Untitled record

Our act number: 94196-5397 / LT

1ο1 3 ^ 5 / -

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section ski administration;

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The present invention relates to methods of administering a growth hormone secretagogue to a patient ("secretagogue" means a secretion stimulating agent). Preferably, the method comprises the stepwise administration of a growth hormone secretagogue.

Growth hormone (GH), which is secreted by the pituitary gland, stimulates the growth of all growth tissues in the body. In addition, the following effects of growth hormone on metabolic processes are known:

First essentially increasing the protein synthesis of each cell;

reducing carbohydrate nutrient exchange in cells;

and

3.

increasing the mobilization of free fatty acids and using fatty acids for energy production.

Insufficient growth hormone production and / or secretion can result in a number of diseases or conditions such as dwarfism, massive lean weight loss and, consequently, total fat growth, especially in the tribal body, decreased skeletal and cardiac mass and strength results in a significant reduction in ability, general weakness, which is typically associated with old age, cardiac dyspnea, insulin resistance,

Our file number: 94947-4185 / LT • · - · · · · ·

.......... .. · ·· / · fractures, bone loss, delayed wound healing and osteoporosis. Administration of exogenous growth hormone reverses the abovementioned metabolic changes and lowers plasma low density lipoprotein (LDL) cholesterol and improves physiological well-being.

With the rapid growth of the global population over the age of 65, age-related general weakness may become a growing public health problem. Weakness, in addition to its impact on day-to-day functioning and social relationships, has significant health consequences such as injuries, falls, pool breaks and hospitalization. Every year, 10% of weak adults over the age of 74 suffer a traumatic fall in the United States.

The cause of the long-term decline in muscle and bone mass, which is 0.5-1% per year on average in both men and women after the age of 40, is unknown. Decreased synthesis / secretion of endogenous anabolic hormones may contribute to age-related changes in body composition characterized by decreased muscle and bone mass and relative obesity. For example, growth hormone (GH, also called somatotropin) secretion in both men and women is reduced by 50% between the ages of 30 and 70.

The body naturally releases GH in batches, typically in large doses during sleep, and then releases smaller doses of GH later. Growth hormone secretagogue (GHRH, also known as growth hormone secretagogue factor (GRH)) is believed to release the pituitary gland in a pulsed or intermittent manner and consequently to stimulate GH release in a similar batch. Other factors, including peptides related to the release of somatostatin and growth hormone, also contribute to the pulse rate and peak height of growth hormone secretion.

In cases where elevated levels of growth hormone are desired, the problem is usually addressed by administering exogenous growth hormone or by administering a compound that stimulates growth hormone production or secretion. Typically, these compounds were peptide in nature and had to be injected. Alternatively, products known as secretagogues have been developed that stimulate endogenous growth hormone production and / or release in the pituitary gland.

The present invention relates to methods of administering a growth hormone secretagogue to a patient comprising administering to a patient in need thereof a therapeutically effective amount of a growth hormone secretagogue.

In a preferred embodiment, the growth hormone secretagogue is administered to a human.

In a preferred embodiment, the growth hormone secretagogue is administered every other day.

In another preferred embodiment, the growth hormone secretagogue is administered every three days.

In another preferred embodiment, the growth hormone secretagogue is administered three times per week.

In another preferred embodiment, the growth hormone secretagogue is administered four times per week.

In another preferred embodiment, the growth hormone secretagogue is administered every four or five days.

In another preferred embodiment, the growth hormone secretagogue is administered orally.

In another preferred embodiment of the methods, the growth hormone secretagogue is administered in an immediate release formulation.

In another preferred embodiment, the growth hormone secretagogue is administered in a controlled release formulation.

In a preferred embodiment, when the growth hormone secretagogue is administered in a controlled release formulation, the controlled release formulation is a sustained release formulation, a sustained release formulation, or a combination thereof.

In another preferred embodiment, the growth hormone secretagogue is administered in a combination of immediate release and controlled release formulations.

’/·

In another preferred embodiment of the methods, the secretion of growth hormone is 2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro) -pyrazolo [4,3c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxoethyl] isobutyramide or a pharmaceutically acceptable salt or prodrug thereof or a salt of the prodrug.

In another preferred embodiment of the methods, the growth hormone secretagogue is 2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro) -pyrazolo [4,3c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxoethyl] -isobutyramide L-tartrate.

In another preferred embodiment of the methods, the secretion of growth hormone is 2-amino-N- {1- (R) - (2,4-difluorobenzyloxymethyl) -2-ΟΧΟ-2- [3-oxo-3a- (R) -pyridine -2-methyl-2- (2,2,2-trifluoroethyl) -2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl] ethyl} -2-methyl propionamide or a pharmaceutically acceptable salt or prodrug thereof or a salt of the prodrug.

In another preferred embodiment, the growth hormone secretagogue is 2-amino-N- {1- (R) - (2,4-difluorobenzyloxymethyl) -2-oxo-2- [3-oxo-3a- (R) - Pyridin-2-ylmethyl-2- (2,2,2-trifluoroethyl) -2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl] ethyl} -2- (+) - tartaric acid salt of methyl propionamide.

In another preferred embodiment, the growth hormone secretagogue is administered using a tablet or capsule.

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In another preferred embodiment, the growth hormone secretagogue is administered once, twice or three times daily on the days of administration.

The present invention also provides processes for 2-aminoN- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxoethyl] -isobutyramide L-tartrate in a patient suffering from a deficiency in which 2-amino-N- [2- (3- (R) -benzyl- 2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] isobutyramide A therapeutically effective amount of L-tartrate is administered intermittently.

2-Amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridine-5) -yl) -1- (R) benzyloxymethyl-2-oxoethyl] -isobutyramide In a preferred embodiment of the methods for administering L-tartrate to a patient suffering from a deficiency thereof, 2-amino-N- [2 (3a- (R) - benzyl 2-methyl-3-oxo-2,3,3a, 4,6,7,7-hexahydropyrazolo [4,3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxoethyl] - isobutyramide L-tartrate is administered every other day.

2-Amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridine-5) -yl) -1- (R) benzyloxymethyl-2-oxoethyl] -isobutyramide In another preferred embodiment of the methods for administering L-tartrate to a patient in need thereof, 2-aminoN- [2- (3a- (R) - benzyl 2-methyl-3-oxo-2,3,3a, 4,6,7,7-hexahydropyrazolo [4,3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxoethyl] - isobutyramide L-tartrate is administered every third day.

2-Amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridine-5) -yl) -1- (R) benzyloxymethyl-2-oxoethyl] -isobutyramide In another preferred embodiment of the methods for administering L-tartrate to a patient in need thereof, 2-aminoN- [2- (3a- (R) - benzyl 2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxoethyl] - isobutyramide L-tartrate is administered orally in the form of tablets or capsules.

2-Amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridine-5) -yl) -1- (R) benzyloxymethyl-2-oxoethyl] -isobutyramide In a preferred embodiment of the methods for administering L-tartrate to a patient suffering from a deficiency thereof, 2-amino-N- [2 (3a- (R) - benzyl 2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxoethyl] - isobutyramide L-tartrate is administered in an amount of about 1-10 mg per day on the days of administration.

2-Amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridine-5) -yl) -1- (R) benzyloxymethyl-2-oxoethyl] -isobutyramide In a preferred embodiment of the methods for administering L-tartrate to a patient suffering from a deficiency thereof, 2-amino-N- [2 (3a- (R) - benzyl 2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo [4, Intermittent administration of 3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-o-ethylethyl] -isobutyramide L-tartrate results in peak plasma concentrations of growth hormone in humans of about 5 ng / ml.

In a preferred embodiment of the methods of administering a growth hormone secretagogue to a patient, the patient suffers from obesity or general weakness, osteoporosis, congestive heart failure, or insulin resistance.

The invention also relates to a kit comprising:

the. a composition comprising a growth hormone secretagogue;

b. packaging containing the composition;

c. instructions for intermittent administration of a composition containing growth hormone secretagogue.

In a preferred embodiment of the kit, the growth hormone secretagogue is 2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [a] 4,3c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxoethyl] isobutyramide L-tartrate.

In another preferred embodiment, in addition to the growth hormone secretagogue, the kit contains another compound which may be used to treat obesity, general weakness, osteoporosis, cardiac arrest, or insulin resistance.

In another preferred embodiment of the kit, the composition comprising the growth hormone secretagogue is a tablet or capsule.

The present invention relates to methods of administering a growth hormone secretagogue to a patient, comprising administering to a patient in need of a growth hormone secretagogue a therapeutically effective amount of a growth hormone secretagogue. In a preferred embodiment, the batch administration is not on consecutive days.

Growth hormone secretagogue stimulates growth hormone production and / or secretion when administered to a patient. In addition, administration of growth hormone secretagogue generally increases the plasma concentration of insulin-like growth factor-1 (IGF-1).

Daily administration of growth hormone secretagogue, using a combination of controlled release, immediate release, or controlled release and immediate release formulations, results in increased plasma concentrations of growth hormone; however, the mean peak plasma concentration of growth hormone decreases over time, generally to less than 2 ng / ml in humans, although plasma concentrations of IGF-1 are elevated compared to placebo and do not appear to decrease to the same extent over time. like growth hormone. It is believed that it is therapeutically desirable to achieve average peak plasma concentrations of growth hormone of about 5 ng / ml or greater.

Unexpectedly and surprisingly, it has been found that intermittent administration of a therapeutically effective amount of growth hormone secretagogue results in a mean peak plasma concentration of growth hormone of 5 ng / ml or greater. In other words, it has been unexpectedly and surprisingly found that higher plasma concentrations of growth hormone can be

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instead of daily dosing. Interestingly, with intermittent administration, plasma levels of IGF-1 are slightly elevated compared to placebo but not increased to the extent associated with daily administration. In addition to achieving permanently elevated plasma concentrations of growth hormone while maintaining the desired biological effects, intermittent administration eliminates many of the side effects of daily administration. For example, the incidence of glucose intolerance, edema, and hypertension is reduced or absent when growth hormone secretagogue is administered intermittently, as opposed to daily dosing. Thus, intermittent dosing provides sustained high plasma concentrations of growth hormone and results in a lower incidence of side effects. Batch administration is preferred to growth hormone secretagogues with a half-life of less than 24 hours. More preferably, batch administration is preferred over half-life growth hormone secretagogues of less than 12 hours.

By "intermittent," we mean that growth hormone secretagogue or a combination of growth hormone secretagogues is not administered every day, as is the case with most therapeutic agents, but every other day, every third day, every quarter, twice a week, three times a week, four times a week, and so on, give it. Also, intermittent means that growth hormone secretagogue is administered on consecutive days followed by days when growth hormone is not administered. For example, growth hormone secretagogue may be administered on the first and second day, then again on the fifth and sixth day, and so on. Many variations of intermittent administration will be apparent to those skilled in the art; such variations are included in the invention.

The intermittent administration of growth hormone secretagogue according to the invention is illustrated below. For example, growth hormone secretagogue may be administered to the patient every three days. On the first day of treatment, growth hormone secretagogue is administered. On the second and third days of treatment, no growth hormone secretagogue is administered. On the fourth day, growth hormone secretagogue is administered again. Similarly, growth hormone secretagogue may be administered every other day. On the first day, growth hormone secretagogue is administered. On day two, no growth hormone secretagogue is administered and on day three, growth hormone secretagogue and so forth. A preferred embodiment of the invention is the administration of growth hormone secretagogue three times a week, preferably using an immediate release formulation.

The term "sick" refers to animals such as dogs, cats, cows, horses, sheep, and humans. Preferably, the diseased mammals, including both males and females, are more preferably human.

By "pharmaceutically acceptable," it is meant that a substance or mixture of substances is compatible with the other ingredients of the formulation and not deleterious to the patient.

»· ··/·

The terms "treat," "treat," or "treat" include preventive (i.e., prophylactic) and palliative treatments.

The term "therapeutically effective amount" means an amount of growth hormone secretagogue that ameliorates, attenuates, or resolves one or more diseases or conditions associated with growth hormone secretion.

By "immediate release" is meant that the majority of the active ingredient or compounds become available to the patient for absorption or distribution relatively soon after administration. In a typical immediate release formulation using an oral tablet or capsule, the active ingredient or compounds are released in the stomach.

By "controlled release" is meant that the active ingredient or agents become available for absorption or distribution to the patient at a specified time after administration, at a particular site in the intestinal tract, or for a specified period, or a combination thereof. The term controlled release includes sustained release formulations, sustained release formulations, or a combination thereof.

By "sustained release" is meant that the active ingredient or drugs are not released immediately for absorption or distribution, for example, in the stomach, but after a specified time after administration or at a particular location in the intestinal tract. For example, a composition may be designed to release the active ingredient (s) in the small intestine. Alternatively, a composition may be designed to release the active ingredient or compounds one hour after administration.

By "sustained release" is meant that the active ingredient or compounds are released over a period of time. Preferably, the amount of compound released over a period of time is relatively constant. For example, a formulation containing about 60 mg of active ingredient may be designed to release 10 mg every hour for 6 hours.

Obviously, a formulation may be sustained release and sustained release. For example, a formulation may be designed so that the active ingredient is released in the small intestine instead of the stomach and released over a period of time. In addition, they can be both immediate release and controlled release forms. For example, a tablet may be designed to release a certain amount of the active ingredient in the stomach immediately after oral ingestion and then release the active ingredient in the intestine over a period of time. The design, application and manufacture of immediate release and controlled release formulations, including sustained and / or delayed release formulations, are well known to those skilled in the art.

By "active ingredient" or "active reagent" is meant a compound having a therapeutic effect on a patient. These terms include salts and prodrugs of the compound and salts of the prodrugs.

Preferably, the patient suffering from growth hormone secretagogue deficiency, osteoporosis, congestive heart failure or insulin resistance, or obese patient.

Administration of growth hormone secretagogue to a patient also accelerates the healing of bone fractures, attenuates post-operative catabolic response, reduces deterioration and protein loss caused by chronic diseases such as AIDS or cancer, accelerates wound healing, and accelerates the recovery of burn injured or major surgical patients. Administration of growth hormone secretagogue also improves sleep quality, as described in WO97 / 24369. discloses International Publication Number. Growth hormone secretagogue may be administered to patients with one or more of the conditions or symptoms listed above. Applications of growth hormone are disclosed in WO97 / 24369. International Publication Number.

The growth hormone secretagogue administration methods of the invention can be used to treat any disease or condition that can be treated by administration of a growth hormone secretagogue. It is also noted that growth hormone secretagogue can be administered not only to humans, and such administration is useful for treating growth hormone deficiency, stimulating growth and / or feed utilization of meat-producing animals, increasing milk yield, improving bone and wound healing, and animal protein. / fat ratio. Thus, the growth hormone secretagogue according to the invention can be administered intermittently to a female

- ··&lt;»

WO99 / ​​09 991,

WO95 / 14666,

U.S. 5,726,319 to a non-human animal in need of growth hormone administration.

Growth hormone secretagogue is a compound that, when administered to a patient, increases growth hormone secretion relative to the basal plasma concentration of growth hormone. Thus, to identify growth hormone secretagogue, it is simply necessary to measure the growth hormone basal plasma concentration over a period of time, e.g., one day, and compare the growth hormone plasma concentration after administration of the growth hormone secretagogue to the period basal plasma concentration. Several examples of growth hormone secretagogues are provided herein. It is anticipated that any growth hormone secretagogue may be used in the methods of administration described herein. Preferred growth hormone secretagogues of the invention have an in vivo half-life in humans of less than 24 hours, and more preferably less than 12 hours.

The following U.S. Patents and International Publication discloses growth hormone secretagogues which may be used alone or in combination with other growth hormone secretagogues or other therapeutically active agents in the methods of the present invention: WO98 / 46569, WO98 / 51687, WO98 / 58950, WO99 / 08697, WO95 / 13069, US 5,492,916, US 5,494,919, WO94 / 19367, WO94 / 13696,

WO95 / 17422,

WO94 / 11012,

WO95 / 17423,

WO95 / 11029,

WO95 / 34311, WO96 / 02530, WO96 / 22996, WO96 / 22997, WO96 / 24580, WO96 / 24587, US 5,559,128, WO96 / 32943, WO96 / 33189,

WO96 / 15148, WO97 / 00894, WO97 / 07117, WO97 / 06803, WO97 / 11697

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WO97 / 15573, WO97 / 22367, WO97 / 23508, WO97 / 22620, WO97 / 22004, WO97 / 21730, US 5,663,171, WO97 / 34604, WO97 / 36873, WO97 / 40071, WO97 / 40023, WO97 / 41878, WO97 / 41879, WO97 / 46252, WO97 / 44042, WO97 / 38709, WO98 / 03473, WO97 / 43278, US 5,721,251, US 5,721,250, WO98 / 10653, WO96 / 38471, WO96 / 35713, US 5,919,777, and US 5,830,433.

In addition, the following growth hormone secretagogues may be used according to the present invention: MK-0677 (Merck); NM703 (Novo Nordisk); L-162752 and L-163022 (Merck); hexarelin (Pharmacia &amp; Upjohn); GPA-748, KP102 and

GHRP-2 (American Home Products); ipamorelin (Novo Nordisk); LY444711 (Eli Lilly); Geref (Ares / Serono); GHRH (1-44) [BioNebraska]; Somatorelin (GRF 1-44) (Fujisawa / ICN); and ThGRF (Theratechnologies).

