HK1179165B - Pharmaceutical composition containing a tetrahydrofolic acid - Google Patents

Description

Pharmaceutical compositions comprising tetrahydrofolic acid

The present application is a divisional application of the Chinese patent application with application number 200780025570.4, application date June 29, 2007, and invention name “Pharmaceutical composition containing tetrahydrofolic acid”.

Field of the Invention

The present invention relates to solid pharmaceutical compositions, in particular oral contraceptives, comprising tetrahydrofolic acid, such as 5-methyl-(6S)-tetrahydrofolate calcium. The compositions provided by the present invention allow for good stability of the tetrahydrofolic acid during storage, while still ensuring rapid and reliable release of the estrogen and progestogen present in the composition.

Background of the Invention

In pregnant women, correction of low serum folate levels requires at least two months, and the reservoir lasts only a few weeks. Therefore, according to public health service recommendations, all women of childbearing potential should consume 400 μg/day of folic acid to reduce the risk of birth defects (MMWR Morb. Mortal. Wkly. Rep. 1992;41(RR-14):1-7). Folic acid supplementation immediately before stopping oral contraceptive use or immediately after a positive pregnancy test may not be sufficient to optimally protect the developing fetus. Furthermore, multiple studies of women taking oral contraceptives have demonstrated decreased serum folate levels relative to negative controls. Postulated mechanisms for this phenomenon include decreased absorption of polyglutamate, increased excretion of folic acid, increased production of folate-binding proteins, and induction of folate-dependent hepatic microsomal enzymes. Therefore, decreased serum folate levels in oral contraceptive users pose an additional risk to these users should they become pregnant within three to six months of discontinuing use.

Therefore, folic acid should ideally be added to oral contraceptives because adequate folic acid intake during the peri-pregnancy period helps protect against many congenital malformations, including neural tube defects such as spina bifida (incomplete closure of the spinal cord and spine), anencephaly (severe underdevelopment of the brain), and encephalocele (protrusion of brain tissue through an abnormal opening in the skull into the skin). All of these defects occur during the first 28 days of pregnancy, often before a woman even knows she is pregnant.

However, the addition of folic acid to oral contraceptives may pose a serious health risk because it will suppress the symptoms of vitamin B12 deficiency, such as anemia. For example, folic acid can correct anemia associated with vitamin B12 deficiency, but unfortunately, folic acid will not correct the changes in the nervous system caused by vitamin B12 deficiency. If vitamin B12 deficiency is not treated, permanent nerve damage may occur. Therefore, the present inventors have proposed the addition of tetrahydrofolic acid, such as 5-methyl-(6S)-tetrahydrofolic acid, a natural folic acid derivative, to oral contraceptives, which is formed in the rather complex catabolic pathway of the prodrug folic acid. The addition of tetrahydrofolic acid, such as 5-methyl-(6S)-tetrahydrofolic acid, to oral contraceptives may provide all the beneficial effects associated with folic acid without masking the potential drawbacks of anemia caused by vitamin B12 deficiency.

However, tetrahydrofolic acid is extremely unstable and highly sensitive to oxidation and moisture. Therefore, from a formulation perspective, incorporating tetrahydrofolic acid into solid oral pharmaceuticals such as oral contraceptives presents a significant challenge. Not only should the resulting solid pharmaceutical composition exhibit satisfactory stability (with respect to tetrahydrofolic acid) upon storage, but even the preparation of the composition itself is considered problematic, as exposure to oxidizing excipients, humidity, and/or open air during the preparation process is expected to cause degradation of tetrahydrofolic acid and should therefore be avoided. Furthermore, as will become apparent from the examples provided herein, the problem of stabilizing tetrahydrofolic acid cannot be solved alone, as it has been demonstrated that stabilizing tetrahydrofolic acid in many cases surprisingly results in insufficient release of the other active agents of the composition.

Furthermore, tetrahydrofolic acid is considered an active ingredient in oral contraceptives. Therefore, standard stability measures typically used for vitamin supplements, such as overdose or wider regulatory limits, are not applicable to oral contraceptives. Typical overdose rates for vitamin supplements can be as high as 25%, and the dosage in some vitamin supplements is 0.6-5.6 mg, exceeding the recommended daily dose (0.45 mg). Because stability issues are more pronounced when incorporated into pharmaceutical compositions at low concentrations, the preparation of stable pharmaceutical compositions containing low-dose tetrahydrofolic acid is inherently challenging.

Nevertheless, by careful selection of key excipients and/or manufacturing processes, the present inventors have surprisingly succeeded in preparing oral contraceptives which, on the one hand, have satisfactory stability of tetrahydrofolic acid and, on the other hand, still meet the necessary requirements for release and therefore bioavailability of the estrogen and progestogen present in the composition.

WO 03/070255 describes a kit for contraception and hormone replacement therapy comprising one or more steroids such as estrogens and progestogens; one or more tetrahydrofolate components; and vitamin B12.

US 6190693 relates to a pharmaceutical composition comprising folic acid suitable as an oral contraceptive or for use in hormone replacement therapy.

US 6011040 relates to the use of tetrahydrofolate for influencing homocysteine levels, in particular for assisting homocysteine remethylation.

US 6,441,168 describes stable crystalline salts of 5-methyltetrahydrofolate.

SUMMARY OF THE INVENTION

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

In another aspect, the present invention relates to a solid oral dosage form comprising a composition of the present invention.

Other aspects of the invention will become apparent from the ensuing disclosure and appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the stability of 5-methyl-(6S)-tetrahydrofolate calcium in tablets prepared as described in Example 1. The Y-axis indicates the percentage of 5-methyl-(6S)-tetrahydrofolate calcium remaining after storage and the sum of decomposition products. The X-axis indicates 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).

Figure 2 shows the dissolution of drospirenone, ethinylestradiol, and 5-methyl-(6S)-tetrahydrofolate calcium from tablets prepared in Example 1. The Y-axis indicates the amount dissolved, and the X-axis indicates the dissolution measurement time in minutes. ▲ Drospirenone; ■ Ethinylestradiol; ◆ 5-methyl-(6S)-tetrahydrofolate calcium.

Figure 3 shows the dissolution of drospirenone from the tablets prepared in the examples. The Y-axis indicates the amount of dissolution, and the X-axis indicates the dissolution measurement time in minutes. ◆Example 1; ■Example 4; ▲Example 5; XExample 6;

Detailed Description of the Invention

The term "estrogen" is intended to include all compounds (natural or synthetic, steroidal or non-steroidal) with estrogenic activity. These compounds include, in particular, conjugated estrogens, estrogen receptor-specific agonists, and non-steroidal compounds with estrogenic activity. The term is also intended to include all isomeric and physical forms of the estrogen, including hydrates, solvates, salts, and complexes, such as complexes with cyclodextrins. More specifically, the estrogen can be selected from 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 sulfate, equilenin sulfate, 17β-dihydroequilenin sulfate, and 17α-dihydroequilenin sulfate. Particularly interesting estrogens are selected from ethinylestradiol, estradiol, estradiol sulfamate, estradiol valerate, estradiol benzoate, estrone, mestranol and estrone sulfate. More preferably, the estrogen is selected from ethinylestradiol, estradiol and mestranol. The most preferred estrogen is ethinylestradiol.

