WO2008003432A1 - Pharmaceutical composition containing a tetrahydrofolic acid - Google Patents

Pharmaceutical composition containing a tetrahydrofolic acid Download PDF

Info

Publication number
WO2008003432A1
WO2008003432A1 PCT/EP2007/005764 EP2007005764W WO2008003432A1 WO 2008003432 A1 WO2008003432 A1 WO 2008003432A1 EP 2007005764 W EP2007005764 W EP 2007005764W WO 2008003432 A1 WO2008003432 A1 WO 2008003432A1
Authority
WO
WIPO (PCT)
Prior art keywords
amount
composition
dosage form
oral dosage
solid oral
Prior art date
Application number
PCT/EP2007/005764
Other languages
French (fr)
Inventor
Kristina King
Original Assignee
Bayer Schering Pharma Aktiengesellschaft
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=36763829&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2008003432(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to CN2007800255704A priority Critical patent/CN101484143B/en
Priority to RU2009103649/15A priority patent/RU2479306C2/en
Priority to MX2009000079A priority patent/MX2009000079A/en
Priority to JP2009517003A priority patent/JP2009542591A/en
Priority to NO20090578A priority patent/NO347567B1/en
Priority to ES07764936T priority patent/ES2626838T5/en
Priority to UAA200900637A priority patent/UA100228C2/en
Priority to AU2007271449A priority patent/AU2007271449B2/en
Priority to EP07764936.6A priority patent/EP2040683B2/en
Priority to NZ573766A priority patent/NZ573766A/en
Priority to KR1020137006954A priority patent/KR20130042638A/en
Priority to BRPI0713565A priority patent/BRPI0713565B8/en
Priority to CA2656131A priority patent/CA2656131C/en
Application filed by Bayer Schering Pharma Aktiengesellschaft filed Critical Bayer Schering Pharma Aktiengesellschaft
Publication of WO2008003432A1 publication Critical patent/WO2008003432A1/en
Priority to IL196027A priority patent/IL196027A0/en
Priority to TNP2008000543A priority patent/TNSN08543A1/en
Priority to CU2009000004A priority patent/CU20090004A7/en
Priority to ZA2009/00868A priority patent/ZA200900868B/en
Priority to HK09111877.6A priority patent/HK1131917A1/en
Priority to PH12012501774A priority patent/PH12012501774A1/en
Priority to IL224484A priority patent/IL224484A/en
Priority to IL245355A priority patent/IL245355B/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/18—Feminine contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/30—Oestrogens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/34—Gestagens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods

