US20060058272A1 - Pharmaceutical composition for use as a contraceptive - Google Patents
Pharmaceutical composition for use as a contraceptive Download PDFInfo
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- US20060058272A1 US20060058272A1 US11/266,395 US26639505A US2006058272A1 US 20060058272 A1 US20060058272 A1 US 20060058272A1 US 26639505 A US26639505 A US 26639505A US 2006058272 A1 US2006058272 A1 US 2006058272A1
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- daily dosage
- ethinylestradiol
- drospirenone
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- 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
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- 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
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- 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
Definitions
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising drospirenone and ethinylestradiol, a method of providing dissolution of drospirenone, methods of inhibiting ovulation by administration of drospirenone and the use of drospirenone and ethinylestradiol for inhibiting ovulation.
- Oral contraceptives containing a combination of a gestagen and an estrogen component have been used since the 1960's.
- the earliest contraceptive preparations consisted of 21 tablets containing the combination of active agents and 7 tablets containing no active agent, and the amount of each active agent was the same in each tablet (the so-called one-phase preparations).
- preparations were developed that consisted of tablets containing different amounts and ratios of the active agents over the cycle of administration (the so-called multiple-phase preparations).
- the daily dosage should be at least the minimum of what is needed for the gestagen in question to inhibit ovulation effectively.
- the estrogen component acts to increase the ovulation inhibitory effect of gestagen and to ensure cycle stability. Since the introduction of oral contraceptives, the daily dosage of gestagen has been reduced through the development of new and more efficient gestagens than were present in the earlier contraceptive preparations. It has also been possible to reduce the daily dosage of estrogen.
- the gestagen-like activity of the compound and its consequent utility as a contraceptive agent is described at dosage levels of 0.5-50 mg of drospirenone per day. It is also noted that the mechanism of action of the compound is very similar to that of the natural corpus luteum hormone progesterone, and that it does not give rise to increased blood pressure for which reason it may be administrated to women who have or are at risk of developing increased blood pressure. It is further described that drospirenone may be administered together with ethinylestradiol in an amount of 0.03-0.05 mg per day.
- DE 30 51 166 discloses the use of the drospirenone for the treatment of gynaecological irregularities and for contraception at a dosage level of 0.5-50 mg per day.
- EP 398'460 discloses the use of drospirenone for the treatment of androgen-induced disorders, aldosterone-induced disorders and hormonal irregularities as well as for contraception at dosage levels of 0.5-50 mg, preferably 1-10 mg per day.
- Ethinylestradiol may be co-administered at a level of 0.02-0.04 mg per day.
- U.S. Pat. No. 5,756,490 discloses pharmaceutical combination preparations comprising 23 or 24 dosage units containing a combination of a gestagen and an estrogen and 4-10 dosage units containing estrogen alone.
- Drospirenone is mentioned as a possible, but not preferred, gestagenic compound and ethinylestradiol is mentioned as a possible, but not preferred, estrogenic compound.
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising, as a first active agent, 6 ⁇ ,7 ⁇ ;15 ⁇ ,16 ⁇ -dimethylene-3-oxo-17 ⁇ -pregn-4-ene-21,17-carbolactone (drospirenone) in an amount corresponding to a daily dosage, on administration of the composition, of from about 2 mg to about 4 mg, and, as a second active agent, 17 ⁇ -ethinylestradiol (ethinylestradiol) in an amount corresponding to a daily dosage of from about 0.01 mg to about 0.05 mg, together with one or more pharmaceutically acceptable carriers or excipients.
- a first active agent 6 ⁇ ,7 ⁇ ;15 ⁇ ,16 ⁇ -dimethylene-3-oxo-17 ⁇ -pregn-4-ene-21,17-carbolactone (drospirenone) in an amount corresponding to a daily dosage, on administration of the composition, of from about 2 mg to about 4 mg
- an ester or prodrug of drospirenone may be employed in the present composition, e.g. an oxyiminopregnane carbolactone as disclosed in WO 98/24801.
- esters or ethers of ethinylestradiol may be included in the composition.
- the invention relates to a method of inhibiting ovulation in a mammal, in particular a human, comprising administering, to said mammal, drospirenone in an amount in the range of from about 2 mg to about 4 mg of per day, together with ethinylestradiol in an amount of from about 0.01 mg to about 0.05 mg per day, said amounts being effective to inhibit ovulation in said mammal.
- the invention relates to the use of drospirenone combined with ethinylestradiol for preparing a pharmaceutical preparation for the inhibition of ovulation in a mammal, in particular a human, the composition comprising an amount of drospirenone corresponding to a daily dosage, on administration of the composition, of from about 2 mg to about 4 mg, and comprising an amount of ethinylestradiol corresponding to a daily dosage, on administration of the composition, of from about 0.01 to about 0.05 mg.
- FIG. 1 is a graph showing the in vitro dissolution rate of drospirenone from tablet cores, V1-V7 being batches containing micronized drospirenone, and V8 being a batch containing macrocrystalline drospirenone;
- FIG. 2 is a graph showing the in vitro dissolution rate of drospirenone from tablet cores, different lines representing different test batches;
- FIG. 3 is a graph showing the in vitro dissolution rate of drospirenone from film-coated tablets, different lines representing different test batches;
- FIG. 4 is a graph showing the in vitro dissolution rate of ethinylestradiol from tablet cores, different lines representing different test batches.
- FIG. 5 is a graph showing the in vitro dissolution rate of ethinylestradiol from film-coated tablets, different lines representing different test batches.
- Drospirenone which may be prepared substantially as described in, e.g., U.S. Pat. No. 4,129,564 or WO 98/06738, is a sparingly soluble substance in water and aqueous buffers at various pH values. Furthermore, drospirenone is rearranged to an inactive isomer under acid conditions and hydrolysed under alkaline conditions. To ensure good bioavailability of the compound, it is therefore advantageously provided in a form that promotes rapid dissolution thereof.
- drospirenone when drospirenone is provided in micronized form (so that particles of the active substance have a surface area of more than 10,000 cm 2 /g, and the following particle size distribution as determined under the microscope: not more than 2 particles in a given batch with a diameter of more than 30 ⁇ m, and preferably ⁇ 20 particles with a diameter of ⁇ 10 ⁇ m and ⁇ 30 ⁇ m) in a pharmaceutical composition, rapid dissolution of the active compound from the composition occurs in vitro (“rapid dissolution” is defined as the dissolution of at least 70% over about 30 minutes, in particular at least 80% over about 20 minutes, of drospirenone from a tablet preparation containing 3 mg of drospirenone in 900 ml of water at 37° C.
- drospirenone in micronized form, it is possible to dissolve it in a suitable solvent, e.g. methanol or ethyl acetate, and spray it onto the surface of inert carrier particles followed by incorporation of the particles containing drospirenone on their surface in the composition.
- a suitable solvent e.g. methanol or ethyl acetate
- ethinylestradiol which is also a sparingly soluble substance, though less sensitive to degradation than drospirenone under conditions prevailing in the gastrointestinal tract, it is also an advantage to provide it in micronized form or sprayed from a solution, e.g. in ethanol, onto the surface of inert carrier particles. This has the added advantage of facilitating a more homogenous distribution of the ethinylestradiol throughout the composition which might otherwise be difficult to obtain because ethinylestradiol is incorporated in extremely small amounts.
- ethinylestradiol When ethinylestradiol is provided in micronized form, it preferably has the following particle size distribution as determined under the microscope: 100% of the particles have a diameter of ⁇ 15.0 ⁇ m, 99% of the particles have a diameter of ⁇ 12.5 ⁇ m, 95% of the particles have a diameter of ⁇ 10.0 ⁇ m, and 50% of the particles have a diameter of ⁇ 3.0 ⁇ m. Furthermore, no particle is larger than 20 ⁇ m, and ⁇ 10 particles have a diameter of ⁇ 15 ⁇ m and ⁇ 20 ⁇ m.
- carriers or excipients which act to promote dissolution of both active substances.
- carriers and excipients include substances that are readily soluble in water such as cellulose derivatives, carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, gelled starch, gelatin or polyvinylpyrrolidone.
- polyvinylpyrrolidone might be particularly helpful to promote dissolution.
- the composition of the invention preferably comprises drospirenone in an amount corresponding to a daily dosage of from about 2.5 mg to about 3.5 mg, in particular about 3 mg.
- the amount of ethinylestradiol preferably corresponds to a daily dosage of from about 0.015 mg to about 0.04 mg, in particular from about 0.015 mg to about 0.03 mg.
- the present composition comprises an amount of drospirenone corresponding to a daily dosage of from about 3.0 to about 3.5 mg and ethinylestradiol in an amount corresponding to from about 0.015 to about 0.03 mg.
- composition of the invention has been found to possess pronounced anti-androgenic properties and may therefore be used in the prevention or treatment of androgen-induced disorders, in particular acne. Such use may be independent from or concomitant with the use as a contraceptive disclosed above.
- drospirenone is an aldosterone antagonist, it has diuretic properties and is therefore suitable for counteracting the water-retentive properties of ethinylestradiol.
- the invention relates to a pharmaceutical preparation consisting of a number of separately packaged and individually removable daily dosage units placed in a packaging unit and intended for oral administration for a period of at least 21 consecutive days, wherein each of said daily dosage units comprises a combination of drospirenone in an amount of from about 2 mg to about 4 mg and ethinylestradiol in an amount from about 0.01 to about 0.05 mg.
- the preparation further comprises 7 or less said daily dosage units containing no active agent.
- the preparation may be a one-phase composition, i.e. a preparation wherein the amounts of either active agent remains constant for the entire at least 21-day period, or the amounts of either or both active agents may be varied over the at least 21-day period to generate a multiple-phase preparation, e.g. a two- or three-phase preparation, substantially as disclosed in, e.g., EP 148 724.
- a multiple-phase preparation e.g. a two- or three-phase preparation, substantially as disclosed in, e.g., EP 148 724.
- the number of daily dosage units comprising the combination of drospirenone and ethinylestradiol may be 21, 22, 23 or 24, and the number of daily dosage units containing no active agent may then be 7, 6, 5 or 4, as the case may be.
- the number of daily dosage units comprising the combination of drospirenone and ethinylestradiol is 28, or a multiple of 28 such as 2-4, in particular 2 or 3, times 28.
- the invention relates to a contraceptive preparation consisting of a number of separately packaged and individually removable daily dosage units placed in a packaging unit and intended for oral administration for a period of at least 28 consecutive days, wherein at least 21 of said daily dosage units comprises a combination of drospirenone in an amount of from about 2 mg to about 4 mg and ethinylestradiol in an amount from about 0.01 to about 0.05 mg, and wherein 7 or less of said daily dosage units contain ethinylestradiol alone in an amount from about 0.01 to about 0.05 mg.
- the preparation may be one in which the amounts of either active agent remains constant for the entire at least 21-day period (i.e. a two-phase preparation), or the amounts of either or both active agents may be varied over the at least 21-day period to generate a multiple-phase preparation, e.g. a three- or four-phase preparation, substantially as disclosed in, e.g., EP 148 724.
- a multiple-phase preparation e.g. a three- or four-phase preparation, substantially as disclosed in, e.g., EP 148 724.
- the number of daily dosage units comprising the combination of drospirenone and ethinylestradiol may be 21, 22, 23 or 24, and the number of daily dosage units containing ethinylestradiol alone may then be 7, 6, 5 or 4, as the case may be.
- the method comprises administering, to said mammal, on each day of at least 21 consecutive days, a daily dosage unit comprising a combination of drospirenone in an amount of from about 2 mg to about 4 mg and ethinylestradiol in an amount from about 0.01 to about 0.05 mg, followed by administering, on each day of 7 or less consecutive days, a daily dosage unit containing no active agent, or alternatively, administering no dosage units for 7-days or less.
