Pharmaceutical composition containing tetrahydrofolic acid

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine, namely pharmacy and may be used for creating an oral solid dosage form. The dosage form contains a pharmaceutically acceptable salt of an alkaline-earth metal of 5-methyk-(6S)-tetrahydrofolic acid and granules containing progestogen, oestrogen and microcrystalline cellulose. What is also presented is a pharmaceutical kit for females for providing the concentrations or treating the diseases, conditions or symptoms associated with endogenous oestrogen deficiency.

EFFECT: group of inventions provides the good storage stability of tetrahydrofolic acid, and at the same time provides rapid and reliable release of oestrogen and progestogen being parts of the composition.

13 cl, 3 dwg, 4 tbl, 6 ex

 

The technical field to which the invention relates.

The present invention relates to solid pharmaceutical compositions, in particular to oral contraceptives containing tetrahydrofolic acid, such as 5-methyl-(6S)-tetrahydrofolate calcium. The compositions provided in the present invention, allow a good stability of tetrahydrofolate acid during storage, and thus they provide a quick and accurate release of estrogen and progestogen that is present in the composition.

Background of invention

Pregnant women correcting low levels of phosphate in the blood serum occurs at least in two months and may persist for only a few weeks. Therefore, in accordance with the recommendations of the Ministry of health, all women who could become pregnant should consume 400 µg/day of folic acid to reduce the risk of congenital malformations (MMWR Morb. Mortal. Wkly. Rep.1992; 41(RR-14):1-7). Replenishment of folic acid immediately after the abolition of the use of oral contraceptives or immediately after receiving a positive pregnancy test may not be sufficient for optimal protection of the developing fetus. Additionally, in various studies conducted on women who use errorline contraceptives, been shown to decrease levels of folate in serum compared with negative controls. Suggested mechanisms described for this phenomenon include reduced absorption polyglutamates, increased excretion volievykh acids, increased production of proteins that bind folate, and induction palatalising microsomal enzymes in the liver. Thus, lower levels of folate in the serum is an additional risk factor for those consumers who zaberemennet within three to six months after discontinuation of use.

Therefore, folic acid, which should ideally be added to oral contraceptives in preconceptually period, helps to protect from various birth defects, including defects of the brain tube, such as spina bifida (incomplete closure of the spinal cord and spine), anencephaly (severe underdevelopment of the brain) and herniation of the brain (where the tissue is brain acts on the skin surface of the abnormal hole in the skull). All these defects occur during the first 28 days of pregnancy, usually before a woman finds out about the pregnancy.

However, the inclusion of folic acid in oral contraceptives can be a serious risk factor for human health, the village is olcu it will suppress the symptoms of vitamin B12 deficiency such as anemia. For example, folic acid can correct the anemia associated with vitamin B12 deficiency, but, unfortunately, folic acid will not adjust to the changes of the nervous system that develop due to vitamin B12 deficiency. Therefore, there can be long-term changes in the nervous system, if not to treat vitamin B12 deficiency. Thus, the inventor of the present invention proposes to include tetrahydrofolic acid, such as a derivative of natural folic acid, 5-methyl-(6S)-folic acid, which is formed in a very complex catabolic path prodrugs of folic acid, oral contraceptives. The inclusion tetrahydrofolic acids, such as 5-methyl-(6S)-tetrahydrofolate acid, oral contraceptives can provide all the positive actions associated with folic acid, but without the potential adverse effects dropout anemia due to vitamin B12 deficiency.

However tetrahydrofolate acids are very unstable and extremely sensitive to oxidation and moisture. Therefore, the inclusion of tetrahydrofolate acid in solid oral medicines such as oral contraceptives, is very difficult from the point of view is prigotovleniya medicines. Suppose that the obtained solid pharmaceutical composition must not only have sufficient stability (with respect to tetrahydrofolate acid) during storage, but also the preparation of the composition can be problematic due to the impact of oxidative fillers, moisture and/or air access, and these factors can cause the decomposition of tetrahydrofolate acid and therefore should be avoided. Consequently, and as will be shown in the examples in the present invention, the problem of stabilization of tetrahydrofolate acid cannot be solved separately, as it turns out that the stabilization of tetrahydrofolate acid in many cases unexpectedly, leads to insufficient release of other active components of the composition.

In addition, oral contraceptive tool tetrahydrofolate acid is considered as an active component. Therefore, standard methods for the determination of stabilization that are typically used in products with vitamin supplements, such as overdose and wider limit allowed, unsuitable for oral contraceptives. Usually overdose products with vitamin supplements provide up to 25% and the dose of Metafolin®some foods with vitamin supplements is above 0.6 and 5.6 mg what about compared to the recommended daily dose (0.45 mg). Because of the stability issues are more pronounced when included in pharmaceutical compositions in low concentrations, the preparation of stable pharmaceutical compositions containing tetrahydrofolic acid in low doses, is an extremely important task.

Despite this, the inventor of the present invention unexpectedly, through careful selection determining fillers and/or preparation processes, succeeded in obtaining oral contraceptives, which, on the one hand, exhibit sufficient stability with respect to tetrahydrofolate acid, and on the other hand, still meet the requirements with respect to the release and, hence, bioavailability of estrogen and progestogen, which are contained in the composition.

In the application WO 03/070255 described sets for contraception and hormone replacement therapy, which contain one or more steroids, such as estrogens and POCs; one or more tetrahydrofolate components and vitamin B12.

In the US 6190693 described pharmaceutical compositions suitable as oral contraceptives or hormone replacement therapy containing folic acid.

US 6011040 relates to the application of tetrahydrofolate to influence the level of homocysteine, on the feature to facilitate the re-methylation of homocysteine.

In the US 6441168 described stable crystalline salts of 5-methyltetrahydrofolate acid.

The invention

In the first aspect, the present invention relates to a solid pharmaceutical composition containing a progestogen, estrogen, tetrahydrofolic acid or its salt and at least one pharmaceutically acceptable excipient or carrier.

In another aspect, the present invention relates to a solid dosage form for oral administration containing composition in accordance with the invention.

Other aspects of the present invention will become clear from the following description and the attached claims.

Brief description of figures

The figure 1 shows the stability of 5-methyl-(6S)-tetrahydrofolate calcium in the tablet prepared as described in example 1. The Y-axis denotes % of 5-methyl-(6S)-tetrahydrofolate calcium, remaining after storage, as well as the amount of degradation products. On the X-axis indicate the storage time in months. • 25°C/60% RH (closed container); ♦ 40°C/75% RH (closed container); ■ 25°C/60% RH (closed container); ▲ 40°C/75% RH (closed container).

The figure 2 shows the dissolution of drospirenone, ethinyl estradiol and 5-methyl-(6S)-tetrahydrofolate calcium tablets prepared in example 1. The Y-axis denotes the dissolved quantity, and on the X-axis shows the time what I study solubility in minutes. ▲ drospirenone; ■ ethinyl estradiol; ♦ 5-methyl-(6S)-tetrahydrofolate calcium.

The figure 3 shows the dissolution of drospirenone tablets prepared in examples. The Y-axis denotes the dissolved quantity, and on the X-axis indicates the time of the study solubility in minutes. ♦ example 1; ■ example 4; ▲ example 5; X example 6; Δ Yasmin®; □ Yaz®.

A detailed description of the invention

The term "estrogen" includes all compounds (natural or synthetic, steroidal or non-steroidal compounds)that exhibit estrogenic activity. Such compounds include, in particular, conjugated estrogens, specific agonists of estrogen receptor and non-steroidal compounds that exhibit estrogenic activity. The term additionally includes all isomeric and physical forms of estrogen, including a hydrate, solvate, salt and complexes, such as complexes with cyclodextrins. More preferably, the estrogen may be selected from the group comprising ethinylestradiol, estradiol, estradiol sulfamate, estradiol valerate, estradiol benzoate, estrone, mestranol, estriol, estriol succinate and conjugated estrogens, including conjugated equine estrogens such as estrone sulfate, 17β-estradiol sulfate, 17α-estradiol sulfate, equilin sulfate, 17β-dihydroequilin sulfate, 17α-dihydroequilin su is that, equilenin sulfate, 17β-dihydroequilin sulfate and 17α-dihydroequilin sulfate. Estrogens, which are of special interest selected from the group comprising ethinylestradiol, estradiol, estradiol sulfamate, estradiol valerate, estradiol benzoate, estrone, mestranol and estrone sulfate. More preferably, the estrogen is selected from the group including levonorgestrel, estradiol and mestranol. The most preferred estrogen is ethinylestradiol.

In the context of the present invention, the term "progestogen" (also in some places referred to as "gestagen") covers synthetic hormonal compounds that exhibit anti-estrogenic (counteract the effects of estrogen in the body) and antigonadotropin (inhibit the production of sex steroids and gonads) properties. Specific examples of the POCs are, but not limited to, POCs, selected from the group comprising levo-norgestrel, norgestrel, norethindrone (norethisterone), dienoguest, norethindrone (norethisterone) acetate, ethynodiol diacetate, dydrogesterone, medroxyprogesterone acetate, norethynodrel, allylestrenol, lynestrenol, hingeston acetate, medrogestone, norgestrienone, dimethisterone, ethisterone, chlormadinone acetate, megestrol, promegestone, desogestrel, 3-keto-desogestrel, norgestimate, gestodene, tibolone ciproteron acetate and drospirenone. Especially preferred progestogen is drospirenone.