Definitions

  • the present invention relates to solid pharmaceutical compositions, in particular to oral 5 contraceptives, comprising a tetrahydrofolic acid, such as calcium 5-methyl-(6S)- tetrahydrofolate.
  • a tetrahydrofolic acid such as calcium 5-methyl-(6S)- tetrahydrofolate.
  • the compositions provided by the present invention allow for good stability of the tetrahydrofolic acid upon storage while still ensuring a fast and reliable release of the estrogen and the progestogen present in the composition.
  • folic acid should ideally be added to oral contraceptives since adequate folic acid intake during the pe ⁇ conceptional period helps protect against a number of congenital malformations, including neural tube defects, such as spina bifida (an incomplete closure of the spinal cord and spinal column), anencephaly (severe underdevelopment of the brain) and
  • incorporation of folic acid in oral contraceptives may pose a serious health risk in 35 that it will suppress symptoms of vitamin B12 deficiency, such as anemia.
  • vitamin B12 deficiency such as anemia.
  • folic acid can correct the anemia associated with vitamin B12 deficiency, but, unfortunately, folic acid will not correct changes in the nervous system that result from vitamin B12 deficiency. Permanent nerve damage could therefore occur if vitamin B12 deficiency is not treated.
  • the present inventor has therefore suggested to incorporate a tetrahydrofolic acid, such as the natural folic acid de ⁇ vate, 5-methyl-(6S)-tetrahydrofohc, which is formed in the rather complicated catabolic pathway of the prodrug folic acid, in an oral contraceptive Incoporation of tetrahydrofolic acids, such as 5-methyl-(6S)- tetrahydrofolic acid, in oral contraceptive could provide all the beneficial effects associated with folic acid, but without the potential disadvantage of masking the anemia of vitamin B12 deficiency.
  • a tetrahydrofolic acid such as the natural folic acid de ⁇ vate, 5-methyl-(6S)-tetrahydrofohc, which is formed in the rather complicated catabolic pathway of the prodrug folic acid
  • tetrahydrofolic acids are extremely unstable and are highly susceptible to oxidation and moisture. Accordingly, incorporation of a tetrahydrofolic acid into solid oral pharmaceuticals, such as oral contraceptives, represents a big challenge from a formulation point of view. Not only should the resulting solid pharmaceutical composition exhibit a satisfactory stability (with respect to the tetrahydrofolic acid) upon storage, but the very manufacture of the composition itself is considered problematic as exposure to oxidising excipients, humidity and/or open air during the manufacturing process are expected to cause degradation of the tetrahydrofolic acid and should hence be avoided.
  • the tetrahydrofolic acid is considered an active ingredient. Therefore, standard stabilisation measures typically used in vitamin supplement products, such as overdosing and broader specification limits, are not applicable in connection with oral contraceptives.
  • Typical overdoses in vitamin supplement products are up to 25% and the dose of Metafohn ® in some vitamin supplement products is from 0.6- 5.6 mg higher than the recommended daily dose (0.45 mg) . Since stability problems are more pronounced when incorporated in pharmaceutical compositions in low concentrations, preparation of stable pharmaceutical compositions containing low dosages of a tetrahydrofolic acid is a challenging task in its own respect.
  • the present inventor has surprisingly, via careful selection of critical excipients and/or manufacturing processes, succeeded in preparing oral contraceptives which, one the one hand, exhibit a satisfactory stability with respect to the tetrahydrofolic acid, and, on the other hand, still fulfil the necessary requirements with respect to release, and hence bioavailability, of the estrogen and the progestogen present in the composition.
  • kits for contraception and hormone replacement therapy which contain one or more steroids, such as estrogens and progestogens; one or more tetrahydrofolate component; and vitamin B12.
  • US 6, 190,693 is directed to pharmaceutical compositions, suitable as oral contraceptive or in hormone replacement therapy, containing folic acid.
  • US 6,011,040 relates to the use of tetrahydrofolates for influencing the homocysteine level, in particular for assisting the remethylation of homocysteine.
  • the present invention relates to a solid pharmaceutical composition
  • a solid pharmaceutical composition comprising a progestogen, an estrogen, a tetrahydrofolic acid or a salt thereof, and at least one pharmaceutical acceptable excipient or carrier.
  • the present invention relates to a solid oral dosage form comprising a composition according to the invention.
  • Fig. 1 shows the stability of calcium 5-methyl-(6S)-tetrahydrofolate in a tablet prepared as described in Example 1.
  • the Y-axis indicates the percentage of calcium 5-methyl-(6S)- tetrahydrofolate remaining after storage, as well as the sum of decomposition products.
  • the X-axis indicates the storage time in months. • 25°C/60% RH (closed container);
  • Fig. 2 shows the dissolution of drospirenone, ethinylestradiol and calcium 5-methyl-(6S)- tetrahydrofolate from the tablets prepared in Example 1.
  • the Y-axis indicates the amount dissolved, and the X-axis indicates the dissolution testing time in minutes.
  • Fig. 3 shows the dissolution of drospirenone from tablets prepared in the Examples.
  • the Y- axis indicates the amount dissolved, and the X-axis indicates the dissolution testing time in minutes.
  • estradien is meant to encompass all compounds (natural or synthetic, steroidal or non-steroidal compounds) exhibiting estrogenic activity. Such compounds encompass inter alia conjugated estrogens, estrogen receptor specific agonists and non-steroidal compounds exhibiting estrogenic activity. The term is further meant to encompass all isomeric and physical forms of the estrogens including hydrates, solvates, salts and complexes, such as complexes with cyclodextrins.
  • the estrogen may be selected from the group consisting of ethinylestradiol, estradiol, estradiol sulfamates, estradiol valerate, estradiol benzoate, estrone, mestranol, est ⁇ ol, estriol succinate and conjugated estrogens, including conjugated equine estrogens such as estrone sulfate, 17 ⁇ - estradiol sulfate, 17 ⁇ -estrad ⁇ ol sulfate, equilin sulfate, 17 ⁇ -d ⁇ hydroequ ⁇ l ⁇ n sulfate, 17 ⁇ - dihydroequihn sulfate, equilenin sulfate, 17 ⁇ -d ⁇ hydroequ ⁇ len ⁇ n sulfate and 17 ⁇ - dihydroequilenin sulfate.
  • conjugated equine estrogens such as estrone sulfate, 17 ⁇ - estradiol sulfate, 17
  • Particular interesting estrogens are selected from the group consisting of ethinylestradiol, estradiol, estradiol sulfamates, estradiol valerate, estradiol benzoate, estrone, mestranol and estrone sulfate. More preferably, the estrogen is selected from the group consisting of ethinylestradiol, estradiol and mestranol. The most preferred estrogen is ethinylestradiol
  • progestogen also sometimes referred to as "gestagen” covers synthetic hormone compounds which exert anti-estrogenic (counteracting the effects of estrogens in the body) and anti-gonadotropic (inhibiting the production of sex steroids and gonads) properties.
  • progestogens include, but is not limited to, progestogens selected from the group consisting of levo-norgestrel, norgestrel, norethindrone (norethisterone), dienogest, norethindrone (norethisterone) acetate, ethynodiol diacetate, dydrogesterone, medroxyprogesterone acetate, norethynodrel, allylestrenol, lynestrenol, quingestanol acetate, medrogestone, norgest ⁇ enone, dimethisterone, ethisterone, chlormadinone acetate, megestrol, promegestone, desogestrel, 3-keto-desogestrel, norgestimate, gestodene, tibolone, cyproterone acetate and drospirenone.
  • a particular preferred progestogen is d
  • ethinylestradiol means that other estrogens are administered in amounts which give rise to the same therapeutic effect as does the specified amount of ethinylestradiol.
  • drospirenone means that other progestogens are administered in amounts which give rise to the same therapeutic effect as does the specified amount of drospirenone. It is routine for those skilled in the art to determine therapeutically equivalent amounts or dosages of such other estrogens and/or progestogens when the effective dose of ethinylestradiol and/or drospirenone is known.
  • micronised is intended to mean that the particle size distribution is so that at least 90% of the particles have a particle diameter of less than 30 ⁇ m (calculated from the volume distribution curve under the presumption of spherical particles), i.e. a d 90 value of at the most 30 ⁇ m. Therefore, it is important to note that whenever the terms “particle size distribution”, “particle diameter”, “d 90 ", etc. are used herein it should be understood that the specific values or ranges used in connection therewith are always meant to be determined from the volume distribution curve under the presumption of spherical particles.
  • the term "fast-release” or “immediate-release”, when used in connection with the term estrogen, means that at least 70% of the estrogen, e.g. ethinylestradiol, is dissolved from the composition within 30 minutes, as determined by the USP XXIX Paddle Method II using water, or 0.1N HCI, at 37°C as the dissolution media and 50 rpm as the stirring rate.
  • the term “fast-release” or “immediate-release” is used in connection with the term progestogen, this means that at least 70% of the progestogen, e.g. drospirenone, is dissolved from the composition within 30 minutes, as determined by the USP XXIX Paddle Method II using water, or 0.1N HCI, at 37°C as the dissolution media and 50 rpm as the stirring rate.
  • at least 75%, more preferably at least 80%, even more preferably at least 85% of the progestogen, e.g. drospirenone is dissolved from the composition within 30 minutes when assayed as described above.
  • tetrahydrofolic acid e.g. calcium 5-methyl-(6S)-tetrahydrofolate
  • fast-release or immediate-release is used in connection with the term tetrahydrofolic acid
  • tetrahydrofolic acid e.g. calcium 5-methyl-(6S)-tetrahydrofolate
  • the tetrahydrofolic acid e.g. calcium 5-methyl-(6S)-tetrahydrofolate
  • granulate composition refers to a composition of a powder, wherein the particle size of the powder is either increased upon processing with a liquid or by compression.
  • the liquid may be any kind of suitable aqueous or organic solvents, or mixtures thereof, optionally further comprising a binder.
  • granulate composition covers granules, pellets and compressed powder or any particle formed by granulation, pelletation or compression of powder such that a mean particle size (d 50 ) of at least about 100 ⁇ m is formed.
  • granulating and “granulation” are understood a mechanical process whereby a powder comprising the active component(s) and excipients are partly agglomerated into particles and/or granules having a larger particle size than the unprocessed powder.
  • the powdery mixture is contacted with a granulation liquid, which may contain a binder, swelled, partly dissolved or completely dissolved in the granulation liquid.
  • the granulation liquid may be any suitable solvent, but generally aqueous solutions or just water are applicable.
  • the powdery mixture is contacted with the granulation liquid using suitable equipment for wet- granulation, such as fluidised bed equipment. Furthermore, high shear granulation can be used instead of fluidised bed granulation.
  • estradien-cyclodext ⁇ n complex or "estrogen complexed with cyclodextrin” is intended to mean a complex between an estrogen and a cyclodextrin, wherein the estrogen molecule is at least partially inserted into the cavity of a cyclodextrin molecule.
  • the molar ratio between the estrogen and the cyclodextrin may be adjusted to any desirable value.
  • a molar ratio between the estrogen and the cyclodextrin is from about 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.
  • the estrogen molecule may at least partially be inserted into the cavity of two or more cyclodextrin molecules, e.g. a single estrogen molecule may be inserted into two cyclodextrin molecules to give 2: 1 ratio between cyclodextrin and estrogen.
  • the complex may contain more than one estrogen molecule at least partially inserted into a single cyclodextrin molecule, e.g. two estrogen molecules may be at least partially inserted into a single cyclodextrin molecule to give a 1 :2 ratio between cyclodextrin and estrogen.
  • Complexes between estrogens and cyclodextrins may be obtained by methods known in the art, e.g. as described in US 5,798,338 and EP 1 353 700.
  • ethmylestradiol- ⁇ -cyclodext ⁇ n complex is intended to mean a complex, of any molar ratio, between ethinylestradiol and ⁇ -cyclodext ⁇ n.
  • the ethmylestradiol- ⁇ - cyclodext ⁇ n complex described herein is typically a complex between one molecule of ethinylestradiol and two molecules of ⁇ -cyclodextnn, i.e. a 1 : 2 ethinylestradiol- ⁇ - cyclodext ⁇ n complex.
  • progestogen-cyclodext ⁇ n complex or "progestogen complexed with cyclodextrin” is intended to mean a complex between a progestogen and a cyclodextrin, wherein the progestogen molecule is at least partially inserted into the cavity of a cyclodextrin molecule.
  • the molar ratio between the progestogen and the cyclodextrin may be adjusted to any desirable value.
  • a molar ratio between the progestogen and the cyclodextrin is from about 2: 1 to 1 : 10, preferably from about 1 : 1 to 1 : 5, most preferably from about 1 : 1 to 1 :3.
  • the progestogen molecule may at least partially be inserted into the cavity of two or more cyclodextrin molecules, e.g. a single progestogen molecule may be inserted into two cyclodextrin molecules to give 2: 1 ratio between cyclodextrin and progestogen.
  • the complex may contain more than one progestogen molecule at least partially inserted into a single cyclodextrin molecule, e.g. two progestogen molecules may be at least partially inserted into a single cyclodextrin molecule to give a 1 :2 ratio between cyclodextrin and progestogen.
  • Complexes between progestogens and cyclodextrins may be obtained by methods known in the art, e.g. as described in US 6,610,670 and references therein.
  • drospirenone- ⁇ -cyclodext ⁇ n complex is intended to mean a complex, of any molar ratio, between drospirenone and ⁇ -cyclodext ⁇ n as described in US 6,610,670.
  • the drospirenone- ⁇ -cyclodext ⁇ n complex is typically a complex between one molecule of drospirenone and three molecules of ⁇ -cyclodext ⁇ n, i.e. a 1 :3 drospirenone- ⁇ - cyclodext ⁇ n complex.
  • cyclodext ⁇ n is intended to mean a cyclodextrin or a derivative thereof as well as mixtures of various cyclodext ⁇ ns, mixtures of various derivatives of cyclodext ⁇ ns and mixtures of various cyclodext ⁇ ns and their derivatives.
  • the cyclodextrin may be selected from the group consisting of ⁇ -cyclodext ⁇ n, ⁇ -cyclodext ⁇ n, ⁇ -cyclodext ⁇ n and derivatives thereof.
  • the cyclodextrin may be modified such that some or all of the primary or secondary hydroxyl groups of the macrocycle are alkylated or acylated.
  • hydroxyl groups of the cyclodextrin may have been substituted with an O-R group or an O-C(O)-R gropu, wherein R is an optionally substituted C 1 6 alkyl, an optionally substituted C 2 6 alkenyl, an optionally substituted C 2 6 alkynyl, an optionally substituted aryl or heteroaryl group.
  • R may be a methyl, an ethyl, a propyl, a butyl, a pentyl, or a hexyl group, i.e.
  • O-C(O)-R may be an acetate.
  • the hydroxyl groups may be per- benzylated, per-benzoylated, benzylated or benzoylated on just one face of the macrocycle, i.e. only 1, 2, 3, 4, 5 or 6 hydroxyl groups is/are benzylated or benzoylated.
  • the hydroxyl groups may also be per-alkylated or per-acylated, such as per- methylated or per-acetylated, alkylated or acylated, such as methylated or acetylated, on just one face of the macrocycle, i.e. only 1, 2, 3, 4, 5 or 6 hydroxyl groups is/are alkylated or acylated, such as methylated or acetylated.
  • the solid composition of the invention contains at least one, such as one, estrogen as defined above.
  • the estrogen may be selected from the group consisting of ethmylestradiol, estradiol, estradiol sulfamates, estradiol valerate, estradiol benzoate, estrone, mestranol and estrone sulphate, including micronised forms thereof.
  • the estrogen is ethmylestradiol, in particular micronised ethmylestradiol.
  • the estrogen, in particular ethmylestradiol is complexed with a cyclodextrin, such as described in EP 1 353 700.
  • the cyclodextrin is typically selected from the group consisting of ⁇ -cyclodext ⁇ n, ⁇ - cyclodext ⁇ n, ⁇ -cyclodext ⁇ n and derivatives thereof.
  • the cyclodextrin is ⁇ -cyclodext ⁇ n or derivatives thereof.
  • the estrogen- cyclodext ⁇ n complex may advantageously be in micronised form.
  • the solid composition of the invention contains at least one, such as one, progestogen as defined above.
  • the progestogen may be selected from the group consisting of levo-norgestrel, norgestrel, norethindrone (norethisterone), norethindrone (norethisterone) acetate, dienogest, ethynodiol diacetate, dydrogesterone, medroxyprogesterone acetate, norethynodrel, allylestrenol, lynestrenol, quingestanol acetate, medrogestone, norgestnenone, dimethisterone, ethisterone, chlormadinone acetate, megestrol, promegestone, desogestrel, 3-keto-desogestrel, norgestimate, gestodene, tibolone, cyproterone acetate and drospiren
  • the progestogen is selected from the group consisting of levo-norgestrel, norgestrel, norethindrone (norethisterone), norethindrone (norethisterone) acetate, dienogest, ethynodiol diacetate, desogestrel, norgestimate, gestodene, cyproterone acetate and drospirenone.
  • the progestogen is drospirenone, in particular micronised drospirenone.
  • the composition comprises levo- norgestrel and ethmylestradiol, norgestrel and ethinylestradiol, norethindrone (norethisterone) and ethinylestradiol, norethindrone (norethisterone) acetate and ethinylestradiol, dienogest and ethinylestradiol, ethynodiol diacetate and ethinylestradiol, desogestrel and ethinylestradiol, norgestimate and ethinylestradiol, gestodene and ethinylestradiol, cyproterone acetate and ethinylestradiol, and drospirenone and ethinylestradiol.
  • the composition comprises drospirenone and ethinylestradiol, more preferably micronised drospirenone and micronised ethinylestradiol, e.g. micronised drospirenone and a micronised ethinylestradiol-cyclodext ⁇ n complex, such as micronised drospirenone and a micronised eth ⁇ nylestrad ⁇ ol- ⁇ -cyclodext ⁇ n complex.
  • composition of the invention further comprises a tetrahydrofolic acid or a salt thereof.
  • tetrahydrofolic acids include 5-methyl-(6S)-tetrahydrofol ⁇ c acid, (6S)-tetrahydrofol ⁇ c acid, 5-formyl-(6S)- tetrahydrofohc acid, 10-formyl-(6R)-tetrahydrofol ⁇ c acid, 5, 10-methylene-(6R)- tetrahydrofohc acid, 5, 10-methenyl-(6R)-tetrahydrofol ⁇ c acid, 5-form ⁇ m ⁇ no-(6S)- tetrahydrofolic acid, including pharmaceutically acceptable salts of these tetrahydrofolic acids and glutamyl derivatives of these tetrahydrofolic acids.
  • the tetrahydrofolic acid is 5-methyl-(6S)-tetrahydrofol ⁇ c acid or a pharmaceutically acceptable salt thereof.
  • the salt of 5-methyl-(6S)-tetrahydrofol ⁇ c acid is an alkaline earth metal salt, in particular the calcium salt.
  • the salt, such as the calcium salt, of 5-methyl-(6S)-tetrahydrofol ⁇ c acid should preferably be in crystalline form, such as the Type I crystalline form described in US 6,441,168.
  • the type I crystalline form of calcium 5-methyl-(6S)-tetrahydrofolate is commercially available from Merck KGaA under the trademark Metafohn ® .
  • composition of the invention does not contain other vitamins, in particular that the composition of the invention does not contain a vitamin B, such as vitamin B6 and/or vitamin B12. Accordingly, in a preferred embodiment of the invention, the composition contains a tetrahydrofolic acid as the sole vitamin component.
  • the solid pharmaceutical composition of the invention contains one or more pharmaceutically acceptable excipients. These excipients may, for example, be:
  • Inert diluents or fillers such as sucrose, sorbitol, sugars, mannitol, microcrystalline cellulose, starches, sodium chloride, sodium phosphate, calcium carbonate, calcium phosphate, calcium sulfate, lactose, e.g. lactose monohydrate, or a combination thereof.
  • the inert diluent or filler is typically present in an amount from 10-99% by weight of the composition.
  • the inert diluent or filler is present in an amount from 50-99% by weight of the composition, more preferably in an amount from 75-99% by weight of the composition, even more preferably in an amount from 80-97% by weight of the composition, most preferably in an amount from 85-97% by weight of the composition.
  • highly preferred inert fillers are lactose, in particular lactose monohydrate, and microcrystalline cellulose.
  • the composition of the invention comprises lactose monohydrate, microcrystalline cellulose or a combination of lactose monohydrate and microcrystalline cellulose in the amounts indicated supra.
  • the composition comprises microcrystalline cellulose.
  • the microcrystalline cellulose is typically present in an amount from 10-99% by weight of the composition, preferably in an amount from 50-99% by weight of the composition, more preferably in an amount from 75-99% by weight of the composition, even more preferably in an amount from 80-97% by weight of the composition, most preferably in an amount from 85-97% by weight of the composition.
  • the microcrystalline cellulose may be the only or sole filler present in the composition, i.e. the composition of the invention may be free from other fillers than microcrystalline cellulose.
  • the composition comprises lactose monohydrate.
  • the lactose monohydrate is typically present in an amount from 10-99% by weight of the composition, preferably in an amount from 50-99% by weight of the composition, more preferably in an amount from 75-99% by weight of the composition, even more preferably in an amount from 80-97% by weight of the composition, most preferably in an amount from 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 invention may be free from other fillers than lactose monohydrate.
  • the composition comprises microcrystalline cellulose and lactose monohydrate.
  • microcrystalline cellulose is typically present in an amount from 20-80% by weight of the composition and lactose monohydrate in an amount from 20-80% by weight of the composition.
  • microcrystalline cellulose constitutes the major part of the microcrystalline cellulose-lactose monohydrate filler system, i.e. the composition comprises lactose monohydrate in an amount from 20-60% by weight of the composition and microcrystalline cellulose in an amount from 40-80% by weight of the composition, such as lactose monohydrate in an amount from 20-45% by weight of the composition and microcrystalline cellulose in an amount from 40-70% by weight of the composition, e.g.
  • lactose monohydrate in an amount from 25-36% by weight of the composition and microcrystalline cellulose in an amount from 52-63% by weight of the composition.
  • the microcrystalline cellulose and the lactose monohydrate may be the only fillers present in the composition, i.e. the composition of the invention may be free from other fillers than microcrystalline cellulose and lactose monohydrate.
  • lactose monohydrate constitutes the major part of the microcrystalline cellulose-lactose monohydrate filler system, i.e. the composition comprises microcrystalline cellulose in an amount from 20- 60% by weight of the composition and lactose monohydrate in an amount from 40-80% by weight of the composition.
  • the composition comprises microcrystalline cellulose in an amount from 20-45% by weight of the composition and lactose monohydrate in an amount from 40-70% by weight of the composition. Most preferably, the composition comprises microcrystalline cellulose in an amount from 25-36% by weight of the composition and lactose monohydrate in an amount from 52-63% by weight of the composition.
  • the microcrystalline cellulose and the lactose monohydrate may be the only fillers present in the composition, i.e. the composition of the invention may be free from other fillers than microcrystalline cellulose and lactose monohydrate.
  • Microcrystalline cellulose is commercially available in different particle sizes and moisture grades.
  • Examples of commercially available microcrystalline cellulose preparations include the Avicel ® PH-se ⁇ es from FMC Biopolymer, the Emcocel ® M-se ⁇ es from Penwest Pharmaceuticals Co. and the V ⁇ vapur ® -ser ⁇ es from Rettenmaier & Sohne GmbH.
  • a particular preferred commercial product to be used for the purposes described herein is Avicel ® PH-IOl.
  • various lactose monohydrate grades having different physical properties, such as particle size distribution and flow characteristics are commercially available. The grade of the lactose monohydrate may vary dependent on the specific dosage form to be prepared.
  • lactose monohydrate such as Tablettose ® (agglomerated) or grades for powder blends, such as Pharmatose ® DCL 11 (spray-dried), have better flow properties and are more compressible than powdered or crystalline lactose monohydrate.
  • lactose monohydrate preparations are not particularly preferred for the purposes described herein. Rather, the more fine grade lactose monohydrate preparations are preferred, such as powdered or crystalline lactose monohydrate, in particular crystalline lactose monohydrate where 90% of the particles have a diameter of less than 0.1 mm.
  • Binders such as sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatine, starch, pregelatinised starch, magnesium aluminium silicate, carboxymethylcellulose sodium (CMC sodium), methylcellulose, ethylcellulose, hydroxypropylmethylcellulose ( HPMC), hydroxy- propylcellulose ( HPC), polyvinylacetate or polyethylene glycol.
  • the binder is typically present in an amount from 0.1-10% by weight of the composition.
  • the binder is present in an amount from 0.2-5% by weight of the composition, such as from 0.5-5% by weight of the composition, more preferably in an amount from 1-3% by weight of the composition.
  • the binder is HPC.
  • PVP polyvinylpyrrolidone
  • the amount of PVP in the composition of the invention should be kept at an absolute minimum and should preferably be avoided.
  • the composition of 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 of the invention is essentially free from PVP.
  • Lubricants including glidants and antiadhesives, such as magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils or talc.
  • the lubricant is typically present in an amount from 0.1-10% by weight of the composition.
  • the lubricant is present in an amount from 0.2-5% by weight of the composition, such as from 0.5-5% by weight of the composition, more preferably in an amount from 1-3% by weight of the composition.
  • the lubricant is magnesium stearate.
  • Carboxymethylcellulose-based disintegrants such as, sodium starch glycolate, maize starch, rice starch, potato starch, cross-linked povidone or carboxymethylcellulose-based disintegrants.
  • Carboxymethylcellulose-based disintegrants may be present as free acid, but is preferably in the form of a salt, e.g . in the form of an alkali metal salt, such as the potassium salt or the sodium salt, in particular the sodium salt, or in the form of a salt of a divalent metal ion, such as the magnesium salt, the calcium salt or the zinc salt, in particular the calcium salt.
  • the carboxymethylcellulose- based disintegrant may be cross-linked or non-cross-linked.
  • carboxymethyl- cellulose calcium carbmellose calcium
  • carboxymethylcellulose sodium carboxymethylcellulose sodium
  • the carboxymethylcellulose-based disintegrant is cross-linked.
  • a specific example of a preferred cross-linked carboxymethylcellulose-based disintegrant is cross- linked carboxymethylcellulose sodium (croscarmellose sodium). Croscarmellose sodium is commercially available under the tradenames Ac-Di-Sol ® , Explocel ® and Solutab ® .
