CN1553815A - Pharmaceutical formulation for the intramuscular administration of fulvestrant - Google Patents
Pharmaceutical formulation for the intramuscular administration of fulvestrant Download PDFInfo
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- CN1553815A CN1553815A CNA028171888A CN02817188A CN1553815A CN 1553815 A CN1553815 A CN 1553815A CN A028171888 A CNA028171888 A CN A028171888A CN 02817188 A CN02817188 A CN 02817188A CN 1553815 A CN1553815 A CN 1553815A
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- fulvestrant
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- ethanol
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- VWUXBMIQPBEWFH-WCCTWKNTSA-N Fulvestrant Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 title claims abstract description 185
- 229960002258 fulvestrant Drugs 0.000 title claims abstract description 184
- 239000008194 pharmaceutical composition Substances 0.000 title abstract description 6
- 238000007918 intramuscular administration Methods 0.000 title description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 289
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims abstract description 37
- WBHHMMIMDMUBKC-QJWNTBNXSA-M ricinoleate Chemical compound CCCCCC[C@@H](O)C\C=C/CCCCCCCC([O-])=O WBHHMMIMDMUBKC-QJWNTBNXSA-M 0.000 claims abstract description 35
- 229940066675 ricinoleate Drugs 0.000 claims abstract description 35
- 238000002347 injection Methods 0.000 claims abstract description 18
- 239000007924 injection Substances 0.000 claims abstract description 18
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 303
- 238000002360 preparation method Methods 0.000 claims description 294
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 claims description 212
- 235000019441 ethanol Nutrition 0.000 claims description 156
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- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical compound CCCCCCC(O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(O)CCCCCC)COC(=O)CCCCCCC\C=C/CC(O)CCCCCC ZEMPKEQAKRGZGQ-AAKVHIHISA-N 0.000 claims description 92
- 238000010255 intramuscular injection Methods 0.000 claims description 39
- 239000007927 intramuscular injection Substances 0.000 claims description 39
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- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 claims description 4
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- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 claims description 4
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- 229940074928 isopropyl myristate Drugs 0.000 claims description 3
- XUGNVMKQXJXZCD-UHFFFAOYSA-N isopropyl palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC(C)C XUGNVMKQXJXZCD-UHFFFAOYSA-N 0.000 claims description 3
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- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 abstract description 4
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- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 10
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- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
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- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 2
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- ZEMPKEQAKRGZGQ-VBJOUPRGSA-N triricinolein Chemical compound CCCCCC[C@@H](O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/C[C@H](O)CCCCCC)COC(=O)CCCCCCC\C=C/C[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-VBJOUPRGSA-N 0.000 description 1
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- 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
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
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- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
The invention relates to a sustained release pharmaceutical formulation adapted for administration by injection containing the compound fulvestrant, 7alpha-[9-(4,4,5,5,5-pentafluoropentylsulphiny1)nony1]oestra-1,3,5(10)-triene-3,17beta-diol, at concentration of at least 100mg/ml in solution in a ricinoleate vehicle which additionally comprises at least one alcohol and a non-aqueous ester solvent which is miscible in the ricinoleate vehicle.
Description
The present invention relates to be applicable to sustained release pharmaceutical formulation by drug administration by injection, described pharmaceutical preparation inclusion compound fulvestrant, promptly 7 α-[9-(4; 4; 5,5,5-five fluorine amyl group sulfinyls) nonyl] female-1; 3; 5 (10)-triolefins-3,17-isoallopregnane-3 is as the solution in the ricinoleate carrier; the concentration of chemical compound fulvestrant is at least 100mg/ml, and comprises at least a pure and mild a kind of non-aqueous ester solvent that can be miscible with described ricinoleate carrier in addition.
The blocking-up estrogen action is very important to treating many optimum and virulent mastopathy and genital diseases.Premenopausal women achieves the above object surgical operation, radiotherapy or the measure of internal medicine medicine of ovary defunctionalization by execution, and the postmenopausal women then uses aromatase inhibitor.
The alternative medicine of blocking-up estrogen action is with estrogen antagonist medicine antagonism estrogen action.These medicines combine and competition with estrogen receptor (ER) in being present in estrogen response histiocyte nuclear.Conventional on-steroidal estrogen antagonist medicine (as tamoxifen) effective competition ER combination, but its curative effect usually is subject to the part agonism that they presented, and cause to block fully estrogen-mediated activity (Furr and Jordan, Pharmacology ﹠amp; Therapeutics, 25:127-206,1984; May and Westley, J Biol Chem 262:15894-15899,1987).
Because on-steroidal estrogen antagonist medicine may have agonist properties, impel thus and seek novel chemical compound, this compounds should combine with ER with high-affinity, but does not activate replying of any normal transcription hormone, thereby does not have estrogen action.This quasi-molecule will be " pure " estrogen antagonist medicine, with the similar part of tamoxifen tangible difference be arranged, and can eliminate estrogenic Nutrition fully.This compounds is referred to as estrogen receptor downward modulation regulator (E.R.D).Design and the ultimate principle of testing novel pure antiestrogen medicine are seen Bowler etc. 1989, Wakeling1990a, 1990b, 1990c; Wakeling and Bowler 1987,1988.
At 7 α bit strips the estradiol steroid analog of alkyl sulfenyl base side chain being arranged is the examples of compounds (Bowler etc. 1989) that the first kind does not have estrogen activity.Chemical compound 7 α-[9-(4 to have selected one of them; 4; 5; 5; 5-five fluorine amyl group sulfinyls) nonyl] female-1,3,5-(10)-triolefin-3; 17-isoallopregnane-3 has carried out intensive research, and its reason is that this chemical compound has pure estrogen antagonist activity and its estrogen antagonist usefulness obviously is better than other existing estrogen antagonist medicine.About 7 α-[9-(4,4,5; 5,5-five fluorine amyl group sulfinyls) nonyl] female-1,3; 5 (10)-triolefins-3, the results of in vitro studies of 17-isoallopregnane-3 and early stage clinical experience impel this medicinal do treatment estrogen of exploitation to rely on disease (as breast carcinoma and some optimum gynaecopathia) medicine.
7 α-[9-(4,4,5,5,5-five fluorine amyl group sulfinyls) nonyl] is female-1,3,5 (10)-triolefins-3, and the international generic name of 17-isoallopregnane-3 or ICI 182,780 is a fulvestrant, uses this title hereinafter.When mentioning fulvestrant, should comprise its pharmaceutically acceptable salt and its any possible solvate.
Fulvestrant is similar to estradiol in conjunction with the affinity of ER, and at the external growth stimulation of blocking estradiol to the human breast cancer cell fully; In this respect, it is stronger and more effective than tamoxifen.Fulvestrant is blocked estradiol fully at rat, mice, the intravital uterotrophic effect of monkey, also blocks the uterus nutritional activities of tamoxifen.
Because fulvestrant does not have clinical effective estrogen antagonist medicine such as tamoxifen or the distinctive estrogen-like stimulation activity of toremifene fully, so its therapeutic activity strengthens, it is faster, more complete or the persistent period is longer that characteristic shows as tumor regression; Incidence rate reduction of treatment resistance and tumor are soaked the power of attacking and are reduced.
In perfecting the adult rat body, give fulvestrant can not damage the dosage that rings bone density or can not cause gonadotrophin secretion to increase, degenerated in the uterus.If also like this in human body, then these results of study are of crucial importance clinically.Bone density reduces to have limited endometriosis is continued to adopt the time of blocking the estrogen action therapy.Fulvestrant is not blocked hypothalamic ER.The blocking-up estrogen action also causes or aggravates hot flush and other menopausal symptoms; Fulvestrant will can not produce these effects, because it can not pass through blood brain barrier.
European Patent Application No. 0138504 disclosed some steroid derivatives is effective estrogen antagonist medicine.The disclosure comprises the data that relates to the steroid derivatives preparation.Especially it is female-1,3 to disclose chemical compound 7 α-[9-(4,4,5,5,5-five fluorine amyl group sulfinyls) nonyl] in embodiment 35,5 (10)-triolefins-3, and 17-isoallopregnane-3 has specifically been enumerated this chemical compound in claim 4.The chemical compound that it also discloses that invention can provide use with pharmaceutical composition (steroid derivatives and the pharmaceutically acceptable diluent or carrier that comprise this invention) form.Point out that wherein described compositions can be the form that is fit to oral or parenterai administration.
The same with other steroid type chemical compound, some physical property of fulvestrant makes them be difficult to preparation.Even compare with other steroid, fulvestrant also is lipophilic especially molecule, and its water solublity is extremely low, approximately 10ngml-1 (being the solute estimator in water/solvent mixture, because can not the so low solute amount of measurement in the water only arranged).
At present, many business-like steroid release injectable preparations are arranged.General these preparations use oil to make solvent, and wherein may add excipient.
At US 5,183, among 814 embodiment 3, the oily injection preparation of fulvestrant has been described, described preparation contains the Oleum Ricini (making the volume of making solution is 1ml) of fulvestrant 50mg, benzyl alcohol 400mg and q.s.At US 5,183, the described preparation of the industrial-scale production described in 814 relates to use high concentration alcohol.Therefore, need to reduce the determining alcohol in the fulvestrant preparation, will prevent fulvestrant from preparation, to precipitate simultaneously and separate out.
Following table has been listed the dissolubility of fulvestrant in various different solvents.
The dissolubility of fulvestrant
| Solvent | Dissolubility (mg/ml, 25 ℃) |
| Water | ????0.001 |
| Oleum Arachidis hypogaeae semen | ????0.45 |
| Oleum sesami | ????0.58 |
| Oleum Ricini | ????20 |
| ????Miglyol?810 | ????3.06 |
| ????Miglyol?812 | ????2.72 |
| Ethyl oleate | ????1.25 |
| Benzyl benzoate | ????6.15 |
| Isopropyl myristate | ????0.80 |
| Span 85 (surfactant) | ????3.79 |
| Ethanol | ????＞200 |
| Benzyl alcohol | ????＞200 |
As seen from the above table, fulvestrant is obvious than easier dissolving in other any test oil in Oleum Ricini.Known Oleum Ricini has bigger solvability to steroid, its reason is that castor oil acid has great amount of hydroxy group, and castor oil acid is the main fatty acid composition-referring to (J.Pharm.Sci. such as Riffkin, (1964) of the triglyceride that exists in the Oleum Ricini, 53,891).
We early stage application PCT/GB01/00049, WO01/51056 have described some fulvestrant preparation, and fulvestrant concentration is 50mg/ml in the most preferred preparation.This application disclose a kind of dissolubility up to the preparation of 102mg/ml referring to last preparation in the table 3, its every volume is that the preparation of carrier contains 15% weight ethanol, 15%% weight benzyl alcohol, 15% weight benzyl benzoate with the ricinoleate.But, still exist needs, so that with high dose or low interval administration to other preparations that contain the high concentration fulvestrant.
