Title:  Wet granulation formulation of a growth hormone secretagogue

United States Patent:  6,123,964

Inventors:  Asgharnejad; Mandana (Lansdale, PA); Draper; Jerome (Elkins Park, PA); Dubost; David (Collegeville, PA); Kaufman; Michael (New Hope, PA); Storey; David (Lansdale, PA)

Appl. No.:  066469

PCT Filed:  October 23, 1996

371 Date:  October 27, 1998

PCT PUB.NO.:  WO97/15191

The present invention relates to a pharmaceutical composition and a process for the preparation of a tablet containing a growth hormone secretagogue as the active ingredient. The tablet is prepared by forming a powder blend of the active ingredient N-[1(R)-[(1,2-dihydro-1-methanesulfonyl-spiro[3H-indole-3,4'-piperdin]-1'- yl)carbonyl]-2-(phenylmethyl-oxy)ethyl]-2-amino-2-methyl-propanamide, or a pharmaceutically acceptable salt thereof, in particular the methanesulfonate salt, with a binder/diluent, a first diluent, a second diluent, a first portion of a disintegrant, and a lubricant; wet granulating the powder blend with a solution of ethanol/water to form granules; drying the granules to remove the ethanol/water; adding a second portion of a disintegrant; lubricating the granules; and compressing the dried granules into the desired tablet form. The present invention further relates to a novel amorphous form of the compound N-[1(R)-[(1,2-dihydro-1-methanesulfonyl-spiro[3H-indole-3,4'-piperdin]-1'- yl)carbonyl]-2-(phenylmethyl-oxy)ethyl]-2-amino-2-methylpropanamide methanesulfonate which is produced directly as a result of the process of tablet formulation.

BACKGROUND OF THE INVENTION

Growth hormone, which is secreted from the pituitary, stimulates growth of all tissues of the body that are capable of growing. In addition, growth hormone is known to have the following basic effects on the metabolic processes of the body: (1) Increased rate of protein synthesis in all cells of the body; (2) Decreased rate of carbohydrate utilization in cells of the body; (3) Increased mobilization of free fatty acids and use of fatty acids for energy. A deficiency in growth hormone secretion can result in various medical disorders, such as dwarfism.

Various ways are known to release growth hormone. For example, chemicals such as arginine, L-3,4dihydroxyphenylalanine (L-DOPA), glucagon, vasopressin, and insulin induced hypoglycemia, as well as activities such as sleep and exercise, indirectly cause growth hormone to be released from the pituitary by acting in some fashion on the hypothalamus perhaps either to decrease somatostatin secretion or to increase the secretion of the known secretagogue growth hormone releasing factor (GRF) or an unknown endogenous growth hormone-releasing hormone or all of these.

In cases where increased levels of growth hormone were desired, the problem was generally solved by providing exogenous growth hormone or by administering GRF or a peptidal compound which stimulated growth hormone production and/or release. In either case the peptidyl nature of the compound necessitated that it be administered by injection. Initially the source of growth hormone was the extraction of the pituitary glands of cadavers. This resulted in a very expensive product and carried with it the risk that a disease associated with the source of the pituitary gland could be transmitted to the recipient of the growth hormone. Recombinant growth hormone has become available which, while no longer carrying any risk of disease transmission, is still a very expensive product which must be given by injection or by a nasal spray.

Other compounds have been developed which stimulate the release of endogenous growth hormone such as analogous peptidyl compounds related to GRF or the peptides of U.S. Pat. No. 4,411,890. These peptides, while considerably smaller than growth hormones are still susceptible to various proteases. As with most peptides, their potential for oral bioavailability is low. Non peptidal growth hormone secretagogues with a benzolactam structure are disclosed e.g., in U.S. Pat. Nos. 5,206,235, 5,283,241, 5,284,841, 5,310,737, 5,317,017, 5,374,721, 5,430,144, 5,434,261, 5,438,136 and PCT Publications WO 95/03289, WO 95/03290, WO 95/09633. Other growth hormone secretagogues are disclosed in PCT Patent Publications WO 94/11012, WO 94/13696, WO 94/19367, WO 95/13069 and WO 95/14666.

In particular, U.S. Pat. No. 5,536,716 (PCT Patent Publication WO 94/13696) and Proc. Natl. Acad. Sci. USA, 92, 7001-7005 (July 1995) disclose the compound N-[1(R)-[(1,2-dihydro-1-methanesulfonyl-spiro[3H-indole-3,4'-piperdin]-1'- yl)carbonyl]-2-(phenylmethyl-oxy)ethyl]-2-amino-2-methylpropanamide, and salts thereof, especially the methanesulfonate salt.