Particularly preferred compounds useful in the present invention are disclosed in WO97 / 24369. and WO98 / 58947. International Patent Application Publication No. 2, including 2-amino-N- [2 (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3] c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxoethyl] -isobutyramide; 2-amino-N- {1- (R)) - (2,4-difluorobenziloximetil) -2-oxo-2- [3-oxo-3a- (R) -pyridin-5-ylmethyl-2- (2,2 , 2-trifluoro-ethyl) -2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3c] pyridin-5-yl] -ethyl} -2-methyl-propionamide; 2-Amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) ) -1- (R) -benzyloxymethyl-2-chloroethyl] -isobutyramide L-tartrate, and 2-amino-N- {1- (R) - (2,4-difluorobenzyloxymethyl) -2-oxo-2- [ 3-Oxo-3a- (R) -pyridin-2-ylmethyl-2- (2,2,2-trifluoroethyl) -2,3,3a, 4,6,7,7-hexahydro-17 pyrazolo [4,3-c] pyridine -5-yl] ethyl} -2-methylpropionamide (L) (+) - tartaric acid salt a.

Growth hormone secretagogue may be administered alone or as part of a pharmaceutically acceptable composition. As used herein, "formulation" is synonymous with formulation. The compositions may be administered simultaneously, for example, by a large injection, or several times, such as a series of tablets. In addition, a single growth hormone secretagogue may be administered or a growth hormone secretagogue may be administered in combination with other growth hormone secretagogues or other therapeutic agents.

Other therapeutic agents may target a disease or condition treated with a growth hormone secretagogue or other disease or condition. For example, growth hormone secretagogue can be administered with other reagents to treat weakness, osteoporosis, cardiac arrest, wound healing, insulin resistance, or the like.

If the patient is or will be receiving more than one pharmaceutically active compound, the compounds may be administered simultaneously or in any order. In the case of tablets, for example, the active compounds may be in the form of a single tablet or in separate tablets which may be administered simultaneously or in any order. In addition, it will be appreciated that the formulations may take various forms. For example, one or more compounds may be administered as tablets, while others may be administered by injection or oral syrup. According to the invention, the growth hormone secretagogue is to be administered intermittently. It will be appreciated that any other drug, other than a growth hormone secretagogue, may be administered intermittently, usually with the growth hormone secretagogue, or daily. For example, growth hormone secretagogue may be administered with another compound useful in the treatment of osteoporosis. The growth hormone secretagogue is administered intermittently and the other compound is administered daily. In other words, the administration regimen of any additional compound may be independent of that of the growth hormone secretagogue.

The growth hormone secretagogue and, optionally, other therapeutic agents used in combination with growth hormone secretagogue may be administered to a patient either orally, rectally, parenterally (e.g., intravenously, intravesicularly or subcutaneously), intracisternally, intravaginally, intraperitoneally, locally (e.g. - or nasal spray. The preferred route of administration is orally in the form of tablets or capsules.

Formulations suitable for parenteral administration may contain physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous solutions, diluents, solvents or carriers include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like) and mixtures thereof, triglycerides including vegetable oils such as olive oil, and injectable organic esters. such as ethyl oleate. Can proper fluidity be maintained, for example, by using coatings, by using coatings such as lecithin, and by maintaining dispersions of the required particle size? · * · * * ** ··· ........ ··· ··· and using surfactants.

These compositions may contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. Microbial contamination of the compositions can be prevented by various bacterial and fungicidal reagents such as parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to use isotonic reagents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical compositions may be achieved by the use of absorption delaying agents such as aluminum monostearate and gelatin.

Solid dosage forms for oral administration include capsules, tablets, powders, and granules. In such solid dosage forms, the active ingredient is admixed with at least one conventional inert binder (or carrier), such as sodium citrate or dicalcium phosphate, or: (a) a filler or plasticizer such as starch, lactose, sucrose, mannitol or silica; (b) a binder such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose or acacia; (c) a liquid carrier such as glycerol; (d) a disintegrant such as agar-agar, calcium carbonate, potato or tapioca starch, algae acid, certain complex silicates or sodium carbonate; (e) a dissolution retardant such as paraffin; (f) an absorption accelerator such as quaternary ammonium compounds; (g) a humectant such as cetyl alcohol or glycerol monostearate; (h) an adsorbent such as kaolin or bentonite and / or (i)

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lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate or mixtures thereof. In the case of capsules and tablets, the dosage forms may also contain puffs.

Solid compositions of a similar type may be used to fill soft or hard gelatine capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols or the like.

Solid dosage forms such as tablets, dragees, capsules and granules may be prepared with a coating or shell, such as a enteric coating, and other coatings well known in the art. They may contain opacifying reagents and may also contain formulations which release the active ingredient or compounds in the delayed and / or sustained manner described above. Examples of embedding compositions that can be used are polymers and waxes. The active compounds may also be in the form of microcapsules, optionally with one or more of the excipients described above.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may include inert diluents commonly used, such as water and other solvents, solubilizers, and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular cottonseed oil, peanut oil, maize germ oil, oleoresin oil, castor oil and sesame seed oil, Miglyol®, glycerol, fatty acid esters of tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan, or mixtures thereof, or the like.

In addition to such inert diluents, the composition may contain adjuvants such as wetting agents, emulsifying agents, suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions may contain reagents suspending the active ingredient, such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar or tragacanth, or a mixture thereof.

Dosage forms for topical administration of a compound of the invention include oils, powders, sprays and inhalants. The active ingredient or compounds are sterile admixed with a physiologically acceptable carrier and any necessary preservatives, buffers or propellants.

Growth hormone secretagogues may be administered to a patient in a dosage range of about 0.01 mg to about 7000 mg per day. A dosage range of about 0.01 to 100 mg / kg body weight is typically sufficient for a normal adult human being weighing 70 kg. The specific dosage and dosage range employed will depend on many factors, including the needs of the patient, the severity of the condition or disease being treated, and the therapeutic activity of the growth hormone secretagogue administered. Dosing Range and Optimal Dosing though22

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storage for a particular patient is obvious to the practitioner. A preferred dosage range for growth hormone secretagogue in humans is from about 0.1 mg to about 700 mg per day. A more preferred dosage range is from about 0.5 mg to about 25 mg per administration day, and a more preferred dosage range is about 110 mg per administration day.

The following paragraphs provide illustrative formulations, dosages, etc. for non-human animals. describes it. Growth hormone secretagogue may be administered orally or otherwise, for example by injection. An amount of a compound (hereinafter referred to as a "reagent") is administered such that an effective dose will be obtained, generally such that the oral dose is about 0.01-100 mg / day / kg body weight, preferably 0.1-50 mg / day / kg. kg body weight. Suitably, the treatment can be performed with drinking water so that the therapeutic dose of the reagent is delivered with a daily dose of water. The reagent may be directly added to water, preferably in the form of a liquid, water-soluble concentrate (such as an aqueous solution of a water-soluble salt). Suitably, the reagent may be administered directly as part of the feed or as an animal feed supplement, also known as a premix or concentrate. The premix or concentrate in therapeutic vehicle support is increasingly being used to deliver the reagent into feed. Suitable carriers are, as desired, liquid or solid, such as water, various flours such as lucerne meal, soybean meal, cottonseed meal, linseed meal, corn cob meal or corn meal, molasses, urea, bone meal, or mineral blends such as those usually ba23.

<img file="HU0103494A2_D0008.tif" />

used for rum feed. A particularly effective carrier is the animal feed itself; that is, a small part of the feed. The carrier promotes the uniform distribution of the reagent in the finished feed with which the premix is ​​mixed. It is important that the reagent is thoroughly mixed in the premix and later in the feed. Accordingly, the reagent may be dispersed or dissolved in a suitable oily material such as soybean oil, corn oil, cottonseed oil, and the like, or in a volatile organic solvent and then mixed in a carrier. It will be appreciated that the proportion of reagent in the concentrate may vary within wide limits as the amount of reagent in the finished feed can be controlled by mixing the appropriate amount of premix in the feed to achieve the desired level of reagent in the feed.

The feed manufacturer may blend high potency concentrates with proteinaceous carriers such as soybean oil and other flours as described above to produce concentrated supplements suitable for direct animal feed. In such cases, the animals may receive their normal diet. Alternatively, such a concentrated supplement may be added directly to the feed to produce a nutritionally balanced finished feed containing a therapeutically effective amount of a compound of the invention. The mixtures are thoroughly mixed by conventional techniques such as twin-shell mixing to ensure homogeneity.

When applied to the feed, the supplement also helps to ensure even distribution of the active ingredient.

... .... .. .

"* · · '. *. **::. · ··. .... .. "··; · on top of sprinkled fodder.

Preferred medicated feeds for pigs, cattle, sheep and goats generally contain from about 1 g to about 400 g of active ingredient per tonne, with an optimal amount for these animals being about 50 g to about 300 g per ton of feed.

Preferred poultry and pet feeds generally contain from about 1 to about 400 g, and preferably from about 10 to about 400 g per ton of active ingredient per ton.

For parenteral administration to animals, the growth hormone secretagogue can be prepared in the form of a cream or pellet and is usually administered by subcutaneous implantation into the head or ear of the animal.

In general, parenteral administration may be by injection of an appropriate amount of a growth hormone secretagogue so that the animal receives a dose of about 0.01 to about 100 mg / kg of body weight of the active ingredient per day. Preferred dosages for poultry, pigs, cattle, sheep, goats and pets are in the range of about 0.1 to 50 mg / kg body weight / day.

Cream formulations may be prepared by dispersing the active ingredient in a pharmaceutically acceptable oil, such as peanut oil, sesame oil, corn oil, or the like.

Pellets containing an effective amount of growth hormone secretagogue may be prepared by mixing growth hormone secretagogue with a diluent such as carbo wax, carnauba wax, and the like, and lubricating agents such as magnesium or calcium stearate may be added to promote pellet formation.

Preferred non-human growth hormone secretagogues include WO98 / 58947. International Patent Publication No. 3,600,198.

Growth hormone secretagogue may be administered to a patient as a pharmaceutically acceptable salt or prodrug. The term "pharmaceutically acceptable salt or prodrug" includes the secretagogue salt or prodrug of growth hormone and, where possible, zwitterionic forms which, according to accepted medical judgment, are suitable for use in patients without undue toxicity, irritation, allergic reaction, and the like. / risk ratio and are effective for the intended application.

The term "salts" refers to inorganic and organic salts of growth hormone secretagogue. Such salts may be prepared in situ during the final isolation or purification of the compound, or by reacting the purified compound separately with an organic or inorganic acid or base, as appropriate, and isolating the salt so formed. Typical salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, besylate, silicate, citrate, maleate, fumarate, tartrate, , mesylate, glucoheptonate, lactobionate, and lauryl sulfonate salts, and the like.

These may include alkali and alkaline earth cations, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations. ·. ·. · • ···· * ·. Examples include ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. See, for example, SM Berge et al. [Pharmaceutical Salts, J. Pharm. Sci., 66, 1-19.

p. (1977)].

The term "prodrug" refers to a compound that is converted in vivo to growth hormone secretagogue. The conversion can be accomplished by a number of mechanisms, such as hydrolysis in the blood. The use of the prodrugs is described by T. Higuchi and W. Stella (Proactive compounds as Increased Delivery Systems, ACS Symposium Series, Vol. 14; Bioreversible Carriers in Active Compound Design, edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press (1987).

For example, if the growth hormone secretagogue contains a carboxyl functional group, the prodrug may be an ester which may be formed by substitution of the hydrogen atom of the acid group with a group such as (Ci-C).₈) alkyl, (C2-C12) alkanoyloxymethyl, 1- (alkanoyloxy) ethyl with 4 to 9 carbon atoms, 1-methyl-1- (alkanoyloxy) ethyl with 5 to 10 carbon atoms, alkoxycarbonyloxymethyl with 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl 4 -7 carbon, 1-methyl-1- (alkoxycarbonyloxy) ethyl

C 5-8, N- (alkoxycarbonyl) aminomethyl C 3-9, 1- (N- (alkoxycarbonyl) amino) ethyl C 4-10, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, diN, N- (C₂) alkylamino (C 2 -C 3) alkyl (such as (β-dimethylaminoethyl), carbamoyl (C 1 -C₂) alkyl, N, N-di (C 1 -C 4)₂) alkylcarbamoyl (C 1 -C 4)₂) alkyl and piperidino, pyrrolidino or morpho27 lino (C2-C3) alkyl.

Similarly, when the growth hormone secretagogue contains an alcohol functional group, a prodrug may be formed by replacing the hydrogen atom of the alcohol group with a group such as (C1-C4).₆) alkanoyloxymethyl, 1 ((C 1 -C 6) alkanoyloxy) ethyl, 1-methyl-1 - ((C 1 -C_s) alkanoyloxy) ethyl, (C 1 -C 4)₆) alkoxycarbonyloxymethyl, N- (C 1 -C 4)₆) alkoxycarbonylaminomethyl, succinoyl, (C 1 -C 4)₆) alkanoyl, α-amino (C 1 -C 4) alkanoyl, arylacyl and α-aminoacyl, or o-aminoacyl-α-aminoacyl, wherein each α-aminoacyl group is independently selected from natural L-amino acids, P (0) ( OH)₂, Ρ (0) {O (Ci-C₆) alkyl) 2 or glycosyl (the radical obtained by removing the hydrogen of the hydroxyl group of the hemiacetal form of the carbohydrate).

When the growth hormone secretagogue contains an amine functional group, a prodrug may be formed by replacing the hydrogen atom of the amine group with a group such as R-carbonyl, RO-carbonyl, NRR'-carbonyl, wherein R and R 'are independently (C1-C10). alkyl, (C₃C₇) cycloalkyl, or benzyl, or R-carbonyl, natural aaminoacyl or natural α-aminoacyl-natural α-aminoacyl, -C (OH) C (O) OY, wherein Y is H, (C 1 -C₆) alkyl or benzyl, -C (OY₀) Yi, where Y_She is (C 1 -C 4) alkyl and Υχ is ((C 1 -C 4) alkyl)₆) alkyl, carboxy (C 1 -C 6) alkyl, amino (C 1 -C 5) alkyl or mono-N- or di-N, N- (C 1 -C₆) alkylaminoalkyl, -C (Y₂) Y₃, where Y₂ is H or methyl and Y₃ denotes mono-N- or di-N, N- (C 1 -C 4)₆) alkylamino, morpholino, piperidin-1-yl or pyrrolidin-1-yl.

A growth hormone secretagogue may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. All stereoisomeric forms of growth hormone secretagogue and mixtures thereof, including racemic mixtures, are within the scope of the present invention. In addition, all geometric and positional isomers are within the scope of the invention. For example, if the growth hormone secretagogue contains a double bond, both the cis and trans forms, as well as mixtures thereof, are within the scope of the invention.

Mixtures of isomers, including stereoisomers, may be separated into their individual components according to their physico-chemical differences by methods well known in the art, such as chromatography and / or fractional crystallization. The enantiomers may be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with the appropriate optically active substance (e.g., alcohol), then separating the diastereomers and converting each diastereomer to the corresponding pure enantiomers (e.g., hydrolysis). Further, some of the compounds of the invention may be atropisomers (e.g., substituted baryls) and are within the scope of the invention.

Growth hormone secretagogue can exist in both solvate and non-solvate forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. Both solvate and non-solvate forms are within the scope of the invention.

<img file="HU0103494A2_D0009.tif" />

It is also possible that growth hormone secretagogue exists in various tautomeric forms. All tautomeric forms are within the scope of the invention. For example, all tautomeric forms of the imidazole group are within the scope of the invention. All forms of growth hormone secretagogue are also within the scope of the invention. One skilled in the art will recognize that any compound name described herein is based on a tautomeric form of the compound. Although it is possible that only one tautomeric form is used, all tautomers are understood to mean that tautomeric name and all tautomeric forms are within the scope of the invention.

The invention also includes isotopically-labeled compounds that are identical to those cited herein except that one or more atoms are replaced by an atomic mass or atomic number that is different from the naturally occurring atomic mass or atomic number. Examples of compounds that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as²H, ³H, ¹³C ¹⁴C ¹⁵N, ¹⁸0, ¹⁷0, ³¹P, ³²P, ³⁵And, ¹⁸F and ³⁶C1. Growth hormone secretagogues containing the above isotopes and / or other isotopes of other atoms are within the scope of the present invention. Certain isotopically labeled growth hormone secretagogues, for example, into which radioactive isotopes such as³H and ¹⁴C - incorporated, can be used to test the distribution of the drug and / or substrate in tissues. Tricolor, that is³H, and carbon 14, · ·· ««

• ·* """ · say ¹⁴C isotopes are particularly preferred because of their ease of preparation and detection. Furthermore, with heavier isotopes such as deuterium, that is²Substitution with H provides certain therapeutic benefits, such as increased in vivo half-life or reduced need for administration, and thus may be beneficial under certain circumstances.