Another aspect of the present invention provides a kind of pharmaceutical preparation that is suitable for intramuscular injection, described pharmaceutical preparation comprises 100mg/ml or above fulvestrant, 10% weight/volume preparations carrier or above pharmaceutically acceptable alcohol, 5% weight/volume preparations carrier or above pharmaceutically-acceptable non-aqueous ester solvent and 5% weight/volume preparations carrier or above ricinoleate excipient, condition is the ethanol that described preparations carrier comprises at least 5% weight/volume preparations carrier, and described preparation is not following preparation: the fulvestrant that reaches 102mg/ml, the ethanol of 15% weight/volume preparations carrier, the benzyl alcohol of 15% weight/volume preparations carrier, the benzyl benzoate of 15% weight/volume preparations carrier and 30% weight/volume preparations carrier or above ricinoleate excipient.
A kind of pharmaceutical preparation that preferably is suitable for intramuscular injection, described pharmaceutical preparation comprises 105mg/ml or above fulvestrant, 10% weight/volume preparations carrier or above pharmaceutically acceptable alcohol, 5% weight/volume preparations carrier or above pharmaceutically-acceptable non-aqueous ester solvent and 5% weight/volume preparations carrier or above ricinoleate excipient, condition is the ethanol that described preparation comprises at least 5% weight/volume preparations carrier.
A kind of preferred pharmaceutical preparation that is suitable for intramuscular injection, described pharmaceutical preparation comprises 110mg/ml or above fulvestrant, 10% weight/volume preparations carrier or above pharmaceutically acceptable alcohol, 5% weight/volume preparations carrier or above pharmaceutically-acceptable non-aqueous ester solvent and 5% weight/volume preparations carrier or above ricinoleate excipient, condition is the ethanol that described preparations carrier comprises at least 5% weight/volume preparations carrier.
A kind of preferred pharmaceutical preparation that is suitable for intramuscular injection, described pharmaceutical preparation comprises 115mg/ml or above fulvestrant, 10% weight/volume preparations carrier or above pharmaceutically acceptable alcohol, 5% weight/volume preparations carrier or above pharmaceutically-acceptable non-aqueous ester solvent and 5% weight/volume preparations carrier or above ricinoleate excipient, condition is the ethanol that described preparations carrier comprises at least 5% weight/volume preparations carrier.
A kind of preferred pharmaceutical preparation that is suitable for intramuscular injection, described pharmaceutical preparation comprises 120mg/ml or above fulvestrant, 10% weight/volume preparations carrier or above pharmaceutically acceptable alcohol, 5% weight/volume preparations carrier or above pharmaceutically-acceptable non-aqueous ester solvent and 5% weight/volume preparations carrier or above ricinoleate excipient, condition is the ethanol that described preparations carrier comprises at least 5% weight/volume preparations carrier.
A kind of preferred pharmaceutical preparation that is suitable for intramuscular injection, described pharmaceutical preparation comprises 130mg/ml or above fulvestrant, 15% weight/volume preparations carrier or above pharmaceutically acceptable alcohol, 5% weight/volume preparations carrier or above pharmaceutically-acceptable non-aqueous ester solvent and 5% weight/volume preparations carrier or above ricinoleate excipient, condition is the ethanol that described preparations carrier comprises at least 5% weight/volume preparations carrier.
A kind of preferred pharmaceutical preparation that is suitable for intramuscular injection, described pharmaceutical preparation comprises 140mg/ml or above fulvestrant, 15% weight/volume preparations carrier or above pharmaceutically acceptable alcohol, 12.5% weight/volume preparations carrier or above pharmaceutically-acceptable non-aqueous ester solvent and 5% weight/volume preparations carrier or above ricinoleate excipient, condition is the ethanol that described preparations carrier comprises at least 10% weight/volume preparations carrier.
A kind of preferred pharmaceutical preparation that is suitable for intramuscular injection, described pharmaceutical preparation comprises 150mg/ml or above fulvestrant, 15% weight/volume preparations carrier or above pharmaceutically acceptable alcohol, 17.5% weight/volume preparations carrier or above pharmaceutically-acceptable non-aqueous ester solvent and 5% weight/volume preparations carrier or above ricinoleate excipient, condition is the ethanol that described preparations carrier comprises at least 10% weight/volume preparations carrier.
Another aspect of the present invention provides the aforesaid preparation that does not comprise minimum ethanol content condition.For example, become at the preparation described in the preceding paragraph: a kind of pharmaceutical preparation that is suitable for intramuscular injection, described pharmaceutical preparation comprises 150mg/ml or above fulvestrant, 15% weight/volume preparations carrier or above pharmaceutically acceptable alcohol, 17.5% weight/volume preparations carrier or above pharmaceutically-acceptable non-aqueous ester solvent and 5% weight/volume preparations carrier or above ricinoleate excipient.
One side more of the present invention provides a kind of fulvestrant dissolubility that is suitable for intramuscular injection to be at least the pharmaceutical preparation of Ymg/ml, and described pharmaceutical preparation comprises:
100mg/ml or above fulvestrant;
Every volume of formulation carrier contains 5% weight/volume or above Oleum Ricini; With
By formula Y=-29.77+5.44xETOH+2.38xBA+1.57xBB definite ethanol (ETOH), benzyl alcohol (BA), the benzyl benzoate (BB) of following amount (in % weight/volume preparations carrier) at least, wherein x is at least 100, ETOH is at least 5, and BA is at least 5, and BB is at least 5.
A kind of preferred drug substances is that wherein Y is selected from 105,110,115,120,125,130,135,140,145,150,155,160,170,180,190 and 200 preparation.
A kind of preferred pharmaceutical preparation is that wherein Y is selected from 120,125,130,135,140,145,150,155,160,170,180,190 and 200 preparation.
A kind of preferred pharmaceutical preparation is that wherein Y is selected from 150,155,160,170,180,190 and 200 preparation.
A kind of preferred pharmaceutical preparation is that wherein Y is selected from 150,155,160,170,180,190 and 200 preparation and described preparation and comprises the fulvestrant of 150mg/ml at least.
A kind of preferred pharmaceutical preparation is that wherein Y is that 200 preparation and described preparation comprise the fulvestrant of 200mg/ml at least.
One side more of the present invention provides a kind of fulvestrant dissolubility of intramuscular injection that is applicable to be at least the pharmaceutical preparation of 100mg/ml, and described pharmaceutical preparation comprises:
100mg/ml or above fulvestrant;
Every volume of formulation carrier contains 5% weight/volume or above Oleum Ricini; With
By formula Y=-29.77+5.44xETOH+2.38xBA+1.57xBB definite ethanol (ETOH), benzyl alcohol (BA), the benzyl benzoate (BB) of following amount (in % weight/volume preparations carrier) at least; And condition is not comprise following preparation: up to the fulvestrant of 102mg/ml, the ethanol of 15% weight/volume preparations carrier, the benzyl alcohol of 15% weight/volume preparations carrier, the benzyl benzoate of 15% weight/volume preparations carrier and 30% weight/volume preparations carrier or above Oleum Ricini.
Also one side of the present invention provides a kind of pharmaceutical preparation of the fulvestrant of 100mg/ml concentration at least that comprises, wherein said preparation is suitable for intramuscular injection in human body, and in the treatment produce effects blood plasma fulvestrant concentration that can in human body, obtain at least 2 months after the injection, condition is not comprise following preparation: up to the fulvestrant of 102mg/ml, the ethanol of 15% weight/volume preparations carrier, the benzyl alcohol of 15% weight/volume preparations carrier, the benzyl benzoate of 15% weight/volume preparations carrier and 30% weight/volume preparations carrier or above ricinoleate excipient.
Of the present inventionly also on the one hand provide a kind of pharmaceutical preparation that comprises fulvestrant again, wherein said preparation is suitable for intramuscular injection in human body, and in the treatment produce effects blood plasma fulvestrant concentration that can in human body, obtain at least 2 months after the injection.
The present invention also provides a kind of pharmaceutical preparation of the fulvestrant of 100mg/ml concentration at least that comprises, wherein said preparation is suitable for intramuscular injection in human body, and in the treatment produce effects blood plasma fulvestrant concentration that can in human body, obtain at least 2 months after the injection.
The present invention also provides a kind of pharmaceutical preparation of the fulvestrant of 150mg/ml concentration at least that comprises, wherein said preparation is suitable for intramuscular injection in human body, and in the treatment produce effects blood plasma fulvestrant concentration that can in human body, obtain at least 2 months after the injection.
The present invention also provides a kind of pharmaceutical preparation of the fulvestrant of 200mg/ml concentration at least that comprises again, and wherein said preparation is suitable for intramuscular injection in human body, and in the treatment produce effects blood plasma fulvestrant concentration that can in human body, obtain at least 2 months after the injection.
The present invention provides a kind of pharmaceutical preparation of the fulvestrant of 300mg/ml concentration at least that comprises in addition again, and wherein said preparation is suitable for intramuscular injection in human body, and in the treatment produce effects blood plasma fulvestrant concentration that can in human body, obtain at least 2 months after the injection.