In the context of this invention, the term "progestogen" (sometimes also referred to as "progestagen") covers synthetic hormone compounds that exert antiestrogenic (opposing the effects of estrogens in the body) and antigonadotropic (suppressing the production of sex steroids and gonads) properties. Specific examples of progestogens include, but are not limited to, progestogens selected from the group consisting of levonorgestrel, norgestrel, norethisterone, dienogest, norethisterone acetate, norethindrone diacetate, dydrogesterone, medroxyprogesterone acetate, norethisterone, allylestradiol, linegestrel, vindesone acetate, medrogestone, norgestrel, demethinone, ethinylestradiol, chlormadinone acetate, megestrol acetate, promegestone, desogestrel, 3-keto-desogestrel, norgestimate, gestodene, tibolone, cyproterone acetate, and drospirenone. A particularly preferred progestogen is drospirenone.

The term "therapeutically equivalent amount of ethinylestradiol" refers to an amount of another estrogen that produces the same therapeutic effect as a specific amount of ethinylestradiol. Similarly, the term "therapeutically equivalent amount of drospirenone" refers to an amount of another progestogen that produces the same therapeutic effect as a specific amount of drospirenone. For those skilled in the art, determining the therapeutically equivalent amount or dosage of these other estrogens and/or progestogens is routine when the effective dose of ethinylestradiol and/or drospirenone is known. For example, the paper by Timmer and Geurts provides guidance on how to determine equivalent doses (see "Bioequivalence assessment of three different estradiol formulations in postmenopausal women in an open, randomized, single-dose, 3-way cross-over", in European Journal of Drug Metabolism and Phannacokinetics, 24(1): 47-53, 1999). In addition, reference may be made to EP 1253607, which provides a detailed description of therapeutically equivalent amounts of ethinylestradiol and estradiol on the one hand and of therapeutically equivalent amounts of various progestogens on the other hand. For further details on determining equivalent doses of various estrogens and progestins, reference is made to "Probleme der Dosisfindung: Sexualhormone" [Problems of Dose-Finding: Sex Hormones]; F. Neumann et al., in "Arzneimittelforschung" (Pharmaceutical Agent Research) 27, 2a, 296-318 (1977), and "Aktuelle Entwicklungen in der honnonalen Kontrazeption" [Current Developments in Hormonal Conraception]; H. Kuhl, in [Gynecologist] 25: 231-240 (1992).

As used herein, the term "micronized" means a particle size distribution such that at least 90% of the particles have a particle size of less than 30 μm (calculated from the volume distribution curve under the assumption of spherical particles), i.e., a _d90 value of up to 30 μm. Therefore, it is important to note that whenever "particle size distribution,""particlesize,"" _d90 ," etc. are used herein, it should be understood that the specific value or range used therewith always refers to that determined from the volume distribution curve under the assumption of spherical particles.

It will be understood from this disclosure, including the examples provided herein, that what is most important is that the estrogen and the progestin are released in a rapid and reliable manner under neutral or acidic conditions. Therefore, in the context of this invention, when used in conjunction with the term estrogen, the term "rapid release" or "immediate release" means that at least 70% of the estrogen, such as ethinyl estradiol, is dissolved from the composition within 30 minutes, as determined according to USP XXIX Paddle Method II, using 37°C water or 0.1N HCl as the dissolution medium and 50 rpm as the stirring speed. In a preferred embodiment of the invention, at least 75%, more preferably at least 80%, even more preferably at least 85% of the estrogen, such as ethinyl estradiol, is dissolved from the composition within 30 minutes, when determined as described above.

In a similar manner, whenever the term "fast release" or "immediate release" is used in conjunction with the term progestogen, it means that at least 70% of the progestogen, such as drospirenone, is dissolved from the composition within 30 minutes, as measured according to USP XXIX Paddle Method II using water at 37°C or 0.1N HCl as the dissolution medium and a stirring speed of 50 rpm. In a preferred embodiment of the present 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 measured as described above.

Likewise, whenever the term "fast release" or "immediate release" is used in conjunction with the term tetrahydrofolic acid, it means that at least 70% of the tetrahydrofolic acid, such as 5-methyl-(6S)-tetrahydrofolate calcium, is dissolved from the composition within 30 minutes as determined according to USP XXIX Paddle Method II using 0.03% aqueous ascorbic acid (adjusted to pH 3.5 with 0.05 M phosphate buffer) at 37° C. and a stirring speed of 50 rpm. In a preferred embodiment of the present invention, at least 75%, more preferably at least 80%, even more preferably at least 85% or at least 90% of the tetrahydrofolic acid, such as 5-methyl-(6S)-tetrahydrofolate calcium, is dissolved from the composition within 30 minutes when determined as described above.

The term "granular composition" refers to a composition of a powder wherein the particle size of the powder increases upon processing with a liquid or compression. The liquid may be any suitable aqueous or organic solvent or mixture thereof, optionally further comprising a binder. Thus, the term "granular composition" covers granules, pellets and compressed powders or any particles formed by granulation, pelletization or compression of a powder to form an average particle size ( _d50 ) of at least about 100 μm.

The terms "granulating" and "granulation" are understood to mean a mechanical process whereby a powder comprising an active ingredient and an excipient is partially agglomerated into particles and/or granules having a particle size greater than that of the unprocessed powder. In one embodiment, the powdery mixture is contacted with a granulation liquid which may contain a binder, swells, and is partially or completely dissolved in the granulation liquid. The granulation liquid may be any suitable solvent, but generally an aqueous solution or simply water is suitable. In one embodiment, the powdery mixture is contacted with the granulation liquid using a suitable apparatus for wet granulation, such as a fluidized bed apparatus. In addition, high shear granulation may be used instead of fluidized bed granulation.

The term "estrogen-cyclodextrin complex" or "estrogen complexed with cyclodextrin" means a complex between an estrogen and a cyclodextrin, wherein the estrogen molecule is at least partially inserted into the cavity of the cyclodextrin molecule. The ratio between the estrogen and the cyclodextrin can be adjusted to any desired value. In an interesting embodiment of the present invention, the molar ratio between the estrogen and the cyclodextrin is about 2:1-1:10, preferably about 1:1-1:5, and most preferably about 1:1-1:3, such as 1:1 or 1:2. In addition, the estrogen molecule can be at least partially inserted into the cavity of two or more cyclodextrin molecules, for example, a single estrogen molecule can be inserted into two cyclodextrin molecules so that the ratio between the cyclodextrin and the estrogen is 2:1. Similarly, the complex can contain more than one estrogen molecule at least partially inserted into a single cyclodextrin molecule, for example, two estrogen molecules can be at least partially inserted into a single cyclodextrin molecule so that the ratio between the cyclodextrin and the estrogen is 1:2. The complex between estrogen and cyclodextrin can be obtained by methods known in the art, for example as described in US Pat. No. 5,798,338 and EP 1,353,700.

The term "ethinylestradiol-β-cyclodextrin complex" refers to a complex between ethinylestradiol and β-cyclodextrin at any molar ratio. However, the ethinylestradiol-β-cyclodextrin complex described herein is typically a complex between one ethinylestradiol molecule and two β-cyclodextrin molecules, i.e., a 1:2 ethinylestradiol-β-cyclodextrin complex.

The term "progestogen-cyclodextrin complex" or "progestogen complexed with cyclodextrin" means a complex between a progestogen and a cyclodextrin, wherein the progestogen molecule is at least partially inserted into the cavity of the cyclodextrin molecule. The ratio between the progestogen and the cyclodextrin can be adjusted to any desired value. In an interesting embodiment of the present invention, the molar ratio between the progestogen and the cyclodextrin is about 2:1-1:10, preferably about 1:1-1:5, and most preferably about 1:1-1:3. In addition, the progestogen molecule can be at least partially inserted into the cavity of two or more cyclodextrin molecules, for example, a single progestogen molecule can be inserted into two cyclodextrin molecules so that the ratio between cyclodextrin and progestogen is 2:1. Likewise, the complex can contain more than one progestogen molecule at least partially inserted into a single cyclodextrin molecule, for example, two progestogen molecules can be at least partially inserted into a single cyclodextrin molecule so that the ratio between cyclodextrin and progestogen is 1:2. The complex between the progestogen and the cyclodextrin can be obtained by methods known in the art, for example as described in US 6610670 and references therein.

