Pressed tablets desogestrel made by way of the dry granulation

 

(57) Abstract:

The invention relates to medicine, in particular to pharmacology concerns the pressed tablets desogestrel made by dry granulating method, and method of manufacturing of tablets, capsules or granules, containing desogestrel, by roller compaction or by moulding blanks, in which desogestrel optionally with other active compounds and/or fillers in the first step of the method is then pressed at high pressure, after which the second stage breaks up the particles and in the third stage of these particles produce tablets or fill their capsules with known methods. The method is less expensive than known methods, and how minimally problematic from the point of view of the harm to the environment, and the particles have improved stability. 2 S. and 2 C.p. f-crystals, 1 table.

The invention relates to extruded tablets manufactured by way of the dry granulation, containing desogestrel, and the method of their manufacture.

Desogestrel is a contraceptive steroid, widespread in the preparations under various trade names.

It was found that desogestrel tends to move from tablets and granules. This is of particular concern when the kernel tablets or granules contain very small doses of desogestrel. Tablets containing desogestrel as the active ingredient, usually contain 25-150 µg, in the typical case - 25, 50, 75, 100, or 150 micrograms of desogestrel. For desogestrel, which is used as active ingredient in contraceptive pills or drugs for GST (hormone replacement therapy), it is unacceptable from the point of view of their safety and reliability. For example, the loss of 10% of the active substance over a period of retention has a radical impact on the amount of active ingredient in the tablet and can lead to a pill that contains the amount of active ingredient is less than the threshold value, will not show its activity in full.

The authors of the present invention have found that to prevent the movement of desogestrel from tablets or pellets into the environment, you can use the pressing of the dry mixture, containing desogestrel. In addition desogestrel tablet or granule may additionally include estrogen.

Examples of estrogens include Lariat and other compounds having estrogen activity. Preferred estrogen is ethinylestradiol and estradiol.

Used in the present description, the term "transfer" includes any process by which desogestrel prematurely leaves the metering unit.

The term "metering unit" generally refers to physically discrete units suitable for use as a uniform doses to humans and animals, each of which contains a certain amount of active material (desogestrel and/or estrogen), designed to obtain the desired effect. Examples of such dispensing units are tablets, granules, powders and pills.

Methods and compositions for the production of different dosing units are well known in the art. For example, methods and compositions for making tablets and pills are described in Remington's (18th edition, A. R. Gennaro Ed., Mack Publishing Co. Easton, Pa, 1990) p 1633-1665.

The concentration of the steroid or steroids included in the tablet mixture and, ultimately, in the dosing unit will be, of course, depend on its purpose and the final mass of the dosing unit. The number of desogestrel used in the dosing unit is the rule includes a diluent and, optional linking agent. Preferably the tablet core or granules also include loosening agent.

Diluents or fillers" are agents that add in the dosing unit to increase the weight of the granules and the resulting dosing units, as well as to improve the properties of the dry binding. From this point of view the preferred diluent for use is lactose. Other diluents include mannitol, sorbitol, lactose (spray dried), cellulose (microcrystalline), ethylcellulose, xylitol, amylose, starch, derivatives of starch, dextrose, fructose, calcium carbonate, calcium phosphate, NaCaPO4, sucrose and mixtures thereof. The diluent is usually from 70 to 95% by weight of the final loaded steroid pellets.

Binding agents are used to impart properties of adhesion of the granules or tablets, resulting in a more stable physically dosing units, and include hydroxypropylcellulose, amylopectin, starch, povidone (polyvinylpyrrolidone), hypromellose, gelatin, polyethylene glycols, ethylcellulose, Arabian gum, glycerin and binding agents on the basis of pyrrolidon. The binding agent is usually from 0.5 to 20% by weight of the final loaded steroid pellet cores or granules, preferably from 0.5 to 5 wt.%.

Loosening agents or "leavening agents" are substances or mixture of substances that add a tablet to facilitate its destruction or disintegration after administration. Typically, such agents are modified or unmodified starches, clays, VFR cross, modified or unmodified cellulose resin or algini. Currently, the most preferred agents are: corn starch, potato starch, wheat starch and modified starch. Leavening agents typically comprise from 5 to 50%, preferably from 5 to 15% by weight of the final tablet mix.