- the daily dosage units comprising the combination of drospirenone and ethinylestradiol may be administered for 21, 22, 23 or 24 consecutive days, and the daily dosage units containing no active agent may then be administered for 7, 6, 5 or 4 consecutive days, as appropriate. Furthermore, the daily dosage units comprising the combination of drospirenone and ethinylestradiol may be administered for 28 consecutive days.
- the daily dosage units comprising the combination of drospirenone and ethinylestradiol are administered for 2-4, preferably 2- or 3, times 28 consecutive days, followed by administration of the daily dosage units comprising the combination of drospirenone and ethinylestradiol for 21, 22, 23 or 24 consecutive days and subsequently administration of the daily dosage units containing no active agent, or administration of no daily dosage units, for 7, 6, 51 or 4 consecutive days.
- the present method comprises administering, on each day of at least 21 consecutive days, a daily dosage unit comprising a combination of drospirenone in an amount of from about 2 mg to about 4 mg and ethinylestradiol in an amount from about 0.01 to about 0.05 mg, followed by administering, on each day of 7 or less consecutive days, a daily dosage unit containing ethinylestradiol alone in an amount of from about 0.01 mg to about 0.05 mg.
- the daily dosage units comprising the combination of drospirenone and ethinylestradiol may suitably be administered for 21, 22, 23 or 24 consecutive days, and wherein the daily dosage units comprising ethinylestradiol alone may then be administered for 7, 6, 5 or 4 consecutive days, as appropriate.
- the daily dosage units comprising the combination of drospirenone and ethinylestradiol are administered for 2-4, preferably 2 or 3, times 28 consecutive days, followed by administration of the daily dosage units comprising the combination of drospirenone and ethinylestradiol for 21 consecutive days and subsequently administration of the daily dosage units comprising ethinylestradiol alone for 7 consecutive days.
- the pharmaceutical preparation may suitably be in the form of a number of separately packaged and individually removable daily dosage units placed in a packaging unit and intended for oral administration for a period of at least 21 consecutive days, wherein each of said daily dosage units each comprises a combination of drospirenone in an amount of from about 2 mg to about 4 mg and ethinylestradiol in an 0.30 amount from about 0.01 to about 0.05 mg.
- the preparation may further comprise 7 or less daily dosage units containing no active agent (or may contain 7 or less empty “places”, e.g. in the form of empty blisters in a blister pack, marking the days on which no daily dosage units are administered).
- the pharmaceutical preparation may be in the form of a number of separately packaged and individually removable daily dosage units placed in a packaging unit and intended for oral administration for a period of at least 28 consecutive days, wherein at least 21 of said daily dosage units each comprises a combination of drospirenone in an amount of from about 2 mg to about 4 mg and ethinylestradiol in an amount of from about 0.01 to about 0.05 mg, said packaging unit further comprising 7 or less daily dosage units comprising ethinylestradiol alone in an amount of from about 0.01 mg to about 0.05 mg.
- composition of the invention may be formulated in any manner known in the pharmaceutical art.
- the composition may be formulated by a method comprising providing drospirenone and, if desired, ethinylestradiol in micronized form in said unit dosage form, or sprayed from a solution onto particles of an inert carrier in admixture with one or more pharmaceutically acceptable excipients that promote dissolution of the drospirenone and ethinylestradiol so as to promote rapid dissolution of drospirenone and preferably ethinylestradiol on oral administration.
- suitable excipients include fillers, e.g.
- sugars such as lactose, glucose or sucrose, sugar alcohols such as mannitol, sorbitol or xylitol, starch such as wheat, corn or potato starch, modified starch or sodium starch glycolate, lubricants such as talc, magnesium stearate, calcium stearate, colloidal silica or stearic acid, and binders such as polyvinylpyrrolidone, cellulose derivatives, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose or gelatin, for making oral dosage forms such as tablets, pills or capsules.
- starch such as wheat, corn or potato starch, modified starch or sodium starch glycolate
- lubricants such as talc, magnesium stearate, calcium stearate, colloidal silica or stearic acid
- binders such as polyvinylpyrrolidone, cellulose derivatives, carboxymethyl cellulose, hydroxypropyl cellulose,
- Tablets may conveniently be coated with a suitable film-forming agent, e.g. hydroxypropylmethyl cellulose, hydroxypropyl cellulose or ethyl cellulose, to which a suitable excipient may optionally be added, e.g. a softener such as glycerol, propylene glycol, diethylphthalate or glycerol triacetate, filler such as sucrose, sorbitol, xylitol, glucose or lactose, a colorant such as titanium hydroxide, etc.
- a suitable film-forming agent e.g. hydroxypropylmethyl cellulose, hydroxypropyl cellulose or ethyl cellulose
- a suitable excipient e.g. a softener such as glycerol, propylene glycol, diethylphthalate or glycerol triacetate
- filler such as sucrose, sorbitol, xylitol, glucose or lactose,
- the present composition may also be formulated in liquid form, e.g. as a solution, suspension or emulsion, together with conventional diluents or excipients in a manner known per se in the pharmaceutical art.
- a packaging unit comprising the daily dosage units 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 at least 21, or for particular applications, 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.
- Each blister container may conveniently be numbered or otherwise marked, e.g.
- the present composition may be in the form of a parenteral formulation such as a subcutaneous implant or transdermal formulation.
- the active agents may suitably be formulated together with one or more polymers that are gradually eroded or degraded when in use, e.g. silicone polymers, ethylene vinylacetate, polyethylene or polypropylene.
- transdermal formulations are concerned, they may be prepared in the form of matrices or membranes or as fluid or viscous formulations in oil or hydrogels.
- an adhesive which is compatible with the skin should be included, such as polyacrylate, a silicone adhesive or polyisobutylene, as well as a foil made of, e.g. polyethylene, polypropylene, ethylene vinylacetate, polyvinylchloride, polyvinylidene chloride or polyester, and a removable protective foil made from, e.g., polyester or paper coated with silicone or a fluoropolymer.
- water or organic solvents or mixtures thereof may be used.
- Transdermal gels may furthermore contain one or more suitable gelling agents or thickeners such as silicone, tragacanth, starch or starch derivatives, cellulose or cellulose derivatives or polacrylic acids or derivatives thereof.
- Transdermal formulations may also suitably contain one or more substances that enhance absorption though the skin, such as bile salts or derivatives thereof and/or phospholipids. Suitable transdermal formulations may, for instance, be made in a manner analogous to that described in WO 94/04157 for 3-ketodesogestrel.
- transdermal formulations may be prepared according to a method disclosed in, e.g., BW Barry, “Dermatological Formulations, Percutaneous Absorption”, Marcel Dekker Inc., New York—Basel, 1983, or Yw Chien, “Transdermal Controlled Systemic Medications”, Marcel Dekker Inc., New York—Basel, 1987.
- the rate of dissolution of drospirenone from the tablets prepared in Example 1 was determined by the USP XXIII Paddle Method using a USP Dissolution Test Apparatus 2 including 6 covered glass vessels and 6 paddles. Tablets were placed in 900 ml water at a temperature of 37° C. ( ⁇ 0.5° C.) and stirred at 50 rpm.
- FIGS. 1, 2 and 4 The results appear from FIGS. 1, 2 and 4 . From FIG. 1 , it appears that the batch numbered V8 containing macrocrystalline drospirenone (but otherwise identical to the tablets prepared in Example 1) exhibited an extremely slow dissolution rate of drospirenone, whereas all batches containing micronized drospirenone exhibited a dissolution rate of more than 70% within 30 minutes.
- FIG. 2 and FIG. 4 shows the results of dissolution of drospirenone from tablet cores and film-coated tablets, respectively. In both cases more than 70% of the active agent is dissolved within 30 minutes. Thus, the film coating did not significantly influence the rate of dissolution.
- the rate of dissolution of ethinylestradiol from tablets prepared as described in Example 1 was determined according to the USP Paddle Method as described in Example 2 for drospirenone. The results appear from FIGS. 3 and 5 showing the dissolution rates from tablet cores and film-coated tablets, respectively. In both cases, more than 70% of the active agent was dissolved within 30 minutes. Thus, the film coating did not significantly influence the rate of dissolution.
- the bioavailability was determined using serum concentrations of each active agent as parameters. Compared to the oral suspension, the relative bioavailability of drospirenone and ethinylestradiol from the tablets is 107% and 117%, respectively. It was therefore concluded that both drospirenone and ethinylestradiol are completely released from the tablets in vivo.
- the absolute bioavailability of drospirenone was determined in two studies to be 76% ⁇ 13% after oral administration of 2 mg drospirenone to 8 young healthy women and 85% ⁇ 24% after oral administration of a microcrystalline suspension containing 3.13 mg drospirenone to 6 postmenopausal women.
- the two trial preparations were equally good as regards the subjective and objective tolerance.
- HDL was influenced positively in the sense of an increase.
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Abstract
A pharmaceutical composition comprises, as a first active agent, 6β,7β;15β,16β-dimethylene-3-oxo-17α-pregn-4-ene-21,17-carbolactone (drospirenone) in an amount corresponding to a daily dosage, on administration of the composition, of from about 2 mg to about 4 mg, and, as a second active agent, 17α-ethinylestradiol (ethinylestradiol) in an amount corresponding to a daily dosage of from about 0.01 mg to about 0.05 mg, together with one or more pharmaceutically acceptable carriers or excipients. In a specific embodiment, the composition consists of a number of separately packaged and individually removable daily dosage units placed in a packaging unit and intended for oral administration for a period of at least 21 consecutive days, wherein said daily dosage units comprises the combination of drospirenone and ethinylestradiol. The composition may further comprise 7 or less daily dosage units containing no active agent or containing ethinylestradiol alone.
Description
- The present invention relates to a pharmaceutical composition comprising drospirenone and ethinylestradiol, a method of providing dissolution of drospirenone, methods of inhibiting ovulation by administration of drospirenone and the use of drospirenone and ethinylestradiol for inhibiting ovulation.
- Oral contraceptives containing a combination of a gestagen and an estrogen component have been used since the 1960's. The earliest contraceptive preparations consisted of 21 tablets containing the combination of active agents and 7 tablets containing no active agent, and the amount of each active agent was the same in each tablet (the so-called one-phase preparations). Subsequently, preparations were developed that consisted of tablets containing different amounts and ratios of the active agents over the cycle of administration (the so-called multiple-phase preparations).
- Contraceptive reliability is mainly provided by the gestagen component. The daily dosage should be at least the minimum of what is needed for the gestagen in question to inhibit ovulation effectively. The estrogen component acts to increase the ovulation inhibitory effect of gestagen and to ensure cycle stability. Since the introduction of oral contraceptives, the daily dosage of gestagen has been reduced through the development of new and more efficient gestagens than were present in the earlier contraceptive preparations. It has also been possible to reduce the daily dosage of estrogen.
- 6β,7β;15β,16β-dimethylene-3-oxo-17α-pregn-4-ene-21,17-carbolactone (drospirenone) is known from DE 26 52 761 in which its use as a diuretic compound is disclosed.
- In
DE 30 22 337, the gestagen-like activity of the compound and its consequent utility as a contraceptive agent is described at dosage levels of 0.5-50 mg of drospirenone per day. It is also noted that the mechanism of action of the compound is very similar to that of the natural corpus luteum hormone progesterone, and that it does not give rise to increased blood pressure for which reason it may be administrated to women who have or are at risk of developing increased blood pressure. It is further described that drospirenone may be administered together with ethinylestradiol in an amount of 0.03-0.05 mg per day. -
DE 30 51 166 discloses the use of the drospirenone for the treatment of gynaecological irregularities and for contraception at a dosage level of 0.5-50 mg per day. - EP 398'460 discloses the use of drospirenone for the treatment of androgen-induced disorders, aldosterone-induced disorders and hormonal irregularities as well as for contraception at dosage levels of 0.5-50 mg, preferably 1-10 mg per day. Ethinylestradiol may be co-administered at a level of 0.02-0.04 mg per day.