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

The term "cyclodextrin" refers to cyclodextrin or its derivatives, as well as mixtures of various cyclodextrins, mixtures of various cyclodextrin derivatives, and mixtures of various cyclodextrins and their derivatives. The cyclodextrin can be selected from α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, and their derivatives. The cyclodextrin can be modified so that some or all of the primary or secondary hydroxyl groups of the macrocycle are alkylated or acylated. Methods for modifying these hydroxyl groups are well known to those skilled in the art, and many of these modified cyclodextrins are commercially available. Thus, some or all of the hydroxyl groups of the cyclodextrin can be substituted with OR groups or OC(O)-R groups, where R is an optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted aryl, or heteroaryl group. Thus, R can be methyl, ethyl, propyl, butyl, pentyl, or hexyl, i.e., OC(O)-R can be acetate. Furthermore, the hydroxyl groups may be per-benzylated, per-benzoylated, benzylated, or benzoylated on only one side of the macrocycle, i.e., only 1, 2, 3, 4, 5, or 6 hydroxyl groups are benzylated or benzoylated. Of course, the hydroxyl groups may also be per-alkylated, per-acylated (e.g., per-methylated or per-acetylated), alkylated, or acylated (e.g., methylated or acetylated) on only one side of the macrocycle, i.e., only 1, 2, 3, 4, 5, or 6 hydroxyl groups are alkylated or acylated, e.g., methylated or acetylated.

It will be appreciated that the solid compositions of the present invention comprise at least one (e.g., one) estrogen as defined above. The estrogen may be selected from the group consisting of ethinylestradiol, estradiol, estradiol sulfamate, estradiol valerate, estradiol benzoate, estrone, mestranol, and estrone sulfate, including micronized forms thereof. In a highly preferred embodiment of the present invention, the estrogen is ethinylestradiol, especially micronized ethinylestradiol. In one embodiment of the present invention, the estrogen, especially ethinylestradiol, is complexed with a cyclodextrin, such as described in EP 1353700. The cyclodextrin is typically selected from α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, and derivatives thereof. In particularly interesting embodiments of the present invention, the cyclodextrin is β-cyclodextrin or a derivative thereof. The estrogen-cyclodextrin complex may advantageously be in micronized form.

In addition, the solid composition of the present invention comprises at least one (e.g., one) progestogen as defined above. The progestogen may be selected from the group consisting of levonorgestrel, norgestrel, norethisterone, norethindrone acetate, dienogest, norethindrone diacetate, dydrogesterone, medroxyprogesterone acetate, norgestrel, allylestradiol, linegestrel, vindecyl acetate, medrogestrel, norgestrel, demethinone, ethinylestradiol, chlormadinone acetate, megestrol acetate, promegestone, desogestrel, 3-keto-desogestrel, norgestimate, gestodene, tibolone, cyproterone acetate, and drospirenone. In a preferred embodiment of the present invention, the progestogen is selected from the group consisting of levonorgestrel, norgestrel, norethindrone, norethindrone acetate, dienogest, norethindrone diacetate, desogestrel, norgestimate, gestodene, cyproterone acetate, and drospirenone. In a highly preferred embodiment of the invention, the progestogen is drospirenone, especially micronized drospirenone.

Thus, in a preferred embodiment of the present invention, the composition comprises levonorgestrel and ethinylestradiol, norgestrel and ethinylestradiol, norethindrone and ethinylestradiol, norethindrone acetate and ethinylestradiol, dienogest and ethinylestradiol, norethindrone diacetate and ethinylestradiol, desogestrel and ethinylestradiol, norgestimate and ethinylestradiol, gestodene and ethinylestradiol, cyproterone acetate and ethinylestradiol and drospirenone and ethinylestradiol. In a highly preferred embodiment of the present invention, the composition comprises drospirenone and ethinylestradiol, more preferably micronized drospirenone and micronized ethinylestradiol, for example micronized drospirenone and micronized ethinylestradiol-cyclodextrin complex, for example micronized drospirenone and micronized ethinylestradiol-β-cyclodextrin complex.

In addition to the estrogen and progestogen, the composition of the present invention also comprises tetrahydrofolic acid or a salt thereof. Specific examples of these tetrahydrofolic acids include: 5-methyl-(6S)-tetrahydrofolic acid, (6S)-tetrahydrofolic acid, 5-formyl-(6S)-tetrahydrofolic acid, 10-formyl-(6R)-tetrahydrofolic acid, 5,10-methylene-(6R)-tetrahydrofolic acid, 5-iminomethyl-(6S)-tetrahydrofolic acid, including pharmaceutically acceptable salts of these tetrahydrofolic acids and glutamyl derivatives of these tetrahydrofolic acids. In a preferred embodiment of the present invention, the tetrahydrofolic acid is 5-methyl-(6S)-tetrahydrofolic acid or a pharmaceutically acceptable salt thereof. In a more preferred embodiment of the present invention, the salt of 5-methyl-(6S)-tetrahydrofolic acid is an alkaline earth metal salt, especially a calcium salt. The salt of 5-methyl-(6S)-tetrahydrofolic acid, such as the calcium salt, should preferably be in crystalline form, such as the Type I crystalline form described in US Pat. No. 6,441,168. The Type I crystalline form of 5-methyl-(6S)-tetrahydrofolic acid calcium is commercially available from Merck KGaA under the trade name Calcium Hydroxide. Preferably, the composition of the present invention does not contain other vitamins, and in particular, the composition of the present invention does not contain B vitamins, such as vitamin B6 and/or vitamin B12. Therefore, in a preferred embodiment of the present invention, the composition comprises tetrahydrofolic acid as the sole vitamin component.

The solid pharmaceutical composition of the present invention comprises one or more pharmaceutically acceptable excipients. These excipients can be, for example:

- inert diluents or fillers,

The inert diluent or filler is present in an amount of 50-99% by weight of the composition. Preferably, the inert diluent or filler is present in an amount of 75-99% by weight of the composition, more preferably in an amount of 80-97% by weight of the composition, and most preferably in an amount of 85-97% by weight of the composition. As will be appreciated from the examples provided herein, highly preferred inert fillers are lactose, especially lactose monohydrate and microcrystalline cellulose.

