CN1585644A - 基于微粉化孕酮的药物组合物及其制造方法和用途 - Google Patents
基于微粉化孕酮的药物组合物及其制造方法和用途 Download PDFInfo
- Publication number
- CN1585644A CN1585644A CNA028224868A CN02822486A CN1585644A CN 1585644 A CN1585644 A CN 1585644A CN A028224868 A CNA028224868 A CN A028224868A CN 02822486 A CN02822486 A CN 02822486A CN 1585644 A CN1585644 A CN 1585644A
- Authority
- CN
- China
- Prior art keywords
- oil
- progesterone
- pharmaceutical composition
- oleum
- micronization
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 title claims abstract description 137
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 31
- 229960001207 micronized progesterone Drugs 0.000 title abstract 2
- 238000002360 preparation method Methods 0.000 title description 22
- 239000003921 oil Substances 0.000 claims abstract description 51
- 235000019198 oils Nutrition 0.000 claims abstract description 49
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 claims abstract description 22
- 229940083466 soybean lecithin Drugs 0.000 claims abstract description 22
- 239000000203 mixture Substances 0.000 claims abstract description 21
- 239000004006 olive oil Substances 0.000 claims abstract description 16
- 239000008168 almond oil Substances 0.000 claims abstract description 15
- 235000019489 Almond oil Nutrition 0.000 claims abstract description 14
- 235000003434 Sesamum indicum Nutrition 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 12
- 230000006259 progesterone secretion Effects 0.000 claims abstract description 5
- 239000000186 progesterone Substances 0.000 claims description 61
- 229960003387 progesterone Drugs 0.000 claims description 61
- 235000015112 vegetable and seed oil Nutrition 0.000 claims description 15
- 241000207961 Sesamum Species 0.000 claims description 13
- 235000008390 olive oil Nutrition 0.000 claims description 13
- 239000000725 suspension Substances 0.000 claims description 13
- 238000003756 stirring Methods 0.000 claims description 12
- 239000007901 soft capsule Substances 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 239000000262 estrogen Substances 0.000 claims description 5
- 229940011871 estrogen Drugs 0.000 claims description 5
- DNXHEGUUPJUMQT-UHFFFAOYSA-N (+)-estrone Natural products OC1=CC=C2C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 DNXHEGUUPJUMQT-UHFFFAOYSA-N 0.000 claims description 4
- RSEPBGGWRJCQGY-RBRWEJTLSA-N Estradiol valerate Chemical compound C1CC2=CC(O)=CC=C2[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CCCC)[C@@]1(C)CC2 RSEPBGGWRJCQGY-RBRWEJTLSA-N 0.000 claims description 4
- DNXHEGUUPJUMQT-CBZIJGRNSA-N Estrone Chemical compound OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 DNXHEGUUPJUMQT-CBZIJGRNSA-N 0.000 claims description 4
- BFPYWIDHMRZLRN-SLHNCBLASA-N Ethinyl estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 BFPYWIDHMRZLRN-SLHNCBLASA-N 0.000 claims description 4
- 229960004766 estradiol valerate Drugs 0.000 claims description 4
- 229960003399 estrone Drugs 0.000 claims description 4
- 229940126601 medicinal product Drugs 0.000 claims description 4
- 239000003075 phytoestrogen Substances 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 3
- 235000014698 Brassica juncea var multisecta Nutrition 0.000 abstract 1
- 235000006008 Brassica napus var napus Nutrition 0.000 abstract 1
- 240000000385 Brassica napus var. napus Species 0.000 abstract 1
- 235000006618 Brassica rapa subsp oleifera Nutrition 0.000 abstract 1
- 235000004977 Brassica sinapistrum Nutrition 0.000 abstract 1
- 244000020551 Helianthus annuus Species 0.000 abstract 1
- 235000003222 Helianthus annuus Nutrition 0.000 abstract 1
- 240000007817 Olea europaea Species 0.000 abstract 1
- 244000000231 Sesamum indicum Species 0.000 abstract 1
- 239000000828 canola oil Substances 0.000 abstract 1
- 230000004962 physiological condition Effects 0.000 abstract 1