- U.S. Pat. No. 5,756,490 discloses pharmaceutical combination preparations comprising 23 or 24 dosage units containing a combination of a gestagen and an estrogen and 4-10 dosage units containing estrogen alone. Drospirenone is mentioned as a possible, but not preferred, gestagenic compound and ethinylestradiol is mentioned as a possible, but not preferred, estrogenic compound.
- In the course of research leading to the present invention, it has surprisingly been found that a hitherto undisclosed minimum dosage level of drospirenone is required for reliable contraceptive activity. Similarly, a preferred maximum dosage has been identified at which unpleasant side effects, in particular excessive diuresis, may substantially be avoided.
- Accordingly, in a first aspect, the present invention relates to a pharmaceutical composition comprising, as a first active agent, 6β,7β;15β,16β-dimethylene-3-oxo-17α-pregn-4-ene-21,17-carbolactone (drospirenone) in an amount corresponding to a daily dosage, on administration of the composition, of from about 2 mg to about 4 mg, and, as a second active agent, 17α-ethinylestradiol (ethinylestradiol) in an amount corresponding to a daily dosage of from about 0.01 mg to about 0.05 mg, together with one or more pharmaceutically acceptable carriers or excipients.
- Apart form the active sub stances themselves, it is envisaged that an ester or prodrug of drospirenone may be employed in the present composition, e.g. an oxyiminopregnane carbolactone as disclosed in WO 98/24801. Likewise, it is envisaged that esters or ethers of ethinylestradiol may be included in the composition.
- In a further aspect, the invention relates to a method of inhibiting ovulation in a mammal, in particular a human, comprising administering, to said mammal, drospirenone in an amount in the range of from about 2 mg to about 4 mg of per day, together with ethinylestradiol in an amount of from about 0.01 mg to about 0.05 mg per day, said amounts being effective to inhibit ovulation in said mammal.
- In a still further aspect, the invention relates to the use of drospirenone combined with ethinylestradiol for preparing a pharmaceutical preparation for the inhibition of ovulation in a mammal, in particular a human, the composition comprising an amount of drospirenone corresponding to a daily dosage, on administration of the composition, of from about 2 mg to about 4 mg, and comprising an amount of ethinylestradiol corresponding to a daily dosage, on administration of the composition, of from about 0.01 to about 0.05 mg.
- The invention is further described with reference to the drawings in which
-
FIG. 1 is a graph showing the in vitro dissolution rate of drospirenone from tablet cores, V1-V7 being batches containing micronized drospirenone, and V8 being a batch containing macrocrystalline drospirenone; -
FIG. 2 is a graph showing the in vitro dissolution rate of drospirenone from tablet cores, different lines representing different test batches; -
FIG. 3 is a graph showing the in vitro dissolution rate of drospirenone from film-coated tablets, different lines representing different test batches; -
FIG. 4 is a graph showing the in vitro dissolution rate of ethinylestradiol from tablet cores, different lines representing different test batches; and -
FIG. 5 is a graph showing the in vitro dissolution rate of ethinylestradiol from film-coated tablets, different lines representing different test batches. - Drospirenone, which may be prepared substantially as described in, e.g., U.S. Pat. No. 4,129,564 or WO 98/06738, is a sparingly soluble substance in water and aqueous buffers at various pH values. Furthermore, drospirenone is rearranged to an inactive isomer under acid conditions and hydrolysed under alkaline conditions. To ensure good bioavailability of the compound, it is therefore advantageously provided in a form that promotes rapid dissolution thereof.
- It has surprisingly been found that when drospirenone is provided in micronized form (so that particles of the active substance have a surface area of more than 10,000 cm2/g, and the following particle size distribution as determined under the microscope: not more than 2 particles in a given batch with a diameter of more than 30 μm, and preferably ≦20 particles with a diameter of ≧10 μm and ≦30 μm) in a pharmaceutical composition, rapid dissolution of the active compound from the composition occurs in vitro (“rapid dissolution” is defined as the dissolution of at least 70% over about 30 minutes, in particular at least 80% over about 20 minutes, of drospirenone from a tablet preparation containing 3 mg of drospirenone in 900 ml of water at 37° C. determined by the USP XXIII Paddle Method using a USP dissolution test apparatus 2 at 50 rpm). Instead of providing the drospirenone in micronized form, it is possible to dissolve it in a suitable solvent, e.g. methanol or ethyl acetate, and spray it onto the surface of inert carrier particles followed by incorporation of the particles containing drospirenone on their surface in the composition.
- Without wishing to be limited to any particular theory, it appears that the in vitro dissolution rate of drospirenone is connected to the dissolution rate in vivo resulting in rapid absorption of drospirenone in vivo on oral administration of the compound. This is an advantage because isomerization of the compound in the gastric environment and/or hydrolysis in the intestine is substantially reduced, leading to a high bioavailability of the compound.
- With respect to ethinylestradiol which is also a sparingly soluble substance, though less sensitive to degradation than drospirenone under conditions prevailing in the gastrointestinal tract, it is also an advantage to provide it in micronized form or sprayed from a solution, e.g. in ethanol, onto the surface of inert carrier particles. This has the added advantage of facilitating a more homogenous distribution of the ethinylestradiol throughout the composition which might otherwise be difficult to obtain because ethinylestradiol is incorporated in extremely small amounts. When ethinylestradiol is provided in micronized form, it preferably has the following particle size distribution as determined under the microscope: 100% of the particles have a diameter of ≦15.0 μm, 99% of the particles have a diameter of ≦12.5 μm, 95% of the particles have a diameter of ≦10.0 μm, and 50% of the particles have a diameter of ≦3.0 μm. Furthermore, no particle is larger than 20 μm, and ≦10 particles have a diameter of ≧15 μm and ≦20 μm.
- To obtain a more rapid rate of dissolution, it is preferred to include carriers or excipients which act to promote dissolution of both active substances. Examples of such carriers and excipients include substances that are readily soluble in water such as cellulose derivatives, carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, gelled starch, gelatin or polyvinylpyrrolidone. In particular, it appears as though polyvinylpyrrolidone might be particularly helpful to promote dissolution.
- The composition of the invention preferably comprises drospirenone in an amount corresponding to a daily dosage of from about 2.5 mg to about 3.5 mg, in particular about 3 mg. The amount of ethinylestradiol preferably corresponds to a daily dosage of from about 0.015 mg to about 0.04 mg, in particular from about 0.015 mg to about 0.03 mg. More particularly, the present composition comprises an amount of drospirenone corresponding to a daily dosage of from about 3.0 to about 3.5 mg and ethinylestradiol in an amount corresponding to from about 0.015 to about 0.03 mg.
- Apart from its ability to inhibit ovulation, the composition of the invention has been found to possess pronounced anti-androgenic properties and may therefore be used in the prevention or treatment of androgen-induced disorders, in particular acne. Such use may be independent from or concomitant with the use as a contraceptive disclosed above. Furthermore, since drospirenone is an aldosterone antagonist, it has diuretic properties and is therefore suitable for counteracting the water-retentive properties of ethinylestradiol.
- In a particular embodiment, the invention relates to a pharmaceutical preparation consisting of a number of separately packaged and individually removable daily dosage units placed in a packaging unit and intended for oral administration for a period of at least 21 consecutive days, wherein each of said daily dosage units comprises a combination of drospirenone in an amount of from about 2 mg to about 4 mg and ethinylestradiol in an amount from about 0.01 to about 0.05 mg.
- In one embodiment, the preparation further comprises 7 or less said daily dosage units containing no active agent. Alternatively, it is possible to include, in the dosage regimen, a period of 7 days or less during which no dosage units are ingested. For compliance reasons, however, it may be preferred to include an appropriate number of blanks in the preparation, in which case the total number of daily dosage units in the preparation is at least 28. The inclusion of blanks, or the pill-free days, will then trigger withdrawal bleeding.
- The preparation may be a one-phase composition, i.e. a preparation wherein the amounts of either active agent remains constant for the entire at least 21-day period, or the amounts of either or both active agents may be varied over the at least 21-day period to generate a multiple-phase preparation, e.g. a two- or three-phase preparation, substantially as disclosed in, e.g., EP 148 724. In case of multiple-phase preparation, it may be possible to include a natural estrogen such as estradiol, e.g. in an amount of from about 0.5 mg to about 4 mg per day, instead of ethinylestradiol.
- In suitable embodiments of the present preparation, the number of daily dosage units comprising the combination of drospirenone and ethinylestradiol may be 21, 22, 23 or 24, and the number of daily dosage units containing no active agent may then be 7, 6, 5 or 4, as the case may be. In a further embodiment of the present preparation, the number of daily dosage units comprising the combination of drospirenone and ethinylestradiol is 28, or a multiple of 28 such as 2-4, in particular 2 or 3, times 28.
- In an alternative embodiment, the invention relates to a contraceptive preparation consisting of a number of separately packaged and individually removable daily dosage units placed in a packaging unit and intended for oral administration for a period of at least 28 consecutive days, wherein at least 21 of said daily dosage units comprises a combination of drospirenone in an amount of from about 2 mg to about 4 mg and ethinylestradiol in an amount from about 0.01 to about 0.05 mg, and wherein 7 or less of said daily dosage units contain ethinylestradiol alone in an amount from about 0.01 to about 0.05 mg.
- By including an appropriate number of dosage units comprising ethinylestradiol alone, high contraceptive reliability, low follicular development and satisfactory cycle control with little or no intermenstrual bleeding may be obtained.
- In this case, too, the preparation may be one in which the amounts of either active agent remains constant for the entire at least 21-day period (i.e. a two-phase preparation), or the amounts of either or both active agents may be varied over the at least 21-day period to generate a multiple-phase preparation, e.g. a three- or four-phase preparation, substantially as disclosed in, e.g., EP 148 724. In case of multiple-phase preparation, it may be possible to include a natural estrogen such as estradiol, e.g. in an amount of from about 0.5 mg to about 4 mg per day, instead of ethinylestradiol.
- In suitable embodiments of the present preparation, the number of daily dosage units comprising the combination of drospirenone and ethinylestradiol may be 21, 22, 23 or 24, and the number of daily dosage units containing ethinylestradiol alone may then be 7, 6, 5 or 4, as the case may be.
- In one embodiment of the present method of inhibiting ovulation, the method comprises administering, to said mammal, on each day of at least 21 consecutive days, a daily dosage unit comprising a combination of drospirenone in an amount of from about 2 mg to about 4 mg and ethinylestradiol in an amount from about 0.01 to about 0.05 mg, followed by administering, on each day of 7 or less consecutive days, a daily dosage unit containing no active agent, or alternatively, administering no dosage units for 7-days or less.
- In suitable embodiments of this method, the daily dosage units comprising the combination of drospirenone and ethinylestradiol may be administered for 21, 22, 23 or 24 consecutive days, and the daily dosage units containing no active agent may then be administered for 7, 6, 5 or 4 consecutive days, as appropriate. Furthermore, the daily dosage units comprising the combination of drospirenone and ethinylestradiol may be administered for 28 consecutive days. In a variant of this embodiment, the daily dosage units comprising the combination of drospirenone and ethinylestradiol are administered for 2-4, preferably 2- or 3, times 28 consecutive days, followed by administration of the daily dosage units comprising the combination of drospirenone and ethinylestradiol for 21, 22, 23 or 24 consecutive days and subsequently administration of the daily dosage units containing no active agent, or administration of no daily dosage units, for 7, 6, 51 or 4 consecutive days.