Therefore, in a preferred embodiment, the composition of the present invention comprises lactose monohydrate, microcrystalline cellulose or a combination of lactose monohydrate and microcrystalline cellulose in the amounts shown above. Therefore, in an interesting embodiment of the present invention, the composition comprises microcrystalline cellulose. The microcrystalline cellulose is usually present in an amount of 10-99% of the weight of the composition, preferably in an amount of 50-99% of the weight of the composition, more preferably in an amount of 75-99% of the weight of the composition, even more preferably in an amount of 80-97% of the weight of the composition, most preferably in an amount of 85-97% of the weight of the composition. The microcrystalline cellulose can be the only or sole filler present in the composition, i.e., the composition of the present invention may not contain other fillers except microcrystalline cellulose. In another interesting embodiment of the present invention, the composition comprises lactose monohydrate. The lactose monohydrate is typically present in an amount of 10-99% by weight of the composition, preferably in an amount of 50-99% by weight of the composition, more preferably in an amount of 75-99% by weight of the composition, even more preferably in an amount of 80-97% by weight of the composition, and most preferably in an amount of 85-97% by weight of the composition. The lactose monohydrate may be the only or sole filler present in the composition, i.e. the composition of the present invention may contain no other fillers other than lactose monohydrate. In a highly preferred embodiment of the present invention, the composition comprises microcrystalline cellulose and lactose monohydrate. The microcrystalline cellulose is typically present in an amount of 20-80% by weight of the composition and the lactose monohydrate is typically present in an amount of 20-80% by weight of the composition. In one embodiment of this aspect of the invention, microcrystalline cellulose constitutes the major portion of the microcrystalline cellulose-lactose monohydrate filler system, i.e., the composition comprises 20-60% lactose monohydrate by weight of the composition and 40-80% microcrystalline cellulose by weight of the composition, for example 20-45% lactose monohydrate by weight of the composition and 40-70% microcrystalline cellulose by weight of the composition, for example 25-36% lactose monohydrate by weight of the composition and 52-63% microcrystalline cellulose by weight of the composition. The microcrystalline cellulose and lactose monohydrate may be the only fillers present in the composition, i.e., the composition of the invention may be free of fillers other than microcrystalline cellulose and lactose monohydrate. In another and presently preferred embodiment of this aspect of the invention, lactose monohydrate constitutes the major portion of the microcrystalline cellulose-lactose monohydrate filler system, i.e., the composition comprises 20-60% microcrystalline cellulose by weight of the composition and 40-80% lactose monohydrate by weight of the composition. More preferably, the composition comprises 20-45% microcrystalline cellulose by weight of the composition and 40-70% lactose monohydrate by weight of the composition. Most preferably, the composition comprises 25-36% microcrystalline cellulose by weight of the composition and 52-63% lactose monohydrate by weight of the composition. The microcrystalline cellulose and lactose monohydrate may be the only fillers present in the composition, i.e., the composition of the present invention may contain no fillers other than microcrystalline cellulose and lactose monohydrate.

Microcrystalline cellulose is commercially available in various grades of particle size and moisture content. Examples of commercially available microcrystalline cellulose formulations include the PH-series from FMC Biopolymer, the M-series from Penwest Pharmaceuticals Co., and the -series from Rettenmaier & GmbH. A particularly preferred commercial product for the purposes described herein is PH-101. Similarly, various lactose monohydrate grades with different physical properties, such as particle size distribution and flow characteristics, are commercially available. The grade of lactose monohydrate can vary depending on the specific dosage form to be prepared. For example, direct compression grades of lactose monohydrate such as (agglomerated) or grades used for powder blends such as DCL 11 (spray-dried) have better flow properties and are more compressible than powdered or crystalline lactose monohydrate. These lactose monohydrate formulations are not particularly preferred for the purposes described herein. Instead, more refined grades of lactose monohydrate are preferred, such as powdered or crystalline lactose monohydrate, especially crystalline lactose monohydrate in which 90% of the particles have a diameter of less than 0.1 mm.

- adhesives,

For example, sucrose, glucose, sorbitol, gum arabic, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, magnesium aluminum silicate, sodium carboxymethylcellulose (CMC sodium), methylcellulose, ethylcellulose, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinyl acetate or polyethylene glycol. Binders are generally present in an amount of 0.1-10% of the composition weight. Preferably, the binder is present in an amount of 0.2-5% of the composition weight, for example, in an amount of 0.5-5% of the composition weight, more preferably in an amount of 1-3% of the composition weight. In a preferred embodiment of the present invention, the binder is HPC. It should be noted that although polyvinylpyrrolidone (PVP) is "selective binder" in many cases, especially when combined with wet granulation process, due to the oxidative potential of the excipient, it is undesirable to add PVP to the composition of the present invention. In fact, the present inventors found that PVP accelerated the decomposition of 5-methyl-(6S)-tetrahydrofolate (data not shown).

Therefore, due to the degradation of oxidation-sensitive tetrahydrofolate, the amount of PVP in the compositions of the present invention should be kept to an absolute minimum and should preferably be avoided. Thus, the compositions of the present invention typically comprise less than 2% PVP by weight of the composition, preferably less than 1% PVP by weight of the composition, and more preferably less than 0.5% PVP by weight of the composition. Most preferably, the compositions of the present invention are substantially free of PVP.

- Lubricants, including glidants and anti-binding agents,

The lubricant may be a lubricant comprising a lubricant having a weight of 0.1-10%, preferably a lubricant having a weight of 0.2-5%, more preferably a lubricant having a weight of 1-3%, or a combination thereof. In a preferred embodiment of the present invention, the lubricant is a lubricant comprising a lubricant having a weight of 0.5-5%, more preferably a lubricant having a weight of 1-3%, or a combination thereof.

- disintegrants,

For example, sodium starch glycolate, corn starch, rice starch, potato starch, cross-linked povidone or carboxymethylcellulose disintegrants. The carboxymethylcellulose disintegrant may be present as a free acid, but is preferably in the form of a salt, for example, in the form of an alkali metal salt, such as a potassium salt or a sodium salt, especially a sodium salt, or in the form of a salt of a divalent metal ion, such as a magnesium salt, a calcium salt or a zinc salt, especially a calcium salt. The carboxymethylcellulose disintegrant may be cross-linked or non-cross-linked. Specific examples of preferred non-cross-linked carboxymethylcellulose disintegrants include: carboxymethylcellulose calcium (carboxymethylcellulose calcium) and carboxymethylcellulose sodium (carboxymethylcellulose sodium), especially carboxymethylcellulose calcium. In a highly preferred embodiment of the present invention, the carboxymethylcellulose disintegrant is cross-linked. A specific example of a preferred cross-linked carboxymethylcellulose disintegrant is cross-linked carboxymethylcellulose sodium (croscarmellose sodium). Croscarmellose sodium is commercially available under the trade name CROSS-LINK. The disintegrant is typically present in an amount of 0.1-10% by weight of the composition. Preferably, the disintegrant is present in an amount of 0.2-5% by weight of the composition, such as 0.5-5% by weight of the composition, more preferably 1-4% by weight of the composition.

- surfactants and wetting agents,

For example, naturally occurring phospholipids, such as lecithin or soy lecithin; condensation products of ethylene oxide with, for example, fatty acids, long-chain fatty alcohols, or partial esters derived from fatty acids and hexitol or hexitol anhydrides, such as polyoxyethylene stearate, polyoxyethylene sorbitol monooleate, polyoxyethylene sorbitan monooleate, etc.; or salts of long-chain aliphatic phosphates, such as sodium lauryl sulfate.

Examples of other pharmaceutically acceptable excipients that may be incorporated into the solid pharmaceutical composition of the present invention include colorants, flavorings, plasticizers, humectants, buffers, and the like.

In case the pharmaceutical preparation is in the form of a solid oral dosage form, in particular a solid unit dosage form, such as a tablet, sachet or capsule, in particular a tablet, the dosage form is suitable for oral administration and may have a coating, such as a film coating, a sugar coating, etc. Thus, a coating suitable for the dosage form of the invention may be, for example, a sugar coating or a film coating based on one or more of the following ingredients: hydroxypropylmethylcellulose (HPMC), methylcellulose, ethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, acrylate polymers (for example), polyethylene glycol or polyvinylpyrrolidone.

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

Uncoated tablets typically have a weight of 50-150 mg, such as 60-125 mg, for example 60-100 mg, preferably 70-90 mg, for example about 80 mg.