The term "therapeutically equivalent amount of ethinyl estradiol" means that other estrogen is administered in amounts that cause the same therapeutic effect as a specified number of ethinyl estradiol. Similarly, the term "therapeutically equivalent amount of drospirenone means that other POCs administered in amounts that cause the same therapeutic effect as a specified number of drospirenone. The average expert in the art can easily determine a therapeutically equivalent amount or dose such other and/or POCs, if known effective dose ethinylestradiol and/or drospirenone. For example, article Timmer and Geurts provides guidance for the determination of equivalent doses (see "Bioequivalence assessment of three different estradiol formulations in postmenopausal women in an open, randomised, single-dose, 3-way cross-over" in European Journal of Drug Metabolism and Pharmacokinetics, 24(1):47-53, 1999). In addition, you can refer to EP 1253607, which provides a detailed description of therapeutically equivalent amounts of ethinyl estradiol and estradiol, on the one hand, and various POCs, on the other hand. Additional details regarding the determination of the dose equivalents to various estrogens and POCs can result from a link to "Problem der Dosisfindung: Sexualhormone" [Problems of Dose-Finding: Sex Hormones]; F. Neumann and others in "Arzneimittelforschung" (Pharmaceutical Agent Research) 27, 2a, 296-318 (1977), and "Aktuelle Entwicklungen in der hormonalen Kontrazeption" [Current Developments in Hormonal Contraception]; H. Kuhl in Gynäkologe" [Gynecologist] 25: 231-240 (1992).

As used in the present invention, the term "micronized" refers to the distribution of particle sizes such that at least 90% of the particles have a particle diameter less than 30 μm (calculated according to the curve of volume distribution for admitted spherical particles), i.e. the value of d90in most 30 μm. Therefore, it is important to note that whenever in the present invention uses the terms "distribution of particle size, particle diameter", "d90" and so, it should be understood that the specific values or ranges used in connection with the foregoing, are always defined according to the volume distribution curve for admitted spherical particles.

From the description of the present invention will become clear, including the examples provided in the present invention, which is extremely important is the release of estrogen and progestogen quick and reliable way in a neutral or acidic conditions. Thus, in the context of the present invention, the term "quick release" or "for immediate release"when used with respect to the term estrogen means, that at least 70% of estrogen, such as ethinyl estradiol, is dissolved from the composition within 30 minutes, as determined in accordance with the described in the US Pharmacopoeia XXIX paddle method II using water or 0.1 N. HCl, at 37°C as a medium for dissolving and the stirring speed of 50 rpm In the preferred embodiment of the invention at least 75%, more preferably at least 80%, even more preferably at least 85% of estrogen, such as ethinyl estradiol, is dissolved from the composition within 30 minutes when conducting research as explained above.

Similarly, whenever the term "quick release" or "immediate release" is used to refer to the term progestogen, it means that at least 70% of the progestogen, such as drospirenone, is dissolved from the composition within 30 minutes, as determined in accordance with the described in the US Pharmacopoeia XXIX paddle method II using water or 0.1 N. HCl, at 37°C as a medium for dissolving and the stirring speed of 50 rpm In the preferred embodiment of the invention at least 75%, more preferably at least 80%, even more preferably at least 85% of the progestogen, such as drospirenone, is dissolved from the composition within 30 minutes when PR is conducting research as explained above.

Similarly, whenever the term "quick release" or "immediate release" is used to refer to the term tetrahydrofolate acid, it means that at least 70% of tetrahydrofolate acid, for example 5-methyl-(6S)-tetrahydrofolate calcium is dissolved from the composition within 30 minutes, as determined in accordance with the described in the US Pharmacopoeia XXIX paddle method II using 0,03% aqueous solution of ascorbic acid (brought to pH 3.5 with 0.05 M phosphate buffer) at 37°C as a medium for dissolving and when the stirring speed of 50 rpm In the preferred embodiment of the invention at least 75%, more preferably at least 80%, even more preferably at least 85% or at least 90% of tetrahydrofolate acid, for example 5-methyl-(6S)-tetrahydrofolate calcium is dissolved from the composition within 30 minutes of the study, as described above.

The term "granulated composition" refers to compositions of the powder, where the particle size of the powder is increased by treating with a liquid or by pressing. The fluid may be a suitable aqueous or organic solvents of any type or mixtures thereof, optionally additionally contains a binder. Thus, the term "Gras is wirawansa composition comprises granules, pellets and pressed powder or any particles formed by granulation, pelletierine or pressing of the powder so formed particles with an average size (d50at least approximately 100 microns.

The terms "grain" and "granulation" understand the mechanical process in which a powder containing the active(s) component(s) and fillers, partially aglomerados into particles and/or granules, having a larger particle size than the raw powder. In one embodiment, the powder mixture is introduced into contact with the granulation liquid, which may contain a binder, swollen, partially dissolved or completely dissolved in the granulation liquid. Granulation liquid may be any suitable solvent, but is generally applicable aqueous solutions or water. In one embodiment, the powder mixture is introduced into contact with the granulation liquid, using the right equipment for wet granulation, such as equipment for granulation in pseudouridine layer. In addition, instead of granulation in pseudouridine layer can be used granulation with a large shearing force.

The term "complex estrogen-cyclodextrin or estrogen in combination with a cyclodextrin" refers to a complex between estrogen and cyclade the Stryn, in which a molecule of estrogen at least partially inserted into the cavity of the cyclodextrin molecules. The molar ratio between estrogen and a cyclodextrin can be increased to any desired value. In the interest embodiments of the invention, the molar ratio between estrogen and a cyclodextrin is an approximately 2:1 to 1:10, preferably from about 1:1 to 1:5, most preferably from about 1:1 to 1:3, such as 1:1 or 1:2. In addition, the molecule of estrogen may be at least partially inserted into the cavity of two or more molecules of cyclodextrin, for example, one molecule of estrogen can be inserted into two molecules of cyclodextrin with obtaining the ratio of 2:1 between the cyclodextrin and estrogen. Similarly, the complex may contain more than one molecule of estrogen, which is at least partially inserted into one molecule of cyclodextrin, for example, two molecules of estrogen may be at least partially inserted into one molecule of cyclodextrin with obtaining the ratio of 1:2 between the cyclodextrin and estrogen. Complexes between estrogen and a cyclodextrin can be obtained using methods known in this field, for example as described in US 5798338 and EP 1353700.

The term "complex ethinyl estradiol-β-cyclodextrin" denoted by the AET complex, in any molar ratio between ethinyl estradiol and β-cyclodextrin. However, the complex ethinyl estradiol-β-cyclodextrin, as described in this application is typically a complex between one molecule of ethinyl estradiol and two molecules of β-cyclodextrin, i.e. a complex of 1:2 ethinyl estradiol-β-cyclodextrin.

The term "complex progestogen-cyclodextrin or progestogen in complex with cyclodextrin" refers to a complex between progestogen and a cyclodextrin, in which the molecule progestogen at least partially inserted into the cavity of the cyclodextrin molecules. The molar ratio between the progestogen and the cyclodextrin can be increased to any desired value. In the interest embodiments of the invention, the molar ratio between the progestogen and the cyclodextrin is an approximately 2:1 to 1:10, preferably from about 1:1 to 1:5, most preferably from about 1:1 to 1:3. In addition, the molecule of progestogen may be at least partially inserted into the cavity of two or more molecules of cyclodextrin, for example, one molecule of progestogen may be inserted into two molecules of cyclodextrin with obtaining the ratio of 2:1 between the cyclodextrin and progestogen. Similarly, the complex may contain more than one molecule p is gestogen, at least partially inserted into one molecule of cyclodextrin, for example, two molecules of progestogen may be at least partially inserted into one molecule of cyclodextrin with obtaining the ratio of 1:2 between the cyclodextrin and progestogen. Complexes between POCs and cyclodextrins can be obtained using methods known in this field, for example as described in US 6610670 and the references cited in this patent.

The term "complex drospirenone-β-cyclodextrin" refers to a complex in any molar ratio between drospirenone and β-cyclodextrin as described in US 6610670. However, the complex drospirenone-β-cyclodextrin is usually a complex between one molecule of drospirenone and three molecules of β-cyclodextrin, i.e. a complex of 1:3 drospirenone-β-cyclodextrin.

The term "cyclodextrin" refers to a cyclodextrin or its derivative, and a mixture of various cyclodextrins, and mixtures of different derivatives of cyclodextrins, and mixtures of different cyclodextrins and their derivatives. The cyclodextrin may be selected from the group comprising α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin and derivatives thereof. The cyclodextrin may be modified so that some or all of the primary or secondary hydroxyl groups of the macrocycle is alkylated or etilirovany. Methods the s versions of these hydroxyl groups are well known to the specialist in the art and many such modified cyclodextrins are commercially available. Thus, some or all of the hydroxyl groups of the cyclodextrin can be substituted by O-R group, or O-C(O)-R group, where R represents an optionally substituted C1-6alkyl, optionally substituted C2-6alkenylphenol, optionally substituted C2-6alkylamino, optionally substituted aryl or heteroaryl group. Thus, R can be a methyl, ethyl, through boutelou, pentelow or hexoloy group, that is, O-C(O)-R can be an acetate. In addition, the hydroxyl group can be per-benzilidene, per-benzopyrane, basiliani or benzoylurea only on one side of the macrocycle, i.e. only 1, 2, 3, 4, 5 or 6 hydroxyl groups are benzyladenine or benzoylecognine. Naturally, the hydroxyl group can also be per-alkylated or per-etilirovany, such as TRANS-methylated or per-azetilirovanny, alkylated or etilirovany, such as methylated or azetilirovanny, only on one side of the macrocycle, i.e. only 1, 2, 3, 4, 5 or 6 hydroxyl groups are alkylated or acetylated, such as methylated or acetylated.

Assume that the solid composition according to the invention contains at least one estrogen, as described above. Estrogen may be you are the wounds from the group includes ethinyl estradiol, estradiol, estradiol sulfamate, estradiol valerate, estradiol benzoate, estrone, mestranol and estrone sulfate, including micronized form. In a highly preferred embodiment of the invention, the estrogen is a levonorgestrel, in particular ethinyl estradiol micronized. In one embodiment of the invention, the estrogen, in particular, levonorgestrel, forms a complex with a cyclodextrin, for example as described in EP 1353700. Cyclodextrin is usually chosen from the group comprising α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin and derivatives thereof. In the embodiment of the invention, which is of particular interest, the cyclodextrin is a β-cyclodextrin or its derivatives. Estrogen-cyclodextrin complex can favorably be in micronized form.

