Tablet, capsule or granule containing desogestrel, and how you can get it (options)

 

(57) Abstract:

In tablet, capsule or granule for oral administration desogestrel mixed with solid or dissolved in a solid. Solid material is a lubricating substance that does not contain organic solvents, or waxy substance, which is not a lubricant. The solid is selected from phospholipids, glycolipids, lipoproteins, hydrophilic or lipophilic waxy materials, fatty alcohols, glycols, polyoxyethylenated sorbitolovy fatty acids or their esters, and mixtures thereof. The mass ratio of desogestrel and solids is from 1:4.2 to 1:400. Received dosage forms are stable and have the ability to hold desogestrel from migration under extreme conditions. 4 S. and 2 C.p. f-crystals, 1 table.

The present invention relates to tablets, capsules or granules for oral administration, containing desogestrel.

Pharmaceutical compositions containing desogestrel, known in this area. For example, they are described in U.S. patent 4914089. Known compositions containing desogestrel, however, less suitable is the meet of great importance, as the granules contain a very small dose of desogestrel. Tablets obtained from granules containing desogestrel, as active compounds, typically include a 25 - 150 micrograms of desogestrel, usually 25, 50, 75, 100 or 150 mg. Loss, for example, 10% of the active compounds within the shelf life of the medicinal product, has a critical impact on the number of active connections in the tablet and can lead to the fact that the tablet will contain the number, the smaller the threshold amount of the active ingredient necessary for the manifestation of full activity. For desogestrel, which is used as active ingredient in the contraceptive drugs, it is not valid from the point of view of its safety and reliability. It is now established that the tablet, capsule or granule for oral administration, in which desogestrel mixed with solid or dissolved in a solid substance selected from lubricants not containing organic solvents, and oily substances, non-lubricating, be stable and have the ability to hold desogestrel even under extreme conditions.

Preferably desogestrel mixed the, hydrophilinae or lipophilic waxy materials, fatty alcohols, glycols, polyoxyethylene derivatives sorbitolovy fatty acids, fatty acids or their esters, and mixtures thereof.

Most preferably desogestrel mixed or dissolved in a solid fatty acid or its esters with polyhydric alcohol, or glycerin.

Solid waxy fillers for dissolving or mixing with desogestrel can be natural or synthetic. Fats of vegetable origin are mostly composed of (mixed) triglycerides. Examples of other acceptable waxy fillers are stearic acid, stearyl alcohol, Preziral (Precirol), magnesium stearate, gidrirovannoe castor oil (Cutina HP), gidrirovannoe peanut butter and lecithin. Mulgirigala waxes can also be used for dispersion of the active compounds. A typical example is the filler Gelucira, which consists of partial glycerides and polyglycerol fatty esters with controlled hydrophilic properties. Above waxy substances may be mixed with additives. Specific examples of such additives for the formation of the solid on the palmitic acid, stearic acid, lecithins, sucrose polyester, Mygliol, Tween, glycerin, propylene glycol and polyethylene glycol.

The pharmaceutical composition in accordance with the present invention may optionally contain estrogen. Examples of estrogen is ethinylestradiol, mestranol (17-ethinyl estradiol-3-methyl ether), estrone, estradiol, estradiolvalerate and other compounds with estrogenic activity. Preferred estrogen it is thought that is levonorgestrel.

Solid matrix in accordance with the present invention holds desogestrel from migration into the environment. Also found that desogestrel mixed with or dissolved in a solid matrix containing waxy material that is less degradable.

The solid matrix can be converted into tablets, granules, capsules and similar products. Such methods are well known in this field and are described in standard literature, for example in the work of Gennaro et al., Remington''s Pharmaceutical Sciences (18th-th, ed., Mack Publishing Company, 1990 (see part 8 - Pharmaceutical Preparations and Their Manufacture).

For administration of desogestrel and optional estrogen in a waxy form in (mix) wax (or fatty) components, UP>oC), it is most preferable to dissolve the active compound (I) together with wax (or fatty) components in an acceptable organic solvent, such as acetone, ethanol or methanol. This solution can be distributed on the material carrier comprising a composite pellets or a single component, such as crystalline cellulose. After evaporation of the solvent, the drug deposited on the carrier may be mixed with adjuvants to optimize the yield of media (colloidal silicon dioxide) and/or lubricating agents, e.g. magnesium stearate). The resulting mixture is coated with the drug can granulomatis or pressoffice into tablets, or it can be filled with gelatin or starch capsules. To obtain a homogeneous mixture of drugs with low effective dose, with waxy compounds with a relatively high melting temperature (>45oC), such as, for example, the lubricant, the mixture can also be prepared without the use of solvents, and then repeats the above procedure. Powdered drugs should be mixed thoroughly using techniques and equipment, the indicators and processed into capsules, granules or tablets using conventional technologies. Moreover, it is possible to directly cool the liquid dispersion of the active ingredients in the waxy substance, and then sift the solid material to small particles for further processing the mixture to tablets or capsules.

The solid matrix containing desogestrel, include conventional excipients, such as carriers, diluents, lubricants and binders. The solid matrix can be treated as granules. General methods of obtaining granules described, for example, in the book of Pharmaceutical Dosage Forms: Tablets Volume 1). - ed. H. A. Lieberman, L. Lachman & J. B. Schwartz (1989), Marcel Dekker Inc, New Yorc and Basel, pp. 131-190.

Preferably, the solid matrix containing desogestrel, will also contain disintegrity agent.