The dosage form typically comprises an amount of the progestogen equivalent to 0.25-4 mg of therapeutically equivalent drospirenone, for example an amount equivalent to 1-4 mg of therapeutically equivalent drospirenone, for example an amount equivalent to 2-4 mg of therapeutically equivalent drospirenone, preferably an amount equivalent to 2.5-3.5 mg of therapeutically equivalent drospirenone, most preferably an amount equivalent to about 3 mg of therapeutically equivalent drospirenone. As discussed above, the progestogen may be complexed with a cyclodextrin.

Furthermore, the solid oral dosage form typically comprises an amount of estrogen equivalent to 0.005-0.05 mg of therapeutically equivalent ethinyl estradiol, for example, an amount equivalent to 0.01-0.05 mg of therapeutically equivalent ethinyl estradiol, preferably an amount equivalent to 0.015-0.035 mg of therapeutically equivalent ethinyl estradiol, and most preferably an amount equivalent to about 0.02 mg or about 0.03 mg of therapeutically equivalent ethinyl estradiol. As discussed above, the estrogen can be complexed with a cyclodextrin.

Thus, in a particularly interesting embodiment of the present invention, the dosage form comprises 0.25-4 mg drospirenone and 0.005-0.05 mg ethinylestradiol, for example 1-4 mg drospirenone and 0.005-0.05 mg ethinylestradiol, for example 2-4 mg drospirenone and 0.01-0.05 mg ethinylestradiol, preferably 2.5-3.5 mg drospirenone and 0.015-0.035 mg ethinylestradiol, more preferably about 3 mg drospirenone and about 0.03 mg ethinylestradiol, or about 3 mg drospirenone and about 0.02 mg ethinylestradiol.

Although the preferred progestogen is drospirenone, the incorporation of other progestogens is within the scope of the present invention. More specifically, the dosage form may comprise: desogestrel in an amount of 0.05-0.5 mg, preferably 0.075-0.25 mg, such as 0.1 mg, 0.125 mg or 0.15 mg; norethindrone diacetate in an amount of 0.25-2 mg, preferably 0.75-1.5 mg, such as 1 mg; levonorgestrel in an amount of 0.025-0.3 mg, preferably 0.075-0.25 mg, such as 0.1 mg or 0.15 mg; norethindrone in an amount of 0.2-1.5 mg, preferably 0.3-1.25 mg, such as 0.4 mg, 0.5 mg or 1 mg; norethindrone acetate in an amount of 0.5-2 mg, preferably The present invention also provides a method for preparing an estrogen containing 1 to 1.5 mg, such as 1 mg or 1.5 mg; norgestrel in an amount of 0.1 to 1 mg, preferably 0.25 to 0.75 mg, such as 0.3 mg or 0.5 mg; norgestimate in an amount of 0.1 to 0.5 mg, preferably 0.15 to 0.3 mg, such as 0.18 mg, 0.215 mg or 0.25 mg; cyproterone acetate in an amount of 1 to 2 mg, preferably 2 mg; dienogest in an amount of 2 to 3 mg, preferably 2 mg; gestodene in an amount of 0.05 to 0.1 mg, preferably 0.06 to 0.075 mg, such as 0.075 mg; and tibolone in an amount of 2 to 3 mg, such as 2.5 mg. Similarly, although the preferred estrogen is ethinylestradiol, the incorporation of other estrogens is also within the scope of the present invention. More specifically, the dosage form may contain: estradiol in an amount of 1-4 mg or mestranol in an amount of 0.01-0.1 mg, preferably 0.025-0.075 mg, for example 0.05 mg. The following table gives specific examples of progestogen-estrogen combinations, including preferred dosages:

The solid oral dosage form typically comprises tetrahydrofolic acid in an amount of 0.1-5 mg, for example 0.1-2.5 mg, for example 0.2-0.8 mg, preferably 0.3-0.7 mg, more preferably 0.4-0.6 mg, and most preferably 0.42-0.49 mg. As explained above, the tetrahydrofolic acid is preferably 5-methyl-(6S)-tetrahydrofolic acid or a pharmaceutically acceptable salt thereof, for example an alkaline earth metal salt, especially a calcium salt. Salts of the 5-methyl-(6S)-tetrahydrofolic acid, such as the calcium salt, should preferably be in crystalline form, for example the Type I crystalline form described in US6441168.

The various excipients can be incorporated into the dosage form of the present invention in the amounts shown above. However, in an interesting embodiment of the present invention, the dosage form comprises microcrystalline cellulose, lactose monohydrate, or a combination of microcrystalline cellulose and lactose monohydrate. Therefore, in an interesting embodiment of the present invention, the dosage form comprises 5-80 mg of microcrystalline cellulose, for example, 10-80 mg of microcrystalline cellulose. Preferably, the dosage form comprises 40-80 mg of microcrystalline cellulose. More preferably, the dosage form comprises 60-80 mg of microcrystalline cellulose. Even more preferably, the dosage form comprises 65-80 mg of microcrystalline cellulose. Most preferably, the dosage form comprises 65-77 mg of microcrystalline cellulose. The microcrystalline cellulose may be the only or sole filler present in the dosage form, i.e., the dosage form of the present invention may not contain other fillers other than microcrystalline cellulose. In another interesting embodiment of the present invention, the dosage form comprises 5-80 mg of lactose monohydrate, for example, 10-80 mg of lactose monohydrate. Preferably, the dosage form comprises lactose monohydrate in an amount of 40-80 mg. More preferably, the dosage form comprises lactose monohydrate in an amount of 60-80 mg. Even more preferably, the dosage form comprises lactose monohydrate in an amount of 65-80 mg. Most preferably, the dosage form comprises lactose monohydrate in an amount of 65-77 mg. The lactose monohydrate may be the only or sole filler present in the dosage form, i.e., the dosage form of the present invention may not contain any other filler other than lactose monohydrate. In a highly interesting embodiment of the present invention, the dosage form comprises 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, microcrystalline cellulose constitutes the major part of the microcrystalline cellulose-lactose monohydrate filler system, i.e., the dosage form comprises lactose monohydrate in an amount of 15-50 mg and microcrystalline cellulose in an amount of 25-65 mg. Even more preferably, the dosage form comprises lactose monohydrate in an amount of 15-35 mg and microcrystalline cellulose in an amount of 30-55 mg. Most preferably, the dosage form comprises lactose monohydrate in an amount of 20-30 mg and microcrystalline cellulose in an amount of 40-50 mg. In another and currently preferred embodiment of this aspect of the invention, lactose monohydrate constitutes the major portion of the microcrystalline cellulose-lactose monohydrate filler system, i.e., the dosage form comprises microcrystalline cellulose in an amount of 15-50 mg and lactose monohydrate in an amount of 25-65 mg. Even more preferably, the dosage form comprises microcrystalline cellulose in an amount of 15-35 mg and lactose monohydrate in an amount of 30-55 mg. Most preferably, the dosage form comprises microcrystalline cellulose in an amount of 20-30 mg and lactose monohydrate in an amount of 40-50 mg.

The inventors have surprisingly found that the problems concerning the stability of tetrahydrofolic acid and the problems associated with obtaining a rapid release of the progestogen from tablets prepared by direct compression can in fact be solved at least in part by preparing the composition by granulation, i.e., in a preferred embodiment, the composition of the invention is a granular composition. Due to the exposure to mechanical stress and humidity during the granulation process, the skilled person would not attempt to prepare a composition comprising tetrahydrofolic acid by granulation, as he would expect that tetrahydrofolic acid, which is sensitive to air and moisture, would degrade significantly under these preparation conditions. However, the inventors have challenged this prejudice and, by combining appropriate selection of excipients with granulation, have found that a stable (for tetrahydrofolic acid) granular composition can be obtained, which simultaneously meets the necessary requirements for a rapid release of both the estrogen and the progestogen.

