Stabilized tibolone compositions

Details Stabilized tibolone compositions Stabilized tibolone compositions

2002-04-08

2003-02-04

Reamer, James (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Cyclopentanohydrophenanthrene ring system doai

C424S465000

Reexamination Certificate

active

06514958

ABSTRACT:

The invention pertains to a pharmaceutical dosage unit, such as a tablet or a capsule, comprising an effective amount of tibolone (generally of from 0.1 to 10 % by weight) and a pharmaceutically acceptable carrier, the carrier containing a water-insoluble starch product.
Compositions comprising tibolone, (7&agr;, 17&agr;)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one (hereinafter also denoted as “Org OD 14”) and a pharmaceutically acceptable solid carrier have been described in EP 389 035, which disclosure is incorporated herein by reference. Tablets are available on the market under the name of Livial®.
Another disclosure in which reference is made to compositions comprising tibolone are EP 707 848 and U.S. Pat. No. 4,701,450. These are not the customary formulations known in practice.
A typical known formulation for tibolone is a 100 mg dosage unit having 2,5 mg of tibolone contained therein, a relatively small amount (e.g. approximately 1% by weight) of pharmaceutically acceptable auxiliaries, and a carrier making up the body of the tablet. The carrier typically is composed of 10% by weight of starch, e.g. potato starch, and 90% by weight of lactose, optionally with other non-starch ingredients such as amylopectin (see, e.g., U.S. Pat. No. 4,701,450) or special types of cellulose, such as microcrystalline celluloses like Avicel (see, e.g., EP 707 848).
The known tablets can be stably stored very well for, typically, 2 years at ambient temperature. A sufficiently humid atmosphere (e.g. 50-70% relative humidity) makes for a better storage stability than a relatively dry atmosphere (e.g. 45% relative humidity or below that). It is an object of the invention to further improve upon the storage stability, in that particularly the shelf-life under relatively dry circumstances is enhanced. Further desirable objectives are that the stability is enhanced in an absolute sense, and also that dosage forms having a lower content of tibolone (which are more prone to stability problems than regular dosage forms) can be suitably kept for a prolonged period.
The invention serves to meet these objectives by providing tibolone dosage units of the above-identified type, wherein the carrier contains more than 10% by weight of the starch product.
Surprisingly, increasing the amount of starch used in the carrier serves as a novel method of making a dosage unit comprising tibolone with an improved stability. It should be noted that a dosage unit comprising tibolone in this invention is intended to mean any dosage unit in which either tibolone substantially alone, or tibolone together with its impurities and/or degradation products, is present as a medicinal agent. The desired stability refers to the situation in which the relative amount of impurities and/or degradation products formed upon storage is as low as possible. The absolute amount of such products will depend, of course, on the amount initially present. E.g., a simple degradation product such as that in which only the double bond is rearranged, might be introduced on purpose at a predetermined level. Important is that this level will remain sufficiently constant during storage, which is the case with the dosage units according to the invention, also in dry circumstances.
The dosage units of the invention not only provide substantively better stability as such, but, moreover, they surprisingly provide the possibility to incorporate a lower amount of tibolone. The customary amount of tibolone in the known dosage unit is 2.5 mg in tablets or capsules of 100 mg, i.e. 2.5%. For the sake of providing therapies better tailored to the individual woman's needs, it is desired to provide dosage units having a lower amount. However, if a known formulation with 10% of starch is adapted by simply including a lower amount of tibolone, the stability of the dosage unit is substantially decreased. E.g., if a 2.5 mg tibolone dosage unit has a shelf-life of, e.g., 2-3 years at room temperature, the same unit upon lowering the amount of tibolone to e.g. 0.3 mg can only be kept at 4° C. for a period of 6-12 months. Such a lower stability being unacceptable in daily practice, it is a great advantage of the present invention that tibolone dosage units can be provided which have a low tibolone content, i.e. 2% by weight or less and, preferably, 1% by weight or less, and yet display sufficient stability. This advantage being manifest particularly if the starch content in the carrier is at least 40% by weight, higher contents are preferred. The content of the starch product more preferably is at least 50% by weight, and most preferably of from 90 to 100% by weight. As particularly upon using lower amounts of tibolone higher polysaccharide contents are preferred, the ratio of the weight percentage of tibolone and the starch percentage in the carrier plays a role in the present invention. Preferably, this ratio is at most 0.02.
The pharmaceutical dosage units of the present invention will generally take the form of tablets or capsules, but other solid or dry pharmaceutical preparations are included. Methods for making such dosage units 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 and capsules include the wet-granulation, dry-granulation, and direct compression methods.
Wet-granulation methods involve weighing out ingredients (actives and excipients, including a solvent), mixing the ingredients, granulating them, screening them damp, drying them, dry screening, lubrication, and compressing the resultant admixture into tablets or filling capsules with it. Such procedures result in tablets or capsules having at least adequate homogeneity.
Direct compression methods involve weighing out direct-compression vehicles (including carriers) and active ingredients, mixing of the ingredients, lubrication, and compressing the resulting admixture into tablets, or filling capsules with it.
In the case of steroids, such as tibolone, when making dosage units with only very low doses of the active compound per tablet (e.g. <1.0 milligrams (mg)/100 mg tablet), a problem may occur in that the compound does 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. In this respect a suitable method of making the dosage units that according to the invention are preferred, viz. those having relatively low amounts of tibolone, is a dry-mix procedure such as disclosed in EP-A-0 503 521.
Carriers for active subtances in pharmaceutical dosage units generally are in one of two forms. A carrier can be a direct compression carrier, i.e. a material (usually an agglomerate) which does not need to be granulated but can be compressed, after mixing with, e.g., active ingredients, so as to form a dosage unit having material of desired shape, or it can be in the form of a basic granulate. Thus, the carriers of the present invention will be generally in the form of an agglomerate or basic granulate containing the water-insoluble starch product. The tibolone can be directly incorporated into the agglomerates or granulates, using wet-granulation techniques, but most preferably the tibolone is dry-mixed with wet-granulated dry carriers and/or with direct compression carriers.
Wet granulation distinguishes from dry granulation and dry-mixing in that water is 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-massing method in which a liquid is added to a powder or granulate in a vessel equipped with any type of agitation that will provide granules or agglomerates. Various operations

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