This compound is a growth hormone secretagogue which stimulates the release of growth hormone in humans and animals. This property can be utilized to promote the growth of food animals to render the production of edible meat products more efficient, and in humans, to treat physiological or medical conditions characterized by a deficiency in growth hormone secretion, and to treat medical conditions which are improved by the anabolic effects of growth hormone.

U.S. Pat. No. 5,536,716 and PCT Patent Publication WO 94/13696 disclose methods for preparing this compound (see Examples 18, 19 and 55). In particular, Example 55 states that the compound prepared by recrystallization from ethyl acetate-ethanol-water had a melting point of 166-168^oC. Proc. Natl. Acad. Sci. USA, 92, 7001-7005 (July 1995) notes that this compound isolated as a monohydrate had a melting point of 168-170^oC.

Standard methods for tablet formulation of the active ingredient such as direct compression suffer from problems. In particular, this compound is relatively unstable in standard pharmaceutical formulations. In addition, this compound as a bulk drug suffers from poor flow properties, nevertheless, wet granulation was discovered to overcome these difficulties preparing tablet formulations. Tablets prepared by the wet granulation method produced excellent content uniformity, coupled with suitable tablet dissolution and stability. The tablets of the present invention, prepared by wet granulation, possessed good hardness at normal machine pressures.

The present invention is also concerned with pharmaceutical formulations prepared by the subject process and their use in the treatment of certain disorders and diseases.

Exemplifying the present invention is the process comprising the steps of:

(1) forming a powder blend of the active ingredient with a binder/diluent, a first diluent, a second diluent, and a disintegrant, from 2 to 25 minutes using a mixer;

(2) wet granulating the powder blend by adding a solution of ethanol/water to the powder blend while mixing over a 1 to 30 minute period to form granules;

(3) drying the granules to remove the ethanol/water with heated air in a fluid bed dryer or tray dryer for 10 minutes to 24 hours;

(4) milling the dried granules to a uniform size;

(5) adding and blending a disintegrant with the dried milled particles for 2 to 30 minutes;

(6) adding and blending a lubricant to the mixture containing the disintegrant for 30 seconds to 20 minutes; and

(7) compressing the lubricated granules mixture into a desired tablet form.

Further illustrating the invention is the process wherein the active ingredient is N-[1(R)-[(1,2-dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperdin]-1'-y l)carbonyl]-2-(phenylmethyloxy)ethyl)-2-amino-2-methylpropanamide methanesulfonate.

Additional illustrations of the invention include the process wherein: the binder/diluent is pregelatinized starch; the first diluent is microcrystalline cellulose; the second diluent is calcium phosphate dibasic; the disintegrant is croscarmellose sodium; and the lubricant is magnesium stearate. Preferably, the solution of ethanol/water is in the range of 0% to 80% ethanol in water (w/w), more preferably in the range of 5% to 75% ethanol/water (w/w) and even more preferably approximately 25% ethanol/75% water (w/w).

A further illustration of the invention is the foregoing process further comprising the step of applying a coating to the tablet. More particularly illustrating the invention is the process wherein coating the tablet is accomplished by:

(1) dry blending titanium dioxide (optionally mixed with talc) with hydroxypropyl methylcellulose and hydroxypropyl cellulose to form a dry powdered blend;

(2) adding the dry powdered blend to water to form a slurry;

(3) adding water to the slurry with stirring to form a suspension; and

(4) applying the suspension to the tablets.

More specifically exemplifying the invention is the process comprising the steps of:

(1) forming a powder blend of the active ingredient with pregelatinized starch, microcrystalline cellulose, calcium phosphate dibasic, and croscarmellose sodium, in a mixer for about 3 to 25 minutes;

(2) wet granulating the powder blend by adding a solution of 25% ethanol/75% water (w/w) to the powder blend while mixing over a 1 to 30 minute period to form granules;

(3) drying the granules on a tray dryer or a fluid bed dryer for about 1 to 12 hours to remove the ethanol/water;

(4) milling the dried granules to a uniform size using a Quadro Comill or Fitz type mill;

(5) adding and blending croscarmellose sodium with the dried milled particles for about 5 to 30 minutes;

(6) adding and blending magnesium stearate to the mixture containing the croscarmellose sodium with a V blender for about 1 to 5 minutes; and

(7) compressing the lubricated granules mixture into a desired tablet form.

Another example of the invention is the process wherein the active ingredient is N-[1(R)-[(1,2-dihydro-1-methanesulfonyl-spiro[3H-indole-3,4'-piperdin]-1'- yl)carbonyl]-2-(phenylmethyloxy)-ethyl]-2-amino-2-methylpropanamide methanesulfonate.