Therefore, from the above discussion and the examples provided herein, it will be understood that the compositions of the present invention are preferably prepared by a granulation process, i.e., a granulation process is performed on the drug substance, including tetrahydrofolic acid, together with appropriate excipients, preferably a wet granulation process, such as a fluidized bed granulation process. Therefore, in a preferred embodiment, the composition of the present invention is a granular composition. After the granulation process, the granules can be further processed into the final dosage form. In one embodiment of the present invention, the granules can be filled into sachets or capsules, such as hard gelatin capsules. However, in a preferred embodiment of the present invention, the granules are processed into tablets by tableting and then film coating. It will be understood that, in one embodiment of the present invention, the tetrahydrofolic acid can be added before or during the granulation process. In this case, the tetrahydrofolic acid can be considered an "internal phase" component because it thus forms part of the granules. In another embodiment of the present invention, the tetrahydrofolic acid is added to the granules at the end of the granulation process or after the granulation process has been completed, i.e., the tetrahydrofolic acid can be considered an "external component." Thus, the tetrahydrofolic acid may be incorporated into the granules as an "inner phase" component, as an "external phase" component or as a combination thereof. In a preferred embodiment of the present invention, the tetrahydrofolic acid is present as an "external phase" component.

Therefore, the present invention also relates to a process for preparing the composition of the present invention, said process comprising the steps of:

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

(ii) mixing tetrahydrofolic acid or a salt thereof with the granules formed in step (i), and

(iii) optionally continuing the granulation process, and/or

(iv) optionally collecting the particles.

In step (i), the progestogen, the estrogen and at least one pharmaceutically acceptable excipient such as lactose monohydrate, microcrystalline cellulose or their combination are loaded into a granulator, preferably a fluidized bed granulator. Then a granulation liquid that generally comprises a binder such as HPC is applied, and in the case of fluidized bed granulation, the granulation liquid is continuously sprayed onto the fluidized bed while heating the air flow of the fluidized bed. In order to avoid the tetrahydrofolic acid from degrading during the granulation process, it is preferred that the granules formed by the tetrahydrofolic acid or its salt and step (i) are mixed at the end of, near the end of, or after the end of the granulation process. However, if desired, the granulation process can continue after adding the tetrahydrofolic acid. Typically, the granules formed by the disintegrant and lubricant and step (i) are also mixed together with the tetrahydrofolic acid.

The granules obtained by the above method can be further processed into the desired dosage form, for example, by tableting. Therefore, in another aspect, the present invention also relates to a method for preparing the solid oral dosage form of the present invention, comprising the following steps:

(i) preparing particles according to the method of the present invention, and

(ii) formulating the granules into a solid oral dosage form.

Although the composition of the present invention is preferably a granular composition that can subsequently be processed into the desired dosage form, it is contemplated that in the case of a low-dose progestogen dosage form, the problem of rapid release of the active ingredient is not as significant as when a higher dose of the progestogen, in particular drospirenone, is required in the dosage form. The present invention therefore also relates to tablets, in particular tablets prepared by direct compression, comprising a progestogen, an estrogen, tetrahydrofolic acid or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient or carrier, wherein the amount of the progestogen is 0.025-1.5 mg, for example 0.025-1 mg, 0.05-1 mg, 0.075-0.75 mg or 0.1-0.5 mg. It will be understood that all the statements made above, in particular with regard to preferred excipients, preferred progestogens, preferred estrogens, preferred tetrahydrofolic acid and the relative amounts of these components, apply mutatis mutandis to this aspect of the invention.

Furthermore, while the compositions of the present invention preferably contain a progestogen as well as an estrogen, it will be appreciated that compositions and dosage forms can be prepared according to the present invention that do not contain estrogen. An example of such a dosage form is a ® (also known as a "mini-pellet"), which contains 0.03 mg of levonorgestrel without estrogen. Thus, in another aspect, the present invention relates to a solid pharmaceutical composition comprising a progestogen, tetrahydrofolic acid or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient or carrier. It will be appreciated that all of the above descriptions, in particular with respect to preferred excipients, preferred progestogens, preferred tetrahydrofolic acid, and the relative amounts of these components, apply mutatis mutandis to this aspect of the invention.

With regard to the stability of tetrahydrofolic acid, the normal specification limits for active ingredients must apply. A suitable reference is USP XXIX monograph "Folic Acid Tablets", which stipulates that 90-115% of the labeled amount of folic acid must be subsequently detectable in the product. The compositions and dosage forms provided by the present invention meet the above regulatory requirements. In other words, the composition or dosage form of the present invention has stability such that after storage in a sealed container at 25°C and 60% relative humidity for 24 months, at least 80% of the initial amount of tetrahydrofolic acid is present in the composition or dosage form. Additionally, or alternatively, the composition or dosage form of the present invention has stability such that after storage in a sealed container at 25°C and 60% relative humidity for 12 months, at least 90%, preferably at least 95%, of the initial amount of tetrahydrofolic acid is present in the composition or dosage form. In the present context, the term "initial content" when used in conjunction with tetrahydrofolic acid refers to the measured amount of tetrahydrofolic acid measured immediately after preparation of the composition or dosage form, or alternatively, immediately after storage for no more than 5 days in a sealed container at 25°C and 60% relative humidity. Therefore, the term "initial content" refers neither to the labeled amount of tetrahydrofolic acid nor to the theoretical amount (added amount) of tetrahydrofolic acid, but rather to the measured amount of tetrahydrofolic acid present in the composition or dosage form, as measured immediately after preparation thereof or immediately after short-term storage as described above.

In another embodiment, the composition or dosage form of the present invention has stability such that after 24 months of storage in a sealed container at 25°C and 60% relative humidity, at least 80% of the labeled amount of tetrahydrofolic acid is present in the composition or dosage form. Additionally, or alternatively, the composition or dosage form of the present invention has stability such that after 12 months of storage in a sealed container at 25°C and 60% relative humidity, at least 90%, preferably at least 95%, of the labeled amount of tetrahydrofolic acid is present in the composition or dosage form. In the context of this invention, the term "labeled amount" refers to the officially declared amount of tetrahydrofolic acid present in the composition or dosage form. The labeled amount of tetrahydrofolic acid is generally apparent from the information provided on the label.

In yet another embodiment, the composition or dosage form of the present invention has stability such that after storage in a sealed container at 25°C and 60% relative humidity for 6 months or 12 months, the sum of tetrahydrofolate decomposition products is at most 10%, preferably at most 8%, more preferably at most 6%, even more preferably at most 5%, and most preferably at most 4%. The sum of tetrahydrofolate decomposition products can be determined as described in the section entitled "Determination of Decomposition Products" herein.

In yet another embodiment, the composition or dosage form of the present invention has stability such that after storage in a sealed container at 40°C and 75% relative humidity for 1 month, 2 months, or 3 months, the sum of tetrahydrofolate decomposition products is at most 10%, preferably at most 8%, more preferably at most 6%, even more preferably at most 5%, and most preferably at most 4%. The sum of tetrahydrofolate degradation products can be determined as described in the section entitled "Determination of Decomposition Products" herein.

