Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Patent
1996-07-15
1999-11-02
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
424489, 424490, 424465, 424469, A61K 926
Patent
active
059765704
DESCRIPTION:
BRIEF SUMMARY
This application is A 371 of PCT/US94/14638 filled Dec. 20, 1994.
This invention relates to a new method for preparing solid pharmaceutical compositions for oral administration of low-dose medications whose active ingredients have steroidal or steroid-like structures.
BACKGROUND OF THE INVENTION
The pharmaceutical art recognizes that, when highly active medicaments are prepared in pharmaceutical form for administration to subjects in need of therapy, the even distribution of active ingredient throughout the carrier is important for insuring a proper dosage and no toxic effects due to hot spots of drug. The problem is especially applicable to low dose steroidal compounds; for example, estrogens, progestins, digitalis, spironolactone. These are known to migrate through the carrier upon drying.
The prior art of low dose pharmaceutical formulation is illustrated in the literature for estrogen (e.g., estradiol). Much of the prior art comprises broad disclosures of standard preparative methods; for example, Pasquale, U.S. Pat. No. 4,544,554, etc., or Lerner, U.S. Pat. No. 3,568,828, with no mention of the problem of non-uniform distribution. The latter reference describes the preparation of low dose drugs using conventional wet granulating methods with organic solvents such as chloroform.
DeHaan (Akzo), European Patent Application No. 92103963.2, discusses the problem of uneven distribution of low dose medicaments in solid pharmaceutical dose units. This, as stated above, may be due in part to migration of the medicament. DeHaan further states that liquid granulation methods for preparing solid dosage units of low dose medicaments are also not acceptable because of the cost and environmental handicaps of the organic solvents which are unacceptable for this use.
DeHaan suggests an alternative method of manufacture which uses the compression of a dry solid mix containing an excipient having a prescribed binding-demixing ratio of the medicament to excipient.
There remains a need in the art for other methods of preparing solid dosage forms, mainly tablets of low-dosage medicaments, which can be adapted by manufacturing pharmaceutical companies to available equipment.
SUMMARY OF THE INVENTION
This invention relates to a method for preparing solid pharmaceutical dosage units containing low dose active ingredients using a wet granulation technique which employs aqueous solvents and applicable surfactants.
DETAILED DESCRIPTION OF THE INVENTION
This method utilizes an aqueous medium which contains the active ingredient or ingredients, a quantity of one or more surfactants sufficient to dissolve or suspend said active ingredients uniformly throughout the medium and other manufacturing additives as known to the art. The latter include granulating-binding agents such as gelatin; natural gums, such as acacia, tragacanth; starches, sodium alginate, sugars, polyvinylpyrrolidone; cellulose derivatives such as hydroxypropylmethylcellulose, polyvinyloxoazolidones; pharmaceutical fillers such as lactose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, calcium sulfate, dextrose, mannitol, sucrose; tabletting lubricants if needed such as calcium and magnesium stearate, stearic acid, talc, sterotex (alkaline stearate).
The components are granulated, the resulting granules are dried, sieved and compressed into tablets or filled into capsules. Other oral product forms may be similarly prepared by art methods such as chewable tablets, lozenges, troches, sustained or delayed release products or suspensions.
The active ingredients comprise any medicament which has a low effective dose such as those below 10 mg per dosage unit. Most useful are those medicaments having a steroidal nucleus, the cyclopentanoperhydrophenanthrene ring system, in their chemical structures such as the estrogens or progestins.
Examples of the former are ethinylestradiol, estrone, mestranol, 17-alpha-ethinyl estradiol-3-methylether esterified estrogens, and, especially estradiol, methyl testosterone. The dosage amounts and indication
REFERENCES:
patent: 3568828 (1971-03-01), Lerner
patent: 4544554 (1985-10-01), Pasquale
patent: 4684534 (1987-08-01), Valentine
patent: 5211958 (1993-05-01), Akkerboom et al.
patent: 5275822 (1994-01-01), Valentine et al.
patent: 5395627 (1995-03-01), Dopper et al.
Beasley Martin W.
Caldwell Henry C.
Greaves Frank C.
Suddith Andrew W.
Swarbrick James
Applied Analytical Industries, Inc.
Benston, Jr. William E.
Page Thurman K.
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