- 239000008159 sesame oil Substances 0.000 abstract 1
- 239000002600 sunflower oil Substances 0.000 abstract 1
- 239000002775 capsule Substances 0.000 description 20
- 210000000582 semen Anatomy 0.000 description 20
- 235000019580 granularity Nutrition 0.000 description 10
- 206010020751 Hypersensitivity Diseases 0.000 description 8
- 238000011160 research Methods 0.000 description 8
- 230000007815 allergy Effects 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 208000026935 allergic disease Diseases 0.000 description 6
- 238000009826 distribution Methods 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- 241001597008 Nomeidae Species 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 230000009245 menopause Effects 0.000 description 4
- 239000012047 saturated solution Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 241000196324 Embryophyta Species 0.000 description 3
- 229940126534 drug product Drugs 0.000 description 3
- 230000002349 favourable effect Effects 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 2
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 2
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 2
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 208000008899 Habitual abortion Diseases 0.000 description 2
- 208000019255 Menstrual disease Diseases 0.000 description 2
- 239000005642 Oleic acid Substances 0.000 description 2
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 2
- 206010070834 Sensitisation Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000002745 absorbent Effects 0.000 description 2
- 239000002250 absorbent Substances 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 239000007902 hard capsule Substances 0.000 description 2
- 235000020256 human milk Nutrition 0.000 description 2
- 210000004251 human milk Anatomy 0.000 description 2
- 206010020718 hyperplasia Diseases 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 230000029849 luteinization Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- 230000016087 ovulation Effects 0.000 description 2
- 230000035935 pregnancy Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 150000003146 progesterones Chemical class 0.000 description 2
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 230000008313 sensitization Effects 0.000 description 2
- 239000003549 soybean oil Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 210000004291 uterus Anatomy 0.000 description 2
- 210000001215 vagina Anatomy 0.000 description 2
- 206010000234 Abortion spontaneous Diseases 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 201000005670 Anovulation Diseases 0.000 description 1
- 206010002659 Anovulatory cycle Diseases 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 235000003911 Arachis Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 206010006298 Breast pain Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 108010068370 Glutens Proteins 0.000 description 1
- 241000827798 Hemerocallis citrina Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000005913 Maltodextrin Substances 0.000 description 1
- 229920002774 Maltodextrin Polymers 0.000 description 1
- 208000006662 Mastodynia Diseases 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 208000006399 Premature Obstetric Labor Diseases 0.000 description 1
- 206010036600 Premature labour Diseases 0.000 description 1
- 206010036618 Premenstrual syndrome Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 210000004100 adrenal gland Anatomy 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- 230000002052 anaphylactic effect Effects 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 231100000552 anovulation Toxicity 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 238000011021 bench scale process Methods 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000002079 cooperative effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000003001 depressive effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 208000023965 endometrium neoplasm Diseases 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 230000001076 estrogenic effect Effects 0.000 description 1