- Alternatively, the present method comprises administering, on each day of at least 21 consecutive days, a daily dosage unit comprising a combination of drospirenone in an amount of from about 2 mg to about 4 mg and ethinylestradiol in an amount from about 0.01 to about 0.05 mg, followed by administering, on each day of 7 or less consecutive days, a daily dosage unit containing ethinylestradiol alone in an amount of from about 0.01 mg to about 0.05 mg.
- In this alternative method, the daily dosage units comprising the combination of drospirenone and ethinylestradiol may suitably be administered for 21, 22, 23 or 24 consecutive days, and wherein the daily dosage units comprising ethinylestradiol alone may then be administered for 7, 6, 5 or 4 consecutive days, as appropriate. In a further embodiment of the method, the daily dosage units comprising the combination of drospirenone and ethinylestradiol are administered for 2-4, preferably 2 or 3, times 28 consecutive days, followed by administration of the daily dosage units comprising the combination of drospirenone and ethinylestradiol for 21 consecutive days and subsequently administration of the daily dosage units comprising ethinylestradiol alone for 7 consecutive days.
- For use according to the invention, the pharmaceutical preparation may suitably be in the form of a number of separately packaged and individually removable daily dosage units placed in a packaging unit and intended for oral administration for a period of at least 21 consecutive days, wherein each of said daily dosage units each comprises a combination of drospirenone in an amount of from about 2 mg to about 4 mg and ethinylestradiol in an 0.30 amount from about 0.01 to about 0.05 mg.
- As indicated above, the preparation may further comprise 7 or less daily dosage units containing no active agent (or may contain 7 or less empty “places”, e.g. in the form of empty blisters in a blister pack, marking the days on which no daily dosage units are administered).
- Alternatively, the pharmaceutical preparation may be in the form of a number of separately packaged and individually removable daily dosage units placed in a packaging unit and intended for oral administration for a period of at least 28 consecutive days, wherein at least 21 of said daily dosage units each comprises a combination of drospirenone in an amount of from about 2 mg to about 4 mg and ethinylestradiol in an amount of from about 0.01 to about 0.05 mg, said packaging unit further comprising 7 or less daily dosage units comprising ethinylestradiol alone in an amount of from about 0.01 mg to about 0.05 mg.
- The composition of the invention may be formulated in any manner known in the pharmaceutical art. In particular, as indicated above, the composition may be formulated by a method comprising providing drospirenone and, if desired, ethinylestradiol in micronized form in said unit dosage form, or sprayed from a solution onto particles of an inert carrier in admixture with one or more pharmaceutically acceptable excipients that promote dissolution of the drospirenone and ethinylestradiol so as to promote rapid dissolution of drospirenone and preferably ethinylestradiol on oral administration. Examples of suitable excipients include fillers, e.g. sugars such as lactose, glucose or sucrose, sugar alcohols such as mannitol, sorbitol or xylitol, starch such as wheat, corn or potato starch, modified starch or sodium starch glycolate, lubricants such as talc, magnesium stearate, calcium stearate, colloidal silica or stearic acid, and binders such as polyvinylpyrrolidone, cellulose derivatives, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose or gelatin, for making oral dosage forms such as tablets, pills or capsules.
- Tablets may conveniently be coated with a suitable film-forming agent, e.g. hydroxypropylmethyl cellulose, hydroxypropyl cellulose or ethyl cellulose, to which a suitable excipient may optionally be added, e.g. a softener such as glycerol, propylene glycol, diethylphthalate or glycerol triacetate, filler such as sucrose, sorbitol, xylitol, glucose or lactose, a colorant such as titanium hydroxide, etc.
- The present composition may also be formulated in liquid form, e.g. as a solution, suspension or emulsion, together with conventional diluents or excipients in a manner known per se in the pharmaceutical art.
- A packaging unit comprising the daily dosage units 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 at least 21, or for particular applications, 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. Each blister container may conveniently be numbered or otherwise marked, e.g. starting with the first of the at least 21 dosage units that contain the combination of drospirenone and ethinylestradiol, optionally followed by 7 or less empty blisters or by the 7 or less dosage units that contain no active agent or that only contain ethinylestradiol (although the numbering may also start with the first of the 7 or less dosage units that only contain ethinylestradiol).
- It is also envisaged that the present composition may be in the form of a parenteral formulation such as a subcutaneous implant or transdermal formulation. For making implants, the active agents may suitably be formulated together with one or more polymers that are gradually eroded or degraded when in use, e.g. silicone polymers, ethylene vinylacetate, polyethylene or polypropylene.
- Where transdermal formulations are concerned, they may be prepared in the form of matrices or membranes or as fluid or viscous formulations in oil or hydrogels. For transdermal patches, an adhesive which is compatible with the skin should be included, such as polyacrylate, a silicone adhesive or polyisobutylene, as well as a foil made of, e.g. polyethylene, polypropylene, ethylene vinylacetate, polyvinylchloride, polyvinylidene chloride or polyester, and a removable protective foil made from, e.g., polyester or paper coated with silicone or a fluoropolymer. For the preparation of transdermal solutions or gels, water or organic solvents or mixtures thereof may be used. Transdermal gels may furthermore contain one or more suitable gelling agents or thickeners such as silicone, tragacanth, starch or starch derivatives, cellulose or cellulose derivatives or polacrylic acids or derivatives thereof. Transdermal formulations may also suitably contain one or more substances that enhance absorption though the skin, such as bile salts or derivatives thereof and/or phospholipids. Suitable transdermal formulations may, for instance, be made in a manner analogous to that described in WO 94/04157 for 3-ketodesogestrel. Alternatively, transdermal formulations may be prepared according to a method disclosed in, e.g., BW Barry, “Dermatological Formulations, Percutaneous Absorption”, Marcel Dekker Inc., New York—Basel, 1983, or Yw Chien, “Transdermal Controlled Systemic Medications”, Marcel Dekker Inc., New York—Basel, 1987.
- The present invention is further described in the following examples which are not in any way intended to limit the scope of the invention as claimed.
- Preparation of Tablets Containing Drospirenone and Ethinylestradiol
- Tablet Cores of the Following Composition
micronized drospirenone 3.00 mg micronized ethinylestradiol 0.03 mg lactose monohydrate 48.17 mg corn starch 14.40 mg modified starch 9.60 mg polyvinylpyrrolidone 25,000 4.00 mg magnesium stearate 0.80 mg
were prepared by charging a fluidized bed granulator with 31.68 kg corn starch, 21.12 kg modified starch, 6.60 micronized drospirenone, 0.066 kg micronized ethinylestradiol and 105.974 kg lactose monohydrate and activating the fluidized bed. An aqueous solution of 8.80 kg polyvinylpyrrolidone 25,000 in 46.20 kg purified water was sprayed continuously onto the fluidized bed while drying by heating the air stream of the fluidized bed. At the end of the process 1.76 kg magnesium stearate was sucked into the granulator and mixed with the granules by maintaining the fluidized bed. The resulting granulate was pressed into tablet cores by compression using a rotary tablet press. - 2.22464 kg of hydroxypropylmethylcellulose and 0.44528 macrogol 6000 were dissolved in 14.67 kg purified water 0.44528 kg talc, 1.22430 kg titanium dioxide and 0.06050 kg ferric oxide pigment were suspended in 10.26 kg purified water with stirring and homogenized. The solution and suspension were combined and used to coat the tablet cores by continuous application of the coating suspension in a coater.
- Dissolution of Drospirenone from Tablets
- The rate of dissolution of drospirenone from the tablets prepared in Example 1 was determined by the USP XXIII Paddle Method using a USP Dissolution Test Apparatus 2 including 6 covered glass vessels and 6 paddles. Tablets were placed in 900 ml water at a temperature of 37° C. (±0.5° C.) and stirred at 50 rpm.
- The results appear from
FIGS. 1, 2 and 4. FromFIG. 1 , it appears that the batch numbered V8 containing macrocrystalline drospirenone (but otherwise identical to the tablets prepared in Example 1) exhibited an extremely slow dissolution rate of drospirenone, whereas all batches containing micronized drospirenone exhibited a dissolution rate of more than 70% within 30 minutes. -
FIG. 2 andFIG. 4 shows the results of dissolution of drospirenone from tablet cores and film-coated tablets, respectively. In both cases more than 70% of the active agent is dissolved within 30 minutes. Thus, the film coating did not significantly influence the rate of dissolution. - Dissolution Rate of Ethinylestradiol from Tablets In Vitro
- The rate of dissolution of ethinylestradiol from tablets prepared as described in Example 1 was determined according to the USP Paddle Method as described in Example 2 for drospirenone. The results appear from
FIGS. 3 and 5 showing the dissolution rates from tablet cores and film-coated tablets, respectively. In both cases, more than 70% of the active agent was dissolved within 30 minutes. Thus, the film coating did not significantly influence the rate of dissolution. - Bioavailability of Drospirenone and Ethinylestradiol from Tablets Containing 3 mg of Drospirenone and 0.03 mg Ethinylestradiol
- 42 healthy women between 18 and 35 years of age were included in an open-label crossover study after their informed consent had been obtained. The aim of the study was to investigate the relative bioavailability of drospirenone and ethinylestradiol from a tablet formulation containing 3 mg drospirenone and 0.03 mg ethinylestradiol with reference to an oral suspension containing 6 mg of drospirenone and 0.06 mg ethinylestradiol per vial.
- The bioavailability was determined using serum concentrations of each active agent as parameters. Compared to the oral suspension, the relative bioavailability of drospirenone and ethinylestradiol from the tablets is 107% and 117%, respectively. It was therefore concluded that both drospirenone and ethinylestradiol are completely released from the tablets in vivo.
- The absolute bioavailability of drospirenone was determined in two studies to be 76%±13% after oral administration of 2 mg drospirenone to 8 young healthy women and 85%±24% after oral administration of a microcrystalline suspension containing 3.13 mg drospirenone to 6 postmenopausal women.
- The oral bioavaliability of ethinylestradiol was determined in several studies, and mean values of from 36% to 59% were reported in the literature, indicating a first-pass effect.
- Contraceptive Efficacy of Formulations Containing Drospirenone and Ethinylestradiol
- An open-label, randomized trial with 52 female volunteers aged 20-35 years whose informed consent had been obtained included 1 pre-treatment cycle, 3 treatment cycles with two different tablet containing 2-mg and 3 mg drospirenone, respectively, but otherwise corresponding to the tablets prepared in Example 1, and a follow-up phase. A wash-out phase of 1 month preceded the treatment.
- At defined time points, selected central and peripheral parameters were investigated: LH, FSH, 17β-estradiol, progesterone, cervical score, “spinnbarkeit”, fern phenomenon. Ovarian function was checked by ultrasound. In addition, SHBG, CBG, prolactine, total testosterone, androstenedione, DHEA-S and selected metabolic parameters (serum glucose, triglycerides, cholesterol, HDL, LDL) were examined. Blood pressure, heart rate, body weight and cycle control were documented.
- The results of the study showed that both LH and FSH were clearly suppressed with both trial preparations. Accordingly, the secretion of estradiol and progesterone were greatly reduced over all three treatment cycles with the exception of 3 volunteers receiving the 2 mg drospirenone preparation. This result was, in principle, confirmed by the accompanying ultrasound examinations. Follicular ripening occurred in several cases with both trial preparations. Although three ovulations were diagnosed with the preparation containing 2 mg drospirenone (one of which was described as “equivocal” and the other as a “tablet-taking error”), no differences were demonstrable statistically (p>0.05) between the two trial preparations as regards the hormones LH, FSH, estradiol and progesterone, and the parameter “ovulation during the treatment cycles”. In keeping with the hormones, cervical function was greatly limited and the “spinnbarkeit” and crystallisability of the cervical mucus was greatly reduced with both trial preparations. Prolactin increased minimally and SHBG and CBG distinctly with both preparations. Triglycerides and HDL levels increased with both trial preparations, while LDL levels decreased. Total cholesterol was largely unchanged in both treatment groups. Oral glucose tolerance remained virtually unchanged or was slightly decreased. Testosterone, androstenedione and DHEA-S decreased minimally.
