WO1989002742A1 - Tablet for use in the treatment of progesterone deficiency - Google Patents
Tablet for use in the treatment of progesterone deficiency Download PDFInfo
- Publication number
- WO1989002742A1 WO1989002742A1 PCT/US1988/003406 US8803406W WO8902742A1 WO 1989002742 A1 WO1989002742 A1 WO 1989002742A1 US 8803406 W US8803406 W US 8803406W WO 8902742 A1 WO8902742 A1 WO 8902742A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- progesterone
- wax
- composition
- mixture
- tablet
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Definitions
- TECHNICAL FIELD This invention relates generally to the administration of progesterone in the treatment of progesterone deficiency in the human female, and particularly to tabletized progesterone compositions.
- Progesterone is a naturally occurring steroid which is biosynthesized in the ovaries and the adrenal cortices in nonpregnant women. Progesterone is medically administered in the treatment of progesterone deficiency as well as in the treatment of other disorders such as pregnancy complications and menstrual abnormalities. Even though it has been synthesized commercially since 1934, its clinical usefulness has been limited because of its extensive degradation by the liver following ingestion and because of its short shelf life. Orally administered, synthetic progestational agents known as progestins, which do not degrade rapidly, have been used for treatment of some disorders. They however produce undesirable side effects. Thus efforts have continued to devise a manner to administer natural progesterone. Since intramuscular injection of progesterone is not therapeutically practical, and since vaginal and rectal administration is inconvenient and aesthetically displeasing, attempts have continued to develop a natural progesterone composition that can be administered orally.
- the other approach is to micronize the progesterone by placing it in powdered form in an environment that creates breakage of the particles to very small sizes, mostly under 10 microns. In micronized form it is absorbed so rapidly that massive dosages saturate the metabolic capacity of the liver to a point that a significant amount can go through the liver without breakdown. Massive dosages for any significant period, however, would be both clinically harmful and not economically feasible.
- micronized natural progesterone By thoroughly blending micronized natural progesterone with a wax having a melting point above body temperature, such as carnauba wax, degradation of the progesterone by the liver is sufficiently limited so as to achieve good serum level increases in progesterone on a sustained and substantially predictable basis.
- a limited quantity of safflower oil has also been found to be beneficial in this regard.
- EXAMPLE I micronized progesterone 1000 grams Brazilian carnauba wax 1000 grams Avicel 102 1000 grams microsilica gel 15 grams stearic acid 30 grams
- the preparation is made by placing the progesterone in micronized, powdered form having particle sizes less than about 10 microns into a blender with the powdered Brazilian carnauba wax and blending the mixture for 15 minutes.
- the Avicel 102, AC DI SOL, the microsilica gel and stearic acid are premixed to a uniform blend and then thoroughly blended with the progesterone and wax mixture for 10 minutes.
- the magnesium stearate is added to the mixture and blended for another 5 minutes.
- the blend is then conventionally compressed to form tablets that are stored under refrigeration at 40°F or less.
- micronized progesterone enters into the bowel in sufficient quantity to be available for absorption at effective rates with the administration of only the three tablets per day of 100 mg progesterone each. Not only does it enter the bowel in sufficient quantity but it also is present there for release from the wax at good sustained release rates.
- the Avicel 102 cellulose filler is added to provide bulk. It should be present in a concentration of 20% to 50% of total weight.
- the AC DI SOL a specialized cellulose filler, is provided at 1/2% to 1% of total weight as a disintegrant.
- the stearic acid and magnesium stearate serve as lubricants to prevent adherence of the composition to the tabletizing apparatus.
- the stearic acid and magnesium stearate are each provided at 1% to 2% of total tablet weight.
- the microsilica gel acts as a desiccant and flowing agent and should be present from
- the wax must have a melting point above body temperature and should be at a concentration of 20% to 150% by weight of the progesterone. Concentrations of less than 20% suffer from adverse losses of absorption and of sustain release properties. Concentrations above 150% restrict absorption of the progesterone from the intestinal track.