  • the disintegrant is typically present in an amount from 0.1-10% by weight of the composition.
  • the disintegrant is present in an amount from 0.2-5% by weight of the composition, such as from 0.5-5% by weight of the composition, more preferably in an amount from 1-4% by weight of the composition.
  • - Surfactants and wetting agents such as naturally occurring phosphatides, e.g. lechitin or soybean lechitin; condensation products of ethylene oxide with e.g. a fatty acid, a long chain fatty alcohol, or a partial ester derived from fatty acids and a hexitol or a hexitol anhydride, for example polyoxyethylene stearate, polyoxyethylene sorbitol monooleate, polyoxyethylene sorbitan monooleate, etc.; or salts of long-chain aliphatic phosphates, such as sodium lauryl sulphate.
  • naturally occurring phosphatides e.g. lechitin or soybean lechitin
  • condensation products of ethylene oxide with e.g. a fatty acid, a long chain fatty alcohol, or a partial ester derived from fatty acids and a hexitol or a hexitol anhydride for example polyoxyethylene stearate, polyoxyethylene
  • Examples of other pharmaceutically acceptable excipients which may be incorporated in the solid pharmaceutical composition of the invention include colorants, flavouring agents, plasticizers, humectants, buffering agents, etc.
  • the dosage form is adapted for oral administration and may be provided with a coating, such as a film coating, a sugar coating, or the like.
  • a suitable coating for the dosage form according to the invention may, for example, be a sugar coating or a film coating based on one or more of the ingredients: Hydroxypropylmethylcellulose (HPMC), methylcellulose, ethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose sodium, acrylate polymers (e.g. Eudragit ® ), polyethylene glycols or polyvinylpyrrolidone.
  • the dosage form is in the form of a tablet, preferably a coated tablet, more preferably a film-coated tablet.
  • the uncoated tablet typically has a weight in the range from 50-150 mg, such as in the range of 60-125 mg, e.g. in the range of 60-100 mg, preferably in the range of 70-90 mg, e.g. about 80 mg.
  • the dosage form typically contains an amount of progestogen corresponding to a therapeutically equivalent amount of drospirenone from 0 25-4 mg, such as in an amount corresponding to a therapeutically equivalent amount of drospirenone from 1-4 mg, e.g.
  • the progestogen may be complexed with a cyclodextrin.
  • the solid oral dosage form typically contains an amount of estrogen corresponding to a therapeutically equivalent amount of ethinylestradiol from 0.005-0.05 mg, such as in an amount corresponding to a therapeutically equivalent amount of ethinylestradiol from 0.01-0.05 mg, preferably in an amount corresponding to a therapeutically equivalent amount of ethinylestradiol from 0.015-0.035 mg, most preferably in an amount corresponding to a therapeutically equivalent amount of ethinylestradiol of about 0.02 mg or about 0.03 mg.
  • the estrogen may be complexed with a cyclodextrin.
  • the dosage form comprises 0.25-4 mg drospirenone and 0.005-0.05 mg ethinylestradiol, such as 1-4 mg drospirenone and 0.005-0.05 mg ethinylestradiol, e.g. 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.
  • ethinylestradiol such as 1-4 mg drospirenone and 0.005-0.05 mg ethinylestradiol, e.g. 2-4 mg drospirenone and 0.01-0.05 mg ethinylestradiol, preferably 2.5-3.5
  • the dosage form may comprise desogestrel in an amount from 0.05-0.5 mg, preferably from 0.075-0.25 mg, such as 0.1 mg, 0.125 mg or 0.15 mg; ethynodiol diacetate in an amount from 0.25-2 mg, preferably 0.75-1.5 mg, such as 1 mg; levo-norgestrel in an amount from 0.025-0.3 mg, preferably from 0.075-0.25 mg, such as 0.1 mg or 0.15 mg; norethindrone (norethisterone) in an amount from 0.2-1.5 mg, preferably 0.3-1.25 mg, such as 0.4 mg, 0.5 mg or 1 mg; norethindrone (norethisterone) acetate in an amount from 0.5-2 mg, preferably 1-1.5 mg, such as 1 mg or 1.5 mg; norgestrel in an amount from 0.1-1 mg,
  • the dosage form may comprise estradiol in an amount from 1-4 mg or mestranol from 0.01-0.1 mg, preferably from 0.025-0.075 mg, such as 0.05 mg.
  • estradiol in an amount from 1-4 mg or mestranol from 0.01-0.1 mg, preferably from 0.025-0.075 mg, such as 0.05 mg.
  • Desogestrel Ethinylestradiol 0.05-0.5 mg 0.01-0.05 mg 0.075-0.25 mg 0.015-0.035 mg 0.15 mg 0.03 mg Desogen ® , monophasic
  • Norethindrone acetate Ethinylestradiol 0.5-2 mg 0.01-0.05 mg 1-1.5 mg 0.015-0.035 mg 1 mg 0.02 mg Loestrin 1-20 ® , monophasic 1 mg 0.02 mg Loestrin 24 FE ® , 24 day regimen 1.5 mg 0.03 mg Loestrin 1.5-30 ® , monophasic
  • the solid oral dosage form typically contains a tetrahydrofolic acid in an amount from 0.1- 5 mg, such as in an amount from 0.1-2.5 mg, e.g. in an amount from 0.2-0.8 mg, preferably in an amount from 0.3-0.7 mg, more preferably in an amount from 0.4-0.6 mg, most preferably in an amount from 0.42-0.49 mg.
  • the tetrahydrofolic acid is preferably 5-methyl-(6S)-tetrahydrofol ⁇ c acid or a pharmaceutically acceptable salt thereof, such as an alkaline earth metal salt, in particular the calcium salt.
  • the salt, such as the calcium salt, of 5-methyl-(6S)-tetrahydrofol ⁇ c acid should preferably be in crystalline form, such as the Type I crystalline form described in US 6,441,168.
  • the dosage form comprises microcrystalline cellulose, lactose monohydrate or a combination of microcrystalline cellulose and lactose monohydrate
  • the dosage form comprises microcrystalline cellulose in an amount from 5-80 mg, such as from 10-80 mg.
  • the dosage form comprises microcrystalline cellulose in an amount from 40-80 mg.
  • the dosage form comprises microcrystalline cellulose in an amount from 60-80 mg.
  • the dosage form comprises microcrystalline cellulose in an amount from 65-80 mg.
  • the dosage form comprises microcrystalline cellulose in an amount from 65-77 mg.
  • the microcrystalline cellulose may be the only or sole filler present in the dosage form, i.e. the dosage form of the invention may be free from other fillers than microcrystalline cellulose.
  • the dosage form comprises lactose monohydrate in an amount from 5-80 mg, such as from 10-80 mg.
  • the dosage form comprises lactose monohydrate in an amount from 40-80 mg.
  • the dosage form comprises lactose monohydrate in an amount from 60- 80 mg.
  • the dosage form comprises lactose monohydrate in an amount from 65-80 mg.
  • the dosage form comprises lactose monohydrate in an amount from 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 invention may be free from other fillers than lactose monohydrate.
  • the dosage form comprises microcrystalline cellulose in an amount from 15-65 mg and lactose monohydrate in an amount from 15-65 mg.
  • 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 from 15-50 mg and microcrystalline cellulose in an amount from 25-65 mg.
  • the dosage form comprises lactose monohydrate in an amount from 15-35 mg and microcrystalline cellulose in an amount from 30-55 mg. Most preferably, the dosage form comprises lactose monohydrate in an amount from 20- 30 mg and microcrystalline cellulose in an amount from 40-50 mg.
  • lactose monohydrate constitutes the major part of the microcrystalline cellulose-lactose monohydrate filler system, i.e. the dosage form comprises microcrystalline cellulose in an amount from 15-50 mg and lactose monohydrate in an amount from 25-65 mg. Even more preferably, the dosage form comprises microcrystalline cellulose in an amount from 15-35 mg and lactose monohydrate in an amount from 30-55 mg. Most preferably, the dosage form comprises microcrystalline cellulose in an amount from 20-30 mg and lactose monohydrate in an amount from 40-50 mg
  • the present inventor surprisingly found that the problem concerning stability of a tetrahydrofolic acid as well as the problem associated with obtaining fast-release of the progestogen from tablets prepared by direct compression could in fact be, at least partly, solved by preparing the composition by means of granulation, i.e. in a preferred embodiment the composition of the invention is a granulate composition; Due to the exposure to mechanical stress and humidity during the granulation process, the skilled person would not contemplate preparing a tetrahydrofolic acid-containing composition by granulation as he would expect the air- and moisture-sensitive tetrahydrofolic acid to degrade significantly under such manufacturing conditions.
  • the composition of the invention is preferably prepared by means of a granulation process, i.e. the drug substances, including the tetrahydrofolic acid, together with appropriate excipients, are subjected to a granulation process, preferably a wet granulation process, such as a fluid bed granulation process.
  • a granulation process preferably a wet granulation process, such as a fluid bed granulation process.
  • the composition of the invention is a granulate composition.
  • the granules can be processed further into the final dosage form.
  • the granules may be filled into sachets or capsules, such as hard gelatine capsules.
  • the granules are processed into tablets by compression and subsequently film-coated.
  • the tetrahydrofolic acid may, in one embodiment of the invention, be added before or during the granulation process.
  • the tetrahydrofolic acid can be regarded as an "inner phase” component since it forms part of the granule as such.
  • the tetrahydrofolic acid is added to the granules at the end of the granulations process, or after the granulation process has been completed, i.e. the tetrahydrofolic acid can be regarded as an "outer component".
  • the tetrahydrofolic acid may be incorporated in the granules as an "inner phase” component, as an “outer phase” component or as a combination thereof.
  • the tetrahydrofolic acid is present as an "outer phase” component.
  • the present invention is also directed to a process for the manufacture of a composition according to the invention, which comprises the steps of:
  • step ( ⁇ ) the progestogen, the estrogen and at least one pharmaceutical acceptable excipient, such as lactose monohydrate, microcrystalline cellulose or a combination thereof, is loaded into a granulator, preferably a fluidised bed granulator.
  • a granulation liquid typically containing a binder such as HPC, is then applied and, in the case of fluidised bed granulation, the granulation liquid is sprayed continuously onto the fluidised bed while heating the air stream of the fluidised bed.
  • the tetrahydrofolic acid or a salt thereof is mixed with the granules formed in step ( ⁇ ) at the end of, near the end of, or after, the granulation process. If desired, the granulation process may, however, be continued after addition of the tetrahydrofolic acid.
  • a disintegrant and a lubricant are also mixed with the granules formed in step ( ⁇ ) together with the tetrahydrofolic acid.
  • the granules obtainable by the above process may be further process into a desired dosage form, e.g. a tablet, by compression.
  • a desired dosage form e.g. a tablet
  • the present invention is also directed to a process for the manufacture of a solid oral dosage form according to the invention, which comprises the steps of:
  • composition of the invention is preferably in the form of a granulate composition which may subsequently be processed into the desired dosage form, it is contemplated that in case low-dose progestogen dosage forms are prepared, the fast-release problems associated with this active component will not be as pronounced as when higher doses of the progestogen, in particular drospirenone, are required in the dosage form.
  • the present invention also relates to a tablet, in particular a tablet prepared by direct compression, comprising a progestogen, an estrogen, a tetrahydrofolic acid or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical acceptable excipient or carrier, wherein the amount of the progestogen is from 0.025- 1.5 mg, such as 0.025- 1 mg, 0.05- 1 mg, 0.075-0.75 mg or 0.1-0.5 mg.
  • a tablet in particular a tablet prepared by direct compression, comprising a progestogen, an estrogen, a tetrahydrofolic acid or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical acceptable excipient or carrier, wherein the amount of the progestogen is from 0.025- 1.5 mg, such as 0.025- 1 mg, 0.05- 1 mg, 0.075-0.75 mg or 0.1-0.5 mg.
  • compositions and dosage forms may be prepared according to the present invention, but where such compositions and dosage forms does not contain an estrogen.
  • a dosage form is Microlut ® (also known as the "mini-pill"), which contains 0.03 mg levo-norgestrel and no estrogen.
  • the present invention relates to a solid pharmaceutical composition comprising a progestogen, a tetrahydrofolic acid or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical acceptable excipient or carrier.
  • compositions and the dosage forms provided by the present invention fulfil the above-mentioned regulatory requirements.
  • the composition or the dosage form of the invention has a stability such that at least 80% of the initial amount of the tetrahydrofolic acid is present in the composition or in the dosage form after storage in a closed container for 24 months at 25°C and 60% relative humidity.
  • the composition or the dosage form of the invention has a stability such that at least 90%, preferably at least 95%, of the initial amount of the tetrahydrofolic acid is present in the composition or in the dosage form after storage in a closed container for 12 months at 25°C and 60% relative humidity.
  • the term "initial content", when used in connection with a tetrahydrofolic acid refers to the measured amount of the tetrahydrofolic acid determined immediately after the manufacture of the composition or dosage form or, alternatively, after storage in a closed container for not more than 5 days at 25°C and 60% relative humidity.
  • the term "initial amount” neither refers to the declared amount of the tetrahydrofolic acid, nor to the theoretical amount of (added) tetrahydrofolic acid, but rather to the measured amount of the tetrahydrofolic acid present in the composition or dosage form determined immediately after its manufacture or after storage for a short period of time as described above.
  • the composition or the dosage form of the invention has a stability such that at least 80% of the declared amount of the tetrahydrofolic acid is present in the composition or in the dosage form after storage in a closed container for 24 months at 25°C and 60% relative humidity.
  • the composition or the dosage form of the invention has a stability such that at least 90%, preferably at least 95%, of the declared amount of the tetrahydrofolic acid is present in the composition or in the dosage form after storage in a closed container for 12 months at 25°C and 60% relative humidity.
  • the term "declared amount” refers to the officially declared amount of the tetrahydrofolic acid present in the composition or the dosage. The declared amount of the tetrahydrofolic acid is normally apparent from the information provided in the leaflet.
  • the composition or the dosage form of the invention has a stability such that the sum of the tetrahydrofolic acid decomposition products is at the most 10%, preferably at the most 8%, more preferably at the most 6%, even more preferably at the most 5%, most preferably at the most 4%, after storage in a closed container for 6 months or 12 months at 25 0 C and 60% relative humidity.
  • the sum of tetrahydrofolic acid decomposition products may be determined as described in the section entitled "Determination of decomposition products" herein.
  • the composition or the dosage form of the invention has a stability such that the sum of tetrahydrofolic acid decomposition products is at the most 10%, preferably at the most 8%, more preferably at the most 6%, even more preferably at the most 5%, most preferably at the most 4%, after storage in a closed container for 1 month, 2 months or 3 months at 40 0 C and 75% relative humidity.
  • the sum of the tetrahydrofolic acid decomposition products may be determined as described in the section entitled "Determination of decomposition products" herein.
  • the compositions or the dosage forms of the invention are suitable for inhibition of ovulation in a female, i.e. for providing female contraception.
  • the compositions and dosage forms of the invention are also useful for the treatment or prevention of folate deficiency, including anemia and bleedings.
  • the present invention relates to a pharmaceutical preparation or kit consisting essentially of 21, 22, 23 or 24, in particular 21 or 24, separately packed and individually removable solid oral dosage units according to the invention placed in a packaging unit, and 7, 6, 5 or 4, in particular 7 or 4, separately packed and individually removable solid oral dosage units containing a tetrahydrofolic acid as the sole active agent placed in a packaging unit.
  • the dosage forms containing a tetrahydrofolic acid as the sole active agent may be prepared by any method known in the art as long as the tetrahydrofolic acid still fulfils the stability criteria discussed herein.
  • the dosage form containing a tetrahydrofolic acid as the sole active agent is essentially identical to the dosage forms described herein, but no progestogens and estrogens are included.
  • the preparation may be a one-phase preparation, i.e. a preparation wherein the amounts of the progestogen and the estrogen remain constant for the entire 21-, 22-, 23- or 24-day period.
  • amounts of either or both active agents i.e. the progestogen and the estrogen
  • a multiple-phase preparation e.g. a two- or three-phase preparation, such as descried in, e.g., US 4,621,079.
  • the preparation may be a one-phase or a multiple phase preparation
  • the amount of the tetrahydrofolic acid preferably remains constant throughout the entire cycle, i.e. for all 28 days.
  • a packaging unit comprising the dosage forms described above may be prepared in a manner analogous to that of making other oral contraceptives.
  • This may for instance be a conventional blister pack or any other form known for this purpose, for instance a pack comprising the appropriate number of dosage units (in this case typically 28 or a multiple of 28) in a sealed blister pack with a cardboard, paperboard, foil or plastic backing and enclosed in a suitable cover.
  • compositions or the dosage forms of the invention are also suitable for treatment of diseases, conditions or symptoms associated with deficient endogenous levels of estrogen in women.
  • the above-mentioned progestogens are preferably combined with an estrogen selecetd from the group consisting of estradiol, estradiol sulfamates, estradiol valerate, estradiol benzoate.
  • a specific example of a preferred dosage form comprises 0.25-3 mg drospirenone and 0.5-2 mg estradiol, such as 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 (Angehq ® ).
  • Other examples include compositions or dosage forms comprising estradiol valerate and cyproterone acetate, estradiol valerate and dienogest, ethinylestradiol and gestodene, and ethinylestradiol and levo-norgestrel.
  • Deficient levels of estrogen can occur for a variety of reasons.
  • deficient levels of estrogen may be caused by e.g. natural menopause, pen-menopause, post-menopause, hypogonadism, castration or primary ovarian failure.
  • Symptoms, diseases and conditions range from merely being inconvenient to life threatening.
  • the compositions and dosage forms described herein provide effective alleviation of all physiological and psychological signs of estrogen deficiency.
  • Transient symptoms, such as vasomotor signs and psychological symptoms are certainly embodied with the realm of therapy.
  • Vasomotor signs comprise but are not limited to hot flushes, sweating attacks such as night sweats, and palpitations.
  • Psychological symptoms of estrogen deficiency comprise, but are not limited to, insomnia and other sleep conditions, poor memory, loss of confidence, mood changes, anxiety, loss of libido, difficulties in concentration, difficulty in making decisions, diminished energy and drive, irritability and crying spells.
  • the treatment of the aforementioned symptoms can be associated with the pe ⁇ -menopausal phase of a woman's life or after, sometimes long time after, menopause. It is anticipated that the compositions and dosage forms described herein are applicable to these and other transient symptoms during the pe ⁇ -menopausal phase, menopause, or post-menopausal phase.
  • compositions or dosage forms described herein are used for the treatment of permanent effects of estrogen deficiency.
  • Permanent effects comprise physical changes such as urogenital atrophy, atrophy of the breasts, cardiovascular disease, changes in hair distribution, thickness of hair, changes in skin condition and osteoporosis.
  • Urogenital atrophy, and conditions associated with it such as vaginal dryness, increase in vaginal pH and subsequent changes in flora, or events which lead to such atrophy, such as decreases in vascularity, fragmentation of elastic fibres, fusion of collagen fibres, or decreases in cell volume, are symptoms thought to be particularly relevant to be treated with the compositions or dosage forms described herein. Furthermore, the compositions or dosage forms described herein are thought to be relevant to other urogenital changes associated with estrogen deficiency, decreases in mucus production, changes in cell population, decreases in glycogen production, decreases in growth of lactobacilli or increases in growth of streptococci, staphylococci, or coliform bacilli.
  • compositions or dosage forms described herein are those that may render the vagina susceptible to injury or infection, such as exudative discharges, vaginitis, and dyspareunia.
  • infections of the urinary tract and incontinence are other common symptoms associated with lowered estrogen levels.
  • Other embodiments of the invention include the prevention or alleviation of physical changes associated with estrogen deficiency, such as changes in the skin, changes in hair distribution, thickness of hair, atrophy of the breasts, or osteoporosis.
  • the prevention and management of osteoporosis most notably post-menopausal osteoporosis, is a particularly interesting embodiment of the invention.
  • osteoporosis is an interesting therapeutic application of the compositions or dosage forms of the invention.
  • a particularly interesting embodiment of the invention is directed to lessening the frequency, persistence, duration and/or severity of hot flushes, sweating attacks, palpitations, sleep conditions, mood changes, nervousness, anxiety, poor memory, loss of confidence, loss of libido, poor concentration, diminished energy, diminished drive, irritability, urogenital atrophy, atrophy of the breasts, cardiovascular disease, changes in hair distribution, thickness of hair, changes in skin condition and osteoporosis (including prevention of osteoporosis), most notably hot flushes, sweating attacks, palpitations, sleep conditions, mood changes, nervousness, anxiety, urogenital atrophy, atrophy of the breasts, as well as prevention or management of osteoporosis.
  • Another interesting embodiment of the invention is directed to treatment of hot flushes, sweating attacks, palpitations, sleep conditions, mood changes, nervousness, anxiety, poor memory, loss of confidence, loss of libido, poor concentration, diminished energy, diminished drive, irritability, urogenital atrophy, atrophy of the breasts, cardiovascular disease, changes in hair distribution, thickness of hair, changes in skin condition and osteoporosis (including prevention of osteoporosis), most notably hot flushes, sweating attacks, palpitations, sleep conditions, mood changes, nervousness, anxiety, urogenital atrophy, atrophy of the breasts, as well as prevention or management of osteoporosis.
  • Injection volume 10 ⁇ l Column: Steel, length: 5 cm; Inner diameter: 4.6 mm
  • Dissolution of ethinylestradiol and drospirenone was investigated by the USP XXIX Paddle Method II using water at 37°C as the dissolution media and 50 rpm as the stirring rate.
  • Dissolution of calcium 5-methyl-(6S)-tetrahydrofolate was investigated by the USP XXIX Paddle Method II using a 0 03% ascorbic acid aqueous solution (adjusted to pH 3.5 with 0 05 M phosphate buffer) at 37°C as the dissolution media and 50 rpm as the stirring rate.
  • Example 1 Direct compression; microcrystalline cellulose
  • a tablet core of 80 mg having the following composition was prepared by direct compression:
  • Ethinylestradiol (as micronised ⁇ -cyclodext ⁇ n 0.030 complex)
  • Microcrystalline cellulose (Avicel ® PH-IOl) 73.319
  • Fig. 2 The dissolution profiles are shown in Fig. 2. As can be seen from Fig. 2, ethinylestradiol and calcium 5-methyl-(6S)-tetrahydrofolate were released immediately from the tablet composition, whereas the dissolution of drospirenone was unsatisfactory slow. This finding was surprising, in particular since the tablet disintegrated within 5 minutes under the conditions used.
  • Example 2 Direct compression; Cellactose ® (lactose monohydrate/cellulose powder)
  • a tablet core of 80 mg having the following composition was prepared by direct compression :
  • Magnesium stearate 1.600 The stability of calcium 5-methyl-(6S)-tetrahydrofolate upon storage under various conditions was tested. The following stability data (see Tables 3 and 4 below) were obtained upon storage at 25°C/60% RH and 40°C/75% RH, respectively. Stability was tested in open as well as closed containers.
  • Example 3 Direct compression; Tablettose ® (lactose monohydrate)
  • a tablet core of 80 mg having the following composition was prepared by direct compression :
  • Ethinylestradiol (as micronised ⁇ -cyclodextrin 0.030 complex)
  • Example 4 Direct compression; microcrystalline cellulose/lactose monohydrate
  • Example 2 In order to investigate whether the dissolution of drospirenone could be increased, it was decided to prepare a tablet according to Example 1, but where about one third of the microcrystalline cellulose was replaced by lactose monohydrate (despite lactose monohydrate's destabilising effect on calcium 5-methyl-(6S)-tetrahydrofolate, cf. Examples 2 and 3).
  • a tablet core of 80 mg having the following composition was prepared by direct compression:
  • Ethinylestradiol (as micronised ⁇ -cyclodextrin 0.030 complex)
  • Microcrystalline cellulose (Avicel ® PH-IOl) 48.899
  • Lactose monohydrate (Pharmatose ® DCL 11) 24.420 Croscarmellose sodium 1.600
  • Example 5 Fluidised bed granulation; microcrystalline cellulose/lactose monohydrate
  • a tablet core of 80 mg having the following composition was prepared
  • Ethinylestradiol (as micronised ⁇ -cyclodext ⁇ n 0.020 complex)
  • Microcrystalline cellulose (Avicel ® PH 101) 24.800
  • a granulate preparation was prepared by charging a fluidised bed granulator with drospirenone, ethinylestradiol, lactose monohydrate, microcrystalline cellulose and activating the fluidised bed.
  • An aqueous solution of binder (HPC) was sprayed continuously onto the fluidised bed while drying by heating the air stream of the fluidised bed.
  • HPC binder
  • calcium 5-methyl-(6S)-tetrahydrofolate, crosscarmellose and magnesium stearate were sucked into the granulator and mixed with the granules by maintaining the fluidised bed.
  • the resulting granulates were compressed into tablet cores using a tablet press.
  • a tablet core of 80 mg having the following composition was prepared
  • Ethinylestradiol (as micromsed ⁇ -cyclodext ⁇ n 0.030 complex)
  • a granulate preparation was prepared by as described in Example 5. A satisfactory stability of calcium 5-methyl-(6S)-tetrahydrofolate upon various storage conditions was observed.
  • drospirenone was released slower from this tablet compared to the tablet prepared in Example 5.
  • the drospirenone-release was still satisfactory and comparable to the dropirenone-containing oral contraceptive Yaz ® .