One aspect of the present invention provides following any pharmaceutical preparation, and described preparation comprises approximately
i)
The ethanol of 10% weight/volume
The benzyl alcohol of 20% weight/volume
The benzyl benzoate of 15% weight/volume
The fulvestrant of the final preparation 500-555mg of every 5ml
Oleum Ricini with surplus;
ii)
The ethanol of 10% weight/volume
The benzyl alcohol of 20% weight/volume
The benzyl benzoate of 30% weight/volume
The fulvestrant of the final preparation 500-700mg of every 5ml
Oleum Ricini with surplus;
iii)
The ethanol of 10% weight/volume
The benzyl alcohol of 20% weight/volume
The benzyl benzoate of 50% weight/volume
The fulvestrant of the final preparation 500-750mg of every 5ml
Oleum Ricini with surplus;
iv)
The ethanol of 20% weight/volume
The benzyl alcohol of 20% weight/volume
The benzyl benzoate of 30% weight/volume
The fulvestrant of the final preparation 500-1175mg of every 5ml
Oleum Ricini with surplus;
v)
The ethanol of 15% weight/volume
The benzyl alcohol of 10% weight/volume
The benzyl benzoate of 50% weight/volume
The fulvestrant of the final preparation 500-810mg of every 5ml
Oleum Ricini with surplus;
vi)
The ethanol of 15% weight/volume
The benzyl alcohol of 20% weight/volume
The benzyl benzoate of 50% weight/volume
The fulvestrant of the final preparation 500mg of every 5ml
Oleum Ricini with surplus;
vii)
The ethanol of 15% weight/volume
The benzyl alcohol of 20% weight/volume
The benzyl benzoate of 30% weight/volume
The fulvestrant of the final preparation 500-630mg of every 5ml
Oleum Ricini with surplus;
viii)
The ethanol of 10% weight/volume
The benzyl alcohol of 20% weight/volume
The benzyl benzoate of 50% weight/volume
The fulvestrant of the final preparation 750mg of every 5ml
Oleum Ricini with surplus;
ix)
The ethanol of 20% weight/volume
The benzyl alcohol of 20% weight/volume
The benzyl benzoate of 30% weight/volume
The fulvestrant of the final preparation 750mg of every 5ml
Oleum Ricini with surplus;
x)
The ethanol of 15% weight/volume
The benzyl alcohol of 10% weight/volume
The benzyl benzoate of 50% weight/volume
The fulvestrant of the final preparation 750mg of every 5ml
Oleum Ricini with surplus;
xi)
The ethanol of 9% weight/volume
The benzyl alcohol of 19% weight/volume
The benzyl benzoate of 47% weight/volume
The fulvestrant of the final preparation 700mg of every 5ml
Oleum Ricini with surplus;
xii)
The ethanol of 14% weight/volume
The benzyl alcohol of 19% weight/volume
The benzyl benzoate of 48% weight/volume
The fulvestrant of the final preparation 700mg of every 5ml
Oleum Ricini with surplus;
xiii)
The ethanol of 15% weight/volume
The benzyl alcohol of 20% weight/volume
The benzyl benzoate of 45% weight/volume
The fulvestrant of the final preparation 750mg of every 5ml
Oleum Ricini with surplus;
xiv)
The ethanol of 9% weight/volume
The benzyl alcohol of 19% weight/volume
The benzyl benzoate of 47% weight/volume
The fulvestrant of the final preparation 750mg of every 5ml
Oleum Ricini with surplus;
xv)
The ethanol of 19% weight/volume
The benzyl alcohol of 19% weight/volume
The benzyl benzoate of 28% weight/volume
The fulvestrant of the final preparation 750mg of every 5ml
Oleum Ricini with surplus;
xvi)
The ethanol of 14% weight/volume
The benzyl alcohol of 9% weight/volume
The benzyl benzoate of 47% weight/volume
The fulvestrant of the final preparation 750mg of every 5ml
Oleum Ricini with surplus;
xvii)
The ethanol of 14% weight/volume
The benzyl alcohol of 19% weight/volume
The benzyl benzoate of 47% weight/volume
The fulvestrant of the final preparation 750mg of every 5ml
Oleum Ricini with surplus;
xviii)
The ethanol of 10% weight/volume
The benzyl alcohol of 20% weight/volume
The benzyl benzoate of 45% weight/volume
The fulvestrant of the final preparation 750mg of every 5ml
Oleum Ricini with surplus;
xix)
The ethanol of 15% weight/volume
The benzyl alcohol of 10% weight/volume
The benzyl benzoate of 45% weight/volume
The fulvestrant of the final preparation 750mg of every 5ml
Oleum Ricini with surplus;
xx)
The ethanol of 20% weight/volume
The benzyl alcohol of 20% weight/volume
The benzyl benzoate of 25% weight/volume
The fulvestrant of the final preparation 750mg of every 5ml
Oleum Ricini with surplus;
xxi)
The ethanol of 10% weight/volume
The benzyl alcohol of 30% weight/volume
The benzyl benzoate of 25% weight/volume
The fulvestrant of the final preparation 750mg of every 5ml
Oleum Ricini with surplus;
xxii)
The ethanol of 10% weight/volume
The benzyl alcohol of 25% weight/volume
The benzyl benzoate of 30% weight/volume
The fulvestrant of the final preparation 750mg of every 5ml
Oleum Ricini with surplus;
xxiii)
The ethanol of 10% weight/volume
The benzyl alcohol of 30% weight/volume
The benzyl benzoate of 30% weight/volume
The fulvestrant of the final preparation 750mg of every 5ml
Oleum Ricini with surplus;
xxiv)
The ethanol of 15% weight/volume
The benzyl alcohol of 25% weight/volume
The benzyl benzoate of 30% weight/volume
The fulvestrant of the final preparation 750mg of every 5ml
Oleum Ricini with surplus;
xxv)
The ethanol of 15% weight/volume
The benzyl alcohol of 25% weight/volume
The benzyl benzoate of 25% weight/volume
The fulvestrant of the final preparation 750mg of every 5ml
Oleum Ricini with surplus; With
xxvi)
The ethanol of 15% weight/volume
The benzyl alcohol of 20% weight/volume
The benzyl benzoate of 30% weight/volume
The fulvestrant of the final preparation 750mg of every 5ml
Oleum Ricini with surplus.
Term herein " comprise approximately " when being meant formulated in the preparation numerical value of each component can change to satisfy the production technology specification that is run into independently by those skilled in the art.In general this means to add deduct 5%, more preferably add deduct 4%, more preferably add deduct 3%, more preferably add deduct 2%, more preferably add deduct 1%.In an embodiment preferred, to compare with other compositions, levels of drugs can be done bigger variation.For example:
| Medicine (± %) | Other compositions (± %) |
| ????5 | 4,3,2 or 1 |
| ????4 | 3,2 or 1 |
| ????3 | 2 or 1 |
| ????2 | ????1 |
Each preparation described in this can comprise other excipient that is usually used in formulation art, comprises for example antioxidant, coloring agent or surfactant.
Another aspect of the present invention provides following any pharmaceutical preparation:
i)
The ethanol of 10% weight/volume
The benzyl alcohol of 20% weight/volume
The benzyl benzoate of 15% weight/volume
The fulvestrant of the final preparation 500-555mg of every 5ml
Oleum Ricini with surplus;
ii)
The ethanol of 10% weight/volume
The benzyl alcohol of 20% weight/volume
The benzyl benzoate of 30% weight/volume
The fulvestrant of the final preparation 500-700mg of every 5ml
Oleum Ricini with surplus;
iii)
The ethanol of 10% weight/volume
The benzyl alcohol of 20% weight/volume
The benzyl benzoate of 50% weight/volume
The fulvestrant of the final preparation 500-750mg of every 5ml
Oleum Ricini with surplus;
iv)
The ethanol of 20% weight/volume
The benzyl alcohol of 20% weight/volume
The benzyl benzoate of 30% weight/volume
The fulvestrant of the final preparation 500-1175mg of every 5ml
Oleum Ricini with surplus;
v)
The ethanol of 15% weight/volume
The benzyl alcohol of 10% weight/volume
The benzyl benzoate of 50% weight/volume
The fulvestrant of the final preparation 500-810mg of every 5ml
Oleum Ricini with surplus;
vi)
The ethanol of 15% weight/volume
The benzyl alcohol of 20% weight/volume
The benzyl benzoate of 50% weight/volume
The fulvestrant of the final preparation 500mg of every 5ml
Oleum Ricini with surplus;
vii)
The ethanol of 15% weight/volume
The benzyl alcohol of 20% weight/volume
The benzyl benzoate of 30% weight/volume
The fulvestrant of the final preparation 500-630mg of every 5ml
Oleum Ricini with surplus;
viii)
The ethanol of 10% weight/volume
The benzyl alcohol of 20% weight/volume
The benzyl benzoate of 50% weight/volume
The fulvestrant of the final preparation 750mg of every 5ml
Oleum Ricini with surplus;
ix)
The ethanol of 20% bulking value
The benzyl alcohol of 20% weight/volume
The benzyl benzoate of 30% weight/volume
The fulvestrant of the final preparation 750mg of every 5ml
Oleum Ricini with surplus;
x)
The ethanol of 15% weight/volume
The benzyl alcohol of 10% weight/volume
The benzyl benzoate of 50% weight/volume
The fulvestrant of the final preparation 750mg of every 5ml
Oleum Ricini with surplus.
A kind of preferably pharmaceutical preparation described in this is the preparation that its pharmaceutically acceptable alcohol is ethanol and benzyl alcohol mixture.
A kind of preferably pharmaceutical preparation described in this is the preparation that its pharmaceutically-acceptable non-aqueous ester solvent is selected from benzyl benzoate, ethyl oleate, isopropyl myristate, isopropyl palmitate or their any mixture.
A kind of preferably pharmaceutical preparation described in this is the preparation that its pharmaceutically-acceptable non-aqueous ester solvent is a benzyl benzoate.
A kind of preferably pharmaceutical preparation described in this is the preparation that its ricinoleate excipient is an Oleum Ricini.
One aspect of the present invention provides a kind of pharmaceutical preparation that is suitable for intramuscular injection, described pharmaceutical preparation comprises 100mg/ml or above fulvestrant, 10% weight/volume pharmaceutical preparation or above pharmaceutically acceptable alcohol, 5% weight/volume pharmaceutical preparation or above pharmaceutically-acceptable non-aqueous ester solvent and 5% weight/volume pharmaceutical preparation or above ricinoleate excipient, condition is:
A) described pharmaceutical preparation comprises the ethanol of at least 5% weight/volume pharmaceutical preparation;
B) if described pharmaceutically acceptable alcohol is less than or equal to 13%, so described pharmaceutical preparation must comprise at least 50% non-aqueous ester solvent; And
C) if described pharmaceutically acceptable alcohol still is less than or equal to 25% more than 20%, so described pharmaceutical preparation must comprise at least 30% non-aqueous ester solvent;
And do not comprise following pharmaceutical preparation: up to the fulvestrant of 102mg/ml, the ethanol of 15% weight/volume preparations carrier, the benzyl alcohol of 15% weight/volume preparations carrier, the benzyl benzoate of 15% weight/volume preparations carrier and 30% weight/volume preparations carrier or above ricinoleate excipient.
A kind of pharmaceutical preparation that preferably is suitable for intramuscular injection is the preparation that comprises following composition: 100mg/ml or above fulvestrant, 20% weight/volume pharmaceutical preparation or above pharmaceutically acceptable alcohol, 5% weight/volume pharmaceutical preparation or above pharmaceutically-acceptable non-aqueous ester solvent and 5% weight/volume pharmaceutical preparation or above ricinoleate excipient, condition is:
A) described pharmaceutical preparation comprises the ethanol of at least 10% weight/volume pharmaceutical preparation;
B) if described pharmaceutically acceptable alcohol is 20%, so described pharmaceutical preparation must comprise at least 22.5% non-aqueous ester solvent; And
C) if described pharmaceutically acceptable alcohol still is less than or equal to 25% more than 20%, so described pharmaceutical preparation must comprise at least 15% non-aqueous ester solvent;
And do not comprise following pharmaceutical preparation: up to the fulvestrant of 102mg/ml, the ethanol of 15% weight/volume preparations carrier, the benzyl alcohol of 15% weight/volume preparations carrier, the benzyl benzoate of 15% weight/volume preparations carrier and 30% weight/volume preparations carrier or above ricinoleate excipient.
A kind of preferred pharmaceutical preparation that is suitable for intramuscular injection is the preparation that comprises following composition: 150mg/ml or above fulvestrant, 25% weight/volume pharmaceutical preparation or above pharmaceutically acceptable alcohol, 30% weight/volume pharmaceutical preparation or above pharmaceutically-acceptable non-aqueous ester solvent and 5% weight/volume pharmaceutical preparation or above ricinoleate excipient, condition is:
A) described pharmaceutical preparation comprises the ethanol of at least 10% weight/volume pharmaceutical preparation;
B) if described pharmaceutically acceptable alcohol is less than 30%, so described pharmaceutical preparation must comprise at least 35% non-aqueous ester solvent.
A kind of particularly preferred pharmaceutical preparation is to comprise that the dissolubility of 15% weight/volume or following ethanol and fulvestrant is at least the preparation of 155mg/ml.
Another aspect of the present invention provides a kind of unit dosage forms of described pharmaceutical preparation in this, and wherein the cumulative volume of preparation is 6ml or following.
Another aspect of the present invention provides a kind of each claim as described above the defined pharmaceutical preparation that is used for the suitable intramuscular injection of therapeutic treatment.
Another aspect of the present invention provide fulvestrant preparation in this definition be used for treating purposes in the pharmaceutical preparation of optimum or malignant galactophore or genital diseases.
Another aspect of the present invention provides fulvestrant, and each claim defines the purposes that is used for treating in optimum or pernicious people's mammary gland or the genital diseases pharmaceutical preparation preparing as described above, and the dosing interval of described pharmaceutical preparation was at least for 8 weeks.