Additionally, the solid composition according to the invention contains at least one progestogen, as described above. Progestogen can be selected from the group comprising levo-norgestrel, norgestrel, norethindrone (norethisterone), norethindrone (norethisterone) acetate, dienoguest, ethynodiol diacetate, dydrogesterone, medroxyprogesterone acetate, norethynodrel, allylestrenol, lynestrenol, hingeston acetate, medrogestone, norgestrienone, dimethisterone, atest is Ron, chlormadinone acetate, megestrol, promegestone, desogestrel, 3-keto-desogestrel, norgestimate, gestodene, tibolone, cyproterone acetate and drospirenone. In a preferred embodiment of the invention, the progestogen is chosen from the group comprising levo-norgestrel, norgestrel, norethindrone (norethisterone), norethindrone (norethisterone) acetate, dienoguest, ethynodiol diacetate, desogestrel, norgestimate, gestodene, cyproterone acetate and drospirenone. In a highly preferred embodiment of the invention, the progestogen is a drospirenone, particularly micronized drospirenone.

Thus, in a preferred embodiment of the invention the composition contains levo-norgestrel and levonorgestrel, norgestrel and levonorgestrel, norethindrone (norethisterone and ethinylestradiol, norethindrone (norethisterone) acetate and ethinyl estradiol, dienoguest and levonorgestrel, ethynodiol diacetate and ethinyl estradiol, desogestrel and ethinyl estradiol, norgestimate and levonorgestrel, gestodene and ethinylestradiol, cyproterone acetate and ethinyl estradiol, drospirenone and ethinyl estradiol. In a highly preferred embodiment of the invention, the composition contains drospirenone and ethinyl estradiol, more preferably micronized micronized drospirenone and ethinyl estradiol, for example mikronizirovanny drospirenone and complex micronized levonorgestrel-cyclodextrin, such as micronized drospirenone and complex micronized ethinyl estradiol-β-cyclodextrin.

In addition to estrogen and progestogen, the composition according to the invention further comprises tetrahydrofolic acid or its salt. Specific examples of tetrahydrofolate acid 5-methyl-(6S)-tetrahydrofolate acid, (6S)-tetrahydrofolate acid, 5-formyl-(6S)-tetrahydrofolate acid, 10-formyl-(6R)-tetrahydrofolate acid, 5,10-methylene-(6R)-tetrahydrofolate acid, 5,10-methenyl-(6R)-tetrahydrofolate acid, 5-trimino-(6S)-tetrahydrofolate acid, including pharmaceutically acceptable salts of these tetrahydrofolic acids and glutamine derivatives of these tetrahydrofolic acids. In a preferred embodiment of the invention, tetrahydrofolate acid represents 5-methyl-(6S)-tetrahydrofolic acid or its pharmaceutically acceptable salt. In a more preferred variant of the invention, the salt of 5-methyl-(6S)-tetrahydrofolate acid is a salt of alkaline-earth metal, especially calcium salt. Salt such as calcium salt, 5-methyl-(6S)-tetrahydrofolate acid preferably should be in crystalline form, such as crystalline form I of the type described in US 6441168. Crystalline form I of 5-IU the Il-(6S)-tetrahydrofolate calcium commercially available from Merck KGaA under the trade mark Metafolin ®. Is preferred if the composition according to the invention does not contain other vitamins, in particular, if the composition according to the invention does not contain vitamin b such as vitamin B6 and/or vitamin B12. Therefore, in a preferred embodiment of the invention, the composition contains tetrahydrofolic acid only vitaminology component.

Solid pharmaceutical composition according to the invention contains one or more pharmaceutically acceptable excipients. These fillers can be, for example:

inert fillers or diluents such as sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starch, sodium chloride, sodium phosphate, calcium carbonate, calcium phosphate, calcium sulfate, lactose, such as lactose monohydrate, or combinations thereof. Inert diluent or filler is typically present in an amount of 10-99% by weight of the composition. Preferably, the inert diluent or filler is present in the amount of 50-99% by weight of the composition, more preferably in the amount of 75-99% by weight of the composition, more preferably in the amount of 80-97% by weight of the composition, most preferably in the amount of 85-97% by weight of the composition. As is evident from the examples in the present invention, it is extremely preferred fillers t is Auda lactose, in particular lactose monohydrate and microcrystalline cellulose.

Thus, in a preferred embodiment, the composition according to the invention contains lactose monohydrate, microcrystalline cellulose, or a combination of lactose monohydrate and microcrystalline cellulose in the amounts specified above. Thus, in one interest embodiment of the invention, the composition comprises microcrystalline cellulose. Microcrystalline cellulose is typically present in an amount of 10-99% by weight of the composition, preferably in the amount of 50-99% by weight of the composition, more preferably in the amount of 75-99% by weight of the composition, more preferably in the amount of 80-97% by weight of the composition, most preferably in the amount of 85-97% by weight of the composition. Microcrystalline cellulose may be the only filler that is present in the composition, i.e. the composition according to the invention may contain other fillers other than microcrystalline cellulose. In another interest embodiment of the invention, the composition contains lactose monohydrate. The lactose monohydrate is typically present in an amount of 10-99% by weight of the composition, preferably in the amount of 50-99% by weight of the composition, more preferably in the amount of 75-99% by weight of the composition, even more preferably in the amount of 80-97% by weight of the composition, most preferably in the amount of 85-97% by weight of the composition. The lactose monohydrate may be the only filler that is present in the composition, i.e. the composition according to the invention may contain other fillers, non-lactose monohydrate. In a highly preferred embodiment of the invention, the composition comprises microcrystalline cellulose and lactose monohydrate. Microcrystalline cellulose is typically present in an amount of 20-80% by weight of the composition and lactose monohydrate in an amount of 20-80% by weight of the composition. In one embodiment of this aspect of the invention, the microcrystalline cellulose is the main part of the system of excipients microcrystalline cellulose-lactose monohydrate, that is, the composition comprises lactose monohydrate in an amount of 20-60% by weight of the composition and microcrystalline cellulose in an amount of 40-80% by weight of the composition, for example lactose monohydrate in an amount of 20-45% by weight of the composition and microcrystalline cellulose in the amount of 40-70% by weight of the composition, for example lactose monohydrate in the number of 25-36% by weight of the composition and microcrystalline cellulose in a number 52-63% by weight of the composition. Microcrystalline cellulose and lactose monohydrate may be the only fillers, contained in the composition, i.e. the composition according to the invention may contain other fillers other than microcrystalline cellulose and lactose monohydrate. In another especially preferred embodiment of this aspect of the invention, the lactose monohydrate is the core part of excipients microcrystalline cellulose-lactose monohydrate, that is, the composition comprises microcrystalline cellulose in an amount of 20-60% by weight of the composition and lactose monohydrate in an amount of 40-80% by weight of the composition. More preferably, the composition comprises microcrystalline cellulose in an amount of 20-45% by weight of the composition and lactose monohydrate in an amount of 40-70% by weight of the composition. Most preferably, the composition comprises microcrystalline cellulose in the amount of 25-36% by weight of the composition and lactose monohydrate in the number 52-63% by weight of the composition. Microcrystalline cellulose and lactose monohydrate may be the only fillers that are contained in the composition, i.e. the composition according to the invention may contain other fillers other than microcrystalline cellulose and lactose monohydrate.

Microcrystalline cellulose is commercially available with different particle sizes and degrees of humidity. Examples of commercially available drugs m crocrystalline cellulose is Avicel ®PH series from FMC Biopolymer, Emcocel®M-series from Penwest Pharmaceuticals Co. and Vivapur®-series from Rettenmaier &Söhne GmbH. Especially preferred commercial product for use for the purposes described in this application is Avicel®PH-101. Similarly, commercially available various types of lactose monohydrate, which have different physical properties, such a distribution of particle sizes and characteristics of fluidity. Type of lactose monohydrate can significantly depend on the particular dosage form, which must be made. For example, the types of lactose monohydrate direct pressing, such as Tablettose®(agglomerated), or types of powder mixtures, such as Pharmatose®DCL 11 (spray dried), have improved properties yield stress and are more compressible than powdered or crystalline lactose monohydrate. These drugs are lactose monohydrate are particularly preferred for the purposes disclosed in the present invention. To some degree is preferred over fine lactose monohydrate, such as powdered or crystalline lactose monohydrate, particularly crystalline lactose monohydrate, in which 90% of particles have a diameter less than 0.1 mm

- Binder

such as sucrose, glucose, sorbitol, gummier the IR, alginic acid, sodium alginate, gelatin, starch, gelatinising starch, magnesium aluminosilicate, carboxymethylcellulose sodium (CMC sodium, methylcellulose, ethylcellulose, hypromellose (receiver array), hydroxypropylcellulose (LDCs), polyvinyl acetate or polyethylene glycol. A binder is usually present in an amount of 0.1-10% by weight of the composition. Preferably, the binder is present in an amount of 0.2-5% by weight of the composition, for example from 0.5 to 5% by weight of the composition, more preferably in the amount of 1-3% by weight of the composition. In a preferred embodiment of the invention, the binder is an LDC. You should take into account that while polyvinylpyrrolidone (PVP) in many cases is the best glue", in particular in connection with the process of wet granulation, but the inclusion of PVP in the composition according to the invention is not desirable due to possible oxidation of the filler. Indeed, the inventor of the present invention, it was found that PVP accelerates the decay of 5-methyl-(6S)-tetrahydrofolate acid (data not shown).

Thus, due to disintegration of the oxidation-sensitive tetrahydrofolate acid, the amount of PVP in the composition of the invention should be maintained at the extremely minimum, and preferably it should be deleted. So about what atom, the composition according to the invention typically contains less than 2% PVP by weight of the composition, preferably less than 1% PVP by weight of the composition, more preferably less than 0.5% PVP by weight of the composition. Most preferably, the composition according to the invention essentially contains no PVP.

- Oiling agents, including substances that contribute to the slide, and antiadhesive,

such as magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oils, or talc. The sizing is usually present in an amount of 0.1-10% by weight of the composition. Preferably, the lubricant is present in an amount of 0.2-5% by weight of the composition, for example from 0.5 to 5% by weight of the composition, more preferably in the amount of 1-3% by weight of the composition. In a preferred embodiment of the invention, the lubricant is a stearate.