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Endocrinology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Reproductive Health (AREA)
  • Diabetes (AREA)
  • Gynecology & Obstetrics (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Steroid Compounds (AREA)

Abstract

The present invention relates to solid pharmaceutical compositions, in particular to oral contraceptives, comprising a progestogen, such as drospirenone; an estrogen, such as ethinylestradiol; a tetrahydrofolic acid or a pharmaceutically acceptable salt thereof, such as calcium 5-methyl-(6S)-tetrahydrofolate; and at least one pharmaceutical acceptable excipient or carrier. The compositions of the invention provide good stability of the tetrahydrofolic acid upon storage while still ensuring a fast and reliable release of the estrogen and the progestogen present in the composition.

Description

PHARMACEUTICAL COMPOSITION CONTAINING A TETRAHYDROFOLIC ACID
FIELD OF THE INVENTION
The present invention relates to solid pharmaceutical compositions, in particular to oral 5 contraceptives, comprising a tetrahydrofolic acid, such as calcium 5-methyl-(6S)- tetrahydrofolate. The compositions provided by the present invention allow for good stability of the tetrahydrofolic acid upon storage while still ensuring a fast and reliable release of the estrogen and the progestogen present in the composition.
10 BACKGROUND OF THE INVENTION
In pregnant women, correction of low folate serum levels takes at least two months, and reserves can last as little as a few weeks. According to a public health service recommendation, all women who can become pregnant should therefore consume 400 μg/day of folic acid to reduce the risk of birth defects (MMWR Morb. Mortal. WkIy. Rep.
15 1992;41(RR-14): l-7). Folic acid supplementation immediately before discontinuing oral contraceptive use, or immediately after a positive pregnancy test has been obtained, may be insufficient to optimally protect the developing foetus. In addition, multiple studies of women taking oral contraceptives show decreased folate serum levels relative to negative controls. Postulated mechanisms reported for this phenomenon include decreased
20 absorption of polyglutamates, increased excretion of folic acids, increased production of folate-binding proteins, and induction of folate-dependent hepatic microsomal enzymes. Thus, a decrease of the folate serum level among oral contraceptive users pose an additional risk for such users who become pregnant within three to six months following discontinuation of use.
25
Accordingly, folic acid should ideally be added to oral contraceptives since adequate folic acid intake during the peπconceptional period helps protect against a number of congenital malformations, including neural tube defects, such as spina bifida (an incomplete closure of the spinal cord and spinal column), anencephaly (severe underdevelopment of the brain) and
30 encephalocele (when brain tissue protrudes out to the skin from an abnormal opening in the skull). All of these defects occur during the first 28 days of pregnancy - usually before a woman even knows she is pregnant
However, incorporation of folic acid in oral contraceptives may pose a serious health risk in 35 that it will suppress 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 correct changes in the nervous system that result from vitamin B12 deficiency. Permanent nerve damage could therefore occur if vitamin B12 deficiency is not treated. The present inventor has therefore suggested to incorporate a tetrahydrofolic acid, such as the natural folic acid deπvate, 5-methyl-(6S)-tetrahydrofohc, which is formed in the rather complicated catabolic pathway of the prodrug folic acid, in an oral contraceptive Incoporation of tetrahydrofolic acids, such as 5-methyl-(6S)- tetrahydrofolic acid, in oral contraceptive could provide all the beneficial effects associated with folic acid, but without the potential disadvantage of masking the anemia of vitamin B12 deficiency.
However, tetrahydrofolic acids are extremely unstable and are highly susceptible to oxidation and moisture. Accordingly, incorporation of a tetrahydrofolic acid into solid oral pharmaceuticals, such as oral contraceptives, represents a big challenge from a formulation point of view. Not only should the resulting solid pharmaceutical composition exhibit a satisfactory stability (with respect to the tetrahydrofolic acid) upon storage, but the very manufacture of the composition itself is considered problematic as exposure to oxidising excipients, humidity and/or open air during the manufacturing process are expected to cause degradation of the tetrahydrofolic acid and should hence be avoided. Furthermore, and as will be apparent from the examples provided herein, the problem of stabilising the tetrahydrofolic acid cannot be solved in isolation as it has turned out that stabilisation of the tetrahydrofolic acid in many cases surprisingly causes insufficient release of other active agents of the composition.
Furthermore, in an oral contraceptive the tetrahydrofolic acid is considered an active ingredient. Therefore, standard stabilisation measures typically used in vitamin supplement products, such as overdosing and broader specification limits, are not applicable in connection with oral contraceptives. Typical overdoses in vitamin supplement products are up to 25% and the dose of Metafohn® in some vitamin supplement products is from 0.6- 5.6 mg higher than the recommended daily dose (0.45 mg) . Since stability problems are more pronounced when incorporated in pharmaceutical compositions in low concentrations, preparation of stable pharmaceutical compositions containing low dosages of a tetrahydrofolic acid is a challenging task in its own respect.
Nevertheless, the present inventor has surprisingly, via careful selection of critical excipients and/or manufacturing processes, succeeded in preparing oral contraceptives which, one the one hand, exhibit a satisfactory stability with respect to the tetrahydrofolic acid, and, on the other hand, still fulfil the necessary requirements with respect to release, and hence bioavailability, of the estrogen and the progestogen present in the composition.
WO 03/070255 describes kits for contraception and hormone replacement therapy which contain one or more steroids, such as estrogens and progestogens; one or more tetrahydrofolate component; and vitamin B12. US 6, 190,693 is directed to pharmaceutical compositions, suitable as oral contraceptive or in hormone replacement therapy, containing folic acid.
US 6,011,040 relates to the use of tetrahydrofolates for influencing the homocysteine level, in particular for assisting the remethylation of homocysteine.
US 6,441, 168 describes stable crystalline salts of 5-methyltetrahydrofolιc acid.
SUMMARY OF THE INVENTION
In a first aspect, the present invention relates to a solid pharmaceutical composition comprising a progestogen, an estrogen, a tetrahydrofolic acid or a salt thereof, and at least one pharmaceutical acceptable excipient or carrier.
In another aspect, the present invention relates to a solid oral dosage form comprising a composition according to the invention.
Other aspects of the present invention will be apparent from the below disclosure and the appended claims.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 shows the stability of calcium 5-methyl-(6S)-tetrahydrofolate in a tablet prepared as described in Example 1. The Y-axis indicates the percentage of calcium 5-methyl-(6S)- tetrahydrofolate remaining after storage, as well as 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); A 40°C/75% RH (closed container).
Fig. 2 shows the dissolution of drospirenone, ethinylestradiol and calcium 5-methyl-(6S)- tetrahydrofolate from the tablets prepared in Example 1. The Y-axis indicates the amount dissolved, and the X-axis indicates the dissolution testing time in minutes. A drospirenone; ■ ethinylestradiol; ♦ calcium 5-methyl-(6S)-tetrahydrofolate.
Fig. 3 shows the dissolution of drospirenone from tablets prepared in the Examples. The Y- axis indicates the amount dissolved, and the X-axis indicates the dissolution testing time in minutes. ♦ Example 1 ; ■ Example 4; A Example 5; X Example 6; Δ Yasmin®; α Yaz®. DETAILED DESCRIPTION OF THE INVENTION
The term "estrogen" is meant to encompass all compounds (natural or synthetic, steroidal or non-steroidal compounds) exhibiting estrogenic activity. Such compounds encompass inter alia conjugated estrogens, estrogen receptor specific agonists and non-steroidal compounds exhibiting estrogenic activity. The term is further meant to encompass all isomeric and physical forms of the estrogens including hydrates, solvates, salts and complexes, such as complexes with cyclodextrins. More particularly, the estrogen may be selected from the group consisting of ethinylestradiol, estradiol, estradiol sulfamates, estradiol valerate, estradiol benzoate, estrone, mestranol, estπol, estriol succinate and conjugated estrogens, including conjugated equine estrogens such as estrone sulfate, 17β- estradiol sulfate, 17α-estradιol sulfate, equilin sulfate, 17β-dιhydroequιlιn sulfate, 17α- dihydroequihn sulfate, equilenin sulfate, 17β-dιhydroequιlenιn sulfate and 17α- dihydroequilenin sulfate. Particular interesting estrogens are selected from the group consisting of ethinylestradiol, estradiol, estradiol sulfamates, estradiol valerate, estradiol benzoate, estrone, mestranol and estrone sulfate. More preferably, the estrogen is selected from the group consisting of ethinylestradiol, estradiol and mestranol. The most preferred estrogen is ethinylestradiol
In the present context, the term "progestogen" (also sometimes referred to as "gestagen") covers synthetic hormone compounds which exert anti-estrogenic (counteracting the effects of estrogens in the body) and anti-gonadotropic (inhibiting the production of sex steroids and gonads) properties. Specific examples of progestogens include, but is not limited to, progestogens selected from the group consisting of levo-norgestrel, norgestrel, norethindrone (norethisterone), dienogest, norethindrone (norethisterone) acetate, ethynodiol diacetate, dydrogesterone, medroxyprogesterone acetate, norethynodrel, allylestrenol, lynestrenol, quingestanol acetate, medrogestone, norgestπenone, dimethisterone, ethisterone, chlormadinone acetate, megestrol, promegestone, desogestrel, 3-keto-desogestrel, norgestimate, gestodene, tibolone, cyproterone acetate and drospirenone. A particular preferred progestogen is drospirenone.
The term "therapeutically equivalent amount of ethinylestradiol", means that other estrogens are administered in amounts which give rise to the same therapeutic effect as does the specified amount of ethinylestradiol. Likewise, the term "therapeutically equivalent amount of drospirenone" means that other progestogens are administered in amounts which give rise to the same therapeutic effect as does the specified amount of drospirenone. It is routine for those skilled in the art to determine therapeutically equivalent amounts or dosages of such other estrogens and/or progestogens when the effective dose of ethinylestradiol and/or drospirenone is known. For example, the paper of Timmer and Geurts provides guidance of how equivalent doses may be determined (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). Moreover, reference is made to EP 1 253 607 which provides a detailed description of therapeutically equivalent amounts of ethinylestradiol and estradiol on the one hand, and various progestogens on the other hand. For further details concerning determination of dose equivalents of various estrogens and progestogens, reference is made to "Probleme der Dosisfmdung : Sexualhormone" [Problems of Dose-Finding : Sex Hormones] ; F. Neumann er a/, in "Arzneimittelforschung" ( Pharmaceutical Agent Research) 27, 2a, 296-318 ( 1977), as well as to "Aktuelle Entwicklungen in der hormonalen Kontrazeption" [Current Developments in Hormonal Contraception] ; H . Kuhl in Gynakologe" [Gynecologist] 25 : 231-240 ( 1992) .
When used herein, the term "micronised" is intended to mean that the particle size distribution is so that at least 90% of the particles have a particle diameter of less than 30 μm (calculated from the volume distribution curve under the presumption of spherical particles), i.e. a d90 value of at the most 30 μm. Therefore, it is important to note that whenever the terms "particle size distribution", "particle diameter", "d90", etc. are used herein it should be understood that the specific values or ranges used in connection therewith are always meant to be determined from the volume distribution curve under the presumption of spherical particles.
As will be understood from the present disclosure, including the examples provided herein, it is of utmost importance that the estrogen as well as the progestogen is released in a fast and reliable manner under neutral or acidic conditions. Thus, in the present context, the term "fast-release" or "immediate-release", when used in connection with the term estrogen, means that at least 70% of the estrogen, e.g. ethinylestradiol, is dissolved from the composition within 30 minutes, as determined by the USP XXIX Paddle Method II using water, or 0.1N HCI, at 37°C as the dissolution media and 50 rpm as the stirring rate. In a preferred embodiment of the invention at least 75%, more preferably at least 80%, even more preferably at least 85% of the estrogen, e.g. ethinylestradiol, is dissolved from the composition within 30 minutes when assayed as described above.
In an analogous manner, whenever the term "fast-release" or "immediate-release" is used in connection with the term progestogen, this means that at least 70% of the progestogen, e.g. drospirenone, is dissolved from the composition within 30 minutes, as determined by the USP XXIX Paddle Method II using water, or 0.1N HCI, at 37°C as the dissolution media and 50 rpm as the stirring rate. In a preferred embodiment of the invention at least 75%, more preferably at least 80%, even more preferably at least 85% of the progestogen, e.g. drospirenone, is dissolved from the composition within 30 minutes when assayed as described above.
Likewise, whenever the term "fast-release" or "immediate-release" is used in connection with the term tetrahydrofolic acid, this means that at least 70% of the tetrahydrofolic acid, e.g. calcium 5-methyl-(6S)-tetrahydrofolate, is dissolved from the composition within 30 minutes, as determined by the USP XXIX Paddle Method II using a 0.03% ascorbic acid aqueous solution (adjusted to pH 3.5 with 0.05 M phosphate buffer) at 37°C as the dissolution media and 50 rpm as the stirring rate. In a preferred embodiment of the invention at least 75%, more preferably at least 80%, even more preferably at least 85% or at least 90% of the tetrahydrofolic acid, e.g. calcium 5-methyl-(6S)-tetrahydrofolate, is dissolved from the composition within 30 minutes when assayed as described above.
The term "granulate composition" refers to a composition of a powder, wherein the particle size of the powder is either increased upon processing with a liquid or by compression. The liquid may be any kind of suitable aqueous or organic solvents, or mixtures thereof, optionally further comprising a binder. Thus, the term "granulate composition" covers granules, pellets and compressed powder or any particle formed by granulation, pelletation or compression of powder such that a mean particle size (d50) of at least about 100 μm is formed.
By the terms "granulating" and "granulation" are understood a mechanical process whereby a powder comprising the active component(s) and excipients are partly agglomerated into particles and/or granules having a larger particle size than the unprocessed powder. In one embodiment, the powdery mixture is contacted with a granulation liquid, which may contain a binder, swelled, partly dissolved or completely dissolved in the granulation liquid. The granulation liquid may be any suitable solvent, but generally aqueous solutions or just water are applicable. In one embodiment, the powdery mixture is contacted with the granulation liquid using suitable equipment for wet- granulation, such as fluidised bed equipment. Furthermore, high shear granulation can be used instead of fluidised bed granulation.
The term "estrogen-cyclodextπn complex" or "estrogen complexed with cyclodextrin" is intended to mean a complex between an estrogen and a cyclodextrin, wherein the estrogen molecule is at least partially inserted into the cavity of a cyclodextrin molecule. The molar ratio between the estrogen and the cyclodextrin may be adjusted to any desirable value. In interesting embodiments of the invention, a molar ratio between the estrogen and the cyclodextrin is from about 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. Furthermore, the estrogen molecule may at least partially be inserted into the cavity of two or more cyclodextrin molecules, e.g. a single estrogen molecule may be inserted into two cyclodextrin molecules to give 2: 1 ratio between cyclodextrin and estrogen. Similarly, the complex may contain more than one estrogen molecule at least partially inserted into a single cyclodextrin molecule, e.g. two estrogen molecules may be at least partially inserted into a single cyclodextrin molecule to give a 1 :2 ratio between cyclodextrin and estrogen. Complexes between estrogens and cyclodextrins may be obtained by methods known in the art, e.g. as described in US 5,798,338 and EP 1 353 700.
The term "ethmylestradiol-β-cyclodextπn complex" is intended to mean a complex, of any molar ratio, between ethinylestradiol and β-cyclodextπn. However, the ethmylestradiol-β- cyclodextπn complex described herein is typically a complex between one molecule of ethinylestradiol and two molecules of β-cyclodextnn, i.e. a 1 : 2 ethinylestradiol-β- cyclodextπn complex.
The term "progestogen-cyclodextπn complex" or "progestogen complexed with cyclodextrin" is intended to mean a complex between a progestogen and a cyclodextrin, wherein the progestogen molecule is at least partially inserted into the cavity of a cyclodextrin molecule. The molar ratio between the progestogen and the cyclodextrin may be adjusted to any desirable value. In interesting embodiments of the invention, a molar ratio between the progestogen and the cyclodextrin is from about 2: 1 to 1 : 10, preferably from about 1 : 1 to 1 : 5, most preferably from about 1 : 1 to 1 :3. Furthermore, the progestogen molecule may at least partially be inserted into the cavity of two or more cyclodextrin molecules, e.g. a single progestogen molecule may be inserted into two cyclodextrin molecules to give 2: 1 ratio between cyclodextrin and progestogen. Similarly, the complex may contain more than one progestogen molecule at least partially inserted into a single cyclodextrin molecule, e.g. two progestogen molecules may be at least partially inserted into a single cyclodextrin molecule to give a 1 :2 ratio between cyclodextrin and progestogen. Complexes between progestogens and cyclodextrins may be obtained by methods known in the art, e.g. as described in US 6,610,670 and references therein.
The term "drospirenone-β-cyclodextπn complex" is intended to mean a complex, of any molar ratio, between drospirenone and β-cyclodextπn as described in US 6,610,670. However, the drospirenone-β-cyclodextπn complex is typically a complex between one molecule of drospirenone and three molecules of β-cyclodextπn, i.e. a 1 :3 drospirenone-β- cyclodextπn complex. The term "cyclodextπn" is intended to mean a cyclodextrin or a derivative thereof as well as mixtures of various cyclodextπns, mixtures of various derivatives of cyclodextπns and mixtures of various cyclodextπns and their derivatives. The cyclodextrin may be selected from the group consisting of α-cyclodextπn, β-cyclodextπn, γ-cyclodextπn and derivatives thereof. The cyclodextrin may be modified such that some or all of the primary or secondary hydroxyl groups of the macrocycle are alkylated or acylated. Methods of modifying these hydroxyl groups are well known to the person skilled in the art and many such modified cyclodextπns are commercially available. Thus, some or all of the hydroxyl groups of the cyclodextrin may have been substituted with an O-R group or an O-C(O)-R gropu, wherein R is an optionally substituted C1 6 alkyl, an optionally substituted C2 6 alkenyl, an optionally substituted C2 6 alkynyl, an optionally substituted aryl or heteroaryl group. Thus, R may be a methyl, an ethyl, a propyl, a butyl, a pentyl, or a hexyl group, i.e. O-C(O)-R may be an acetate. Furthermore, the hydroxyl groups may be per- benzylated, per-benzoylated, benzylated or benzoylated on just one face of the macrocycle, i.e. only 1, 2, 3, 4, 5 or 6 hydroxyl groups is/are benzylated or benzoylated. Naturally, the hydroxyl groups may also be per-alkylated or per-acylated, such as per- methylated or per-acetylated, alkylated or acylated, such as methylated or acetylated, on just one face of the macrocycle, i.e. only 1, 2, 3, 4, 5 or 6 hydroxyl groups is/are alkylated or acylated, such as methylated or acetylated.
As will be understood, the solid composition of the invention contains at least one, such as one, estrogen as defined above. The estrogen may be selected from the group consisting of ethmylestradiol, estradiol, estradiol sulfamates, estradiol valerate, estradiol benzoate, estrone, mestranol and estrone sulphate, including micronised forms thereof. In a highly preferred embodiment of the invention, the estrogen is ethmylestradiol, in particular micronised ethmylestradiol. In one embodiment of the invention, the estrogen, in particular ethmylestradiol, is complexed with a cyclodextrin, such as described in EP 1 353 700. The cyclodextrin is typically selected from the group consisting of α-cyclodextπn, β- cyclodextπn, γ-cyclodextπn and derivatives thereof. In a particular interesting embodiment of the invention, the cyclodextrin is β-cyclodextπn or derivatives thereof. The estrogen- cyclodextπn complex may advantageously be in micronised form.
In addition, the solid composition of the invention contains at least one, such as one, progestogen as defined above. The progestogen may be selected from the group consisting of levo-norgestrel, norgestrel, norethindrone (norethisterone), norethindrone (norethisterone) acetate, dienogest, ethynodiol diacetate, dydrogesterone, medroxyprogesterone acetate, norethynodrel, allylestrenol, lynestrenol, quingestanol acetate, medrogestone, norgestnenone, dimethisterone, ethisterone, 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 selected from the group consisting of levo-norgestrel, norgestrel, norethindrone (norethisterone), norethindrone (norethisterone) acetate, dienogest, ethynodiol diacetate, desogestrel, norgestimate, gestodene, cyproterone acetate and drospirenone. In a highly preferred embodiment of the invention, the progestogen is drospirenone, in particular micronised drospirenone.
Accordingly, in a preferred embodiment of the invention the composition comprises levo- norgestrel and ethmylestradiol, norgestrel and ethinylestradiol, norethindrone (norethisterone) and ethinylestradiol, norethindrone (norethisterone) acetate and ethinylestradiol, dienogest and ethinylestradiol, ethynodiol 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 invention, the composition comprises drospirenone and ethinylestradiol, more preferably micronised drospirenone and micronised ethinylestradiol, e.g. micronised drospirenone and a micronised ethinylestradiol-cyclodextπn complex, such as micronised drospirenone and a micronised ethιnylestradιol-β-cyclodextπn complex.