Another aspect of the present invention provide a kind of comprise each claim as described above the aseptic injection pipe or the phial of defined pharmaceutical preparation.
Used term " pharmaceutical preparation " is meant that medicine adds the combination of preparations carrier in this.Term " final preparation " is all identical with " pharmaceutical preparation " implication with " final pharmaceutical preparation ".
Used term " preparations carrier " is meant the combination (and therefore not comprising medicine itself) of all excipient that are used for described pharmaceutical preparation in this.
Because following reason must be paid attention to the difference between pharmaceutical preparation and preparations carrier.For example, if the concentration of excipient " A " (y% weight/volume) is the concentration that records in preparations carrier, after adding, medicine will cause the concentration of excipient A in final pharmaceutical preparation to be lower than concentration y so.Concentration with " preparations carrier " expression to be converted to the concentration in " final pharmaceutical preparation ", must use displacement value.
" displacement value " is defined as replacing the weight portion of the chemical compound of a weight portion preparations carrier.Displacement value can be used for determining the amount of the metathetical preparations carrier of combined thing.Displacement value is used to calculate the definite composition in the final preparation of excipient ratios.The amount of the required preparations carrier of density influence preparation correct concentration pharmaceutical preparation of chemical compound.One weight portion density equals the chemical compound of preparations carrier will replace isopyknic preparations carrier.The carrier that the replaceable halfbody of chemical compound of twice preparations carrier density is long-pending.Therefore must use displacement value that chemical compound is revised with regard to concrete preparations carrier.
When each component of preparation is used term % weight/volume (percentage by weight of every volume of formulation), for fear of any doubt, we are meant the component that has constant weight percentage ratio in the unit volume preparation, and for example 1% weight/volume preparation is meant and comprises the 1g component in the 100ml preparation.Further following illustrating also.
| X% weight/volume preparation | The weight of x in the 1ml preparation |
| ????30％ ????20％ ????10％ ????5％ ????1％ | ????300mg ????200mg ????100mg ????50mg ????10mg |
When using integer representation % weight/volume preparation, they are meant the number through suitably rounding up.For example 4.6% will be rounding to 5%.
Should understand in when preparation, may comprise excessive dosage and make doctor on duty or nursing staff give required dosage.Therefore, when needs 5ml dosage, have in preparation that the excessive of the highest 0.25ml is suitable, preferably have the excessive of the highest 0.15ml.In general preparation will leave in phial or the prefilled syringe, be preferably to contain the unit dose prefilled syringe of described preparation in this, and these have constituted other features of the present invention.
Described pharmaceutically acceptable alcohol can comprise a kind of alcohol or two or more pure mixture, is preferably the mixture of two kinds of alcohol.The pharmaceutically acceptable alcohol that is preferred for parenteral is the mixture of ethanol, benzyl alcohol or ethanol and benzyl alcohol.
Described pharmaceutically-acceptable non-aqueous ester solvent can comprise the mixture of a kind of pharmaceutically-acceptable non-aqueous ester solvent or two or more these kind solvents, preferably only is a kind of ester.The non-aqueous ester solvent of the preferred pharmaceutical compositions of parenteral is selected from benzyl benzoate, ethyl oleate, isopropyl myristate, isopropyl palmitate or their any mixture.
Those skilled in the art understand the requirement (such as the requirement of American Pharmacopeia, British Pharmacopoeia, European Pharmacopoeia and Japanese Pharmacopoeia) that described pharmaceutically acceptable alcohol satisfies standards of pharmacopoeia qualitatively and may comprise some water and other organic solvents, and for example ethanol is that content is the ethanol of 94.9-96.0% (volume) when measuring for 15.56 ℃ in the American Pharmacopeia.Dehydrated alcohol in the American Pharmacopeia is that 15.56 ℃ of following ethanol contents are not less than the ethanol of 99.5% (volume).
Those skilled in the art understand the requirement (such as the requirement of American Pharmacopeia, British Pharmacopoeia, European Pharmacopoeia and Japanese Pharmacopoeia) that described pharmaceutically-acceptable non-aqueous ester solvent satisfies standards of pharmacopoeia qualitatively.
The combination of the pure and mild pharmaceutically-acceptable non-aqueous ester solvent of preferred pharmaceutical compositions is described below in preparation:
Used term ricinoleate excipient is meant the oil of the ratio of glyceryl triricinoleate in its composition for (at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95% weight/volume).Described ricinoleate carrier can be an artificial oil, and also being fit to is Oleum Ricini, and all meets standards of pharmacopoeia as mentioned above.
We find that uncannily above-mentioned preparation of the present invention provides the release of secular gratifying fulvestrant after intramuscular injection.
Though we find that at other solubilization excipient of preparation injection back be that pure and mild pharmaceutically-acceptable non-aqueous ester solvent disappears fast from preparations carrier and injection site, preparation of the present invention still can discharge the fulvestrant of treatment produce effects level in long-time.
Used term " slow release " is meant the continuous release of at least 4 weeks of acquisition, at least 5 weeks and preferred at least 8 all fulvestrants in this.Under a preferable feature, can obtain at least 8 all i.e. slow release of 2 months, more preferably obtain the slow release at least 12 weeks or 3 months.
Should understand doctor on duty and may wish with divided dose intramuscular injection administration, promptly the 5ml preparation is divided into two independent 2.5ml order administrations, and this is another feature of the present invention.
Simply fulvestrant is added to be dissolved in and to expect to obtain good release profiles in the oil-based fluid preparation.
The dosage of preferred intramuscular injection administration is 5ml.
Conventional other excipient that uses of described formulation art be can use, for example anti-oxidation and antisepsis agent, coloring agent or surfactant comprised.The preferred optional excipient is a surfactant, more preferably antioxidant.
As mentioned above, fulvestrant can be used for treating estrogen dependent conditions for example breast carcinoma and gynaecopathia (as endometriosis).
Except that fulvestrant, the molecule of another similar type is at present just in clinical research.Infer SH-646 (11 β-fluoro-7 α-(14,14,15,15,15-five fluoro-6-methyl isophthalic acid 0-sulfo--6-azepine pentadecyls) female-1,3,5 (10)-triolefins-3,17-isoallopregnane-3) also be the chemical compound that has with fulvestrant same function mode, and it have very similarly chemical constitution.Think that this chemical compound also has similar physical property to fulvestrant, so the present invention also applies for this chemical compound protection together.
Except substituting the fulvestrant with SH-646, other features of this invention as mentioned above.
List of references
1.Bowler J, Lilley TJ, Pittam JD, Wakeling AE.Novel steroidalpure antioestrogens (novel steroid pure antiestrogen medicine) .Steroids, 54:71-100,1989.
2.Wakeling AE.Novel pure antioestrogens:mode of action andtherapeutic prospects (novel pure antiestrogen medicine: model of action and treatment prospect) .American New York Academy Science 1990a; 595:348-56.
3.Wakeling AE.Steroidal pure antioestrogens.In Lippman M, Dickson R, editors.Regulatory mechanisms in breast cancer (steroid pure antiestrogen medicine, be stated from: Lippman M, Dickson R, the chief editor, the breast carcinoma regulation mechanism) .Boston:Kluwer Academic, 1990b:239-57.
4.Wakeling AE.Therapeutic potential of pure antioestrogens in thetreatment of breast cancer (the treatment potential of pure antiestrogen medicine in breast cancer treatment) .Journal Steroid Biochemistry 1990c; 37:771-5.
5.Wakeling AE, Bowler J.Steroidal pure antioestrogens (steroid pure antiestrogen medicine) .Journal Endocrinology 1987; 112:R7-10.
6.Wakeling AE, Bowler J.Biology and mode of action of pureantioestrogens (biology of pure antiestrogen medicine and model of action) .Journal SteroidBiochemistry 1988; 3:141-7.
Now will the present invention will be described by following indefiniteness embodiment, wherein
Fig. 1 has shown the curve of blood plasma that obtains (based on the 3.2kg rabbit, data are by the normalization of rabbit weight) after intramuscular injection, wherein the y axle is concentration (ng/ml), the x axle be the time (my god);
Fig. 2 has shown the comparison of curve of blood plasma, wherein:
Fig. 2 A has shown the curve of blood plasma of A group, and wherein the y axle is concentration (ng/ml), the x axle be the time (my god);
Fig. 2 B has shown the curve of blood plasma of B group, and wherein the y axle is concentration (ng/ml), the x axle be the time (my god);
Fig. 3 has shown the curve of blood plasma of preparation 1,5 and contrast, (based on the 3.2kg rabbit, data by the normalization of rabbit weight), wherein the y axle is concentration (ng/ml), the x axle be the time (my god);
Fig. 4 has shown the muscle residual data from PK research in 3 months, and wherein the y-axle is the percentage fulvestrant residual quantity of each injection position, and the x-axle is the preparation numbering.An injection position (two injection positions of every animal) is represented on every hurdle.
Fig. 5 has shown the relation of prediction dissolubility and actual solubility
Fig. 6 has shown the confidence interval of prediction dissolubility
Fig. 7 has shown the curve of blood plasma after the intramuscular injection, (based on the 3.2kg rabbit, data by the normalization of rabbit weight), wherein the y axle is concentration (ng/ml), the x axle be the time (my god);
Speech slightly contracts
The IM intramuscular
The PK pharmacokinetics
The AUC area under curve
The SD standard deviation
Reference example 1
The mensuration of fulvestrant dissolubility in the preparation
1. material and device
Balance
2mL tool blind nut glass phial
Magnetic stirring apparatus
The temperature control reactor of tool magnetic stirring apparatus
Tool is fit to malleation pipette (PDP) the 20-25 μ L of microsyringe syringe needle
Merlon ultracentrifugation pipe
Supercentrifuge
Tool is fit to the 0.5-200 μ L PDP of microsyringe syringe needle
Tool is fit to 200 μ L-1mL pipettes of plastic spike
The amber Snap Top of 2mL glass HPLC phial
HPLC phial 1mm Snap Caps
HPLC with diode array detector
HPLC is pure for methanol (MeOH)
HPLC is pure for acetonitrile (ACN) far ultraviolet
Ultrapure deionized water
Vortex mixer
Ultra sonic bath
Tool is fit to the 20-200 μ L suction pipe of plastic spike
Aluminum weighing plate 5mL glass volumetric flask
2. experimental procedure
2.1, add Oleum Ricini three components that are fit to weight then and prepare the 1mL preparations carrier by adding the pure and mild benzyl benzoate of an amount of volume
2.2 excessive then adding fulvestrant is up to no longer being visually observed more medicine dissolution.The weight of the fulvestrant that record adds.
2.3 in each phial, put into the magnetic force splash bar.
2.4 all samples covered with nitrogen and with the vial closure loam cake, place reactor and under 4 ℃ the speed with 1000 stir
2.5 use PDP20-200 μ L pipette from each phial sucking-off 200 μ L sample aliquot after 6 days, transfer in the ultracentrifugation pipe.With centrifuge tube under 25 ℃ with 80, centrifugal 30 minutes of the speed of 000rpm.