Agents causing disintegration,

such as sodium salt starch glycolate, corn starch, rice starch, potato starch, transverse cross-linked povidone or agents that cause disintegration, based on carboxymethylcellulose. Agents causing disintegration, on the basis of carboxymethyl cellulose may be present in the form of the free acid, but preferably are in the form of a salt, for example in the form of salts of alkaline metal such as potassium what I salt or sodium salt, in particular the sodium salt, or in the form of a salt ion of the divalent metal such as magnesium salt, calcium salt or zinc salt, in particular the calcium salt. The agent that causes disintegration, on the basis of carboxymethyl cellulose can be cross stitched or not cross stitched. Specific examples of the preferred't cross stitched agents causing disintegration, on the basis of carboxymethyl cellulose is carboxymethylcellulose calcium (carmellose calcium) and carboxymethylcellulose sodium (carmellose sodium), in particular carboxymethylcellulose calcium. In a highly preferred embodiment of the invention, the agent that causes disintegration, on the basis of carboxymethyl cellulose is cross stitched. A specific example of a preferred cross stitched agent that causes disintegration, on the basis of carboxymethyl cellulose is cross stitched carboxymethylcellulose sodium (croscarmellose sodium). Croscarmellose sodium is commercially available under the trademarks Ac-Di-Sol®, Explocel®and Solutab®. The agent that causes disintegration, is typically present in an amount of 0.1-10% by weight of the composition. Preferably, the agent that causes disintegration, is present in amount of 0.2-5% by weight of the composition, for example from 0.5 to 5% by weight of the composition, more prefer is Ino in the amount of 1-4% by weight of the composition.

- Surfactants and wetting means,

such as naturally occurring phosphatides, for example lecithin or soy lecithin; condensation products of ethylene oxide, for example, fatty acid, long chain fatty alcohol, or a partial derivative of ester of fatty acids and exit or anhydride exit, for example polyoxyethylene stearate, polyoxyethylene sorbitol monooleate, polyoxyethylene sorbitan monooleate and others; or salts of long-chain aliphatic phosphates, such as sodium lauryl sulfate.

Examples of other pharmaceutically acceptable excipients that can be included in the solid pharmaceutical composition according to the invention are dyes, fragrances, plasticizers, hygroscopic agents, buffers and other

In some cases, when the drug is in the form of solid dosage forms for oral administration, in particular standard solid dosage forms (e.g. tablets, sachets or capsules, especially the pill), dosage form adapted for oral administration and it may have a coating, such as film coating, sugar coating, or other. Thus, a suitable coating of the dosage form in accordance with the invention may constitute, for example, sugar coating Il the film coating on the basis of one or several components: hypromellose (receiver array), methylcellulose, ethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose sodium, acrylate polymers (e.g., Eudragit®), polyethylene glycol or polyvinylpyrrolidone.

In a highly preferred embodiment of the invention, the dosage form is in the form of tablets, preferably tablets, coated, more preferably the tablets are film-coated.

Tablet without the shell typically has a weight in the range of 50-150 mg, for example in the range 60-125 mg, for example in the range of 60-100 mg, preferably in the range of 70-90 mg, for example about 80 mg

Dosage form typically contains a number of progestogen corresponding therapeutically effective amount of drospirenone 0.25 to 4 mg, such as number, which corresponds to therapeutically effective amount of drospirenone 1-4 mg, for example in a quantity which corresponds to therapeutically effective amount of drospirenone 2-4 mg, preferably in an amount which corresponds to therapeutically effective amount of drospirenone 2.5-3.5 mg, most preferably in the amount that corresponds to a therapeutically effective amount of drospirenone about 3 mg. As discussed above, the progestogen may form a complex with cyclodextrin.

In addition, the solid dosage form for oral administration typically contains a number of estrogen, the corresponding therapeutically effective amount of ethinyl estradiol 0.005 to 0.05 mg, such as number, which corresponds to therapeutically effective amount of ethinyl estradiol 0.01 to 0.05 mg, preferably in an amount which corresponds to therapeutically effective amount of ethinyl estradiol of 0.015-0.035 mg, most preferably in the amount that corresponds to a therapeutically effective amount of ethinyl estradiol by approximately 0.02 mg or about 0.03 mg. As discussed above, estrogen may form a complex with cyclodextrin.

Thus, in the embodiment of the invention, which is of particular interest, dosage form contains 0.25-4 mg drospirenone and 0.005-0.05 mg ethinyl estradiol, for example of 1-4 mg of drospirenone and 0.005-0.05 mg ethinyl estradiol, for example 2-4 mg of drospirenone and 0.01-0.05 mg ethinyl estradiol, preferably 2.5-3.5 mg of drospirenone and 0.015-0.035 mg ethinyl estradiol, more preferably about 3 mg of drospirenone and approximately 0.03 mg of ethinyl estradiol, or about 3 mg of drospirenone and about 0.02 mg of ethinyl estradiol.

Although the preferred progestogen is drospirenone, displacement of this image is etenia also covers the inclusion of other POCs. More preferably, the dosage form may contain desogestrel in the amount of 0.05-0.5 mg, preferably of 0.075-0.25 mg, for example 0.1 mg, 0.125 mg or 0.15 mg; ethynodiol diacetate in the amount of 0.25 to 2 mg, preferably 0.75 to 1.5 mg, for example 1 mg; levo-norgestrel in amount of 0.025-0.3 mg, preferably of 0.075-0.25 mg, for example 0.1 mg or 0.15 mg; norethindrone (norethisterone) in an amount of 0.2 to 1.5 mg, preferably 0.3 to 1.25 mg, for example, 0.4 mg, 0.5 mg or 1 mg; norethindrone (norethisterone) acetate in the amount of 0.5 to 2 mg, preferably 1-1 .5 mg, 1 mg or 1.5 mg; norgestrel in an amount of 0.1-1 mg, preferably 0.25 to 0.75 mg, for example 0.3 mg or 0.5 mg; norgestimate in an amount of 0.1-0.5 mg, preferably 0.15-0.3 mg, for example, 0.18 mg, 0,215 mg or 0.25 mg; cyproterone acetate in the amount of 1-2 mg, preferably 2 mg; dienoguest in the amount of 2-3 mg, preferably 2 mg; gestodene in the amount of 0.05-0.1 mg, preferably 0.06 to 0.075 mg, for example, 0.075 mg; and tibolone in the amount of 2-3 mg, for example the 2.5 mg. similarly, although the preferred estrogen is ethinylestradiol, the scope of the present invention also covers the inclusion of other estrogens. More preferably, the dosage form may contain estradiol in the number of 1-4 mg or mestranol of 0.01-0.1 mg, preferably 0,025-0,075 mg, for example, of 0.05 mg Specific examples of combinations of progestogen-estrogen, including a preference for the equipment dose presented in the table below:

Solid dosage form for oral administration usually contains tetrahydrofolic acid in an amount of 0.1-5 mg, for example in an amount of 0.1-2.5 mg, for example in an amount of 0.2-0.8 mg, preferably in the amount of 0.3-0.7 mg, more preferably in an amount of 0.4-0.6 mg, most preferably in the amount of 0.42-0,49 mg As explained above, tetrahydrofolate acid preferably represents 5-methyl-(6S)-tetrahydrofolic acid or its pharmaceutically acceptable salt, such as salt, alkaline-earth metal, especially calcium salt. Salt such as calcium salt, 5-methyl-(6S)-tetrahydrofolate acid preferably should be in crystalline form, such as crystalline form I of the type described in US 6441168.

In medicinal form according to the invention can be incorporated in various fillers in the amount indicated above. However, in the interest embodiment of the invention, the dosage form contains microcrystalline cellulose, lactose monohydrate, or a combination of microcrystalline cellulose and lactose monohydrate. Therefore, in one interest embodiment of the invention Les is artena form contains microcrystalline cellulose in an amount of 5-80 mg, for example 10-80 mg Preferably, the dosage form contains microcrystalline cellulose in an amount of 40-80 mg More preferably, the dosage form contains microcrystalline cellulose in an amount of 60-80 mg Even more preferably, the dosage form contains microcrystalline cellulose in the amount of 65-80 mg Most preferably, the dosage form contains microcrystalline cellulose in the amount 65-77 mg.

Microcrystalline cellulose may be the only filler that is present in the dosage form, i.e. the dosage form according to the invention may contain other fillers other than microcrystalline cellulose. In another interest embodiment of the invention, the dosage form contains lactose monohydrate in an amount of 5-80 mg, for example 10-80 mg Preferably, the dosage form contains lactose monohydrate in an amount of 40-80 mg More preferably, the dosage form contains lactose monohydrate in an amount of 60-80 mg Even more preferably, the dosage form contains lactose monohydrate in the number of 65-80 mg Most preferably, the dosage form contains lactose monohydrate in the number 65-77 mg lactose Monohydrate may be the only filler that is present in the drug is the first form, that is, the dosage form according to the invention may contain other fillers, non-lactose monohydrate. In the embodiment of the invention, of particular interest, dosage form contains microcrystalline cellulose in an amount of 15-65 mg and lactose monohydrate in an amount of 15-65 mg In one embodiment of this aspect of the invention, the microcrystalline cellulose is the main part of the system of excipients microcrystalline cellulose-lactose monohydrate, that is, the dosage form contains lactose monohydrate in an amount of 15-50 mg microcrystalline cellulose in the amount of 25-65 mg Even more preferably, the dosage form contains lactose monohydrate in an amount of 15-35 mg microcrystalline cellulose in the amount of 30-55 mg Most preferably, the dosage form contains lactose monohydrate in an amount of 20-30 mg microcrystalline cellulose the number of 40-50 mg In another especially preferred embodiment of this aspect of the invention, the lactose monohydrate is the core part of excipients microcrystalline cellulose-lactose monohydrate, that is, the dosage form contains microcrystalline cellulose in an amount of 15-50 mg and monohydrate lactose in the number of 25-65 mg Even more preferably, the dosage form contains micro is kristallicheskuyu cellulose in the amount of 15-35 mg and monohydrate lactose in the amount of 30-55 mg Most preferably, the dosage form contains microcrystalline cellulose in the amount of 20-30 mg and lactose monohydrate in an amount of 40-50 mg

The inventor of the present invention it has been unexpectedly discovered that the problem concerning the stability of tetrahydrofolate acid, as well as problems associated with obtaining quick release of progestogen tablets prepared by direct compression, in fact, can be solved, at least partially, by the preparation of compositions using granulation, that is, in the preferred embodiment, the composition according to the invention is a granulated composition; as a result of exposure to mechanical stress and humidity in the implementation process of granulation, a specialist in this field will not assume to consider the preparation of a composition containing tetrahydrofolate acid, by granulation, as it is to believe, that is sensitive to exposure to air and humidity, tetrahydrofolate acid will be substantially degraded in such conditions. Despite this, the inventor of the present invention acted against this opinion, and he found that by combining the granulation with the right choice of fillers can be obtained stable (with respect to Tetra is hydrofolate acid) granulated composition, that simultaneously meets the requirements for quick release of estrogen and progestogen.