In a subclass is the foregoing process further comprising the step of coating the tablet. Further exemplifying the invention is the foregoing process further comprising the steps of:

(1) dry blending titanium dioxide (optionally mixed with talc) with hydroxypropyl methylcellulose and hydroxypropyl cellulose to form a dry powdered blend;

(2) adding the dry powdered blend to water to form a slurry;

(3) adding water to the slurry with stirring to form a suspension; and

(4) applying the suspension to the tablets.

An additional illustration of the present invention is a solid dosage form containing an active ingredient of N-[1(R)-[(1,2-dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperdin]-1'-y l)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2-methylpropanamide, or a pharmaceutically acceptable salt thereof, in particular the methanesulfonate salt, wherein the dosage form is prepared by the process.

The present invention further relates to a novel amorphous form of the compound N-[1(R)-[(1,2-dihydro-1-methane-sulfonyl-spiro[3H-indole-3,4'-piperdin]-1' -yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2-methylpropanamide methanesulfonate. This amorphous form is produced directly as a result of the instant process of tablet formulation.

The amorphous form of N-[1(R)-[(1,2-dihydro-1-methanesulfonyl-spiro[3H-indole-3,4'-piperdin]-1'- yl)carbonyl]-2-(phenylmethyl-oxy)ethyl]-2-amino-2-methylpropanamide methanesulfonate exhibits a lack of crystallinity. The lack of crystallinity was confirmed by X-ray analysis wherein he X-ray diffraction pattern showed an amorphous halo.

The X-ray powder diffraction (XRPD) pattern was collected using a Phiulips APD3720 Automated Powder Diffraction instrument with copper K.alpha. radiation. Measurements were made from 2^o to 40^o (2 theta) with the sample maintained at ambient room temperature.

In addition, examination of the amorphous form under microscopy showed no biorefringence.

The amorphous form may be prepared by evaporating a concentrated solution of N-[1(R)-[(1,2-dihydro-1-methanesulfonyl-spiro[3H-indole-3,4'-piperdin]- 1'-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2-methylpropanamide methanesulfonate in 25% aqueous ethanol (980 mg/ml) at 40^oC. to give a solid.

Granulation is the process of adding a solvent, such as water or water/ethanol, to a powder mixture until granules are formed. The granulation step may be varied from 2 to 35 minutes, preferably 3 to 10 minutes, most preferably 4 to 8 minutes. Preferably, the granules are dried using a fluid bed dryer or tray dryer. Milling of the dried granules is accomplished using a Quadro Comill or Fitz mill. The lubrication step is the process of adding lubricant to the mixture. The lubrication step may be varied from 30 seconds to 20 minutes, preferably about 1 minute.

The disclosed process may be used to prepare solid dosage forms, particularly tablets or granules, for medicinal administration.

The term "tablet," as used herein, is intended to encompass compressed pharmaceutical dosage formulations of all shapes and sizes, whether coated or uncoated. Substances which may be used for coating include hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), titanium dioxide, talc, sweeteners and colorants.

The term "active ingredient," as used herein includes both the free base N-[1(R)-[(1,2-dihydro-1-methane-sulfonyl-spiro[3H-indole-3,4'-piperdin]-1' -yl)carbonyl)-2-(phenyl-methyl-oxy)ethyl]-2-amino-2-methyl-propanamide, as well as the pharmaceutically acceptable salts thereof, in particular, N-[1(R)-f(1,2-dihydro-1-methane-sulfonyl-spiro[3H-indole-3,4'-piperdin]-1' -yl)carbonyl]-2-(phenyl-methyl-oxy)ethyl]-2-amino-2-methyl-propanamide methanesulfonate and crystal forms thereof. A preferred crystal form for use in the present invention is that designated Form I.

Preferred diluents include: lactose, microcrystalline cellulose, calcium phosphate(s), mannitol, powdered cellulose, pregelatinized starch and other suitable diluents (see, e.g., Remington's Pharmaceutical Sciences, 18th Edition, 1990, p. 1635). Microcrystalline cellulose and calcium phosphate dibasic, are particularly preferred. Specifically, microcrystalline cellulose NF, especially Avicel PH101, the trademarked name for microcrystalline cellulose NF manufactured by FMC Corp. is preferred.

Preferred binders include pregelatinized starch, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone (PVP) and other known binders (see, e.g., Remington's Pharmaceutical Sciences, 18th Edition, 1990, pp. 1635-1636) and mixtures thereof. Most preferably, pregelatinized starch as employed as a binder. Specifically, starch pregelatinized NF 1500 manufactured by Colorcon Corporation is most preferred.