- Post-menopausal women were orally administered 200 mg of the preparation in tablet form while fasting.
- Serum progesterone was measured by radioimmunoassay and bioavailability was assessed by measuring the area under the curve of serum progesterone levels for 8 hours.
- post-menopausal women were orally administered the same preparation with zero safflower oil content and with 200 mg safflower oil. The results are shown in Table II.
- the preparations with safflower oil are prepared by mixing micronized progesterone with the safflower oil and then adding the carnauba wax.
- the excipient Micosolle is added to provide sufficient hardness to the table and for flowability of the powder during compression.
- the magnesium stearate, stearic acid and silica are then added, thoroughly mixed and the preparation conventionally compressed.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Medicinal Preparation (AREA)
- Steroid Compounds (AREA)
Abstract
A tablet comprises micronized progesterone blended with carnuba wax and safflower oil that produces sustained serum level increases of progesterone. The concentration of the wax is between 20 % and 150 % by weight of that of the progesterone. The particle size of the progesterone is largely below 10 microns. By thoroughly blending micronized natural progesterone with a wax having a melting point above body temperature, such as carnuba wax, degradation of the progesterone by the liver is sufficiently limited so as to achieve good serum level increases in progesterone on a sustained and substantially predictable basis. The inclusion of a limited quantity of safflower oil has also been found to be beneficial in this regard.
Description
TABLET FOR USE IN THE TREATMENT
OF PROGESTERONE DEFICIENCY
TECHNICAL FIELD This invention relates generally to the administration of progesterone in the treatment of progesterone deficiency in the human female, and particularly to tabletized progesterone compositions.
BACKGROUND OF THE INVENTION Progesterone is a naturally occurring steroid which is biosynthesized in the ovaries and the adrenal cortices in nonpregnant women. Progesterone is medically administered in the treatment of progesterone deficiency as well as in the treatment of other disorders such as pregnancy complications and menstrual abnormalities. Even though it has been synthesized commercially since 1934, its clinical usefulness has been limited because of its extensive degradation by the liver following ingestion and because of its short shelf life. Orally administered, synthetic progestational agents known as progestins, which do not degrade rapidly, have been used for treatment of some disorders. They however produce undesirable side effects. Thus efforts have continued to devise a manner to administer natural progesterone. Since intramuscular injection of
progesterone is not therapeutically practical, and since vaginal and rectal administration is inconvenient and aesthetically displeasing, attempts have continued to develop a natural progesterone composition that can be administered orally.
Heretofore, two general approaches have been taken in attempts to circumvent the effect that the liver has on orally administered progesterone. One involves bypassing the liver by giving oily preparations of progesterone to encourage its absorption through the lymphatic system. Laboratoires Besins Iscovesco of Paris, France has followed this approach by developing a soft gelatin capsule marketed in Europe under the name Utrogestan. It has progesterone combined with a vegetable oil in gelatin. Its effectiveness however has been limited since serum levels of progesterone following its administration have been found to be erratic, non predictable and not characterized by sustained release. Moreover, its production is messy and inefficient by being encapsulated in gelatin.
The other approach is to micronize the progesterone by placing it in powdered form in an environment that creates breakage of the particles to very small sizes, mostly under 10 microns. In micronized form it is absorbed so rapidly that massive dosages saturate the metabolic capacity of the liver to a point that a significant amount can go through the liver without breakdown. Massive dosages for any significant period, however, would be both clinically harmful and not economically feasible.
Accordingly, it is seen that a need remains for a pharmaceutical product by which natural progesterone may be orally administered with effective absorption rates, improved shelf life, with sustained release properties and in moderate dosages.
SUMMARY OF THE INVENTION It has now been discovered that a tabletized mixture of micronized progesterone and a wax is effective in elevating serum levels of progesterone. The concentration of the wax is between 20% and 150% by weight of that of the progesterone. The particle size of the progesterone is largely below 10 microns. By thoroughly blending micronized natural progesterone with a wax having a melting point above body temperature, such as carnauba wax, degradation of the progesterone by the liver is sufficiently limited so as to achieve good serum level increases in progesterone on a sustained and substantially predictable basis. The inclusion of a limited quantity of safflower oil has also been found to be beneficial in this regard.