2.6 add 1400mL methanol, 450mL water and 150mL acetonitrile preparation HPLC eluent by solvent bottle to 2 liters of plastic coatings
2.7 use the 1mL pipette that 990 μ L HPLC eluents are joined in 60 amber glass HPLC phials
2.8 using PDP0.5-25 μ L pipette draws 3 * 10 μ L supernatant and joins the phial that contains eluent from each ultracentrifugation pipe
2.9 with 10 times of sample redilution.100 μ L samples are joined in the 900 μ L HPLC eluents
2.10 cover amber phial, eddy current stirred for 10 seconds, ultrasonic 10 minutes and place HPLC automatic sampler dish then.
3. the preparation of calibration curve
3.1 accurately taking by weighing about 10mg fulvestrant on the microbalance to the aluminum weighing pan and place 5mL glass volumetric flask.The actual institute of record weighs.
3.2 use plastics Pasteur pipette that about 4.5mL HPLC eluent is added in the flask.Subsequently before being mixed with accurately volume with ultrasonic 5 minutes of flask (obtaining the reference solution of about 2mg/mL).
3.3 use the pipette that is fit to that 0-250 μ L reference solution is joined in the 2mL HPLC phial, use the 1mL pipette volume dilution to be arrived 1mL with the HPLC eluent, as shown in the table:
| Reference solution volume (μ L) | HPLC effluent volume (μ L) | Fulvestrant theoretical concentration (μ g/mL) |
| ????0 | ????1000 | ????0 |
| ????5 | ????995 | ????10 |
| ????25 | ????975 | ????50 |
| ????50 | ????950 | ????100 |
| ????100 | ????900 | ????200 |
| ????150 | ????850 | ????300 |
| ????200 | ????800 | ????400 |
| ????250 | ????750 | ????500 |
3.4 cover the HPLC phial, eddy current mixed for 10 seconds and places on the HPLC automatic sampler dish
3.5 adopt two batches ICI 182780 preparation calibration curves (as described in 3.1-3.4).
4.HPLC condition
Eluent: 70%MeOH/22.5% water/7.5%ACN
Post: 25cm 5 μ Hypersil ODS 4.6mm i.d. tool guard columns
Detect wavelength: 280nm
Flow velocity: 1.2mL/min
Temperature: room temperature
Sample size: 50 μ L
Retention time: about 12 minutes
Embodiment 1
Pharmaceutical preparation
Fulvestrant is mixed with ethanol and benzyl alcohol, stir until dissolving fully.Add benzyl benzoate, add Oleum Ricini weight and stir (for simplicity, operating weight but not volume, operating weight/volume is as unit) to the end.Whole solution covers with nitrogen.The filter of solution by one or two 0.2 μ m aperture filtered degerming.When bacteria-free filtrate being injected under the aseptic condition in washing and refrigerative sterile primary (primary) container (as phial or prefilled syringe), remain under the nitrogen covering.There have slightly in primary package to be excessive so that the taking-up of required dosage.Before sterile sealing, cover primary package with aseptic nitrogen.Following process chart has shown production procedure.
According to the amount of required each component of preparation technique specification requirement selection preparation, example as mentioned above.The amount of for example pressing surface compositions adds each component:
a)
The ethanol of 10% weight/volume
The benzyl alcohol of 20% weight/volume
The benzyl benzoate of 15% weight/volume
The fulvestrant of the final preparation 500mg of every 5ml
Oleum Ricini with surplus;
b)
The ethanol of 10% weight/volume
The benzyl alcohol of 20% weight/volume
The benzyl benzoate of 30% weight/volume
The fulvestrant of the final preparation 500mg of every 5ml
Oleum Ricini with surplus;
c)
The ethanol of 10% weight/volume
The benzyl alcohol of 20% weight/volume
The benzyl benzoate of 50% weight/volume
The fulvestrant of the final preparation 500mg of every 5ml
Oleum Ricini with surplus;
d)
The ethanol of 20% weight/volume
The benzyl alcohol of 20% weight/volume
The benzyl benzoate of 30% weight/volume
The fulvestrant of the final preparation 500mg of every 5ml
Oleum Ricini with surplus;
e)
The ethanol of 15% weight/volume
The benzyl alcohol of 10% weight/volume
The benzyl benzoate of 50% weight/volume
The fulvestrant of the final preparation 500mg of every 5ml
Oleum Ricini with surplus;
f)
The ethanol of 15% weight/volume
The benzyl alcohol of 20% weight/volume
The benzyl benzoate of 30% weight/volume
The fulvestrant of the final preparation 500mg of every 5ml
Oleum Ricini with surplus.
Flow sheet
Composition/component flow process
Embodiment 2
Select 4 months stability studies of stable 100mg/mL pharmaceutical preparation
| The preparation numbering | Fulvestrant | 96% ethanol | Benzyl alcohol | Benzyl benzoate | Oleum Ricini | The visual examination result |
| (mg/ml) | The % weight/volume | The % weight/volume | The % weight/volume | The % weight/volume | 4 months | |
| Sample 1 | ?100 | ?5 | ?10 | ?15 | To 100% | Precipitation |
| Sample 2 | ?100 | ?5 | ?10 | ?30 | To 100% | Precipitation |
| Sample 3 | ?100 | ?7.5 | ?10 | ?15 | To 100% | Precipitation |
| Sample 4 | ?100 | ?7.5 | ?10 | ?30 | To 100% | Precipitation |
| Sample 5 | ?100 | ?10 | ?10 | ?15 | To 100% | Precipitation |
| Sample 6 | ?100 | ?10 | ?10 | ?17.5 | To 100% | Precipitation |
| Sample 7 | ?100 | ?10 | ?10 | ?20 | To 100% | Precipitation |
| Sample 8 | ?100 | ?10 | ?10 | ?22.5 | To 100% | Solution |
| Sample 9 | ?100 | ?10 | ?10 | ?25 | To 100% | Solution |
| Sample 10 | ?100 | ?10 | ?10 | ?27.5 | To 100% | Solution |
| Sample 11 | ?100 | ?10 | ?10 | ?30 | To 100% | Solution |
| Sample 12 | ?100 | ?10 | ?10 | ?40 | To 100% | Solution |
| Sample 13 | ?100 | ?10 | ?10 | ?50 | To 100% | Solution |
| Sample 14 | ?100 | ?10 | ?15 | ?15 | To 100% | Solution |
| Sample 15 | ?100 | ?10 | ?15 | ?30 | To 100% | Solution |
| Sample 16 | ?100 | ?10 | ?15 | ?40 | To 100% | Solution |
| Sample 17 | ?100 | ?10 | ?15 | ?50 | To 100% | Solution |
| Sample 18 | ?100 | ?10 | ?20 | ?15 | To 100% | Solution |
| Sample 19 | ?100 | ?10 | ?20 | ?30 | To 100% | Solution |
| Sample 20 | ?100 | ?10 | ?20 | ?40 | To 100% | Solution |
| Sample 21 | ?100 | ?10 | ?20 | ?50 | To 100% | Solution |
| Sample 22 | ?100 | ?15 | ?10 | ?15 | To 100% | Solution |
| Sample 23 | ?100 | ?15 | ?10 | ?30 | To 100% | Solution |
| Sample 24 | ?100 | ?15 | ?10 | ?40 | To 100% | Solution |
| Sample 25 | ?100 | ?15 | ?10 | ?50 | To 100% | Solution |
| Sample 26 | ?100 | ?20 | ?5 | ?15 | To 100% | Solution |
| Sample 27 | ?100 | ?20 | ?5 | ?30 | To 100% | Solution |
| Sample 28 | ?100 | ?20 | ?10 | ?15 | To 100% | Solution |
| Sample 29 | ?100 | ?20 | ?10 | ?30 | To 100 | Solution |
| Sample | ||||||
| 30 | ?100 | ?20 | ?10 | ?40 | To 100% | Solution |
| Sample 31 | ?100 | ?20 | ?10 | ?50 | To 100% | Solution |
| Sample 32 | ?100 | ?15 | ?15 | ?15 | To 100% | Solution |
| Sample 33 | ?100 | ?15 | ?15 | ?30 | To 100% | Solution |
| Sample 34 | ?100 | ?15 | ?15 | ?40 | To 100 | Solution |
| Sample | ||||||
| 35 | ?100 | ?15 | ?15 | ?50 | To 100% | Solution |
| Sample 36 | ?100 | ?15 | ?20 | ?15 | To 100% | Solution |
| Sample 37 | ?100 | ?15 | ?20 | ?30 | To 100% | Solution |
| Sample 38 | ?100 | ?15 | ?20 | ?50 | To 100% | Solution |
| Sample 39 | ?100 | ?20 | ?20 | ?15 | To 100 | Solution |
| Sample | ||||||
| 40 | ?100 | ?20 | ?20 | ?30 | To 100% | Solution |
| To in the same old way | ?52.16 | ?10 | ?10 | ?15 | 60 | Solution |
Described control sample is meant following pharmaceutical preparation: fulvestrant 50mg/mL, and ethanol 10% weight/volume, benzyl alcohol 10% weight/volume, benzyl benzoate 15% weight/volume is also used the Oleum Ricini standardize solution.
Embodiment 3
Selection is used for the pharmaceutical preparation of internal deposition and external precipitation research
Pharmaceutical preparation is further studied below embodiment 2 selects
| Preparation | Fulvestrant | 95% ethanol | Benzyl alcohol | Benzyl benzoate | Oleum Ricini |
| The % weight/volume | The % weight/volume | The % weight/volume | The % weight/volume | The % weight/volume | |
| Sample 1 | ????10 | ????10 | ????10 | ????30 | To 100% |
| Sample 2 | ????10 | ????10 | ????10 | ????50 | To 100% |
| Sample 3 | ????10 | ????10 | ????20 | ????15 | To 100% |
| Sample 4 | ????10 | ????10 | ????20 | ????30 | To 100% |
| Sample 5 | ????10 | ????10 | ????20 | ????50 | To 100% |
| Sample 6 | ????10 | ????20 | ????5 | ????15 | To 100% |
| Sample 7 | ????10 | ????20 | ????5 | ????30 | To 100% |
| Sample 8 | ????10 | ????20 | ????20 | ????15 | To 100% |
| Sample 9 | ????10 | ????20 | ????20 | ????30 | To 100% |
| Sample 10 | ????10 | ????15 | ????10 | ????15 | To 100% |
| Sample 11 | ????10 | ????15 | ????10 | ????30 | To 100% |
| Sample 12 | ????10 | ????15 | ????10 | ????50 | To 100% |
| Sample 13 | ????10 | ????15 | ????20 | ????15 | To 100 |
| Sample 14 | ????10 | ????15 | ????20 | ????50 | To 100 |
| Sample 15 | ????10 | ????15 | ????20 | ????30 | To 100 |
| Sample 16 | ????5 | ????10 | ????10 | ????15 | To 100 |
Determine further evaluation in the outer precipitation of substrate donor of 7 pharmaceutical preparatioies (sample 3,4,5,9,12,14 and 16-are referring to the following examples 4) and the study on deposition.Sample 16 is contrast.Precipitation experiment is included in ethanol evaporation and causes each sample of visualization under the condition of drug precipitation.