The disintegrant may be one or more of several starches, clays, celluloses, algins, gums or crosslinked polymers known to those skilled in the art (See, e.g., Remington's Pharmaceutical Sciences, 18th Edition, 1990, p. 1637) and mixtures thereof. Preferably, one or more of several modified starches or modified cellulose polymers, such as microcrystalline cellulose and croscarmellose sodium, are used. Croscarmellose sodium Type A, commercially available under the trade name "Ac-di-sol," is particularly preferred.

Preferred lubricants include magnesium stearate, zinc stearate, calcium stearate, stearic acid, surface active agents such as sodium lauryl sulfate, magnesium lauryl sulfate, propylene glycol, sodium dodecane sulfonate, sodium oleate sulfonate and sodium laurate mixed with stearates and talc, sodium stearyl fumarate, hydrogenated vegetable oils, glyceryl palmitostearate, glyceryl behenate, sodium benzoate, mineral oil, talc and other known lubricants (see, e.g., Remington's Pharmaceutical Sciences, 18th Edition, 1990, pp. 1636-1637), and mixtures thereof. An especially preferred lubricant is magnesium stearate.

The active ingredient, N-[1(R)-[(1,2-di-hydro-1-methanesulfonylspiro[3H-indole-3,4'-piperdin]-1'- yl)carbonyl)-2-(phenylmethyloxy)ethyl]-2-amino-2-methylpropanamide, may be prepared according to the methods disclosed in U.S. Pat. No. 5,536,716, PCT Patent Publication WO 94/13696 and the methods disclosed herein.

The pharmaceutically acceptable salts of N-[1(R)-[(1,2-dihydro-1-methane-sulfonyl-spiro[3H-indole-3,4'-piperdin]-1' -yl)carbonyl]-2-(phenyl-methyl-oxy)ethyl]-2-amino-2-methylpropanamide may be employed in the instant invention. Examples of pharmaceutically acceptable salts include the pharmaceutically acceptable acid addition salts, such as the salts derived from using inorganic and organic acids. Examples of such acids are hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, maleic, succinic, malonic, methane sulfonic and the like.

The pharmaceutical compositions of the present invention comprise 0.1 to 50% by weight of an active ingredient, N-[1(R)-[(1,2-dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperdin]-1'-y l)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2-methylpropanamide, or a pharmaceutically acceptable salt thereof, preferably N-[1(R)-[(1,2-dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperdin]-1'-y l)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2-methylpropanamide methanesulfonate; 0 to 77% by weight of a binder/diluent; 0 to 77% by weight of a first diluent; 0 to 77% by weight of a second diluent; 0 to 6% by weight of a disintegrant; and 0 to 5% by weight of a lubricant. It will be appreciated by one skilled in the art that the sum of the proportions of the active ingredient, the binder/diluent, the first diluent, the second diluent, the disintegrant, and the lubricant are not greater than 100% by weight.

More specifically, the binder/diluent is selected from hydroxy-propyl methylcellulose, hydroxypropyl cellulose, pregelatinized starch or polyvinylpyrrolidone; the first and second diluents are independently selected from lactose, microcrystalline cellulose, calcium phosphate dibasic, mannitol, powdered cellulose or pregelatinized starch; the disintegrant is selected from microcrystalline or croscarmellose sodium; and the lubricant is selected from magnesium stearate, calcium stearate, steric acid or a surface active agent.

In a specific embodiment, the binder/diluent is pregelatinized starch; the first diluent is microcrystalline cellulose; the second diluent is calcium phosphate dibasic; the disintegrant is croscarmellose sodium; and the lubricant is magnesium stearate.

The pharmaceutical compositions of the present invention are preferably in the form of tablets. The tablets may be, for example, from 50 mg to 1.0 g in net weight, preferably 100 to 800 mg net weight, more preferably 100 to 400 mg net weight.

Preferred pharmaceutical compositions comprise about 1 to 30% by weight of the active ingredient; about 20 to 40% by weight of pregelatinized starch; about 10 to 20% by weight of microcrystalline cellulose; about 20 to 50% by weight of calcium phosphate dibasic; about 5 to 15% by weight of croscarmellose sodium; and about 0.05 to 5% by weight of magnesium stearate.

It will be appreciated by one skilled in the art that the sum of the above proportions of the active ingredient, pregelatinized starch, microcrystalline cellulose, calcium phosphate dibasic, croscarmellose sodium, and magnesium stearate are not greater than 100% by weight.