There is a need for a simple method of manufacture, which does not require wet granulation with organic solvents or water and an additional stage of drying. The present invention relates to such method and provides pressed tablets or granules containing desogestrel. More specifically, the present invention relates to a method of manufacturing granules, capsules or the torus at the first stage of this method desogestrel, optionally with other active compounds and/or fillers, are mixed, and then pressed at high pressure, after which the second stage to destroy particles and in the third stage of the obtained particles after mixing with lubricating agent can produce tablets or to fill their capsules with methods known to the specialists.

This method is less expensive in comparison with earlier methods, which include a separate stage granulation, organic solvents or water, or more expensive fillers, as well as the stage of drying. In addition, the present method can be easily adapted to a specific scale. Further, it does not use organic solvents, which makes this method minimally problematic from the point of view of the harm to the environment, while particles have improved stability.

In most cases there is no need to use lubricating agents, however, to prevent sticking of the powder of desogestrel and/or estrogen to rollers during roller compaction in powder you can add small amounts of lubricating agent, preferably magnesium stearate, stearic Celine about 0.25 wt.%.

Powder and, optionally, a lubricating agent such as magnesium stearate or stearic acid) pressed, preferably using molding blanks or roller compaction. The first step of this method is the step of dry granulation, which does not use solvents, and powder containing desogestrel, granulated into particles. In the present invention the plate or disk of desogestrel, of estrogen and of the filler obtained after pressing, not necessarily degraded to particles of different sizes. As an additional step, the granules can be sifted to obtain particles of the desired size and small particles. Small particles can then be returned to the hopper roller press or machine for tableting.

During pressing, the important parameter is the applied pressure. When the supply pressure temperature between the rolls increases. The increasing pressure roller pressing on-allows more high strength molded plate and, respectively, low fragility. In addition, the yield increases with increasing pressure. A suitable pressure to ensure low fragility and destruction, as well as high output FR of approximately 200-400 MPa and ensures minimal loss of activity and maximum output.

The press can be anything, for example convex or concave, straight or profiled rollers or helical lines for transport of powder of different designs. The most suitable pressure seems roller press Alexander WP120. Usually extruded powder needs to be destroyed to smaller particles. This stage of destruction is important for the distribution of particle size, which depends on the applied method of destruction. In principle you can use any grinder, such as a pyramid or a roller grinder, preferably with crushing sieve roller press Alexander, with conical pellet Comil or crushing Frewitt sieve. When using this type of sieve is usually easily achieved with a yield of about 50%. Small particles that cannot be used, discarded and can return to the stage of compression.

The preferred embodiment is molded workpieces, in which the pressed billet or large tablets with equipment large capacity for pressing tablets, and then grind to a granulate with desirable properties.

These granules can be tablet or placed in capsules, for example hard gel capsules, still, containing desogestrel, of the following composition (see table).

Tablets And in accordance with the present invention were made by pre-mixing of desogestrel and EE in the turbula mixer with approximately 10% mannitol and sieving the mixture through a sieve with openings of 250 μm. The sieved mass is mixed with the remaining mannitol and glycolate, sodium starch, and then with 1.5% stearic acid (< 250 μm) in a Lodige mixer. Blanks were merged at a pressure of 340 MPa. After the destruction of the blanks was going dry granules of a size less than 710 μm and mixed with 0.5% stearic acid in the turbula mixer. This mixture is extruded at teletrauma car Korsch PH 106 and received a tablet weight of 65 mg.

Tablets (formerly known tablets) was obtained by pre-mixing of desogestrel and EE in the turbula mixer with approximately 10% mannitol and sieving the mixture through a sieve with openings of 250 μm. The sieved mass was mixed with the remaining mannitol and glycolate, sodium starch, and then with 1.5% stearic acid (< 250 μm) in a Lodige mixer. Mixing was continued with 0.5% stearic acid in the turbula mixer. This mixture is extruded at teletrauma car Korsch PH 106 and received tablets Vesenniy spray lactose (Pharmatose DCL-11) in the mixer Gral High Shear. Then to this mixture was mixed into the rest of the fillers and directly extruded into tablets weighing 60 mg.