The growth hormone secretagogue may be administered in combination with one or more other growth hormone secretagogues or other therapeutic agents. Preferred compositions comprise a growth hormone secretagogue and a compound used to treat a disease or condition treated by a growth hormone secretagogue. For example, growth hormone secretagogue can be used to treat osteoporosis. Other compounds known to treat osteoporosis and used in combination with a growth hormone secretagogue include estrogen agonists / antagonists (also known as selective estrogen receptor modulators (SERMs)) such as tamoxifen, droloxifene lasofoxifene (5,552,412). United States Patent No. 5,198), raloxifene, idoxifene and bisphosphonates such as alendronate, tiludronate, dimethyl-ADP, rizedronate, etidronate, YM-175, clodronate, pamidronate and BM-210995 (ibandronate). Another class of compounds useful in the treatment of osteoporosis and co-administered with a growth hormone secretagogue are prostaglandin E2 antagonists. Examples of prostaglandin E2 antagonists for use with growth hormone secretagogue include WO99 / ​​19300 and WO98 / 28264. compounds disclosed in International Publication No. * * · ·. Other compounds useful in the treatment of osteoporosis and for use with growth hormone secretagogue include Premarin®, progesterone, Evista®, calcitonin and estrogen. The term "estrogen agonists / antagonists" refers to compounds that bind to the estrogen receptor. Estrogen agonists are preferably compounds that are capable of binding to the estrogen receptor and mimicking the effects of estrogen. Estrogen antagonists are compounds that are capable of binding to the estrogen receptor and inhibiting estrogen function. Illustrative estrogen agonists / antagonists include droloxifene and other compounds disclosed in U.S. Patent 5,047,431, tamoxifen and other compounds disclosed in U.S. Patent Nos. 4,536,516 and 4,623,660, and raloxifene and the like. a 4,839,155. Other compounds disclosed in U.S. Pat. In addition, the compounds disclosed in U.S. Patent Nos. 5,552,412 and 4,133,814, which are estrogen agonists / antagonists, are useful in the present invention.

Preferred estrogen agonists / antagonists for use in the present invention include those disclosed in U.S. Patent No. 5,552,412, such as:

cis-6- (4-fluorophenyl) -5- [4- (2-piperidin-l-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydro-naphthalene-2-ol;

(-) - cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -4

5,6,7,8-tetrahydro-naphthalene-2-ol;

cis-6-phenyl-5- [4- (2-pyrrolidin-l-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydro-naphthalene-2-ol;

cis-1- [6'-pyrrolodinoethoxy-3'-pyridyl] -2-phenyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene, ·

1- (4'-pyrrolidinoethoxyphenyl) -2- (4-fluorophenyl) -6-hydroxy-1,2,3,4-tetrahydroisoquinoline;

cis-6- (4-hydroxyphenyl) -5- [4- (2-piperidin-l-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydro-naphthalene-2-ol; and

1- (4'-pyrrolidinoethoxyphenyl) -2-phenyl-6-hidroxi1,2,3,4-tetrahydroisoquinoline.

Growth hormone secretagogue can also be used in combination with other growth stimulating and anabolic reagents such as thyrotropin releasing hormone (TRH), parathyroid hormone (PTH), diethylstilbestrol, β-agonists, theophylline, anabolic steroids, enkefakins, E-series prostaglandins 239,345; 4,036,979; and 4,411,890.

The compounds disclosed in U.S. Pat.

Growth hormone secretagogues of the present invention which can be used alone or in combination with other growth hormone secretagogues include GHRP-2, GHRP-6 and GHRP-1 growth hormone releasing peptides. Growth hormone releasing hormone, growth hormone and analogues thereof can also be used according to the invention. Other compounds useful in the present invention include hexarelin, somatomedins such as IGF-1 and IGF-2, or adrenergic agonists such as clonidine (No. 3,202,660).

Λ * - * '· * * *' - ί ». , * 'V * in U.S. Patent), xylazine (U.S. Patent No. 3,235,550), detomidine and medetomidine (U.S. Patent 4,544,664), and serotonin5HTID agonists such as sumitripan. , or somatostatin or release inhibitors such as physostigmine and pyridostigmine.

Growth hormone secretagogue may also be used in combination with one or more compounds for treating obesity. Classes of compounds for treating obesity include the active ingredient (s) of an appetite suppressant such as Adipex®, Bontril®, Desoxin Gradumet®, Fastin®, Ionamin® and Meridia®, and lipase inhibitors such as Xenical®.

Other anti-obesity agents for use with growth hormone secretagogue include p₃-adrenergic receptor agonists, cholecystokinin-A agonists, monoamine reuptake inhibitors, sympathomimetic reagents, serotonergic reagents, dopamine agonists, melanocyte-stimulating hormone receptor antagonists or mimetics, melanocyte-stimulating hormone receptor analogs, cannabinoid concentrating hormone antagonists, leptins, leptin analogues, leptin receptor antagonists, galanin antagonists, bombezin agonists, neuropeptide Y-antagonists (including NPY-1 and NPY-5), thymomimetic reagents, dehydroepiandrosterone or analogs thereof, glucocorticoid receptor agonists or antagonists, orexin receptor antagonists, urocortin binding protein anta34 ··· · · ···· Gonists, glucagon-like peptide-1 receptor agonists, and ciliary neurotrophic factor.

Particularly preferred anti-obesity agents for use with growth hormone secretagogue include any of the following: sibutramine, fenfluramine, dexfenfluramine, bromocriptine, phentermine, ephedrine, leptin, phenylpropanolamine-pseudoephedrine, {4- [2- (2- [6-aminopyridine-3-11] -2 (R) -hydroxyethylamino) -ethoxy] -phenyl} -acetic acid, {4 - [2- (2- [6-aminopyridin-3-yl] -2 (R) -hydroxyethylamino) ethoxy] phenyl} benzoic acid, {4- [2- (2- [6-aminopyridin-3-yl] -2 ( R) -hydroxyethylamino) ethoxy] phenyl] propionic acid and {4- [2- (2- [6-aminopyridin-3-yl] -2 (R) -hydroxyethylamino) ethoxy] phenoxy} acetic acid.

Examples of thromimetics for use with growth hormone secretagogue include compounds disclosed in U.S. Provisional Patent Applications Nos 60/178,968 and 60/177,987.

Examples of glucocorticoid receptor ligands for use with growth hormone secretagogue include those disclosed in U.S. Patent Application Serial No. 60 / 132,230.

Examples of neuropeptide Y antagonists for use with growth hormone secretagogue include WO 98/23603. compounds disclosed in U.S. Patent Nos. 5,900,415, 5,914,329 and US Provisional Patent Application 60/132,029 (NPY-5).

·· · · ·«··· ··· ···· · · ·· ·

For use with growth hormone secretagogue p₃examples of adrenergic receptor agonists include WO 96/35671. Compounds disclosed in International Publication No. 3,646,198.

Growth hormone secretagogue can also be used in combination with a compound that is useful in treating heart failure. Examples of classes of compounds for the treatment of cardiac congestion include diuretics, angiotensin converting enzyme (ACE) inhibitors, angiotensin-II receptor inhibitors, digitalis, β-inhibitors and corticotropin-releasing factor (CRF) antagonists. Examples of CRF antagonists for use with growth hormone secretagogue include WO 95/33750. Compounds disclosed in International Publication No. 3,646,198. WO 95/33750. Preferred compounds disclosed in International Patent Application Publication No. 3,600,900 include:

4- (1-ethylpropoxy) -2,5-dimethyl-6- (2,4,6-trimethylbenzyl) pyrimidine;

2- (4-bromo-2,6-dimethyl-phenoxy) -4- (1-ethyl-propoxy) -3,6-dimethyl-pyridine;

2- (4-ethyl-2,6-dimethyl-phenoxy) -4- (1-ethyl-propoxy) -3,6-dimethyl-pyridine;

3-ethyl-4- (1-ethyl-propoxy) -6-methyl-2- (2,4,6-trimethyl-phenoxy) -pyridine;

2- (2,6-dimethyl-4-propyl-phenoxy) -4- (1-ethyl-propoxy) 3,6-dimethyl-pyridine;

4- (1-ethylpropoxy) -2- (4-methoxy-2,6-dimethylphenoxy) 3,6-dimethylpyridine;

- 36 - .............

• · · · · · · ·«· · · ····· ·· · · ····· ··· ···· ·-&gt; ·· ·

2- (4-ethoxy-2,6-dimethyl-phenoxy) -4- (1-ethyl-propoxy) -3,6-dimethyl-pyridine;

2- (4-chloro-2,6-dimethyl-phenoxy) -4- (1-ethyl-propoxy) -3,6-dimethyl-pyridine;

4- (1-methoxymethyl-propoxy) -3,6-dimethyl-2- (2,4,6-trimethyl-phenoxy) -pyridine;

[3,6-dimethyl-2- (2,4,6-trimethyl-phenoxy) -pyridin-4-yl] diethyl-amine;

[3,6-dimethyl-2- (2,4,6-trimethyl-phenoxy) -pyridin-4-yl] -ethyl-propylamine;

[2,5-dimethyl-6- (2,4,6-trimethyl-phenoxy) -pyrimidin-4-yl] (1-ethyl-propyl) -amine;

butyl- [3,6-dimethyl-2- (2,4,6-trimethyl-phenoxy) -pyridin-4-yl] ethylamine;

4- (1-ethyl-propoxy) -3,6-dimethyl-2- (2,4,6-trimetilfenilszulfanil) pyridine;

butyl [2- (4-chloro-2,6-dimethylphenoxy) -3,6-dimethylpyridine-4-yl] ethylamine;

Methyl 4- (1-ethyl-propylamino) -6-methyl-2- (2,4,6-trimethyl-phenoxy) -nicotinic acid;

[3,6-dimethyl- [2- (2,4,6-trimethyl-phenylsulfanyl) -pyridin-4-yl] -ethyl-propyl-amine;

4- (1-ethyl-propylamino) -6-methyl-2- (2,4,6-trimethyl-phenoxy) -pyridin-3-yl] -methanol;

[2- (4-chloro-2,6-dimethylphenoxy) -3,6-dimethyl-pyridin-411] -ethyl-propylamine;

1- (ethyl-propyl) - [6-methyl-3-nitro-2- (2,4,6-trimethyl-phenoxy) -pyridin-4-yl] -amine;

4- (1-ethyl-propyl) -6-methyl-3-nitro-N2- (2,4,6-trimethyl-phenyl) -pyridine-2,4-diamine;

N4- (1-ethylpropyl) -6-methyl-2- (2,4,6-trimethyl-phenoxy) -pyridin-3,4-diamine;

3,6-dimethyl-2- (2,4,6-trimethyl-phenoxy) -pyridin-4-yl] ethyl (2,2,2-trifluoro-ethyl) -amine;

N4- (1-ethylpropyl) -6-methyl-N2- (2,4,6-trimethylphenyl) pyridine-2,3,4-triamine;

[3-Chloromethyl-6-methyl-2- (2,4,6-trimethyl-phenoxy) -pyridin-4-yl] - (1-ethyl-propyl) -amine;

[3,6-dimethyl-2- (2,4,6-trimethyl-phenoxy) -pyridin-4-yl] (1-ethyl-propyl) -amine;

(1-ethyl-propyl) - [2-methyl-5-nitro-6- (2,4,6-trimethylpyridine-3-yloxy) -pyrimidin-4-yl] -amine;

(1-ethyl-propyl) - [3-methoxymethyl-6-methyl-2- (2,4,6-trimethyl-phenoxy) -pyridin-4-yl] -amine;

(N- (1-ethyl-propyl) -2-methyl-5-nitro-N '- (2,4,6-trimethylpyridin-3-yl) -pyrimidine-4,6-diamine;

[2- (4-Chloro-2,6-dimethyl-phenoxy) -3,6-dimethyl-pyridin-4-yl] -diethylamine;

4- (1-ethyl-propoxy) -3,6-dimethyl-2- (2,4,6-trimethyl-phenoxy) -pyridine;

butyl- [2,5-dimethyl-7- (2,4,6-trimethylphenyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-4-yl] ethylamine;

4- (butylethylamino) -2,5-dimethyl-7- (2,4,6-trimethylphenyl-5,7-dihydropyrrolo [2,3-d] pyrimidin-6-one;

4- (1-ethylpropoxy) -2,5-dimethyl-6- (2,4,6-trimethylphenoxy) pyrimidine;

·«· · · ····· • · · · ····· ··· »··· ·· »· ^c glitazone, rosiglitazone; PPAR gamma agonists; inhibitors of fatty acid oxidation: clomoxir, etomoxir; α-glucosidase inhibitors: acarbose, miglitol, emiglitate, voglibose, MDL-25,637, kamiglibose, MDL-73,945; β-agonists: BRL 35135, BRL 37344, Ro 16-8714, ICI D7114, CL 316 243; phosphodiesterase inhibitors: L-386,398; lipid-lowering reagents: benfluorex;

anti-obesity reagents: fenfluramine; vanadate and vanadium complexes (e.g. Naglivan®) and peroxovanadium complexes; amylin antagonists; glucagon antagonists; gluconeogenesis inhibitors; somatostatin analogs and antagonists; antilipolytic reagents: nicotinic acid, acipimox, WAG 994. Also included are pramlintide acetate (Symlin ™), AC2993 and nateglinide for use with growth hormone secretagogue.

Since one embodiment of the present invention is the treatment of the disclosed diseases / conditions by a combination of pharmaceutically active reagents which can be administered separately in any order, the invention further provides a combination of different pharmaceutical compositions in kit form. The kit contains two different pharmaceutical compositions: a composition comprising a growth hormone secretagogue and a second composition comprising a second pharmaceutical compound. The kit contains a container containing different formulations, such as a split bottle or split film package. Other examples of containers include syringes, cartons, bags, and the like. Typically, the kit contains instructions for administering the various components. THE

<img file="HU0103494A2_D0010.tif" />

days when the tablets or capsules so marked should be taken. Another example of such a reminder is the calendar printed on the card, for example, "First week, Monday, Tuesday, ... Second week, Monday, Tuesday, etc." Other versions of reminders are obvious. “The daily dose may be one tablet or capsule, or multiple tablets and capsules may be taken on a single day. Further, the daily dose of growth hormone secretagogue may consist of one tablet or capsule, while the daily dose of the second compound may consist of several tablets or capsules, and vice versa. The reminder should show this and help correct administration of the active reagents. It is also conceivable that even if the growth hormone secretagogue is to be administered alone (i.e. without the other active ingredient), a kit may be provided to help the patient remember when to administer the growth hormone secretagogue, since administration is intermittent and the may be useful at the time of dosing. In this way, the kit may include doses of growth hormone secretagogue and a means to remind the patient when to take the dose. For example, an automatic dispenser designed to dispense doses individually in the order in which they are intended to be administered may be provided. Preferably, the dispensing machine is provided with a reminder to further assist with the treatment. An example of such a reminder is a mechanical counter which indicates the number of daily doses delivered. Another example of such a reminder is a battery microchip memory connected to a liquid crystal display or an audible reminder transducer42, which reads, for example, the date when the last daily dose was issued and / or reminds when to take the next dose.

Growth hormone secretagogue or a mixture of growth hormone secretagogues may be administered using the sustained release formulation of the invention. For purposes of discussion, and not limitation, the following many embodiments may be grouped into classes according to design and function.

A first class of sustained release dosage forms described below are matrix systems, which include, but are not limited to: 1) non-disintegrating matrices, tablets, compound granules, and hydrogel-based systems; 2) hydrophilic dispersible, dispersible or soluble matrix systems, tablets or composite granules; and 3) coated matrix systems. The second class includes storage systems in which the release of the active ingredient is controlled by a membrane, such as capsules and coated tablets or composite granules. The third class comprises osmosis-based systems such as: 1) coated bilayer tablets; 2) coated homogeneous tablet cores; 3) coated composite granules; and 4) osmotic capsules. The fourth class comprises swelling systems in which the active ingredient is released by swelling and protrusion of the core components through the passage of the coating or surrounding hard shell or outer layer.

The first class includes matrix systems in which growth hormone secretagogue (GHSEC) is dissolved, embedded or dispersed in a matrix of another substance which is intended to retard GHSEC release into an aqueous medium (e.g., gastrointestinal (GI) cavity fluid). When GHSEC is dissolved, embedded or dispersed in such a matrix, the release of the active ingredient occurs substantially from the surface of the matrix. Thus, after diffusion into the surrounding fluid, the GHSEC is released from the surface of the device containing the matrix, or when the surface of the device dissolves or diffuses, making the active ingredient available. In some embodiments, both mechanisms may work simultaneously. The matrix system may be large, i.e., tablet size (about 1 cm) or small (less than 0.3 cm). The system may be uniform, may be subdivided into several subunits (e.g., multiple tablets forming a single dose) which may be administered substantially simultaneously, may comprise a plurality of small tablets in a capsule, or may contain a plurality of particles referred to herein as composite pellets. Composite granules can have a variety of formulation applications. For example, compound granules may be used to fill small beads or powders in capsules, compressed into tablets, or used alone with food (e.g., ice cream) for convenience, or as a pouch, which may be dispersed in a liquid such as fruit juice or water.

The variety of variables that influence the release of GHSEC from matrix devices allows flexibility in the design of devices of different materials, sizes and release times.