EXAMPLE I micronized progesterone 1000 grams Brazilian carnauba wax 1000 grams Avicel 102 1000 grams microsilica gel 15 grams stearic acid 30 grams
AC DI SOL 30 grams magnesium stearate 15 grams
The preparation is made by placing the progesterone in micronized, powdered form having particle sizes less than about 10 microns into a blender with the powdered Brazilian carnauba wax and blending the mixture for 15 minutes. The Avicel 102, AC DI SOL, the microsilica gel and stearic acid are premixed to a uniform blend and then thoroughly blended with the progesterone and wax mixture for 10 minutes. Following this the magnesium stearate is added to the mixture and blended for another 5 minutes. The blend is then conventionally compressed to form
tablets that are stored under refrigeration at 40°F or less.
Clinical studies have found that the oral ingestion during the midluteal phase of the menstrual cycle of tablets having 100 milligrams of progesterone in the morning and having 200 milligrams of progesterone at bedtime, of the Example I composition, increases the serum concentration of progesterone for sustained periods of time sufficient to evoke progestinal responses in the responsive end organs. Clinical tests have shown the following serum levels to be achieved:
*Curve being a plot of serum progesterone in ng/ml against time in hours.
Though the physiological mechanism at work here is still not fully understood, apparently the presence of the wax finely blended with progesterone in micronized form limits the effectiveness of the liver in degrading the progesterone during liver transit. Thus, micronized progesterone enters into the bowel in sufficient quantity to be available for absorption at effective rates with the administration of only the three tablets per day of 100 mg progesterone each. Not only does it enter the
bowel in sufficient quantity but it also is present there for release from the wax at good sustained release rates.
The Avicel 102 cellulose filler is added to provide bulk. It should be present in a concentration of 20% to 50% of total weight. The AC DI SOL, a specialized cellulose filler, is provided at 1/2% to 1% of total weight as a disintegrant. The stearic acid and magnesium stearate serve as lubricants to prevent adherence of the composition to the tabletizing apparatus. The stearic acid and magnesium stearate are each provided at 1% to 2% of total tablet weight. The microsilica gel acts as a desiccant and flowing agent and should be present from
0.5% to 2% of total weight. The wax must have a melting point above body temperature and should be at a concentration of 20% to 150% by weight of the progesterone. Concentrations of less than 20% suffer from adverse losses of absorption and of sustain release properties. Concentrations above 150% restrict absorption of the progesterone from the intestinal track.
EXAMPLE II micronized progesterone 200 mg
Brazilian carnauba wax 100 mg silica-based excipient* 400 mg safflower oil 50 mg silica powder 2% stearic acid 1% magnesium stearate 1%
*Micosolle, available from Biomicotek, Inc. of Torrance, California
Post-menopausal women were orally administered 200 mg of the preparation in tablet form while fasting.
Blood samples were obtained hourly for 6 hours, then at 8 hours and 24 hours. Serum progesterone was measured by
radioimmunoassay and bioavailability was assessed by measuring the area under the curve of serum progesterone levels for 8 hours. For comparison, post-menopausal women were orally administered the same preparation with zero safflower oil content and with 200 mg safflower oil. The results are shown in Table II.
*Curve being a plot of serum progesterone in ng/ml against time in hours.
It thus is seen that the bioavailability of orally ingested micronized progesterone was increased significantly with the addition of safflower oil in limited quantities. The preparations with safflower oil are prepared by mixing micronized progesterone with the safflower oil and then adding the carnauba wax. The excipient Micosolle is added to provide sufficient hardness to the table and for flowability of the powder during compression. The magnesium stearate, stearic acid and silica are then added, thoroughly mixed and the preparation conventionally compressed.
Claims
1. A pharmaceutical composition suitable for orally administering progesterone comprising a tabletized mixture of progesterone in powdered form and a wax in powdered form having a melting point above body temperature.
