Wet granulation formulation of a growth hormone secretagogue

Details Wet granulation formulation of a growth hormone secretagogue Wet granulation formulation of a growth hormone secretagogue

1998-10-27

2000-09-26

Page, Thurman K.

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

424468, 424480, 424464, 424470, A61K 914

Patent

active

06123964&

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The present invention relates to solid dosage formulations comprising a growth hormone secretagogue and process for their manufacture. More specifically, the invention relates to a wet granulation formulation of a growth hormone secretagogue compound. The present invention further relates to an amorphous form of a growth hormone secretagogue, processes for its preparation and uses thereof.


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, Examples 18, 19 and 55 of 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, which has the structure: ##STR1##
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

REFERENCES:
patent: 5723616 (1998-03-01), Houghton et al.
patent: 5767124 (1998-06-01), Draper et al.

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