- 230000004720 fertilization Effects 0.000 description 1
- 210000003754 fetus Anatomy 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- 210000002149 gonad Anatomy 0.000 description 1
- 230000010224 hepatic metabolism Effects 0.000 description 1
- 239000003688 hormone derivative Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000031891 intestinal absorption Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 150000004668 long chain fatty acids Chemical class 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 229940035034 maltodextrin Drugs 0.000 description 1
- 230000003821 menstrual periods Effects 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 239000004531 microgranule Substances 0.000 description 1
- 208000015994 miscarriage Diseases 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 210000002826 placenta Anatomy 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 208000026440 premature labor Diseases 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 238000004513 sizing Methods 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 208000000995 spontaneous abortion Diseases 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
-
- 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
- A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/63—Oleaceae (Olive family), e.g. jasmine, lilac or ash tree
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/06—Antiabortive agents; Labour repressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/30—Oestrogens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/32—Antioestrogens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/34—Gestagens
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Endocrinology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Diabetes (AREA)
- Microbiology (AREA)
- Alternative & Traditional Medicine (AREA)
- Biotechnology (AREA)
- Botany (AREA)
- Medical Informatics (AREA)
- Mycology (AREA)
- Reproductive Health (AREA)
- Pregnancy & Childbirth (AREA)
- Gynecology & Obstetrics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Steroid Compounds (AREA)
Abstract
本发明涉及一种药物组合物，该组合物包含微粉化孕酮、大豆卵磷脂和至少一种选自向日葵油、橄榄油、芝麻籽油、菜籽油、杏仁油的油，本发明还涉及该药物组合物的制备方法，本发明还涉及该药物组合物在治疗与孕酮分泌不足有关的生理状况中应用。
Description
本发明涉及一种药物组合物，所述组合物包含微粉化孕酮、大豆卵磷脂和至少一种选自向日葵油、橄榄油、芝麻籽油、菜籽油、杏仁油的油。本发明还涉及包含上述药物组合物的药物产品。
本发明还涉及制造该药物组合物的方法，还涉及该药物组合物的用途。
孕酮是一种在女性中合成的激素，特别是在排卵后或黄体期由卵巢合成(更确切的说是卵巢细胞合成)，还有少量是由肾上腺和胎盘在怀孕的第二期中分泌的。孕酮的非内分泌合成，特别是在神经细胞，也是可能的。
妇女孕酮分泌不足的结果是其生物学作用的损失：怀孕作用、抗雄激素作用(作用于皮肤)和抗雌激素作用(高雌激素血症的结果是潮热、焦虑或抑郁型的心理障碍、体重增加等)。孕酮不足会导致功能障碍和不同的临床表现，特别是：
--经期前综合症，
--由于排卵中止(disovulation)或停止排卵导致月经不调，
--良性乳房病，
--围绝经(perimenopause)和绝经。
但是，由于孕酮的肠道吸收不佳和强烈的肝代谢(血浆半衰期短)，口服施用孕酮有许多不利因素。到目前为止，只有阴道、直肠和肌肉内通路才可能在黄体期维持血液孕酮水平在生理水平达几个小时。
为了改善天然孕酮在消化道吸收的质量和强度，LABORATOIRES BESINS-ISCOVESCO已经在专利申请FR 76 36007中提出了解决方案。特别的是，他们开发了软胶囊制剂，该制剂包含在油性悬液中的微粉化孕酮。微粉化的协同效应和使用含有长链脂肪酸的分子使该制剂有可能明显提高口服孕酮的生物利用度。该制剂已在世界范围内为人所知。在法国该制剂以商品名UTROGESTAN销售。
在UTROGESTAN中用作油性悬液中基础部分的油是花生油。
花生(Arachis hypogae)是豆科植物，一种每年开黄花的灌木，属于蝶形花科(Papilionacea family)。
在过去的15年间，花生过敏已经成为相当可观的变态反应问题。
Dutau等(La Presse Medicale[Medical出版社]，第28卷，1553页)注意到花生过敏的流行估计已达到普通人口的1.3％。食品中使用花生增多，经常以外壳形式，也许能解释这种发展趋势。
已经有描述在婴儿中早期敏感性增高，这些婴儿从未使用过常规形式的花生，但很明显这些婴儿在子宫内或通过母乳成为过敏，通过含有植物脂肪(花生油)的母乳或通过有油性溶液的医学配制品而过敏。
UTROGESTAN在许多情况下用于治疗，包括体外受精(IVF)循环中黄体期的补充治疗，和用于有流产危险的情况和预防由于黄体不足导致的反复流产，直至怀孕的12周。所以从理论上讲，胎儿有可能在子宫内接触UTROGESTAN。
到现在为止，当花生的致敏效果是明确时，仍然存在有关花生油导致过敏反应能力的争论。关于这个主题可以引用许多文献，包括：Taylor等，J.Allergy Clin.Immunol.，第68卷，372页(1981)；Moneret-Vautrin等，Pediatr.Allergy Immunol.第5卷，184页(1994)；Sabbah和Lauret，Allergie et Immunologie，第26卷，380页(1994)；de Montis等，Arch.Pediatr.，第2卷，25页(1995))。
