US20080160004A1 - Pharmaceutical composition comprising progestogens and/or estrogens and 5-methyl-(6s)-tetrahydrofolate - Google Patents
Pharmaceutical composition comprising progestogens and/or estrogens and 5-methyl-(6s)-tetrahydrofolate Download PDFInfo
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- US20080160004A1 US20080160004A1 US11/938,688 US93868807A US2008160004A1 US 20080160004 A1 US20080160004 A1 US 20080160004A1 US 93868807 A US93868807 A US 93868807A US 2008160004 A1 US2008160004 A1 US 2008160004A1
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- 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
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- 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
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Definitions
- the present invention relates to a pharmaceutical composition which comprises progestogens, estrogens and 5-methyl-(6S)-tetrahydrofolate, can be employed as oral contraceptive and moreover prevents disorders and malformations caused by folate deficiency, without at the same time masking the symptoms of vitamin B 12 deficiency.
- a number of diseases is regarded as being connected with a folate deficiency.
- administration of folates for example in the form of folic acid may minimize the risk of cardiovascular disorders and certain malignant disorders (such as, for example, carcinoma of the breast or colon).
- Neural tube defects are the commonest congenital malformations of the central nervous system. They arise through incomplete closure of the neural tube in about the third to fourth week of embryonic development. Neural tube defects include spina bifida (in some cases with meningocele or meningomyelocele), encephalocele and anencephalies which are characterized by partial or complete absence of areas of the brain. Children with anencephaly are virtually incapable of survival. Spina bifida is distinguished by incomplete closure of vertebral arches. Its result, depending on the nature of the lesion, is life-long disability in the form of various sensory but also motor deficits—thus, for example, two thirds of children and adults are dependent on wheelchairs owing to muscular paralyses. Therapy entails covering the defect, fitting a shunt to drain the CSF and lengthy orthopedic and neurological rehabilitation. The costs of the medical treatment average 500 000 per child.
- An erythrocyte folate level of at least 906 nmol/l is generally regarded as desirable for reducing the frequency of neural tube defects.
- Kafrissen achieved this object by adding folic acid to an oral contraceptive.
- folic acid into oral contraceptives itself involves a serious health risk, because it may mask the early symptoms, which are still treatable, of a vitamin B 12 deficiency such as, for example, a megaloblastic anemia.
- a vitamin B 12 deficiency such as, for example, a megaloblastic anemia.
- the neuropsychiatric symptoms such as, for example, paresthesia and ataxia then remain untreated, however, and might deteriorate irreversibly.
- Coelingh Bennink achieves this object by adding vitamin B 12 to an oral contraceptive.
- MTHFR C677T methylenetetrahydrofolate reductase
- This polymorphism leads to a reduced activity of methylenetetrahydrofolate reductase, so that the women affected are unable to metabolize sufficiently the supplied folate and tetrahydrofolate into 5-methyl-(6S)-tetrahydrofolate, which is active in the body.
- This polymorphism is an acknowledged risk factor for disorders caused by folate deficiency, in particular for neural tube defects.
- folic acid is a substance which does not naturally occur in foodstuffs. In order to be biologically active, it must first be converted metabolically by the enzyme dihydrofolate reductase into 7,8-dihydrofolate and (6S)-tetrahydrofolate.
- the metabolic capacity, in particular the first activation step, for conversion of the provitamin folic acid into its active reduced form is limited and moreover varies greatly from individual to individual. Since the enzyme dihydrofolate reductase does not play a role in the metabolism of metafolin, interactions between medicaments which inhibit dihydrofolate reductase, such as, for example, methotrexate and dihydrofolate reductase are not to be expected.
- EP 0898965 proposes the use of 5-methyl-(6S)-tetrahydrofolic acid or appropriate pharmaceutically acceptable salts as dietary supplement or as ingredient of medicaments.
- EP 1044975 A1 discloses inter alia stable crystalline salts of 5-methyl-(6S)-tetrahydrofolic acid and processes for their preparation.
- the present invention is based on the object of producing an oral contraceptive which, although able to prevent diseases caused by folate deficiency, at the same time is unable to mask the symptoms of vitamin B 12 deficiency.
- the invention is further based on the object of disclosing an administration regime which ensures that the consumer of the pharmaceutical composition of the invention is reliably protected also for a certain time after discontinuation from disorders or malformations caused by folate deficiency, in particular from neural tube defects. Both these also apply in the case of a homozygous or heterozygous polymorphism of methylenetetrahydrofolate reductase in the user, which adversely affects the utilizability of folic acid by the body and thus its biological activity to prevent neural tube defects.
- the object is achieved according to the invention by a pharmaceutical composition
- a pharmaceutical composition comprising one or more progestogens and/or estrogens and 5-methyl-(6S)-tetrahydrofolate, and pharmaceutically acceptable excipients and carriers.