- The subjective and objective tolerance was good with both treatments. This was also the case for cycle control with the exception of the first cycle with 2 mg drospirenone. Blood pressure, heart rate and body weight remained constant in the majority of cases or showed a slight tendency to decrease.
- After three months' treatment, it was concluded:
- The two trial preparations were equally good as regards the subjective and objective tolerance.
- No negative metabolic effects were observed with either preparation. HDL was influenced positively in the sense of an increase.
- The results confirmed the results of earlier studies that the 2 mg drospirenone preparation was in the threshold region of ovulation inhibition, whereas the 3 mg drospirenone preparation had a demonstrable ovulation-inhibiting effect in all cases examined.
- The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
- Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The preceding preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
- The entire disclosure of all applications, patents and publications, cited above and below, and of corresponding U.S. application Ser. No. 09/386,274, are hereby incorporated by reference.
- From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.
Claims (35)
1. A pharmaceutical composition comprising, as a first active agent, 6β,7β;15β,16β-dimethylene-3-oxo-17α-pregn-4-ene-21,17-carbolactone (drospirenone) in an amount corresponding to a daily dosage, on administration of the composition, of from about 2 mg to about 4 mg, and, as a second active agent, 17α-ethinylestradiol (ethinylestradiol) in an amount corresponding to a daily dosage of from about 0.01 mg to about 0.05 mg, together with one or more pharmaceutically acceptable carriers or excipients.
2. A composition according to claim 1 wherein the drospirenone is in micronized form or sprayed from a solution onto particles of an inert carrier.
3. A composition according to claim 1 , comprising drospirenone in an amount corresponding to a daily dosage of from about 2.5 mg to about 3.5 mg, in particular about 3 mg.
4. A composition according to claim 1 wherein the ethinylestradiol is in micronized form or sprayed from a solution onto particles of an inert carrier.
5. A composition according to claim 1 , comprising ethinylestradiol in an amount corresponding to a daily dosage of from about 0.015 mg to about 0.04 mg, in particular from about 0.02 mg to about 0.03 mg.
6. A composition according to claim 1 , comprising an amount of drospirenone corresponding to a daily dosage of from about 3.0 to about 3.5 mg and ethinylestradiol in an amount corresponding to from about 0.015 to about 0.03 mg, in particular comprising an amount of drospirenone corresponding to a daily dosage of about 3.0 mg and ethinylestradiol in an amount corresponding to a daily dosage of 0.03 mg.
7. A composition according to claim 1 wherein the pharmaceutically acceptable carrier or excipient is selected so as to promote rapid dissolution of the first and second active agents.
8. A composition according to claim 1 wherein at least 70% of the first and second active substance are released within 30 minutes of administration thereof.
9. A composition according to claim 8 , wherein at least 80% of the first and second active agents are released within 20 minutes of administration thereof.
10. A pharmaceutical preparation consisting of a number of separately packaged and individually removable daily dosage units placed in a packaging unit and intended for oral administration for a period of at least 21 consecutive days, wherein said daily dosage units comprises a combination of drospirenone in an amount of from about 2 mg to about 4 mg and ethinylestradiol in an amount from about 0.01 to about 0.05 mg.
11. A preparation according to claim 10 , which additionally comprises 7 or less daily dosage units containing no active agent intended for oral administration subsequent to the period of at least 21 consecutive days, the total number of daily dosage units being at least 28.
12. A preparation according to claim 10 , wherein the number of daily dosage units comprising the combination of drospirenone and ethinylestradiol is 21, 22, 23 or 24, and wherein the number of daily dosage units containing no active agent is 7, 6, 5 or 4.
13. A preparation according to claim 10 , wherein the number of daily dosage units comprising the combination of drospirenone and ethinylestradiol is 28, or a multiple of 28 such as 2-4, in particular 2 or 3, times 28.
14. A preparation according to claim 13 , which additionally comprises a number of daily dosage units comprising the combination of drospirenone and ethinylestradiol of 21, 22, 23 or 24, and a number of daily dosage units containing no active agent of 7, 6, 5 or 4.
15. A preparation according to claim 10 , wherein the at least 21 daily dosage units comprise drospirenone and ethinylestradiol in micronized form or sprayed from a solution onto particles of an inert carrier.
16. A preparation according to claim 10 wherein the at least 21 daily dosage units comprise drospirenone in an amount of from about 2.5 mg to about 3.5 mg, in particular about 3 mg, and ethinylestradiol in an amount of from about 0.015 mg to about 0.04 mg, in particular from about 0.015 mg to about 0.03 mg.
17. A preparation according to claim 10 , wherein the at least 21 daily dosage units comprise drospirenone in an amount of from about 3.0 to about 3.5 mg and ethinylestradiol in an amount corresponding to from about 0.015 to about 0.03 mg.
18. A pharmaceutical preparation consisting of a number of separately packaged and individually removable daily dosage units placed in a packaging unit and intended for oral administration for a period of at least 28 consecutive days, wherein at least 21 of said daily dosage units comprises a combination of drospirenone in an amount of from about 2 mg to about 4 mg and ethinylestradiol in an amount from about 0.01 to about 0.05 mg, and wherein 7 or less of said daily, dosage units contain ethinylestradiol alone in an amount from about 0.01 to about 0.05 mg.
19. A preparation according to claim 18 , wherein the number of daily dosage units comprising the combination of drospirenone and ethinylestradiol is 21, 22, 23 or 24, and wherein the number of daily dosage units comprising ethinylestradiol alone is 7, 6, 5 or 4.
20. A preparation according to claim 18 or 19 , wherein the at least 21 daily dosage units comprise drospirenone and ethinylestradiol in micronized form or sprayed from a solution onto particles of an inert carrier.
21. A preparation according to claim 18 , wherein the at least 21 daily dosage units comprise drospirenone in an amount of from about 2.5 mg to about 3.5 mg, in particular about 3 mg, and ethinylestradiol in an amount of from about 0.015 mg to about 0.04 mg, in particular from about 0.02 mg to about 0.03 mg.
22. A preparation according to claim 18 , wherein the at least 21 daily dosage units comprise drospirenone in an amount of from about 3.0 to about 3.5 mg and ethinylestradiol in an amount corresponding to from about 0.015 to about 0.03 mg.
23. A method of inhibiting ovulation in a mammal, in particular a human, comprising administering, to said mammal, drospirenone in an amount in the range of from about 2 mg to about 4 mg of per day, together with ethinylestradiol in an amount of from about 0.01 mg to about 0.05 mg per day, said amounts being effective to inhibit ovulation in said mammal.
24. A method according to claim 23 , wherein the amount of drospirenone is in the range of from about 2.5 mg to about 3.5 mg, in particular about 3 mg of drospirenone per day.
25. A method according to claim 23 , wherein the amount of ethinylestradiol is from about 0.015 mg to about 0.04 mg, in particular from about 0.015 to about 0.03 mg per day.
26. A method of preventing or treating androgen-induced disorders in a female mammal, in particular a female human, comprising administering, to said mammal, an amount of drospirenone in the range of from about 2 mg to about 4 mg per day, together with an amount of ethinylestradiol of from about 0.01 mg to about 0.05 mg per day, said amounts being effective to prevent or treat androgen-induced disorders in said mammal.
27. A method according to claim 26 , wherein the androgen-induced disorder is acne.
28. A method of inhibiting ovulation in a mammal, in particular a human, comprising administering, to said mammal, on each day of at least 21 consecutive days, a daily dosage unit comprising a combination of drospirenone in an amount of from about 2 mg to about 4 mg and ethinylestradiol in an amount from about 0.01 to about 0.05 mg, followed by administering, on each day of 7 or less consecutive days, a daily dosage unit containing no active agent, or alternatively administering no daily dosage units for 7 or less consecutive days.
29. A method according to claim 28 , wherein the daily dosage units comprising the combination of drospirenone and ethinylestradiol are administered for 21, 22, 23 or 24 consecutive days, and wherein no daily dosage units or daily dosage units containing no active agent are administered for 7, 6, 5 or 4 consecutive days.
30. A method according to claim 28 , wherein the daily dosage units comprising the combination of drospirenone and ethinylestradiol are administered for 28 consecutive days.
31. A method according to claim 28 , wherein the daily dosage units comprising the combination of drospirenone and ethinylestradiol are administered for 2-4, preferably 2 or 3, times 28 consecutive days, followed by administration of the daily dosage units comprising the combination of drospirenone and ethinylestradiol for 21 consecutive days and subsequently administration of the daily dosage units containing no active agent, or alternatively no daily dosage units, for 7 consecutive days.
32. A method of inhibiting ovulation in a mammal, in particular a human, comprising administering, to said mammal, on each day of at least 21 consecutive days, a daily dosage unit comprising a combination of drospirenone in an amount of from about 2 mg to about 4 mg and ethinylestradiol in an amount from about 0.01 to about 0.05 mg, followed by administering, on each day of 7 or less consecutive days, a daily dosage unit containing ethinylestradiol alone in an amount of from about 0.01 mg to about 0.05 mg.
33. A method according to claim 32 , wherein the daily dosage units comprising the combination of drospirenone and ethinylestradiol are administered for 21, 22, 23 or 24 consecutive days, and wherein the daily dosage units comprising ethinylestradiol alone are administered for 7, 6, 5 or 4 consecutive days.
34. A method according to claim 32 , wherein the daily dosage units comprising the combination of drospirenone and ethinylestradiol are administered for 2-4, preferably 2 or 3, times 28 consecutive days, followed by administration of the daily dosage units comprising the combination of drospirenone and ethinylestradiol for 21 consecutive days and subsequently administration of the daily dosage units comprising ethinylestradiol alone for 7 consecutive days.