More preferred pharmaceutical compositions in accordance with the present invention include those comprising the noted ingredients:

(1) about 1 to 2% by weight of the active ingredient; about 25 to 35% by weight of pregelatinized starch; about 10 to 20% by weight of microcrystalline cellulose; about 45-55% by weight of calcium phosphate dibasic; about 4 to 8% by weight of croscarmellose sodium; and about 0.1 to 1% by weight of magnesium stearate.

(2) about 5 to 10% by weight of the active ingredient, about 25 to 35% by weight of pregelatinized starch; about 10 to 20% by weight of microcrystalline cellulose; about 40 to 50% by weight of calcium phosphate dibasic; about 4 to 8% by weight of croscarmellose sodium; and about 0.1 to 1% by weight of magnesium stearate.

(3) about 25 to 35% by weight of the active ingredient, about 15 to 25% by weight of pregelatinized starch; about 10 to 20% by weight of microcrystalline cellulose; about 15-25% by weight of calcium phosphate dibasic; about 10 to 20% by weight of croscarmellose sodium; and about 0.1 to 1% by weight of magnesium stearate.

It will be appreciated by one skilled in the art that the sum of the above proportions of the active ingredient, pregelatinized starch, microcrystalline cellulose, calcium phosphate dibasic, croscarmellose sodium, and magnesium stearate are not greater than 100% by weight.

Especially referred pharmaceutical compositions as envisioned for commercial development are as follows:

Tablets of 1.0 mg potency free base:

about 1.18% by weight of active ingredient as the methanesulfonate salt; about 30.0% by weight of pregelatinized starch; about 15.0% by weight of microcrystalline cellulose; about 47.3% by weight of calcium phosphate dibasic; about 6.0% by weight of croscarmellose sodium; and about 0.5% by weight of magnesium stearate. This composition comprises about 1.2 mg of active ingredient as the methanesulfonate salt; about 30 mg of pregelatinized starch; about 15 mg of microcrystalline cellulose; about 47.3 mg of calcium phosphate dibasic; about 6.0 mg of croscarmellose sodium; and about 0.5 mg of magnesium stearate per dosage unit.

Optionally, the 1.0 mg potency tablet may be coated with a coating comprising about 0.8% by weight of hydroxypropyl methylcellulose; about 0.8% by weight of hydroxypropyl cellulose; about 0.32% by weight of titanium dioxide; and about 0.08% by weight of talc (as a percentage of the core tablet weight).

Tablets of 5.0 mg potency free base:

about 1.48% by weight of active ingredient as the methanesulfonate salt; about 30.0% by weight of pregelatinized starch; about 15.0% by weight of microcrystalline cellulose; about 47.0% by weight of calcium phosphate dibasic; about 6.0% by weight of croscarmellose sodium; and about 0.5% by weight of magnesium stearate. This composition comprises about 6 mg of active ingredient as the methanesulfonate salt; about 120 mg of pregelatinized starch; about 60 mg of microcrystalline cellulose; about 188 mg of calcium phosphate dibasic; about 24 mg of croscarmellose sodium; and about 2 mg of magnesium stearate per dosage unit.

Optionally, the 5.0 mg potency tablet may be coated with a coating comprising about 0.8% by weight of hydroxypropyl methylcellulose; about 0.8% by weight of hydroxypropyl cellulose; about 0.32% by weight of titanium dioxide; and about 0.08% by weight of talc (as a percentage of the core tablet weight).

Tablets of 25 mg potency free base:

about 7.39% by weight of active ingredient as the methanesulfonate salt; about 282% by weight of pregelatinized starch; about 14.2% by weight of microcrystalline cellulose; about 43.6% by weight of calcium phosphate dibasic; about 6.0% by weight of croscarmellose sodium; and about 0.5% by weight of magnesium stearate. This composition comprises about 30 mg of active ingredient as the methanesulfonate salt; about 113 mg of pregelatinized starch; about 57 mg of microcrystalline cellulose; about 174 mg of calcium phosphate dibasic; about 24 mg of croscarmellose sodium; and about 2 mg of magnesium stearate per dosage unit.

Optionally, the 25 mg potency tablet may be coated with a coating comprising about 0.8% by weight of hydroxypropyl methylcellulose; about 0.8% by weight of hydroxypropyl cellulose; about 0.32% by weight of titanium dioxide; and about 0.08% by weight of talc (as a percentage of the core tablet weight).

Tablets of 100 mg potency free base:

about 29.5% by weight of active ingredient as the methanesulfonate salt; about 19.5% by weight of pregelatinized starch; about 15.0% by weight of microcrystalline cellulose; about 20.4% by weight of calcium phosphate dibasic; about 15.0% by weight of croscarmellose sodium; and about 0.5%o by weight of magnesium stearate. This composition comprises about 118 mg of active ingredient as the methanesulfonate salt; about 78 mg of pregelatinized starch; about 60 mg of microcrystalline cellulose; about 82 mg of calcium phosphate dibasic; about 60 mg of croscarmellose sodium; and about 2 mg of magnesium stearate per dosage unit.