- the invention is based on the realization, which is surprising in relation to WO 03/070255, that treatment and prevention of disorders caused by folate deficiency is possible even without masking symptoms of vitamin B 12 deficiency by administering solely 5-methyl-(6S)-tetrahydrofolate. Administration of vitamin B 12 is therefore no longer necessary in order to avoid the health risk described in WO 03/070255. Despite the administration of 5-methyl-(6S)-tetrahydrofolate, a physician is able to diagnose and, where appropriate, treat vitamin B 12 deficiency.
- vitamin B 12 in addition.
- further vitamins such as, for example, vitamin B 6 or vitamin B 2 is likewise optionally possible.
- the invention is further based on the realization, which is surprising in relation to WO 03/070255, that, unlike the administration of folates or other tetrahydrofolates, use solely of 5-methyl-(6S)-tetrahydrofolate in a contraceptive enables, even in a case of homozygous or heterozygous polymorphism of methylenetetrahydrofolate reductase, unlimited and adequate utilizability of the folate component by the body and thus its biological activity to prevent congenital malformations caused by folate deficiency.
- FIG. 1 depicts folate metabolism, wherein THF is tetrahydrofolate, MTHFR is methylenetetrahydrofolate reductase, MS is methionine synthase, SAM is S-adenosylmethionine and SAH is S-adenosylhomocysteine and
- FIG. 2 depicts the results of the in vitro dissolution tests presented in Table 6 .
- 5-Methyl-(6S)-tetrahydrofolate is synthesized metabolically (see FIG. 1 ) from 5,10-methylene-(6R)-tetrahydrofolate.
- This biochemical reaction is catalyzed by the enzyme methylenetetrahydrofolate reductase (MTHFR), of which various genetic mutations are known, some of which are manifested by restricted biological activity (MTHFR C677T polymorphism).
- MTHFR methylenetetrahydrofolate reductase
- 5-Methyl-(6S)-tetrahydrofolate is converted in a further step which is catalyzed by the enzyme methionine synthase (MS) into tetrahydrofolate.
- MS methionine synthase
- 5-methyl-(6S)-tetrahydrofolate can be synthesized only from 5,10-methylene-(6R)-tetrahydrofolate and can be further metabolized only by conversion into tetrahydrofolate.
- the first enzymatic reaction (MTHFR) is irreversible under physiological conditions
- the second enzymatic reaction (MS) is vitamin B 12 -dependent, meaning that if there is a vitamin B 12 deficiency then 5-methyl-(6S)-tetrahydrofolate accumulates and cannot be metabolized further. This phenomenon is also known under the name methyl trap.
- 5-Methyl-(6S)-tetrahydrofolate is the only naturally occurring folate which does not mask vitamin B 12 deficiency. This is of particular importance on use of 5-methyl-(6S)-tetrahydrofolate in combination with oral contraceptives and is an aspect of the present invention.
- Suitable estrogens are ethinylestradiol, mestranol, quinestranol, estradiol, estrone, estrane, estriol, estetrol and conjugated equine estrogens.
- ethinylestradiol, estradiol and mestranol are preferred, and ethinylestradiol is particularly preferred.
- the amounts used according to the invention of the respective progestogens and/or estrogens correspond to the amounts normally known in contraceptives.
- Drospirenone 0.5-5 mg Levonorgestrel 30-250 ⁇ g Norgestimate 180-250 ⁇ g Norethisterone acetate 0.5-1 mg Cyproterone acetate 1-2 mg Desogestrel 20-150 ⁇ g Dienogest 2-3 mg Gestodene 60-75 ⁇ g Tibolone 2.5 mg
- the preferred amount administered each day according to the present invention is for example 0.5 to 5 mg, particularly preferably 3 mg, of drospirenone.
- the amount of estrogen used according to the invention is for instance for the estrogens mentioned below:
- the preferred amount administered each day according to the invention is for example 10 to 50 ⁇ g, particularly preferably 10 to 30 ⁇ g, very particularly preferably 20 to 30 ⁇ g, of ethinylestradiol.
- Reference to 5-methyl-(6S)-tetrahydrofolates in the form according to the invention means the free acid form and pharmaceutically acceptable salts and modifications of 5-methyl-(6S)-tetrahydrofolic acid (N-[4-[[(2-amino-1,4,5,6,7,8-hexahydro-4-oxo-5-methyl-(6S)-pteridinyl)methyl]amino]benzoyl]-L-glutamic acid).
- Pharmaceutically acceptable salts are intended to be both pharmacologically and pharmaceutically acceptable.
- Such pharmacologically and pharmaceutically acceptable salts may be alkali metal or alkaline earth metal salts, preferably sodium, potassium, magnesium or calcium salts.
- the calcium salt is particularly preferred.
- the amount used for example of the calcium salt, which is particularly preferred according to the invention, of 5-methyl-(6S)-tetrahydrofolic acid (metafolin) is between 0.1 and 10 mg, preferably 0.4 to 1 mg, particularly preferably 451 ⁇ g (equivalent to 400 ⁇ g of folic acid or 416 ⁇ g of 5-methyl-(6S)-tetrahydrofolic acid).
- Crystalline modifications disclosed in EP 1044975 are preferably employed as modification of 5-methyl-(6S)-tetrahydrofolates.