2. The composition of claim 1 wherein said progesterone has particle sizes generally less than 10 microns.
3. The composition of claim 1 wherein said wax is present at a concentration of between 20% and 150% by weight that of said progesterone.
4. The composition of claim 1 wherein said wax is carnauba wax
5. The composition of claim 1 further comprising a cellulose filler in an amount of between 20% and 50% of total composition weight.
6. The composition of claim 1 further comprising 1% to 2% of total weight of magnesium stearate as a lubricating agent.
7. The composition of claim 1 further comprising 1% to 2% of total weight of microsilica gel as a flow agent.
8. The composition of claim 1 further comprising 1% to 2% of total composition weight of stearic acid as a lubricant.
9. The composition of claim 1 further comprising safflower oil.
10. The composition of claim 9 wherein safflower oil is present at a concentration not exceeding that of the progesterone concentration.
11. A method of making a tablet for oral ingestion to elevate blood level contents of progesterone wherein the method comprises the steps of (a) mixing progesterone in powder form with a wax in powdered form; (b) blending the mixture of progesterone and wax; (c) adding a filler in powdered form to the mixture; (d) blending the mixture of progesterone, wax and filler, and (3) compressing the blended mixture.
12. The method of claim 11 wherein step (a) progesterone in powder form is mixed with carnauba wax in powder form.
13. The method of claim 11 wherein step (a) progesterone in powder form of a particle size less than 10 microns is mixed with wax in powder form.
14. The method of claim 11 wherein step (a) the powdered wax is mixed with powder progesterone in a concentration of between 20% and 150% by weight of the progesterone.
15. The method of claim 11 wherein step (c) a cellulose filler is added to the mixture in an amount between 20% and 50% by weight of the total weight of the composition.
16. The method of treating progesterone deficiency in the human female which comprises the steps of orally administering a tablet comprised of a mixture of powdered progesterone and powdered wax with the concentration of wax in the tablet being sufficient to achieve rendered sustained release of progesterone after passage through the liver.
17. The treatment method of claim 16 wherein the tablet is orally administered during the midluteal phase of the menstrual cycle.
18. The treatment method of claim 16 wherein the orally administered tablet also comprises safflower oil.
19. The method of making a tablet for oral ingestion to elevate blood level contents of progesterone wherein the method comprises the steps of:
(a) mixing progesterone in powder form with safflower oil;
(b) adding carnauba wax and blending the mixture of progesterone, safflower oil and wax;
(c) adding an excipient; and
(d) blending and compressing the blended mixture in tablet form.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE8989900392T DE3874320T2 (en) | 1987-10-05 | 1988-10-03 | TABLET TO TREAT PROGESTERONE DEFICIENCY. |
AT89900392T ATE80037T1 (en) | 1987-10-05 | 1988-10-03 | PROGESTERONE DEFICIENCY TREATMENT TABLET. |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10480887A | 1987-10-05 | 1987-10-05 | |
US104,808 | 1987-10-05 | ||
US23061688A | 1988-08-10 | 1988-08-10 | |
US230,616 | 1988-08-10 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1989002742A1 true WO1989002742A1 (en) | 1989-04-06 |
Family
ID=26801969
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1988/003406 WO1989002742A1 (en) | 1987-10-05 | 1988-10-03 | Tablet for use in the treatment of progesterone deficiency |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP0335970B1 (en) |