Non-disintegrating matrix tablets providing sustained release of GHSEC can be prepared using GHSEC and water-insoluble materials such as waxes, cellulose and other water-insoluble polymers. Matrix materials suitable for the preparation of these dosage forms include microcrystalline cellulose such as Avicel® (EMC Corp., Philadelphia, PA), including microcrystalline cellulose species to which binders such as hydroxypropylmethyl cellulose have been added, waxes such as paraffin, modified vegetable oils, carnauba wax, hydrogenated castor oil, beeswax, and the like, as well as polymers such as cellulose, cellulose esters, cellulose ethers, polyvinyl chloride, copolymers of polyvinyl acetate, vinyl acetate and ethylene, polystyrene, and the like. Optional water-soluble binders and release-modifying reagents that can be incorporated into the matrix include water-soluble polymers such as hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), methylcellulose, poly (N-vinyl-2-pyrrolidinone) (PVP), polyethylene oxide (PEO), polyvinyl alcohol (PVA), xanthan gum, carrageenan, and other such natural and synthetic materials. In addition, release modifying agents include water soluble materials such as sugars and salts. Preferred water-soluble materials include lactose, sucrose, glucose and mannitol, as well as HPC, HPMC and PVP. In addition, they include, but are not limited to, dissolution-aiding acid binders such as organic acids

<img file="HU0103494A2_D0011.tif" />

malic acid, citric acid, coral acid, ascorbic acid, adipic acid, glutamic acid, maleic acid, aconitic acid, fumaric acid, succinic acid, tartaric acid and aspartic acid, and solubilizers such as sodium bitartrate and cyclodextrins can be added to the tablets. increasing the amount of GHSEC released and potentially increasing the absorption and consequent bioavailability of GHSEC, especially for matrix formulations that release GHSEC for 6 hours or more.

In addition to the components of the matrix system, the size of the matrix system may also influence the rate of release of GHSEC; therefore, the composition of a large matrix system such as a tablet is generally different from the smaller ones in order to achieve a similar GHSEC release profile. The effect of the size of the matrix system on the release kinetics of GHSEC follows a design principle well known to those skilled in the art. For illustration purposes, the following table shows the GHSEC diffusion coefficient through a matrix required to achieve a 10 hour specific release time for different sized matrix systems that are released by a GHSEC diffusion based mechanism (and not by a disintegration or disintegration mechanism).

radius (cm) diffusion coefficient (cm²/ Sec)

0, 0025 (50 µm diameter) 1.7 x 10¹⁰

0.1 (2mm diameter) 3 χ 10 '⁷

0.5 (1 cm diameter) 7 x 10 ~⁶

The table above illustrates that the diffusion coefficient required to achieve the intended specific release time may vary in magnitude as the desired device size changes. Matrix materials suitable for providing the GHSEC diffusion coefficient at the lower end of the diffusion coefficient scale are polymers such as cellulose acetate. In contrast, materials at the top end of the scale are, for example, hydrogel-forming or swelling polymers. The diffusion rate can be adapted to any particular device by the choice of material or materials and the structure of the matrix.

For further illustration, to achieve sustained release with a non-dispersible matrix in a particle size of about 50 µm, a polymer, such as cellulose acetate or the like, would be required to counteract the short distances typical of small particle size. Conversely, in order to achieve sustained release in a large device (e.g., 1 cm), a liquid (e.g., hydrogel or water soluble polymer) or higher porosity material would be required. In medium-sized devices, i.e., about 1 mm in diameter, a transient matrix composition may be used.

It is noted that the effective diffusion coefficient of GHSEC in the matrix can be increased to the desired value by the addition of emollients, pores or pore forming reagents known in the art. Slowly hydrating agents may also be used to effectively reduce the GHSEC diffusion rate, particularly shortly after administration. In addition to altering the effective diffusion coefficient, the rate of release can be altered by using the more soluble salts of GHSEC (relative to the base) or by binding agents, such as acids, which dissolve the

GHSEC.

Another non-disintegrating sustained release matrix system contains GHSEC dispersed in a hydrogel. This embodiment differs from the hydrophilic matrix tablet in that the hydrogel of this embodiment is not a compressed tablet of soluble or disintegrating particulate material, but a homogeneous polymer network. As is known in the art, a hydrogel is a water-swellable network polymer. Hydrogels can be prepared in many forms, such as capsules, tablets, and compound granules. For example, tablets containing 10-80% crosslinkable polymer may be prepared by conventional methods. Once the tablets are ready, the polymer can be cross-linked using a chemical cross-linking reagent such as glutaraldehyde or UV to form a hydrogel matrix. Hydrogels are a preferred material for matrix devices because they are capable of absorbing or containing water in high volume, thereby allowing diffusion of the dissolved drug within the matrix. The diffusion coefficient of the active compounds in hydrogels is characteristically high and in very swollen gels the diffusion coefficient of the active ingredient can be close to that of pure water. This high diffusion coefficient allows for release rates that are practicable for relatively large devices (i.e., not necessarily microparticles). Ha48 · «·« · • · · Λ · &lt;

although hydrogel devices may be made, they may be filled, stored, distributed and dispensed with GHSEC in a fully hydrated state, preferably in a dry state, distributed and dispensed. In addition to stability and comfort, dry administration of hydrogel devices can provide good GHSEC release kinetics. type of transport (i.e., by swelling of the hydrogel and diffusion of the active ingredient from the hydrogel). Preferred materials for forming a hydrogel include hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate and polyethylene oxide. Particularly preferred are poly (2-hydroxyethyl methacrylate), poly (acrylic acid), poly (methacrylic acid), poly (N-vinyl-2-pyrrolidinone), polyvinyl alcohol) and each other and hydrophobic monomers such as methyl methacrylate, vinyl acetate, and similar - copolymers thereof. Synthetic polyurethanes containing large polyethylene oxide blocks are also preferred. Other preferred materials include hydrogels containing interpenetrating networks of polymers, which may be formed by addition or condensation polymerization, and whose components may include, for example, the hydrophilic and hydrophobic monomers just listed.

Non-disintegrating matrix tablets can be prepared by standard tableting techniques in the pharmaceutical industry. Preferred embodiments of non-disintegrating matrix tablets are about 1-80% GHSEC, about 5-50% insoluble matrix material such as cellulose, cellulose acetate or ethyl cellulose, and optionally about 5-85% soft 49 · · «· * Ι * ·· &lt;

a pelletizing agent, a pore-forming agent or a dissolution aid, and optionally about 0.25% to 2% of a tabletting lubricant such as magnesium stearate, sodium stearyl fumarate, zinc stearate, calcium stearate, stearic acid, ethanol, talc or a mixture of magnesium stearate and sodium lauryl sulfate. These materials can be mixed, granulated and tabletted using equipment commonly used in many pharmaceutical industries.

It consists of a plurality of particles of GHSEC containing non-dispersible composite particles, each of which is a binder capable of forming a matrix limiting the dissolution rate of one or more GHSECs in an aqueous medium. The matrix materials used in this embodiment are generally water-insoluble materials such as triglycerides, waxes, cellulose or other water-insoluble polymer. Optionally, the matrix materials may be formulated with water-soluble materials which may be used as binders or permeation reagents. Matrix materials suitable for the preparation of these dosage forms include microcrystalline cellulose such as Avicel® (EMC Corp., Philadelphia, PA), including microcrystalline cellulose species to which binders such as hydroxypropylmethyl cellulose have been added, waxes such as paraffin, modified vegetable oils, carnauba wax, hydrogenated castor oil, beeswax and the like, and synthetic polymers such as polyvinyl chloride, polyvinyl acetate, copolymers of vinyl acetate and ethylene, polystyrene, and the like. Optionally the •• «V ♦ *« *. · ··. · • · · «« V * • · «« * · 1 I »»

V · «· * ···», 'í t ♦ · »** &lt;&lt;

water-soluble release-modifying reagents that can be incorporated into a matrix include water-soluble polymers such as HPC, HPMC, methylcellulose, PVP, PEO, PVA, xanthan gum, carrageenan, and the like. In addition, release modifying agents include water soluble materials such as sugars and salts. Preferred water-soluble materials include lactose, sucrose, glucose and mannitol, as well as HPC, HPMC and PVP. In addition, any of the aforementioned dissolution aids and binders can be incorporated into matrix composite particles to increase the release rate of GHSEC, increase the total GHSEC release, and potentially increase the absorption and consequent bioavailability of GHSEC, especially for 6 hours or GHSEC will be further released.

A preferred process for producing matrix composite particles is the extrusion / spheronization process. For this procedure, GHSEC is wet mixed with binder, pressed through a perforated plate or mold, and placed on a rotating disk. Ideally, the pressed material is split into pieces that turn into spheres, ellipsoids or rounded rods on the rotating plate. The preferred method and composition of this process comprises about 2099% microcrystalline cellulose and about 80-1% GHSEC, respectively, based on the aqueous weight.

A preferred process for producing matrix composite particles is the rotating granulation process. For this process, GHSEC and binders, such as microcrystalline cellulose, are placed in a rotary vessel of a fluid bed processing apparatus. The active ingredient and excipient are liquefied while spraying a solution which binds the active ingredient and excipients into granules or composite particles. The solution sprayed into the liquid bed may be water or an aqueous solution of binding agents such as polyvinylpyrrolidone or hydroxypropylmethylcellulose. A preferred composition of this process comprises about 1-80% GHSEC, about 10-60% microcrystalline cellulose, and about 0-25% binding reagent.

A further preferred process for the production of matrix composite granules comprises the coating of GHSEC, matrix-forming binders, and, optionally, release modifying or solubilizing reagents on cores such as sugar cores, so-called non-pareils. Such coatings may be applied by a variety of methods well known in the pharmaceutical art, such as spray coating in a fluid bed coating, spray drying, and granulation techniques such as liquid bed or rotary granulation. Coatings can be applied from aqueous, organic or molten solutions and suspensions.

Another preferred process for the production of matrix composite granules is the production of wax granules by the melt-cure process. In this process, the desired amount of GHSEC is mixed with liquid wax to form a homogeneous mixture, cooled and passed through a sieve to form granules. Alternatively, the homogeneous mixture may be added to a rotating disk where the mixture is disintegrated into droplets&gt; · - »♦ ***. · Ϊ · * «· · * · * &lt;

• · «« · · «- *» / '* * »· * *' &lt;Leaving the edge of V. These droplets are then cooled and solidified before reaching the collection chamber. Preferred matrix materials are waxy. Particularly preferred are hydrogenated castor oil, glyceryl behenate, microcrystalline wax, carnauba wax and stearyl alcohol.

Another preferred process for producing matrix composite particles is the use of an organic solvent to mix GHSEC with the matrix material. This method can be used when it is desirable to use a matrix material which has an undesirably high melting point that would result in degradation of the active ingredient or matrix material in the molten state or would result in an unacceptable melt viscosity that would prevent GHSEC from being mixed with the matrix material. . The GHSEC and matrix material can be mixed with a small amount of solvent to form a pulp and then passed through a sieve to form granules, from which the solvent is removed. Alternatively, the GHSEC and the matrix material are mixed with as many solvents as necessary to completely dissolve the matrix material and spray dried to form a particulate dosage form by spraying the resulting solution (which may contain solids). This method is advantageous when the matrix material is a high molecular weight synthetic polymer such as cellulose ether or cellulose ester. Typically used solvents include acetone, ethanol, isopropanol, ethyl acetate, and mixtures of two or more.

Another preferred process for the production of matrix composite particles is the use of an aqueous solution or suspension of GHSEC and matrix constituents. The solution or suspension may be spray-dried or sprayed into a stop bath or through a light chamber to initiate crosslinking and droplet solidification of the matrix materials. In this way, a matrix can be prepared from latexes (e.g., with dispersed ethylcellulose softener such as oleic acid, or with a water-miscible solvent such as acetone or ethanol) by spray drying techniques. Matrices of water-soluble polymer or rubber can also be prepared by this method. For example, sodium alginate may be cross-linked by spraying with a solution containing soluble calcium salts, cross-linked with polyvinyl alcohol by spraying with a solution containing glutaraldehyde, and di- and tri-acrylates may be cross-linked by UV radiation.

Once prepared, the GHSEC matrix composite granules may be blended with compressible binders such as lactose, mannitol, microcrystalline cellulose, dicalcium phosphate, and the like, and compressed into tablets. Spraying reagents such as sodium starch glycolate, croscarmellose sodium or cross-linked polyvinylpyrrolidone are also useful. Tablets made by this process will disintegrate when placed in an aqueous medium (such as the gastrointestinal tract), thereby providing the compound particulate matrix from which the GHSEC is released. GHSEC matrix composite granules may also be filled into capsules, such as hard gelatin capsules. Compound granules may also be added directly as a woody mixture, mixed with water or other suitable drink or · sprayed directly onto the food.

Another embodiment of the matrix system is a GHSEC-containing hydrophilic matrix tablet which is ultimately dissolved or dispersed in water and the amount of hydrophilic polymer sufficiently regulates the release of GHSEC. From such matrices, GHSEC may be released by diffusion, matrix disintegration or dissolution, or a combination of these mechanisms. Suitable hydrophilic polymers for forming a hydrophilic matrix include HPMC, HPC, hydroxyethylcellulose (HEC), PEO, PVA, polyacrylic acid, xanthan gum, carbomer, carrageenan and zooglan. HPMC is the preferred material. Other similar hydrophilic polymers may be used. During operation, the hydrophilic material swells and eventually dissolves or disperses in water. The release rate of GHSEC from hydrophilic matrix formulations can be controlled by the amount and molecular weight of the hydrophilic polymer employed. Generally, the use of a higher amount of hydrophilic polymer reduces the release rate, as does the use of a higher molecular weight polymer. The use of a lower molecular weight polymer increases the release rate. The release rate can also be controlled using water-soluble additives such as sugars, salts and soluble polymers. Examples of these additives are sugars such as lactose, sucrose or mannitol, salts such as NaCl, KCl, NaHCO₃, and water soluble polymers such as PVP, low molecular weight HPC or HMPC or methylcellulose. Generally, the composition has a solubility content55

<img file="HU0103494A2_D0012.tif" />

increasing the release rate increases the release rate. In addition, any of the aforementioned dissolution aids or excipients may be incorporated into the matrix tablets to increase the release rate of GHSEC, increase the amount of total GHSEC released, and potentially increase the absorption and consequent bioavailability of GHSEC, especially in matrix formulations. hours or more to release GHSEC. A hydrophilic matrix tablet typically contains from about 1% to about 90% by weight of GHSEC and from about 8% to about 10% of polymer.

Preferred hydrophilic matrix tablets are typically about 3% to about 80% by weight of GHSEC, about 5% to about 35% HPMC, about 0% to about 55% lactose or mannitol, about 0% to about 15% PVP, about 0% to about 20% microcrystalline cellulose. , and contains from about 0.25% to about 2% magnesium stearate.

Mixtures of polymers and rubbers may also be used to form hydrophilic matrix systems. For example, homopolysaccharide gums, such as galactomannans (e.g., gorse gum or guar gum), mixed with heteropolysaccharide gums (e.g., xanthan gum or derivatives) may provide a synergistic effect that provides faster formation and more rigid matrices for release of the active ingredient. 5,512,297. United States Patent Nos. Optionally, crosslinking agents such as calcium salts may be added to improve the matrix properties.

Hydrophilic matrix formulations which eventually dissolve or disperse also form composite granules56 • «· · • ·

I can be made. Hydrophilic matrix composite particles can be fabricated on non-dispersible matrix composite particles by methods previously described. Preferred manufacturing methods are to coat GHSEC, hydrophilic matrix material and optionally release modifying reagents by spray coating on cores (e.g., "non-pareils") or to form composite granules such as GHSEC, hydrophilic matrix material and case, by rotating granulation of the release modifying reagent.

A class of matrix systems is a frequently reported phenomenon of non-constant release of active ingredient from a matrix. This may be due to the release of the drug by the diffusion mechanism, and modification of the geometry of the dosage form and / or coating or partial coating of the dosage form can advantageously be used to make the release rate of the drug more stable as follows.

In another embodiment, the GHSEC matrix tablet is coated with an impermeable coating and an opening (e.g., a circular hole or rectangular slot) is provided to allow the tablet contents to contact the aqueous gastrointestinal tract. These embodiments are disclosed in U.S. Patent No. 4,792,448 to Ranade and Hansson et al. [J. Pharm.

Sci., 77, 322-324.old. (1988)]. The orifice is typically of such a size that the exposed GHSEC area is less than about 40% of the surface of the device, preferably less than about ν

15%.

In another embodiment, the GHSEC matrix tablet is coated with an impermeable coating on a portion of its surface, such as one or both tablet surfaces, or on the surface of the tablet rim.

In another embodiment, the GHSEC matrix tablet is coated with an impermeable coating and an opening is drilled through the coating for drug delivery. The orifice may only be through the coating or extend as a passageway in the tablet.

In another embodiment, the GHSEC matrix tablet is coated with an impermeable coating and a passageway is drilled through the entire tablet at the cost of drug delivery.

In another embodiment, the GHSEC matrix tablet is coated with an impermeable coating and one or more passageways are provided for transporting the active ingredient by removing one or more strips of the impermeable coating or by cutting one or more gaps through the coating, preferably on the rim or tablet surface.

In another embodiment, the GHSEC matrix tablet is shaped as a suppository and completely coated with an impermeable coating. By cutting off the tip of the suppository, a passageway is prepared for drug delivery.

In another embodiment, the GHSEC matrix tablet is hemispherical and completely coated with an impermeable coating. Circle of flat side of hemisphere58 · · *

I

<img file="HU0103494A2_D0013.tif" />

by drilling a zepene hole to form a passageway for drug delivery.