- Vitamin B 6 may be used in a dose between 1 mg and 5 mg, preferably between 1 mg and 3 mg per day on normally dosed use.
- Vitamin B 2 can be employed in a dose between 1 mg and 5 mg, preferably between 1 mg and 2 mg per day on normally dosed use, and between 2 and 5 mg per day on high-dosed use.
- the progestogens and/or estrogens are the substances with contraceptive efficacy in this case.
- 5-Methyl-(6S)-tetrahydrofolate is added as vitamin in order to prevent disorders and malformations caused by folate deficiency without, however, at the same time masking the symptoms of vitamin B 12 deficiency which may be present.
- those women who, because of their reduced MTHFR enzymic activity are capable of only restricted metabolism of folic acid, but also of reduced folates, also profit from 5-methyl-(6S)-tetrahydrofolate.
- the amount of drospirenone administered each day is 0.5 to 5 mg, preferably 3 mg, that of ethinylestradiol is 10 to 50 ⁇ g, preferably 10 to 30 ⁇ g, particularly preferably 20 to 30 ⁇ g.
- the calcium salt of 5-methyl-(6S)-tetrahydrofolic acid is present in an amount of from 0.1 to 10 mg, preferably 0.4 to 1 mg, particularly preferably 451 ⁇ g (equivalent to 400 ⁇ g of folic acid) in this preferred variant of the present invention.
- the formulation of pharmaceutical products based on the novel pharmaceutical composition takes place in a manner known per se by processing the active ingredients with the carrier substances, fillers, substances influencing disintegration, binders, humectants, lubricants, absorbents, diluents, masking flavors, colorants and so on which are used in pharmaceutical technology, and converting into the desired administration forms, which also include slow-release forms.
- the estrogen and the progestogen, and the 5-methyl-(6S)-tetrahydrofolate may, however, also be formulated in separate dose units.
- Polyvinylpyrrolidone is particularly suitable because of its wetting properties for hormone formulations (Moneghini et al., Int J Pharm 175, 1998, 177-183).
- formulation of 5-methyl-(6S)-tetrahydrofolate with PVP increases the rate of degradation of 5-methyl-(6S)-tetrahydrofolate (compare Table 2 and 3; process 3).
- a further object on which this application was based and which is achieved by the present invention is therefore to make stable formulation of ethinylestradiol in the presence of 5-methyl-(6S)-tetrahydrofolate and optionally of vitamin B 12 possible.
- Example 1 Corresponding formulations of the invention are described in Example 1 (compare composition A, B and D).
- Starch consists of amylose and amylopectin. Both are polysaccharides based on ⁇ -glucose units.
- corn starch in pharmaceutical formulations for example rice starch, potato starch or wheat starch.
- the starch is employed swollen, suspended or dissolved as binding liquid or as solid. It may be unmodified or partly modified.
- the starch used in pharmaceutical formulations serves only in part as pure filler. It is used otherwise as binder. 1-5%, preferably ⁇ 1.8-3% of the tablet weight are to be added according to the invention as binder in the form of corn starch.
- a starch compound such as maltodextrin, or cellulose derivatives such as, for example, carboxymethylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose or methylcellulose as binder.
- Part of the corn starch used in the formulation preferred according to the invention may be replaced by low-substituted hydroxypropylcellulose (HPC) in a concentration of 0.5-5% (w/w), preferably 1-3% (w/w), particularly preferably 2% (w/w).
- HPC hydroxypropylcellulose
- the hydroxypropylcellulose has low substitution when no fewer than 5% and no more than 16% of its hydroxyl groups are esterified or etherified.
- Table 2 shows the 5-methyl-(6S)-tetrahydrofolate content per tablet in % based on the specified content of 100% as a function of the binder used immediately after preparation.
- the 5-methyl-(6S)-tetrahydrofolate content shown was measured in the content uniformity test (CUT).
- the investigated formulation was prepared (process 2) by mixing the ingredients, granulating with the part of the corn starch used as binder, absorbing the 5-methyl-(6S)-tetrahydrofolate after completion of the granulation process, renewed mixing and tableting.
- polyvinylpyrrolidone was added as binder instead of corn starch to the formulation by process 3.
- the 5-methyl-(6S)-tetrahydrofolate content in the formulation prepared by process 3 is lower.
- Metafolin content as a function of the binder immediately after preparation Metafolin content Metafolin content absorption, PVP absorption, corn starch (process 3) (process 2) Average 90.5% 96.1%
- Table 3 shows the 5-methyl-(6S)-tetrahydrofolate content as a function of the binder used after storage at defined temperatures and humidity for one month. The tendency, evident from Table 2, for 5-methyl-(6S)-tetrahydrofolate formulated with PVP to be less stable is confirmed in particular on storage under conditions at 40° C. and 75% relative humidity (rH).
- An oral formulation is normally prepared by granulation, tableting and film-coating.
- 5-methyl-(6S)-tetrahydrofolate is, because of its sensitivity to oxygen and moisture, degraded even during the granulation.
- the further degradation of 5-methyl-(6S)-tetrahydrofolate during storage is, however, particularly noteworthy.