AT (1) | ATE80037T1 (en) |
AU (1) | AU2807089A (en) |
CA (1) | CA1315681C (en) |
DE (1) | DE3874320T2 (en) |
WO (1) | WO1989002742A1 (en) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0351580A2 (en) * | 1988-07-18 | 1990-01-24 | Shionogi Seiyaku Kabushiki Kaisha | Sustained-release preparations and the process thereof |
WO2001021155A1 (en) * | 1999-09-17 | 2001-03-29 | Universiteit Gent | Cushioning wax beads for making solid shaped articles |
WO2003065924A1 (en) | 2002-02-08 | 2003-08-14 | Advanced Animal Technology Limited | Control of a biological function |
WO2006127637A2 (en) | 2005-05-20 | 2006-11-30 | Actavis Group Hf | Compressed pharmaceutical composition comprising coated pellets and a direct compression mixture, and method of preparation thereof |
US7163699B2 (en) | 2001-03-01 | 2007-01-16 | Laboratories Besins International | Progestin co-micronized with a surfactant pharmaceutical composition comprising same methods for making same and uses thereof |
FR2947178A1 (en) * | 2009-06-29 | 2010-12-31 | Effik | PHARMACEUTICAL COMPOSITION BASED ON MICRONIZED PROGESTERONE AND USES THEREOF |
WO2018034626A1 (en) | 2016-08-18 | 2018-02-22 | İlko İlaç Sanayi Ve Ticaret Anonim Şirketi | Antiparkinson tablet formulation with improved dissolution profile |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2772617B1 (en) * | 1997-12-19 | 2001-03-09 | Besins Iscovesco Lab | PROGESTERONE TABLET AND PROCESS FOR THE PREPARATION THEREOF |
Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2880135A (en) * | 1952-10-30 | 1959-03-31 | Upjohn Co | 11-keto-progesterone compositions and methods of treating ketosis therewith |
US2895881A (en) * | 1957-04-04 | 1959-07-21 | Wynn Pharmacal Corp | Quinidine gluconate sustained medication tablet |
US3193457A (en) * | 1961-06-07 | 1965-07-06 | Syntex Corp | Oral administration of 6, 16alpha-dimethyl-progesterones |
US3402240A (en) * | 1957-06-25 | 1968-09-17 | Pfizer & Co C | Medicinal tablet and process of making same |
US3459850A (en) * | 1964-09-04 | 1969-08-05 | A Wander Sa Dr | Sustained-release tablets,a process and a composition for their preparation |
US3535419A (en) * | 1965-12-15 | 1970-10-20 | Syntex Corp | Veterinary compositions and methods |
US3920630A (en) * | 1970-09-24 | 1975-11-18 | Upjohn Co | 2,2{40 -Anhydro-ara-cytidine compounds and process of preparation |
US4159346A (en) * | 1976-09-07 | 1979-06-26 | Fmc Corporation | Tablet compositions |
US4209513A (en) * | 1974-02-14 | 1980-06-24 | Burroughs Wellcome Co. | Tablet formulation |
US4439432A (en) * | 1982-03-22 | 1984-03-27 | Peat Raymond F | Treatment of progesterone deficiency and related conditions with a stable composition of progesterone and tocopherols |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2408345A1 (en) * | 1976-11-30 | 1979-06-08 | Besins Jean Louis | NEW COMPOSITION WITH ANTI-CONCEPTIONAL ACTION |
JPS6124516A (en) * | 1984-07-12 | 1986-02-03 | Fujisawa Pharmaceut Co Ltd | Long active tablet |
AT385654B (en) * | 1984-09-04 | 1988-05-10 | Arcana Chem Pharm | Process for the production of oil-containing preparations in granule form for oral administration |
-
1988
- 1988-10-03 AU AU28070/89A patent/AU2807089A/en not_active Abandoned
- 1988-10-03 EP EP89900392A patent/EP0335970B1/en not_active Expired - Lifetime
- 1988-10-03 DE DE8989900392T patent/DE3874320T2/en not_active Expired - Lifetime
- 1988-10-03 AT AT89900392T patent/ATE80037T1/en not_active IP Right Cessation
- 1988-10-03 WO PCT/US1988/003406 patent/WO1989002742A1/en active IP Right Grant
- 1988-10-04 CA CA000579278A patent/CA1315681C/en not_active Expired - Fee Related