In another embodiment, the GHSEC matrix tablet is semi-cylindrical and completely coated with an impermeable coating. For the GHSEC transport, a passageway is made by cutting a gap (or removing a strip) in the centerline of the flat side of the half-cylinder through the impermeable coating. One of ordinary skill in the art will recognize that geometric modifications to the embodiments described above may be produced in an equivalent manner by more than one method.

By "impermeable material" is meant a material that is sufficiently thick and impermeable for GHSEC to release most of the GHSEC through the gateway rather than through the "impermeable material" for the intended release of the active ingredient. Such a coating can be obtained by selecting a coating material having a sufficiently low diffusion coefficient for GHSEC and applying it at a sufficient thickness. Essentially any material having a GHSEC diffusion coefficient of less than about 10 'is suitable to form an impermeable coating according to these embodiments.⁷ cm²/ Sec. It is noted that this diffusion coefficient may be ample to enable the release of GHSEC from a previously discussed matrix device. However, in a device of the type discussed herein, which has a macroscopic aperture or passageway, material having this coefficient is effectively impermeable to GHSEC.

Compared to GHSEC's transport through the gateway. Preferred coating materials include film-forming polymers and waxes. Particularly preferred are thermoplastic polymers such as poly (ethylene-co-vinyl acetate), polyvinyl chloride, ethyl cellulose and cellulose acetate. These materials exhibit the desired low GHSEC penetration rate when the coating thickness is greater than about 100 µm.

The second class of sustained release dosage forms of the invention include membrane controlled or storage systems, such as membrane-coated diffusion-based capsules, tablets or composite granules. Capsules, tablets and composite granules may also be storage systems such as those based on membrane-coated diffusion. In this class, the GHSEC storage is surrounded by a speed limiting membrane. GHSEC passes through the membrane via mass transport mechanisms well known in the art, including, but not limited to, diffusion through the membrane after dissolution in the membrane or diffusion through pores filled with fluid in the membrane. These individual storage system dosage forms may be large, such as in the case of a tablet with a large storage space, or in the form of a composite granule, such as a capsule containing a plurality of individual membrane-coated storage particles. The coating may be non-porous but still permeable to GHSEC (e.g., GHSEC may directly diffuse through the membrane) or may be porous.

• · · « • ··.* •4

Sustained-release coatings known in the art may be used to form the membrane, particularly polymer coatings such as cellulose ester or ether, acrylic polymer, or a mixture of polymers. Preferred materials include ethyl cellulose, cellulose acetate and cellulose acetate butyrate. The polymer may be used as a solution in an organic solvent or as an aqueous dispersion or latex. The coating process may be carried out in conventional equipment such as a liquid bed coat, a Wurster coat or a rotary bed coat.

If desired, the permeability of the coating may be varied by mixing two or more materials. A particularly suitable method for adjusting the porosity of the coating is the addition of a predetermined amount of finely divided water soluble material, such as sugars, salts, or water soluble polymers, to the solution or dispersion (e.g., aqueous latex) of the membrane-forming polymer employed. When the dosage form enters the aqueous medium of the gastrointestinal tract, these water-soluble membrane additives leak out of the membrane, leaving pores that promote release of the active ingredient. The membrane coating may also be modified by the addition of plasticizers, as is known in the art.

In a particularly preferred embodiment of the membrane coating process, the coating polymer is dissolved in a mixture of solvents which, upon drying of the coating, undergo phase inversion in the applied coating polymer to form a porous membrane. Several examples of such coating systems are disclosed in U.S. Patent No. 5,612,059.

The morphology of the membrane is not critical as long as the listed permeability properties are present. However, specific membrane forms may have membrane morphological conditions to achieve the desired permeability. The membrane may be amorphous or crystalline. Any type of morphology may be prepared by any specific method, and may include, for example, a surface polymerized membrane (containing a thin rate limiting crust on a porous support), a porous hydrophilic membrane, a porous hydrophobic membrane, a hydrogel membrane, an ionic membrane, and other membranes controlled by GHSEC characterized.

A suitable storage system embodiment is a capsule having a rate limiting membrane formed from any one of the membrane materials discussed above and filled with a GHSEC drug formulation. A particular advantage of this configuration is that the capsule can be manufactured independently of the active ingredient, thereby applying process conditions that can be detrimental to the active ingredient. In a preferred embodiment, the capsule shell is made of a porous or permeable polymer by a hot forming process. In a particularly preferred embodiment, the shell of the capsule has an asymmetric membrane, i.e. a thin and dense portion on one surface of the membrane, and most of its thickness is made up of highly permeable porous material. A preferred process for preparing asymmetric membrane capsules is solvent exchange phase inversion, wherein a phase separation is induced in a solution of the polymer in capsule form with a non-solvent miscible with the solvent. Examples of asymmetric membranes suitable for use in the present invention are disclosed in U.S. Patent Nos. 5,698,220 and 5,612,059.

Tablets may also be storage systems. Tablet cores containing GHSEC can be prepared by methods conventional in many pharmaceutical industries. These cores may be coated with a rate limiting coating as described above to allow the GHSEC in the storage site to diffuse at the desired rate through the coating.

Another embodiment of storage systems is composite granules in which each particle is coated with a sustained release polymer of GHSEC. Each particle of the composite particle contains GHSEC and one or more binders as required by manufacture and performance. The size of the individual particles, as mentioned above, is generally in the range of about 50 µm to about 3 mm, although beads of a size outside this range may be suitable. Generally, the beads contain one or more binders. Because it is generally desirable to formulate dosage forms that are small and easy to swallow, beads having a high GHSEC ratio of binders are preferred. Preferred binders for the production of these beads include microcrystalline cellulose (e.g., Avicel®, EMC Corp.), HPC, HPMC, and related materials, or combinations thereof. Generally, binders for granulation and tabletting,

<img file="HU0103494A2_D0014.tif" />

starches, gelatinized starches and PVP can also be used in compound granules.

GHSEC composite granular storage systems can be prepared by methods known to those of ordinary skill in the art, including, without limitation, extraction and spheronization, wet granulation, liquid bed granulation, melt freezing, and rotary bed granulation. In addition, the beads may be prepared by applying the GHSEC formulation (GHSEC and binders) to the cores (e.g., "non-pareils") by drug layering, such as powder coating, or by applying the GHSEC formulation to a solution of GHSEC in a suitable binder solution. or by spraying its dispersion onto the cores in a fluid bed device such as a Wurster coating or rotary processor. An example of a suitable formulation and process is a spray dispersion of GHSEC / hydroxypropyl cellulose formulation in water.

A preferred process in this embodiment is the extrusion / spheronization process as discussed above for matrix composite particles. A preferred method and composition for this process is the use of about 599% microcrystalline cellulose and about 951% GHSEC, based on the aqueous weight. Particularly preferred is about 95-50% microcrystalline cellulose and suitably about 5-50%

Application of GHSEC.

A preferred process for producing composite granular cores according to this embodiment is the rotating granulation process as discussed above for matrix composite granules.

Another preferred process for producing composite particulate cores according to this embodiment is the melt-freezing process, as discussed above for matrix composite grains.

Another preferred method of making composite granular cores of this embodiment is to coat the cores with GHSEC and optionally other binders, as discussed previously for matrix composite granules.

Sustained-release coatings known in the art, in particular polymer coatings, can be used for membrane fabrication, as discussed previously for storage systems. Suitable and preferred polymeric coating materials, equipment and coating methods include those discussed above.

The rate of GHSEC release from the coated composite particles can also be controlled by factors such as the composition and binder content of the active ingredient core, the coating thickness and permeability, and the surface to volume ratio of the composite particles. One skilled in the art will recognize that increasing the thickness of the coating may decrease the rate of release, while increasing the permeability or surface to volume ratio of the composite particles may increase the rate of release. Optionally, the permeability of the coating may be changed by mixing two or more materials. Suitable series of coatings include mixtures of water-soluble and water-insoluble polymers, such as ethyl cellulose and hydroxypropyl methylcellulose.

Particularly suitable for coating modification finely divided water65 · ···

<img file="HU0103494A2_D0015.tif" />

addition of a soluble substance such as sugars or salts. When placed in an aqueous medium, these water-soluble membrane additives leak out of the membrane leaving pores that promote release of the active ingredient. The membrane coating may also be modified by the addition of plasticizers as known to those skilled in the art. In a particularly preferred embodiment of the membrane coating process, the coating polymer is dissolved in a mixture of solvents which, upon drying of the coating, undergoes phase inversion in the applied coating solution to form a porous membrane.

A preferred embodiment of the composite core particles comprises from about 1% to about 50% GHSEC and comprises about 10% to about 70% of one or more of microcrystalline cellulose, lactose, mannitol, glyceryl behenate, stearyl alcohol, microcrystalline wax, PVP, HPC and HPMC. The individual cores are coated either with an aqueous dispersion of ethyl cellulose, which dries to form a continuous film, or with a cellulose acetate film containing PEG, sorbitol or glycerol as the release modifier.

A third class of sustained release dosage forms comprises osmotic delivery devices known in the art as an "osmotic pump". The osmotic pumps consist of a core containing an osmotically active composition and a semipermeable membrane surrounding it. "Semi-permeable in this sense means that water can pass through the membrane, but

6 ··· · · · * ϊ • · · ·?

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Dissolves through the membrane at a significantly slower rate than water. During use, when placed in an aqueous medium, the device absorbs water due to the osmotic activity of the composition in the core. Due to the semi-permeability of the surrounding membrane, the contents of the device (including the active ingredient and any binders) are unable to penetrate through non-porous portions of the membrane and, due to osmotic pressure, force the device to leave through an opening or passageway is formed in the dosage form or otherwise in situ in the gastrointestinal tract by deliberately rupturing the coating's weakened points under osmotic pressure, or otherwise generated in situ in the gastrointestinal tract by dissolution and removal of water-soluble pore-formers incorporated into the coating. Osmotically effective formulations include water-soluble materials that produce colloidal osmotic pressure and swellable polymers. The active ingredient itself (if highly water soluble) may be the osmotically active component of the mixture. 2-amino- N - [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridine-5) -yl) -1- (R) -benzyloxymethyl-2-oxoethyl] -isobutyramide L-tartrate, having a solubility of more than 150 mg / ml, provides an osmotic pressure of about 4 atmospheres sufficient to contribute somewhat to the osmotic drive . Because of this GHSEC base, its solubility has a higher acidic pH η. Thus, the osmotic efficacy of GHSEC can be enhanced by the presence of acidic buffers in the formulation. The active compound formulation is movable

<img file="HU0103494A2_D0016.tif" />

partition or piston can be used to separate the osmotically active components.

Suitable materials for making semipermeable membranes include polyamides, polyesters and cellulose derivatives. Cellulose ethers and esters are preferred. Particularly preferred are cellulose acetate, cellulose acetate butyrate and ethyl cellulose. Particularly suitable materials include those which spontaneously form one or more passageways, either during manufacture or when introduced into the application medium. These preferred materials are porous polymers whose pores are formed by phase inversion during manufacture as described below or by dissolution of the water soluble component present in the membrane.

A particular class of materials useful in forming semipermeable membranes for use in osmotic release devices is porous hydrophobic polymers and vapor permeable films as disclosed in U.S. Patent No. 5,827,538. These materials are very impermeable to water, but very impermeable to substances dissolved in water. These materials are highly permeable to water due to the presence of many microscopic pores (i.e., pores that are much larger than molecular sizes). Despite their porosity, these materials are impermeable to molecules in aqueous solutions because the pores are not wetted by liquid water. The vapor phase water easily passes through the membranes made of these materials. Such membranes are also referred to as vapor permeable membranes.

A preferred embodiment of this class of osmotic delivery devices is a coated bilayer tablet. The coating of such a tablet is water-permeable, but essentially consists of a membrane impermeable to GHSEC and binders contained therein. The coating comprises one or more exits connected to the GHSEC-containing layer to release the GHSEC. The core of the tablet consists of two layers: one layer containing the GHSEC formulation (including optional osmotic reagents and hydrophilic water soluble polymers) and the other layer containing water swellable material with or without additional osmotic reagents.

When placed in an aqueous medium, the tablet absorbs water through the membrane, thereby causing the aqueous composition to be liberated from the GHSEC composition and expanding the swelling layer, which presses the GHSEC composition and squeezes it through the exit. The GHSEC preparation may also swell, helping to squeeze the GHSEC through the exit. GHSEC is released from this type of system, either dissolved or dispersed, in an exudate formulation.

The rate of GHSEC release is controlled by factors such as coating thickness and permeability, osmotic pressure of the GHSEC-containing layer, water activity of the swelling layer, and surface of the device. It will be apparent to those skilled in the art that increasing coating thickness may decrease release rate, while increasing coating permeability or hydrogel layer water activity or GHSEC-containing layer osmotic pressure or device surface may increase release rate.

Illustrative materials for the formulation of GHSEC include, in addition to GHSEC itself, HPMC, PEO, and PVP, and other pharmaceutically acceptable carriers. In addition, osmotic reagents such as sugars and salts, in particular sucrose, lactose, mannitol or sodium bitartrate, may be added. Suitable materials for forming the swellable layer include sodium carboxymethyl cellulose, poly (ethylene oxide), poly (acrylic acid), sodium (polyacrylate), hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), and other high molecular weight materials. hydrophilic materials. In addition, osmotic reagents such as sugars and salts may be added. Polyethylene oxides having a molecular weight of about 5,000,000 to 7,500,000 are particularly suitable.

Suitable coating materials are cellulose esters, cellulose ethers and cellulose ester ethers. Cellulose acetate and ethyl cellulose and optionally PEG as a permeation modifier are preferred.

The exit must be on the side of the GHSEC tablet. There may be more than one such exit. The exit may be made mechanically either by laser drilling or by creating a hard-to-cover area on the tablet by special machining during tablet compression or otherwise. The rate of GHSEC release from the device can be optimized by developing a method for using GHSEC in a mammal to determine the optimal therapeutic effect.

Osmotic systems can also be made with a homogeneous core and a semipermeable membrane coating surrounding it. GHSEC may be incorporated into a tablet core containing other suitable osmotic propellant excipients and optionally solubility excipients such as acids. The semipermeable membrane coating can be applied by conventional tableting techniques, such as a pan coating. Thereafter, a drug release exit may be provided in this coating by drilling a hole, laser or mechanically. Alternatively, the exit may be formed by breaking a portion of the coating, or by creating a difficult to coat portion on the tablet, as described above.

The core may contain one or more pharmaceutically active agents, water-soluble materials for inducing osmosis, non-swellable solubilizers, non-swellable (water-soluble or water-insoluble) impregnating reagents, swellable hydrophilic polymers, binders, and lubricants.

The osmotically active (water soluble) reagent is typically a sugar alcohol, such as mannitol or sorbitol, or a combination of sugars and polysaccharides, such as dextrose and maltose, or a physiologically tolerable salt, such as sodium or potassium chloride, compatible with the other components. Another osmotic reagent is urea. Examples of water soluble materials that induce osmosis include: inorganic salts such as magnesium chloride or magnesium sulfate, lithium, sodium or potassium chloride, lithium, sodium or potassium hydrogen or dihydrogen phosphate, organic salts thereof, such as sodium or potassium acetate, magnesium succinate, sodium benzoate, sodium citrate or sodium ascorbate; carbohydrates such as sorbitol or mannitol (hexite), arabinose, dextrose, ribose or xylose (pentose), glucose, fructose, galactose or mannose (hexose), sucrose, maltose or lactose (disaccharides) or raffinose (trisaccharides); water-soluble amino acids such as glycine, leucine, alanine or methionine, urea, and the like, and mixtures thereof. The proportion of these water-soluble binders in the core may be from about 0.01% to about 45% by weight based on the total weight of the therapeutic system.

Non-swellable solubilizing reagents include (a) reagents that inhibit or complex any crystallization of the drug; (b) high HLB (hydrophilic lipophilic equilibrium) micelle-forming surfactants, especially nonionic and / or anionic surfactants; (c) citrate esters; and combinations thereof, in particular complexing reagents and anionic surfactants. Examples of reagents that inhibit or otherwise complex crystallization of the drug include polyvinylpyrrolidone, polyethylene glycol (especially PEG8000), cyclodextrins and modified cyclodextrins. Examples of high HLB micelle-forming surfactants include Tween-20, Tween-60, Tween-80, polyoxyethylene or polyethylene-containing surfactants, or other long-chain anionic surfactants, especially sodium lauryl sulfate. Preferred examples of citrate ester derivatives include alkyl esters, especially triethyl citrate.

• - «*· 2 ·«« #**» * ·*

Particularly preferred combinations thereof are polyvinylpyrrolidone sodium lauryl sulfate and polyethylene glycol sodium lauryl sulfate.