- the residue remaining after a storage time of one month at 40° C. and 75% relative humidity in closed vials was only just 60% (compare Table 5) of the originally employed 5-methyl-(6S)-tetrahydrofolate.
- the losses during the granulation process can be reduced by absorbing the 5-methyl-(6S)-tetrahydrofolate only after completion of the granulation process. Dry admixture during the preparation thus leads to stabilization of the 5-methyl-(6S)-tetrahydrofolate. However, in addition, this also surprisingly has the effect of further stabilization during storage.
- the 5-methyl-(6S)-tetrahydrofolate content in a formulation prepared by later absorption is above 90% with identical storage times under identical conditions (compare Table 5).
- Table 4 shows the 5-methyl-(6S)-tetrahydrofolate content per tablet in % as a function of the preparation process used immediately after preparation. The difference between process 1 and process 2 derives from the time at which the 5-methyl-(6S)-tetrahydrofolate was added during the preparation of the investigated tablet. In process 1, the 5-methyl-(6S)-tetrahydrofolate was present in the mixture even during the granulation, whereas in process 2 it was absorbed only after the granulation. The 5-methyl-(6S)-tetrahydrofolate content in the formulation prepared by process 1 is distinctly lower.
- Table 5 shows the 5-methyl-(6S)-tetrahydrofolate content as a function of the preparation process used after storage for one month at defined temperatures and humidity. The tendency, evident from Table 4, for 5-methyl-(6S)-tetrahydrofolate added before the granulation to be less stable is confirmed in particular on storage under conditions of 40° C. and 75% relative humidity (rH).
- Regular intake of the pharmaceutical composition of the invention with the particularly preferred dose of 451 ⁇ g of the calcium salt of 5-methyl-(6S)-tetrahydrofolic acid per day leads to an increase in the folate concentrations in the serum and erythrocytes until a steady state is reached.
- the corresponding erythrocyte folate invasion kinetics are described by half-life of from 6 to 10 weeks. On the basis of this half-life, about 97% of the steady-state erythrocyte folate level can be expected to be reached after about 5 half-lives (corresponding to about 30 to 50 weeks). If daily intake of the pharmaceutical composition of the invention is continued, the erythrocyte folate levels remain in the region of the steady-state concentrations.
- the erythrocyte folate levels slowly fall with a half-life likewise of about 6 to 10 weeks.
- the erythrocyte folate levels thus remain even without further continuation of intake of the pharmaceutical composition of the invention for several weeks in a range above the limit of 906 nmol/l which is generally regarded as sufficient to prevent neural tube defects.
- the product of the invention thus ensures a reduction in the risk of disorders caused by folate deficiency and congenital malformations caused by folate deficiency, even after termination of long-term intake of the medicament of the invention (“pill”).
- 5-methyl-(6S)-tetrahydrofolate one or more estrogens and/or progestogens, and optionally vitamin B 6 and/or vitamin B 2 , and pharmaceutically acceptable excipients and carriers for producing a medicament for reducing the risk of disorders caused by folate deficiency and congenital malformations caused by folate deficiency for at least 8 weeks after termination of previous long-term and continual intake of this medicament is also according to the invention.
- kits comprising at least 20 daily dose units comprising the medicament of the invention and at least one daily dose unit comprising 5-methyl-(6S)-tetrahydrofolate, and optionally vitamin B 12 , vitamin B 6 and/or vitamin B 2 , where the number of all the dose units present in the kit is at least 28, and the dose units are disposed so that first the dose units comprising the medicament of the invention, and then the dose units comprising neither estrogen nor progestogen, are to be taken.
- At least 20 daily dose units comprising the medicament of the invention for the 5-methyl-(6S)-tetrahydrofolate to be formulated separately and to be disposed spatially as additional dose units such that joint intake of both dose units is evident from this disposition.
- kits of the below numbered paragraphs and claims Further developments of the invention for different kits are reflected in kits of the below numbered paragraphs and claims.
- the medicament of the invention is administered in a so-called extended regime.
- extended regime continuous administration of the medicament for more than 28 days, the extended cycle of use being completed by administration for 1 to 7 days of dose units exclusively comprising 5-methyl-(6S)-tetrahydrofolate or by intake of 1 to 7 placebos (dose units active agent) or 1 to 7 blank pill days (no administration of any dose unit).
- composition of tablets (80 mg) of the invention can be found in Table 7.
- composition of tablets of the invention Amount Composition
- Ingredient A B C D Drospirenone 3 mg 3 mg — 3 mg Ethinylestradiol* 0.03 mg 0.02 mg — 0.03 mg
- the ethinylestradiol-beta-cyclodextrin complex is used, about ten times the amount is to be employed. This is because the ethinylestradiol content in the ⁇ -cyclodextrin complex is about 9.5 to 12.5% (compare WO 02/49675). **the part of the corn starch identified by ** can be replaced by an alternative binder such as, for example, 1.6 mg of low-substituted hydroxypropyl-cellulose. ***the amount of corn starch ** employed as binder may also be for example 1.8 mg.