Patent Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2880135A (en) * | 1952-10-30 | 1959-03-31 | Upjohn Co | 11-keto-progesterone compositions and methods of treating ketosis therewith |
US2895881A (en) * | 1957-04-04 | 1959-07-21 | Wynn Pharmacal Corp | Quinidine gluconate sustained medication tablet |
US3402240A (en) * | 1957-06-25 | 1968-09-17 | Pfizer & Co C | Medicinal tablet and process of making same |
US3193457A (en) * | 1961-06-07 | 1965-07-06 | Syntex Corp | Oral administration of 6, 16alpha-dimethyl-progesterones |
US3459850A (en) * | 1964-09-04 | 1969-08-05 | A Wander Sa Dr | Sustained-release tablets,a process and a composition for their preparation |
US3535419A (en) * | 1965-12-15 | 1970-10-20 | Syntex Corp | Veterinary compositions and methods |
US3920630A (en) * | 1970-09-24 | 1975-11-18 | Upjohn Co | 2,2{40 -Anhydro-ara-cytidine compounds and process of preparation |
US4209513A (en) * | 1974-02-14 | 1980-06-24 | Burroughs Wellcome Co. | Tablet formulation |
US4159346A (en) * | 1976-09-07 | 1979-06-26 | Fmc Corporation | Tablet compositions |
US4439432A (en) * | 1982-03-22 | 1984-03-27 | Peat Raymond F | Treatment of progesterone deficiency and related conditions with a stable composition of progesterone and tocopherols |
Non-Patent Citations (1)
Title |
---|
See also references of EP0335970A4 * |
Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0351580A3 (en) * | 1988-07-18 | 1990-05-09 | Shionogi Seiyaku Kabushiki Kaisha | Sustained-release preparations and the process thereof |
US5023089A (en) * | 1988-07-18 | 1991-06-11 | Shionogi & Co., Ltd. | Sustained-release preparations and the process thereof |
EP0351580A2 (en) * | 1988-07-18 | 1990-01-24 | Shionogi Seiyaku Kabushiki Kaisha | Sustained-release preparations and the process thereof |
WO2001021155A1 (en) * | 1999-09-17 | 2001-03-29 | Universiteit Gent | Cushioning wax beads for making solid shaped articles |
US6923984B1 (en) | 1999-09-17 | 2005-08-02 | Universiteit Gent | Cushioning wax beads for making solid shaped articles |
US7163699B2 (en) | 2001-03-01 | 2007-01-16 | Laboratories Besins International | Progestin co-micronized with a surfactant pharmaceutical composition comprising same methods for making same and uses thereof |
WO2003065924A1 (en) | 2002-02-08 | 2003-08-14 | Advanced Animal Technology Limited | Control of a biological function |
WO2006127637A2 (en) | 2005-05-20 | 2006-11-30 | Actavis Group Hf | Compressed pharmaceutical composition comprising coated pellets and a direct compression mixture, and method of preparation thereof |
WO2006127637A3 (en) * | 2005-05-20 | 2007-06-14 | Actavis Group Hf | Compressed pharmaceutical composition comprising coated pellets and a direct compression mixture, and method of preparation thereof |
FR2947178A1 (en) * | 2009-06-29 | 2010-12-31 | Effik | PHARMACEUTICAL COMPOSITION BASED ON MICRONIZED PROGESTERONE AND USES THEREOF |
EP2269592A1 (en) * | 2009-06-29 | 2011-01-05 | Effik | Pharmaceutical composition of micronised progesterone and its use |
WO2011001039A1 (en) * | 2009-06-29 | 2011-01-06 | Effik | Micronised progesterone pharmaceutical composition and uses thereof |
WO2018034626A1 (en) | 2016-08-18 | 2018-02-22 | İlko İlaç Sanayi Ve Ticaret Anonim Şirketi | Antiparkinson tablet formulation with improved dissolution profile |
Also Published As
Publication number | Publication date |
---|---|
EP0335970A4 (en) | 1990-03-28 |
EP0335970B1 (en) | 1992-09-02 |
AU2807089A (en) | 1989-04-18 |
DE3874320D1 (en) | 1992-10-08 |
CA1315681C (en) | 1993-04-06 |
DE3874320T2 (en) | 1992-12-17 |
ATE80037T1 (en) | 1992-09-15 |
EP0335970A1 (en) | 1989-10-11 |
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