In addition to the estrogen and the progestogen, the composition of the invention further comprises a tetrahydrofolic acid or a salt thereof. Specific examples of such tetrahydrofolic acids include 5-methyl-(6S)-tetrahydrofolιc acid, (6S)-tetrahydrofolιc acid, 5-formyl-(6S)- tetrahydrofohc acid, 10-formyl-(6R)-tetrahydrofolιc acid, 5, 10-methylene-(6R)- tetrahydrofohc acid, 5, 10-methenyl-(6R)-tetrahydrofolιc acid, 5-formιmιno-(6S)- tetrahydrofolic acid, including pharmaceutically acceptable salts of these tetrahydrofolic acids and glutamyl derivatives of these tetrahydrofolic acids. In a preferred embodiment of the invention, the tetrahydrofolic acid is 5-methyl-(6S)-tetrahydrofolιc acid or a pharmaceutically acceptable salt thereof. In a more preferred embodiment of the invention the salt of 5-methyl-(6S)-tetrahydrofolιc acid is an alkaline earth metal salt, in particular the calcium salt. The salt, such as the calcium salt, of 5-methyl-(6S)-tetrahydrofolιc acid should preferably be in crystalline form, such as the Type I crystalline form described in US 6,441,168. The type I crystalline form of calcium 5-methyl-(6S)-tetrahydrofolate is commercially available from Merck KGaA under the trademark Metafohn®. It is preferred that the composition of the invention does not contain other vitamins, in particular that the composition of the invention does not contain a vitamin B, such as vitamin B6 and/or vitamin B12. Accordingly, in a preferred embodiment of the invention, the composition contains a tetrahydrofolic acid as the sole vitamin component. The solid pharmaceutical composition of the invention contains one or more pharmaceutically acceptable excipients. These excipients may, for example, be:
- Inert diluents or fillers, such as sucrose, sorbitol, sugars, mannitol, microcrystalline cellulose, starches, sodium chloride, sodium phosphate, calcium carbonate, calcium phosphate, calcium sulfate, lactose, e.g. lactose monohydrate, or a combination thereof. The inert diluent or filler is typically present in an amount from 10-99% by weight of the composition. Preferably, the inert diluent or filler is present in an amount from 50-99% by weight of the composition, more preferably in an amount from 75-99% by weight of the composition, even more preferably in an amount from 80-97% by weight of the composition, most preferably in an amount from 85-97% by weight of the composition. As will be understood from the examples provided herein, highly preferred inert fillers are lactose, in particular lactose monohydrate, and microcrystalline cellulose.
Thus, in a preferred embodiment the composition of the invention comprises lactose monohydrate, microcrystalline cellulose or a combination of lactose monohydrate and microcrystalline cellulose in the amounts indicated supra. Accordingly, in one interesting embodiment of the invention, the composition comprises microcrystalline cellulose. The microcrystalline cellulose is typically present in an amount from 10-99% by weight of the composition, preferably in an amount from 50-99% by weight of the composition, more preferably in an amount from 75-99% by weight of the composition, even more preferably in an amount from 80-97% by weight of the composition, most preferably in an amount from 85-97% by weight of the composition. The microcrystalline cellulose may be the only or sole filler present in the composition, i.e. the composition of the invention may be free from other fillers than microcrystalline cellulose. In another interesting embodiment of the invention, the composition comprises lactose monohydrate. The lactose monohydrate is typically present in an amount from 10-99% by weight of the composition, preferably in an amount from 50-99% by weight of the composition, more preferably in an amount from 75-99% by weight of the composition, even more preferably in an amount from 80-97% by weight of the composition, most preferably in an amount from 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 invention may be free from other fillers than lactose monohydrate. In a highly preferred embodiment of the invention, the composition comprises microcrystalline cellulose and lactose monohydrate. The microcrystalline cellulose is typically present in an amount from 20-80% by weight of the composition and lactose monohydrate in an amount from 20-80% by weight of the composition. 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 composition comprises lactose monohydrate in an amount from 20-60% by weight of the composition and microcrystalline cellulose in an amount from 40-80% by weight of the composition, such as lactose monohydrate in an amount from 20-45% by weight of the composition and microcrystalline cellulose in an amount from 40-70% by weight of the composition, e.g. lactose monohydrate in an amount from 25-36% by weight of the composition and microcrystalline cellulose in an amount from 52-63% by weight of the composition. The microcrystalline cellulose and the lactose monohydrate may be the only fillers present in the composition, i.e. the composition of the invention may be free from other fillers than microcrystalline cellulose and lactose monohydrate. In another, and currently preferred, embodiment of this aspect of the invention lactose monohydrate constitutes the major part of the microcrystalline cellulose-lactose monohydrate filler system, i.e. the composition comprises microcrystalline cellulose in an amount from 20- 60% by weight of the composition and lactose monohydrate in an amount from 40-80% by weight of the composition. More preferably, the composition comprises microcrystalline cellulose in an amount from 20-45% by weight of the composition and lactose monohydrate in an amount from 40-70% by weight of the composition. Most preferably, the composition comprises microcrystalline cellulose in an amount from 25-36% by weight of the composition and lactose monohydrate in an amount from 52-63% by weight of the composition. The microcrystalline cellulose and the lactose monohydrate may be the only fillers present in the composition, i.e. the composition of the invention may be free from other fillers than microcrystalline cellulose and lactose monohydrate.
Microcrystalline cellulose is commercially available in different particle sizes and moisture grades. Examples of commercially available microcrystalline cellulose preparations include the Avicel® PH-seπes from FMC Biopolymer, the Emcocel® M-seπes from Penwest Pharmaceuticals Co. and the Vιvapur®-serιes from Rettenmaier & Sohne GmbH. A particular preferred commercial product to be used for the purposes described herein is Avicel® PH-IOl. Likewise, various lactose monohydrate grades having different physical properties, such as particle size distribution and flow characteristics, are commercially available. The grade of the lactose monohydrate may vary dependent on the specific dosage form to be prepared. For example, direct-compression grades of lactose monohydrate, such as Tablettose® (agglomerated) or grades for powder blends, such as Pharmatose® DCL 11 (spray-dried), have better flow properties and are more compressible than powdered or crystalline lactose monohydrate. Such lactose monohydrate preparations are not particularly preferred for the purposes described herein. Rather, the more fine grade lactose monohydrate preparations are preferred, such as powdered or crystalline lactose monohydrate, in particular crystalline lactose monohydrate where 90% of the particles have a diameter of less than 0.1 mm. - Binders, such as sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatine, starch, pregelatinised starch, magnesium aluminium silicate, carboxymethylcellulose sodium (CMC sodium), methylcellulose, ethylcellulose, hydroxypropylmethylcellulose ( HPMC), hydroxy- propylcellulose ( HPC), polyvinylacetate or polyethylene glycol. The binder is typically present in an amount from 0.1-10% by weight of the composition. Preferably, the binder is present in an amount from 0.2-5% by weight of the composition, such as from 0.5-5% by weight of the composition, more preferably in an amount from 1-3% by weight of the composition. In a preferred embodiment of the invention, the binder is HPC. It should be noted that while polyvinylpyrrolidone ( PVP) in many situations is the "binder of choice", in particular in connection with wet granulation processes, incorporation of PVP in the composition of the invention is not desirable due to the oxidising potential of this excipient. In fact, it was found by the present inventor that PVP accelerated the break-down of 5- methyl-(6S)-tetrahydrofolιc acid (data not shown).
Thus, due to degradation of the oxidation-sensitive tetrahydrofolic acid, the amount of PVP in the composition of the invention should be kept at an absolute minimum and should preferably be avoided. Thus, the composition of 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 of the invention is essentially free from PVP.
- Lubricants, including glidants and antiadhesives, such as magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils or talc. The lubricant is typically present in an amount from 0.1-10% by weight of the composition. Preferably, the lubricant is present in an amount from 0.2-5% by weight of the composition, such as from 0.5-5% by weight of the composition, more preferably in an amount from 1-3% by weight of the composition. In a preferred embodiment of the invention, the lubricant is magnesium stearate.
- Disintegrants, such as, sodium starch glycolate, maize starch, rice starch, potato starch, cross-linked povidone or carboxymethylcellulose-based disintegrants. Carboxymethylcellulose-based disintegrants may be present as free acid, but is preferably in the form of a salt, e.g . in the form of an alkali metal salt, such as the potassium salt or the sodium salt, in particular the sodium salt, or in the form of a salt of a divalent metal ion, such as the magnesium salt, the calcium salt or the zinc salt, in particular the calcium salt. The carboxymethylcellulose- based disintegrant may be cross-linked or non-cross-linked. Specific examples of preferred non-cross-linked carboxymethylcellulose-based disintegrants include carboxymethyl- cellulose calcium (carmellose calcium) and carboxymethylcellulose sodium (carmellose sodium), in particular carboxymethylcellulose calcium. In a highly preferred embodiment of the invention the carboxymethylcellulose-based disintegrant is cross-linked. A specific example of a preferred cross-linked carboxymethylcellulose-based disintegrant is cross- linked carboxymethylcellulose sodium (croscarmellose sodium). Croscarmellose sodium is commercially available under the tradenames Ac-Di-Sol®, Explocel® and Solutab®. The disintegrant is typically present in an amount from 0.1-10% by weight of the composition. Preferably, the disintegrant is present in an amount from 0.2-5% by weight of the composition, such as from 0.5-5% by weight of the composition, more preferably in an amount from 1-4% by weight of the composition.
- Surfactants and wetting agents, such as naturally occurring phosphatides, e.g. lechitin or soybean lechitin; condensation products of ethylene oxide with e.g. a fatty acid, a long chain fatty alcohol, or a partial ester derived from fatty acids and a hexitol or a hexitol anhydride, for example polyoxyethylene stearate, polyoxyethylene sorbitol monooleate, polyoxyethylene sorbitan monooleate, etc.; or salts of long-chain aliphatic phosphates, such as sodium lauryl sulphate.
Examples of other pharmaceutically acceptable excipients which may be incorporated in the solid pharmaceutical composition of the invention include colorants, flavouring agents, plasticizers, humectants, buffering agents, etc.
In those cases where the pharmaceutical formulation is in the form of a solid oral dosage form, in particular a solid unit dosage form (e.g. a tablet, sachet or capsule, in particular a tablet), the dosage form is adapted for oral administration and may be provided with a coating, such as a film coating, a sugar coating, or the like. Thus, a suitable coating for the dosage form according to the invention may, for example, be a sugar coating or a film coating based on one or more of the ingredients: Hydroxypropylmethylcellulose (HPMC), methylcellulose, ethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose sodium, acrylate polymers (e.g. Eudragit®), polyethylene glycols or polyvinylpyrrolidone.
In a highly preferred embodiment of the invention, the dosage form is in the form of a tablet, preferably a coated tablet, more preferably a film-coated tablet.
The uncoated tablet typically has a weight in the range from 50-150 mg, such as in the range of 60-125 mg, e.g. in the range of 60-100 mg, preferably in the range of 70-90 mg, e.g. about 80 mg. The dosage form typically contains an amount of progestogen corresponding to a therapeutically equivalent amount of drospirenone from 0 25-4 mg, such as in an amount corresponding to a therapeutically equivalent amount of drospirenone from 1-4 mg, e.g. in an amount corresponding to a therapeutically equivalent amount of drospirenone from 2-4 mg, preferably in an amount corresponding to a therapeutically equivalent amount of drospirenone from 2.5-3.5 mg, most preferably in an amount corresponding to a therapeutically equivalent amount of drospirenone of about 3 mg. As discussed above, the progestogen may be complexed with a cyclodextrin.
Moreover, the solid oral dosage form typically contains an amount of estrogen corresponding to a therapeutically equivalent amount of ethinylestradiol from 0.005-0.05 mg, such as in an amount corresponding to a therapeutically equivalent amount of ethinylestradiol from 0.01-0.05 mg, preferably in an amount corresponding to a therapeutically equivalent amount of ethinylestradiol from 0.015-0.035 mg, most preferably in an amount corresponding to a therapeutically equivalent amount of ethinylestradiol of about 0.02 mg or about 0.03 mg. As discussed above, the estrogen may be complexed with a cyclodextrin.
Thus, in a particular interesting embodiment of the invention, the dosage form comprises 0.25-4 mg drospirenone and 0.005-0.05 mg ethinylestradiol, such as 1-4 mg drospirenone and 0.005-0.05 mg ethinylestradiol, e.g. 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.
While the preferred progestogen is drospirenone, incorporation of other progestogens is indeed also within the scope of the present invention. More particularly, the dosage form may comprise desogestrel in an amount from 0.05-0.5 mg, preferably from 0.075-0.25 mg, such as 0.1 mg, 0.125 mg or 0.15 mg; ethynodiol diacetate in an amount from 0.25-2 mg, preferably 0.75-1.5 mg, such as 1 mg; levo-norgestrel in an amount from 0.025-0.3 mg, preferably from 0.075-0.25 mg, such as 0.1 mg or 0.15 mg; norethindrone (norethisterone) in an amount from 0.2-1.5 mg, preferably 0.3-1.25 mg, such as 0.4 mg, 0.5 mg or 1 mg; norethindrone (norethisterone) acetate in an amount from 0.5-2 mg, preferably 1-1.5 mg, such as 1 mg or 1.5 mg; norgestrel in an amount from 0.1-1 mg, preferably from 0.25-0.75 mg, such as 0.3 mg or 0.5 mg; norgestimate in an amount from 0.1-0.5 mg, preferably 0.15-0.3 mg, such as 0.18 mg, 0.215 mg or 0.25 mg; cyproterone acetate in an amount from 1-2 mg, preferably 2 mg; dienogest in an amount from 2-3 mg, preferably 2 mg; gestodene in an amount from 0.05-0.1 mg, preferably from 0.06-0.075 mg, such as 0.075 mg; and tibolone in an amount from 2-3 mg, such as 2.5 mg. Likewise, while the preferred estrogen is ethinylestradiol, incorporation of other estrogens is indeed also within the scope of the present invention . More particularly, the dosage form may comprise estradiol in an amount from 1-4 mg or mestranol from 0.01-0.1 mg, preferably from 0.025-0.075 mg, such as 0.05 mg. Specific examples of progestogen-estrogen combinations, including preferred dosages, are given in the below table:
Progestogen Estrogen Product name
Drospirenone Ethinylestradiol 0.25-4 mg 0.005-0.05 mg
1-4 mg 0.005-0.05 mg
2-4 mg 0.01-0.05 mg
2.5-3.5 mg 0.015-0.035 mg
3 mg 0.03 mg Yasmin®, monophasic 3 mg 0.02 mg Yaz®, monophasic, 24 day regimen
cyproterone acetate Ethinylestradiol 1-2 mg 0.01-0.05 mg 2 mg 0.035 mg Dιane-35®, monophasic
Dienogest Ethinylestradiol 2-3 mg 0.01-0.05 mg 2 mg 0.03 mg Valette®, monophasic
Gestodene Ethinylestradiol 0.05-0.1 mg 0.01-0.05 mg 0.06-0.075 mg 0.015-0.035 mg 0.075 mg 0.03 mg Femovan®, monophasic
Desogestrel Ethinylestradiol 0.05-0.5 mg 0.01-0.05 mg 0.075-0.25 mg 0.015-0.035 mg 0.15 mg 0.03 mg Desogen®, monophasic
0.15 mg (21 days) 0.02 mg (21 days) Mircette®, biphasic 0.01 mg (5 days) 0.1 mg 0.025 mg Cyclessa®, triphasic
0.125 mg 0.025 mg
0.15 mg 0.025 mg
Ethynodiol diacetate Ethinylestradiol
0.25-2 mg 0.01-0.05 mg
0.75-1.5 mg 0.015-0.035 mg
1 mg 0.035 mg Demulen 1/35®, monophasic
1 mg 0.05 mg Demulen 1/50®, monophasic
Levo-norgestrel Ethinylestradiol
0.025-0.3 mg 0.01-0.05 mg
0.075-0.25 mg 0.015-0.035 mg
0.1 mg 0.02 mg Levlite®, Miranova®, monophasic 0.125 mg 0.03 mg Monostep®, monophasic
0.15 mg 0.03 mg Levlen®, Microgynon®, monophasic
0.05 mg 0.03 mg Triphasil®, Novastep®, Triquilar®,
0.075 mg 0.04 mg triphasic 0.125 mg 0.03 mg
Norethindrone Ethinylestradiol
0.2-1.5 mg 0.01-0.05 mg
0.3-1.25 mg 0.015-0.035 mg 0.4 mg 0.035 mg Ovcon-35®, monophasic
0.5 mg 0.035 mg Modicon®, monophasic
1 mg 0.035 mg Ortho-Novum 1-35®, monophasic
1 mg 0.05 mg Ovcon 50®, monophasic
0.5 mg 0.035 mg Ortho Novum 10-11®, Diphasic
1 mg 0.035 mg
0.5 mg 0.035 mg Ortho Novum 7-7-7®, triphasic
0.75 mg 0.035 mg 1 mg 0.035 mg
0.5 mg 0.035 mg Tri-Norinyl®, triphasic
1 mg 0.035 mg
0.5 mg 0.035 mg Norethindrone Mestranol 0.2-1.5 mg 0.01-0.1 mg 0.3-1.25 mg 0.025-0.075 mg 1 mg 0.050 mg Ortho-Novum 1-50®, monophasic
Norethindrone acetate Ethinylestradiol 0.5-2 mg 0.01-0.05 mg 1-1.5 mg 0.015-0.035 mg 1 mg 0.02 mg Loestrin 1-20®, monophasic 1 mg 0.02 mg Loestrin 24 FE®, 24 day regimen 1.5 mg 0.03 mg Loestrin 1.5-30®, monophasic
1 mg 0.02 mg Estrostep®, triphasic 1 mg 0.03 mg
1 mg 0.035 mg
Norgestrel Ethinylestradiol 0.1-1 mg 0.01-0.05 mg 0.25-0.75 mg 0.015-0.035 mg 0.3 mg 0.03 mg Lo-Ovral®, monophasic 0.5 mg 0.05 mg Ovral®, monophasic
Norgestimate Ethinylestradiol 0.1-0.5 mg 0.01-0.05 mg 0.15-0.3 mg 0.015-0.035 mg 0.25 mg 0.025 mg Ortho Tri-Cyclen Lo® 0.25 mg 0.035 mg Ortho-Cyclen®, monophasic
0.18 mg 0.035 mg Ortho- Tri-Cyclen®, triphasic 0.215 mg 0.035 mg 0.25 mg 0.035 mg
0.18 mg 0.025 mg Ortho- Tri-Cyclen Lo®, triphasic 0.215 mg 0.025 mg 0.25 mg 0.025 mg The solid oral dosage form typically contains a tetrahydrofolic acid in an amount from 0.1- 5 mg, such as in an amount from 0.1-2.5 mg, e.g. in an amount from 0.2-0.8 mg, preferably in an amount from 0.3-0.7 mg, more preferably in an amount from 0.4-0.6 mg, most preferably in an amount from 0.42-0.49 mg. As explained above, the tetrahydrofolic acid is preferably 5-methyl-(6S)-tetrahydrofolιc acid or a pharmaceutically acceptable salt thereof, such as an alkaline earth metal salt, in particular the calcium salt. The salt, such as the calcium salt, of 5-methyl-(6S)-tetrahydrofolιc acid should preferably be in crystalline form, such as the Type I crystalline form described in US 6,441,168.
The various excipients may be incorporated in the dosage form of the invention in the amount indicated previously. However, in an interesting embodiment of the invention the dosage form comprises microcrystalline cellulose, lactose monohydrate or a combination of microcrystalline cellulose and lactose monohydrate Accordingly, in one interesting embodiment of the invention the dosage form comprises microcrystalline cellulose in an amount from 5-80 mg, such as from 10-80 mg. Preferably, the dosage form comprises microcrystalline cellulose in an amount from 40-80 mg. More preferably, the dosage form comprises microcrystalline cellulose in an amount from 60-80 mg. Even more preferably, the dosage form comprises microcrystalline cellulose in an amount from 65-80 mg. Most preferably, the dosage form comprises microcrystalline cellulose in an amount from 65-77 mg. The microcrystalline cellulose may be the only or sole filler present in the dosage form, i.e. the dosage form of the invention may be free from other fillers than microcrystalline cellulose. In another interesting embodiment of the invention the dosage form comprises lactose monohydrate in an amount from 5-80 mg, such as from 10-80 mg. Preferably, the dosage form comprises lactose monohydrate in an amount from 40-80 mg. More preferably, the dosage form comprises lactose monohydrate in an amount from 60- 80 mg. Even more preferably, the dosage form comprises lactose monohydrate in an amount from 65-80 mg. Most preferably, the dosage form comprises lactose monohydrate in an amount from 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 invention may be free from other fillers than lactose monohydrate. In a highly interesting embodiment of the invention the dosage form comprises microcrystalline cellulose in an amount from 15-65 mg and lactose monohydrate in an amount from 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 from 15-50 mg and microcrystalline cellulose in an amount from 25-65 mg. Even more preferably, the dosage form comprises lactose monohydrate in an amount from 15-35 mg and microcrystalline cellulose in an amount from 30-55 mg. Most preferably, the dosage form comprises lactose monohydrate in an amount from 20- 30 mg and microcrystalline cellulose in an amount from 40-50 mg. In another, and currently preferred, embodiment of this aspect of the invention lactose monohydrate constitutes the major part of the microcrystalline cellulose-lactose monohydrate filler system, i.e. the dosage form comprises microcrystalline cellulose in an amount from 15-50 mg and lactose monohydrate in an amount from 25-65 mg. Even more preferably, the dosage form comprises microcrystalline cellulose in an amount from 15-35 mg and lactose monohydrate in an amount from 30-55 mg. Most preferably, the dosage form comprises microcrystalline cellulose in an amount from 20-30 mg and lactose monohydrate in an amount from 40-50 mg
The present inventor surprisingly found that the problem concerning stability of a tetrahydrofolic acid as well as the problem associated with obtaining fast-release of the progestogen from tablets prepared by direct compression could in fact be, at least partly, solved by preparing the composition by means of granulation, i.e. in a preferred embodiment the composition of the invention is a granulate composition; Due to the exposure to mechanical stress and humidity during the granulation process, the skilled person would not contemplate preparing a tetrahydrofolic acid-containing composition by granulation as he would expect the air- and moisture-sensitive tetrahydrofolic acid to degrade significantly under such manufacturing conditions. Nevertheless, the present inventor went against this prejudice and found, by combining granulation with proper selection of excipients, that a stable (with respect to the tetrahydrofolic acid) granulate composition, which simultaneously fulfilled the necessary requirements with respect to fast-release of the estrogen and the progestogen, could be obtained.
Thus, as will be understood from the discussion supra as well as the examples provided herein, the composition of the invention is preferably prepared by means of a granulation process, i.e. the drug substances, including the tetrahydrofolic acid, together with appropriate excipients, are subjected to a granulation process, preferably a wet granulation process, such as a fluid bed granulation process. Accordingly, in a preferred embodiment the composition of the invention is a granulate composition. After the granulation process, the granules can be processed further into the final dosage form. In one embodiment of the invention the granules may be filled into sachets or capsules, such as hard gelatine capsules. However, in a preferred embodiment of the invention the granules are processed into tablets by compression and subsequently film-coated. As will be understood, the tetrahydrofolic acid may, in one embodiment of the invention, be added before or during the granulation process. In this case the tetrahydrofolic acid can be regarded as an "inner phase" component since it forms part of the granule as such. In another embodiment of the invention, the tetrahydrofolic acid is added to the granules at the end of the granulations process, or after the granulation process has been completed, i.e. the tetrahydrofolic acid can be regarded as an "outer component". Thus, the tetrahydrofolic acid may be incorporated in the granules as an "inner phase" component, as an "outer phase" component or as a combination thereof. In a preferred embodiment of the invention, the tetrahydrofolic acid is present as an "outer phase" component.
Accordingly, the present invention is also directed to a process for the manufacture of a composition according to the invention, which comprises the steps of:
(ι) subjecting a progestogen, an estrogen and at least one pharmaceutical acceptable excipient to a granulation process,
(ιι) mixing a tetrahydrofolic acid or a salt thereof with the granules formed in step
(ι), and
(in) optionally continuing the granulation process, and/or
(ιv) optionally collecting the granules.