Therefore, as becomes clear from the above discussion and examples presented in the present invention, the composition according to the invention is preferably prepared by a process of granulation, that is, medicinal substances, including tetrahydrofolic acid, together with suitable fillers are subjected to a granulation process, preferably the process of wet granulation, such as the process of granulation in the fluidized bed. Thus, in a preferred embodiment, the composition according to the invention is a granulated composition. After granulation, the granules can be further processed into final dosage form. In one embodiment of the invention the granules can fill sachets or capsules, such as hard gelatin capsules. However, in the preferred embodiment of the invention the granules are treated in the tablet by pressing and then cover with a film cover. It is clear that tetrahydrofolate acid may be added, in one embodiment of the invention, before or during the granulation process. In this case, tetrahydrofolate acid can be considered is as a component of the "internal phase", because it forms part of the granules as such. In another embodiment of the invention, tetrahydrofolic acid is added to the granules at the completion of the granulation process or after completion of the granulation process, i.e. tetrahydrofolic acid can be considered as "external component". Therefore, tetrahydrofolate acid may be included in the granules as a component of the "internal phase"and component "external phase" or as combinations thereof. In a preferred embodiment of the invention, tetrahydrofolate acid is present as a component of "external phase".

Thus, the present invention also relates to a method for preparation of compositions in accordance with the invention, which involves the following stages:

(i) the exposure of the progestogen, estrogen and at least one pharmaceutically acceptable excipient to the granulation process,

(ii) mixing tetrahydrofolate acid or its salt granules formed in stage (i), and

(iii) optional continuation of the process of granulation, and/or

(iv) optional collection of granules.

At stage (i), progestogen, estrogen and at least one pharmaceutically acceptable excipient, such as lactose monohydrate, microcrystalline cellulose or a combination of them, are loaded into granulate is, preferably granulator fluidized bed. Then apply granulation liquid, which usually contains a binder, such as LDCs, and, in the case of granulation in the fluidized bed, the granulation liquid is continuously sprayed on the fluidized bed, while the heated air flow fluidized bed. To avoid decomposition of tetrahydrofolate acid in the implementation process of granulation is preferred when tetrahydrofolic acid or its salt are mixed with the granules formed in stage (i) at the end, close to the end or after the granulation process. However, if it is desired, the granulation process can continue after you add tetrahydrofolate acid. Usually the agent that causes disintegration, and the sizing is also mixed with the granules formed in stage (i), together with tetrahydrofolate acid.

The granules obtained by the above process, in the future can turn into a desired dosage form, for example in the tablet by pressing. Thus, in a further aspect, the present invention also provides a method for preparing solid dosage forms for oral administration in accordance with the invention, which involves the following stages:

(i) obtaining granules according JV is the property in accordance with the invention, and

(ii) preparation of granules in solid dosage forms for oral administration.

Since the composition according to the invention preferably is in the form of a granular composition, which can then be converted into the desired dosage form, provided that in the case of preparation of dosage forms containing progestogen low doses of problems quick release associated with this active ingredient, will not be so pronounced as in the case of high doses of progestogen, especially drospirenone required in the dosage form. Therefore, the present invention also relates to a tablet, especially a tablet prepared by direct compression, containing a progestogen, estrogen, tetrahydrofolic acid or its pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient or carrier, in which the amount of progestogen is 0.025-1.5 mg, for example of 0.025-1 mg, 0.05 to 1 mg, of 0.075-0.75 mg, or 0.1 to 0.5 mg Should be taken into account that all of the statements above, in particular statements regarding the preferred fillers, preferred POCs, preferred estrogen, the preferred acids tetrahydrofolate and other relevant quantities such components will apply mtatis mutandis to this aspect of the invention.

In addition, despite the fact that the composition according to the invention preferably contains progestogen and estrogen should be taken into account that in accordance with the present invention can be prepared compositions and dosage forms, but such compositions and dosage forms do not contain estrogen. One example of such a dosage form is Microlut®(also known as "pill with a low content of active substance"), which contains 0.03 mg of the left-norgestrela and does not contain estrogen. Thus, in a further aspect, the present invention relates to a solid pharmaceutical composition, which contains progestogen, tetrahydrofolic acid or its pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient or carrier. You should take into account that all of the statements above, in particular statements regarding the preferred fillers, preferred POCs, preferred tetrahydrofolic acids, as well as relevant quantities of such components, shall apply mutatis mutandis to this aspect of the invention.

Regarding the stability of tetrahydrofolate acid should apply the normal limits of the active component. The appropriate link is the USP XXIX monograph "Tablets of folic acid", which indicates that later in the product should be identified content 90-115% of the declared amount of folic acid. Compositions and dosage forms provided in the present invention correspond to the above regulatory requirements. In other words, the composition or dosage form according to the invention has a stability that is at least 80% of the initial amount of tetrahydrofolate acid is present in the composition or dosage form after storage in a closed container for 24 months at 25°C and a relative humidity of 60%. Additionally or alternatively, the composition or dosage form according to the invention has a stability that is at least 90%, preferably at least 95%, of the initial amount of tetrahydrofolate acid is present in the composition or dosage form after storage in a closed container for 12 months at 25°C and a relative humidity of 60%. In the context of the present invention, the term "initial contents", when used relative to tetrahydrofolate acid, refers to the measured amount of tetrahydrofolate acid determined immediately after preparation of the composition or dosage form or, alternatively, after storage in a closed container n is more than 5 days at a temperature of 25°C and a relative humidity of 60%. Thus, the term "initial number" does not apply to the declared number of tetrahydrofolate acid, nor to theoretical amount (added) tetrahydrofolate acid, and refers to a specific amount of tetrahydrofolate acid contained in the composition or dosage form as defined immediately after cooking or after storage for a short period of time, as described above.

In another embodiment, the composition or dosage form according to the invention has a stability that is at least 80% of the declared amount of tetrahydrofolate acid is present in the composition or dosage form after storage in a closed container for 24 months at 25°C and a relative humidity of 60%. Additionally or alternatively, the composition or dosage form according to the invention has a stability that is at least 90%, preferably at least 95%of the declared amount of tetrahydrofolate acid is present in the composition or dosage form after storage in a closed container for 12 months at 25°C and a relative humidity of 60%. In the context of the present invention, the term "claimed amount" refers to the officially declared the number of tetrahydrofolate acid, which prisutstvuet is in the composition or dosage. The stated amount of tetrahydrofolate acid you can usually tell from the information given in the insert.

In yet another embodiment, the composition or dosage form according to the invention has such stability that the sum of the products of decomposition of tetrahydrofolate acid is at most 10%, preferably at most 8%, more preferably at most 6%, more preferably at most 5%, most preferably at most 4%, after storage in a closed container for 6 months or 12 months at 25°C and a relative humidity of 60%. The sum of the products of decomposition of tetrahydrofolate acid can be defined as described in the section of this application the Definition of the decay products".

In yet another embodiment, the composition or dosage form according to the invention has such stability that the sum of the products of decomposition of tetrahydrofolate acid is at most 10%, preferably at most 8%, more preferably at most 6%, more preferably at most 5%, most preferably at most 4%, after storage in a closed container for 1 month, 2 months or 3 months at 40°C and a relative humidity of 75%. The sum of the products of decomposition of tetrahydrofolate acid can be defined as described in the section of this application the Definition of the decay products".

As is evident from the disclosure of this application, the composition or dosage form according to the invention are suitable for inhibiting ovulation in women, that is, to provide contraception for women. Additionally, due to the presence of tetrahydrofolate acid or its salts, compositions and dosage forms according to the invention is also suitable for the treatment or prevention of folate deficiency, including anemia and bleeding.

In another further preferred embodiment, the present invention relates to a pharmaceutical product or kit, consisting essentially of 21, 22, 23 or 24, in particular 21 or 24, separately Packed and individually remove solid dosage forms for oral administration in accordance with the invention, placed in one package, and 7, 6, 5 or 4, in particular, 7 or 4, separately Packed and individually remove solid dosage forms for oral administration containing as the sole active component tetrahydrofolic acid, placed in one package.

Dosage forms containing as the sole active component tetrahydrofolic acid, can be prepared using any method known in this field, provided that tetrahydrofolate acid still meets the criteria of stability to the e discussed in this application. In one embodiment, a dosage form containing as the sole active component tetrahydrofolic acid, essentially identical dosage forms described in the present invention, but it contains POCs and estrogen.

The drug (or set) can be a single-phase drug, i.e. a drug, in which the amount of progestogen and estrogen remain constant throughout the 21-, 22-, 23 - or 24-day period. Alternatively, the number of one or both active ingredients (that is, a progestogen and estrogen) may change during the 21-, 22-, 23 - or 24-day period to obtain multiphase drug, such as two - or three-drug, such as described, for example, in US 4621079. Thus, while the drug may be single phase or multiphase drug, the amount of tetrahydrofolate acid preferably remains constant during the entire cycle, then there is every 28 days.