35. A method of promoting rapid dissolution of drospirenone from a unit dosage form on oral administration, the method comprising providing drospirenone in micronized form in said unit dosage form, or sprayed from a solution onto particles of an inert carrier in admixture with one or more pharmaceutically acceptable excipients that promote dissolution of the drospirenone.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11/266,395 US20060058272A1 (en) | 1999-08-31 | 2005-11-04 | Pharmaceutical composition for use as a contraceptive |
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US13/900,790 Abandoned US20140050794A1 (en) | 1999-08-31 | 2013-05-23 | Pharmaceutical composition for use as a contraceptive |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090269403A1 (en) * | 2008-04-24 | 2009-10-29 | Shaked Ze Ev | Oral contraceptive dosage forms and methods of making such dosage forms |
Families Citing this family (37)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE19654609A1 (en) * | 1996-12-20 | 1998-06-25 | Schering Ag | Therapeutic progestogens for the treatment of premenstrual dysphoric disorder |
US6787531B1 (en) * | 1999-08-31 | 2004-09-07 | Schering Ag | Pharmaceutical composition for use as a contraceptive |
US20020132801A1 (en) * | 2001-01-11 | 2002-09-19 | Schering Aktiengesellschaft | Drospirenone for hormone replacement therapy |
US7964216B2 (en) * | 2001-01-12 | 2011-06-21 | Sun Pharma Advanced Research Company Limited | Spaced drug delivery system |
RU2324475C2 (en) * | 2001-04-10 | 2008-05-20 | Сан Фармасьютикал Индастриз Лимитед | Composition released in pulse mode at preset time |
WO2003049744A1 (en) | 2001-12-05 | 2003-06-19 | Barr Laboratories, Inc. | Oral contraceptives to prevent pregnancy and diminish premenstrual symptomatology |
US20060210633A1 (en) * | 2003-04-03 | 2006-09-21 | Sun Pharmaceutical Industries Limited | Programmed drug delivery system |
EP1624848A4 (en) * | 2003-05-02 | 2009-02-25 | Duramed Pharmaceuticals Inc | Methods of hormornal treatment utilizing extended cycle contraceptive regimens |
WO2005007112A2 (en) * | 2003-07-16 | 2005-01-27 | Duramed Pharmaceuticals, Inc. | Methods of hormonal treatment utilizing contraceptive regimens with continuous estrogen administration |
MY142989A (en) * | 2004-03-10 | 2011-02-14 | Bayer Schering Pharma Ag | Stabilised supersaturated solids of lipophilic drugs |
US20050220825A1 (en) * | 2004-03-10 | 2005-10-06 | Adrian Funke | Molecular dispersions of drospirenone |
CN107875388A (en) * | 2004-04-30 | 2018-04-06 | 拜耳知识产权有限责任公司 | Control to break-through bleeding in the hormonal contraceptive regimens of extension |
MY151322A (en) * | 2004-04-30 | 2014-05-15 | Bayer Ip Gmbh | Management of breakthrough bleeding in extended hormonal contraceptive regimens |
AU2011226911B2 (en) * | 2004-04-30 | 2014-06-19 | Bayer Intellectual Property Gmbh | Management of breakthrough bleeding in extended hormonal contraceptive regimens |
WO2005120432A1 (en) * | 2004-06-07 | 2005-12-22 | Duramed Pharmaceuticals, Inc. | Dispenser for progestin used for acute and maintenance treatment of dub |
US20070111975A1 (en) | 2004-10-07 | 2007-05-17 | Duramed Pharmaceuticals, Inc. | Methods of Hormonal Treatment Utilizing Ascending-Dose Extended Cycle Regimens |
UY29527A1 (en) | 2005-05-13 | 2006-12-29 | Schering Ag | PHARMACCUTIC COMPOSITION CONTAINING GESTRGENS AND / OR ESTRNGENS AND 5-METHYL - (6S) - TETRHYDROPHOLATE. |
EA015155B1 (en) * | 2005-05-26 | 2011-06-30 | Тева Вуменс Хелс, Инк. | Oral dosage forms comprising progesterone and methods of making and using the same |
US8475838B2 (en) * | 2005-06-03 | 2013-07-02 | Sandoz Ag | Rapidly-dissolving pharmaceutical composition for inhibiting ovulation |
DE102006030416A1 (en) * | 2006-06-29 | 2008-01-03 | Bayer Schering Pharma Ag | 18-methyl-19-nor-androst-4-ene-17,17-spiroethers (18-methyl-19-nor-20-spirox-4-en-3-ones) and pharmaceutical compositions containing them |
US8617597B2 (en) | 2006-07-06 | 2013-12-31 | Bayer Intellectual Property Gmbh | Pharmaceutical composition containing a tetrahydrofolic acid |
EP1900359A1 (en) * | 2006-09-16 | 2008-03-19 | KAIROSmed GmbH | Oral modified release formulations containing drospirenon and 8-prenylnaringenin for use in female contraception |
CA2662956A1 (en) * | 2006-09-16 | 2008-03-20 | Bayer Schering Pharma Aktiengesellschaft | Oral modified release formulations |
EP1958628A1 (en) * | 2007-02-16 | 2008-08-20 | KAIROSmed GmbH | Combination of immediately liberated drospirenone with a modified releasing formulation containing 8-prenylnaringenin for use in oral contraception and hormone replacement therapy |
US20090035374A1 (en) * | 2007-07-31 | 2009-02-05 | Katrin Mittmann | Method of making a single-stage pharmaceutical preparation for oral therapy to regulate blood pressure and kit containing same |
US20090035373A1 (en) * | 2007-07-31 | 2009-02-05 | Katrin Mittmann | Pharmaceutical composition for contraception and blood pressure regulation, kit for contraception containing same and method of production of same |
HUP0700826A3 (en) * | 2007-12-20 | 2010-03-29 | Richter Gedeon Nyrt | Coated tablet containing drospirenone and process for producing the same |
US20090325999A1 (en) * | 2008-06-27 | 2009-12-31 | Jie Du | Personalized pharmaceutical kits, packaging and compositions for the treatment of allergic conditions |
US20130140210A1 (en) * | 2010-04-15 | 2013-06-06 | Bayer Intellectual Property Gmbh | Low-dosed solid oral dosage forms for hrt |
AR081670A1 (en) | 2010-06-29 | 2012-10-10 | Leon Farma Sa Lab | PHARMACEUTICAL COMPOSITION INCLUDING DROSPIRENONE AND ANTI-ECONCEPTIVE KIT |
US11351122B1 (en) | 2010-07-28 | 2022-06-07 | Laboratorios Leon Farma Sa | Synthetic progestogens and pharmaceutical compositions comprising 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 |
US9301920B2 (en) | 2012-06-18 | 2016-04-05 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
CA2856520C (en) | 2011-11-23 | 2021-04-06 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
US11266661B2 (en) | 2012-12-21 | 2022-03-08 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US9180091B2 (en) | 2012-12-21 | 2015-11-10 | Therapeuticsmd, Inc. | Soluble estradiol capsule for vaginal insertion |
WO2016171543A1 (en) | 2015-04-22 | 2016-10-27 | Cadens Beheer B.V. | Improved contraceptive methods and compositions and devices for use therein |
Citations (78)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2243887A (en) * | 1935-11-09 | 1941-06-03 | Schering Corp | Tertiary carbinols of the cyclopentano-polyhydrophenanthrene series and a method of producing the same |
US3568828A (en) * | 1967-03-01 | 1971-03-09 | Squibb & Sons Inc | Modified sequential oral contraceptive |
US3836618A (en) * | 1971-12-23 | 1974-09-17 | American Home Prod | Process for the uniform distribution of a drug on a granulated base |
US3942641A (en) * | 1972-05-05 | 1976-03-09 | Syntex Corporation | Dispensing packages containing novel cyclic progestogen-interrupted estrogen oral contraceptive regimens |
US4012497A (en) * | 1974-09-24 | 1977-03-15 | Schering Aktiengesellschaft | Drug excipient of silicone rubber |
US4082780A (en) * | 1975-11-27 | 1978-04-04 | Takeda Chemical Industries, Ltd. | Estradiol derivatives |
US4129564A (en) * | 1976-11-16 | 1978-12-12 | Schering, A.G. Patentabteilung | Spirolactones |
US4196188A (en) * | 1976-11-30 | 1980-04-01 | Besins Jean Louis A | Orally administrable form of progesterone |
US4217347A (en) * | 1977-12-27 | 1980-08-12 | E. R. Squibb & Sons, Inc. | Method of treating hypertension and medicaments therefor |
US4230686A (en) * | 1971-11-20 | 1980-10-28 | Schering Aktiengesellschaft | Drug excipient of silicone rubber |
US4291029A (en) * | 1979-05-31 | 1981-09-22 | Schering, Aktiengesellschaft | 6β,7β;15,16-Dimethylene-1,4-androstadien-3-ones, their preparation and use as medicinal agents |
US4489026A (en) * | 1982-09-07 | 1984-12-18 | The Upjohn Company | Process for preparing solid unit dosage forms of ultra-low dose drugs |
US4616006A (en) * | 1983-09-26 | 1986-10-07 | Ortho Pharmaceutical Corporation | Triphasic oral contraceptive |
US4621079A (en) * | 1983-12-22 | 1986-11-04 | Schering Aktiengesellschaft | Multistage combination preparation and its use for oral contraception |
US4727064A (en) * | 1984-04-25 | 1988-02-23 | The United States Of America As Represented By The Department Of Health And Human Services | Pharmaceutical preparations containing cyclodextrin derivatives |
US4755386A (en) * | 1986-01-22 | 1988-07-05 | Schering Corporation | Buccal formulation |
US4826831A (en) * | 1983-08-05 | 1989-05-02 | Pre Jay Holdings Limited | Method of hormonal treatment for menopausal or post-menopausal disorders involving continuous administration of progestogens and estrogens |
US4900734A (en) * | 1987-08-27 | 1990-02-13 | Maxson Wayne S | Novel pharmaceutical composition containing estradiol and progesterone for oral administration |
US4904462A (en) * | 1984-04-13 | 1990-02-27 | Schering Aktiengesellschaft | Multiply-tritiated steroidal-20,17-spirolactones and their use as tracer compounds |
US4913865A (en) * | 1985-07-15 | 1990-04-03 | Research Development Corp Of Japan | Process for preparing ultrafine particles of organic compounds |
US4927816A (en) * | 1987-08-20 | 1990-05-22 | Ester George C | Formulae and methods for sublingual ingestion of natural progesterone |
US5001113A (en) * | 1987-10-14 | 1991-03-19 | Merck & Co., Inc. | Di- or tripeptide renin inhibitors containing lactam conformational restriction in ACHPA |
US5073374A (en) * | 1988-11-30 | 1991-12-17 | Schering Corporation | Fast dissolving buccal tablet |
US5108995A (en) * | 1987-09-24 | 1992-04-28 | Jencap Research Ltd. | Hormone preparation and method |
US5202129A (en) * | 1989-08-04 | 1993-04-13 | Tanabe Seiyaku Co., Ltd. | Process for micronizing slightly-soluble drug |
US5256421A (en) * | 1987-09-24 | 1993-10-26 | Jencap Research Ltd. | Hormone preparation and method |
US5276022A (en) * | 1987-09-24 | 1994-01-04 | Jencap Research Ltd. | Hormone preparation and method |
US5354563A (en) * | 1985-07-15 | 1994-10-11 | Research Development Corp. Of Japan | Water dispersion containing ultrafine particles of organic compounds |
US5382434A (en) * | 1991-03-12 | 1995-01-17 | Akzo N.V. | Low steroid dose dry pharmaceutical preparation |
US5422119A (en) * | 1987-09-24 | 1995-06-06 | Jencap Research Ltd. | Transdermal hormone replacement therapy |
US5478571A (en) * | 1993-02-23 | 1995-12-26 | Warner-Lambert Company | Process for the preparation of substantially alcohol free pharmaceutical compositions |
US5534270A (en) * | 1995-02-09 | 1996-07-09 | Nanosystems Llc | Method of preparing stable drug nanoparticles |