基于上述事实，该申请公司致力于开发新的药物组合物，用没有高致敏危险的其他油取代花生油，而同时努力保留前述制剂的优点。
经过对许多植物油的大量研究和试验，选出了向日葵油、橄榄油、芝麻籽油、菜籽油、杏仁油。特别的是，使用这些油有希望排除过敏反应的危险，而同时保留了前述UTROGESTAN制剂的理化和动力学特性，那些使该制剂成功的特性。考虑到工业化规模生产前述UTROGESTAN制剂的方法包括许多精细执行的步骤，申请公司相信能成功地改进制剂而不增加生产困难。
在本发明的内容中，油可以是精炼的或非精炼的。精炼油是从原料油中获得的并经过一系列提炼步骤的油。精炼油是一种纯化油，精炼油有很少的杂质，特别是很少有高致敏蛋白如谷蛋白。
在本发明的药物组合物中，微粉化孕酮悬浮在向日葵油、橄榄油、芝麻籽油、菜籽油、杏仁油或上述几种或全部油的混合物中较佳。
申请公司知道GENESIS SYSTEMS CORPORATION(Maxson等)的美国专利5,140,021描述了一种软胶囊，该软胶囊含有在高度不饱和油的悬液中的微粉化孕酮。向日葵油出现在该专利所述的几种油中。但是，所述美国专利5,140,021的发明人已经尽力与药物产品UTROGESTAN进行区分，也就是说，由申请公司开发和现在销售的制剂是基于花生油的。因此，该GENESIS SYSTEMS的专利中使用的微粉化孕酮被描述为有特定的粒度分布，这与UTROGESTAN中使用的微粉化孕酮不同。
美国专利5,140,021仅描述了该孕酮胶囊的试验室规模的制备，没有提供工业化规模制备该胶囊的成分。而且，根据上述美国专利所述的该孕酮胶囊不包含大豆卵磷脂，大豆卵磷脂是本发明中药物组合物的一种基础成分。特别是，大豆卵磷脂作为在向日葵油中悬浮孕酮微粒的作用物和作为在工业化规模封装内容物时的润滑剂。
因此，本发明涉及一种药物组合物，该合成物包含微粉化孕酮、大豆卵磷脂和至少一种选自向日葵油、橄榄油、芝麻籽油、菜籽油、杏仁油的油。
根据本发明所述药物组合物的有利实施方案，该微粉化孕酮悬浮在油中或悬浮在上述几种或全部油的混合物中。
在本发明的上下文中，术语“微粉化孕酮”规定至少80％孕酮颗粒的粒度在1μm和15μm之间，50％孕酮颗粒的粒度在1μm和10μm之间较佳，25％孕酮颗粒的粒度在1μm和5μm之间更佳，这些粒度以本专利申请实施例所述的过程用Malvern型激光微粒筛选器来测量。
在选择油之前的研究中，申请公司意外观察到大豆卵磷脂和根据本发明选出的油的组合物是十分有利，因为该组合物并不改变悬浮在油中微粉化孕酮的粒度。而且，在基于花生油的组合物与含有按照本发明使用的油的组合物之间，悬液中的微粉化孕酮的粒度分布没有明显区别。
关于其他测试的油，在有大豆卵磷脂和没有大豆卵磷脂的情况下，粒度是不同的。根据本发明选出的油在理化条件上与花生油相比，主要优点在于能同时保证：
在微粉化孕酮饱和时有相同的溶解度；
悬液有相同的粒度；和
相同的体外溶出曲线。
现在，在饱和状态下粒度和溶解度明显影响孕酮的体内生物利用度。
因此，选择这些油有可能更好地控制油性悬液中微粉化孕酮的粒度分布，和油中溶解的孕酮的量，因而能综合所有的保持与UTROGESTAN相似的体内生物利用度所需的条件。
根据本发明所述药物组合物的较佳实施方案，孕酮/油的比值在0.15/1和3/1之间，在0.25/1和2/1之间较佳，在0.40/1和1/1之间更佳，0.67/1最佳。
根据本发明所述药物组合物的较佳实施方案，大豆卵磷脂/油的比值在0.005/1和0.3/1之间，在0.01/1和0.2/1之间较佳，在0.040/1和0.1/1之间更佳，0.067/1最佳。
本发明所述的药物组合物也可以包含雌激素或其酯类衍生物，选自17-β-雌二醇、雌酮、17-α-乙炔雌二醇和戊酸雌二醇或植物雌激素较佳，17-β-雌二醇更佳。
本发明所述的药物组合物也可以是其他形式，尤其是软胶囊、硬胶囊、片剂或可饮用的悬液。
当本发明所述的药物组合物被结合至药物产品中，每个剂量单位含有2-600mg微粉化孕酮是有利的，含有30-300mg微粉化孕酮较佳，含有100-200mg微粉化孕酮更佳。
根据治疗说明，本发明所述的药物组合物可以口服或阴道施用。
在出现孕酮的副作用(口服吸收后嗜睡)或口服施用禁忌症(肝病)时，可用阴道给药代替口服给药。
根据本发明所述药物组合物的较佳实施方案，该胶囊包括明胶或同等物。
本发明还涉及药物组合物的制备方法，所述药物组合物包含微粉化孕酮、大豆卵磷脂和至少一种选自向日葵油、橄榄油、芝麻籽油、菜籽油、杏仁油的油。
所述方法包括下列连续步骤：
—把油与大豆卵磷脂混合，搅拌，以获得混合物；
—在上述混合物中加入微粉化孕酮，搅拌，以获得均匀悬液。
所述悬液可以可饮用悬液的形式施用，或以软胶囊或硬胶囊形式施用，但也可以粉剂形式注入吸收剂支持物。
该吸收剂支持物可以是麦芽糊精和/或衍生物、二氧化硅和/或衍生物、环糊精和/或衍生物或纤维素粉剂和/或衍生物种类，或是上述物质的组合物，或是其他有相同特性的药物原材料。
获得的粉剂可以表现为硬胶囊形式或片剂形式。包含该粉剂的硬胶囊或片剂还可以包含粘合剂、分裂剂、稀释剂和/或润滑剂。
本发明还涉及微粉化孕酮、大豆卵磷脂和至少一种选自向日葵油、橄榄油、芝麻籽油、菜籽油、杏仁油的油在制造用于治疗与孕酮分泌不足有关的生理状况的药用产品中的应用。
上述生理状况的例子可以包括：黄体不足、月经不调、经前综合症、乳房痛、良性乳房病、围绝经(perimenopause)、由于黄体不足导致的不育、绝经引起的紊乱、局部避孕、预防由于黄体不足导致的反复流产、早产的危险、痤疮、脱发、预防骨质疏松、子宫内膜肿瘤和癫痫。
本发明还涉及微粉化孕酮、大豆卵磷脂、和至少一种选自向日葵油、橄榄油、芝麻籽油、菜籽油、杏仁油的油以及雌激素在制造用于治疗与孕酮分泌不足有关的生理状况的药用产品中的应用。所述雌激素选自17-β-雌二醇、雌酮、17-α-乙炔雌二醇和戊酸雌二醇或植物雌激素较佳，17-β-雌二醇更佳。
使用下述非限制性实施例，本发明可以被更清楚地理解。
实施例1：本发明所述软胶囊形式的药物组合物
本发明所述的软胶囊的成分在下表1中描述。
表1
| 化合物名称 | 百分比制剂(％)每单位(mg) | 功能 | 参考标准 | |
| 活性物质·微粉化孕酮赋形剂·本发明所述的油或油的混合物大豆卵磷脂 | 40.0059.600.40 | 100.00149.001.00 | 活性物质稀释剂乳化剂 | Ph.Eur.第三版Ph.Eur.第三版USP 24，NF 19，2471页 |
申请公司还制备了与上述250mg胶囊类似的500mg胶囊。所述500mg胶囊含有200mg微粉化孕酮、2mg大豆卵磷脂和(例如)298mg向日葵油。
实施例2：不同油中微粉化孕酮溶解度的研究
为了选择最佳的油性载体以取代花生油，而同时保留前述制剂的理化特性，对下列植物油中孕酮的溶解度进行了测试：
—花生油
—橄榄油
—向日葵油
—高油酸含量的向日葵油
—菜籽油
—杏仁油
—大豆油
—芝麻籽油
—玉米油
标准溶液制备如下：
—浓缩溶液：孕酮 批号A0098 10mg
油 20ml
—稀释溶液：浓缩溶液 1ml
四氢呋喃(THF) 10ml
乙腈 20ml
磁性搅拌： 5分钟。
饱和溶液的制备如下：
所述饱和溶液在每种油中在室温下搅拌一小时，随后用直径25mm孔径0.45μm的尼龙过滤注射器过滤。
饱和溶液稀释200倍：
—饱和溶液：0.5ml
—THF： 50ml
—乙腈： 100ml
结果如下表2所示：
表2
| 测试的油 | 饱和浓度(mg/ml) | 饱和浓度的相对差异*(％) |
| 花生油 | 16.77 | - |
| 菜籽油 | 18.14 | +8.2％ |
| 向日葵油 | 17.50 | +4.4％ |
| 高油酸含量的向日葵油 | 8.29 | -50.6％ |
| 橄榄油 | 17.46 | +4.1％ |
表3
| 测试的油 | 饱和浓度(mg/ml) | 饱和浓度的相对差异*(％) |
| 花生油 | 18.80 | - |
| 杏仁油 | 18.98 | +1.0％ |
| 大豆油 | 16.19 | -13.9％ |
| 芝麻籽油 | 19.80 | +5.3％ |
| 玉米油 | 15.60 | -17.0％ |
*花生油＝参照油
在本次对饱和时溶解度研究后选出菜籽油、向日葵油、橄榄油、芝3麻种籽油和杏仁油。
记述各种油的供应商，如：
—橄榄油：LESSIEUR；
—向日葵油：HENRY LAMOTTE。
实施例3：本发明所述的微粉化孕酮软胶囊的制造
本发明所述的基于微粉化孕酮的软胶囊的制造按下述步骤进行：该胶囊的制备是按照本领域熟练技术人员实质上熟知的方法进行的。一批2,300,000个胶囊，每个胶囊含有100mg孕酮，按照以下步骤进行：空气控制在22℃±3℃，相对湿度控制在35％±10％。
对下列成分进行称重：
