Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Patent
1997-09-16
1999-06-29
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
424464, 424470, 424488, 424489, 514960, 514841, 514843, A61K 920, A61K 926
Patent
active
059165936
DESCRIPTION:
BRIEF SUMMARY
The invention relates to a process of making dosage units comprising at least desogestrel or Org 30659 (17.alpha.-17-hydroxy-11-methylene-19-norpregna-4,15-dien-20-yn-3-one) present in an amount of about 0.005 to 1.0 percent by weight of each pharmaceutical dosage unit.
Methods for making tablets and other solid or dry pharmaceutical preparations are well-known. For example in the standard English language text Gennaro et al., Remington's Pharmaceutical Sciences, (18th ed., Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical Preparations and Their Manufacture), methods of making tablets, capsules and pills and their respective components are described.
Three methods of making tablets include the wet-granulation, dry-granulation, and direct compression methods. Wet-granulation methods involve weighing out ingredients (including a solvent), mixing the ingredients, granulating them, screening them damp, drying them, dry screening, lubrication, and compressing the resultant admixture into tablets. Such procedures result in tablets having at least adequate tablet homogeneity. Wet-granulation methods may have a disadvantage when certain solvents, which may not be desired in view of environmental and safety concerns, are used.
An additional problem occurs in providing optimal tablet homogeneity when used with certain very potent medicinal compounds. For example, compounds such as certain extremely potent steroids require only very low doses of the compound per tablet (e.g. <1.0 milligrams (mg)/100 mg tablet) and do not always distribute entirely evenly throughout a tableting mixture possibly resulting in some tablets having relatively high amounts of steroid (i.e. "superpotent tablets"), while others have very low amounts of steroid or possibly none at all.
Very few solutions for these problems are offered, among which a dry-mix procedure as disclosed in European patent application 503,521.
The present invention offers a novel solution for obtaining tablets comprising low dosage of the micronised or finely milled steroidal progestogens desogestrel or Org 30659 with excellent content uniformity, by using a wet-granulation technique, in which the progestogen, and optionally pharmaceutically acceptable excipients, are mixed with water and granulated. The granulate obtained may optionally be mixed with pharmaceutically acceptable auxiliaries, and compressed into tablets.
The method is very suitable for tablets comprising the low dosage steroidal progestogens desogestrel or Org 30569, which are present in an amount of about 0.005 to 1.0, and preferably of about 0.01 to 0.5 percent by weight of each pharmaceutical dosage unit. Under desogestrel is also to understand its active metabolite 3-keto-desogestrel.
The progestogens desogestrel and Org 30659 can be admixed with estrogens selected from ethinyl estradiol (EE), estradiol, and mestranol. Usually mixtures of progestogens and estrogens are used. Most preferred are tablets comprising desogestrel and ethinyl estradiol.
Since tablets containing desogestrel (and also tablets containing Org 30659) are known to be unstable towards moisture, many attempts are done to exclude water in the manufacture process, for instance by using a dry-granulating method, or by using water-free organic solvents in wet-granulating methods. The marketed product (Marvelon.RTM.), for instance, is packed in a water impermeable sachet to prevent contact between the tablet and surrounding. Most remarkably it has now been found that the process of this invention, comprising granulation in an aqueous medium, provides a granulate of desogestrel or Org 30659 and ethinyl estradiol, from which tablets can be prepared which are much more stable towards moisture, than the previously aqueous-free prepared tablets.
Wet granulation distinguishes from dry granulation in that water or organic solvents are applied in wet granulation to produce agglomeration or granules.
The most widely used granulation methods in the pharmaceutical industry are the fluidized bed granulation and the wet-massi
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H.H. El-Shattawy, Drug Dev. and Ind. Pharmacy, 7:4:439-451, 1981.
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H.H. El-Shattawy, Drug Dev. and Ind. Pharmacy, 7:439-451 1981.
de Haan Pieter
Zwinkels Jocominus Antonius Maria
Akzo Nobel N.V.
Gormley Mary E.
Page Thurman K.
Seidleck Brian K.
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