. For DHT, median C from adjusted baseline after application of No.1 compositionmaxMedian C from adjusted baseline after administration of C-1 compositionmaxAbout 2.5% higher.
For T, mean AUC after administration of No.1 composition0-24Average AUC after administration of C-1 composition0-24About 30% higher. For FT, mean AUC after administration of No.1 composition0-24Average AUC after administration of C-1 composition0-24About 45% higher. For DHT, mean AUC after administration of No.1 composition0-24Mean AUC over administration of C-1 composition0-24About 20% higher.
Normal total testosterone (T) concentrations (300ng/dL to 100ng/dL) in adult males are maintained over a period of time after administration of one 5g dose of the No.1 composition.
Three concentration maxima were observed within 48 hours after application when using the No.1 and C-1 compositions. These maxima occur 3-4 hours, 8-10 hours and 18-24 hours after administration.
Comparative example C-2
The following areA composition for use in a patch, the patch being a transdermal patch for the release of testosterone: testosterone USP, alcohol USP, glycerol monooleate, methyl dodecanoate, purified water USP, and acrylic acid copolymer.
The patch has six components. Starting from the outer side towards the surface to be attached to the skin, the system consists of: (A) a layer of metallized polyester-(an ethylene-methacrylic acid copolymer/ethylene vinyl acetate backing film with alcohol resistant ink); (B) a reservoir containing the above composition; (C) a permeable polyethylene microporous membrane; and (D) a peripheral acrylic adhesive layer surrounding the central active drug release region of the system. Prior to opening the system and application to the skin, the central delivery surface of the system is sealed with a peelable laminate wafer of a five layer laminate comprising polyester, polyester urethane adhesive, aluminum foil, polyester urethane adhesive and polyethylene. The wafer was adhered to a release liner (a silicone coated polyester film) and removed with the system prior to use.
Comparative use of the example 1 composition ("No. 1 composition") and the example C-2 composition (hereinafter "C-2 composition") is described below.
406 males between 20 and 80 years of agePatients received treatment in 43 centers in the united states. These patients are hypogonadal, show morning total testosterone (T) concentrations less than or equal to 10.4nmol/L at the time of screening (measured in the central laboratory), and exhibit one or more symptoms of low testosterone (e.g., fatigue, decreased muscle mass, decreased libido, and decreased sexual function). In addition to male hypogonadism, patients are generally healthy. Patients were excluded from this study if they had any systemic skin irritation or disease that could interfere with androgen absorption, had received any androgen therapy, a luteinizing hormone-releasing hormone antagonist or human growth hormone therapy, or had a history of drug abuse within 12 months. Also exclude the use within 30 daysOr patients treated with testosterone or anabolic supplements within 6 weeks prior to the study. The characteristics of the patients (shown below) divided in each test group are summarized in table 4 below. The compositions labeled "No. 1", "C-2" and "placebo" in Table 4 were administered to patients in each test group as explained in the discussion following Table 4.
TABLE 4
Patient characteristics
Population statistics are expressed as mean ± standard deviation
n is the number of patients
*BMI-body mass index
Testosterone (8 am) serum concentration at screening
106 patients received 10g per day of the No.1 composition in two 5 g/day tubes (hereinafter referred to as "10 g/day No.1 group"); 99 patients received 5g per day of the No.1 composition in one 5 g/day tube and 5g per day of placebo gel in another 5 g/day tube (hereinafter referred to as "5 g/day No.1 group"); 102 patients used two parts per dayPatch treatments, each patch containing a C-2 composition containing 12.2mg testosterone, each releasing about 2.5 mg/day testosterone, for a total dose of 5.0 mg/day testosterone (hereinafter referred to as "group C-2"); 99 patients received 10g per day of the above placebo gel contained in two 5 g/day tubes (hereinafter referred to as "placebo group"). Placebo gels were made according to the composition of No.1, but without testosterone and with the addition of additional ethanol. For group No.1 and placebo, the study was double-blind and the label-open approach was used for group C-2.
All study drugs were administered in the morning and repeated at the same time on each day during the study. Each patient in group No.1 and placebo was administered two tubes of contents per day, one tube of contents applied to the skin of one shoulder and the other tube applied to the skin of the other shoulder. Patients who were assigned to receive patches containing the C-2 composition were administered two adhesive patches per day. Sites of application include intact and clean back, abdomen, upper arm and thigh skin. The patch will be used for 24 hours and then replaced each morning at about the same time.
44% of patients originally assigned to the administration of 5 g/day of the No.1 composition had an average total testosterone concentration (C) on day 30arg) Below 10.4nmol/L (300ng/dL) and then escalated to a dose of 10 g/day on day 60. 4% of patients originally assigned to the administration of 10 g/day No.1 composition had C on day 30avgGreater than 34.7nmol/L (1,000ng/dL) and then tapering to a dose of 5 g/day of the composition on day 60.
90% of the patients of group No.1, 92% of the patients of placebo and 75% of the patients of group C-2 completed the 90-day study. The major reason for the higher disruption rate of group C-2 is the adverse reaction (17%), most of which is associated with irritation at the site of application. Compliance of the study protocol was 94.9% for the placebo group, 95.5% for the C-2 group, and 97.1% for the No.1 group. Compliance was 80% or higher in 93% of patients.