孕酮 230.00kg
向日葵油 342.70kg
大豆卵磷脂 2.30kg
将容积为600升的搅拌器置于真空下。
真空下在搅拌器中加入四分之三量的向日葵油，加入大豆卵磷脂。
将搅拌器重新置于真空下(0.7-0.9巴之间)，随后以10-15rpm低速搅拌。
在真空下加入孕酮，随后加入剩余的四分之一向日葵油，温度调至23℃±3℃。然后剧烈搅拌直至均匀。
将进行剧烈搅拌的搅拌器置于最大1巴的压力下。
用500μm的筛子连续筛选，并将混合物转移至储存容器。
储存容器置于真空，随后以2400-2000rpm搅拌15分钟。再置于真空下，以2000-2500rpm的速度再搅拌30分钟。
停止搅拌，容器在真空下放置5分钟。
用精通此领域的技术人员熟知的常规方法进行封装。
实施例4：确定本发明所述胶囊中颗粒的大小
在UTROGESTAN胶囊和本发明所述的包含向日葵油的胶囊之间进行比较粒度的研究。
使用材料如下：
—Mastersizer 2000激光微粒筛选器
—Hydro 2000 SM测量单元
根据下列方法：
·每次测量的样本的量：用吸液管取1或2滴沉淀
·媒介：过滤后的饱和向日葵油。该油以磁性搅拌制备，保持温度在37℃达1小时，随后在滤纸上过滤。
—折射率：(油的平均)1.4671
—媒介体积：100ml
·搅拌速度：1800rpm
·浑浊百分比：在10％-20％之间
·加权剩余百分比：＜3％
—每个制备品的测量次数：2。测量在浑浊百分比稳定30分钟后开始。
下文图1的结果表明两种胶囊的粒度有高度可比性。
申请公司进一步的研究表明孕酮在芝麻籽油、橄榄油、菜籽油或杏仁油的大小分布也与孕酮在花生油中的大小分布有可比性。
实施例5：在UTROGESTAN
胶囊和本发明所述的胶囊之间进行体外溶解度的对比
研究
使用带旋转篮(rotating basket)的SOTAX AT7溶解设备。
20mg精确称量的孕酮在200ml测容积烧瓶(A级)中溶解在2ml乙醇中，随后应用超声波并使用溶解介质(1％环糊精)把体积补足到容量刻度线。
对照溶液使用孔径1μm的玻璃纤维注射器过滤器进行过滤。
7个容器置于保持温度的水浴中，随后1000ml溶解介质被转移到每一个容器中。
6个容器内放入1个胶囊，随后篮子浸入溶解介质中，位置在该篮子与该容器底部的距离在25mm±2mm。
搅动该篮子，随后准备对照溶液。
在每个预定的时间间隔(5、10、15、30、45、60、90、120、150、180、225、270、315和360分钟)收集样品，用UV分光光度计分析。(λ：248nm)。
下文中图2的结果表明UTROGESTAN胶囊的体外溶解曲线和本发明所述的包含向日葵油的胶囊的体外溶解曲线事实上是相同的。
本发明所述的制剂保留了现有制剂的理化特性。
实施例6：在UTROGESTAN
胶囊和本发明所述药物组合物之间进行生物等价性研
究
为了比较本发明所述胶囊和UTROGESTAN胶囊，进行生物等价性研究，本发明所述胶囊在向日葵油悬液中含有100mg孕酮。
该研究在60名饥饿状况下的妇女中进行。
该研究的结果显示本发明的胶囊和UTROGESTAN之间有生物等价性(见其后图3和图4)。
Claims (10)
1.一种药物组合物，其特征在于，所述组合物包含微粉化孕酮、大豆卵磷脂和至少一种选自向日葵油、橄榄油、芝麻籽油、菜籽油、杏仁油的油。
2.如权利要求1所述的药物组合物，其特征在于，孕酮/油的比值在0.15/1和3/1之间，在0.25/1和2/1之间较佳，在0.40/1和1/1之间更佳，0.67/1最佳。
3.如权利要求1或2所述的药物组合物，其特征在于，大豆卵磷脂/油的比值在0.005/1和0.3/1之间，在0.01/1和0.2/1之间较佳，在0.040/1和0.1/1之间更佳，0.067/1最佳
4.如权利要求1-3中任一项所述的药物组合物，其特征在于，所述药物组合物包含雌激素或其酯类衍生物，选自17-β-雌二醇、雌酮、17-α-乙炔雌二醇和戊酸雌二醇或植物雌激素较佳，17-β-雌二醇更佳。
5.如权利要求1-4中任一项所述的药物组合物，其特征在于，至少孕酮悬浮在油中。
6.如权利要求1-5中任一项所述的药物组合物，其特征在于，所述药物组合物是软胶囊形式。
7.如权利要求1-6中任一项所述的药物组合物，其特征在于，每个剂量单位含有2mg-600mg微粉化孕酮，含有30mg-300mg微粉化孕酮较佳，含有100mg-200mg微粉化孕酮更佳。
8.制造如权利要求1-6中任一项所述的药物组合物的方法，其特征在于，所述方法包括以下连续步骤：
—把选自向日葵油、橄榄油、芝麻籽油、菜籽油、杏仁油的油与大豆卵磷脂混合，搅拌，以获得混合物；
—在上述混合物中加入微粉化孕酮，搅拌，以获得均匀悬液。
9.微粉化孕酮、大豆卵磷脂和至少一种选自向日葵油、橄榄油、芝麻籽油、菜籽油、杏仁油的油在制造用于治疗与孕酮分泌不足有关的生理状况的药用产品中的应用。
10.如权利要求9所述的应用，其特征在于，所述药用产品还包含雌激素或其酯类衍生物，选自17-β-雌二醇、雌酮、17-α-乙炔雌二醇和戊酸雌二醇或植物雌激素较佳，17-β-雌二醇更佳。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR01/14653 | 2001-11-13 | ||
| FR0114653A FR2832065B1 (fr) | 2001-11-13 | 2001-11-13 | Composition pharmaceutique a base de progesterone micronisee son procede de preparation et ses utilisations |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1585644A true CN1585644A (zh) | 2005-02-23 |
| CN1263453C CN1263453C (zh) | 2006-07-12 |
Family
ID=8869332
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB028224868A Expired - Lifetime CN1263453C (zh) | 2001-11-13 | 2002-11-13 | 基于微粉化孕酮的药物组合物及其制造方法和用途 |
Country Status (25)
| Country | Link |
|---|---|
| US (5) | US20030092691A1 (zh) |
| EP (1) | EP1443940B1 (zh) |
| KR (1) | KR100911790B1 (zh) |
| CN (1) | CN1263453C (zh) |
| AT (1) | ATE339958T1 (zh) |
| AU (1) | AU2002352334B2 (zh) |
| BR (1) | BRPI0214043B8 (zh) |
| CY (1) | CY1106293T1 (zh) |
| DE (1) | DE60214876T2 (zh) |
| DK (1) | DK1443940T3 (zh) |
| EA (1) | EA006550B1 (zh) |
| ES (1) | ES2272793T3 (zh) |
| FR (1) | FR2832065B1 (zh) |
| HK (1) | HK1064606A1 (zh) |
| HU (1) | HU229341B1 (zh) |
| IL (2) | IL161668A0 (zh) |
| MA (1) | MA27081A1 (zh) |
| NO (1) | NO335044B1 (zh) |
| NZ (1) | NZ532659A (zh) |
| OA (1) | OA12726A (zh) |
| PL (1) | PL206096B1 (zh) |
| PT (1) | PT1443940E (zh) |
| UA (1) | UA77451C2 (zh) |
| WO (1) | WO2003041720A1 (zh) |
| ZA (1) | ZA200403288B (zh) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011072509A1 (zh) * | 2009-12-14 | 2011-06-23 | 浙江爱生药业有限公司 | 黄体酮制剂组合物及其制备方法 |
| CN103957888A (zh) * | 2011-09-29 | 2014-07-30 | PLx制药公司 | 用于将药物沿胃肠道靶向释放的pH依赖性载体、其组合物及其制备和应用 |
