The method of obtaining dosing units by wet granulation

 

(57) Abstract:

The invention relates to the field of pharmaceutical industry, namely the method of production of pharmaceutical dosage units. The invention consists in that the method comprises at least desogestrel or Org 30659 (17--17-hydroxy-11-methylene-19-norpregna-4,15-Dien-20-in-3-one) in an amount of from about 0.005-1.0 wt.% in each pharmaceutical dosage unit, in which the steroid agent and, if necessary, pharmaceutically acceptable excipients are mixed with water and granularit. The invention provides for preventing aggregation of the components. 2 s and 5 C.p. f-crystals, 3 tables.

The invention relates to a method for dosing units, including at least desogestrel or Opr 30659 (17 -- 17-hydroxy-11-methylene-19-norpregna-4,15-Dien-20-in-3-one) is present in an amount of from about 0.005-1.0 wt.% pharmaceutical dosage units.

Methods of making tablets and other solid or dry pharmaceutical preparations are well known. For example, in the usual textbook Gennaro et. al English Remington's Pnarmaceutical Sciences (18th ed. Mack Publishing Company, 1990, see specific part 8: Pharmaceutical preparations and their production and method of producing tablets include wet granulation, dry granulation and direct pressing.

How wet granulation include the weighing of the ingredients (including the solvent), the mixture of ingredients, granulating, their silovanje when wet, drying, dry silovanje, lubricant and compressing the mixture into tablets. Such procedures result in tablets with at least a sufficient uniformity of tablets. How wet granulation can have drawbacks if they are using certain solvents, which may be undesirable from the standpoint of environment and relative safety.

An additional problem occurs while ensuring uniformity of tablets, when using certain highly effective medications. For example, highly active steroids requires very little on the tablet (for example, less than 1.0 mg/100 mg tablets) and not always the distribution is completely uniformly throughout tableting mixture, leading, perhaps due to a certain amount of tablets that have a relatively high amount of steroid (i.e., to "cursillistas tablets"), while others have very Nizna method of dry mixing, disclosed in European patent application 503521.

The present invention offers a new solution to obtain tablets containing low amounts of ionized or micronized steroid gestagen - desogestrel or Org 30659, with complete uniformity of content of the component through the use of technology wet granulation, in which the gestagen and, optionally, pharmaceutically acceptable excipients are mixed with water and granularit. The obtained granulate is optionally may be mixed with pharmaceutically acceptable auxiliary and compressed into tablets.

The method is most appropriate for tablets with a low content of steroid progestogen - desogestrel or Org 30659, is present in an amount of about 0.005 to 1.0, and preferably from about 0.01 to 0.5 weight. % each pharmaceutical dosage unit. Under desogestrel understand its active metabolite, 3-keto-desogestrel.

The progestogen - desogestrel and Org 30659 - can be mixed with estrogen selected from ethinyl estradiol (EE), estradiol and mestranol. Usually use a mixture of Progestogens and estrogens. Most preferred are tablets, including the containing Org 30659), as you know, are unstable with respect to moisture, there have been many attempts to exclude water in the production process, for example by the method of dry granulation or by use in the methods of wet granulation of organic solvents that do not contain water. The product on the market (Marvelon), for example, Packed in waterproof sachet to prevent contact between the tablet and the environment. It was found that the method of the present invention, including granulation in an aqueous environment, provides a granulate desogestrel or Org 30659 and ethinyl estradiol, which can be prepared tablets, which is more moisture resistant than previously known tablets obtained in the absence of water.

Wet granulation is different from the dry granulation of the fact that in the wet granulation is used water or organic solvents for the occurrence of granulation or granules.

The most widely used in the pharmaceutical industry, methods of granulation include granulation in the fluidized bed and the granulation wet weight (wet-massing), in which fluid is added to the powder or granulate in a vessel equipped with any of tiie when wet (massing) granulation, includes grinding of drug and excipients, the mixture of powders obtained, obtaining a solution of a binder, a mixture of a solution of the binder with the powder mixture with the formation of the wet mass, coarse screenings wet mass, drying the wet granules, chippings dry granules, the mixture of these granules are lubricated with baking powder and finally filling the granules into capsules or compressing the granulate into tablets. Obviously, depending on the selected fillers, some operations may be combined or may be incorporated into certain transactions. General methods for producing granules, for example, describe in encyclopedia standard Pharmaceutical form of the medicinal product: Tablets volume 1 ed. N. A. Lieberman, L. Lachman, J. B. Schwartz (1989) Marcel Dekker Inc. New York and Basel, pp. 131-190.

Advantages of wet granulation include cohesively and the compressibility of powders, good distribution and homogeneous content-ionized or micronized dosage forms low concentration, reducing large amounts of dust and air pollution, prevention of segregation of components.