Packaging containing dosage forms described above, can be prepared in a manner analogous to the preparation of other oral contraceptives. She may represent, for example, conventional blister packaging, or any other form known for this purpose, for example a package, containing a suitable quantity of dosage units (in this case the e is usually 28 or a multiple of 28) in a sealed blister pack with cardboard, paper, foil or plastic base and covered with a suitable coating.

Moreover, the composition or dosage form according to the invention is also suitable for the treatment of diseases, conditions or symptoms associated with the deficiency of endogenous levels of estrogen in women. In this case, the above POCs preferably combined with an estrogen selected from the group comprising estradiol, estradiol sulfamate, estradiol valerate, estradiol benzoate. A specific example of a preferred dosage form contains 0.25-3 mg of drospirenone and 0.5-2 mg of estradiol, such as 1-3 mg of drospirenone and 0.5-2 mg of estradiol, preferably 1.5 to 2.5 mg of drospirenone and 0.5-1.5 mg of estradiol, more preferably about 2 mg of drospirenone and approximately 1 mg of estradiol (Angeliq®). Other examples include compositions or dosage forms containing estradiol valerate and cyproterone acetate, estradiol valerate and dienoguest, ethinylestradiol and gestodene and ethinylestradiol and levo-norgestrel. Insufficient levels of estrogen can occur due to various reasons. For example, insufficient levels of estrogen can be caused, for example, natural menopause, peri-menopause, post-menopause, hypogonadism, castration or primary ovarian disorders. Low levels of estrogen, independently of oprichina, lead to a deterioration in the overall quality of life of women. Symptoms, diseases and conditions vary from minor discomfort to life-threatening. Compositions and dosage forms described in this invention provide effective relief of all physiological and psychological symptoms of low estrogen. Passing symptoms, such as vasomotor symptoms and physiological symptoms will undoubtedly be covered by this therapy. Vasomotor symptoms include, but are not limited to, hot flashes, attacks of sweating, such as nocturnal attacks of sweating, and palpitations. Psychological symptoms of estrogen deficiency include, but are not limited to, insomnia and other sleep disorders, poor memory, loss of confidence, mood changes, anxiety, loss of libido, difficulty with concentration, difficulty in making decisions, decreased energy and libido, irritability and causeless weeping. The treatment of the above symptoms may be associated with peri-menopausal phase in a woman's life or after, for a long time after menopause. Suppose that the compositions and dosage forms described in the present invention, suitable for these and other moveable symptoms during the peri-menopausal phase, menopause or post-menopausal the phase. In addition, the above symptoms may be reduced, if the reason for the deficiency of estrogen is hypogonadism, castration or primary dysfunction of the ovaries. In another embodiment of the invention, the composition or dosage form described in the present invention, suitable for continuous treatment of the effects of estrogen deficiency. Continuous exposure include physical changes, such as atrophy of the urogenital system, atrophy of the Breasts, cardiovascular disease, changes owolosenia, thickness of hair, changes in skin condition and osteoporosis. Atrophy urogenital system and conditions associated with this pathology, such as vaginal dryness, increase the value of vaginal pH and subsequent changes to the microflora, or processes leading to such atrophy, such as reduced vascularization, fragmentation of elastic fibers, the fusion of collagen fibers or decrease in cell volume, are symptoms which are considered to be extremely relevant for treatment using the compositions or dosage forms described in the present invention. In addition, the compositions or dosage forms described in the present invention are considered to be relevant in relation to other changes in the genitourinary system, associated with a deficiency of estrogen, reduce the group of of mucus production, the change in the population of cells, the decreased production of glycogen, reduced growth of lactobacilli or increased growth of streptococci, staphylococci or E. coli. Other associated changes that are thought to be prevented by the introduction of the compositions or dosage forms described in the present invention, are changes that can affect the sensitivity of the vagina to injury or infection, such as pleural discharge, vaginitis and dyspareunia. In addition, urinary tract infections and incontinence are other common symptoms associated with reduced levels of estrogen. Other embodiments of the invention include the prevention or relief of physical changes associated with estrogen deficiency, such as skin changes, changes owolosenia, thickness of hair, atrophy of the mammary glands or osteoporosis. Prevention and treatment of osteoporosis, particularly post-menopausal osteoporosis is an extremely preferred embodiment of the invention. In addition, I believe that bone demineralization, reduced bone mass and bone density, thickness and interruption of trabeculae and/or the subsequent increase in bone fractures or bone deformities are particularly relevant. Prophylactic treatment of the OST is oporoza is of interest therapeutic use of the compositions or dosage forms according to the invention. A variant of the invention, of particular interest, is aimed at reducing the frequency, stability, duration and/or severity of hot flushes, attacks of sweating, palpitations, sleep disturbances, mood changes, nervousness, anxiety, poor memory, loss of confidence, loss of libido, poor concentration, diminished energy, diminished drive, irritability, urogenital atrophy of the system, atrophy of the Breasts, cardiovascular disease, changes owolosenia, thickness of hair, changes in skin condition and osteoporosis (including prevention of osteoporosis), especially tides, bouts of sweating, palpitations, sleep disturbances, mood changes, nervousness, anxiety, urogenital atrophy of the system, atrophy of the mammary glands, as well as the prevention or treatment of osteoporosis. Other interest a variant embodiment of the invention is directed to the treatment of the tides, bouts of sweating, palpitations, sleep disturbances, mood changes, nervousness, anxiety, poor memory, loss of confidence, loss of libido, poor concentration, diminished energy, diminished drive, irritability, urogenital atrophy of the system, atrophy of the Breasts, cardiovascular disease, changes in owolosenia, strata who have hair, state changes of the skin and osteoporosis (including prevention of osteoporosis), especially tides, bouts of sweating, palpitations, sleep disturbances, mood changes, nervousness, anxiety, urogenital atrophy of the system, atrophy of the mammary glands, as well as the prevention or treatment of osteoporosis.

Further, the invention is illustrated by the following non-limiting examples.

Materials and methods

Determination of the decay products

Separation and quantitative determination of 5-methyl-(6S)-tetrahydrofolate calcium, as well as its decay products was performed using the HPLC column reversed-phase (European Pharmacopoeia (Ph. Eur. 2,2,9, USP <621>, JP No. 27)), using external standard calibration. Samples should be investigated without delay.

Dissolution

Dissolution of ethinyl estradiol and drospirenone investigated using the steps described in the US Pharmacopoeia XXIX paddle method II using water at 37°C as a medium for dissolving and the stirring speed of 50 rpm

Dissolve 5-methyl-(6S)-tetrahydrofolate calcium was investigated using the steps described in the US Pharmacopoeia XXIX paddle method II using 0,03% aqueous solution of ascorbic acid (brought to pH 3.5 with 0.05 M phosphate buffer) at 37°C as a medium for dissolving and soon the STI mixing 50 rpm

Example

Example 1 - Direct pressing; microcrystalline cellulose

The core tablets 80 mg having the following composition was prepared by direct pressing:

ComponentAmount (mg)
Ethinylestradiol (as complex
micronized β-cyclodextrin)0,030
Micronized drospirenone3,000
Metafolin®0,451
Microcrystalline cellulose (Avicel®PH-101)73,319
Croscarmellose sodium1,600
Magnesium stearate1,600

Investigated the stability of 5-methyl-(6S)-tetrahydrofolate calcium during storage under different conditions. The following data were obtained stability (see tables 1 and 2 below) when stored at 25°C/60% RH and 40°C/75% RH, respectively. The stability was investigated both in open and in closed containers.

Table 1
The amount of degradation products in %
Months25°C/60% RH25°C/60% RH40°C/75% RH
40°C/75% RH
closedoutdoorclosedoutdoor
02,12,12,12,1
12,42,63,07,2
32,72,63,215,0
63,2-4,2-
9 3,6-5,1-
125.2---

Table 2
The number of Metafolin®in %
Months25°C/60% RH40°C/75% RH
closedclosed
0101,2101,2
1103,1101,2
399/296,0
699,894,3
998,896,6
12103.1-
As can be seen from the presented data, satisfactory stability 5-methyl-(6S)-tetrahydrofolate calcium was obtained at 25°C, even when the tablet was subjected to air. In addition, satisfactory stability was obtained at 40°C (closed container), while observed a significant decomposition of 5-methyl-(6S)-tetrahydrofolate calcium during storage of the tablets at 40°C and, at the same time, when it was exposed to air. The above data stability is also presented in figure 1.

The dissolution profiles shown in figure 2. As you can see in figure 2, ethinyl estradiol and 5-methyl-(6S)-tetrahydrofolate calcium released from the tablet, whereas the dissolution of drospirenone was unsatisfactory slow. These findings were unexpected, especially since the tablet dissolves within 5 minutes in the studied conditions.

Example 2 - Direct pressing; Cellactose®(monohydrate lactose/cellulose powder)

The core tablets 80 mg having the following composition were prepared by direct compression:

ComponentAmount (mg)
Ethinylestradiol (as complex
micronized β-cyclodextrin)
0,030
Micronized drospirenone3,000
Metafolin®0,451
Cellactose®73,319
Croscarmellose sodium1,600
Magnesium stearate1,600

Investigated the stability of 5-methyl-(6S)-tetrahydrofolate calcium during storage under different conditions. Obtained the following data stability (see tables 3 and 4 below) when stored at 25°C/60% RH and 40°C/75% RH, respectively. The stability was investigated both in open and in closed containers.

As can be seen, satisfactory stability 5-methyl-(6S)-tetrahydrofolate calcium 25°C. However, as in example 1, the dissolution of drospirenone was unsatisfactory slow.

Example 3 - Direct pressing; Tablettose®(lactose monohydrate)

The core tablets 80 mg having the following composition were prepared by direct compression:

ComponentAmount (mg)
Ethinylestradiol (as complex
micronized β-cyclodextrin)0,030
Micronized drospirenone3,000
Metafolin®0,451
Tablettose®
Starch 1500®
74,119
1,600
Magnesium stearate0.800 to

It was found that the stability of 5-methyl-(6S)-tetrahydrofolate calcium was not satisfactory when stored at 25°C/60% RH and 40°C/75% RH, respectively. As in examples 1 and 2, the solubility of drospirenone was unsatisfactory slow.