Non-swellable wetting agents are used to create channels or pores in the tablet core. This facilitates the flow of water through the core through physical absorption. Preferred absorbing reagents do not swell to any appreciable extent. These materials can be water soluble and water insoluble. Suitable water-soluble reagents for the wetting reagent include surfactants such as alkyl sulfate anionic surfactants such as sodium, potassium or magnesium lauryl sulfate, n-tetradecyl sulfate, n-hexadecyl sulfate or n-octadecyl sulfate; alkyl ether-type anionic surfactants, such as sodium, potassium or magnesium n-dodecyloxyethyl sulfate, n-tetradecyloxyethyl sulfate, n-hexadecyloxyethyl sulfate or n-octadecyloxyethyl sulfate; anionic surfactants of the alkyl sulfonate type, such as sodium, potassium or magnesium n-dodecane sulfonate, n-tetradecane sulfonate, n-hexadecane sulfonate or n-octadecane sulfonate. Other suitable surfactants include non-ionic surfactants of the fatty acid polyhydroxy alcohol ester type, such as sorbitan monolaurate, sorbitan trisisterate or triolate, polyethylene glycol fatty acid esters such as polyoxyethyl stearate, polyethylene glycol-400 stearate, stearate, preferably

Polyethylene oxide / pro73 * of Pluronic® (BASF, Parsippany, NJ) or Synperonic® (ICI Surfactants, Everberg, Belgium) ·

<img file="HU0103494A2_D0017.tif" />

pilene oxide block copolymers, polyglycerol fatty acid esters or glycerol fatty acid esters. Sodium lauryl sulfate is particularly suitable. When present, a preferred amount of these surfactants is from about 0.2% to about 2% of the total weight of the core. Other soluble wetting agents include low molecular weight polyvinylpyrrolidone and m-pyrrole.

Non-limiting examples of water-insoluble materials suitable for use as a wetting reagent include colloidal silica, kaolin, titanium dioxide, fumed silica, aluminum, niacinamide, bentonite, magnesium aluminum silicate, polyester, polyethylene. Particularly suitable insoluble absorbent reagents include colloidal silica.

Suitable materials for forming a semipermeable wall include microporous materials disclosed in U.S. Patent Nos. 3,916,899 and 3,977,404. Acylated cellulose derivatives (cellulose esters) substituted with 1 to 3 acetyl groups or substituted with one or two acetyl groups and an additional non-acetyl acyl group, such as cellulose acetate, cellulose triacetate, agar may be used. acetate, amylose acetate, beta-glucan acetate, beta-glucan triacetate, ethyl cellulose, cellulose acetate ethyl carbamate, cellulose acetate phthalate, cellulose acetate methyl carbamate, cellulose acetate succinate, cellulose acetate dimethylaminoacetate, cellulose acetate ethyl carbonate, cellulose acetate chloroacetate, cellulose acetate ethyl oxalate, cellulose acetate74

........

... ·. ·························································································································································································································. acetate derivatives. Suitable semi-permeable membrane materials include acacia gum triacetate, methylcellulose, hydroxypropylmethylcellulose and polymeric epoxides, copolymers of alkylene oxides, polyvinylmethyl ether polymers and alkyl glycidyl ethers, polyglycols and their derivatives. other derivatives. Mixtures of insoluble polymers which, upon coating, form a semi-permeable film, such as copolymers of water-insoluble acrylates such as ethyl acrylate and methyl methacrylate, may also be used.

A second water-soluble component may be added to increase the permeability of the coating. A preferred water-soluble component is C₂-C₄alkylene glycol, preferably polyethylene glycol.

An embodiment of the GHSEC sustained release osmotic dosage form of the present invention comprises a GHSEC osmotic-containing tablet surrounded by an asymmetric membrane having one or more thin dense portions of the membrane with less dense portions. This type of membrane, which is similar to that used in the reverse osmosis industry, generally allows for greater osmotic flow of water than can be achieved with dense membranes. When used in an active agent formulation such as a tablet, an asymmetric membrane allows for high drug flow and well controlled sustained release. This asymmetric membrane is a semipermeable polymeric material

<img file="HU0103494A2_D0018.tif" />

it is a substance which is permeable to water and substantially impermeable to salts and organic solutes such as GHSEC.

Suitable materials for forming semipermeable membranes include polyamides, polyesters and cellulose derivatives. Cellulose ethers and esters are preferred. Particularly preferred are cellulose acetate, cellulose acetate butyrate and ethyl cellulose. Particularly suitable materials include those which spontaneously form one or more passageways, either during manufacture or when introduced into the application medium. These preferred materials contain porous polymers whose pores are formed by phase inversion during manufacture as described below or by dissolution of the water-soluble component present in the membrane.

The asymmetric membrane is formed by a phase inversion method. The coating polymer, such as ethyl cellulose or cellulose acetate, is dissolved in a solvent mixture containing solvents (e.g. acetone) and non-solvents (e.g. water). The components of the solvent mixture are selected so that the solvent (e.g. acetone) is more volatile than the non-solvent (e.g. water). When the tablet is immersed in such a solution, taken out and dried, the solvent component of the solvent mixture evaporates faster than the non-solvent. During drying, this change in the solvent composition results in a phase inversion, which results in the polymer precipitating on the tablet as a dense outer porous solid coating. There are many pores in this outer region through which the active substance can be released.

In a preferred embodiment of the asymmetric membrane coated tablet, the polymer / solvent / non-solvent mixture is sprayed onto tablets in a tablet coating device such as Freund HCT-30 tablet coating (Freund Industrial Co., Tokyo, Japan).

In the application medium, i.e. in the gastrointestinal tract, water is absorbed through the semipermeable asymmetric membrane into the core of the tablet. A soluble substance dissolves in the tablet core and forms an osmotic gradient across the membrane. When the hydrostatic pressure in the membrane-surrounded core exceeds the pressure of the application medium (i.e., the gastrointestinal tract cavity), the GHSEC-containing solution is "pumped" out of the dosage form through pre-formed pores in the semipermeable membrane. Constant membrane osmotic pressure results in consistent, well-controlled release of GHSEC into the application medium. Part of the GHSEC dissolved in the tablet is released by diffusion.

In this asymmetric membrane coated embodiment, highly soluble GHSEC salts are preferred. Also preferred are one or more solubilizers, ascorbic acid, erythorbic acid, citric acid, fumaric acid, succinic acid, tartaric acid, sodium bitartrate, glutamic acid, aspartic acid, partial glycerides, glycerides, glycerol esters, polyethylene glycols, polyethylene glycols, esters, polyoxyethylene ethers, sorbitan esters, polyoxyethylene sorbitan esters, saccharide esters • · · ·

<img file="HU0103494A2_D0019.tif" />

blends of spaces, phospholipids, polyethylene oxide-polypropylene oxide block copolymers and polyethylene glycols. Most preferred dissolution aids are fumaric acid, ascorbic acid, succinic acid and aspartic acid.

Osmotic tablets may be prepared by encapsulating a core of tablets containing osmogens and / or dissolution aids, first with an active ingredient layer and secondly with a semi-permeable coating. Tablet cores containing osmogens and / or dissolution aids may be prepared by conventional tableting techniques known in the pharmaceutical industry. The semi-permeable coating can then be applied by a variety of methods known in the art, such as by spraying or immersion coating as described hereinabove. The drug-containing layer may be applied by coating techniques around the core, whereby a solution or dense suspension of the drug and binders is applied as a coating on the tablet core. The active ingredient and excipients may be layered around the tablet core by providing a "layered" type configuration using a tablet press to form a second active ingredient layer around the core. This type of compression coating can also be used to apply a powder coating (without solvents) around the tablet core.

Another embodiment of the GHSEC sustained release osmotic dosage form of the invention comprises a composite particle of GHSEC osmotic content surrounded by an asymmetric membrane. GHSEC-containing composite granules are prepared, for example, by extraction / spheronization or liquid bed granulation or by coating non-para-nuclei with a mixture of GHSEC and water soluble polymer as previously described. The GHSEC-containing composite particles are then spray-coated with a polymer in a mixture of solvent and non-solvent to produce a composite film coated with an asymmetric membrane. This spray coating operation is preferably carried out in a liquid bed coating apparatus, such as a Glatt GPCG-5 liquid bed coating (Glatt Air Techniques, Inc., Ramsey, NJ). The polymer used to form the semipermeable asymmetric membrane is selected as described above for the asymmetric membrane coated tablets. Similarly, the binders for the composite particle cores may be selected as described above for asymmetric membrane coated tablets.

Osmotic capsules may be prepared using the same or similar components as described above for osmotic tablets and composite granules. The capsule shell or a portion of the capsule shell may be semi-permeable and may be made from the materials described above. The capsule can then be filled with a powder or liquid containing GHSEC, binders for osmotic potential, and optionally solubilizers. The capsule core may also be made so as to have a bilayer or multilayer structure analogous to the bilayer tablet described above.

The fourth class of sustained release dosage forms of the invention include coated swellable tablets and composite granules which are

.... · »····.”. j

........: .

"* · · '·.? - dependent on U.S. Patent Application Serial No. 07 / 296,464 (filed Jan. 12, 1989, published as EP-A-378404 A2) : July 7, 1990). Coated swellable tablets contain GHSEC and a tablet core containing a swellable material, preferably a hydrophilic polymer, which contains holes or pores through which the hydrophilic polymer can protrude and carry GHSEC in an aqueous application medium. Alternatively, the membrane may comprise polymeric or low molecular weight water-soluble pores which dissolve in the aqueous application medium and form pores through which the hydrophilic polymer and GHSEC can protrude. Examples of pore former are water-soluble polymers such as hydroxypropylmethylcellulose and low molecular weight compounds such as glycerol, sucrose, glucose and sodium chloride. In addition, pores may be formed in the coating by drilling holes using a laser or other mechanical means. In this fourth class of sustained release GHSEC dosage forms, the membrane material may include any film forming polymer, including water permeable or impermeable polymers, provided that the membrane applied to the tablet core comprises porous or water soluble pore formers or macroscopic holes. it has water inlet and GHSEC release. Compound granules (or beads) can be similarly prepared with a GHSEC / swelling core coated with a porous or pore-forming membrane. The embodiments of this fourth class of GHSEC sustained release dosage80 • · · »may be multilayered, as in

EP 378 404 A2. European Publication Number.

Sustained-release formulations may be prepared with the initial rapid release of a portion of the dose followed by sustained release of the remainder of the dose.

Formulations that release a portion of the dose as a bolus shortly after administration and then sustainably release the remainder of the dose over a period of time, such as 2 to 18 hours or more, can be prepared by a variety of methods. For example, a bilayer tablet may be formulated with one layer containing a sustained release matrix and the other with an immediate release formulation. After ingestion, the immediate release layer disintegrates and only the sustained release matrix tablet remains. Alternatively, a matrix or osmotic tablet or sustained release composite granule may be coated with an active ingredient coating. The coating may be applied using typical coating equipment conventional in the pharmaceutical industry. The active ingredient can be either a solution or a suspension and is typically mixed with a water-soluble polymer in the coating solution. In addition, a compound dosage form can be prepared by mixing sustained release compound particles and immediate release compound particles in a single dosage form. A preferred process for preparing a formulation comprising an immediate release component and a sustained release component is by applying an extruded coating to an osmotic coating.

··· • ·· / tablet.

Osmotic tablets contain a tablet core which contains the active ingredient and may contain binders having an osmotic potential greater than that of the fluid of the application medium or water swellable materials. The tablet core is surrounded by a semipermeable coating that allows water to be absorbed into the tablet core. During operation, it is important that this semi-permeable membrane remains intact if the coating is cracked or broken, dose spills may occur, or the release rate may be significantly increased. An extruded coating is prepared by compressing a powder granule around a tablet core to form an outer layer or coating. This is done in specialized tablet presses where the core is placed in the powder / granulate during the extrusion step. The immediate release drug layer can be applied around an osmotic tablet core without breaking or breaking the semi-permeable coating, i.e. without affecting the release rate of the osmotic tablet within the extruded coating.

In addition to sustained release dosage forms, the invention also encompasses sustained release dosage forms. The delayed-release dosage form may operate in a manner sensitive to the environment in which it is used, by delaying the release of growth hormone secretagogue until it enters the small intestine. This type of delayed release dosage form is dependent on the gastrointestinal tract location and is independent of the particular gastrointestinal tract.

- · · time, and referred to herein as "spatial dosage form, or" spatially delayed release. Once the dosage form has entered the small intestine, it can release growth hormone secretagogue immediately, “immediate release! meaning that there is no component or device in the dosage form that will deliberately delay or delay release after the delay period has expired. Examples of space-delayed dosage forms are (1) pH-initiated dosage forms that delay the release of growth hormone secretagogue until the dosage form reaches a small intestine medium with a pH greater than 6, and (2) initiated dosage forms that delay the release of growth hormone secretagogue until the coating of the dosage form is adequately altered by interaction with lipases, esterases or proteases in the small intestine. In one embodiment, spatially delayed dosage forms generally begin to release growth hormone secretagogue within about 30 minutes, preferably within 15 minutes of passing from the stomach to the small intestine. Alternatively, the spatially delayed dosage form may release the growth hormone secretagogue over a period of time after the delay period.

In addition to the space-delayed dosage forms discussed above, the dosage form may also function by delaying the release of growth hormone secretagogue for a specified period of time. This type of dosage form is referred to herein as a "delayed release or a delayed release". A time delay is the delay after ingestion of the dosage form, which delay is not related to the location of the dosage form in the gastrointestinal tract. Time-delayed dosage forms may be considered to be initiated in the presence of water and are a means of delayed release of growth hormone secretagogue after release into an aqueous medium for a defined period of time.

It is well known that the retention time of the dosage form in the stomach depends on whether the subject has eaten. Certain dosage forms, such as non-disintegrating tablets, may remain in the stomach until the food is substantially transported in the douden and the retention time in the stomach may be up to 3 hours. Compound particle dosage forms also spend more time in a full stomach than in an empty stomach, although in this case the increased residence reflects the longer half-life of the elimination of these small compound particles from the stomach.

A first-space delayed release embodiment is a pH-dependent coated tablet comprising an immediate release tablet or tablet core coated with a substance which is substantially impermeable to growth hormone secretagogue at gastric pH but which is permeable to the small intestine. the pH. "Essentially impervious to spatially delayed-release dosage forms, it allows for the release of very small amounts of growth hormone secretagogue.

Through a coating so that no more than 10% of the growth hormone secretagogue is released in the stomach. Such polymers become permeable through dissolution, degradation, or other degradation and are freely permeable to growth hormone secretagogue. The tablet or tablet core may contain additional excipients such as disintegrants, lubricants, fillers and / or other conventional formulation ingredients. All such ingredients and / or excipients, regardless of dosage form, are referred to herein as the pharmaceutically acceptable carrier. The core is coated with a substance, preferably a polymer, which is substantially insoluble and impermeable to the pH of the stomach and more permeable to the pH of the small intestine. Preferably, the coating polymer is substantially insoluble and impermeable below pH 5 and water soluble or water soluble at pH 5. Mixtures of pH-sensitive polymers with water-insoluble polymers may also be used. Relatively insoluble and impermeable at the pH of the stomach, but more soluble or disintegrating or permeable at the pH of the small intestine and colon, include polyacrylamides, phthalate derivatives such as acid phthalates of carbohydrates, amylose cellulose phthalate, Acetate phthalate, other cellulose ester phthalates, cellulose ether phthalates, hydroxypropyl cellulose phthalate, hydroxypropyl ethyl cellulose phthalate, hydroxypropyl methylcellulose phthalate, methylcellulose phthalate, polyvinyl acetate phthalate, polyvinyl acetate hydrogen phthalate, sodium cellulose acetate beverage starch acid phthalate cellulose acetate trimellite,

<img file="HU0103494A2_D0020.tif" />

styrene and maleic dibutyl phthalate copolymer, styrene and maleic polyvinyl acetate phthalate copolymer, styrene and maleic acid copolymers, polyacrylic acid derivatives such as acrylic acid and acrylic ester copolymers, polymethacrylic acid and esters, polyacrylic acid, acetate and crotonic acid copolymers.

Preferred ph-sensitive polymers include shellac, phthalate derivatives, especially cellulose acetate phthalate, polyvinyl acetate phthalate, and hydroxypropyl methylcellulose phthalate; cellulose acetate trimellitate; polyacrylic acid derivatives, in particular copolymers containing acrylic acid and at least one acrylic acid ester; polymethyl methacrylate mixed with acrylic acid and acrylic ester copolymers; and copolymers of vinyl acetate and crotonic acid.

Particularly preferred groups of pH-sensitive polymers include anionic acrylic copolymers of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, methacrylic acid and methyl methacrylate, and copolymers of acrylic acid and at least one acrylic acid ester.

In a further embodiment of spatially delayed dosage forms, beads comprising a growth hormone secretagogue and a carrier having a pH-dependent coated bead of 0.4 to 2.0 mm in diameter are coated with one or more of the aforementioned pH-sensitive polymers. The coated beads may be encapsulated or compressed into tablets, taking care to avoid damage to the polymer coating on each bead during compression. Preferred coated beads show essentially no growth hormone secretagogue release. ί »*« * · ♦ »·&gt; w ·^r (i.e., less than 10%) of the dosage form, as discussed above, until the beads leave the stomach, thereby ensuring that minimal amounts of growth hormone secretagogue are released in the stomach. The coating may range from 5% to 200% by weight of the uncoated core. Preferably, the coating is 10,100% by weight of the uncoated core.

A further embodiment of spatially delayed multiparticulate dosage forms, according to the &amp; quot; pH-dependent coated particle, is that the dosage form comprises small particles of growth hormone secretagogue and carrier having a diameter of 0.1-0.4 mm. The particles are coated with one or more of the aforementioned pH-sensitive polymers. The coated particles can be formulated in unit dose packets, or encapsulated or compressed into tablets, taking care to avoid damage to the polymer coating on each of the particles during compression. Preferred coated particles exhibit substantially no growth hormone secretagogue release (i.e., less than 10%) from the dosage form until the beads leave the stomach, thereby ensuring that minimal amount of growth hormone secretagogue is released in the stomach. Mixtures of pH-sensitive polymers and water-insoluble polymers can also be used.