Production on a small scale can be done at the expense of mesepimeron two-chamber mixers, double-cone mixers, planetary mixers, rotary granulators, wysokosciowe mixers and equipment for granulation in the fluidized bed. Conventional methods of mixing open encyclopedia: standard Pharmaceutical form of the medicinal product (volume 2) ed. H. A. Lieberman, L. Lachman, J. B. Schwartz (1990), Marcel Dekker Inc. New York and Basel, pp. 1-71. Dry fillers and ionized or finely ground active ingredients are mixed in an appropriate mixing device, preferably in the mixer, which can be performed by both processes of mixing and granulation, for example, in wysokosciowe Gral mixer, then add aqueous solution of the binder. Another preferred method is to suspendirovanie active ingredients in an aqueous solution of the binder, suspendu which add to dry mixture of fillers and granularit.

The granules and tablets obtained by wet granulation, consist of several inert materials, which, in General, can be in conventional solid standard oral dosage forms. The ingredients can be classified on the fillers, which can help to give a composition satisfactory characteristics Perera will rigaut the desired physical characteristics of the finished tablet, similar to the disintegrator and coloring agents. If necessary, the tablets may be film-coated, for example, as disclosed in encyclopedia standard Pharmaceutical form of the medicinal product (volume 3) ed. H. A. Lieberman, L. Lachman, J. B. Schwartz (1990), Marcel Dekker Inc. New York and Basel, pp. 93-125.

The diluents (fillers) or agents to make the drug mass usually make up a large part of the tablet. A group of the most commonly used diluents include water-insoluble calcium phosphate (two - and trekhosnovnye), dihydrofolate calcium, calcium carbonate, starch, modified starches and microcrystalline cellulose and water-soluble lactose, sucrose, dextrose, mannitol and sorbitol.

Substances that bind the powders together and provide cohesively composition for tablets, are binding agents or adhesives. A binding agent may be added in dry form or mixed with diluents and drug. In this case, the binder is activated by adding water or other solvents. Other methods of producing the adhesive is dissolved or suspended in a liquid and in this form is added to the mixed powders. Conventional binders include gelatin, naturalnie and synthetic resins, that use, including tragakant, marialullaby silicate, acacia, monically alginate, sodium alginate, carboxymethylcellulose, hydroxypropylcellulose, methylcellulose, hypromellose, polyvinylpyrrolidone, polyethylene glycol and clay, similar Veegum. For example, depending on the solubility in various liquids binder may be added to the powder mixture in the form of a solution in water, in the form of a solution in a mixture of water-solvent in the form of a solution in an organic solvent.

Materials to improve the flow characteristics are called galantai. As an example, silicon dioxide, magnipapillata, marialineskisas, magnesium oxide, talc or clay may be introduced into the composition to reduce friction between the particles and to avoid the problems associated with the fluidity of the materials from large to smaller apertures when the pressing of the tablets.

Before filling capsules or sachets or pressing tablets usually add lubrication to prevent friction and save in the process. Some lubricants also have protivorededivne properties that may occur in the event of sticking of the granules of the tablet to overhearing acid, sodium polarisiert, gidrirovannoe vegetable oil, high-melting wax, and corn starch.

Component introduced in tablets to facilitate the destruction and dissolution of the tablets release the active component, represents the disintegrator. The full amount of the cage can be added during granulation immediately before pressing, can be added to the total mass of powdery material before will be the process of wet granulation, or may simply be divided into one portion that is added to wet granulation, and one portion added in dry form to the granules. Examples of groups of the disintegrator, which can be used are starch (Starch 1500), microcrystalline cellulose (Avicel PH 101 and Avicel PH 102), purified wood cellulose, alginic acid, sodium starch glycolate, guar gum, cross-carmellose sodium, crosslinked polyvinylpyrrolidone and ion exchange resins.

The tablets obtained according to the method of the present invention, do not contain organic solvents include gestagen selected from desogestrel and Org 30659 present in an amount of about 0.005 to 1.0 wt.% each pharmaceutical dosage obyazatelno estrogen. Preferably the gestagen is a desogestrel and estrogen is a levonorgestrel. The amount of water may vary and depends on the drying conditions. Tablets, however, always contain a small amount of water, usually less than 10 wt.% and preferably about 0.5 - 10 wt.%.

The invention is further illustrated by the following examples.

Example I. Homogeneous granulation processed active ingredients, including (on the tablet):

Desogestrel (ionized) - 150 mcg

EE (ionized) - 30 mg

Hydroxypropylcellulose - 1,95 mg

Corn starch - 6,50 mg

Colloidal silicon dioxide - 0,98 mg

Magnesium stearate - 0.33 mg

Lactose - Up to 65 mg

Wysokosciowe Gral mixer 10 with a load of 1 kg was filled with lactose 200 M and cornstarch. After stirring for 1 minute was added to the mass quantitatively in portions dispersion of desogestrel and (ethinyl estradiol) in aqueous granulation solution hydroxypropylcellulose (125 ml). Then 25 ml of water washed the container and sequentially added to the mixture. The mixture was granulated for 2.5 min with the Gral mixer 10. The obtained wet mass was dried for 4 hours in a vacuum Cabinet Marius is massively with colloidal silicon dioxide and magnesium stearate. The granulate is extruded into pellets.

Example II

Received the granules with the composition of example 1. Granulation was performed in a solution of a binder with ethanol instead of water.