It will be clear from the disclosure herein that the compositions or dosage forms of the present invention are suitable for inhibiting female ovulation, i.e., for providing female contraception. In addition, due to the presence of tetrahydrofolic acid or its salts, the compositions and dosage forms of the present invention can also be used to treat or prevent folate deficiency, including anemia and bleeding.

In other embodiments, the present invention relates to a pharmaceutical preparation or kit consisting essentially of 21, 22, 23 or 24, in particular 21 or 24, individually packaged and individually removable solid oral dosage units of the present invention placed in a packaging unit, and 7, 6, 5 or 4, in particular 7 or 4, individually packaged and individually removable solid oral dosage units comprising tetrahydrofolic acid as the only active agent placed in a packaging unit.

The dosage form comprising tetrahydrofolic acid as the only active agent can be prepared by any method known in the art, so long as the tetrahydrofolic acid still meets the stability criteria discussed herein. In one embodiment, the dosage form comprising tetrahydrofolic acid as the only active agent is substantially the same as the dosage form described herein, but does not comprise a progestogen and an estrogen.

The formulation (or kit) may be a monophasic formulation, i.e., a formulation in which the amounts of the progestogen and estrogen remain constant over a period of 21, 22, 23, or 24 days. Alternatively, the amounts of one or both active agents (i.e., the progestogen and estrogen) may be varied over a period of 21, 22, 23, or 24 days to produce a multiphasic formulation, such as a two- or three-phase formulation, as described, for example, in US 4,621,079. Thus, although the formulation may be a monophasic or multiphasic formulation, the amount of tetrahydrofolate is preferably kept constant over the entire cycle (i.e., all 28 days).

The packaging unit containing the above dosage form can be prepared in a similar manner to that for other oral contraceptives. This can be, for example, a conventional blister pack or any other known form for this purpose, such as a package containing an appropriate number of dosage units (in this case usually 28 or multiples of 28) in a sealed blister pack having a cardboard, paperboard, foil or plastic backing and enclosed in a suitable cover.

Similarly, the compositions or dosage forms of the present invention are also suitable for treating diseases, conditions or symptoms associated with insufficient endogenous levels of estrogen in women. In this case, the above-mentioned progestogen is preferably used in conjunction with an estrogen selected from estradiol, estradiol sulfamate, estradiol valerate, and estradiol benzoate. The specific example of a preferred dosage form comprises 0.25-3 mg drospirenone and 0.5-2 mg estradiol, for example 1-3 mg drospirenone and 0.5-2 mg estradiol, preferably 1.5-2.5 mg drospirenone and 0.5-1.5 mg estradiol, more preferably about 2 mg drospirenone and about 1 mg estradiol. Other examples include compositions or dosage forms comprising estradiol valerate and cyproterone acetate, estradiol valerate and dienogest, ethinylestradiol and gestodene, and ethinylestradiol and levonorgestrel. Insufficient estrogen levels can occur for a variety of reasons. For example, insufficient estrogen levels may be caused by, for example, natural menopause, perimenopause, postmenopause, hypogonadism, castration, or primary ovarian failure. Regardless of the cause, low levels of estrogen lead to an overall decline in a woman's quality of life. Symptoms, diseases, and conditions range from merely inconvenient to life-threatening. The compositions and dosage forms described herein provide effective relief for all physiological and psychological signs of estrogen deficiency. Short-term symptoms such as vasomotor signs and psychological symptoms are certainly included within the scope of the treatment. Vasomotor signs include, but are not limited to, hot flashes, sweating episodes such as night sweats, and palpitations. Psychological symptoms of estrogen deficiency include, but are not limited to, insomnia and other sleep disorders, poor memory, loss of self-confidence, mood changes, anxiety, lack of libido, difficulty concentrating, difficulty making decisions, decreased energy and drive, irritability, and frequent crying spells. Treatment of the above symptoms may be relevant during the perimenopausal stage of a woman's life or after menopause, sometimes long after menopause. It is expected that the compositions and dosage forms described herein are suitable for these and other transient symptoms of perimenopause, menopause, or postmenopause. Furthermore, if the cause of the estrogen deficiency is hypogonadism, castration, or primary ovarian failure, the above symptoms may be alleviated. In another embodiment of the present invention, the compositions or dosage forms described herein are used to treat the permanent effects of estrogen deficiency. Permanent effects include physical changes such as urogenital atrophy, breast atrophy, cardiovascular disease, changes in hair distribution, hair density, changes in skin condition, and osteoporosis. Urogenital atrophy and associated conditions such as vaginal dryness, increased vaginal pH and subsequent changes in the flora, or events leading to such atrophy such as decreased vascularity, elastic fiber disruption, collagen fiber fusion, or decreased cell volume are considered to be particularly relevant symptoms to be treated with the compositions or dosage forms described herein. In addition, the compositions or dosage forms described herein are believed to be associated with other urogenital changes associated with estrogen deficiency, decreased mucus production, changes in cell mass, decreased glycogen production, decreased growth of Lactobacilli, or increased growth of Streptococci, Staphylococci, or Escherichia coli. Other relevant changes that are believed to be preventable by administering the compositions or dosage forms described herein are changes that may make the vagina susceptible to injury or infection (e.g., exudative discharges, vaginitis, and dyspareunia). In addition, urinary tract infections and incontinence are other common symptoms associated with declining estrogen levels. Other embodiments of the present invention include the prevention or alleviation of the body changes associated with estrogen deficiency, such as skin changes, changes in hair distribution, thickening of hair, breast atrophy, or osteoporosis. Osteoporosis, most particularly the prevention and management of postmenopausal osteoporosis, is an especially interesting embodiment of the present invention. In addition, bone demineralization, decreased bone mass and density, trabecular thinning and interruption, and/or the increase in fractures or bone deformations that occur as a result are considered to be particularly relevant. The preventive treatment of osteoporosis is an interesting therapeutic application of the compositions or dosage forms of the present invention. Particularly interesting embodiments of the present invention relate to reducing the frequency, persistence, duration and/or severity of hot flashes, sweating episodes, palpitations, sleep disorders, mood changes, nervousness, anxiety, memory loss, loss of self-confidence, lack of libido, poor concentration, decreased energy, decreased drive, irritability, urogenital atrophy, breast atrophy, cardiovascular disease, changes in hair distribution, hair thickness, changes in skin condition and osteoporosis (including prevention of osteoporosis), most particularly hot flashes, sweating episodes, palpitations, sleep disorders, mood changes, nervousness, anxiety, urogenital atrophy, breast atrophy, and preventing or managing osteoporosis. Another interesting embodiment of the present invention relates to the treatment of hot flashes, sweating episodes, palpitations, sleep disorders, mood changes, nervousness, anxiety, memory loss, loss of self-confidence, lack of libido, poor concentration, decreased energy, decreased drive, irritability, urogenital atrophy, breast atrophy, cardiovascular disease, changes in hair distribution, hair thickness, changes in skin condition, and osteoporosis (including the prevention of osteoporosis), most particularly the treatment of hot flashes, sweating episodes, palpitations, sleep disorders, mood changes, nervousness, anxiety, urogenital atrophy, breast atrophy, and the prevention or management of osteoporosis.

The present invention is further illustrated by the following non-limiting examples.

Materials and methods

Determination of decomposition products

5-Methyl-(6S)-tetrahydrofolate calcium and its degradation were separated and quantified by HPLC on a reverse phase column (Ph. Eur. 2.2.9, USP <621>, JP No. 27) using an external calibration standard. The samples had to be analyzed immediately without delay.

Dissolution

The dissolution rates of ethinyl estradiol and drospirenone were studied by USP XXIX Paddle Method II using water at 37°C as the dissolution medium and a stirring speed of 50 rpm.

