Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2002-02-12
2003-10-07
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S474000, C424S475000, C424S482000
Reexamination Certificate
active
06630166
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to conjugated estrogen formulations and methods of administering such compositions. Accordingly, this invention covers the fields of pharmaceutical sciences, medicine, cosmetics, and related sciences.
BACKGROUND OF THE INVENTION
Conjugated estrogens have been used for years as an estrogen supplement in order to treat or prevent a variety of conditions that are induced or exacerbated by estrogen hormone deficiency. Particularly, conditions experienced by peri-menopausal, menopausal, and post-menopausal women such as osteoporosis, hot flashes, vaginal atrophy, and loss of protection against heart attacks, can be ameliorated using conjugated estrogens as part of an estrogen replacement therapy routine.
Although conjugated estrogens may be administered using various routes of administration, oral tablet administration has traditionally been the most common. Such formulations have not only contained conjugated estrogens, but have also included other hormones, such as progesterone in order to balance the physiological effects of estrogen supplementation. For example, oral estrogen replacement tablets containing either a conjugated estrogen, or combination of conjugated estrogen and medroxyprogesterone acetate are currently marketed under the trade names PREMARIN®, PREMPRO™, and PREMPHASE®, by Wyeth-Ayerst Laboratories, Inc.
While oral tablet regimens of conjugated estrogen have been able to achieve acceptable therapeutic results, various drawbacks to known oral tablet formulations still exist. Example of such a drawbacks include erratic drug release, degradation of the conjugated estrogen, and cracking of the tablet formulation during storage.
A variety oral tablet formulations of both instant and sustained release for administering conjugated estrogen are currently known. For example, U.S. Pat. No. 5,395,627, which is incorporated herein by reference in its entirety, discloses pharmaceutical granulates and process for making granulates to be used in oral tablet manufacture, which are very resistant to segregation, and which display an increased stability for certain steroids, such as estrogens and progestogens.
U.S. Pat. No. 5,547,948, which is incorporated herein by reference in its entirety, discloses a sugar coating composition for application to a compressed medicinal tablet used to co-deliver two or more pharmacologically-active agents. Particularly, the sugar coating composition includes sugar, a therapeutic amount of a hormonal steroid, and a hormonal steroid release-controlling amount of microcrystalline cellulose. The tablet core contains a medicinal agent which is conventionally co-delivered with the specific steroid in the sugar coating.
U.S. Pat. No. 5,720,977, which is incorporated herein by reference in its entirety, discloses an effervescent oral formulation containing a water-soluble and stable estrogen compound, such as estropipate, or estrone, a water soluble calcium salt, and a pharmaceutically acceptable excipient. The effervescent activity of the tablet is purported to aid the body's absorption of estrone and other estrogens due to their water insoluble nature. Further, the calcium component of the effervescent causing ingredients may be used as a calcium supplement to further protect against bone loss and osteoporosis.
U.S. Pat. No. 5,908,638, which is incorporated herein by reference in its entirety, discloses a solid dosage unit form containing low dose conjugated estrogens that are released at regular increments (i.e. sustained release) upon oral administration. Generally, the sustained release of estrogens and other hormones, when included, is accomplished by the inclusion of a high molecular weight hydroxypropylmethylcellulose, which may be further combined with other hydrophilic gums. In addition to controlled release, this patent discloses that strict control of moisture content within the formulation is essential to stabilizing conjugated estrogens and achieving a uniform release thereof.
In spite of the foregoing, problems such as insolubility, instability, and tablet cracking associated with oral conjugated estrogen tablets still persist. Therefore, an oral tablet formulation which overcomes, or at least ameliorates, these shortcomings continues to be sought through ongoing research and development efforts.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides, a pharmaceutical composition in a solid oral dosage form which does not crack after storage at about 40° C. and about 75% relative humidity for about 2 months. In other words, the compositions are stable under ambient conditions in most environments. In one aspect, the solid oral dosage form may be a tablet having a core containing a therapeutically effective amount of a conjugated estrogen, or a hormonal component thereof, at least one organic excipient, at least one inorganic excipient. A variety of specific conjugated estrogens and specific amounts thereof may be included. However, in one aspect, the conjugated estrogen maybe present in an amount of from about 0.1 mg to about 3 mg. In another aspect, the amount may be about 0.625 mg.
A variety of organic excipients may be used in the core of the present oral formulation. In one aspect, the organic excipients may include less than about 25% w/w of a cellulose ingredient, and less than 50% w/w of a sugar ingredient. Further, while a variety of inorganic excipients may be used, in one aspect, the inorganic excipients may include less than about 10% w/w of a calcium phosphate tribasic ingredient.
In addition to the core recited above, the oral formulation of the present invention may include an outer coating. In one aspect, the coating may be substantially free of hormones. In another aspect, the coating may contain one or more sugar ingredients. In yet another aspect, the coating may include one or more acrylic polymers.
REFERENCES:
patent: 2565115 (1951-08-01), Bates et al.
patent: 2720483 (1955-10-01), Stiller et al.
patent: 5395627 (1995-03-01), Dopper et al.
patent: 5547948 (1996-08-01), Barcomb
patent: 5720977 (1998-02-01), Deghenghi
patent: 5908638 (1999-06-01), Huber et al.
Sheikh Humera N.
Thorpe North & Western LLP
Watson Pharmaceuticals, Inc.
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