US5569652A (en) * | 1989-05-16 | 1996-10-29 | Schering Aktiengesellschaft | Dihydrospirorenone as an antiandrogen |
US5583129A (en) * | 1993-12-22 | 1996-12-10 | Spona; Juergen | Composition for contraception |
US5620705A (en) * | 1994-08-04 | 1997-04-15 | Alza Corporation | Progestin tablet |
US5633242A (en) * | 1994-08-12 | 1997-05-27 | Oettel; Michael | Pharmaceuticals for contraception/hormone substitution containing a biogenous estrogen component |
US5686097A (en) * | 1993-09-29 | 1997-11-11 | Alza Corporation | Monoglyceride/lactate ester permeation enhancer for codelivery of steroids |
US5700486A (en) * | 1990-11-22 | 1997-12-23 | Vectorpharma International S.P.A. | Pharmaceutical compositions in the form of particles suitable for the controlled release of pharmacologically active substances and process for preparing the same compositions |
US5756490A (en) * | 1994-03-30 | 1998-05-26 | Schering Aktiengesellschaft | Pharmaceutical combination preparation for hormonal contraception |
US5827843A (en) * | 1993-09-09 | 1998-10-27 | Saturnus A.G. | Preparation for substitution therapy, containing at least one progestogen and at least one estrogen |
US5842476A (en) * | 1989-11-16 | 1998-12-01 | Alza Corporation | Method for controlling fertility |
US5849329A (en) * | 1990-07-27 | 1998-12-15 | Jagotec Ag | Process for preparing pharmaceutical composition having an increased active substance dissolution rate, and the compositions obtained |
US5858405A (en) * | 1996-07-26 | 1999-01-12 | American Home Products Corporation | Oral contraceptive |
US5888543A (en) * | 1996-07-26 | 1999-03-30 | American Home Products Corporation | Oral contraceptives |
US5891868A (en) * | 1997-11-21 | 1999-04-06 | Kaiser Foundation Health Plan, Inc. | Methods for treating postmenopausal women using ultra-low doses of estrogen |
US5891867A (en) * | 1995-08-01 | 1999-04-06 | Laboratoire Theramex | Hormonal medicaments and their use for the correction of oestrogenic deficiencies |
US5897539A (en) * | 1995-09-28 | 1999-04-27 | Schering Aktiengesellschaft | Hormone replacement therapy method and hormone dispenser |
US5908638A (en) * | 1995-07-26 | 1999-06-01 | Duramed Pharmaceuticals, Inc. | Pharmaceutical compositions of conjugated estrogens and methods for their use |
US5916593A (en) * | 1994-09-22 | 1999-06-29 | Akzo Nobel, N.V. | Process of making dosage units by wet granulation |
US5928668A (en) * | 1993-12-21 | 1999-07-27 | Applied Analytical Industries, Inc. | Method for dry blend compression of medicaments |
US5980940A (en) * | 1995-04-08 | 1999-11-09 | Schering Ag | Pharmaceutical combination preparation for hormonal contraception |
US6043234A (en) * | 1994-07-27 | 2000-03-28 | Schering Aktiengesellschaft | Method for treating endometriosis or leiomyomata uteri with a competitive progesterone antagonist and a gestagen |
US6083528A (en) * | 1995-09-28 | 2000-07-04 | Schering Aktiengesellschaft | Hormone replacement therapy method and hormone dispenser |
US6121465A (en) * | 1996-08-12 | 2000-09-19 | Schering Aktiengesellschaft | Process for production drospirenone and intermediate products of the process |
US6161465A (en) * | 1996-11-16 | 2000-12-19 | Zf Friedrichshafen Ag | Pneumatic or hydraulic control motor with a shutoff device |
US6177416B1 (en) * | 1996-12-01 | 2001-01-23 | Schering Aktiengesellschaft | Oxyiminopregnancarbolactones |
US20010020015A1 (en) * | 1997-08-27 | 2001-09-06 | Michael Kafrissen | Combination progestin oral contraceptive regimen |
US6290931B1 (en) * | 1996-12-16 | 2001-09-18 | Jenapharm Gmbh & Co. Kg | Homogeneous preformulations containing high concentrations of steroids, for producing low-dose solid and semi-solid pharmaceutical preparations |
US20010027189A1 (en) * | 1996-06-25 | 2001-10-04 | Bennink Herman Jan Tijmen Coelingh | Progestogen-anti-progestogen regimens |
US6346269B1 (en) * | 2000-05-08 | 2002-02-12 | Standard Chem. & Pharm. Co., Ltd. | Method for preparing an oral formulation containing acid-sensitive drugs and oral formulation made thereby |
US20020132801A1 (en) * | 2001-01-11 | 2002-09-19 | Schering Aktiengesellschaft | Drospirenone for hormone replacement therapy |
US20020142028A1 (en) * | 1995-09-28 | 2002-10-03 | Jorg Elliesen | Hormone replacement therapy method |
US20020165209A1 (en) * | 1999-03-30 | 2002-11-07 | Jencap Research Ltd. | Low dose estrogen interrupted hormone replacement therapy |
US20020173669A1 (en) * | 2000-12-14 | 2002-11-21 | Thomas Schultz | Steroid hormone products and methods for preparing them |
US20020173487A1 (en) * | 2000-12-20 | 2002-11-21 | Schering Aktiengesellschaft | Cyclodextrin-drospirenone inclusion complexes |
US20030004145A1 (en) * | 2001-05-16 | 2003-01-02 | Leonard Thomas W. | Treatment of conditions relating to hormone deficiencies by administration of progestins |
US20030050289A1 (en) * | 2001-07-13 | 2003-03-13 | Schering Ag | Combination of drospirenone and an estrogen sulphamate for HRT |
US20030087884A1 (en) * | 1995-02-10 | 2003-05-08 | G.D. Searle & Co. | Use of low dose amount of spironolactone for treatment of cardiovascular disease |
US6610670B2 (en) * | 2000-12-20 | 2003-08-26 | Schering Aktiengesellschaft | Cyclodextrin-drospirenone inclusion complexes |
US6630166B1 (en) * | 2001-02-12 | 2003-10-07 | Watson Pharmaceuticals, Inc. | Compositions for conjugated estrogens and associated methods |
US20030229057A1 (en) * | 2002-03-11 | 2003-12-11 | Caubel Patrick Michel | Continuous sulfatase inhibiting progestogen hormone replacement therapy |
US6667050B1 (en) * | 1999-04-06 | 2003-12-23 | Galen (Chemicals) Limited | Chewable oral contraceptive |
US6787531B1 (en) * | 1999-08-31 | 2004-09-07 | Schering Ag | Pharmaceutical composition for use as a contraceptive |
US20050032756A1 (en) * | 1995-10-28 | 2005-02-10 | Michael Dittgen | Multistage preparation for contraception based on natural estrogens |
US20050250750A1 (en) * | 1998-11-19 | 2005-11-10 | The Regents Of The University Of California | Methods for treating postmenopausal women using ultra-low doses of estrogen |
US20050282790A1 (en) * | 1996-12-20 | 2005-12-22 | Norman Nashed | Therapeutic gestagens for the treatment of premenstrual dysphoric disorder |
US6987101B1 (en) * | 1996-12-20 | 2006-01-17 | Schering Aktiengesellschaft | Therapeutic gestagens for the treatment of premenstrual dysphoric disorder |
US20060275362A1 (en) * | 2005-06-03 | 2006-12-07 | Pablo Davila | Rapidly-dissolving pharmaceutical composition for inhibiting ovulation |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3022337A1 (en) | 1980-06-11 | 1982-01-07 | Schering Ag Berlin Und Bergkamen, 1000 Berlin | Compsns. for contraception or treatment of gynaecological disorders - contg. 6 beta, 7 beta; 15 delta, 16 beta-di:methylene-3-oxo-4-androstene-17(beta-1')-spiro-5'-per:hyd- ro-furan-2'-one |
DK174724B1 (en) | 1986-07-15 | 2003-10-06 | Wyeth Corp | Use of a composition comprising an estrogen and a progestogen for the preparation of a dosage form to provide hormone replacement therapy and contraception for women during the premenopause and pack to provide the composition |
DE4227989A1 (en) | 1992-08-21 | 1994-06-09 | Schering Ag | Agent for transdermal application containing 3-keto-desogestrel |
DE19525017A1 (en) | 1995-06-28 | 1997-01-02 | Schering Ag | Pharmaceutical combination preparation, kit and method for hormonal contraception |
FR2739029B1 (en) | 1995-09-21 | 1997-11-21 | Roussel Uclaf | NEW THERAPEUTIC APPLICATION OF ANTIMINERALOCORTICOID COMPOUNDS |
DE19540253C2 (en) | 1995-10-28 | 1998-06-04 | Jenapharm Gmbh | Multi-phase preparation for contraception based on natural estrogens |
WO1998004269A1 (en) | 1996-07-26 | 1998-02-05 | American Home Products Corporation | Monophasic contraceptive method and kit comprising a combination of a progestin and estrogen |
AU3888697A (en) | 1996-07-26 | 1998-02-20 | American Home Products Corporation | Progestin/estrogen oral contraceptive |
-
2000
- 2000-08-31 US US09/654,227 patent/US6787531B1/en not_active Expired - Fee Related
-
2003
- 2003-02-06 US US10/359,069 patent/US20030119798A1/en not_active Abandoned
- 2003-02-06 US US10/359,082 patent/US20030114429A1/en not_active Abandoned
-
2005
- 2005-11-04 US US11/266,395 patent/US20060058272A1/en not_active Abandoned
-
2013
- 2013-05-23 US US13/900,790 patent/US20140050794A1/en not_active Abandoned
Patent Citations (93)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2243887A (en) * | 1935-11-09 | 1941-06-03 | Schering Corp | Tertiary carbinols of the cyclopentano-polyhydrophenanthrene series and a method of producing the same |
US3568828A (en) * | 1967-03-01 | 1971-03-09 | Squibb & Sons Inc | Modified sequential oral contraceptive |
US4230686A (en) * | 1971-11-20 | 1980-10-28 | Schering Aktiengesellschaft | Drug excipient of silicone rubber |
US3836618A (en) * | 1971-12-23 | 1974-09-17 | American Home Prod | Process for the uniform distribution of a drug on a granulated base |
US3942641A (en) * | 1972-05-05 | 1976-03-09 | Syntex Corporation | Dispensing packages containing novel cyclic progestogen-interrupted estrogen oral contraceptive regimens |
US4012497A (en) * | 1974-09-24 | 1977-03-15 | Schering Aktiengesellschaft | Drug excipient of silicone rubber |
US4082780A (en) * | 1975-11-27 | 1978-04-04 | Takeda Chemical Industries, Ltd. | Estradiol derivatives |
US4129564A (en) * | 1976-11-16 | 1978-12-12 | Schering, A.G. Patentabteilung | Spirolactones |
US4196188A (en) * | 1976-11-30 | 1980-04-01 | Besins Jean Louis A | Orally administrable form of progesterone |
US4217347A (en) * | 1977-12-27 | 1980-08-12 | E. R. Squibb & Sons, Inc. | Method of treating hypertension and medicaments therefor |
US4291029A (en) * | 1979-05-31 | 1981-09-22 | Schering, Aktiengesellschaft | 6β,7β;15,16-Dimethylene-1,4-androstadien-3-ones, their preparation and use as medicinal agents |
US4489026A (en) * | 1982-09-07 | 1984-12-18 | The Upjohn Company | Process for preparing solid unit dosage forms of ultra-low dose drugs |
US4826831A (en) * | 1983-08-05 | 1989-05-02 | Pre Jay Holdings Limited | Method of hormonal treatment for menopausal or post-menopausal disorders involving continuous administration of progestogens and estrogens |
USRE36247E (en) * | 1983-08-05 | 1999-07-06 | Woco Investments, Ltd. | Method of hormonal treatment for menopausal or post-menopausal disorders involving continuous administration of progestogens and estrogens |
US4616006A (en) * | 1983-09-26 | 1986-10-07 | Ortho Pharmaceutical Corporation | Triphasic oral contraceptive |
US4621079A (en) * | 1983-12-22 | 1986-11-04 | Schering Aktiengesellschaft | Multistage combination preparation and its use for oral contraception |