Optionally, the 100 mg potency tablet may be coated with a coating comprising about 0.8% by weight of hydroxypropyl methylcellulose; about 0.8% by weight of hydroxypropyl cellulose; about 0.32% by weight of titanium dioxide; and about 0.08% by weight of talc (as a percentage of the core tablet weight).

The tablets of the 1.0 mg potency are preferably formulated in an 100 mg tablet by using 30 .mu.l of a solution of 25% ethanol/75% water per tablet. The tablets of the 5.0 mg potency are preferably formulated in an 400 mg tablet by using 120 .mu.l of a solution of 25% ethanol/75% water per tablet. The tablets of the 25 mg potency are preferably formulated in an 400 mg tablet by using 120 .mu.l of a solution of 25% ethanol/75% water per tablet. The tablets of the 100 mg potency are preferably formulated in an 400 mg tablet by using 120 .mu.l of a solution of 25% ethanol/75% water per tablet.

In a particularly preferred embodiment, the tablet formulations of the instant invention are coated. In the pharmaceutical compositions envisioned for commercial development described above, the tablets of 1.0 mg, 5.0 mg, 25 mg and 100 mg potency free base are coated with about 0.8% by weight of hydroxypropyl methylcellulose; about 0.8% by weight of hydroxypropyl cellulose; about 0.32% by weight titanium dioxide; and about 0.08% by weight of purified talc.

In the most preferred embodiment, the active ingredient in the above-described pharmaceutical compositions is N-[1(R)-[(1,2-dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperdin]-1'-y l)carbonyl]-2-(phenylmethyloxy)ethyl)-2-amino-2-methylpropanamide methanesulfonate.

The compositions of the present invention are in a form for oral administration and may take the form of tablets, capsules, granules, powders, tablets or granules for buccal administration, or liquid preparations such as suspensions. Granules and powders may be ingested directly, or dispersed in water or other suitable vehicle prior to administration. Capsules may be of the hard or soft gelatin type, including soft gelatin capsules.

The pharmaceutical compositions of the present invention may also contain other excepients conventional in the art such as flavorings, sweeteners, and the like. Suitable flavorings include for example fruit flavors or natural or synthetic mint or peppermint flavors. Suitable sweeteners include for example sugar, saccharin or aspartame.

The utility of the active ingredient of the formulation of the present invention as growth hormone secretagogues may be demonstrated by methodology known in the art, such as an assay described by Smith, et al., Science, 260, 1640-1643 (1993) (see text of FIG. 2 therein). In particular, the active ingredient used in the formulation the present invention had activity as a growth hormone secretagogue in the aforementioned assay. Such a result is indicative of the activity of the formulation of the present invention as a growth hormone secretagogue.

The formulations of the present invention may be administered to animals, including man, to release growth hormone in vivo. For example, the formulations can be administered to commercially important animals such as swine, cattle, sheep and the like to accelerate and increase their rate and extent of growth, to improve feed efficiency and to increase milk production in such animals. In addition, these formulations can be administered to humans in vivo as a diagnostic tool to directly determine whether the pituitary is capable of releasing growth hormone. For example, the formulation of the present invention can be administered in vivo to children. Serum samples taken before and after such administration can be assayed for growth hormone. Comparison of the amounts of growth hormone in each of these samples would be a means for directly determining the ability of the patient's pituitary to release growth hormone.

Accordingly, the present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, the compound N-[1(R)-[(1,2-dihydro-1-methane-sulfonyl-spiro[3H-indole-3,4'-piperdin]-1' -yl)carbonyl]-2-(phenyl-methyl-oxy)ethyl]-2-amino-2-methyl-propanamide in association with a pharmaceutical carrier or diluent. Optionally, the active ingredient of the pharmaceutical compositions may comprise an anabolic agent in addition to the compound N-[1(R)-[(1,2-dihydro-1-methane-sulfonyl-spiro[3H-indole-3,4'-piperdin]-1' -yl)carbonyl]-2-(phenyl-methyl-oxy)ethyl]-2-amino-2-methyl-propanamide or another composition which exhibits a different activity, e.g., an antibiotic growth permittant or an agent to treat osteoporosis or in combination with a corticosteroid to minimize the catabolic side effects or with other pharmaceutically active materials wherein the combination enhances efficacy and minimizes side effects.