Embodiment 4
Research in the body
Determine the pharmaceutical preparation of further donor inner evaluation
Numbering fulvestrant (the heavy excipient (% weight/volume) of %
Amount/volume) ethanol 96% benzyl alcohol benzyl benzoate Oleum Ricini
F1????????10?????????????10?????????20?????????15????????45
F2????????10?????????????10?????????20?????????30????????30
F3????????10?????????????10?????????20?????????50????????10
F4????????10?????????????20?????????20?????????30????????20
F5????????10?????????????15?????????10?????????50????????15
F6????????10?????????????15?????????20?????????50????????5
F7????????10?????????????15?????????20?????????30????????25
To in the same old way 5 10 10 15 60
(a) with 3 months the body giving drugs into nose being carried out in these 7 kinds of pharmaceutical preparatioies studies for kinetics (PK); The result is shown in Fig. 1,2 and 3.
The pharmacokinetic interpretation of result
Pro-blood plasma level comparison variation in the same old way in 30 days is big; After this change to similar in the same old way.After 2 months, levels of drugs equals 1 month level in the same old way, shows that comparison action time is long in the same old way.This release profiles is amazing because with localized precipitation medicine not to compare in the same old way, think that originally the localized precipitation that is subjected to the test preparation injection site can destroy its release profiles.
Pro-notices in 30 days that curve has some differences, therefore they is divided into two groups (preparation F7 has shown intermediate characteristic).
The A group, early stage rapid release (50% benzyl benzoate and low Oleum Ricini≤15%)-referring to Fig. 2 A
The B group, low release, more flat curve (≤30% benzyl benzoate and higher Oleum Ricini 〉=20%)-referring to Fig. 2 B
(b) histopathology
Estimate 7 pharmaceutical preparatioies and in the same old way to the local tolerance of intramuscular injection.In 51 time, observe infringement.All pharmaceutical preparatioies cause the tissue reaction that comparison is big in the same old way.
(c) at the blood plasma level (ng/ml) of material time point 100mg dosage
Formulation dosage (mg) time point (my god)
28????????56??????????84
1????????????100??????????8.7???????4.6?????????3.5
2????????????100??????????8.0???????3.6?????????2.6
3????????????100??????????9.4???????3.5?????????2.0
4????????????100??????????7.7???????5.0?????????3.4
5????????????100??????????9.1???????4.5?????????2.6
6????????????100??????????9.9???????3.3?????????1.9
7????????????100??????????9.9???????5.5?????????3.2
To in the same old way 50 3.3 1.7
Conclusion
Minimum 2 months of the action time of 100mg dosage.
Minimum 3 months of the action time of 150mg dosage.
(d) mensuration of fulvestrant dissolubility in 7 kinds of pharmaceutical preparation after 6 days
Preparation is dissolubility (mg/ml) after 6 days
F1???????????????????????????111
F2???????????????????????????140
F3???????????????????????????175
F4???????????????????????????235
F5???????????????????????????162
F6???????????????????????????212
F7???????????????????????????126
Fulvestrant dissolubility model
The dissolubility of fulvestrant in various preparations carriers
Preparation is numbered the fluorine prediction dissolving that 96% ethanol benzyl alcohol % Benzyl Benzoate Oleum Ricini % records
% weight/body weight/body ester % w/w/the group of body dimension department solubility
The long-pending degree of separating (mg/ml) of long-pending volume
(mg/ml)
Sample 1550 is to 100% 27 9.4
Sample 255 15 is to 100% 36 32.8
Sample 3 10 50 is to 100% 46 48.5
Sample 4 10 5 15 is to 100% 54 36.6
Sample 6 10 10 15 is to 100% 65 72
Sample 7 15 15 0 is to 100% 76 87.6
Sample 8 15 15 15 is to 100% 102 111.1
Sample 9 11 22 17 is to 100% 111 109.8
Sample 11 11 22 56 is to 100% 175 135.8
Sample 12 22 22 33 is to 100% 235 174.4
Sample 13 17 11 56 is to 100% 162 170.6
Sample 14 17 22 56 is to 100% 212 200.9
Ethanol, benzyl alcohol and benzyl benzoate % level are as the dissolubility data match linear regression model (LRM) of independent variable from 15 samples in the use preparation.Obtained to have the model of 93.2%R square value.
Dissolubility=-29.77+5.44xETOH+2.38xBA+1.57xBB
Benzyl alcohol=BA, benzyl benzoate=BB, ethanol=ETOH.
The dissolubility that records is unit with mg/mL.
Fig. 5 and Fig. 6 are based on following data
| Measured value | Lower limit C.L. | Predictive value | Upper limit C.L. |
| ????27 | ????0 | ????9.4 | ????31.1 |
| ????36 | ????10 | ????32.8 | ????55.7 |
| ????45 | ????31.6 | ????48.5 | ????65.4 |
| ????46 | ????17.1 | ????36.6 | ????56.1 |
| ????54 | ????40.9 | ????60.1 | ????79.2 |
| ????65 | ????59 | ????72 | ????85 |
| ????76 | ????64.7 | ????87.6 | ????110.6 |
| ????102 | ????95.6 | ????111.1 | ????126.7 |
| ????111 | ????85.4 | ????109.8 | ????134.1 |
| ????126 | ????149 | ????166.1 | ????183.1 |
| ????140 | ????114.2 | ????135.8 | ????157.5 |
| ????162 | ????142.5 | ????174.4 | ????206.3 |
| ????175 | ????143.4 | ????170.6 | ????197.9 |
| ????212 | ????179.6 | ????200.9 | ????222.2 |
| ????235 | ????168.7 | ????196.3 | ????224 |
Following table has shown the prediction dissolubility of the pharmaceutical preparation substrate that is used to measure dissolubility.It is well relevant with the visualization value.
Fulvestrant preparation-stability
| The preparation numbering | Fulvestrant | 95% ethanol | Benzyl alcohol | Benzyl benzoate | Oleum Ricini | The visual examination result | The prediction dissolubility |
| ??(mg/ml) | The % weight/volume | The % weight/volume | The % weight/volume | The % weight/volume | 4 months | ??(mg/ml) | |
| Sample 1 | ??100 | ????5 | ????10 | ??15 | ????60 | Precipitation | ??53.1 |
| Sample 2 | ??100 | ????5 | ????10 | ??30 | ????45 | Precipitation | ??79.2 |
| Sample 3 | ??100 | ????7.5 | ????10 | ??15 | ????57.5 | Precipitation | ??68.2 |
| Sample 4 | ??100 | ????7.5 | ????10 | ??30 | ????42.5 | Precipitation | ??94.3 |
| Sample 5 | ??100 | ????10 | ????10 | ??15 | ????55 | Precipitation | ??83.3 |
| Sample 6 | ??100 | ????10 | ????10 | ??17.5 | ????52.5 | Precipitation | ??87.6 |
| Sample 7 | ??100 | ????10 | ????10 | ??20 | ????50 | Precipitation | ??92.0 |
| Sample 8 | ??100 | ????10 | ????10 | ??22.5 | ????47.5 | Solution | ??96.4 |
| Sample 9 | ??100 | ????10 | ????10 | ??25 | ????45 | Solution | ??100.7 |
| Sample 10 | ??100 | ????10 | ????10 | ??27.5 | ????42.5 | Solution | ??105.1 |
| Sample 11 | ??100 | ????10 | ????10 | ??30 | ????40 | Solution | ??109.5 |
| Sample 12 | ??100 | ????10 | ????10 | ??40 | ????30 | Solution | ??126.9 |
| Sample 13 | ??100 | ????10 | ????10 | ??50 | ????20 | Solution | ??144.3 |
| Sample 14 | ??100 | ????10 | ????15 | ??15 | ????50 | Solution | ??96.5 |
| Sample 15 | ??100 | ????10 | ????15 | ??30 | ????35 | Solution | ??122.7 |
| Sample 16 | ??100 | ????10 | ????15 | ??40 | ????25 | Solution | ??140.1 |
| Sample 17 | ??100 | ????10 | ????15 | ??50 | ????15 | Solution | ??157.6 |
| Sample 18 | ??100 | ????10 | ????20 | ??15 | ????45 | Solution | ??109.7 |
| Sample 19 | ??100 | ????10 | ????20 | ??30 | ????30 | Solution | ??135.9 |
| Sample 20 | ??100 | ????10 | ????20 | ??40 | ????20 | Solution | ??153.3 |
| Sample 21 | ??100 | ????10 | ????20 | ??50 | ????10 | Solution | ??170.8 |
| Sample 22 | ??100 | ????15 | ????10 | ??15 | ????50 | Solution | ??113.5 |
| Sample 23 | ??100 | ????15 | ????10 | ??30 | ????35 | Solution | ??139.7 |
| Sample 24 | ??100 | ????15 | ????10 | ??40 | ????25 | Solution | ??157.1 |
| Sample 25 | ??100 | ????15 | ????10 | ??50 | ????15 | Solution | ??174.6 |
| Sample 26 | ??100 | ????20 | ????5 | ??15 | ????50 | Solution | ??130.5 |
| Sample 27 | ??100 | ????20 | ????5 | ??30 | ????35 | Solution | ??156.7 |
| Sample 28 | ????100 | ????20 | ????10 | ????15 | ????45 | Solution | ??143.7 |
| Sample 29 | ????100 | ????20 | ????10 | ????30 | ????30 | Solution | ??169.9 |
| Sample 30 | ????100 | ????20 | ????10 | ????40 | ????20 | Solution | ??187.3 |
| Sample 31 | ????100 | ????20 | ????10 | ????50 | ????10 | Solution | ??204.8 |
| Sample 32 | ????100 | ????15 | ????15 | ????15 | ????45 | Solution | ??126.7 |
| Sample 33 | ????100 | ????15 | ????15 | ????30 | ????30 | Solution | ??152.9 |
| Sample 34 | ????100 | ????15 | ????15 | ????40 | ????20 | Solution | ??170.3 |
| Sample 35 | ????100 | ????15 | ????15 | ????50 | ????10 | Solution | ??187.8 |
| Sample 36 | ????100 | ????15 | ????20 | ????15 | ????40 | Solution | ??140.0 |
| Sample 37 | ????100 | ????15 | ????20 | ????30 | ????25 | Solution | ??166.1 |
| Sample 38 | ????100 | ????15 | ????20 | ????50 | ????5 | Solution | ??201.0 |
| Sample 39 | ????100 | ????20 | ????20 | ????15 | ????35 | Solution | ??170.2 |
| Sample 40 | ????100 | ????20 | ????20 | ????30 | ????20 | Solution | ??196.3 |
| To (Faslode x) in the same old way | ????52.16 | ????10 | ????10 | ????15 | ????60 | Solution | ??72.0 |
Following table has shown the prescription prediction for various fulvestrant dissolubility, " X " expression solution wherein.Comprised some non-practicable prescriptions in the attention table, its each component and greater than 100%.Main purpose is to be used to illustrate that the present invention is used to obtain the multiple combination of the ethanol/benzyl alcohol of different fulvestrant dissolubility/benzyl benzoate.
Embodiment 6
Use contains the body giving drugs into nose of compositions of 140mg/mL fulvestrant for dynamics research
Embodiment 4 described preparation F3 and F4 are revised as the fulvestrant that contains 140mg/mL.As described below, amended preparation called after F8 and F9.