- the oral formulation is produced by mixing the abovementioned ingredients, granulating with the part of the corn starch used as binder, absorbing the calcium salt of 5-methyl-(6S)-tetrahydrofolic acid after completion of the granulation process, renewed mixing, tableting and film-coating.
- Blood is taken at 8-week intervals from 80 healthy young women of childbearing age, and the erythrocyte folate level is determined using a validated microbiological, immunological or instrumental (e.g. HPLC, LC-MS/MS) method or a suitable combination of these methods.
- a validated microbiological, immunological or instrumental e.g. HPLC, LC-MS/MS
- composition C 8 Weeks after the first blood sampling (screening phase), 451 ⁇ g of the calcium salt of 5-methyl-(6S)-tetrahydrofolic acid each day is administered over a period of 40 weeks or, alternatively: 3 mg of drospirenone, 30 ⁇ g of ethinylestradiol and 451 ⁇ g of the calcium salt of 5-methyl-(6S)-tetrahydrofolic acid is administered simultaneously on each of the first 21 days of the respective cycle (tablet of composition A in Example 1). Administration of 451 ⁇ g of the calcium salt of 5-methyl-(6S)-tetrahydrofolic acid is continued for 7 days in a phase immediately subsequent thereto (composition C).
- composition A 3 mg of drospirenone, 30 ⁇ g of ethinylestradiol and 451 ⁇ g of the calcium salt of 5-methyl-(6S)-tetrahydrofolic acid (composition A) are again administered for a further 21 days (second cycle), and only 451 ⁇ g of the calcium salt of 5-methyl-(6S)-tetrahydrofolic acid (composition C) are administered for a further 7 days, and so on (medication phase).
- 5-Methyl-(6S)-tetrahydrofolate is no longer administered after 48 weeks.
- drospirenone and ethinylestradiol can be administered further for a further 40 weeks or likewise be discontinued.
- the last blood sample is taken after 88 weeks.
- the drop-out rate may be up to 50% because of the long-term nature of the study.
- Blood is taken at 8-week intervals from 80 healthy young women of childbearing age, and the erythrocyte folate level is determined using a validated microbiological, immunological or instrumental (e.g. HPLC, LC-MS/MS) method or a suitable combination of these methods.
- a validated microbiological, immunological or instrumental e.g. HPLC, LC-MS/MS
- composition B 3 mg of drospirenone, 20 ⁇ g of ethinylestradiol and 451 ⁇ g of the calcium salt of 5-methyl-(6S)-tetrahydrofolic acid
- composition C administration of 451 ⁇ g of the calcium salt of 5-methyl-(6S)-tetrahydrofolic acid is continued for 7 days (composition C).
- composition B 3 mg of drospirenone and 20 ⁇ g of ethinylestradiol and 451 ⁇ g of the calcium salt of 5-methyl-(6S)-tetrahydrofolic acid (composition B) are again administered, and only 451 ⁇ g of the calcium salt of 5-methyl-(6S)-tetrahydrofolic acid (composition C) are administered for a further 7 days, and so on.
- 5-Methyl-(6S)-tetrahydrofolate is no longer administered after 48 weeks, while drospirenone and ethinylestradiol is administered further for a further 40 weeks or likewise discontinued.
- the last blood sample is taken after 88 weeks.
- the drop-out rate may be up to 50% because of the long-term nature of the study.
- the initial erythrocyte folate level in the subjects is about 500 to 700 nmol/l, depending on the eating habits, but is in every case below 906 nmol/l. This value rises on administration of the pharmaceutical composition of the invention in subsequent days, while the eating habits remain the same, and reaches a value of about 906 nmol/l after only 6 to 8 weeks—i.e. after the second cycle. After continuous administration for at least 30 weeks (corresponding to five times the lower limit of the half-life), while the eating habits remain the same, the erythrocyte folate level reaches about 1200 to 1600 nmol/l (steady state). After termination of the administration of 5-methyl-(6S)-tetrahydrofolate, the erythrocyte folate level falls continuously.
- the erythrocyte folate level is expected to fall below 906 nmol/l, and thus the minimum concentration in erythrocytes generally sufficient to prevent neural tube defects, in the eleventh to thirteenth week after discontinuation of the pharmaceutical composition of the invention.
- erythrocyte folate level is determined using a validated microbiological, immunological or instrumental (e.g. HPLC, LC-MS/MS) method or a suitable combination of these methods.
- a validated microbiological, immunological or instrumental e.g. HPLC, LC-MS/MS
- a first group of 90 women receives over a period of 24 weeks administration of simultaneously 3 mg of drospirenone, 30 ⁇ g of ethinylestradiol and 451 ⁇ g of the calcium salt of 5-methyl-(6S)-tetrahydro-folic acid in each of the first 21 days of the respective cycle.
- administration of 451 ⁇ g of the calcium salt of 5-methyl-(6S)-tetrahydrofolic acid is continued for 7 days.
- a group of 90 women receive administration of 3 mg of drospirenone, 30 ⁇ g of ethinylestradiol and 400 ⁇ g of folic acid according to the same administration scheme as control group.