Diluents or fillers are agents that are added to the dosing units to increase granules and final volume of the dosing unit. The preferred diluent for use for these purposes is lactose. Other excipients include mannitol, sorbitol, cellulose, xylitol, dextrose, fructose, calcium phosphate, NaCaPO4, sucrose, and mixtures thereof. The diluent is usually faced the Oh agents, used to impart cohesive properties to the granules and ensure greater physical stability of the dosing unit, and these include hydroxypropylcellulose (GOC), amylopectin, starch, hypromellose (HPMC), gelatin, and binder, starch-based. The preferred binding agent for use in the present invention is a GOC or povidone (polyvinylpyrrolidone). Binder is usually from 0.5 to 5 wt.% based on the final granules containing steroid.

Dezintegriruetsja agents or disintegrators are substances or mixtures that are added to the tablet to facilitate its destruction or dispersion after application. Typically, such agents are modified or unmodified starch, clays, cross-linked polyvinylpyrrolidone, modified or unmodified cellulose, resins or algini. The most preferred agents are corn starch, potato starch, and wheat starch. Disintegrator are usually contained in an amount of 5 to 50 wt.%, preferably from 5 to 15 wt.% based on the granule.

The lubricant under normal upright adhesion of the material of the tablets to the surface of the mouthpieces and presses, reduce the friction between particles and accelerate the ejection of tablets from the cavity of the mouthpiece. Conventional lubricating agents are talc, fatty acids with long chains, magnesium stearate, stearic acid, calcium stearate, polyethylene glycol, palmitic acid, and hydrogenated vegetable oil. Grease is usually from 0.25 to 3 wt.% based on the final granules. In accordance with the present invention the solid lubricants can also be used as filler for mixing with the active ingredient or dissolution of the active ingredient without the use of organic solvents.

Also provides for the use of other conventional additives or additional fillers, such as dyes, stabilizers or antioxidants. Stabilizers, such as EDTU, polyethylene glycol (PEG) and bottled hydroxytoluene, if necessary, can be included, although this is not necessary. Currently, the most preferred antioxidant for use in the present invention is a dI-tocopherol. Other medical agents (for example, 17-estradiol) may also be included in the EP 1.

Sublimation of desogestrel in the solid matrix in accordance with the invention is compared with the sublimation of desogestrel with fillers known in this field. Desogestrel (1.5 mg) is mixed with 600 mg of filler. Samples stored for 72 hours at 70oC at a pressure of 15 kPa (150 mbar). Pair of sublimation collect on the cold test tube at 4oC and determine the number sublimemovies of desogestrel (see table).

Example 2.

Lactose (130,5 kg) and starch (15 kg) loaded into the basket of the fluidized bed reactor and mixed. The resulting mixture granularit by spraying on a layer of mortar binder containing polyvidone (4.5 kg) in water (13,5 l). After spraying the granules are dried and sieved. Download 1,952 kg of the obtained granules in the shopping cart high performance mixer and heated to 50 - 60oC. In a separate vessel melt stearic acid (20 g) and heated to 110oC. Add desogestrel and 4.75 g), ethinylestradiol (0,923 g) and dI-tocopherol (2,462 g) and dissolved. Transparent warm solution is added to the granules in the mixer and mix for 3 to 5 minutes After mixing the pellets are cooled to room temperature and mixed with colloidal silicon dioxide (20 g). Great film coating using 230 g covering suspension, containing 50 g of hydroxypropylmethylcellulose, 10 g of polyethylene glycol 400, 7.5 g of titanium dioxide and 12.5 g of talc in 920 ml of purified water.

1. Tablet, capsule or granule for oral administration, containing desogestrel, wherein desogestrel mixed with or dissolved in a solid, representing a lubricating substance not containing organic solvents, or waxy substance, which is not a lubricant, while the solid is selected from phospholipids, glycolipids, lipoproteins, hydrophilic or lipophilic waxy materials, fatty alcohols, glycols, polyoxyethylenated sorbitolovy fatty acids or their esters, and mixtures thereof.

2. Tablet, capsule or pellet under item 1, wherein desogestrel mixed with or dissolved in a solid fatty acid or its ester with a polyhydric alcohol or its ester with glycerol.

3. Tablet, capsule or pellet under item 1 or 2, characterized in that it additionally contains estrogen.

4. The pellet, containing desogestrel, mixed with or dissolved in a solid, representing a lubricating substance that does not contain organic restoration, lipoproteins, hydrophilic or lipophilic waxy materials, fatty alcohols, glycols, polyoxyethylenated sorbitolovy fatty acids or their esters, and mixtures thereof, to obtain a pharmaceutical composition, which desogestrel do not migrate.

5. The method of producing tablets, capsules or granules, containing desogestrel, characterized in that the tablet, capsule or granule is obtained using a mixture containing waxy substance and desogestrel and optional estrogen, while this mixture is obtained by dissolving desogestrel and optional estrogen in waxy substance, which is not a lubricant, an organic solvent, the mass ratio of desogestrel and waxy substances in the range of 1 : 4.2 to 1 : 400, the resulting mixture is spread on the material of the medium, the organic solvent is evaporated, after which the mixture with the carrier material, and then granularit or pressed into tablets or filled her capsules.

6. The method of producing tablets, capsules or granules, containing desogestrel, characterized in that the tablet, capsule or granule is obtained using a mixture containing washable ogestrel and optional estrogen with a waxy substance in the absence of an organic solvent, when the mass ratio of desogestrel and waxy substances in the range of 1 : 4.2 to 1 : 400, the resulting mixture was melted, cooled liquid dispersion of desogestrel and optional estrogen in waxy substance, the mixture is sieved, and then granularit, or pressed into tablets, or fill it in capsules.

 

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