Growth promoting and anabolic agents include, but are not limited to TRH, diethylstilbesterol, amino acids, estrogens, .beta.-agonists, theophylline, anabolic steroids, enkephalins, E series prostaglandins, compounds disclosed in U.S. Pat. No. 3,239,345, e.g., zeranol, and compounds disclosed in U.S. Pat. No. 4,036,979, e.g., sulbenox or peptides disclosed in U.S. Pat. No. 4,411,890.

A still further use of the formulations of this invention is in combination with other growth hormone secretagogues such as the growth hormone releasing peptides GHRP-6, GHRP-1 as described in U.S. Pat. No. 4,411,890 and publications WO 89/07110, WO 89/07111 and B-HT920 as well as hexarelin and GHRP-2 as described in WO 93/04081 or growth hormone releasing hormone (GHRH, also designated GRF) and its analogs or growth hormone and its analogs or somatomedins including IGF-1 and IGF-2 or .alpha.-adrenergic agonists such as clonidine or serotonin 5HTID agonists such as sumitriptan or agents which inhibit somatostatin or its release such as physostigmine and pyridostigmine. In particular, the formulations of this invention may be used in combination with growth hormone releasing factor, an analog of growth hormone releasing factor, IGF-1, or IGF-2. For example, a formulation of the present invention may be used in combination with IGF-1 for the treatment or prevention of obesity. In addition, a formulation of this invention may be employed in conjunction with retinoic acid to improve the condition of musculature and skin that results from intrinsic aging.

As is well known to those skilled in the art, the known and potential uses of growth hormone are varied and multitudinous. The administration of the formulations of this invention for purposes of stimulating the release of endogenous growth hormone can have the same effects or uses as growth hormone itself. These varied uses of the present formulations thus may be summarized as follows: stimulating growth hormone release in elderly humans; treating growth hormone deficient adults; prevention of catabolic side effects of glucocorticoids; treatment of osteoporosis; stimulation of the immune system, acceleration of wound healing; accelerating bone fracture repair; treatment of growth retardation; treating acute or chronic renal failure or insufficiency; treatment of physiological short stature, including growth hormone deficient children; treating short stature associated with chronic illness; treatment of obesity and growth retardation associated with obesity; treating growth retardation associated with Prader-Willi syndrome and Turner's syndrome; accelerating the recovery and reducing hospitalization of burn patients or following major surgery such as gastrointestinal surgery; treatment of intrauterine growth retardation, and skeletal dysplasia, treatment of peripheral neuropathies; replacement of growth hormone in stressed patients; treatment of osteochondrody-splasias, Noonans syndrome, schizophrenia, depression, Alzheimer's disease, delayed wound healing, and psychosocial deprivation; treatment of pulmonary dysfunction and ventilator dependency; attenuation of protein catabolic response after a major operation; treating malabsorption syndromes; reducing cachexia and protein loss due to chronic illness such as cancer or AIDS; accelerating weight gain and protein accretion in patients on TPN (total parenteral nutrition); treatment of hyperinsulinemia including nesidioblastosis; adjuvant treatment for ovulation induction and to prevent and treat gastric and duodenal ulcers; to stimulate thymic development and prevent the age-related decline of thymic function; adjunctive therapy for patients on chronic hemodialysis; treatment of immunosuppressed patients and to enhance antibody response following vaccination; increasing the total lymphocyte count of a human, in particular, increasing the T₄ /T₈ -cell ratio in a human with a depressed T₄ /T₈ -cell ratio resulting, for example, from physical trauma, such as closed head injury, or from infection, such as bacterial or viral infection, especially infection with the human immunodeficiency virus; improvement in muscle strength, mobility, maintenance of skin thickness, metabolic homeostasis, renal hemeostasis in the frail elderly; stimulation of osteoblasts, bone remodelling, and cartilage growth; stimulation of the immune system in companion animals and treatment of disorders of aging in companion animals; growth promotant in livestock; and stimulation of wool growth in sheep. Further, the instant compounds are useful for increasing feed efficiency, promoting growth, increasing milk production and improving the carcass quality of livestock. Likewise, the instant formulations are useful in a method of treatment of diseases or conditions which are benefited by the anabolic effects of enhanced growth hormone levels.

In particular, the instant formulations are useful in the prevention or treatment of a condition selected from the group consisting of: osteoporosis; catabolic illness; immune deficiency, including that in individuals with a depressed T₄ /T₈ cell ratio; hip fracture; musculoskeletal impairment in the elderly; growth hormone deficiency in adults or in children; obesity; cachexia and protein loss due to chronic illness such as AIDS or cancer; and treating patients recovering from major surgery, wounds or burns, in a patient in need thereof.