Tablets and particles and beads containing growth hormone secretagogues may be coated with polymers having varying solubilities at different pHs. For example, preferred coatings are Eudragit®-Lt or 9: 1-1: 4, ♦ &lt;&lt; 4- ·· ** •• Λ

Eudragit®-L / Eudragit®-St (Rohm America, Inc., Piscataway, NJ).

A further embodiment of space-delayed dosage forms comprises modifying an embodiment of a pH-sensitive polymer-coated tablet, a pH-sensitive polymer-coated bead, and a pH-sensitive polymer-coated particle. The tablet, bead or particle core containing the growth hormone secretagogue is first coated with a boundary coating and then coated with a pH sensitive coating. The function of the boundary coating is to separate the growth hormone secretagogue from the pH dependent coating. The boundary coating prevents early release. Water-soluble materials such as sugars such as sucrose, or water-soluble polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, and the like are suitable suitable coatings. Hydroxypropylcellulose and hydroxypropylmethylcellulose and polyvinylpyrrolidone are preferred. The boundary coating may contain from 1% to 20%, preferably from 2% to 15%, by weight of the tablet, bead or particle core containing the uncoated growth hormone secretagogue.

In further embodiments of spatially delayed dosage forms, a solution or suspension or growth powder of growth hormone secretion is encapsulated in a solvent-soluble water-soluble capsule, such as a hard or soft gelatin capsule known in the art, and the capsule is coated with a pH-sensitive polymer . Growth Hormone Secretagogue Solutions »-« ·· '* «* *

<img file="HU0103494A2_D0021.tif" />

Triglyceride oils and glycols may be used as a solvent for encapsulation purposes.

Preferred solvents are non-water immiscible solvents such as water immiscible oils, including triglyceride vegetable oils such as safflower oil, sesame oil, olive oil, corn oil, castor oil, coconut oil, cottonseed oil, soybean oil, and the like. Synthetic and semi-synthetic medium chain triglyceride oils such as Miglyol® (HulsAmerica, Piscataway, New Jersey) or Captex® (Abitec Corp., Columbus, Ohio) are also suitable. Examples are the triglycerides of caprylic / capric acid (Miglyol®-810, Miglyol®-812, Captex®-300, Captex®-355), triglycerides of caprylic / capri / linolenic acid (Miglyol®-818). Also suitable are long chain triglyceride oils, such as triolene, and other mixed chain triglycerides which are liquid at room temperature.

Non-miscible solvents include monoglycerides and diglycerides such as Capmul (Abitec, Columbus, Ohio) and Imwitor (HulsAmerica, Piscataway, New Jersey). Examples are monoolein (Capmul®-GMO), mono- and diglycerides of octanoic acid and decanoic acid (Imwitor®-742, Capmul®-MCM), and monooctanoin (Imwitor®-308), and the like.

Preferred oils are liquid at room temperature. Preferred are mono-, di-, and triglycerides having an acyl chain length of C₄-C₈.

Other suitable binders include various liquid esters of lower alcohols, such as propylene glycol esters of caprylic / capric acid (Miglyol®-840, · · ·

Captex®-200). Fatty acids that are liquid at room temperature, such as caprylic acid, capric acid, lauric acid, oleic acid, linolenic acid are also suitable.

Other suitable excipients include semi-solid excipients such as those sold under the trademark Gelucire®. Examples are PEG-32-glyceryl laurate (Gelucire® 44/14) and glycerol esters of fatty acids (Gelucire® 33/01).

Other suitable binders include surfactants and emulsifiers that are capable of dissolving growth hormone secretagogue. These surfactants and emulsifiers form micelles in an aqueous medium. Examples are polysorbate-80, nonylphenoxy-polyoxyethylenes, dioctyl sodium sulfosuccinate, PEG-6-glyceryl monooleate (Labrafil® M-1944-CS), PEG-6-glyceryl linoleate (Labrafil® M-2125-CS). ), and the like.

Non-water immiscible solvents may be mixed with surfactants and emulsifiers to achieve spontaneous formation of small or microscopic droplets (microemulsions) when the water immiscible solvent / emulsifier is mixed with water as in the gastrointestinal tract. Such mixtures include triglycerides, or mixtures of mono- and diglycerides and polysorbates, such as mixtures of Capmul®MCM and polysorbate-80, or mixtures of Miglyol®-812 and polysorbate-80 in a ratio of 99/1 to 50/50. Other suitable mixtures include triglycerides, or mixtures of mono- and diglycerides with polysorbates, such as Capmul®MCM / Miglyol®-812 / polysorbate-80, in which Capmul®-MCM is?

<img file="HU0103494A2_D0022.tif" />

40-80% of the vehicle and any combination of the remaining Miglyol®-812 and polysorbate-80. Other suitable mixtures include vegetable oil and a surfactant such as olive oil / polysorbate 80: 99: 1-50:50 or corn oil / Labrafil®-M-2125-CS 99: 150:50. Polyethylene glycols and other water-miscible growth hormone secretagogue solvents, such as glycerol, ethanol, propylene glycol, may be used up to 30% in the vehicle to optimize the solubility of the growth hormone secretagogue in the vehicle or to improve the viscosity of the vehicle.

Growth hormone secretagogue solutions dissolved in vehicles of the type described above are filled into soft gelatin capsules or filled into hard gelatin capsules. When filled into hard gelatin capsules, it is preferred that the seam between the two capsule shells is sealed, for example with a gelatin strip to prevent leakage. Encapsulation in soft gelatin is well known and is described in The Theory and Practice of Industrial Pharmacy [L. Lachman, H. Lieberman, and J. Kanig, published by Lea and Febiger].

The pH-sensitive polymer may be any of those already disclosed, including, but not limited to, anionic acrylic copolymers of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, methacrylic acid and methyl methacrylate, and acrylic acid and at least one acrylic acid.

• · · ·

Coating of tablets, beads, capsules and particles containing growth hormone secretagogue can be accomplished using equipment known in the art. For example, tablet cores and capsules containing growth hormone secretagogue may be coated with a pan coating such as Hi-Coater (Freund Industrial Co.) or Accela-Cota (Manesty Corp., Liverpool). Beads and particles containing growth hormone secretagogue are preferably coated with a fluid bed coating such as a Wurster coating, for example using equipment available from Glatt Air Techniques, Inc. (Ramsey, NJ). Beads may also be coated with a rotary granulator such as a CF granulator (Freund Industrial Co.).

Because devices that are delayed in pH-induced space preferably have a mechanism for detecting that the device has left the stomach, differences in gastric emptying between patients are not a significant problem.

In another embodiment of a spatially delayed growth hormone secretagogue dosage form, the "enzyme-initiated support-liquid membrane device comprises a growth hormone secretagogue as disclosed in WO94 / 12159. is disclosed in the dosage form disclosed in International Publication No. 3,600,198. This embodiment is generally in the form of an immediate release tablet or composite particle (preferably bead) comprising a microporous hydrophobic membrane at least partially but preferably completely surrounding the tablet or bead, and a hydrophobic liquid enclosed in the pores of the membrane. Alternatively, the growth hormone secretagogue and carrier are encapsulated in a microporous hydrophobic membrane capsule with a sealed hydrophobic fluid in the pores of the capsule. The hydrophobic fluid is substantially impermeable to both the aqueous environment and the formulation of growth hormone secretagogue tablets or beads. The hydrophobic fluid can be altered to become permeable to the aqueous environment or growth hormone secretagogue formulation. After the patient has ingested this embodiment, release of growth hormone secretagogue in the gastrointestinal tract is delayed until the dosage form leaves the stomach and enters the small intestine.

In an enzyme-initiated fluid membrane device of growth hormone secretagogue, the entrapped hydrophobic fluid is a fluid that undergoes enzymatically catalyzed transformation in the small intestine cavity and not in the stomach such that the pores become permeable to water and growth hormone secretagogue. Optionally, the core may contain ozraogen, a swelling or scavenger to accelerate the release of growth hormone secretagogue when the dosage form has reached the small intestine. Illustrative hydrophobic liquids are triglycerides, fatty anhydrides, fatty acid esters of cholesterol, hydrophobic amino acid esters, and the like. Preferred triglycerides include triolein, tricaprylin, trilaurine, olive oil, palm oil, coconut oil, sesame seed oil, corn oil, peanut oil, soybean oil, and the like. Preferred fatty anhydrides include caprylic anhydride, lauric anhydride, myristyl anhydride, and the like. Ke93 blends of hydrophobic liquids may also be used. Exemplary microporous hydrophobic backing membranes include cellulose esters, polycarbonates, polyalkenes, polystyrenes, polyvinyl esters, polysiloxanes, polyacrylates, and polyethers. Preferably, the hydrophobic microporous membrane is a hydrophobic fluid-impermeable growth hormone secretagogue while gastrointestinal enzymes have catalyzed the conversion of the hydrophobic oil, as disclosed below.

In the application medium, i.e., the small intestine cavity, lipases and esterases degrade the aforementioned hydrophobic oils, releasing surfactant products in the pores of the microporous membrane of the embodiment, thereby creating aqueous channels through which the growth hormone secretagogue in the nucleus of the device . The release of the growth hormone secretagogue can be accomplished by simple diffusion, osmotic pumping, osmotic rupture, or rupture of a swelling material, such as a hydrogel, in the core of the device containing growth hormone secretagogue.

Hydrophobic oils which are substrates for small intestine proteases such as carboxypeptidase and chymotrypsin can be used in the above-described enzyme-induced supported liquid membrane device for growth hormone secretagogue. Illustrative oils are esters of hydrophobic amino acid derivatives.

In another embodiment of a spatially delayed growth hormone secretagogue dosage form, growth hormone secretagogue tablets, capsules, beads, or powders are coated with components that are enzymatically degraded in the small intestine but not in the stomach cavity. The coating contains waxes or triglycerides of natural or synthetic origin which are solid at body temperature. In preferred embodiments, 2-20% body liquid liquid is degraded by small intestine enzymes (trypsin, chymotrypsin, elastase, lipase). Suitable enzymatically labile fluids for the "enzyme-initiated support-liquid membrane device" are disclosed above.

In an embodiment of a time delayed growth hormone secretagogue dosage form, the &amp; quot; rupturing osmotic core device comprises incorporating a growth hormone secretagogue into an osmotically rupturing device comprising a tablet or bead core containing growth hormone secretagogue and one or more osmogens. Such devices are generally disclosed in U.S. Patent 3,952,741. Examples of osmogens include sugars such as glucose, sucrose, mannitol, lactose, and the like; and salts such as sodium chloride, potassium chloride, sodium carbonate, and the like; water-soluble acids such as tartaric acid, fumaric acid, and the like. The tablet core or bead core comprising the growth hormone secretagogue is coated with a polymer which forms a semipermeable membrane, i.e., permeable to water but impermeable to growth hormone secretagogue. Examples of semi-permeable membrane forming polymers are cellulose acetate, cellulose, butyl acetate, and ethylcellulose, preferably cellulose acetate. A melt blend of polyethylene glycol, such as polyethylene glycol-6000, and a hydrogenated oil, such as hydrogenated castor oil, may also be used as a coating, as disclosed by Yoshino for isoniazid tablets [Capsugel Symposia Series; Current Status on Targeted Active Compound Delivery to the Gastrointestinal Tract, 185-190. p. (1993)]. Preferred semipermeable coatings are cellulose esters and cellulose ethers, polyacrylic acid derivatives such as polyacrylates and polyacrylate esters, and polyvinyl alcohols and polyalkenes such as ethylene vinyl alcohol copolymer. Particularly preferred semi-permeable coating materials are cellulose acetate and cellulose acetate butyrate.

In the thymic, the coated tablet or bead of the rupturing osmotic core is placed in an aqueous medium, water is introduced into the core through the semipermeable membrane and dissolves some of the growth hormone secretagogue and osmogen to produce colloidal osmotic pressure and semipermeable membrane. release of the hormone secretagogue into the aqueous medium. By selecting the size and geometry of the bead or tablet core, the type and amount of osmogen, and the thickness of the semipermeable membrane, the time lag between placing the dosage form in aqueous application and release of the secreted growth hormone secretagogue can be determined.

It will be apparent to those skilled in the art that increasing the surface-to-volume ratio of the dosage form and the osmotic is an osmotic • ··· ···· .. · * • *. · ··· · · ···. . ·. . . ·· / · ··· ···· · * · * increases the activity of the delay time while increasing the thickness of the coating reduces the delay time.

The ruptured osmotic core device does not have a mechanism that senses that the device has left the stomach and entered the small intestine. Thus, such devices are time-delayed devices, i.e., which release growth hormone secretagogue at a defined time after ingestion, i.e., ingestion. In the empty state, indigestible, non-decomposable solids, such as the inventive &amp; quot; ruptured osmotic core devices &amp; quot; in the Interdigestive Migrating Myoelectric Complex (IMMC) III. phase, which occurs approximately every 2 hours in humans. Depending on the phase of the IMMC, when administered to an empty stomach, the ruptured osmotic nucleus may leave the stomach almost immediately after ingestion, or even after 2 hours. In the full state, indigestible, non-decomposable solids less than 11 mm in diameter are slowly cleared from the stomach with food (Khosla and Davis, Int. J. Pharmaceut. 62, R9-R11. p. (1990)]. If the diameter of the indigestible, non-disintegrating solid is greater than 11 mm, i.e. about the size of a typical tablet, it is retained in the stomach for the time of food digestion, and the IMMC III. phase out of the stomach after all the food has been digested and left the stomach.

A further embodiment of a time delayed growth hormone secretagogue dosage form, according to the &amp; quot; ruptured kernel &amp; quot; ruptured core, comprises a tablet or bead of swellable growth hormone secretagogue produced such as swelling colloid (e.g., gelatin) as disclosed in U.S. Patent No. 3,247,066. Preferred swelling agents are hydrogels, i.e., hydrophilic polymers that absorb and swell water, such as polyethylene oxides, polyacrylic acid derivatives such as polymethyl methacrylate, polyacrylamides, polyvinyl alcohol, poly-N-vinyl-2-pyrrolidone, carboxymethyl cellulose. starches, and the like. Preferred swelling agents in this embodiment are polyethylene oxides, cross-linked polyacrylates, and carboxymethylcellulose. The tablet or bead core containing the colloidal / hydrogel-containing growth hormone secretagogue is coated at least partially with a semipermeable membrane. Examples of semipermeable membrane forming polymers are cellulose acetate and cellulose acetate butyrate, and ethylcellulose. A melt blend of polyethylene glycol, such as polyethylene glycol-6000, and a hydrogenated oil, such as hydrogenated castor oil, may also be used as a coating, as disclosed by Yoshino for isoniazid tablets [Capsugel Symposia Series; Current Status on Targeted Active Compound Delivery to the Gastrointestinal Tract, 185-190. p. (1993)]. Preferred semipermeable coatings are cellulose esters and cellulose ethers, polyacrylic acid derivatives such as polyacrylates and polyacrylate esters, and polyvinyl alcohols and polyalkenes such as ethylene vinyl alcohol copolymer. Particularly preferred metallic ligand-permeable coating materials are cellulose acetate and cellulose acetate butyrate.

When the coated tablet or bead of the ruptured coated swellable core is placed in an aqueous medium of use, water enters the core through the semipermeable membrane and causes the core to swell, resulting in rupture of the semipermeable membrane and release of growth hormone secretagogue into the aqueous medium. By selecting the size and geometry of the bead and tablet core, the type and amount of swellable material, and the thickness of the semipermeable membrane, a delay time can be selected between placing the dosage form in an aqueous application medium and releasing the growth hormone secretagogue. The preferred disintegrating coated swelling core devices of the present invention exhibit essentially no growth hormone secretagogue release from the dosage form until the dosage form leaves the stomach, thereby ensuring that minimal amount of growth hormone secretagogue is released in the stomach.

The ruptured coated swelling core device does not have a mechanism that senses that the device has left the stomach and entered the small intestine. Thus, such devices are time-delayed devices, i.e., which release the growth hormone secretagogue at a defined time after ingestion, i.e., ingestion, as discussed in the case of ruptured osmotic nucleated devices, and with the same considerations and preferences. · · To be used in the manufacture of rupture coated expandable core devices.

In a preferred embodiment of a time delayed growth hormone secretagogue dosage form, immediate release growth hormone secretagogue tablets, beads, or particles are prepared for core application by coating with a water-soluble and / or water-dispersible delaying layer. Preferred delay layers include hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), polyethylene oxide, and polyvinylpyrrolidone. For tablets, this coating can be accomplished using a tablet coating device such as HCT-30, HCT-60 or HCT-130 (Freund Inc). The tablets are coated with an aqueous solution of HPMC or other suitable polymer with a final weight of 5 to 50% of the final weight of the tablet. Heavier coatings provide a longer delay before release of growth hormone secretagogue into the application medium (gastrointestinal tract cavity). The retention time can also be increased by incorporating a small or medium amount of a water-insoluble polymer (non-limiting examples include ethylcellulose (EC), cellulose acetate (CA), cellulose acetate butyrate) into the coating. For example, the coating formulation may consist of 95: 5 HPMC / EC to 50:50 HPMC / EC, or 95: 5 HPMC / CA to 50:50 HPMC / CA. Such blended polymer coating systems may require modification of the solvent composition to dissolve a mixture of water-soluble and poorly water-soluble polymers. Optionally, for example, a mixture of acetone and water or a mixture of ethanol and water may be used.