In step (ι), the progestogen, the estrogen and at least one pharmaceutical acceptable excipient, such as lactose monohydrate, microcrystalline cellulose or a combination thereof, is loaded into a granulator, preferably a fluidised bed granulator. A granulation liquid, typically containing a binder such as HPC, is then applied and, in the case of fluidised bed granulation, the granulation liquid is sprayed continuously onto the fluidised bed while heating the air stream of the fluidised bed. In order to avoid degradation of the tetrahydrofolic acid during the granulation process, it is preferred that the tetrahydrofolic acid or a salt thereof is mixed with the granules formed in step (ι) at the end of, near the end of, or after, the granulation process. If desired, the granulation process may, however, be continued after addition of the tetrahydrofolic acid. Typically, a disintegrant and a lubricant are also mixed with the granules formed in step (ι) together with the tetrahydrofolic acid.
The granules obtainable by the above process may be further process into a desired dosage form, e.g. a tablet, by compression. Thus, in a further aspect the present invention is also directed to a process for the manufacture of a solid oral dosage form according to the invention, which comprises the steps of:
(ι) preparing granules according to the process according to the invention, and
(ιι) formulating the granules into solid oral dosage forms. While the composition of the invention is preferably in the form of a granulate composition which may subsequently be processed into the desired dosage form, it is contemplated that in case low-dose progestogen dosage forms are prepared, the fast-release problems associated with this active component will not be as pronounced as when higher doses of the progestogen, in particular drospirenone, are required in the dosage form. Accordingly, the present invention also relates to a tablet, in particular a tablet prepared by direct compression, comprising a progestogen, an estrogen, a tetrahydrofolic acid or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical acceptable excipient or carrier, wherein the amount of the progestogen is from 0.025- 1.5 mg, such as 0.025- 1 mg, 0.05- 1 mg, 0.075-0.75 mg or 0.1-0.5 mg. It should be understood that all statements made above, in particular the statements concerning preferred excipients, preferred progestogens, preferred estrogens, preferred tetrahydrofolic acids as well as relevant amounts of such components, apply mutatis mutandis to this aspect of the invention.
Furthermore, while the composition of the invention preferably comprises a progestogen as well as an estrogen, it should be understood that compositions and dosage forms may be prepared according to the present invention, but where such compositions and dosage forms does not contain an estrogen. One example of such a dosage form is Microlut® (also known as the "mini-pill"), which contains 0.03 mg levo-norgestrel and no estrogen. Accordingly, in a further aspect, the present invention relates to a solid pharmaceutical composition comprising a progestogen, a tetrahydrofolic acid or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical acceptable excipient or carrier. As will be understood, all statements made above, in particular the statements concerning preferred excipients, preferred progestogens, preferred tetrahydrofolic acids as well as relevant amounts of such components, apply mutatis mutandis to this aspect of the invention.
Concerning the stability of the tetrahydrofolic acid, the normal specification limits of an active ingredient must be applied. A suitable reference is the USP XXIX monograph "Folic acid tablets", which specifies that a content of 90-115% of the declared amount of the folic acid must subsequently be identifiable in the product. The compositions and the dosage forms provided by the present invention fulfil the above-mentioned regulatory requirements. Expressed differently, the composition or the dosage form of the invention has a stability such that at least 80% of the initial amount of the tetrahydrofolic acid is present in the composition or in the dosage form after storage in a closed container for 24 months at 25°C and 60% relative humidity. In addition, or in the alternative, the composition or the dosage form of the invention has a stability such that at least 90%, preferably at least 95%, of the initial amount of the tetrahydrofolic acid is present in the composition or in the dosage form after storage in a closed container for 12 months at 25°C and 60% relative humidity. In the present context, the term "initial content", when used in connection with a tetrahydrofolic acid, refers to the measured amount of the tetrahydrofolic acid determined immediately after the manufacture of the composition or dosage form or, alternatively, after storage in a closed container for not more than 5 days at 25°C and 60% relative humidity. Thus, the term "initial amount" neither refers to the declared amount of the tetrahydrofolic acid, nor to the theoretical amount of (added) tetrahydrofolic acid, but rather to the measured amount of the tetrahydrofolic acid present in the composition or dosage form determined immediately after its manufacture or after storage for a short period of time as described above.
In another embodiment, the composition or the dosage form of the invention has a stability such that at least 80% of the declared amount of the tetrahydrofolic acid is present in the composition or in the dosage form after storage in a closed container for 24 months at 25°C and 60% relative humidity. In addition, or in the alternative, the composition or the dosage form of the invention has a stability such that at least 90%, preferably at least 95%, of the declared amount of the tetrahydrofolic acid is present in the composition or in the dosage form after storage in a closed container for 12 months at 25°C and 60% relative humidity. In the present context, the term "declared amount" refers to the officially declared amount of the tetrahydrofolic acid present in the composition or the dosage. The declared amount of the tetrahydrofolic acid is normally apparent from the information provided in the leaflet.
In still another embodiment, the composition or the dosage form of the invention has a stability such that the sum of the tetrahydrofolic acid decomposition products is at the most 10%, preferably at the most 8%, more preferably at the most 6%, even more preferably at the most 5%, most preferably at the most 4%, after storage in a closed container for 6 months or 12 months at 250C and 60% relative humidity. The sum of tetrahydrofolic acid decomposition products may be determined as described in the section entitled "Determination of decomposition products" herein.
In yet another embodiment, the composition or the dosage form of the invention has a stability such that the sum of tetrahydrofolic acid decomposition products is at the most 10%, preferably at the most 8%, more preferably at the most 6%, even more preferably at the most 5%, most preferably at the most 4%, after storage in a closed container for 1 month, 2 months or 3 months at 400C and 75% relative humidity. The sum of the tetrahydrofolic acid decomposition products may be determined as described in the section entitled "Determination of decomposition products" herein. As is evident from the disclosure herein, the compositions or the dosage forms of the invention are suitable for inhibition of ovulation in a female, i.e. for providing female contraception. In addition, due to the presence of a tetrahydrofolic acid or a salt thereof, the compositions and dosage forms of the invention are also useful for the treatment or prevention of folate deficiency, including anemia and bleedings.
In a further particular embodiment, the present invention relates to a pharmaceutical preparation or kit consisting essentially of 21, 22, 23 or 24, in particular 21 or 24, separately packed and individually removable solid oral dosage units according to the invention placed in a packaging unit, and 7, 6, 5 or 4, in particular 7 or 4, separately packed and individually removable solid oral dosage units containing a tetrahydrofolic acid as the sole active agent placed in a packaging unit.
The dosage forms containing a tetrahydrofolic acid as the sole active agent may be prepared by any method known in the art as long as the tetrahydrofolic acid still fulfils the stability criteria discussed herein. In one embodiment, the dosage form containing a tetrahydrofolic acid as the sole active agent is essentially identical to the dosage forms described herein, but no progestogens and estrogens are included.
The preparation (or kit) may be a one-phase preparation, i.e. a preparation wherein the amounts of the progestogen and the estrogen remain constant for the entire 21-, 22-, 23- or 24-day period. Alternatively, amounts of either or both active agents (i.e. the progestogen and the estrogen) may be varied over the 21-, 22-, 23- or 24-day period to generate a multiple-phase preparation, e.g. a two- or three-phase preparation, such as descried in, e.g., US 4,621,079. Thus, while the preparation may be a one-phase or a multiple phase preparation, the amount of the tetrahydrofolic acid preferably remains constant throughout the entire cycle, i.e. for all 28 days.
A packaging unit comprising the dosage forms described above may be prepared in a manner analogous to that of making other oral contraceptives. This may for instance be a conventional blister pack or any other form known for this purpose, for instance a pack comprising the appropriate number of dosage units (in this case typically 28 or a multiple of 28) in a sealed blister pack with a cardboard, paperboard, foil or plastic backing and enclosed in a suitable cover.
Likewise, the compositions or the dosage forms of the invention are also suitable for treatment of diseases, conditions or symptoms associated with deficient endogenous levels of estrogen in women. In this case, the above-mentioned progestogens are preferably combined with an estrogen selecetd from the group consisting of estradiol, estradiol sulfamates, estradiol valerate, estradiol benzoate. A specific example of a preferred dosage form comprises 0.25-3 mg drospirenone and 0.5-2 mg estradiol, such as 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 (Angehq®). Other examples include compositions or dosage forms comprising estradiol valerate and cyproterone acetate, estradiol valerate and dienogest, ethinylestradiol and gestodene, and ethinylestradiol and levo-norgestrel. Deficient levels of estrogen can occur for a variety of reasons. For example, deficient levels of estrogen may be caused by e.g. natural menopause, pen-menopause, post-menopause, hypogonadism, castration or primary ovarian failure. Low levels of estrogen, irrespective of the cause, lead to an overall decreased quality of life for women. Symptoms, diseases and conditions range from merely being inconvenient to life threatening. The compositions and dosage forms described herein provide effective alleviation of all physiological and psychological signs of estrogen deficiency. Transient symptoms, such as vasomotor signs and psychological symptoms are certainly embodied with the realm of therapy. Vasomotor signs comprise but are not limited to hot flushes, sweating attacks such as night sweats, and palpitations. Psychological symptoms of estrogen deficiency comprise, but are not limited to, insomnia and other sleep conditions, poor memory, loss of confidence, mood changes, anxiety, loss of libido, difficulties in concentration, difficulty in making decisions, diminished energy and drive, irritability and crying spells. The treatment of the aforementioned symptoms can be associated with the peπ-menopausal phase of a woman's life or after, sometimes long time after, menopause. It is anticipated that the compositions and dosage forms described herein are applicable to these and other transient symptoms during the peπ-menopausal phase, menopause, or post-menopausal phase. Moreover, the aforementioned symptoms can be alleviated if the cause of the estrogen deficiency is hypogonadism, castration or primary ovarian failure. In another embodiment of the invention, the compositions or dosage forms described herein are used for the treatment of permanent effects of estrogen deficiency. Permanent effects comprise physical changes such as urogenital atrophy, atrophy of the breasts, cardiovascular disease, changes in hair distribution, thickness of hair, changes in skin condition and osteoporosis. Urogenital atrophy, and conditions associated with it such as vaginal dryness, increase in vaginal pH and subsequent changes in flora, or events which lead to such atrophy, such as decreases in vascularity, fragmentation of elastic fibres, fusion of collagen fibres, or decreases in cell volume, are symptoms thought to be particularly relevant to be treated with the compositions or dosage forms described herein. Furthermore, the compositions or dosage forms described herein are thought to be relevant to other urogenital changes associated with estrogen deficiency, decreases in mucus production, changes in cell population, decreases in glycogen production, decreases in growth of lactobacilli or increases in growth of streptococci, staphylococci, or coliform bacilli. Other associated changes that are thought to be preventable by administration of the compositions or dosage forms described herein are those that may render the vagina susceptible to injury or infection, such as exudative discharges, vaginitis, and dyspareunia. Furthermore, infections of the urinary tract and incontinence are other common symptoms associated with lowered estrogen levels. Other embodiments of the invention include the prevention or alleviation of physical changes associated with estrogen deficiency, such as changes in the skin, changes in hair distribution, thickness of hair, atrophy of the breasts, or osteoporosis. The prevention and management of osteoporosis, most notably post-menopausal osteoporosis, is a particularly interesting embodiment of the invention. Furthermore, bone deminerahsation, reduction of bone mass and density, thinning and interruption of trabeculae, and/or consequent increase in bone fractures or bone deformations are thought to be particularly relevant. The prophylactic treatment of osteoporosis is an interesting therapeutic application of the compositions or dosage forms of the invention. A particularly interesting embodiment of the invention is directed to lessening the frequency, persistence, duration and/or severity of hot flushes, sweating attacks, palpitations, sleep conditions, mood changes, nervousness, anxiety, poor memory, loss of confidence, loss of libido, poor concentration, diminished energy, diminished drive, irritability, urogenital atrophy, atrophy of the breasts, cardiovascular disease, changes in hair distribution, thickness of hair, changes in skin condition and osteoporosis (including prevention of osteoporosis), most notably hot flushes, sweating attacks, palpitations, sleep conditions, mood changes, nervousness, anxiety, urogenital atrophy, atrophy of the breasts, as well as prevention or management of osteoporosis. Another interesting embodiment of the invention is directed to treatment of hot flushes, sweating attacks, palpitations, sleep conditions, mood changes, nervousness, anxiety, poor memory, loss of confidence, loss of libido, poor concentration, diminished energy, diminished drive, irritability, urogenital atrophy, atrophy of the breasts, cardiovascular disease, changes in hair distribution, thickness of hair, changes in skin condition and osteoporosis (including prevention of osteoporosis), most notably hot flushes, sweating attacks, palpitations, sleep conditions, mood changes, nervousness, anxiety, urogenital atrophy, atrophy of the breasts, as well as prevention or management of osteoporosis.
The invention is further illustrated by the following non-limiting examples. MATERIALS AND METHODS
Determination of decomposition products
Separation and quantification of calcium 5-methyl-(6S)-tetrahydrofolate as well as of its degradation is conducted by HPLC on a reversed-phase column (Ph. Eur. 2.2.9, USP <621>, JP No. 27) using an external calibration standard. Samples must be analysed without delay.
Detector: UV detection at 280 nm
For identity: DAD detector 210-250 nm
Injection volume: 10 μl Column: Steel, length: 5 cm; Inner diameter: 4.6 mm
Stationary phase: Atlantis® C18; 3 μm or equivalent Temperature of column oven : 35°C Flow rate: 2 ml/min Mobil phase: A: 0.05 M NaH2PO4 adjusted to pH 3.50-3.55 with phosphoric acid
B: Methanol
C: Water Gradient: Time (min) %A (v/v) %B (v/v) %C(v/v) start 99 1 0
26 73 27 0
26 0 27 73
27 0 27 73
27 0 90 10
35 0 90 10
Peak assignment Comments t£ (re\) ABGA degradation product 0.39 L-MEFOX degradation product 0.75 calcium 5-methyl-(6S)- active ingredient 1 tetrahvdrofolate Dissolution
Dissolution of ethinylestradiol and drospirenone was investigated by the USP XXIX Paddle Method II using water at 37°C as the dissolution media and 50 rpm as the stirring rate.
Dissolution of calcium 5-methyl-(6S)-tetrahydrofolate was investigated by the USP XXIX Paddle Method II using a 0 03% ascorbic acid aqueous solution (adjusted to pH 3.5 with 0 05 M phosphate buffer) at 37°C as the dissolution media and 50 rpm as the stirring rate.
EXAMPLES
Example 1 - Direct compression; microcrystalline cellulose
A tablet core of 80 mg having the following composition was prepared by direct compression:
Ingredient Amount (mg)
Ethinylestradiol (as micronised β-cyclodextπn 0.030 complex)
Micronised drospirenone 3.000 Metafolm® 0.451
Microcrystalline cellulose (Avicel® PH-IOl) 73.319
Croscarmellose sodium 1.600
Magnesium stearate 1.600
The stability of calcium 5-methyl-(6S)-tetrahydrofolate upon storage under various conditions was tested. The following stability data (see Tables 1 and 2 below) were obtained upon storage at 25°C/60% RH and 40°C/75% RH, respectively. Stability was tested in open as well as closed containers.
Table 1 Sum of decomposition products in %
Months 25°C/60%RH 25°C/60%RH 40°C/75%RH 40°C/75%RH closed open closed open
0 2.1 2.1 2.1 2.1
1 2.4 2.6 3.0 7.2
3 2.7 2.6 3.2 15.0
6 3.2 - 4.2 -
9 3.6 - 5.1 -
12 5.2 - - - Table 2 Amount of Metafolin® in %
Months 25°C/60%RH 40°C/75%RH closed closed
0 101.2 101.2
1 103.1 101.2
3 99.2 96.0
6 99.8 94.3
9 98.8 96.6
12 103.1 -
As can be seen, a satisfactory stability of calcium 5-methyl-(6S)-tetrahydrofolate was obtained at 25°C, even under conditions were the tablet was allowed to be exposed to open air. Furthermore, a satisfactory stability was obtained at 40°C (closed container), whereas a significant degradation of calcium 5-methyl-(6S)-tetrahydrofolate was seen when the tablet was stored at 400C and, at the same time, exposed to open air. The above stability data are also depicted in Fig. 1.
The dissolution profiles are shown in Fig. 2. As can be seen from Fig. 2, ethinylestradiol and calcium 5-methyl-(6S)-tetrahydrofolate were released immediately from the tablet composition, whereas the dissolution of drospirenone was unsatisfactory slow. This finding was surprising, in particular since the tablet disintegrated within 5 minutes under the conditions used.
Example 2 - Direct compression; Cellactose® (lactose monohydrate/cellulose powder)
A tablet core of 80 mg having the following composition was prepared by direct compression :
Ingredient Amount (mg)
Ethinylestradiol (as micronised β-cyclodextπn 0.030 complex) Micronised drospirenone 3.000
Metafolin® 0.451
Cellactose® 73.319
Croscarmellose sodium 1.600
Magnesium stearate 1.600 The stability of calcium 5-methyl-(6S)-tetrahydrofolate upon storage under various conditions was tested. The following stability data (see Tables 3 and 4 below) were obtained upon storage at 25°C/60% RH and 40°C/75% RH, respectively. Stability was tested in open as well as closed containers.
Table 3: Sum of decomposition products in %
Months 25°C/60%RH 25°C/60%RH 40°C/75%RH 40°C/75%RH closed open closed open
0 2.3 2.3 2.3 2.3
1 3.0 3.3 3.9 12.7
9 4.3 - 5.9 -
12 5.1 _ 7.9 _
Table 4: Amount of Metafohn® in %
Months 25°C/60%RH 40°C/75%RH closed closed
0 96.0 96.0
1 97.0 95.0
9 97.1 94.9
12 96.1 -
As can be seen, a satisfactory stability of calcium 5-methyl-(6S)-tetrahydrofolate was obtained at 25°C. However, like in Example 1, the dissolution of drospirenone was unsatisfactory slow.
Example 3 - Direct compression; Tablettose® (lactose monohydrate)
A tablet core of 80 mg having the following composition was prepared by direct compression :
Ingredient Amount (mg)
Ethinylestradiol (as micronised β-cyclodextrin 0.030 complex)
Micronised drospirenone 3.000
Metafolin® 0.451
Tablettose® 74.119
Starch 1500® 1.600 Magnesium stearate 0.800
The stability of calcium 5-methyl-(6S)-tetrahydrofolate was found not to be satisfactory when stored at 25°C/60% RH and 40°C/75% RH, respectively. Like in Examples 1 and 2, the dissolution of drospirenone was unsatisfactory slow.
Example 4 - Direct compression; microcrystalline cellulose/lactose monohydrate
In order to investigate whether the dissolution of drospirenone could be increased, it was decided to prepare a tablet according to Example 1, but where about one third of the microcrystalline cellulose was replaced by lactose monohydrate (despite lactose monohydrate's destabilising effect on calcium 5-methyl-(6S)-tetrahydrofolate, cf. Examples 2 and 3).
Thus, a tablet core of 80 mg having the following composition was prepared by direct compression:
Ingredient Amount (mg)
Ethinylestradiol (as micronised β-cyclodextrin 0.030 complex)
Micronised drospirenone 3.000
Metafolin® 0.451
Microcrystalline cellulose (Avicel® PH-IOl) 48.899
Lactose monohydrate (Pharmatose® DCL 11) 24.420 Croscarmellose sodium 1.600
Magnesium stearate 1.600
A satisfactory stability of calcium 5-methyl-(6S)-tetrahydrofolate upon various storage conditions was observed.
The dissolution profile is shown in Fig. 3, and as can be seen from Fig. 3 dissolution of drospirenone was unsatisfactory slow and almost identical to the release profile obtained for the tablet prepared in Example 1. Example 5 - Fluidised bed granulation; microcrystalline cellulose/lactose monohydrate
A tablet core of 80 mg having the following composition was prepared
Ingredient Amount (mg)
Ethinylestradiol (as micronised β-cyclodextπn 0.020 complex)
Micronised drospirenone 3.000 Metafolm® 0.451
Microcrystalline cellulose (Avicel® PH 101) 24.800
Lactose monohydrate, crystalline 45.319
HPC, viscosity 5 1.600
Croscarmellose sodium 3.200 Magnesium stearate 1.600
A granulate preparation was prepared by charging a fluidised bed granulator with drospirenone, ethinylestradiol, lactose monohydrate, microcrystalline cellulose and activating the fluidised bed. An aqueous solution of binder (HPC) was sprayed continuously onto the fluidised bed while drying by heating the air stream of the fluidised bed. At the end of the process, calcium 5-methyl-(6S)-tetrahydrofolate, crosscarmellose and magnesium stearate were sucked into the granulator and mixed with the granules by maintaining the fluidised bed. The resulting granulates were compressed into tablet cores using a tablet press.
A satisfactory stability of calcium 5-methyl-(6S)-tetrahydrofolate upon various storage conditions was observed.
Furthermore, and as can be seen from Fig. 3, an immediate-release profile of drospirenone was observed, i.e. the dissolution of drospirenone was comparable to the dissolution profile of the dropirenone-containing oral contraceptive Yasmin®. Example 6 - Fluidised bed granulation; microcrystalline cellulose
A tablet core of 80 mg having the following composition was prepared
Ingredient Amount (mg)
Ethinylestradiol (as micromsed β-cyclodextπn 0.030 complex)
Micromsed drospirenone 3.000 Metafolm® 0.451 Microcrystalline cellulose (Avicel® PH 101) 71.719 HPC, viscosity 5 1.600 Croscarmellose sodium 1.600 Magnesium stearate 1.600
A granulate preparation was prepared by as described in Example 5. A satisfactory stability of calcium 5-methyl-(6S)-tetrahydrofolate upon various storage conditions was observed.
As can be seen from Fig. 3, drospirenone was released slower from this tablet compared to the tablet prepared in Example 5. However, the drospirenone-release was still satisfactory and comparable to the dropirenone-containing oral contraceptive Yaz®.

