Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2001-08-27
2003-11-04
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S400000, C424S451000, C424S458000, C424S464000, C424S468000
Reexamination Certificate
active
06641840
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to sustained release and combination formulations for growth hormone secretagogues.
BACKGROUND OF THE INVENTION
Growth hormone (GH), which is secreted by the pituitary gland, stimulates the growth of all tissues of the body that are capable of growing. In addition, growth hormone is known to have the following effects on metabolic processes:
1. increased rate of protein synthesis in substantially all cells;
2. decreased rate of carbohydrate metabolism in cells; and
3. increased mobilization of free fatty acids and use of fatty acids for energy.
A deficiency in GH production and/or secretion can result in various diseases or conditions, such as dwarfism, profound reduction in lean body mass and concomitant increase in total body fat, particularly in the truncal region, decreased skeletal and cardiac muscle mass and muscle strength that can result in significant decreases in exercise capacity, musculoskeletal frailty, which is typically associated with old age, congestive heart failure, insulin resistance, bone fracture, reduction in bone density, delayed wound healing, and osteoporosis. The administration of exogenous growth hormone has been shown to reverse the above-mentioned metabolic changes and has also been shown to lower plasma low density lipoprotein (LDL) cholesterol and improve psychological well being.
With the rapid worldwide growth of the population aged 65 years and over, aging-associated musculoskeletal frailty will become an increasing public health problem. Frailty, in addition to its personal impact on daily functioning and social interaction, is associated with major health consequences such as injurious falls, hip fractures, and nursing home admissions. Annually, in the United States, up to 10% of frail adults over age 74 experience an injurious fall.
The causes of the long term age-associated decline in muscle and bone mass, which after age 40 in both men and women averages 0.5-1% per year, are unknown. A decline in synthesis/secretion of endogenous anabolic hormones may contribute to age-associated changes in body composition, which are characterized by decreased muscle and bone mass and a relative increase in adiposity. For example, in both men and women, growth hormone (GH, also termed somatotropin) secretion declines by 50% between the ages of 30 and 70.
GH is naturally released by the body in a patterned manner with typically large pulses during sleep and subsequent smaller pulses of GH released later. It is also believed that growth hormone releasing hormone [GHRH, also known as growth hormone releasing factor (GRF)] is released from the hypothalamus in a pulsatile or patterned manner and consequently stimulates the release of GH in a correspondingly patterned manner.
In cases where increased levels of growth hormone are desired, the problem has generally been approached by providing exogenous growth hormone, typically by injection, or by administering a compound that stimulates the secretion of growth hormone. Typically, these compounds are peptidyl in nature and need to be administered by injection. As an alternative approach, compounds termed secretagogues have been developed that stimulate the release of endogenous growth hormone. See, for example, U.S. Pat. No. 5,723,616, WO 95/11029, WO 95/17422, WO 95/11697, and WO 94/13696.
Therapeutic intervention using the growth hormone-Insulin-like Growth Factor-I (IGF-1) system is a developing field, and evidence is accumulating that suggests that therapeutic efficacy for different indications may be optimally achieved by stimulation of GH or IGF-1 or both. For some indications such as osteoporosis, it is believed that secretion of endogenous growth hormone results in the subsequent release of IGF-I, and that IGF-I elicits therapeutic effects, e.g., increased bone density. Thus, it would be desirable to have a therapeutic formulation that stimulates the secretion of IGF-I in a patient, but minimally affects the secretion of growth hormone, particularly over time. Minimizing GH levels in this situation may avoid potential adverse sequelae of continuous GH stimulation such as in acromegaly. A formulation that can be orally administered once per day is preferred. Prior to the present invention, it was not known how to prepare a therapeutic formulation containing a growth hormone secretagogue that could be easily administered, and which stimulated the levels of endogenous IGF-I while minimally affecting the release of GH over time. With a sustained release dosage form, it has been found that with steady state treatment using a growth hormone secretagogue (i.e., after 2 or more weeks of treatment), growth hormone plasma concentration peaks will be higher than in the untreated patient (i.e., baseline), but lower than the growth hormone peaks would be during the first few days of treatment. Typically, IGF-1 would be higher at steady state than either baseline or after the first few days of treatment.
It may also be advantageous for some indications to have an orally administerable therapeutic formulation that provides for both a sustained endogenous release of IGF-I and a small but significant release of GH in order to elicit the effects of IGF-I and non-IGF-I mediated effects of GH. Finally, it may be advantageous in some indications such as improving muscle mass to elevate GH while minimally elevating IGF-1.
SUMMARY OF THE INVENTION
The present invention provides sustained release dosage forms for oral administration to a mammal, the dosage forms comprising a growth hormone secretagogue and a pharmaceutically acceptable carrier, which dosage forms result in a maximum growth hormone secretagogue plasma concentration, C
max
, which is less than 80% of the C
max
that occurs when an equal dose of the growth hormone secretagogue is orally administered using an immediate release dosage form.
In a preferred embodiment, the sustained release dosage forms provide total blood growth hormone secretagogue exposure that is not proportionately decreased as much as C
max
.
In another preferred embodiment of the sustained release dosage from, the dosage form is an osmotic tablet that comprises a core that is coated with an asymmetric membrane, the core comprising:
1) about 4 to about 10 mg of 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-oxo-ethyl]-isobutyramide L-tartrate;
2) about 12 to about 50 wt % of the core of an acid selected from fumaric acid, tartaric acid, succinic acid, citric acid, L-aspartic acid, ascorbic acid, or combinations thereof;
3) about 20 to about 63 wt % of the core of an osmotic agent selected from mannitol, sorbitol, lactose, or combinations thereof;
4) about 22 to about 49 wt % of the core microcrysalline cellulose binder; and
5) about 0.5 to about 1.5 wt % of the core magnesium stearate, and the asymmetric membrane comprising cellulose acetate and polyethylene glycol which adds about 10 to about 18 wt % to the core for a core tablet having a weight of about 200 mg or less or about 8 to about 17 wt % to the core tablet for core tablets having a weight of about 300 mg.
In another preferred embodiment of the sustained release dosage forms, the growth hormone secretagogue exhibits an elimination half-life of less than about 6 hours.
In another preferred embodiment of the sustained release dosage forms, the growth hormone secretagogue is 2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide or a pharmaceutically acceptable salt or prodrug thereof, or a salt of the prodrug; 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-oxo-ethyl]-isobutyra L-tartrate; 2-amino-N-{1-(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-[3-oxo-3a-(R)-pyridin=2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethyl}-2-me
Am Ende Mary T.
Curatolo William J.
Herbig Scott M.
Benson Gregg C.
Joynes Robert M.
Page Thurman K.
Pfizer Inc.
Wichtowski John A.
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