- the last blood is taken in both cases after 24 weeks. This is followed by an observation period of 20 weeks in which the contraceptive product Yasmin® is administered for 20 weeks, i.e. in each of the first 21 days of the respective cycle, 3 mg of drospirenone and 30 ⁇ g of ethinylestradiol are administered simultaneously; directly subsequent thereto, no active substance is administered (placebos or no administration) for 7 days.
- the dropout rate may be up to 30%.
- the initial erythrocyte folate level in the subjects is below 906 nmol/l. This value increases in subsequent days, if the eating habits remain the same, with administration of the pharmaceutical composition of the invention and, in most of the women, reaches a value of about 906 nmol/l after 6 to 8 weeks. After continuous administration for 24 weeks and with the eating habits remaining the same, an erythrocyte folate level is reached in both groups which shows equivalence between the two treatment groups (bioequivalence criterion 80-125%). After termination of administration of 5-methyl-(6S)-tetrahydrofolate, the erythrocyte folate level falls continuously. It is ascertained when the erythrocyte folate level falls below the acknowledged threshold of 906 nmol/l, which is generally regarded as sufficient to avoid neural tube defects.
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Priority Applications (1)
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US14/965,173 US10463666B2 (en) | 2005-05-13 | 2015-12-10 | Pharmaceutical composition comprising progestogens and/or estrogens and 5-methyl-(6S)-tetrahydrofolate |
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DE102005023301.5 | 2005-05-13 | ||
DE102005023301A DE102005023301B4 (de) | 2005-05-13 | 2005-05-13 | Pharmazeutische Zusammensetzung enthaltend Gestagene und/oder Estrogene und 5-Methyl-(6S)-tetrahydrofolat |
DE102006016285A DE102006016285A1 (de) | 2006-04-03 | 2006-04-03 | Pharmazeutische Zusammensetzung enthaltend Gestagene und/oder Estrogene und 5-Methyl-(6S)-tetrahydrofolat |
DE102006016285.4 | 2006-04-03 | ||
PCT/EP2006/004858 WO2006120035A2 (de) | 2005-05-13 | 2006-05-15 | Pharmazeutische zusammensetzung enthaltend gestagene und/oder estrogene und 5-methyl-(6s)-tetrahydrofolat |
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PCT/EP2006/004858 Continuation-In-Part WO2006120035A2 (de) | 2005-05-13 | 2006-05-15 | Pharmazeutische zusammensetzung enthaltend gestagene und/oder estrogene und 5-methyl-(6s)-tetrahydrofolat |
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US11/938,688 Abandoned US20080160004A1 (en) | 2005-05-13 | 2007-11-12 | Pharmaceutical composition comprising progestogens and/or estrogens and 5-methyl-(6s)-tetrahydrofolate |
US14/965,173 Active 2026-12-02 US10463666B2 (en) | 2005-05-13 | 2015-12-10 | Pharmaceutical composition comprising progestogens and/or estrogens and 5-methyl-(6S)-tetrahydrofolate |
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US (2) | US20080160004A1 (ko) |
EP (3) | EP2116249B2 (ko) |
JP (2) | JP2008540482A (ko) |
KR (2) | KR101598735B1 (ko) |
CN (2) | CN101198332B (ko) |
AR (1) | AR054123A1 (ko) |
AT (2) | ATE555791T1 (ko) |
AU (1) | AU2006245921A1 (ko) |
BR (1) | BRPI0611443B8 (ko) |
CA (1) | CA2608639C (ko) |
CL (2) | CL2009002187A1 (ko) |
CR (1) | CR9531A (ko) |
CY (2) | CY1109261T1 (ko) |
DE (1) | DE502006003617D1 (ko) |
DK (2) | DK2116249T3 (ko) |
DO (1) | DOP2006000110A (ko) |
EA (2) | EA028530B1 (ko) |
EC (1) | ECSP078001A (ko) |
ES (2) | ES2387525T3 (ko) |
GT (1) | GT200600200A (ko) |
HK (1) | HK1118729A1 (ko) |
HR (1) | HRP20090418T1 (ko) |
IL (1) | IL187340A (ko) |
MA (1) | MA29448B1 (ko) |
MY (1) | MY147362A (ko) |
NO (1) | NO345807B1 (ko) |
PE (1) | PE20061415A1 (ko) |
PL (2) | PL2116249T3 (ko) |
PT (2) | PT2116249E (ko) |
RS (2) | RS52651B (ko) |
SG (1) | SG169973A1 (ko) |
SI (2) | SI2116249T1 (ko) |
SV (1) | SV2008002527A (ko) |
TN (1) | TNSN07418A1 (ko) |
TW (1) | TWI380820B (ko) |
UY (1) | UY29527A1 (ko) |
WO (1) | WO2006120035A2 (ko) |
ZA (1) | ZA200710811B (ko) |
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---|---|---|---|---|
US20080038343A1 (en) * | 2006-07-06 | 2008-02-14 | Kristina King | Pharmaceutical composition containing a tetrahydrofolic acid |