Claims

1. A solid pharmaceutical composition comprising a progestogen, an estrogen, a tetrahydrofolic acid or a pharmaceutically acceptable salt thereof, and at least one
5 pharmaceutical acceptable excipient or carrier.
2. The composition according to claim 1, wherein the progestogen is selected from the group consisting of levo-norgestrel, norgestrel, norethindrone (norethisterone), norethindrone (norethisterone) acetate, dienogest, ethynodiol diacetate, dydrogesterone,
10 medroxyprogesterone acetate, norethynodrel, allylestrenol, lynestrenol, quingestanol acetate, medrogestone, norgestπenone, dimethisterone, ethisterone, chlormadinone acetate, megestrol, promegestone, desogestrel, 3-keto-desogestrel, norgestimate, gestodene, tibolone, cyproterone acetate and drospirenone.
15 3. The composition according to claim 2, wherein the progestogen is drospirenone.
4. The composition according to any of the preceding claims, wherein the estrogen is selected from the group consisting of ethinylestradiol, estradiol, estradiol sulfamates, estradiol valerate, estradiol benzoate, estrone, mestranol and estrone sulphate.
20
5. The composition according to claim 4, wherein the estrogen is ethinylestradiol.
6. The composition according to any of the preceding claims, wherein the progestogen is drospirenone and the estrogen is ethinylestradiol.
25
7. The composition according to any of the preceding claims, wherein the estrogen is in the form of an estrogen-cyclodextπn complex.
8. The composition according to claim 7, wherein the cyclodextrin is selected from the 30 group consisting of α-cyclodextπn, β-cyclodextπn, γ-cyclodextπn and derivatives thereof.
9. The composition according to claim 8, wherein the cyclodextrin is β-cyclodextπn or derivatives thereof.
35 10. The composition according to any of the preceding claims, wherein the progestogen is micronised.
11. The composition according to any of the preceding claims, wherein the estrogen is micronised.
12. The composition according to any of claims 7- 11, wherein the estrogen-cyclodextπn complex is micronised.
5 13. The composition according to any of the preceding claims, wherein the tetrahydrofolic acid is 5-methyl-(6S)-tetrahydrofolιc acid or a pharmaceutically acceptable salt thereof.
14. The composition according to claim 13, wherein the salt of 5-methyl-(6S)- tetrahydrofohc acid is the calcium salt.
10
15. The composition according to claim 14, wherein the calcium salt of 5-methyl-(6S)- tetrahydrofohc acid is in crystalline form.
16. The composition according to claim 15, wherein the crystalline form is the Type I 15 crystalline form.
17. The composition according to any of the preceding claims, wherein the composition is a granulate composition.
20 18. The composition according to any of the preceding claims, wherein the in vitro dissolution of the progestogen is such that at least 70%, preferably at least 80%, is dissolved from the composition within 30 minutes, as determined by the USP XXIX Paddle Method II using water, or 0.1N HCI, at 37°C as the dissolution media and 50 rpm as the stirring rate.
25
19. The composition according to any of the preceding claims, wherein the in vitro dissolution of the estrogen is such that at least 70%, preferably at least 80%, is dissolved from the composition within 30 minutes, as determined by the USP XXIX Paddle Method II using water, or 0.1N HCI, at 37°C as the dissolution media and 50 rpm as the stirring rate.
30
20. The composition according to any of the preceding claims, wherein the composition has a stability such that at least 80% of the initial amount of the tetrahydrofolic acid is present in the composition after storage in a closed container for 24 months at 250C and 60% relative humidity.
35
21. The composition according to any of the preceding claims, wherein the composition has a stability such that at least 90% of the initial amount of the tetrahydrofolic acid is present in the composition after storage in a closed container for 12 months at 25°C and 60% relative humidity.
22. The composition according to any of the preceding claims, wherein the composition comprises microcrystalline cellulose.
5 23. The composition according to claim 22, wherein the composition comprises microcrystalline cellulose in an amount from 10-99% by weight of the composition, preferably in an amount from 50-99% by weight of the composition, more preferably in an amount from 75-99% by weight of the composition, even more preferably in an amount from 80-97% by weight of the composition, most preferably in an amount from 85-97% by 10 weight of the composition.
24. The composition according to any of the preceding claims, wherein the composition comprises lactose monohydrate.
15 25. The composition according to claim 24, wherein the composition comprises lactose monohydrate in an amount from 10-99% by weight of the composition, preferably in an amount from 50-99% by weight of the composition, more preferably in an amount from 75-99% by weight of the composition, even more preferably in an amount from 80-97% by weight of the composition, most preferably in an amount from 85-97% by weight of the
20 composition.
26. The composition according to any of the preceding claims, wherein the composition comprises microcrystalline cellulose and lactose monohydrate.
25 27. The composition according to claim 26, wherein the composition comprises microcrystalline cellulose in an amount from 20-80% by weight of the composition and lactose monohydrate in an amount from 20-80% by weight of the composition, preferably microcrystalline cellulose in an amount from 20-60% by weight of the composition and lactose monohydrate in an amount from 40-80% by weight of the composition, more
30 preferably microcrystalline cellulose in an amount from 20-45% by weight of the composition and lactose monohydrate in an amount from 40-70% by weight of the composition, most preferably microcrystalline cellulose in an amount from 25-36% by weight of the composition and lactose monohydrate in an amount from 52-63% by weight of the composition.
35
28. The composition according to any of the preceding claims, wherein the composition does not contain a vitamin B, such as vitamin B6 and/or vitamin B12.
29. The composition according to any of the preceding claims, wherein the composition contains less than 2% polyvinylpyrrolidone (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.
5
30. A solid oral dosage form comprising a composition according to any of claims 1-29.
31. The solid oral dosage form according to claim 30, which is in a unit dosage form.
10 32. The solid oral dosage form according to claim 31, wherein the solid oral dosage unit is in the form of a tablet, capsule or sachet.
33. The solid oral dosage form according to claim 32, wherein the solid oral dosage unit is in the form of a tablet.
15
34. The solid oral dosage form according to claim 33, wherein the tablet is coated.
35. The solid oral dosage form according to claim 34, wherein the tablet is film-coated.
20 36. The solid oral dosage form according to any of claims 30-35 comprising an amount of progestogen corresponding to a therapeutically equivalent amount of drospirenone from 0.25-4 mg, such as in an amount corresponding to a therapeutically equivalent amount of drospirenone from 1-4 mg, e.g. in an amount corresponding to a therapeutically equivalent amount of drospirenone from 2-4 mg, preferably in an amount corresponding to a
25 therapeutically equivalent amount of drospirenone from 2.5-3.5 mg, most preferably in an amount corresponding to a therapeutically equivalent amount of drospirenone of about 3 mg.
37. The solid oral dosage form according to any of claims 30-36 comprising an amount of 30 estrogen corresponding to a therapeutically equivalent amount of ethinylestradiol from 0.005-0.05 mg, such as in an amount corresponding to a therapeutically equivalent amount of ethinylestradiol from 0.01-0.05 mg, preferably in an amount corresponding to a therapeutically equivalent amount of ethinylestradiol from 0.015-0.035 mg, most preferably in an amount corresponding to a therapeutically equivalent amount of 35 ethinylestradiol of about 0.02 mg or about 0.03 mg.
38. The solid oral dosage form according to any of claims 30-37 comprising 0.25-4 mg drospirenone and 0.005-0.05 mg ethinylestradiol, such as 1-4 mg drospirenone and 0.005- 0.05 mg ethinylestradiol, e.g. 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.
39 The solid oral dosage form according to any of claims 30-38 comprising the tetrahydrofolic acid in an amount from 0.1-5 mg, such as in an amount from 0.1-2.5 mg, e.g. in an amount from 0.2-0.8 mg, preferably in an amount from 0 3-0.7 mg, more preferably in an amount from 0.4-0 6 mg, most preferably in an amount from 0.42-0.49 mg.
40. The solid oral dosage form according to any of claims 30-39 comprising microcrystalline cellulose in an amount from 10-80 mg, preferably in an amount from 40- 80 mg, more preferably in an amount from 60-80 mg, even more preferably in an amount from 65-80 mg, most preferably in an amount from 65-77 mg.
41. The solid oral dosage form according to any of claims 30-40 comprising lactose monohydrate in an amount from 10-80 mg, preferably in an amount from 40-80 mg, more preferably in an amount from 60-80 mg, even more preferably in an amount from 65-80 mg, most preferably in an amount from 65-77 mg.
42. The solid oral dosage form according to any of claims 30-41 comprising microcrystalline cellulose in an amount from 15-65 mg and lactose monohydrate in an amount from 15-65 mg, preferably microcrystalline cellulose in an amount from 15-50 mg and lactose monohydrate in an amount from 25-65 mg, more preferably microcrystalline cellulose in an amount from 15-35 mg and lactose monohydrate in an amount from 30-55 mg, most preferably microcrystalline cellulose in an amount from 20-30 mg and lactose monohydrate in an amount from 40-50 mg.
43. A process for the manufacture of a composition according to any of claims 1-29 comprising the steps of:
(i) subjecting a progestogen, an estrogen and at least one pharmaceutical 5 acceptable excipient to a granulation process,
(ii) mixing a tetrahydrofolic acid or a salt thereof with the granules formed in step (i), and
10 (iii) optionally continuing the granulation process, and/or
(iv) optionally collecting the granules.
44. The process according to claim 43, wherein the granulation step is performed by fluid 15 bed granulation.
45. Granules obtainable by the process according to claim 43 or 44.
46. A process for the manufacture of a solid oral dosage form according to any of claims 20 30-42, comprising the steps of:
(i) preparing granules according to the process as defined in claim 43 or 44, and
(ii) formulating the granules into solid oral dosage forms. 25
47. A solid oral dosage form obtainable by the process according to claim 46.
48. Use of a composition according to any of claims 1-29 or use of a solid oral dosage form according to any of claims 30-42 for female contraception.
30
49. Use of a composition according to any of claims 1-29 or use of a solid oral dosage form according to any of claims 30-42 for inhibition of ovulation in a female.
50. A method for female contraception comprising administering to a female a composition 35 according to any of claims 1-29 or a solid oral dosage form according to any of claims 30-
42.
51. A method for inhibition of ovulation in a female comprising administering to a female a composition according to any of claims 1-29 or a solid oral dosage form according to any of claims 30-42.
5 52. Use of a composition according to any of claims 1-29 or use of a solid oral dosage form according to any of claims 30-42 for the manufacture of a medicament for the treatment of diseases, conditions or symptoms associated with deficient endogenous levels of estrogen in a woman.
10 53. A method for treatment of diseases, conditions or symptoms associated with deficient endogenous levels of estrogen in a woman comprising administering to said woman a composition according to any of claims 1-29 or a solid oral dosage form according to any of claims 30-42.
15 54. A pharmaceutical preparation or kit consisting essentially of 21, 22, 23 or 24 separately packed and individually removable solid oral dosage units as defined in any of claims 30-42 placed in a packaging unit, and 7, 6, 5 or 4 separately packed and individually removable solid oral dosage units containing a tetrahydrofolic acid as the sole active agent placed in a packaging unit.
PCT/EP2007/005764 2006-07-06 2007-06-29 Pharmaceutical composition containing a tetrahydrofolic acid WO2008003432A1 (en)

Priority Applications (21)

Application Number Priority Date Filing Date Title
RU2009103649/15A RU2479306C2 (en) 2006-07-06 2007-06-29 Pharmaceutical composition containing tetrahydrofolic acid
BRPI0713565A BRPI0713565B8 (en) 2006-07-06 2007-06-29 process for manufacturing a solid oral dosage form
KR1020137006954A KR20130042638A (en) 2006-07-06 2007-06-29 Pharmaceutical composition containing a tetrahydrofolic acid
JP2009517003A JP2009542591A (en) 2006-07-06 2007-06-29 Pharmaceutical composition containing tetrahydrofolic acid
NO20090578A NO347567B1 (en) 2006-07-06 2007-06-29 Pharmaceutical composition containing a tetrahydrofolic acid
ES07764936T ES2626838T5 (en) 2006-07-06 2007-06-29 Pharmaceutical composition containing a tetrahydrofolic acid
UAA200900637A UA100228C2 (en) 2006-07-06 2007-06-29 Pharmaceutical composition containing a tetrahydrofolic acid
AU2007271449A AU2007271449B2 (en) 2006-07-06 2007-06-29 Pharmaceutical composition containing a tetrahydrofolic acid
EP07764936.6A EP2040683B2 (en) 2006-07-06 2007-06-29 Pharmaceutical composition containing a tetrahydrofolic acid
CA2656131A CA2656131C (en) 2006-07-06 2007-06-29 Pharmaceutical composition containing a tetrahydrofolic acid
MX2009000079A MX2009000079A (en) 2006-07-06 2007-06-29 Pharmaceutical composition containing a tetrahydrofolic acid.
CN2007800255704A CN101484143B (en) 2006-07-06 2007-06-29 Pharmaceutical composition containing a tetrahydrofolic acid
NZ573766A NZ573766A (en) 2006-07-06 2007-06-29 Pharmaceutical composition containing a tetrahydrofolic acid
IL196027A IL196027A0 (en) 2006-07-06 2008-12-18 Pharmaceutical composition containing a tetrahydrofolic acid
TNP2008000543A TNSN08543A1 (en) 2006-07-06 2008-12-31 Pharmaceutical composition containing a tetrahydrofolic acid
CU2009000004A CU20090004A7 (en) 2006-07-06 2009-01-06 PHARMACEUTICAL COMPOSITION CONTAINING A TETRAHYDROPHOLIC ACID
ZA2009/00868A ZA200900868B (en) 2006-07-06 2009-02-05 Pharmaceutical composition containing a tetrahydrofolic acid
HK09111877.6A HK1131917A1 (en) 2006-07-06 2009-12-17 Pharmaceutical composition containing a tetrahydrofolic acid
PH12012501774A PH12012501774A1 (en) 2006-07-06 2012-09-06 Pharmaceutical composition containing a tetrahydrofolic acid
IL224484A IL224484A (en) 2006-07-06 2013-01-30 Pharmaceutical composition containing a tetrahydrofolic acid
IL245355A IL245355B (en) 2006-07-06 2016-04-21 Pharmaceutical composition containing a tetrahydrofolic acid

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP06014002.7 2006-07-06
EP06014002 2006-07-06

Publications (1)

Publication Number Publication Date
WO2008003432A1 true WO2008003432A1 (en) 2008-01-10

Family

ID=36763829

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2007/005764 WO2008003432A1 (en) 2006-07-06 2007-06-29 Pharmaceutical composition containing a tetrahydrofolic acid

Country Status (32)

Country Link
EP (2) EP2040683B2 (en)
JP (1) JP2009542591A (en)
KR (2) KR20090033889A (en)
CN (3) CN101489563A (en)
AR (2) AR061958A1 (en)
AU (1) AU2007271449B2 (en)
BR (1) BRPI0713565B8 (en)
CA (2) CA2856344C (en)
CL (1) CL2007001962A1 (en)
CO (1) CO6150125A2 (en)
CR (1) CR10549A (en)
CU (1) CU20090004A7 (en)
EC (1) ECSP099030A (en)
ES (1) ES2626838T5 (en)
GT (1) GT200900001A (en)
HK (1) HK1131917A1 (en)
IL (3) IL196027A0 (en)
MA (1) MA30598B1 (en)
MX (1) MX2009000079A (en)
MY (1) MY169516A (en)
NO (1) NO347567B1 (en)
NZ (1) NZ573766A (en)
PE (3) PE20120375A1 (en)
PH (1) PH12012501774A1 (en)
RU (2) RU2479306C2 (en)
SG (1) SG188869A1 (en)
TN (1) TNSN08543A1 (en)
TW (2) TW201538161A (en)
UA (2) UA105078C2 (en)
UY (1) UY30462A1 (en)
WO (1) WO2008003432A1 (en)
ZA (4) ZA200900868B (en)

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011018482A1 (en) 2009-08-12 2011-02-17 Bayer Schering Pharma Aktiengesellschaft Stabilised particles comprising 5-methyl-(6s)-tetrahydrofolate
EP2558063A1 (en) * 2010-04-15 2013-02-20 Bayer Intellectual Property GmbH Very low-dosed solid oral dosage forms for hrt
EP2781214A1 (en) * 2013-03-22 2014-09-24 Chemo Research, S.L. Formulation of amorphous calcium L-5-methyltetrahydrofolate (L-5-MTHF-Ca)
EP2878600A1 (en) 2013-12-02 2015-06-03 Cerbios-Pharma S.A. Stable complexes of an alkaline earth metal salt of n5-methyl-tetrahydrofolic acid and a polyol
EP2422774B1 (en) 2006-07-06 2015-08-12 Bayer Intellectual Property GmbH Pharmaceutical composition containing a tetrahydrofolic acid
JP2016029101A (en) * 2009-06-16 2016-03-03 アンドルシェルシュ・インコーポレイテッド Treatment of hot flushes, vasomotor symptoms, and night sweats with sex steroid precursors in combination with selective estrogen receptor modulators
US9603860B2 (en) 2010-07-28 2017-03-28 Laboratorios Leon Farma Sa Pharmaceutical compositions comprising active drugs, contraceptive kits comprising active drugs, and methods of administering the same
US10660903B2 (en) 2015-06-18 2020-05-26 Estetra Sprl Orodispersible dosage unit containing an estetrol component
US10844088B2 (en) 2011-07-19 2020-11-24 Estetra Sprl Process for the preparation of estetrol
US10849857B2 (en) 2010-07-28 2020-12-01 Laboratorios Leon Farma Sa Pharmaceutical compositions comprising active drugs, contraceptive kits comprising active drugs, and methods of administering the same
US10888518B2 (en) 2015-06-18 2021-01-12 Estetra Sprl Orodispersible tablet containing estetrol
US10894014B2 (en) 2015-06-18 2021-01-19 Estetra Sprl Orodispersible tablet containing Estetrol
US11147771B2 (en) 2015-06-18 2021-10-19 Estetra Sprl Orodispersible dosage unit containing an estetrol component
US11351122B1 (en) 2010-07-28 2022-06-07 Laboratorios Leon Farma Sa Synthetic progestogens and pharmaceutical compositions comprising the same
US11452733B2 (en) 2018-04-19 2022-09-27 Estetra Sprl Compounds and their uses for alleviating menopause-associated symptoms
US11452695B2 (en) 2010-06-29 2022-09-27 Laboratorios Leon Farma Sa Synthetic progestogens and pharmaceutical compositions comprising the same
US11484539B2 (en) 2018-04-19 2022-11-01 Estetra Sprl Compounds and their uses for alleviating menopause-associated symptoms
US11617751B2 (en) 2006-07-06 2023-04-04 Bayer Pharma AG Pharmaceutical composition containing a tetrahydrofolic acid
US11896602B2 (en) 2016-08-05 2024-02-13 Estetra Srl Method for preventing pregnancy
ES2956541R1 (en) * 2021-04-08 2024-08-14 Ind Chimica Srl Process for the preparation of drospirenone as a fine powder by a double change of crystalline form