Serum samples were taken at 0, 2, 4, 8, 12 and 24 hours within 24 hours of the day prior to the first use of the study drug, and serum concentrations of total testosterone (T), Free Testosterone (FT) and Dihydrotestosterone (DHT) were determined for the patients to obtain a 24-hour baseline profile. On days 30 and 90, a 24 hour profile of T, FT and DHT serum concentrations was measured for the patient using serum sample data collected at 2, 4, 8, 12 and 24 hours before and after dosing. Determination of the mean testosterone concentration (C) over a 24-hour periodavg) Minimum testosterone concentration (C) over a 24 hour periodmin) And maximum testosterone concentration (C) over a 24 hour periodmax). The results are summarized in tables 5 and 6.
T analysis was performed using Coat-a-Total testosterone test kit. FT analysis was performed using Coat-a-Free testosterone test kit. Active from diagnostics Laboratories for DHT analysisTMDihydrotestosterone test kit.
Table 5 below lists the total testosterone concentrations (T) measured in each of the above groups before treatment (baseline) and on days 30 and 90.
TABLE 5
Testosterone pharmacokinetics
Testosterone (nmol/L): average of day 30 and 90
Values are expressed as mean. + -. standard deviation
Significant change from baseline compared to group C-2*p＜0.05，***p＜0.001
For total testosterone (T), average C at baseline for all groupsavgAre all below the normal adult male range (10.4-34.7 nmol/L). On day 30, for group No.1 at 5 g/day, average CavgAbout 50% increase from baseline, similar increase in C-2 group, and average C for 10 g/day No.1 groupavgAn increase of approximately 173% over baseline (significant difference compared to C-2 (P < 0.001)). Placebo group CavgAnd is not changed. Total testosterone values in one day ([ C ] s) in both No.1 groups compared to C-2 groupmax-Cmin]/Cavg) The degree of fluctuation of (a) is significantly smaller. The average Cmin of the two No.1 groups was significantly increased, while C of the C-2 groupminAnd (4) descending. Similar results were observed in the treatment group on day 90. C of approximately 75% of patients in group 5 g/day No.1 and 80% of patients in group 10 g/day No.1avgThe value is higher than 10.4 nmol/L. In comparison, C in 57% of patients in group C-2 and 10% of patients in placeboavgHigher than 10.4 nmol/L. The average Cmin for both No.1 groups increased significantly, while the Cmin for the C-2 group decreased.
Table 6 below summarizes the serum dihydrotestosterone concentrations measured in each of the above groups before treatment (baseline) and on days 30 and 90.
TABLE 6
Dihydrotestosterone pharmacokinetics
Dihydrotestosterone (nmol/L): average of day 30 and 90
Values are expressed as mean. + -. standard deviation
Significant change from baseline compared to group C-2***p＜0.001
For DHT, baseline average C for all groupsavgAre all below the normal adult male range (0.9-2.6 nmol/L). Mean change from baseline to day 30 for groups 5 g/day and 10 g/day No. 1Cavg4-fold and 7-fold higher than the changes observed in the C-2 treated group, respectively (P < 0.001 for each comparison). In addition, Cmin in both No.1 groups increased significantly more than Cmin in the C-2 group (P < 0.001 for each comparison).
The total body weight (TBM), Lean Body Mass (LBM), body Fat Mass (FM) and percent fat (% F) of the above patients were determined by dual energy x-ray absorptiometry the day before the first administration of the study drug and on day 90. These assays were monitored and analyzed centrally by synarc.inc (Maynard, Massachusetts, u.s.a.). On day 90, the LBM in the 10 g/day No.1 group was significantly increased over the C-2 group or the placebo group (P < 0.05 for each comparison), and the mean changes from baseline were 1.5. + -. 4.5, 1.7. + -. 2.6, 0.9. + -. 1.8 and 0.6. + -. 1.8kg for the 5 g/day No.1 group, 10 g/day No.1 group, C-2 group and the placebo group, respectively. All groups except the placebo group showed a reduction in FM that was statistically significant (P < 0.01) compared to the placebo group. The 5 g/day No.1 group, 10 g/day No.1 group, C-2 group and placebo group had reductions of 0.8 + -2.4, 0.8 + -2.0, 0.4 + -1.8 and 0.1 + -1.5 kg, respectively.
The incidence of adverse reactions associated with treatment was 29.1%, 36.9%, 62.7% and 40.4% for 5 g/day No.1 group, 10 g/day No.1 group, C-2 group and placebo group, respectively. Although well tolerated treatment in the No.1 and placebo groups over the 90 day study period, patients in group C-2 experienced a fairly high rate of adverse reactions. Most common are site erythema, site rash, site itching, site reaction and site irritation.
None of the patients in group No.1 discontinued the test due to skin reactions; whereas 15% of patients in group C-2 discontinued the trial due to local skin reactions.
As can be seen, the response occurred mainly in group C-2, while only a few mild responses occurred in group No.1 and the placebo group. In addition, the figure illustrates that the C-2 containing patch acts as an irritant to patients who developed the symptoms typical of contact dermatitis, whereas group No.1 did not develop greater skin irritation than the placebo group.