Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Patent
1996-08-01
1999-07-27
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
424464, 424465, A61K 914
Patent
active
059286687
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to a method of dry blend compression of insoluble potent drug substances using a directly compressible, agglomerated excipient that is not a conventional spray dried polyalcohol or lactose.
BACKGROUND ART
Inadequate distribution of low-dose potent drugs is a constant threat to the uniform potency of tablets and capsules containing such drugs.
The greatest potential for drug-diluent segregation in a tablet system occurs with powder or particulate mixtures intended for direct compression or wet granulation in which the drug migration occurs (Dale E. Fonner et. al., Pharmaceutical Dosage Forms: Tablets, Volume 2, pp. 253.). European Patent Application 92103963.2, AKZO N. V. p. 6 describes the inadequate homogeneity encountered with compositions containing hydrous lactose DT (U.S. Pat. No. 4,544,554 etc. issued to Samuel A. Pasquale). The migration of a low-dose potent drug disrupts the distribution throughout the mix, giving rise to inconsistency in the content uniformity of the dosage form.
U.S. Pat. No. 3,568,828 issued to Leonard Joseph Lerner describes wet processes using potent drug substances such as estrogens with organic solvents such as chloroform. Such processes are now regarded as environmentally unsafe and can incur considerable manufacturing expenses, in that appropriate solvent scrubbing and/or explosion proof equipment must be acquired at substantial capital expenditure.
Estradiol and a number of other low-dose potent drugs precipitate in a variety of polymorphs and/or crystal habits. The changes in the crystal structure on drying can affect the bioavailability of the drug. It is well known in the literature that the micronized form is more bioavailable than larger drug particle size. This invention offers an important alternative to wet granulation, thus eliminating recrystallization and the issue of polymorphism and bioavailability. It also offers the choice of dry mixing or direct compression with materials other than the conventional spray dried polyalcohols or lactoses.
DISCLOSURE THE INVENTION
The following describes the use of low dose medicinal agents such as micronized steroidal medicinal agents; estradiol, equilin, estrone, spironolactone, and non-micronized materials; such as, estropipate, conjugated estrogens, esterified estrogens, progestins or other medicinal agents having the structure which includes the cyclopentanoperhydrophenanthrene ring system which agents are formulated by a drug pharmaceutical preparation. The dry preparation makes use of excipients that have been prepared by agglomeration methods other than by spray drying. Such excipients include granular mannitol, agglomerated maltodextrin, corn syrup solids and mixtures of these agents with added conventional direct compression excipients.
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, conjugated estrogens, methyl testosterone. The dosage amounts and indications of these and other active ingredients are those described in the literature such as the Physician's Desk Reference.
The progestins are 3-ketodesogestrel, desogestrel, levo-desogestrel, norgestrel, gestodene, norethindrone, norethindrone acetate.
Other medications known to the art which are used in low doses are spironolactone, digoxin, glipizide, estazolam, clorazepate dipotassium, albuterol sulfate, clonidine HCL, alprazolam.
The agglomerated excipients used in this method are those listed above. These are differentiated from those used in the AKZO method of reference in not having the AKZO prescribed affinity-demixing range of properties of active ingredient to dry excipient. The latter property gives the method o
REFERENCES:
patent: 3568828 (1971-03-01), Lerner
patent: 4544554 (1985-10-01), Pasquale
patent: 4684534 (1987-08-01), Valentine
patent: 5275822 (1994-01-01), Valentine et al.
patent: 5585370 (1996-12-01), Casper
patent: 5595759 (1997-01-01), Wright et al.
Beasley Martin W.
Greaves Frank C.
Swarbrick James
Applied Analytical Industries, Inc.
Benston W.
Page Thurman K.
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