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102516247A (en) * 2010-12-15 2012-06-27 连云港金康医药科技有限公司 A-type calcium L-5-methyltetrahydrofolate polymorphism and preparation method thereof
CN107812195B (en) * 2014-09-04 2021-04-20 连云港金康和信药业有限公司 Stable pharmaceutical composition of (6S) -5-methyl-tetrahydrofolate calcium salt
CN105030779A (en) * 2015-07-21 2015-11-11 福格森（武汉）生物科技股份有限公司 (6S)-5-methyl tetrahydrophthalic calcium foliate oral nutrition supplement and method for preparing same
CN106336444A (en) * 2016-08-23 2017-01-18 国家卫生计生委科学技术研究所 New crystal form of estradiol
CN107446458A (en) * 2017-08-04 2017-12-08 合众（佛山）化工有限公司 A kind of acrylic acid modified polyurethane hybrid resin water paint of enhanced water resistance
CN110237046B (en) * 2019-03-29 2021-07-30 福格森（武汉）生物科技股份有限公司 Preparation method of L-5-methyltetrahydrofolic acid microcapsules
CN110548034A (en) * 2019-07-12 2019-12-10 广州莎蔓生物科技有限公司 Pregnancy-blocking medicine
CN114569567B (en) * 2021-12-20 2023-03-14 南通联亚药业股份有限公司 Stable norethindrone diacetate ethinyl estradiol compound tablet and preparation method thereof
CN117771389A (en) * 2023-12-28 2024-03-29 浙江圣达生物药业股份有限公司 L-5-methyltetrahydrofolate calcium-gamma-cyclodextrin inclusion compound and preparation method thereof

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5916593A (en) * 1994-09-22 1999-06-29 Akzo Nobel, N.V. Process of making dosage units by wet granulation
WO1999053910A2 (en) * 1998-04-17 1999-10-28 Ortho-Mcneil Pharmaceutical, Inc. Folic acid-containing pharmaceutical compositions, and related methods and delivery systems
WO2001015701A1 (en) * 1999-08-31 2001-03-08 Schering Aktiengesellschaft Pharmaceutical combination of ethinylestradiol and drospirenone for use as a contraceptive
WO2003070255A1 (en) * 2002-02-21 2003-08-28 Schering Aktiengesellschaft Pharmaceutical compositions comprising one or more steroids one or more tetrahydrofolate components and vitamin b12
EP1632237A2 (en) * 2000-12-20 2006-03-08 Schering Aktiengesellschaft Compositions comprising drospirenone and a complex between ethinyl-estradiol and a cyclodextrin
WO2006120035A2 (en) * 2005-05-13 2006-11-16 Bayer Schering Pharma Aktiengesellschaft Pharmaceutical composition containing gestagens and/or estrogens and 5-methyl-(6s)-tetrahydrofolate

Family Cites Families (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3347125A1 (en) 1983-12-22 1985-07-11 Schering AG, 1000 Berlin und 4709 Bergkamen MULTI-STAGE COMBINATION PREPARATION AND ITS USE FOR ORAL CONTRACTION
FR2676927B1 (en) * 1991-05-29 1995-06-23 Ibf MICROSPHERES FOR USE IN THERAPEUTIC VASCULAR OCCLUSIONS AND INJECTABLE SOLUTIONS CONTAINING THEM.
TW390813B (en) * 1994-04-29 2000-05-21 Merck & Co Inc Wet granulation formulation for bisphosphonic acids
DE4426709A1 (en) 1994-07-20 1996-01-25 Schering Ag Solid dosage forms containing steroidal sex hormones
RU2073529C1 (en) * 1995-05-16 1997-02-20 Центральный научно-исследовательский рентгенорадиологический институт Composition for embolization of blood vessels
CH693255A5 (en) 1997-06-13 2003-05-15 Eprova Ag Use of tetrahydrofolates natürlichenstereoisomeren in the form suitable for the preparation of a pharmaceutical composition for influencing the homocysteine ​​level.
US6214815B1 (en) * 1998-12-23 2001-04-10 Ortho-Mcneil Pharmaceuticals, Inc. Triphasic oral contraceptive
CH693905A5 (en) 1999-04-15 2004-04-15 Eprova Ag Stable crystalline salts of 5-methyl tetrahydrofolic acid.
CA2382426C (en) * 1999-08-31 2006-02-28 Schering Aktiengesellschaft Pharmaceutical combination of ethinylestradiol and drospirenone for use as a contraceptive
DE60113809T2 (en) 2000-01-18 2006-06-22 Schering Ag PHARMACEUTICAL COMBINATION OF MICRONIZED DROSPIRENONE AND AN ESTROGEN FOR HORMONIC SITTER THERAPY
US6550482B1 (en) * 2000-04-21 2003-04-22 Vascular Control Systems, Inc. Methods for non-permanent occlusion of a uterine artery
US6864774B2 (en) 2000-10-19 2005-03-08 Matsushita Electric Industrial Co., Ltd. Inductance component and method of manufacturing the same
EP1216712A1 (en) 2000-12-20 2002-06-26 Schering Aktiengesellschaft Cyclodextrin-drospirenone inclusion complexes
US6537569B2 (en) * 2001-02-14 2003-03-25 Microvention, Inc. Radiation cross-linked hydrogels
EP1559440B1 (en) * 2002-10-29 2015-09-23 Toray Industries, Inc. Vascular embolization meterial
CN101489563A (en) 2006-07-06 2009-07-22 拜耳先灵医药股份有限公司 Pharmaceutical preparations for contraception and for preventing the risk of congenital malformations
CA2665788A1 (en) * 2006-07-06 2008-01-10 Bayer Schering Pharma Aktiengesellschaft Pharmaceutical preparations for contraception and for preventing the risk of congenital malformations
RU62008U1 (en) * 2006-10-13 2007-03-27 Закрытое акционерное общество "ААА-КОМПАНИ" MEANS FOR EMBOLIZATION OF VESSELS
RU61120U1 (en) * 2006-10-13 2007-02-27 Закрытое акционерное общество "ААА-КОМПАНИ" MEANS FOR EMBOLIZATION OF VESSELS
US8916188B2 (en) * 2008-04-18 2014-12-23 Abbott Cardiovascular Systems Inc. Block copolymer comprising at least one polyester block and a poly (ethylene glycol) block

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5916593A (en) * 1994-09-22 1999-06-29 Akzo Nobel, N.V. Process of making dosage units by wet granulation
WO1999053910A2 (en) * 1998-04-17 1999-10-28 Ortho-Mcneil Pharmaceutical, Inc. Folic acid-containing pharmaceutical compositions, and related methods and delivery systems
WO2001015701A1 (en) * 1999-08-31 2001-03-08 Schering Aktiengesellschaft Pharmaceutical combination of ethinylestradiol and drospirenone for use as a contraceptive
EP1632237A2 (en) * 2000-12-20 2006-03-08 Schering Aktiengesellschaft Compositions comprising drospirenone and a complex between ethinyl-estradiol and a cyclodextrin
WO2003070255A1 (en) * 2002-02-21 2003-08-28 Schering Aktiengesellschaft Pharmaceutical compositions comprising one or more steroids one or more tetrahydrofolate components and vitamin b12
WO2006120035A2 (en) * 2005-05-13 2006-11-16 Bayer Schering Pharma Aktiengesellschaft Pharmaceutical composition containing gestagens and/or estrogens and 5-methyl-(6s)-tetrahydrofolate

Cited By (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11617751B2 (en) 2006-07-06 2023-04-04 Bayer Pharma AG Pharmaceutical composition containing a tetrahydrofolic acid
EP2422774B1 (en) 2006-07-06 2015-08-12 Bayer Intellectual Property GmbH Pharmaceutical composition containing a tetrahydrofolic acid
EP2040683B1 (en) 2006-07-06 2017-03-01 Bayer Intellectual Property GmbH Pharmaceutical composition containing a tetrahydrofolic acid
US10342805B2 (en) 2009-06-16 2019-07-09 Endorecherche, Inc. Treatment of Alzheimer's disease, loss of cognition, memory loss and dementia with sex steroid precursors in combination with selective estrogen receptor modulators
US11452731B2 (en) 2009-06-16 2022-09-27 Endorecherche, Inc. Method of treating and preventing loss of cognition
JP2016029101A (en) * 2009-06-16 2016-03-03 アンドルシェルシュ・インコーポレイテッド Treatment of hot flushes, vasomotor symptoms, and night sweats with sex steroid precursors in combination with selective estrogen receptor modulators
WO2011018482A1 (en) 2009-08-12 2011-02-17 Bayer Schering Pharma Aktiengesellschaft Stabilised particles comprising 5-methyl-(6s)-tetrahydrofolate
US20120263762A1 (en) * 2009-08-12 2012-10-18 Bayer Pharma Aktiengesellschaft Stabilised particles comprising 5-methyl-(6s)-tetrahydrofolate
EP2558063A1 (en) * 2010-04-15 2013-02-20 Bayer Intellectual Property GmbH Very low-dosed solid oral dosage forms for hrt
US9592245B2 (en) 2010-04-15 2017-03-14 Bayer Intellectual Property Gmbh Very low-dosed solid oral dosage forms for HRT
US11951213B2 (en) 2010-06-29 2024-04-09 Laboratorios Leon Farma Sa Synthetic progestogens and pharmaceutical compositions comprising the same
US12090231B2 (en) 2010-06-29 2024-09-17 Laboratorios Leon Farma Sa Synthetic progestogens and pharmaceutical compositions comprising the same
US11504334B2 (en) 2010-06-29 2022-11-22 Laboratorios Leon Farma Sa Synthetic progestogens and pharmaceutical compositions comprising the same
US11491113B1 (en) 2010-06-29 2022-11-08 Laboratorios Leon Farma Sa Synthetic progestogens and pharmaceutical compositions comprising the same
US11478487B1 (en) 2010-06-29 2022-10-25 Laboratorios Leon Farma Sa Synthetic progestogens and pharmaceutical compositions comprising the same
US11452695B2 (en) 2010-06-29 2022-09-27 Laboratorios Leon Farma Sa Synthetic progestogens and pharmaceutical compositions comprising the same
US9603860B2 (en) 2010-07-28 2017-03-28 Laboratorios Leon Farma Sa Pharmaceutical compositions comprising active drugs, contraceptive kits comprising active drugs, and methods of administering the same
US10849857B2 (en) 2010-07-28 2020-12-01 Laboratorios Leon Farma Sa Pharmaceutical compositions comprising active drugs, contraceptive kits comprising active drugs, and methods of administering the same
US11123299B2 (en) 2010-07-28 2021-09-21 Laboratorios Leon Farma Sa Synthetic progestogens and pharmaceutical compositions comprising the same
US10987364B1 (en) 2010-07-28 2021-04-27 Laboratorios Leon Farma Sa Synthetic progestogens and pharmaceutical compositions comprising the same
US11291632B2 (en) 2010-07-28 2022-04-05 Laboratorios Leon Farma Sa Synthetic progestogens and pharmaceutical compositions comprising the same
US11291633B2 (en) 2010-07-28 2022-04-05 Laboratorios Leon Farma Sa Synthetic progestogens and pharmaceutical compositions comprising the same
US11351122B1 (en) 2010-07-28 2022-06-07 Laboratorios Leon Farma Sa Synthetic progestogens and pharmaceutical compositions comprising the same
US11413249B2 (en) 2010-07-28 2022-08-16 Laboratorios Leon Farma Sa Synthetic progestogens and pharmaceutical compositions comprising the same
US11439598B2 (en) 2010-07-28 2022-09-13 Laboratorios Leon Farma Sa Synthetic progestogens and pharmaceutical compositions comprising the same
US10844088B2 (en) 2011-07-19 2020-11-24 Estetra Sprl Process for the preparation of estetrol
EP2781214A1 (en) * 2013-03-22 2014-09-24 Chemo Research, S.L. Formulation of amorphous calcium L-5-methyltetrahydrofolate (L-5-MTHF-Ca)
WO2014146975A1 (en) * 2013-03-22 2014-09-25 Chemo Research, S.L. FORMULATION OF AMORPHOUS CALCIUM L-5-METHYLTETRAHYDROFOLATE (L-5-MTHF-Ca)
EP2878600A1 (en) 2013-12-02 2015-06-03 Cerbios-Pharma S.A. Stable complexes of an alkaline earth metal salt of n5-methyl-tetrahydrofolic acid and a polyol
US10888518B2 (en) 2015-06-18 2021-01-12 Estetra Sprl Orodispersible tablet containing estetrol
US10894014B2 (en) 2015-06-18 2021-01-19 Estetra Sprl Orodispersible tablet containing Estetrol
US11964055B2 (en) 2015-06-18 2024-04-23 Estetra Srl Orodispersible dosage unit containing an estetrol component
US10660903B2 (en) 2015-06-18 2020-05-26 Estetra Sprl Orodispersible dosage unit containing an estetrol component
US11957694B2 (en) 2015-06-18 2024-04-16 Estetra Srl Orodispersible dosage unit containing an estetrol component
US11793760B2 (en) 2015-06-18 2023-10-24 Estetra Srl Orodispersible dosage unit containing an estetrol component
US11147771B2 (en) 2015-06-18 2021-10-19 Estetra Sprl Orodispersible dosage unit containing an estetrol component
US11896602B2 (en) 2016-08-05 2024-02-13 Estetra Srl Method for preventing pregnancy
US11666585B2 (en) 2018-04-19 2023-06-06 Estetra Srl Compounds and their uses for alleviating menopause-associated symptoms
US11484539B2 (en) 2018-04-19 2022-11-01 Estetra Sprl Compounds and their uses for alleviating menopause-associated symptoms
US11452733B2 (en) 2018-04-19 2022-09-27 Estetra Sprl Compounds and their uses for alleviating menopause-associated symptoms
ES2956541R1 (en) * 2021-04-08 2024-08-14 Ind Chimica Srl Process for the preparation of drospirenone as a fine powder by a double change of crystalline form

Also Published As

Publication number Publication date
EP2040683B2 (en) 2023-08-16
CN102813663A (en) 2012-12-12
BRPI0713565A2 (en) 2012-03-20
SG188869A1 (en) 2013-04-30
BRPI0713565B1 (en) 2021-02-02
EP2040683B1 (en) 2017-03-01
UA100228C2 (en) 2012-12-10
CU20090004A7 (en) 2011-07-11
TW201538161A (en) 2015-10-16
CN101484143A (en) 2009-07-15
ZA201501673B (en) 2016-02-24
NZ573766A (en) 2011-05-27
PH12012501774B1 (en) 2015-09-21
ECSP099030A (en) 2009-02-27
HK1131917A1 (en) 2010-02-12
EP2422774B1 (en) 2015-08-12
CU23902B1 (en) 2013-06-28
PE20150287A1 (en) 2015-03-15
ZA201808084B (en) 2021-06-30
CA2656131A1 (en) 2008-01-10
PH12012501774A1 (en) 2015-09-21
KR20130042638A (en) 2013-04-26
RU2479306C2 (en) 2013-04-20
AU2007271449B2 (en) 2013-07-11
UY30462A1 (en) 2008-02-29
MY169516A (en) 2019-04-22
RU2009103649A (en) 2010-08-20
RU2624236C2 (en) 2017-07-03
ZA201808083B (en) 2021-06-30
RU2012133154A (en) 2014-02-10
TWI508730B (en) 2015-11-21
AR061958A1 (en) 2008-08-10
BRPI0713565B8 (en) 2021-05-25
CA2656131C (en) 2015-10-13
CN101484143B (en) 2012-07-04
MA30598B1 (en) 2009-07-01
CN101489563A (en) 2009-07-22
CA2856344A1 (en) 2008-01-10
NO20090578A (en) 2009-03-09
CL2007001962A1 (en) 2008-01-04
TNSN08543A1 (en) 2010-04-14
EP2040683A1 (en) 2009-04-01
ZA200900868B (en) 2021-05-26
IL245355A0 (en) 2016-06-30
ES2626838T3 (en) 2017-07-26
CO6150125A2 (en) 2010-04-20
GT200900001A (en) 2009-12-08
IL196027A0 (en) 2009-09-01
UA105078C2 (en) 2014-04-10
EP2422774A1 (en) 2012-02-29
ES2626838T5 (en) 2024-03-14
KR20090033889A (en) 2009-04-06
IL224484A (en) 2016-05-31
JP2009542591A (en) 2009-12-03
NO347567B1 (en) 2024-01-15
CR10549A (en) 2009-01-27
IL245355B (en) 2019-05-30
NO20090578L (en) 2009-03-09
TW200812593A (en) 2008-03-16
PE20120375A1 (en) 2012-05-23
CA2856344C (en) 2017-02-28
PE20080273A1 (en) 2008-05-16
CN102813663B (en) 2019-03-22
AR106561A2 (en) 2018-01-24
AU2007271449A1 (en) 2008-01-10
MX2009000079A (en) 2009-01-23

Similar Documents

Publication Publication Date Title
AU2007271449B2 (en) Pharmaceutical composition containing a tetrahydrofolic acid
US11617751B2 (en) Pharmaceutical composition containing a tetrahydrofolic acid
KR102539030B1 (en) Pharmaceutical composition comprising drospirenone and contraceptive kit
JP4880465B2 (en) Progestogen formulation with improved stability
CN101541326A (en) Estrogen/ serm and estrogen/ progestin bi-layer tablets
CN101094656A (en) Oral solid dosage forms containing a low dose of estradiol
AU2013202756B2 (en) Pharmaceutical composition containing a tetrahydrofolic acid
KR102210982B1 (en) Pharmaceutical composition comprising drospirenone and contraceptive kit

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 200780025570.4

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07764936

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 196027

Country of ref document: IL

Ref document number: 573766

Country of ref document: NZ

ENP Entry into the national phase

Ref document number: 0800850

Country of ref document: KE

WWE Wipo information: entry into national phase

Ref document number: 2007271449

Country of ref document: AU

ENP Entry into the national phase

Ref document number: 2656131

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 10642/DELNP/2008

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 2009010004

Country of ref document: EG

WWE Wipo information: entry into national phase

Ref document number: 12009500027

Country of ref document: PH

WWE Wipo information: entry into national phase

Ref document number: 2009517003

Country of ref document: JP

Ref document number: 09000752

Country of ref document: CO

Ref document number: 13101248

Country of ref document: CO

Ref document number: CR2009-010549

Country of ref document: CR

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: MX/A/2009/000079

Country of ref document: MX

ENP Entry into the national phase

Ref document number: 2007271449

Country of ref document: AU

Date of ref document: 20070629

Kind code of ref document: A

REEP Request for entry into the european phase

Ref document number: 2007764936

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2007764936

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: DZP2009000075

Country of ref document: DZ

WWE Wipo information: entry into national phase

Ref document number: 1020097002386

Country of ref document: KR

ENP Entry into the national phase

Ref document number: 2009103649

Country of ref document: RU

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: A200900637

Country of ref document: UA

Ref document number: A20090157

Country of ref document: BY

ENP Entry into the national phase

Ref document number: PI0713565

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20090106

ENP Entry into the national phase

Ref document number: 0154712

Country of ref document: KE

WWE Wipo information: entry into national phase

Ref document number: 224484

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 1020137006954

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 245355

Country of ref document: IL