Example 4 - Direct pressing; microcrystalline cellulose/lactose monohydrate

For the study, can be enhanced solubility of drospirenone, it was decided to prepare a tablet in accordance with example 1, but in which approximately one third of the microcrystalline cellulose was replaced by lactose monohydrate (although lactose monohydrate has a destabilizing effect on 5-methyl-(6S)-tetrahydrofolate calcium, cf. examples 2 and 3).

Thus, the core tablets 80 mg having the following composition were prepared by direct compression:

Component
Amount (mg)
Ethinylestradiol (as complex micronized β-cyclodextrin)0,030
Micronized drospirenone3,000
Metafolin®0,451
Microcrystalline cellulose (Avicel®PH-101)48,899
The lactose monohydrate (Pharmatose®DCL 11)24,420
Croscarmellose sodium1,600
Magnesium stearate1,600

Watched a satisfactory stability of 5-methyl-(6S)-tetrahydrofolate calcium during storage under different conditions.

The dissolution profile is presented in figure 3, and as can be seen from figure 3, the dissolution of drospirenone was slow and unsatisfactory received a number of identical profile release tablets prepared in example 1.

Example 5 - Granulation in the fluidized bed; microcrystalline cellulose/lactose monohydrate

Prepared core tablets 80 mg having the following composition:

ComponentAmount (mg)
Ethinylestradiol (as complex
micronized β-cyclodextrin)
0,020
Micronized drospirenone3,000
Metafolin®0,451
Microcrystalline cellulose (Avicel®PH 101)24,800
Monohydrate lactose, crystalline45,319
LDCs, viscosity 51,600
Croscarmellose sodium3,200
Magnesium stearate1,600

The granulated product was prepared by loading into the granulator with a fluidized bed of drospirenone, ethinyl estradiol, lactose monohydrate, microcrystalline cellulose and activation of the fluidized bed. An aqueous solution of the binder (LDCs) was continuously sprayed on the fluidized bed, while dried by heating air flow fluidized bed. At the end of the process in the pellet were sucking 5-methyl-(6S)-tetrahydrofolate calcium, croscarmellose and magnesium stearate and the mixture is Vali with granules by maintaining a fluidized bed. The obtained granulated material was compressed into core tablets using a tablet press.

Watched a satisfactory stability of 5-methyl-(6S)-tetrahydrofolate calcium during storage under different conditions.

Furthermore, and as can be seen from figure 3, the observed profile immediate release, i.e. the dissolution of drospirenone was comparable to the dissolution profile of oral contraceptive Yasmin®containing drospirenone.

Example 6 - Granulation in the fluidized bed; microcrystalline cellulose

Prepared core tablets 80 mg having the following composition:

ComponentAmount (mg)
Ethinylestradiol (as complex
micronized β-cyclodextrin)
0,030
Micronized drospirenone3,000
Metafolin®0,451
Microcrystalline cellulose (Avicel®PH 101)71,719
LDCs, viscosity 51,600
Croscarmellose sodium1600
Magnesium stearate1,600

The granulated product was prepared as described in example 5. Watched a satisfactory stability of 5-methyl-(6S)-tetrahydrofolate calcium during storage under different conditions.

As can be seen from table 3, drospirenone was released slowly from the tablet, compared to the tablet prepared in example 5. However, the release of drospirenone was still satisfactory and comparable with oral contraceptive device Yaz®containing drospirenone.

1. Solid oral dosage form containing
i), pharmaceutically acceptable salt, alkaline-earth metal 5-methyl-(6S)-tetrahydrofolate acid; and
ii) granules comprising a progestogen, estrogen, and microcrystalline cellulose.

2. Dosage form according to claim 1, in which the progestogen is chosen from the group comprising levo-norgestrel, norgestrel, norethindrone (norethisterone), norethindrone (norethisterone) acetate, dienoguest, ethynodiol diacetate, dydrogesterone, medroxyprogesterone acetate, norethynodrel, allylestrenol, lynestrenol, hingeston acetate, medrogestone, norgestrienone, dimethisterone, ethisterone, chlormadinone acetate, megestrol, promegestone, desogestrel, 3-keto-desogestrel, norgestimate, gestodene, tibolone, tsiproteronatsetat and drospirenone.

3. Dosage form according to claim 2, in which the progestogen is a drospirenone.

4. Dosage form according to any one of the preceding paragraphs, in which the estrogen is selected from the group including ethinyl estradiol, estradiol, estradiol sulfamate, estradiol valerate, estradiol benzoate, estrone, mestranol and estrone sulfate.

5. Dosage form according to claim 4, in which estrogen is a levonorgestrel.

6. Dosage form according to claim 1, in which the progestogen is a drospirenone and estrogen is a levonorgestrel.

7. Dosage form according to claim 6, in which the salt of 5-methyl-(6S)-tetrahydrofolate acid is a calcium salt.

8. Dosage form according to claim 7, in which the calcium salt of 5-methyl-(6S)-tetrahydrofolate acid is in crystalline form.

9. Dosage form of claim 8, in which crystalline form is crystalline form I type.

10. Dosage form according to claim 1, in which the dosage form is in the form of tablets, capsules or sachets.

11. Dosage form according to claim 3, which contains 2-4 mg of drospirenone.

12. Dosage form according to claim 5, which contains from 0.01 to 0.05 mg of ethinyl estradiol.

13. Pharmaceutical set to provide contraception to women or to treat diseases, conditions or symptoms associated with deficiency of EN is agennix levels of estrogen in women where this set consists, essentially, of 21, 22, 23 or 24 separately Packed and individually remove solid dosage forms for oral administration, as defined in any one of claims 1 to 12, placed in one package, and 7, 6, 5 or 4 separately Packed and individually remove solid dosage forms for oral administration containing as the sole active component pharmaceutically acceptable salt of 5-methyl-(6S)-tetrahydrofolate acid, placed in one package.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a diacetate of racemic 18-ethyl-gona-1,3,5(10),8(9)-tetraene-3,17β-diol, having anti-implantation and antioxidant activity with low uterotropic action. Presence of antioxidant activity in said steroid is essential since compounds with such action can be agents for preventing oestrogen-dependent breast cancer.

EFFECT: compounds exhibit anti-implantation and antioxidant activity with low uterotropic action, which is an advantage over agents used in practice.

1 cl, 1 ex, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: as a first active agent a pharmaceutical composition contains drospirenone in the amount equal to a daily dose when administering the composition and making 2 to 4 mg, and as a second active agent - ethinylestradiol in the amount equal to a daily dose and making 0.01 mg to 0.05 mg, together with one or more pharmaceutically acceptable carriers or additives. Drospirenone as a part of the pharmaceutical composition has a particle surface area more than 10000 cm2/g. Preferentially, drospirenone is fine-grained or sprayed from a drospirenone solution by inert carrier particles. The preparation contains a number of separately packed and individually taken daily dosage units in a single package used for oral administration for at least 21 days running with said daily dosage units containing a combination of drospirenone and ethinylestradiol. The preparation may additionally contain 7 and less daily dosage units containing no active agent, or containing ethinylestradiol only.

EFFECT: combination of drospirenone and ethinylestradiol provides reliable contraceptive activity ensured by the use of a maximum dose of drospirenone which causes no side effects, particularly, excess diuresis.

29 cl, 5 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry and relates in particular to medication for women, which has contraceptive and protective action against inflectional diseases: herpes, HIV infections, viral disease. Medication for vaginal application, possessing contraceptive and protective against inflectional diseases action contains actively-acting components and target base. As actively-acting components medication contains contraceptive, bactericidal, anti-inflammatory preparations, and as target base it contains gel-forming biocompatible polymers and L-lysin hydrochloride with specified component ratio per 1 g. Medication presents gel, ointment, cream, liniment.

EFFECT: medication not only has contraceptive action, but also makes it possible to simultaneously prevent sexually transmitted infection diseases.

3 cl, 6 ex

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine, namely to gynaecology, and can be used for female contraception. Inventions include methods of female contraception. That is ensured by the multiple administration of a dosage form started in a day of month marked either by 'n+3', or 'n+4', or 'n+5', or 'n+6' date and taken out in a day marked by 'n' number of the next month for at least two cycles where 'n' is a date either within 1 to 25, or 1 to 24, or 1 to 23, or 1 to 22 respectively. Also, the inventions involve female contraception kits containing at least two dosage forms and patient information leaflets according to the declared modes of contraception. Besides, the inventions comprise a dosing regimen reminder system adjusted in such a manner that it allows to choose one specific date either within 1 to 25, or within 1 to 24, or within 1 to 23, or within 1 to 22 regardless of a month, as a date when the dosage form is always taken out and a date when a new dosage form shall be used either through three, or through four, or through five, or through six days thereafter respectively.

EFFECT: inventions provide convenient administration of contraceptives with maintained efficacy of contraception and its increase in certain cases.

1 tbl, 9 ex

FIELD: medicine.

SUBSTANCE: multiphase pharmaceutical preparation for ovulation inhibition in mammal contains a number of individually packed and individually removed daily units placed in a single package, and used for oral administration for at least 21 days running; specified daily units contain a combination of oestradiol and drospirenone. A daily unit contains 0.5 to 4 mg of oestradiol and 2 to 4 mg of drospirenone. At least 70% of specified drospirenone are released from specified unit within 30 minutes.

EFFECT: invention provides higher oral bioavailability of drospirenone.

6 cl, 5 dwg, 5 ex

FIELD: medicine.

SUBSTANCE: there is claimed application of ethinylestradiol and chlormadinone acetate combination for obtaining medication applied simultaneously for treatment of androgen-induced disorders, for substitution hormonotherapy, for treatment of dismenorea, for stabilisation of menstrual cycle, for treatment of illnesses dependent on menstrual cycle and for women's contraception, said medication being obtained in form of at least 21 hormone-containing day dose, and said combination of hormones contains from 5 to 20 mcg of ethinylestradiol and from 1 to 5 mg of chlormadinone acetate in day dose, if necessary in combination with 7-3 day doses which do not contain hormone.