US20090023693A1 (en) * | 2007-04-05 | 2009-01-22 | Vladimir Hanes | New drospirenone/17beta-estradiol regimen, pharmaceutical combination product and kit for performing this regimen |
US20090170823A1 (en) * | 2007-12-20 | 2009-07-02 | Duramed Pharmaceuticals, Inc. | Dosage Regimens and Pharmaceutical Compositions and Packages for Emergency Contraception |
EP2781214A1 (en) | 2013-03-22 | 2014-09-24 | Chemo Research, S.L. | Formulation of amorphous calcium L-5-methyltetrahydrofolate (L-5-MTHF-Ca) |
Families Citing this family (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
UY29527A1 (es) | 2005-05-13 | 2006-12-29 | Schering Ag | Composicinn farmaccutica que contienen gestrgenos y/o estrngenos y 5-metil - (6s) - tetrhidrofolato. |
CN101489563A (zh) * | 2006-07-06 | 2009-07-22 | 拜耳先灵医药股份有限公司 | 用于避孕和预防先天性畸形风险的药物制剂 |
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WO2009112231A2 (en) * | 2008-03-10 | 2009-09-17 | Schuermann Rolf | New drospirenone/17beta-estradil regimen, pharmaceutical combination product and kit for performing this regimen |
WO2009112232A2 (en) * | 2008-03-10 | 2009-09-17 | Vladimir Hanes | New drospirenone/17beta-estradiol regimen, pharmaceutical combination product and kit for performing this regimen |
AU2011240102B2 (en) | 2010-04-15 | 2015-07-23 | Bayer Intellectual Property Gmbh | Very low-dosed solid oral dosage forms for HRT |
EP2383279A1 (en) | 2011-07-19 | 2011-11-02 | Pantarhei Bioscience B.V. | Process for the preparation of estetrol |
EP2617422A1 (en) * | 2012-01-20 | 2013-07-24 | Isofol Medical AB | Anti-tumor activity of reduced folates like methylene-tetrahydrofolate, tetrahydrofolate or methyl-tetrahydrofolate |
CN107812195B (zh) * | 2014-09-04 | 2021-04-20 | 连云港金康和信药业有限公司 | (6s)‐5‐甲基‐四氢叶酸钙盐的稳定药物组合物 |
PL3310333T3 (pl) | 2015-06-18 | 2020-07-13 | Estetra Sprl | Ulegająca rozpadowi w jamie ustnej jednostka dawkowana zawierająca składnik estetrolowy |
GEP20217308B (en) | 2015-06-18 | 2021-10-25 | Estetra Sprl | Orodispersible dosage unit containing an estetrol component |
MA44205B1 (fr) | 2015-06-18 | 2021-04-30 | Estetra Sprl | Comprimé orodispersible comprenant estetrol |
CA3178291A1 (en) | 2016-08-05 | 2018-04-12 | Estetra Srl | Method for the management of dysmenorrhea and menstrual pain |
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JOP20200260A1 (ar) | 2018-04-19 | 2019-10-19 | Estetra Sprl | مركبات واستخداماتها للتخفيف من الأعراض المصاحبة لانقطاع الطمث |
TWI801561B (zh) | 2018-04-19 | 2023-05-11 | 比利時商依思特拉私人有限責任公司 | 化合物及其用於緩解絕經相關症狀的用途 |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6011040A (en) * | 1997-06-13 | 2000-01-04 | Eprova Ag | Use of tetrahydrofolates in natural stereoisomeric form for the production of a pharmaceutical preparation suitable for influencing the homocysteine level, particularly for assisting the remethylation of homocysteine |
US6083528A (en) * | 1995-09-28 | 2000-07-04 | Schering Aktiengesellschaft | Hormone replacement therapy method and hormone dispenser |
US6190693B1 (en) * | 1998-04-17 | 2001-02-20 | Ortho-Mcneil Pharamceutical, Inc. | Pharmaceutical methods of delivering folic acid |
US20030045510A1 (en) * | 2000-12-15 | 2003-03-06 | Schloss Caroline Maxine | Estrogen-plus |
US6921754B2 (en) * | 2000-05-10 | 2005-07-26 | Basf Aktiengesellschaft | Compositions containing folic acid and reduced folate |
US20050164977A1 (en) * | 2002-02-21 | 2005-07-28 | Coelingh Bennink Herman J.T. | Pharmaceutical compositions comprising one or more steroids one or more tetrahydrofolate components and vitamin b12 |
US20060034954A1 (en) * | 2001-02-02 | 2006-02-16 | Bland Jeffrey S | Medical composition for balancing bodily processes |
Family Cites Families (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DK174724B1 (da) * | 1986-07-15 | 2003-10-06 | Wyeth Corp | Anvendelse af et præparat omfattende et østrogen og et progestogen til fremstilling af en dosisform til tilvejebringelse af hormonerstatningsterapi og kontraception til kvinder i præmenopausen samt pakning til tilvejebringelse af præparatet |
ZA939565B (en) * | 1993-12-21 | 1994-08-11 | Applied Analytical Ind Inc | Method for preparing low dose pharmaceutical products. |