| US11648257B2 (en) | 2020-03-26 | 2023-05-16 | Plx Opco Inc. | Pharmaceutical carriers capable of pH dependent reconstitution and methods for making and using same |
Families Citing this family (32)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2832065B1 (fr) * | 2001-11-13 | 2004-11-05 | Besins Int Belgique | Composition pharmaceutique a base de progesterone micronisee son procede de preparation et ses utilisations |
| ES2592504T3 (es) * | 2003-07-17 | 2016-11-30 | Banner Life Sciences, LLC | Preparaciones de liberación controlada |
| US8663681B2 (en) * | 2005-05-26 | 2014-03-04 | Teva Women's Health, Inc. | Oral dosage forms comprising progesterone and methods of making and using the same |
| US8828981B2 (en) * | 2007-02-06 | 2014-09-09 | George Creasy | Progesterone for the treatment or prevention of spontaneous preterm birth |
| AT12800U1 (de) * | 2007-11-05 | 2012-11-15 | Bayer Schering Pharma Ag | Pharmazeutisches Präparat zur Verwendung bei der oralen Kontrazeption von Frauen mit Laktoseintoleranz |
| FR2947178B1 (fr) | 2009-06-29 | 2012-07-06 | Effik | Composition pharmaceutique a base de progesterone micronisee et ses utilisations |
| US9375437B2 (en) | 2010-06-18 | 2016-06-28 | Lipocine Inc. | Progesterone containing oral dosage forms and kits |
| US8951996B2 (en) | 2011-07-28 | 2015-02-10 | Lipocine Inc. | 17-hydroxyprogesterone ester-containing oral compositions and related methods |
| AU2012307656B2 (en) * | 2011-09-15 | 2016-07-07 | Friulchem Spa | Compositions for oral administration to animals, production methods thereof and uses of same |
| US9301920B2 (en) | 2012-06-18 | 2016-04-05 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
| BR112014012444B1 (pt) | 2011-11-23 | 2021-12-14 | Therapeuticsmd, Inc | Composição farmacêutica compreendendo estradiol solubilizado, progesterona e um agente de solubilização, bem como usos desta para tratar um sintoma relacionado à menopausa em uma mulher |
| US20150196640A1 (en) | 2012-06-18 | 2015-07-16 | Therapeuticsmd, Inc. | Progesterone formulations having a desirable pk profile |
| US20130338122A1 (en) | 2012-06-18 | 2013-12-19 | Therapeuticsmd, Inc. | Transdermal hormone replacement therapies |
| US10806740B2 (en) | 2012-06-18 | 2020-10-20 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
| US10806697B2 (en) | 2012-12-21 | 2020-10-20 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
| US10568891B2 (en) | 2012-12-21 | 2020-02-25 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
| US10537581B2 (en) | 2012-12-21 | 2020-01-21 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
| US11246875B2 (en) | 2012-12-21 | 2022-02-15 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
| 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 |
| US10471072B2 (en) | 2012-12-21 | 2019-11-12 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
| JP2017516768A (ja) | 2014-05-22 | 2017-06-22 | セラピューティックスエムディー インコーポレーテッドＴｈｅｒａｐｅｕｔｉｃｓｍｄ， Ｉｎｃ． | 天然の併用ホルモン補充療法剤及び療法 |
| MX2016013693A (es) | 2014-07-29 | 2017-10-31 | Therapeuticsmd Inc | Crema transdermica. |
| BR112017027688A2 (pt) | 2015-06-22 | 2018-09-04 | Lipocine Inc | Composições orais que contêm éster de 17- hidroxiprogesterona e métodos relacionados |
| US10328087B2 (en) | 2015-07-23 | 2019-06-25 | Therapeuticsmd, Inc. | Formulations for solubilizing hormones |
| US10286077B2 (en) | 2016-04-01 | 2019-05-14 | Therapeuticsmd, Inc. | Steroid hormone compositions in medium chain oils |
| EP3435977A4 (en) | 2016-04-01 | 2019-10-16 | Therapeuticsmd, Inc. | PHARMACEUTICAL COMPOSITION OF STEROID HORMONE |
| EP3395332A1 (en) * | 2017-04-28 | 2018-10-31 | Chemo Research, S.L. | Hormone softgel capsules and a process for the preparation thereof |
| US10285998B1 (en) | 2018-04-04 | 2019-05-14 | The Menopause Method, Inc. | Composition and method to aid in hormone replacement therapy |