Sublimation properties of the tablets (the present invention) were compared with those previously known tablets and C. the Samples were stored for 72 hours at 70oC and a pressure of 15 kPa. Sublimated evaporation gathered on a cold pin when 4oC and quantitatively analyzed subliminality desogestrel: number sublimemovies of desogestrel (% of initial tablet) And - 9,0; B - 12,3; C - 15,2.

Tablets of the present invention (A) showed improved properties in respect of sublimirovanny compared with previously known tablets b and C and, therefore, suggest a longer shelf life.

1. Pressed tablets or granules, containing desogestrel, is made by way of the dry granulation, which are obtained by roller compaction or by molding blanks.

2. The method of manufacture of compressed tablets, capsules or granules, containing desogestrel, is made by way of the dry granulation, wherein desogestrel, optionally together with other active compounds and/or who agrees to particles, and, in the third step, these particles produce tablets or fill their capsules, using known methods.

3. The method according to p. 2, characterized in that the desogestrel and, optionally, other active compounds and/or fillers are pressed using a roller pressing or molding blanks.

4. The method according to p. 2 or 3, characterized in that the applied pressure of 0.5 to 500 MPa, preferably about 200-400 MPa.

 

Same patents:

The invention relates to benzothiophene compounds of formula I, where R1-H, - OH, -O(C1-C4alkyl), - EA6H5-, OCO(C1-C6alkyl), or-OSO2(C2-C6alkyl);

R2IS-H, -OH, -O(C1-C4alkyl), EA6H5, CCA(C1-C6alkyl) , -OSO2(C2-C6alkyl), or halogen; R3- 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, diisopropylamino or 1 hexamethyleneimino; n = 2 or 3; Z Is-O - or-S-, or their pharmaceutically acceptable salts

The invention relates to medicine

The invention relates to medicine, in particular to the composition and method of receiving anticonvulsant and psychotropic drugs
The invention relates to chemical-pharmaceutical industry, namely the production of a widely available non-narcotic analgesic non-steroidal anti-inflammatory drugs

The invention relates to the field of medicine and is suitable for the treatment of cholecystitis, hepatitis, as well as urinary tract infections and gastroenteritis

The invention relates to the field of medicine and is suitable for the treatment of fungal diseases, and the prevention and treatment of fungal complications of antibiotic therapy
The invention relates to the pharmaceutical industry, namely soluble effervescent dosage forms
The invention relates to medicine, in particular to pharmacology, relates to a method of obtaining tablets of alpha-fetoprotein, including the mixing of alpha-fetoprotein from human albumin, adding filler, consisting of microcrystalline cellulose and potato starch or lactose, the mixture is covered with a shell consisting of acetylcellulose, at a specific ratio of ingredients
The invention relates to pharmaceutical industry and relates to a therapeutic combination of vitamin and calcium in a single galenical form of tablets, the method of preparation and use

The invention relates to medicine, specifically to Hematology, and can be used for pharmacological correction of disorders in the blood system under cytostatic mielodepressii

The invention relates to pharmaceutical industry and relates to a composition for the treatment of respiratory distress syndrome

The invention relates to medicine and pharmaceutical industry, in particular to the creation and production of anti-inflammatory and antimicrobial agents for local use

The invention relates to the field of medicine and is suitable for the treatment of rheumatism, rheumatic inflammatory diseases, diseases of Edison, acute insufficiency of the adrenal cortex, bronchial asthma, acute and chronic allergic diseases, hepatitis, hepatic coma, hypoglycemic conditions, diseases of the kidneys, the blood, skin and eye diseases, systemic diseases of connective tissue
The invention relates to a method of extraction of biologically active compounds from plant material
The invention relates to a method of extraction of biologically active compounds from plant material

The invention relates to medicine
Up!