CA2234817A1 (en) * | 1995-10-27 | 1997-05-01 | Mandana Asgharnejad | Wet granulation formulation of a growth hormone secretagogue |
JP3602141B2 (ja) | 1996-01-31 | 2004-12-15 | サウス、アラバマ、メディカル、サイエンス、ファウンデーション | 還元されたフォレートの天然異性体を含む食品およびビタミン製剤 |
ID24568A (id) * | 1997-11-06 | 2000-07-27 | American Home Prod | Kontrasepsi oral yang mengandung anti-estrogen plus progestin |
US6326392B1 (en) | 1997-11-06 | 2001-12-04 | American Home Products Corporation | Anti-estrogen plus progestin containing oral contraceptives |
EP1121139A1 (en) * | 1998-10-19 | 2001-08-08 | MERCK PATENT GmbH | Natural formulation for the treatment and prevention of depression, containing st john's wort and derivatives of dihydro- and tetrahydrofolic acid |
US7014865B1 (en) | 1998-10-19 | 2006-03-21 | Merck Patent Gmbh | Natural formulation for the treatment and prevention of depression, containing St. John's Wort and derivatives of dihydro- and tetrahydrofolic acid |
CH693905A5 (de) | 1999-04-15 | 2004-04-15 | Eprova Ag | Stabile kristalline Salze von 5-Methyltetrahydrofolsäure. |
HU225779B1 (en) | 1999-07-28 | 2007-08-28 | Chinoin Gyogyszer Es Vegyeszet | Pharmaceutical composition containing paracetamol and drotaverine and process for producing it |
US6787531B1 (en) | 1999-08-31 | 2004-09-07 | Schering Ag | Pharmaceutical composition for use as a contraceptive |
HU227207B1 (en) | 1999-08-31 | 2010-11-29 | Bayer Schering Pharma Ag | Use of a pharmaceutical combination of ethinylestradiol and drospirenone for producing pharmaceutical compositions having contraceptive activity |
US6479545B1 (en) | 1999-09-30 | 2002-11-12 | Drugtech Corporation | Formulation for menopausal women |
UA73119C2 (en) | 2000-04-19 | 2005-06-15 | American Home Products Corpoir | Derivatives of cyclic thiocarbamates, pharmaceutical composition including noted derivatives of cyclic thiocarbamates and active ingredients of medicines as modulators of progesterone receptors |
JP2004538262A (ja) * | 2000-12-14 | 2004-12-24 | タフツ ユニバーシティー | 関節炎状態を治療するための化合物および方法 |
EP1216713A1 (en) | 2000-12-20 | 2002-06-26 | Schering Aktiengesellschaft | Compositions of estrogen-cyclodextrin complexes |
US20040220118A1 (en) * | 2001-02-02 | 2004-11-04 | Bland Jeffrey S. | Medical composition for balancing bodily processes |
UY29527A1 (es) | 2005-05-13 | 2006-12-29 | Schering Ag | Composicinn farmaccutica que contienen gestrgenos y/o estrngenos y 5-metil - (6s) - tetrhidrofolato. |
-
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- 2013-02-18 JP JP2013029277A patent/JP5883810B2/ja active Active
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Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6083528A (en) * | 1995-09-28 | 2000-07-04 | Schering Aktiengesellschaft | Hormone replacement therapy method and hormone dispenser |
US6011040A (en) * | 1997-06-13 | 2000-01-04 | Eprova Ag | Use of tetrahydrofolates in natural stereoisomeric form for the production of a pharmaceutical preparation suitable for influencing the homocysteine level, particularly for assisting the remethylation of homocysteine |
US6190693B1 (en) * | 1998-04-17 | 2001-02-20 | Ortho-Mcneil Pharamceutical, Inc. | Pharmaceutical methods of delivering folic acid |
US6921754B2 (en) * | 2000-05-10 | 2005-07-26 | Basf Aktiengesellschaft | Compositions containing folic acid and reduced folate |
US20030045510A1 (en) * | 2000-12-15 | 2003-03-06 | Schloss Caroline Maxine | Estrogen-plus |
US20060034954A1 (en) * | 2001-02-02 | 2006-02-16 | Bland Jeffrey S | Medical composition for balancing bodily processes |
US20050164977A1 (en) * | 2002-02-21 | 2005-07-28 | Coelingh Bennink Herman J.T. | Pharmaceutical compositions comprising one or more steroids one or more tetrahydrofolate components and vitamin b12 |
Non-Patent Citations (2)
Title |
---|
Foster RH, Wilde MI. Dienogest. Drugs. 1998 Nov;56(5):825-33. * |
Smith OP, Critchley HO. Progestogen only contraception and endometrial break through bleeding. Angiogenesis. 2005;8(2):117-26. Epub 2005 Oct 7. * |
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EP2781214A1 (en) | 2013-03-22 | 2014-09-24 | Chemo Research, S.L. | Formulation of amorphous calcium L-5-methyltetrahydrofolate (L-5-MTHF-Ca) |
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