Preparation is formed
In PK research shown in the table composed as follows of institute's preparaton.
| The preparation numbering | Fulvestrant (% weight/volume) | 96% ethanol (% weight/volume) | Benzyl alcohol (% weight/volume) | Benzyl benzoate (% weight/volume) | Oleum Ricini (% weight/volume) |
| ??F8 | ????14 | ????9 | ????19 | ????47 | To 100% |
| ??F9 | ????14 | ????14 | ????19 | ????48 | To 100% |
The PK curve
Result such as Fig. 7.To in the same old way composition with identical described in the embodiment 4.Composition F 8 and F9 have with to similar curve in the same old way, but improving aspect the high-caliber fulvestrant sustained-release.
Embodiment 7
The compositions that contains the 150mg/mL fulvestrant
Be prepared as follows the compositions that is similar to F3, F4, F5 and F6 (referring to embodiment 4) but contains the 150mg/mL fulvestrant.
| The preparation numbering | Fulvestrant (% weight/volume) | 96% ethanol (% weight/volume) | Benzyl alcohol (% weight/volume) | Benzyl benzoate (% weight/volume) | Oleum Ricini (% weight/volume) |
| F10 | ????15 | ????10 | ????20 | ????50 | To 100% |
| F11 | ????15 | ????20 | ????20 | ????30 | To 100% |
| F12 | ????15 | ????15 | ????10 | ????50 | To 100% |
| F13 | ????15 | ????15 | ????20 | ????45 | To 100% |
| F14 | ????15 | ????9 | ????19 | ????47 | To 100% |
| F15 | ????15 | ????19 | ????19 | ????28 | To 100% |
| F16 | ????15 | ????14 | ????9 | ????47 | To 100% |
| F17 | ????15 | ????14 | ????19 | ????47 | To 100% |
| F18 | ????15 | ????10 | ????20 | ????45 | To 100% |
| F19 | ????15 | ????15 | ????10 | ????45 | To 100% |
| F20 | ????15 | ????20 | ????20 | ????25 | To 100% |
| F21 | ????15 | ????10 | ????30 | ????25 | To 100% |
| F22 | ????15 | ????10 | ????25 | ????30 | To 100% |
| F23 | ????15 | ????10 | ????30 | ????30 | To 100% |
| F24 | ????15 | ????15 | ????25 | ????30 | To 100% |
| F25 | ????15 | ????15 | ????25 | ????25 | To 100% |
| F26 | ????15 | ????15 | ????20 | ????30 | To 100% |
Claims (26)
1. pharmaceutical preparation that is suitable for intramuscular injection, described pharmaceutical preparation comprises 100mg/ml or above fulvestrant, 10% weight/volume preparations carrier or above pharmaceutically acceptable alcohol, 5% weight/volume preparations carrier or above pharmaceutically-acceptable non-aqueous ester solvent and 5% weight/volume preparations carrier or above ricinoleate excipient, condition is the ethanol that described preparations carrier comprises at least 5% weight/volume preparations carrier, and described preparation is not following preparation: up to the fulvestrant of 102mg/ml, the ethanol of 15% weight/volume preparations carrier, the benzyl alcohol of 15% weight/volume preparations carrier, the benzyl benzoate of 15% weight/volume preparations carrier and 30% weight/volume preparations carrier or above ricinoleate excipient.
2. the pharmaceutical preparation that is suitable for intramuscular injection of claim 1, described pharmaceutical preparation comprises 105mg/ml or above fulvestrant, 10% weight/volume preparations carrier or above pharmaceutically acceptable alcohol, 5% weight/volume preparations carrier or above pharmaceutically-acceptable non-aqueous ester solvent and 5% weight/volume preparations carrier or above ricinoleate excipient, condition is the ethanol that described preparation comprises at least 5% weight/volume preparations carrier.
3. the pharmaceutical preparation that is suitable for intramuscular injection of claim 1, described pharmaceutical preparation comprises 110mg/ blood or above fulvestrant, 10% weight/volume preparations carrier or above pharmaceutically acceptable alcohol, 5% weight/volume preparations carrier or above pharmaceutically-acceptable non-aqueous ester solvent and 5% weight/volume preparations carrier or above ricinoleate excipient, condition is the ethanol that described preparations carrier comprises at least 5% weight/volume preparations carrier.
4. the pharmaceutical preparation that is suitable for intramuscular injection of claim 1, described pharmaceutical preparation comprises 115mg/ml or above fulvestrant, 10% weight/volume preparations carrier or above pharmaceutically acceptable alcohol, 5% weight/volume preparations carrier or above pharmaceutically-acceptable non-aqueous ester solvent and 5% weight/volume preparations carrier or above ricinoleate excipient, condition is the ethanol that described preparations carrier comprises at least 5% weight/volume preparations carrier.
5. the pharmaceutical preparation that is suitable for intramuscular injection of claim 1, described pharmaceutical preparation comprises 120mg/ml or above fulvestrant, 10% weight/volume preparations carrier or above pharmaceutically acceptable alcohol, 5% weight/volume preparations carrier or above pharmaceutically-acceptable non-aqueous ester solvent and 5% weight/volume preparations carrier or above ricinoleate excipient, condition is the ethanol that described preparations carrier comprises at least 5% weight/volume preparations carrier.
6. the pharmaceutical preparation that is suitable for intramuscular injection of claim 1, described pharmaceutical preparation comprises 130mg/ml or above fulvestrant, 15% weight/volume preparations carrier or above pharmaceutically acceptable alcohol, 5% weight/volume preparations carrier or above pharmaceutically-acceptable non-aqueous ester solvent and 5% weight/volume preparations carrier or above ricinoleate excipient, condition is the ethanol that described preparations carrier comprises at least 5% weight/volume preparations carrier.
7. the pharmaceutical preparation that is suitable for intramuscular injection of claim 1, described pharmaceutical preparation comprises 140mg/ml or above fulvestrant, 15% weight/volume preparations carrier or above pharmaceutically acceptable alcohol, 12.5% weight/volume preparations carrier or above pharmaceutically-acceptable non-aqueous ester solvent and 5% weight/volume preparations carrier or above ricinoleate excipient, condition is the ethanol that described preparations carrier comprises at least 10% weight/volume preparations carrier.
8. the pharmaceutical preparation that is suitable for intramuscular injection of claim 1, described pharmaceutical preparation comprises 150mg/ml or above fulvestrant, 15% weight/volume preparations carrier or above pharmaceutically acceptable alcohol, 17.5% weight/volume preparations carrier or above pharmaceutically-acceptable non-aqueous ester solvent and 5% weight/volume preparations carrier or above ricinoleate excipient, condition is the ethanol that described preparations carrier comprises at least 10% weight/volume preparations carrier.
9. a fulvestrant dissolubility that is suitable for intramuscular injection is at least the pharmaceutical preparation of Ymg/ml, and described pharmaceutical preparation comprises:
100mg/ml or above fulvestrant;
Every volume of formulation carrier contains 5% weight/volume or above Oleum Ricini; With
By formula Y=-29.77+5.44ETOH+2.38BA+1.57BB definite ethanol (ETOH), benzyl alcohol (BA), the benzyl benzoate (BB) of following amount (in % weight/volume preparations carrier) at least, wherein Y is at least 100, ETOH is at least 5, and BA is at least 5, and BB is at least 5.
10. the pharmaceutical preparation of claim 9, wherein Y is selected from 105,110,115,120,125,130,135,140,145,150,155,160,170,180,190 and 200.
11. the pharmaceutical preparation of claim 9, wherein Y is selected from 120,125,130,135,140,145,150,155,160,170,180,190 and 200.
12. the pharmaceutical preparation of claim 9, wherein Y is selected from 150,155,160,170,180,190 and 200.
13. the pharmaceutical preparation of claim 9, wherein Y is selected from 150,155,160,170,180,190 and 200, and described preparation comprises 150mg/ml fulvestrant at least.
14. the pharmaceutical preparation of claim 9, wherein Y is 200, and described preparation comprises the fulvestrant of 200mg/ml at least.
15. one kind comprises the pharmaceutical preparation of the fulvestrant of 100mg/ml concentration at least, wherein said preparation is suitable for intramuscular injection in human body, and in the treatment produce effects blood plasma fulvestrant concentration that can in human body, obtain at least 2 months after the injection, condition is not comprise following preparation: up to the fulvestrant of 102mg/ml, the ethanol of 15% weight/volume preparations carrier, the benzyl alcohol of 15% weight/volume preparations carrier, the benzyl benzoate of 15% weight/volume preparations carrier and 30% weight/volume preparations carrier or above ricinoleate excipient.
16. one kind comprises the pharmaceutical preparation of the fulvestrant of 150mg/ml concentration at least, wherein said preparation is suitable for intramuscular injection in human body, and in the treatment produce effects blood plasma fulvestrant concentration that can in human body, obtain at least 2 months after the injection.