US4904462A (en) * | 1984-04-13 | 1990-02-27 | Schering Aktiengesellschaft | Multiply-tritiated steroidal-20,17-spirolactones and their use as tracer compounds |
US4727064A (en) * | 1984-04-25 | 1988-02-23 | The United States Of America As Represented By The Department Of Health And Human Services | Pharmaceutical preparations containing cyclodextrin derivatives |
US5354563A (en) * | 1985-07-15 | 1994-10-11 | Research Development Corp. Of Japan | Water dispersion containing ultrafine particles of organic compounds |
US4913865A (en) * | 1985-07-15 | 1990-04-03 | Research Development Corp Of Japan | Process for preparing ultrafine particles of organic compounds |
US4755386A (en) * | 1986-01-22 | 1988-07-05 | Schering Corporation | Buccal formulation |
US4927816A (en) * | 1987-08-20 | 1990-05-22 | Ester George C | Formulae and methods for sublingual ingestion of natural progesterone |
US4900734A (en) * | 1987-08-27 | 1990-02-13 | Maxson Wayne S | Novel pharmaceutical composition containing estradiol and progesterone for oral administration |
US5108995A (en) * | 1987-09-24 | 1992-04-28 | Jencap Research Ltd. | Hormone preparation and method |
US5256421A (en) * | 1987-09-24 | 1993-10-26 | Jencap Research Ltd. | Hormone preparation and method |
US5276022A (en) * | 1987-09-24 | 1994-01-04 | Jencap Research Ltd. | Hormone preparation and method |
US5585370A (en) * | 1987-09-24 | 1996-12-17 | Jencap Research Ltd. | Hormone preparation and method |
US5382573A (en) * | 1987-09-24 | 1995-01-17 | Jencap Research Ltd. | Hormone preparation and method |
US5422119A (en) * | 1987-09-24 | 1995-06-06 | Jencap Research Ltd. | Transdermal hormone replacement therapy |
US5001113A (en) * | 1987-10-14 | 1991-03-19 | Merck & Co., Inc. | Di- or tripeptide renin inhibitors containing lactam conformational restriction in ACHPA |
US5073374A (en) * | 1988-11-30 | 1991-12-17 | Schering Corporation | Fast dissolving buccal tablet |
US5569652A (en) * | 1989-05-16 | 1996-10-29 | Schering Aktiengesellschaft | Dihydrospirorenone as an antiandrogen |
US5202129A (en) * | 1989-08-04 | 1993-04-13 | Tanabe Seiyaku Co., Ltd. | Process for micronizing slightly-soluble drug |
US5842476A (en) * | 1989-11-16 | 1998-12-01 | Alza Corporation | Method for controlling fertility |
US5849329A (en) * | 1990-07-27 | 1998-12-15 | Jagotec Ag | Process for preparing pharmaceutical composition having an increased active substance dissolution rate, and the compositions obtained |
US5700486A (en) * | 1990-11-22 | 1997-12-23 | Vectorpharma International S.P.A. | Pharmaceutical compositions in the form of particles suitable for the controlled release of pharmacologically active substances and process for preparing the same compositions |
US5382434A (en) * | 1991-03-12 | 1995-01-17 | Akzo N.V. | Low steroid dose dry pharmaceutical preparation |
US5478571A (en) * | 1993-02-23 | 1995-12-26 | Warner-Lambert Company | Process for the preparation of substantially alcohol free pharmaceutical compositions |
US5827843A (en) * | 1993-09-09 | 1998-10-27 | Saturnus A.G. | Preparation for substitution therapy, containing at least one progestogen and at least one estrogen |
US5686097A (en) * | 1993-09-29 | 1997-11-11 | Alza Corporation | Monoglyceride/lactate ester permeation enhancer for codelivery of steroids |
US5928668A (en) * | 1993-12-21 | 1999-07-27 | Applied Analytical Industries, Inc. | Method for dry blend compression of medicaments |
USRE37838E1 (en) * | 1993-12-22 | 2002-09-10 | Schering Aktiengesellschaft | Composition for contraception |
USRE37564E1 (en) * | 1993-12-22 | 2002-02-26 | Schering Aktiengesellschaft | Composition for contraception |
US5824667A (en) * | 1993-12-22 | 1998-10-20 | Schering Aktiengesellschaft | Composition for contraception |
US5583129A (en) * | 1993-12-22 | 1996-12-10 | Spona; Juergen | Composition for contraception |
USRE38253E1 (en) * | 1993-12-22 | 2003-09-16 | Schering Aktiengesellschaft | Composition for contraception |
US5756490A (en) * | 1994-03-30 | 1998-05-26 | Schering Aktiengesellschaft | Pharmaceutical combination preparation for hormonal contraception |
US6043234A (en) * | 1994-07-27 | 2000-03-28 | Schering Aktiengesellschaft | Method for treating endometriosis or leiomyomata uteri with a competitive progesterone antagonist and a gestagen |
US5620705A (en) * | 1994-08-04 | 1997-04-15 | Alza Corporation | Progestin tablet |
US5770227A (en) * | 1994-08-04 | 1998-06-23 | Alza Corporation | Progesterone replacement therapy |
US5633242A (en) * | 1994-08-12 | 1997-05-27 | Oettel; Michael | Pharmaceuticals for contraception/hormone substitution containing a biogenous estrogen component |
US5916593A (en) * | 1994-09-22 | 1999-06-29 | Akzo Nobel, N.V. | Process of making dosage units by wet granulation |
US5534270A (en) * | 1995-02-09 | 1996-07-09 | Nanosystems Llc | Method of preparing stable drug nanoparticles |
US20030087884A1 (en) * | 1995-02-10 | 2003-05-08 | G.D. Searle & Co. | Use of low dose amount of spironolactone for treatment of cardiovascular disease |
US5980940A (en) * | 1995-04-08 | 1999-11-09 | Schering Ag | Pharmaceutical combination preparation for hormonal contraception |
US5908638A (en) * | 1995-07-26 | 1999-06-01 | Duramed Pharmaceuticals, Inc. | Pharmaceutical compositions of conjugated estrogens and methods for their use |
US5891867A (en) * | 1995-08-01 | 1999-04-06 | Laboratoire Theramex | Hormonal medicaments and their use for the correction of oestrogenic deficiencies |
US5922349A (en) * | 1995-09-28 | 1999-07-13 | Schering Aktiengesellschaft | Hormone replacement therapy method and hormone dispenser |
US5897539A (en) * | 1995-09-28 | 1999-04-27 | Schering Aktiengesellschaft | Hormone replacement therapy method and hormone dispenser |
US6083528A (en) * | 1995-09-28 | 2000-07-04 | Schering Aktiengesellschaft | Hormone replacement therapy method and hormone dispenser |
US6551611B2 (en) * | 1995-09-28 | 2003-04-22 | Schering Aktiengesellschaft | Hormone replacement therapy method |
US20020142028A1 (en) * | 1995-09-28 | 2002-10-03 | Jorg Elliesen | Hormone replacement therapy method |
US20050032756A1 (en) * | 1995-10-28 | 2005-02-10 | Michael Dittgen | Multistage preparation for contraception based on natural estrogens |
US20030078245A1 (en) * | 1996-06-25 | 2003-04-24 | Bennink Herman Jan Tijmen Coelingh | Progestogen-anti-progestogen regimens |
US20010027189A1 (en) * | 1996-06-25 | 2001-10-04 | Bennink Herman Jan Tijmen Coelingh | Progestogen-anti-progestogen regimens |
US5858405A (en) * | 1996-07-26 | 1999-01-12 | American Home Products Corporation | Oral contraceptive |
US5888543A (en) * | 1996-07-26 | 1999-03-30 | American Home Products Corporation | Oral contraceptives |
US6121465A (en) * | 1996-08-12 | 2000-09-19 | Schering Aktiengesellschaft | Process for production drospirenone and intermediate products of the process |
US6161465A (en) * | 1996-11-16 | 2000-12-19 | Zf Friedrichshafen Ag | Pneumatic or hydraulic control motor with a shutoff device |
US6177416B1 (en) * | 1996-12-01 | 2001-01-23 | Schering Aktiengesellschaft | Oxyiminopregnancarbolactones |
US6290931B1 (en) * | 1996-12-16 | 2001-09-18 | Jenapharm Gmbh & Co. Kg | Homogeneous preformulations containing high concentrations of steroids, for producing low-dose solid and semi-solid pharmaceutical preparations |
US6987101B1 (en) * | 1996-12-20 | 2006-01-17 | Schering Aktiengesellschaft | Therapeutic gestagens for the treatment of premenstrual dysphoric disorder |
US20050282790A1 (en) * | 1996-12-20 | 2005-12-22 | Norman Nashed | Therapeutic gestagens for the treatment of premenstrual dysphoric disorder |
US20010020015A1 (en) * | 1997-08-27 | 2001-09-06 | Michael Kafrissen | Combination progestin oral contraceptive regimen |
US5891868A (en) * | 1997-11-21 | 1999-04-06 | Kaiser Foundation Health Plan, Inc. | Methods for treating postmenopausal women using ultra-low doses of estrogen |
US20050250750A1 (en) * | 1998-11-19 | 2005-11-10 | The Regents Of The University Of California | Methods for treating postmenopausal women using ultra-low doses of estrogen |
US6747019B2 (en) * | 1999-03-30 | 2004-06-08 | Jencap Research, Ltd. | Low dose estrogen interrupted hormone replacement therapy |
US20020165209A1 (en) * | 1999-03-30 | 2002-11-07 | Jencap Research Ltd. | Low dose estrogen interrupted hormone replacement therapy |
US20040180867A1 (en) * | 1999-03-30 | 2004-09-16 | Casper Robert F. | Low dose estrogen interrupted hormone replacement therapy |
US6667050B1 (en) * | 1999-04-06 | 2003-12-23 | Galen (Chemicals) Limited | Chewable oral contraceptive |
US6787531B1 (en) * | 1999-08-31 | 2004-09-07 | Schering Ag | Pharmaceutical composition for use as a contraceptive |
US6346269B1 (en) * | 2000-05-08 | 2002-02-12 | Standard Chem. & Pharm. Co., Ltd. | Method for preparing an oral formulation containing acid-sensitive drugs and oral formulation made thereby |
US20020173669A1 (en) * | 2000-12-14 | 2002-11-21 | Thomas Schultz | Steroid hormone products and methods for preparing them |
US20020173487A1 (en) * | 2000-12-20 | 2002-11-21 | Schering Aktiengesellschaft | Cyclodextrin-drospirenone inclusion complexes |
US6610670B2 (en) * | 2000-12-20 | 2003-08-26 | Schering Aktiengesellschaft | Cyclodextrin-drospirenone inclusion complexes |
US6958326B2 (en) * | 2000-12-20 | 2005-10-25 | Schering Ag | Cyclodextrin-drospirenone inclusion complexes |
US20020132801A1 (en) * | 2001-01-11 | 2002-09-19 | Schering Aktiengesellschaft | Drospirenone for hormone replacement therapy |
US6630166B1 (en) * | 2001-02-12 | 2003-10-07 | Watson Pharmaceuticals, Inc. | Compositions for conjugated estrogens and associated methods |
US20030004145A1 (en) * | 2001-05-16 | 2003-01-02 | Leonard Thomas W. | Treatment of conditions relating to hormone deficiencies by administration of progestins |
US6869941B2 (en) * | 2001-07-13 | 2005-03-22 | Schering Ag | Combination of drospirenone and an estrogen sulphamate for HRT |
US20030050289A1 (en) * | 2001-07-13 | 2003-03-13 | Schering Ag | Combination of drospirenone and an estrogen sulphamate for HRT |
US20030229057A1 (en) * | 2002-03-11 | 2003-12-11 | Caubel Patrick Michel | Continuous sulfatase inhibiting progestogen hormone replacement therapy |
US20060275362A1 (en) * | 2005-06-03 | 2006-12-07 | Pablo Davila | Rapidly-dissolving pharmaceutical composition for inhibiting ovulation |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090269403A1 (en) * | 2008-04-24 | 2009-10-29 | Shaked Ze Ev | Oral contraceptive dosage forms and methods of making such dosage forms |
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US6787531B1 (en) | 2004-09-07 |
US20030114429A1 (en) | 2003-06-19 |
US20140050794A1 (en) | 2014-02-20 |
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