The dissolution of 5-methyl-(6S)-tetrahydrofolate calcium was studied by USP XXIX Paddle Method II using 0.03% ascorbic acid in water (adjusted to pH 3.5 with 0.05 M phosphate buffer) at 37°C as the dissolution medium and a stirring speed of 50 rpm.

Example

Example 1 - Direct Compression; Microcrystalline Cellulose

An 80 mg core tablet of the following composition was prepared by direct compression:

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

Table 1: Percentage of total degradation products

Table 2: Amount (%)

It can be seen that even under conditions where the tablets were allowed to be exposed to open air, satisfactory stability of 5-methyl-(6S)-tetrahydrofolate calcium was still achieved at 25°C. In addition, satisfactory stability was achieved at 40°C (closed container), whereas significant degradation of 5-methyl-(6S)-tetrahydrofolate calcium was observed when the tablets were stored at 40°C while exposed to open air. The above stability data are also depicted in Figure 1.

The dissolution profiles are shown in Figure 2. As can be seen from Figure 2, ethinylestradiol and 5-methyl-(6S)-tetrahydrofolate calcium are immediately released from the tablet composition, while the dissolution rate of drospirenone is unsatisfactorily slow. This finding is surprising, especially since the tablet disintegrated within 5 minutes under the conditions used.

Example 2 - Direct Compression; (Lactose Monohydrate/Cellulose Powder)

An 80 mg core tablet of the following composition was prepared by direct compression:

The stability of 5-methyl-(6S)-tetrahydrofolate calcium was tested under various storage conditions. The following stability data (see Tables 3 and 4 below) were obtained when stored at 25°C/60% RH and 40°C/75% RH, respectively. Stability was tested in both open and closed containers.

Table 3: Sum of decomposition products (%)

Table 4: Percentage of

It can be seen that satisfactory stability of 5-methyl-(6S)-tetrahydrofolate calcium was achieved at 25° C. However, like Example 1, the dissolution rate of drospirenone was unsatisfactorily slow.

Example 3 - Direct Compression; (Lactose Monohydrate)

An 80 mg core tablet of the following composition was prepared by direct compression:

The stability of 5-methyl-(6S)-tetrahydrofolate calcium was found to be unsatisfactory when stored at 25°C/60% RH and 40°C/75% RH, respectively. Like Examples 1 and 2, the dissolution of drospirenone was unsatisfactorily slow.

Example 4 - Direct Compression; Microcrystalline Cellulose/Lactose Monohydrate

In order to investigate whether the dissolution rate of drospirenone could be increased, it was decided to prepare tablets according to Example 1, but replacing one-third of the microcrystalline cellulose with lactose monohydrate (although lactose monohydrate has the effect of destabilizing 5-methyl-(6S)-tetrahydrofolate calcium, see Examples 2 and 3).

Therefore, 80 mg core tablets with the following composition were prepared by direct compression:

Satisfactory stability of 5-methyl-(6S)-tetrahydrofolate calcium under various storage conditions was observed.

The dissolution profile is shown in FIG3 , from which it can be seen that the dissolution rate of drospirenone was unsatisfactorily slow, almost identical to the release profile obtained from the tablet prepared in Example 1.

Example 5 - Fluidized Bed Granulation; Microcrystalline Cellulose/Lactose Monohydrate

An 80 mg core tablet having the following composition was prepared:

A granular formulation is prepared by loading drospirenone, ethinylestradiol, lactose monohydrate, and microcrystalline cellulose into a fluidized bed granulator and operating the fluidized bed. An aqueous solution of the binder (HPC) is continuously sprayed onto the fluidized bed while being dried by an airflow that heats the fluidized bed. At the end of the process, 5-methyl-(6S)-tetrahydrofolate calcium, croscarmellose sodium, and magnesium stearate are pumped into the granulator and mixed with the granules while maintaining the fluidized bed. The resulting granules are compressed into tablet cores using a tablet press.

Satisfactory stability of 5-methyl-(6S)-tetrahydrofolate calcium under various storage conditions was observed.

Furthermore, and as can be seen from FIG3 , an immediate release profile of drospirenone was observed, ie the dissolution rate of drospirenone was comparable to the dissolution profile of an oral contraceptive comprising drospirenone.

Example 6 - Fluidized Bed Granulation; Microcrystalline Cellulose

An 80 mg core tablet having the following composition was prepared:

The granular formulation was prepared as described in Example 5. Satisfactory stability of 5-methyl-(6S)-tetrahydrofolate calcium under various storage conditions was observed.

As can be seen from Figure 3, drospirenone is released more slowly from this tablet than from the tablet prepared in Example 5. However, the release of drospirenone is still satisfactory and comparable to that of oral contraceptives containing drospirenone.

Claims (15)

1. A method for preparing a solid oral dosage form, the solid oral dosage form comprising: Progestogen, estrogen, 5-methyl-(6S)-tetrahydrofolic acid or a pharmaceutically acceptable salt thereof and microcrystalline cellulose, wherein The progestogen has an in vitro dissolution rate such that at least 70% dissolves from the solid oral dosage form within 30 minutes as determined by USP XXIX Paddle Method II using water at 37°C as the dissolution medium and a stirring speed of 50 rpm, and The solid oral dosage form does not contain vitamin B12, The method comprises the following steps: (i) performing a granulation process on the progestogen, the estrogen and the microcrystalline cellulose, (ii) mixing 5-methyl-(6S)-tetrahydrofolate or a pharmaceutically acceptable salt thereof with the granules formed in step (i) at or near the end of the granulation process, and (iii) optionally continuing the granulation process, and (iv) formulating the granules into a solid oral dosage form. 2. The method of claim 1, wherein the granulation step is performed by fluidized bed granulation. 3. The method of claim 1 or 2, wherein the progestogen is selected from the group consisting of levonorgestrel, norgestrel, norethindrone, norethisterone acetate, dienogest, norethindrone diacetate, dydrogesterone, medroxyprogesterone acetate, norgestrel, allylestradiol, linegestrel, drenogestrel acetate, methystenol, medrogestone, norgestrel, demethinone, ethinylgestrel, chlormadinone acetate, megestrol acetate, promegestone, desogestrel, 3-keto-desogestrel, norgestimate, gestodene, tibolone, cyproterone acetate, and drospirenone. 4. The method of claim 3, wherein the progestogen is drospirenone. 5. The method according to any one of the preceding claims, wherein the progestogen is micronized. 6. The method of any one of the preceding claims, wherein the estrogen is selected from the group consisting of ethinyl estradiol, estradiol, estradiol sulfamate, estradiol valerate, estradiol benzoate, estrone, mestranol, and estrone sulfate. 7. The method of claim 6, wherein the estrogen is ethinyl estradiol. 8. The method of any one of the preceding claims, wherein the estrogen is micronized. 9. The method of any one of the preceding claims, wherein the progestogen is drospirenone and the estrogen is ethinylestradiol. 10. The method of any one of the preceding claims, wherein the salt of 5-methyl-(6S)-tetrahydrofolate is a calcium salt. 11. The method of claim 10, wherein the calcium salt of 5-methyl-(6S)-tetrahydrofolate is in crystalline form. 12. The method of claim 11, wherein the crystalline form is Form I crystalline form. 13. The method of any one of the preceding claims, wherein the solid oral dosage form is a solid oral unit dosage form. 14. The method of any one of the preceding claims, wherein the solid oral dosage unit is in the form of a tablet, capsule or sachet. 15. The method of claim 14, wherein the solid oral dosage unit is in the form of a tablet.