In addition, the instant formulations may be useful in the treatment of illnesses induced or facilitated by corticotropin releasing factor or stress- and anxiety-related disorders, including stress-induced depression and headache, abdominal bowel syndrome, immune suppression, HIV infections, Alzheimer's disease, gastrointestinal disease, anorexia nervosa, hemorrhagic stress, drug and alcohol withdrawal symptoms, drug addiction, and fertility problems.

It will be known to those skilled in the art that there are numerous compounds now being used in an effort to treat the diseases or therapeutic indications enumerated above. Combinations of these therapeutic agents some of which have also been mentioned above in and with the formulations of this invention will bring additional, complementary, and often synergistic properties to enhance the growth promotant, anabolic and desirable properties of these various therapeutic agents. In these combinations, the therapeutic agents and the active ingredient in the formulations of this invention may be independently present in dose ranges from one one-hundredth to one times the dose levels which are effective when these compounds and active ingredients are used singly.

Combined therapy to inhibit bone resorption, prevent osteoporosis and enhance the healing of bone fractures can be illustrated by combinations of bisphosphonates and the formulations of this invention. The use of bisphosphonates for these utilities has been reviewed, for example, by Hamdy, N. A. T., Role of Bisphosphonates in Metabolic Bone Diseases, Trends in Endocrinol. Metab., 4, 19-25 (1993). Bisphosphonates with these utilities include alendronate, tiludronate, dimethyl-APD, risedronate, etidronate, YM-175, clodronate, pamidronate, and BM-210995. According to their potency, oral daily dosage levels of the bisphosphonate of between 0.1 mg and 5 g and daily dosage levels of the active ingredient of the formulation of this invention of between 0.01 mg/kg to 20 mg/kg of body weight are administered to patients to obtain effective treatment of osteoporosis.

In the case of alendronate daily oral dosage levels of 0.1 mg to 50 mg are combined for effective osteoporosis therapy with 0.01 mg/kg to 20 mg/kg of the active ingredient employed in the formulation of this invention. Osteoporosis and other bone disorders may also be treated with the formulations of this invention in combination with calcitonin, estrogens, raloxifene and calcium supplements such as calcium citrate.

Anabolic effects especially in the treatment of geriatric male patients are obtained with formulations of this invention in combination with anabolic steroids such as oxymetholone, methyltesterone, fluoxymesterone and stanozolol.

The pharmaceutical tablet compositions of the present invention may also contain one or more additional formulation ingredients selected from a wide variety of excipients (also referred to as "additives") known in the pharmaceutical formulation art. According to the desired properties of the tablet, any number of additives may be selected, alone or in combination, based upon their known uses in preparing tablet compositions. Such additives include, but are not limited to, diluents, binders, compression aids, disintegrants, lubricants, flavors, flavor enhancers, sweeteners and preservatives. Due to the bitter taste of the active ingredient, the inclusion of a sweetener may be desired.

The dosage of active ingredient in the compositions of this invention may be varied; however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained. The selected dosage depends upon the desired therapeutic effect, on the route -of administration, and on the duration of the treatment. Generally, dosage levels of between 0.0001 to 10 mg/kg. of body weight daily are administered to patients and animals, e.g., mammals, to obtain effective release of growth hormone. Preferably, the dosage level will be about 0.001 to about 25 mg/kg per day; more preferably about 0.01 to about 10 mg/kg per day.

Claim 1 of 28 Claims

What is claimed is:

1. A pharmaceutical composition comprising:

0.1 to 50% by weight of an active ingredient N-[1(R)-[(1,2-dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperdin]-1'-y l)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2-methyl-propanamide, or a pharmaceutically acceptable salt thereof;

20 to 40% by weight of a binder/diluent which is selected from: hydroxypropyl methylcellulose, hydroxypropyl cellulose, pregelatinized starch and polyvinylpyrrolidone;

10 to 20% by weight of a first diluent which is selected from: lactose, microcrystalline cellulose, calcium phosphate dibasic, mannitol, powdered cellulose and pregelatinized starch;

20 to 50% by weight of a second diluent which is selected from: lactose, microcrystalline cellulose, calcium phosphate dibasic, mannitol, powdered cellulose and pregelatinized starch;

5 to 15% by weight of a disintegrant which is selected from microcrystalline or croscarmellose sodium; and

0.05 to 5% by weight of a lubricant which is selected from magnesium stearate, calcium stearate, and steric acid;

wherein sum of the above proportions of the active ingredient, the binder/diluent, the first diluent, the second diluent, the disintegrant, and the lubricant are not greater than 100% by weight.

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