| US11576920B2 (en) | 2019-03-18 | 2023-02-14 | The Menopause Method, Inc. | Composition and method to aid in hormone replacement therapy |
| US11633405B2 (en) | 2020-02-07 | 2023-04-25 | Therapeuticsmd, Inc. | Steroid hormone pharmaceutical formulations |
| EP4389117A1 (en) | 2022-12-19 | 2024-06-26 | Besins Healthcare Distribution FZ-LLC | Progesterone formulation |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2408345A1 (fr) * | 1976-11-30 | 1979-06-08 | Besins Jean Louis | Nouvelle composition a action anti-conceptionnelle |
| JPS60258110A (ja) * | 1984-06-05 | 1985-12-20 | Daigo Eiyou Kagaku Kk | 静脈注射可能なプロゲステロン乳化注射液 |
| US5140021A (en) * | 1986-04-16 | 1992-08-18 | Genesis Systems Corporation | Method and dosage form for treatment of premenstrual syndrome |
| DK174724B1 (da) * | 1986-07-15 | 2003-10-06 | Wyeth Corp | Anvendelse af et præparat omfattende et østrogen og et progestogen til fremstilling af en dosisform til tilvejebringelse af hormonerstatningsterapi og kontraception til kvinder i præmenopausen samt pakning til tilvejebringelse af præparatet |
| IT1256386B (it) * | 1992-11-13 | 1995-12-04 | Luigi Boltri | Composizioni farmaceutiche comprendenti un farmaco,una sostanza polimerica reticolata,un olio ed un agente tensioattivo |
| ES2102793T3 (es) * | 1993-12-22 | 1997-08-01 | Oreal | Polvo cosmetico o dermatologico, su procedimiento de preparacion y utilizaciones. |
| FR2747042B1 (fr) * | 1996-04-05 | 1998-06-05 | Besins Iscovesco Lab | Medicament a base de progesterone et d'oestradiol |
| GB9608719D0 (en) * | 1996-04-26 | 1996-07-03 | Scherer Ltd R P | Pharmaceutical compositions |
| ES2152671T3 (es) * | 1996-05-01 | 2001-02-01 | Us Gov Health & Human Serv | Derivados de progesterona sustituidos en posicion 21 como nuevos agentes antiprogestacionales. |
| FR2777784B1 (fr) * | 1998-04-27 | 2004-03-19 | Arepa | Composition pharmaceutique a base d'estrogene et de progesterone |
| FR2832065B1 (fr) | 2001-11-13 | 2004-11-05 | Besins Int Belgique | Composition pharmaceutique a base de progesterone micronisee son procede de preparation et ses utilisations |
-
2001
- 2001-11-13 FR FR0114653A patent/FR2832065B1/fr not_active Expired - Fee Related
-
2002
- 2002-03-14 US US10/097,526 patent/US20030092691A1/en not_active Abandoned
- 2002-11-13 PL PL369131A patent/PL206096B1/pl unknown
- 2002-11-13 PT PT02788051T patent/PT1443940E/pt unknown
- 2002-11-13 WO PCT/FR2002/003879 patent/WO2003041720A1/fr active IP Right Grant
- 2002-11-13 BR BRPI0214043A patent/BRPI0214043B8/pt not_active IP Right Cessation
- 2002-11-13 US US10/495,242 patent/US7431941B2/en not_active Expired - Lifetime
- 2002-11-13 UA UA20040503542A patent/UA77451C2/uk unknown
- 2002-11-13 DE DE60214876T patent/DE60214876T2/de not_active Expired - Lifetime
- 2002-11-13 AT AT02788051T patent/ATE339958T1/de active
- 2002-11-13 EA EA200400668A patent/EA006550B1/ru unknown
- 2002-11-13 NZ NZ532659A patent/NZ532659A/en not_active IP Right Cessation
- 2002-11-13 KR KR1020047007199A patent/KR100911790B1/ko active IP Right Grant
- 2002-11-13 AU AU2002352334A patent/AU2002352334B2/en not_active Expired
- 2002-11-13 CN CNB028224868A patent/CN1263453C/zh not_active Expired - Lifetime
- 2002-11-13 IL IL16166802A patent/IL161668A0/xx unknown
- 2002-11-13 HU HU0401935A patent/HU229341B1/hu unknown
- 2002-11-13 ES ES02788051T patent/ES2272793T3/es not_active Expired - Lifetime
- 2002-11-13 EP EP02788051A patent/EP1443940B1/fr not_active Expired - Lifetime
- 2002-11-13 DK DK02788051T patent/DK1443940T3/da active
- 2002-11-13 OA OA1200400137A patent/OA12726A/fr unknown
-
2004
- 2004-04-29 IL IL161668A patent/IL161668A/en active IP Right Grant
- 2004-04-30 ZA ZA2004/03288A patent/ZA200403288B/en unknown
- 2004-05-04 MA MA27665A patent/MA27081A1/fr unknown
- 2004-05-14 NO NO20042002A patent/NO335044B1/no not_active IP Right Cessation