100 • »« * ·*

Beads and particles can be similarly coated with a fluid bed coating apparatus, such as Glatt GPCG-5 Coating (Glatt Air Techniques, Inc). For beads, the coating may be from 10% to 100% by weight of the uncoated core.

In a further embodiment of growth hormone secretagogue time delayed dosage forms, a solution or suspension of growth hormone secretagogue in a solvent is enclosed in a hard or soft gelatin capsule, which is then coated with a water soluble and / or water dispersible polymer as described above for the other core types. Suitable and preferred solvents for growth hormone secretagogue include those used above for spatially delayed capsules. The coating comprises polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene oxide, polyvinylpyrrolidone, cellulose acetate, and ethylcellulose.

It will be apparent to those skilled in the art that the various embodiments of the coated growth hormone secretagogue tablets, beads, and particles described above may be coated using conventional coating devices such as pan coaters (e.g., Hi-Coater, Freund Industrial Co .; Accela-Cota, Manesty Corp., Liverpool), liquid bed coatings such as Wurster coatings (Glatt Air Techniques, Inc., Ramsey, NJ and Aeromatic Corp., Columbia, MD), and a rotary granulator such as a CF granulator (Freund). Industrial Co.). Tablet cores are prepared by conventional tablet presses such as Kilian press (Kilian and Company, Inc., Horsham, PA). Growth hormone secretagogue

<img file="HU0103494A2_D0023.tif" />

« «4 * »· ·«»·

101

<img file="HU0103494A2_D0024.tif" />

beads and particles containing liquid gels are prepared with liquid bed granulators, rotary granulators, and extruders / spheroids.

A preferred method of intermittent administration of growth hormone secretagogue is the use of an immediate release formulation. Batch administration of growth hormone secretagogue is also possible using a combination of an immediate release formulation and a sustained release formulation.

Patents, publications, and other documents are hereby incorporated by reference in their entirety. The clinical trial detailed below is intended to illustrate specific embodiments and is not intended to limit the specification in any way, including the claims.

102 ·**♦ ··♦

Clinical examination

Test population:

The clinical trial was conducted in male and female subjects aged 65 to 84 years with baseline IGF-1 levels below 150 ng / million.

Dosage:

The study was a double-blind, parallel-group, placebo-controlled study.

In the first stage of the assay, 2-amino-N- [2- (3a- (R) benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo [4,3c]) was used. The safety and efficacy of pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxoethyl] isobutyramide L-tartrate were investigated in 4 groups of approximately 24 subjects. The dose was 0 mg (placebo), 1 mg tid, 3 mg tid and 3 mg in the morning and 6 mg in the afternoon (all dosage forms in this part of the study were an immediate release dosage form).

In addition, an extended study was conducted to evaluate the relationship between peak GH or IGF-1 concentrations and additional reactions such as lipid concentration and body composition. A controlled release (CR) formulation was evaluated, either alone or in combination with an immediate release (IR) formulation (24-30 patients per group). [16 mg (10 CR, 6 IR) hs (hs at bedtime); 16 mg (10 CR, 6 IR) hs every three days;

mg CR hs; and placebo.] See below for composition.

103

Administration of test substance:

In the extended assay, 2-amino-N- [2- (3a- (R) benzyl-2-diethyl-3-oxo-2,3,3a, 4,6,7,7-hexahydro-pyrazolo [4,3c] pyridine) was used. -5-yl) -1- (R) -benzyloxymethyl-2-oxoethyl] -isobutyramide L-tartrate was provided in 10 mg or 3 mg controlled release tablets and 3 mg immediate release tablets with appropriate placebo tablets. The test drug was provided in a blister pack and 5 tablets were to be taken at each dose. Subjects were instructed to take the tablets with a glass of water at bedtime.

Design and concept:

Return visits were made 1, 2 and 4 weeks after the start. Blood samples were taken every time with 2 amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridine) -5-yl) -1- (R) benzyloxymethyl-2-oxoethyl] -isobutyramide L-tartrate and IGF-1 levels. Baseline acquisition and subsequent visits were performed at the same time of the day (approximately 8 am to 11 am).

In addition to this schedule, at two selected sites, subjects were enrolled for two nights, the first night of dosing and the 28th day of dosing. Growth hormone secretion and pharmacokinetic sampling were performed.

Post treatment period and end of examination:

The ex-post evaluation was performed after 1, 2 and 4 weeks. Life signs were recorded and the face, torso and arms

104 skin was examined. Blood samples were taken for GH and IGF-1, and 2 amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4 , 3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxoethyl] -isobutyramide L-tartrate.

In addition, subjects were selected at selected study centers overnight on day 28 of dosing. Growth hormone secretion profile, pharmacokinetics, and life assay were performed.

Endpoints for efficacy:

The primary efficacy endpoint was the percentage change in baseline IGF-1. Secondary results included insulin-like growth factor binding protein 3 (IGFBP-3), cholesterol subfractions, and percent change in total adipose tissue and total lean tissue. Changes in secondary efficacy measurements were systematically examined over time, either graphically or tabularly, using appropriate descriptive statistics well known in the art.

Results:

In the first phase of the study, there was a dose-dependent increase in IGF-1 levels, with a similar increase of approximately 35% in both groups receiving 9 mg. IGFBP3 levels were also elevated. There were small changes in body composition consistent with an increase in GH secretion, ie a decrease in adipose tissue and an increase in apparent lean body mass.

105

<img file="HU0103494A2_D0025.tif" />

In the extended study, IGF-1 was elevated in both groups, which was 2-amino-N- [2- (3a- (R) -benzyl2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro) -pyrazolo [4,3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxoethyl] -isobutyramide Ltartrate was administered daily. 2-Amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridine) -5-yl) -1- (R) -benzyloxymethyl-2-oxoethyl] -isobutyramide L-tartrate every three days had a minimal increase in mean IGF-1 of about 10%. The CR-only group had moderate and sporadic GH peaks, averaging less than 4 ng / ml at baseline and 2 ng / ml after 4 weeks. The groups receiving 6 mg IR (along with 10 mg CR) had mean GH peaks of 15 ng / ml or greater, which decreased to 46 ng / ml after 4 weeks. Various analyzes have shown a smaller reduction in the group of 2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo) [4,3-c] Pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxoethyl] -isobutyramide L-tartrate was administered every 3 days. The peak heights of the Q3-day group were on average 1.52 ng / ml higher than those of the QD group. Changes in body composition were again observed and were similar in the two IR-receiving groups, despite the large differences in IGF-1 elevation. Growth of lean tissue was estimated at 0.5-0.6% with a corresponding reduction in adipose tissue.

Specific dosage forms used in the clinical study were as follows, the active ingredient being 2-amino-N- [2106 • · (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6). , 7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (R) -benziloximeti1-2-oxoethyl] isobutyramide.

mg immediate release! tablet

<td>component</td><td>Component purity</td><td>Crowd (Mg / tablet)</td>

<td>agent</td><td>therapeutic</td><td> 1,30^(the)</td>

<td>Calcium phosphate dibasic, anhydrous</td><td>USP</td><td> 35, 08</td>

<td>Microcrystalline Cellulose (Avicel® PH102; EMC Corporation, Philadelphia, PA)</td><td>NF</td><td> 56, 12</td>

<td>Sodium starch glycolate (Explotab; Penwalt, Patterson, NJ)</td><td>NF</td><td> 5, 00</td>

<td>Magnesium stearate</td><td>NF</td><td> 1, 50</td>

mg immediate release! tablet

<td>component</td><td>Component purity</td><td>Crowd (Mg / tablet)</td>

<td>agent</td><td>therapeutic</td><td> 3, 89^Ia)</td>

<td>Calcium phosphate</td><td>USP</td><td> 34, 79</td>

<td>dibasic, anhydrous</td><td></td><td></td>

<td>Microcrystalline Cellulose</td><td>NF</td><td> 54,82</td>

<td>(Avicel® PH102)</td><td></td><td></td>

107

<img file="HU0103494A2_D0026.tif" />

<td>Sodium starch glycolate (Explotab)</td><td>NF</td><td> 5, 00</td>

<td>Magnesium stearate</td><td>NF</td><td> 1,50</td>

mg controlled release tablets

<td>component</td><td>Component purity</td><td>Crowd (Mg / tablet)</td>

<td>agent</td><td>therapeutic</td><td> 3, 89^(the)</td>

<td>mannitol 2080, granulate</td><td>USP</td><td> 34,00</td>

<td>fumaric</td><td>NF</td><td> 12, 00</td>

<td>Microcrystalline Cellulose (Avicel® PH102)</td><td>NF</td><td> 48, 61</td>

<td>Magnesium stearate (Addition 1)</td><td>NF</td><td> 0, 50</td>

<td>Magnesium stearate (Add 2)</td><td>NF</td><td> 1,00</td>

<td>Cellulose Acetate (CA-398-10) Eastman Chemical, Kingsport, TX</td><td>NF</td><td> 11, 90</td>

<td>polyethylene glycol (Carbowax PEG 3350; Union Carbide, Charleston, WV</td><td>NF</td><td> 5, 10</td>

<td>Cleaned water^(B)</td><td>USP</td><td> (35,70)</td>

<td>acetone^(B)</td><td>NF</td><td> (117,30)</td>

108 mg controlled release tablets

<td>component</td><td>Component purity</td><td>Crowd (Mg / tablet)</td>

<td>agent</td><td>therapeutic</td><td> 12,97^(the)</td>

<td>mannitol 2080, granulate</td><td>USP</td><td> 113,32</td>

<td>fumaric</td><td>NF</td><td> 40, 00</td>

<td>Microcrystalline Cellulose (Avicel® PH102)</td><td>NF</td><td> 162,01</td>

<td>Magnesium stearate (Addition 1)</td><td>NF</td><td> 1, 67</td>

<td>Magnesium stearate (Add 2)</td><td>NF</td><td> 3,33</td>

<td>Cellulose Acetate (CA-398-10) Eastman Chemical, Kingsport, TX</td><td>NF</td><td> 33, 00</td>

<td>polyethylene glycol (Carbowax PEG 3350)</td><td>NF</td><td> 22,00</td>

<td>Cleaned water^tb&gt;</td><td>USP</td><td> (126, 50)</td>

<td>acetone^(B)</td><td>NF</td><td> (368,50)</td>

^ta) Based on a theoretical efficacy of 77.1%.

^(BI Purified water and acetone are volatile and are not found in the final dosage form.

109 • · · · · ·

<img file="HU0103494A2_D0027.tif" />

In controlled release dosage forms of 3 and 10 mg, the active ingredient, mannitol, microcrystalline cellulose and magnesium stearate are components of the tablet core.

NF stands for National Pharmacopoeia (National

Formulary).

USP means United States Pharmacopoeia.

mg and 3 mg sustained release dosage forms

This example illustrates a method for preparing an osmotic tablet formulation containing 3 mg and 10 mg of active ingredient, comprising a core containing the active ingredient and a semi-permeable asymmetric membrane coating surrounding it. The preparation of the tablet core comprises the following steps: (1) blending the core components other than magnesium stearate; (2) shredding and re-blending the same components; (3) adding and mixing a portion of the magnesium stearate; (4) dry granulation; (5) grinding / sifting and re-mixing; (6) adding and mixing a residue of magnesium stearate; (7) compressing tablet cores; (8) spraying an asymmetric membrane coating around the core; and (9) drying.

In batches of 6-14 kg, 2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3] -c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxoethyl] -isobutyramide L-tartrate was mixed with all other components except magnesium stearate for 30 minutes in a suitable sized twin-shell blender (15-50 L). Subsequently, the

- no -: ··· ·· '· *' ·:. ··. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · knives, The Fitzpatrick Company, Elmhurst, IL) and again for 30 minutes. Magnesium stearate (addition 1) was then added and mixed for 5 minutes. The partially lubricated mixture was dry granulated in a roller compactor (Freund TF-156 roller compactor, Freund Industrial Co., Tokyo, Japan) at 1012 rpm auger feed rate, 25 kg / cm² pressure and 12 rpm roller speed. The roller compactor was equipped with an oscillating roller granulator (20 mesh) for shredding compacted tapes. The granules were then blended for 30 minutes before the remainder of the magnesium stearate (addition 2) was added and mixed again for 5 minutes.

Using a conventional tablet press (Kilian LX21, Kilian and Co., Inc, Horsham, PA), the final blend was compressed into tablets.

Semi-permeable membrane coating (as disclosed in US Patent No. 5,612,059, Use of Asymmetric Membranes in Delivery Devices) was applied to these tablets using an HCT-30 explosion-proof pan coating (Vector Corporation, Marion, Iowa), 20 g. operated at a spray rate of 4045 ° C inlet temperature and 30 cfm (14158.43 cm)³/ sec) at an air flow rate. Asymmetric membrane coated formulations applied to 3 mg and 10 mg tablet cores released 80% of the dose over 10 to 12 hours in a simulated gastric fluid (sgn) of about 1.2 pH η, a technique well known in the art. and USPXXIII.

111 • « • « · · · * ·

<img file="HU0103494A2_D0028.tif" />

explore. The 3 mg tablets were coated with a mixture of cellulose acetate / polyethylene glycol / water / acetone in a ratio of 7/3/21/69 (w / w), a growth coating of 17 wt% of the starting weight. Similarly, the 10 mg tablet was coated in a 6/4/23/67 formulation, applied at 15.5 w%.

The coated tablets were dried in the coating for 15 minutes at an inlet temperature of 60 ° C and then dried in an oven (Gruenberg solvent tray oven, Gruenberg Oven Company, Williamsport, PA) for 16 hours at 50 ° C before testing the dissolution performance. After drying, the weight of the coating material applied was expressed as a percentage of the weight of the parent tablet core.

mg and 3 mg immediate release dosage forms

First The anhydrous dibasic calcium phosphate, microcrystalline cellulose and sodium starch glycolate were stirred for 5 minutes in a brown glass vessel using a Turbula mixer (20 rpm).

Second The binder mixture from Step 1 was filtered through a 40 mesh filter and stirred for 15 minutes in a brown glass vessel using a Turbula mixer (20 rpm) (WAB, Basel,

Switzerland).

Third Growth hormone secretagogue is added to the binder mixture obtained in Step 2 using geometric dilution. After each dilution, stir for 10 minutes in a brown glass vessel using a Turbula mixer (20 rpm).

112 • · · · » · · · · · «· «* ·

4th The active mixture from Step 3 was filtered through a 40 mesh filter and stirred for 10, 20 and 30 minutes in a brown glass vessel using a Turbula mixer (20 rpm). At each time point, samples are taken from above, from the middle and from below.

5th 1.0% magnesium stearate was added (before granulation) and stirred for 5 minutes in a brown glass vessel using a Turbula mixer (20 rpm).

6th The mixture is compacted with a roller compactor using the TF Freund mini roller compactor, roller pressure: 40 kg / cm²roller speed: 3 rpm feed speed: 10 rpm.

7th The compacted mixture is crushed using a rotating granulator with a 30 mesh filter.

8th 0.5% magnesium stearate was added to the active granulate (after granulation) and stirred for 5 minutes in a brown glass vessel using a Turbula mixer (20 rpm).

9th Tablets were tableted with a single-position press (F-Press, Manesty Machines, Liverpool, England).

and other forms of immediate release dosage forms

First The anhydrous dibasic calcium phosphate, microcrystalline cellulose and sodium starch glycolate were stirred for 15 minutes using a 4 L V mixer.

Second The stirrer was emptied.

Third Approximately equal volume of growth hormone secretagogue and binder mixture obtained in Step 2

113 Place in a brown glass jar and stir for 15 minutes using a Turbula mixer (20 rpm).

4th About half of the binder mixture obtained in step 2 is placed in the V mixer.

5th The drug / binder mixture obtained in Step 3 is filtered through a 40 mesh filter and placed in a V mixer.

Using a mortar and pestle, the agglomerates that do not pass through the filter are reduced in size.

6th The remainder of the binder mixture obtained in step 2 is placed in the V-mixer.

7th Stir for 15 minutes in the V mixer.

8th The mixture obtained in Step 7 is ground in a Fitzpatrick JT grinding machine with a # 1A plate at medium speed with protruding knives (The Fitzpatrick Company, Elmhurst, IL).

9th The binder mixture obtained in Step 8 was placed in a 4 L V mixer and stirred for 15 minutes.

10th 1.0% magnesium stearate was added (before granulation) and blended for 5 minutes.

11th The mixture is compacted with a roller compactor using the Freund TF mini roller compactor, roller pressure: 40 kg / cm²feed rate: 12 rpm roller speed: 3 rpm.

12th The compacted mixture obtained in step 11 is comminuted with a rotating granulator with a 30 mesh filter.

13th The active granulate obtained in step 12 was 4 L

Place in a V-mixer and stir for 15 minutes.

114 · «· ·« • · · · · · · · · · · · · · · · · · · · · · · · ···

14.

Ia hike

15.

0.5% magnesium stearate was added to the active gran (after granulation) and stirred for 15 minutes.

The mixture was tabletted using a Kilian T100 rotary press (Kilan and Company, Horsham, PA).

- 115 »·*♦ &lt;« • · · · · · * •·» ♦ · ·«··· • · · · * *·&gt;