Example III

Tablets of example I and example II were stored at 40oC for two months at a relative humidity (RH) 10 and 95%, respectively. Calculated the decomposition of desogestrel (see tab. 1).

Tablets obtained without aqueous binders, show susceptibility to moisture during storage (example II), whereas the tablets prepared with an aqueous solution of a binder, show less sensitivity to humidity and increased stability (example I).

Example IV. Homogeneous granulation processed ingredients, including:

Org 30659 (fine) - 60 mcg

Hydroxypropylcellulose - 1,95 mg

Corn starch - 6,50 mg

Magnesium stearate - 0,325 mg

Lactose - Up 56,165 mg

Wysokosciowe Gral mixer 10 with a load of 1 kg was filled with lactose 200M and corn starch. After stirring for 1 minute was added in portions to the weight of the dispersion Org 30659 (17 -- 17-hydroxy-11-methylene-19-norpregna-4,15-Dien-20-in-3-one) in aqueous granulation of rest the Mixture was granulated for 2.5 minutes in a mixer Gral 10. The obtained wet mass was dried for 4 hours in a vacuum Cabinet Marius under reduced pressure at 40oC. After drying and sifting through a sieve of 710 μm using an Erweka apparatus granules were mixed with magnesium stearate. The granulate is extruded into pellets.

Example V. the Obtained granules with the composition according to Example IV. Granulation was performed with ethanol instead of water in the solution of the binder.

Example VI. Tablets from example IV and example V was kept at 30oC for one month at a relative humidity (RH) 10 and 95%, respectively in an open glass vessel. Was calculated decomposition Org 30659 (see tab. 2).

The tablets obtained in a solution of binder in the absence of water, show susceptibility to moisture during storage (example V), whereas the tablets prepared with an aqueous solution of a binder, show less sensitivity to humidity and greater stability (example IV).

Example VII. Homogeneous granulation processed active ingredients, including (on the tablet):

Desogestrel (ionized) - 150 mcg

EE (ionized) - 30 mg

Hydroxypropylcellulose - 1,95 mg

Corn starch - 6.50 mg

Colloidal dioxide EOC 1 kg was filled with lactose 200M, corn starch, desogestrel and (ethinyl estradiol). After stirring for 1 min was added to the mass quantitatively in portions of aqueous granulation solution hydroxypropylcellulose (125 ml). Then 25 ml of water washed the tank and successively added to the mixture. The mixture was granulated for 2.5 min in a mixer Gral 10.

The obtained wet mass was dried for 4 hours in a vacuum Cabinet Marius under reduced pressure at 40oC. After drying and sifting through a sieve of 710 μm using an Erweka apparatus granulate was mixed with colloidal silicon dioxide and magnesium stearate. The granulate is extruded into pellets.

Example VIII. Homogeneity was granulated active ingredients, including:

Org 30659 (fine) - 60 mcg

Polyvinylpyrrolidone - 1,95 mg

Corn starch - 6,50 mg

Magnesium stearate - of 0.32 mg

Lactose - Up to 65 mg

was granulated and extruded into pellets according to the method of example IV.

Example IX (a comparative example). Granules having the composition of example VIII was prepared using acetone instead of water. The obtained tablets were stored for 12 months at a relative humidity of 75% at 30 and 40oC in open glass vessels. Tablets primarychannel number in the source (0) time temporizing (see table. 3).

Example XI

Prepared tablets including:

Org 30659 (ionized) - 7,5 mg

Estradiol 2 mg

Hydroxypropylcellulose - 1,95 mg

Corn starch - 30%

Colloidal silicon dioxide - 0,98 mg

Magnesium stearate - 0,325 mg

Lactose - Up to 65 mg

Granulation was performed according to example IV, using 280 ml of granulation liquid to obtain granules. The extruded tablets on a rotary press.

1. A method of obtaining a pharmaceutical dosage units comprising at least one steroid gestagen selected from desogestrel and connections (17--17-hydroxy-11-methylene-19-norpregna-4,15-Dien-20-in-3-one), which is present in an amount of about 0.005 to 1.0 wt.% each pharmaceutically dosage unit, wherein the gestagen and possibly pharmaceutically acceptable fillers is mixed with water and granularit.

2. The method according to p. 1, characterized in that the granulate, possibly mixed with pharmaceutically acceptable excipients, pressed into tablets.

3. The method according to p. 1 or 2, wherein the progestogen is present in an amount of about from 0.01 to 0.5 wt.% each pharmaceutical dosage the x2">

5. The method according to any of paragraphs.1 to 4, wherein the gestagen is a desogestrel, or the fact that desogestrel mixed with ethinyl estradiol.

6. The tablet, which includes gestagen selected from desogestrel and connections (17--17-hydroxy-11-methylene-19-norpregna-4,15-Dien-20-in-3-one) in an amount of about 0.005 to 1.0 wt.% each pharmaceutical dosage unit, and possibly estrogen, a small amount of water not exceeding 20% by weight, as well as fillers that are added to bring the weight up to 100%, while free from organic solvents.

7. Tablet p. 6, wherein the gestagen is a desogestrel and estrogen is a levonorgestrel.

 

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