- 2004-10-04 HK HK04107577A patent/HK1064606A1/xx not_active IP Right Cessation
-
2006
- 2006-12-18 CY CY20061101808T patent/CY1106293T1/el unknown
-
2008
- 2008-02-27 US US12/071,822 patent/US7829115B2/en not_active Expired - Lifetime
-
2010
- 2010-11-01 US US12/916,795 patent/US20110135719A1/en not_active Abandoned
-
2012
- 2012-07-05 US US13/542,164 patent/US8435561B2/en not_active Expired - Lifetime
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011072509A1 (zh) * | 2009-12-14 | 2011-06-23 | 浙江爱生药业有限公司 | 黄体酮制剂组合物及其制备方法 |
| CN102091054B (zh) * | 2009-12-14 | 2014-04-16 | 浙江爱生药业有限公司 | 黄体酮制剂组合物及其制备方法 |
| CN103957888A (zh) * | 2011-09-29 | 2014-07-30 | PLx制药公司 | 用于将药物沿胃肠道靶向释放的pH依赖性载体、其组合物及其制备和应用 |
| US9730884B2 (en) | 2011-09-29 | 2017-08-15 | Plx Opco Inc. | pH dependent carriers for targeted release of pharmaceuticals along the gastrointestinal tract, compositions therefrom, and making and using same |
| US10179104B2 (en) | 2011-09-29 | 2019-01-15 | Plx Opco Inc. | PH dependent carriers for targeted release of pharmaceuticals along the gastrointestinal tract, compositions therefrom, and making and using same |
| US10646431B2 (en) | 2011-09-29 | 2020-05-12 | Plx Opco Inc. | PH dependent carriers for targeted release of pharmaceuticals along the gastrointestinal tract, compositions therefrom, and making and using same |
| US10786444B2 (en) | 2011-09-29 | 2020-09-29 | Plx Opco Inc. | PH dependent carriers for targeted release of pharmaceuticals along the gastrointestinal tract, compositions therefrom, and making and using same |
| US11648257B2 (en) | 2020-03-26 | 2023-05-16 | Plx Opco Inc. | Pharmaceutical carriers capable of pH dependent reconstitution and methods for making and using same |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1263453C (zh) | 基于微粉化孕酮的药物组合物及其制造方法和用途 | |
| CN1142774C (zh) | 降低细胞活性的方法和药物制剂 | |
| CN1835737A (zh) | 由雌二醇和胆固醇组成的稳定形状颗粒的制备方法 | |
| CN1382061A (zh) | 用于口服或局部给药的药物组合物 | |
| CN1868520A (zh) | 复方芦荟软胶囊制剂及其制备方法 | |
| CN1080113C (zh) | 1,2,4－苯并三嗪氧化物的口服凝胶胶囊配方 | |
| CN1843406A (zh) | 一种降血脂的药物及其制备方法 | |
| CN112807277A (zh) | 脂溶性维生素自乳化组合物及其制剂的制备方法 | |
| CN1319534C (zh) | 含番茄红素和辅酶q10的制剂及其制备方法 | |
| CN1827632A (zh) | 齐多夫定棕榈酸酯原料精制方法及制剂 | |
| CN101066256A (zh) | 含有独一味提取物的软胶囊 | |
| CN1644202A (zh) | 葫芦素液体型组方及其制剂 | |
| CN1799550A (zh) | 阿德福韦酯高效制剂及其制备方法 | |
| CN101066932A (zh) | 新的共轭亚油酸衍生物及它的制备方法与用途 | |
| CN1634015A (zh) | 含叶黄素和/或胡萝卜素亚麻酸的配方产品及其制备方法 | |
| CN1899389A (zh) | 一种用于预防和治疗女性衰老性疾病的药物组合物及其制剂的制备方法 | |
| CN118119379A (zh) | 组合物、其制备方法及其用于增加活性物质的溶解度的用途 | |
| EP3838346A1 (en) | Soft gelatin capsules comprising palmitoylethanolamide and alpha-lipoic acid | |
| CN101879212A (zh) | 复方核桃亚麻油脂肪乳静脉注射液及制造方法 | |
| CN1682735A (zh) | 含有氟桂利嗪的软胶囊 | |
| CN1765365A (zh) | 提高苷或苷元类药物在胃内吸收的方法及其组合物 | |
| CN1757637A (zh) | 一种ve烟酸酯原料精制方法 | |
| JP2001097877A (ja) | 崩壊性を改善した生薬含有組成物 | |
| CN1895221A (zh) | 一种口服、快速起效的镇痛药物 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| ASS | Succession or assignment of patent right |
Owner name: BESINS HEALTHCARE LUXEMBOURG S.A.R.L. Free format text: FORMER OWNER: BESINS MANUFACTURING BELGIUM S.A. Effective date: 20120401 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| C56 | Change in the name or address of the patentee |
Owner name: BESINS MANUFACTURING BELGIUM S.A. Free format text: FORMER NAME: BESINS INTERNAT BELGIQUE |
|
| CP03 | Change of name, title or address |
Address after: Brussels Patentee after: Belgian manufacturing Co. Address before: Belgium Pedro Henry Bos Patentee before: Besins International Belgique |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20120401 Address after: Luxemburg Luxemburg Patentee after: Luxemburg medical and health care LLC Address before: Brussels Patentee before: Belgian manufacturing Co. |
|
| CX01 | Expiry of patent term |
Granted publication date: 20060712 |
|
| CX01 | Expiry of patent term |