EFFECT: it is demonstrated that reduction in claimed medication of ethinylestradiol amount does not influence cycle stabilisation, but it can be continuously introduced to women in pre- and perimenopause in order to achieve simultaneously all said aims, as well as for reduction of high blood pressure.

11 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to steroids with (11β)-[4-(aza-aryl)phenyl] substitutes which modulate progesterone receptors, or pharmaceutically acceptable salts and/or hydrated form, and/or prodrug thereof.

EFFECT: compounds exhibit combined activity profile of PR agonist and PR antagonist which makes them suitable for contraception and treating gynaecological disorders.

30 cl, 28 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention distinguishes 28-day and 91-day modes of taking combined oral contraceptives, possibly in combination with antidepressant (fluoxetine hydrochloride) in which full disappearance of estrogen from preparation does not take place. This presupposes that shorter influence of peaks and drops of endogenic progesterone protects against premenstrual disphoric disorder (PMDD) and against symptoms of mood disturbance in women with PMS.

EFFECT: application of estrogen and progesterone for manufacturing medication for contraception, treatment of premenstrual syndrome (PMS) or syndrome of estrogen cessation (versions), respective preparation (versions) and method of pregnancy prevention.

91 cl, 6 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: invention is related to the field of medicines, in particular to tetrahydroquinoline derivatives with common formula (I), where Y-X means C(O)-O, C(O)-NH, S(O)2-NH, NHC(O)-NH, NHC(S)-NH, OC(O)-NH; R6 stands for H, (1-6C)alkyl, 1- or 2-adamantyl(1-4C)alkyl, (3-9C)heteroaryl, (3-6C)cycloalkyl, (2-6C)heterocycloalkyl, alkylthio(1-4C)alkyl, phenyl(1-4C)alkyl, (3-6C)cycloalkyl (1-4C)alkyl, (2-6C)heterocycloalkyl (1-4C)alkyl, R8, R9 aminocarbonyl (1-4C) alkyl, R8, R8R9-amino (1-4C)alkyl, R8-oxycarbonyl (1-4C)alkyl, R8-oxy (1-4C)alkyl, R8-carbonyl (1-4C)alkyl or phenyl, not necessarily substituted with hydroxy, amino, halogen, nitro, trifluoromethyl, (3-9C)heteroaryl, (1- 4C)alkylcarbonylamino, (1-4C)alkylcarbonyloxy, (3-9C)heteroarylcarbonyloxy, (3-9C)heteroarylsulfonyloxy, (2-6C)heterocycloalkylcarbamoyl or diphenylamino.

EFFECT: modulating activity in respect to FSH receptor.

17 cl, 74 ex

FIELD: medicine; pharmacology.

SUBSTANCE: mainly water-free composition for oral or vaginal mucosa lubrication includes at least one polyatomic alcohol and honey as insulation agent. Invention also concerns methods of the composition application for lubrication, active component introduction and dysmenorrhea prevention or treatment. Methods involve application of mainly water-free lubricating composition including at least one polyatomic alcohol and insulation agent selected from honey and isopropylpalmitate, onto oral or vaginal mucosa to produce heating effect.

EFFECT: reduced toxicity and irritation effect.

31 cl, 1 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine and deals with combined pharmaceutical composition, which possesses anti-tuberculosis action. Composition is made in form of solid drug form, which contains combination of levofloxacin, protionamide, pyrazinamide, ethambutol hydrochloride and pyridoxine hydrochloride ad active ingredient, and pharmaceutically acceptable auxiliary substances.

EFFECT: composition is characterised by high therapeutic activity.

10 cl, 2 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to tablet, which is decomposed in mouth, containing D-mannite, active ingredient, disintegrating preparation, selected from crospovidone and carmellose, lubricant, selected from sodium stearylfumarate and sucrose esters of fatty acids, binding agent and starch. D-mannite has average size of particles larger than 30 mcm and specific surface larger than 0.40 m2/g.

EFFECT: claimed tablet has time of decomposition in oral cavity within 30 seconds, excellent sensation in oral cavity and sufficient strength, as a result of which tablet is not decomposed in the process of distribution.

28 cl, 1 dwg, 12 tbl, 51 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to chemical-pharmaceutical industry and represents a pharmaceutical composition containing: {1S-[1α,2α,3β(1S*,2R*),5β]}-3-(7-{[2-(3;4-difluorophenyl)cyclopropyl]amino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol; an excipient representing mixed mannitol and dibasic calcium phosphate dihydrate; a binding agent representing hydroxypropyl cellulose; a disintegrant representing sodium starch glycolate; and one or more lubricating agents.

EFFECT: invention provides preparing the composition of the active compound possessing high stability and high bioavailability of the active agent.

12 cl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and represents a drug preparation containing 97.0-59.5 wt % of naltrexone base, 0.5-3.0 wt % of corticosteroid specified in triamcinolone, betamethasone or dexamethasone, 2.0-37.0 wt % of a nitrogen-containing polymer composition and 0.2-0.5 wt % of stearic acid or magnesium stearate. The nitrogen-containing polymer composition contains N-vinylpyrrolidone and 2-methyl-5-vinylpyridine copolymer or a salt of branched oligomers hexamethylene diamine and guanidine, and polyvinylpyrrolidone. The drug preparation may be used in addictology for treating the alcohol- or opioid-dependent patients.

EFFECT: invention provides prolonged and uniform naltrexone release with a lower probability of the implant rejection caused by an inflammatory response.

2 cl, 3 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine, namely a stable pharmaceutical composition of a water-soluble salt of vinorelbine. The composition contains approximately 56 wt % of a diluent, approximately 2.5 wt % of a binding agent, approximately 5 wt % of a disintegrant, approximately 0.25 wt % of a flow agent and approximately 0.5 wt % of a lubrication agent. The water-soluble salt of vinorelbine is preferentially vinorelbine ditartrate.

EFFECT: pharmaceutical composition is preferentially presented in the form of a gelatine capsule or a tablet.

5 cl, 6 ex, 12 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to pharmacology and medicine. The group of inventions involves pharmaceutical compositions containing 5-azacytidine for the oral introduction wherein the compositions release a cytidine analogue substantially in stomach, a method of treating an individual suffering a disease associated with abnormal cell proliferation which involves the oral introduction of the pharmaceutical composition into the individual, using 5-azacytidine for preparing the pharmaceutical composition for treating the disease associated with abnormal cell proliferation.

EFFECT: invention provides higher clinical effectiveness.

9 tbl, 9 ex, 23 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: pharmaceutical composition applicable for oral administration contains an S1P receptor agonist and mannitol with the composition representing a solid dosage form. Mannitol has a particle specific surface area 1 to 7 m2/g, and the S1P receptor agonist is specified from 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol (FTY720), its pharmaceutically acceptable salt and FTY720-phosphate.

EFFECT: compositions under the invention are characterised by a high level of distribution uniformity of said S1P receptor agonist, and applicable for oral administration in the solid dosage form, eg in the form of a tablet or a capsule.

14 cl, 39 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: method for preparing a pharmaceutical composition consists in mixing an S1P receptor agonist - 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol or its pharmaceutically acceptable salt with sugar alcohols; the mixture is milled and/or granulated, and then mixed with an oil agent. The method under invention is implemented on high-speed automated equipment and enables producing the compositions with high-level distribution uniformity of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol or its pharmaceutically acceptable salt in the composition applicable for oral administration of said S1P receptor agonist.

EFFECT: preparing the pharmaceutically acceptable salt in the composition applicable for oral administration of said S1P receptor agonist.

15 cl, 39 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a pharmaceutical composition for treating and/or preventing depressions. The pharmaceutical composition contains an active substance presented by a selective serotonin reuptake inhibitor (SSRI) specified in a group of fluoxetine, paroxetine, citalopram, escitalopram, sertraline, fluvoxamine differing by the fact that as an active substance, it additionally contains N-acetyl-5-methoxytryptamine (melatonin) in the following proportions, mg: selective serotonin reuptake inhibitor (SSRI) - 10-30 mg, melatonin - 3-8 mg. The pharmaceutical composition may be presented by a solid dosage form - a tablet, a film-coated tablet, a capsule, by a soft dosage form - a rectal suppository.

EFFECT: pharmaceutical composition provides treating depressions and has a number of additional therapeutic properties: easing falling asleep and relieving sleeping disorders, recovering circadian rhythm and seasonal rhythm with reducing a risk of side effects of SSRI.

3 cl, 14 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: invention relates to pharmaceutical and nutriceutical tablets. Composition for tabletting contains matrix with lubricant, which is included into its composition. Said matrix with lubricant included into its composition consists of oily liquid, finely dispersed in oil-insoluble material. Said matrix constitutes from 0.3 to 8.8% of composition and composition does not contain stearate. Claimed is method of manufacturing composition for tabletting and tablet, manufactured by tabletting said composition.

EFFECT: invention makes it possible to improve lubrication of dry nutriceutical and/or pharmaceutical compositions during tabletting.

24 cl, 2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: as an active ingredient, a pharmaceutical composition contains 6β,7β; 15β; 16β-dimethylene-3-oxo-17α-preg-4-ene-21,17-carbolactone (drospirenone, DRSP) together with a pharmaceutically acceptable excipient or carrier. Said composition does not contain estrogen. Drospirenon is prepared in fast soluble dosage form. At least 70% of drospirenone are dissolved within 30 minutes. For ensuring said immediate release, drospirenone is either micronised, or in dosage form of surface area more than 10000 cm2/g, or is applied on the surface of particles of an inert carrier. The composition can be applied for endometriosis treatment and introduced in the form of a multiphase pharmaceutical preparation.

EFFECT: immediate-release drospirenone compositions under the invention exhibits high biological availability when administered orally.

23 cl, 7 ex

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