17. following any pharmaceutical preparation, described pharmaceutical preparation comprise approximately:
i)
The ethanol of 10% weight/volume
The benzyl alcohol of 20% weight/volume
The benzyl benzoate of 15% weight/volume
The fulvestrant of the final preparation 500-555mg of every 5ml and the Oleum Ricini of surplus;
ii)
The ethanol of 10% weight/volume
The benzyl alcohol of 20% weight/volume
The benzyl benzoate of 30% weight/volume
The fulvestrant of the final preparation 500-700mg of every 5ml and the Oleum Ricini of surplus;
iii)
The ethanol of 10% weight/volume
The benzyl alcohol of 20% weight/volume
The benzyl benzoate of 50% weight/volume
The fulvestrant of the final preparation 500-750mg of every 5ml and the Oleum Ricini of surplus;
iv)
The ethanol of 20% weight/volume
The benzyl alcohol of 20% weight/volume
The benzyl benzoate of 30% weight/volume
The fulvestrant of the final preparation 500-1175mg of every 5ml and the Oleum Ricini of surplus;
v)
The ethanol of 15% weight/volume
The benzyl alcohol of 10% weight/volume
The benzyl benzoate of 50% weight/volume
The fulvestrant of the final preparation 500-810mg of every 5ml and the Oleum Ricini of surplus;
vi)
The ethanol of 15% weight/volume
The benzyl alcohol of 20% weight/volume
The benzyl benzoate of 50% weight/volume
The fulvestrant of the final preparation 500mg of every 5ml and the Oleum Ricini of surplus;
vii)
The ethanol of 15% weight/volume
The benzyl alcohol of 20% weight/volume
The benzyl benzoate of 30% weight/volume
The fulvestrant of the final preparation 500-630mg of every 5ml and the Oleum Ricini of surplus;
viii)
The ethanol of 10% weight/volume
The benzyl alcohol of 20% weight/volume
The benzyl benzoate of 50% weight/volume
The fulvestrant of the final preparation 750mg of every 5ml and the Oleum Ricini of surplus;
ix)
The ethanol of 20% weight/volume
The benzyl alcohol of 20% weight/volume
The benzyl benzoate of 30% weight/volume
The fulvestrant of the final preparation 750mg of every 5ml and the Oleum Ricini of surplus;
x)
The ethanol of 15% weight/volume
The benzyl alcohol of 10% weight/volume
The benzyl benzoate of 50% weight/volume
The fulvestrant of the final preparation 750mg of every 5ml and the Oleum Ricini of surplus;
xi)
The ethanol of 9% weight/volume
The benzyl alcohol of 19% weight/volume
The benzyl benzoate of 47% weight/volume
The fulvestrant of the final preparation 700mg of every 5ml and the Oleum Ricini of surplus;
xii)
The ethanol of 14% weight/volume
The benzyl alcohol of 19% weight/volume
The benzyl benzoate of 48% weight/volume
The fulvestrant of the final preparation 700mg of every 5ml and the Oleum Ricini of surplus;
xiii)
The ethanol of 15% weight/volume
The benzyl alcohol of 20% weight/volume
The benzyl benzoate of 45% weight/volume
The fulvestrant of the final preparation 750mg of every 5ml and the Oleum Ricini of surplus;
xiv)
The ethanol of 9% weight/volume
The benzyl alcohol of 19% weight/volume
The benzyl benzoate of 47% weight/volume
The fulvestrant of the final preparation 750mg of every 5ml and the Oleum Ricini of surplus;
xv)
The ethanol of 19% weight/volume
The benzyl alcohol of 19% weight/volume
The benzyl benzoate of 28% weight/volume
The fulvestrant of the final preparation 750mg of every 5ml and the Oleum Ricini of surplus;
xvi)
The ethanol of 14% weight/volume
The benzyl alcohol of 9% weight/volume
The benzyl benzoate of 47% weight/volume
The fulvestrant of the final preparation 750mg of every 5ml and the Oleum Ricini of surplus;
xvii)
The ethanol of 14% weight/volume
The benzyl alcohol of 19% weight/volume
The benzyl benzoate of 47% weight/volume
The fulvestrant of the final preparation 750mg of every 5ml and the Oleum Ricini of surplus;
xviii)
The ethanol of 10% weight/volume
The benzyl alcohol of 20% weight/volume
The benzyl benzoate of 45% weight/volume
The fulvestrant of the final preparation 750mg of every 5ml and the Oleum Ricini of surplus;
xix)
The ethanol of 15% weight/volume
The benzyl alcohol of 10% weight/volume
The benzyl benzoate of 45% weight/volume
The fulvestrant of the final preparation 750mg of every 5ml and the Oleum Ricini of surplus;
xx)
The ethanol of 20% weight/volume
The benzyl alcohol of 20% weight/volume
The benzyl benzoate of 25% weight/volume
The fulvestrant of the final preparation 750mg of every 5ml and the Oleum Ricini of surplus;
xxi)
The ethanol of 10% weight/volume
The benzyl alcohol of 30% weight/volume
The benzyl benzoate of 25% weight/volume
The fulvestrant of the final preparation 750mg of every 5ml and the Oleum Ricini of surplus;
xxii)
The ethanol of 10% weight/volume
The benzyl alcohol of 25% weight/volume
The benzyl benzoate of 30% weight/volume
The fulvestrant of the final preparation 750mg of every 5ml and the Oleum Ricini of surplus;
xxiii)
The ethanol of 10% weight/volume
The benzyl alcohol of 30% weight/volume
The benzyl benzoate of 30% weight/volume
The fulvestrant of the final preparation 750mg of every 5ml and the Oleum Ricini of surplus;
xxiv)
The ethanol of 15% weight/volume
The benzyl alcohol of 25% weight/volume
The benzyl benzoate of 30% weight/volume
The fulvestrant of the final preparation 750mg of every 5ml and the Oleum Ricini of surplus;
xxv)
The ethanol of 15% weight/volume
The benzyl alcohol of 25% weight/volume
The benzyl benzoate of 25% weight/volume
The fulvestrant of the final preparation 750mg of every 5ml and the Oleum Ricini of surplus; With
xxvi)
The ethanol of 15% weight/volume
The benzyl alcohol of 20% weight/volume
The benzyl benzoate of 30% weight/volume
The fulvestrant of the final preparation 750mg of every 5ml and the Oleum Ricini of surplus.
18. each pharmaceutical preparation in the aforementioned claim, wherein said pharmaceutically acceptable alcohol are the mixture of ethanol and benzyl alcohol.
19. each pharmaceutical preparation in the aforementioned claim, wherein said pharmaceutically-acceptable non-aqueous ester solvent is selected from benzyl benzoate, ethyl oleate, isopropyl myristate, isopropyl palmitate or their any mixture.
20. each pharmaceutical preparation in the aforementioned claim, wherein said pharmaceutically-acceptable non-aqueous ester solvent is a benzyl benzoate.
21. each pharmaceutical preparation in the aforementioned claim, wherein said ricinoleate excipient is an Oleum Ricini.
22. the unit dosage forms of each pharmaceutical preparation in the aforementioned claim, the cumulative volume of wherein said preparation are 6ml or following.
23. be used for each the pharmaceutical preparation of suitable intramuscular injection of aforementioned claim of medical treatment.
24. the purposes of fulvestrant in each the defined pharmaceutical preparation that is used for the treatment of optimum or malignant galactophore or genital diseases of the aforementioned claim of preparation.
25. the purposes of fulvestrant in the pharmaceutical preparation of each defined optimum or malignant galactophore that is used for the treatment of the people of the aforementioned claim of preparation or genital diseases, wherein said pharmaceutical preparation can have the medication interval at least 8 weeks.
26. asepsis injector or phial, described asepsis injector or phial comprise the pharmaceutical preparation of each definition in the aforementioned claim.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0116619.8 | 2001-07-07 | ||
| GBGB0116619.8A GB0116619D0 (en) | 2001-07-07 | 2001-07-07 | Formulation |
| US31571101P | 2001-08-30 | 2001-08-30 | |
| US60/315,711 | 2001-08-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1553815A true CN1553815A (en) | 2004-12-08 |
Family
ID=26246290
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA028171888A Pending CN1553815A (en) | 2001-07-07 | 2002-07-03 | Pharmaceutical formulation for the intramuscular administration of fulvestrant |
Country Status (15)
| Country | Link |
|---|---|
| EP (1) | EP1406662A1 (en) |
| JP (1) | JP2004534093A (en) |
| CN (1) | CN1553815A (en) |
| AR (1) | AR037138A1 (en) |
| BR (1) | BR0210898A (en) |
| CA (1) | CA2453111A1 (en) |
| CO (1) | CO5560585A2 (en) |
| HU (1) | HUP0400115A3 (en) |
| IL (1) | IL159576A0 (en) |
| IS (1) | IS7097A (en) |
| MX (1) | MXPA04000028A (en) |
| NO (1) | NO20040047L (en) |
| PL (1) | PL367624A1 (en) |
| RU (1) | RU2004102393A (en) |
| WO (1) | WO2003006064A1 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011022861A1 (en) | 2009-08-31 | 2011-03-03 | 西安力邦医药科技有限责任公司 | Fulvestrant nanosphere/microsphere and preparative method and use thereof |
| CN102600073A (en) * | 2012-03-31 | 2012-07-25 | 加拿大力邦制药有限公司 | Lactate-based fulvestrant or fulvestrant derivative oily preparation and preparation method of oily preparation |
| CN102600064A (en) * | 2012-03-31 | 2012-07-25 | 西安力邦制药有限公司 | Fulvestrant or fulvestrant derivative sustained release preparation and preparation method thereof |
| CN102600065A (en) * | 2012-03-31 | 2012-07-25 | 加拿大力邦制药有限公司 | Fulvestrant or fulvestrant derivative oily preparation and preparation method thereof |
| CN111481559A (en) * | 2019-01-25 | 2020-08-04 | 江苏恒瑞医药股份有限公司 | High-concentration fulvestrant composition and preparation method thereof |
| CN113260353A (en) * | 2019-12-11 | 2021-08-13 | 上海博志研新药物技术有限公司 | Fulvestrant pharmaceutical composition, preparation method and application thereof |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0000313D0 (en) | 2000-01-10 | 2000-03-01 | Astrazeneca Uk Ltd | Formulation |
| US9271990B2 (en) | 2014-02-14 | 2016-03-01 | Fresenius Kabi Usa, Llc | Fulvestrant formulations |
| WO2017175810A1 (en) * | 2016-04-06 | 2017-10-12 | 富士フイルム株式会社 | Medicinal composition |
| US11590077B2 (en) | 2016-05-06 | 2023-02-28 | Eagle Pharmaceuticals, Inc. | Fulvestrant formulations and methods of their use |
| KR102438425B1 (en) * | 2016-05-06 | 2022-09-01 | 이글 파마슈티컬즈 인코포레이티드 | Fulvestrant formulations and methods of use thereof |
| JP6611932B2 (en) | 2016-05-31 | 2019-11-27 | 富士フイルム株式会社 | Pharmaceutical composition |
| CN111479556B (en) * | 2017-11-08 | 2023-09-01 | 伊格尔制药公司 | Fulvestrant formulations and methods of use thereof |
| WO2019113361A1 (en) * | 2017-12-07 | 2019-06-13 | Nevakar Inc. | Concentrated fulvestrant compositions |
| WO2019151353A1 (en) * | 2018-01-31 | 2019-08-08 | 富士フイルム株式会社 | Method for producing preparation for injection |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8813353D0 (en) * | 1988-06-06 | 1988-07-13 | Ici Plc | Therapeutic product |
| GB9525194D0 (en) * | 1995-12-12 | 1996-02-07 | Zeneca Ltd | Pharmaceutical composition |
| GB0000313D0 (en) * | 2000-01-10 | 2000-03-01 | Astrazeneca Uk Ltd | Formulation |
| GB0008172D0 (en) * | 2000-04-05 | 2000-05-24 | Astrazeneca Ab | Therapy |
-
2002
- 2002-07-03 PL PL02367624A patent/PL367624A1/en not_active Application Discontinuation
- 2002-07-03 HU HU0400115A patent/HUP0400115A3/en unknown
- 2002-07-03 IL IL15957602A patent/IL159576A0/en unknown
- 2002-07-03 CN CNA028171888A patent/CN1553815A/en active Pending
- 2002-07-03 RU RU2004102393/15A patent/RU2004102393A/en not_active Application Discontinuation
- 2002-07-03 BR BR0210898-4A patent/BR0210898A/en not_active IP Right Cessation
- 2002-07-03 EP EP02740940A patent/EP1406662A1/en not_active Withdrawn
- 2002-07-03 JP JP2003511869A patent/JP2004534093A/en active Pending
- 2002-07-03 CA CA002453111A patent/CA2453111A1/en not_active Abandoned
- 2002-07-03 WO PCT/GB2002/003092 patent/WO2003006064A1/en not_active Application Discontinuation
- 2002-07-05 AR ARP020102523A patent/AR037138A1/en not_active Application Discontinuation
-
2004
- 2004-01-05 IS IS7097A patent/IS7097A/en unknown
- 2004-01-06 NO NO20040047A patent/NO20040047L/en not_active Application Discontinuation
- 2004-01-07 MX MXPA04000028A patent/MXPA04000028A/en unknown
- 2004-01-07 CO CO04000761A patent/CO5560585A2/en not_active Application Discontinuation
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2011022861A1 (en) | 2009-08-31 | 2011-03-03 | 西安力邦医药科技有限责任公司 | Fulvestrant nanosphere/microsphere and preparative method and use thereof |
| WO2013143298A1 (en) * | 2012-03-31 | 2013-10-03 | 利邦德制药有限公司 | Fulvestrant or fulvestrant derivative oily preparation and preparation method thereof |
| CN102600064A (en) * | 2012-03-31 | 2012-07-25 | 西安力邦制药有限公司 | Fulvestrant or fulvestrant derivative sustained release preparation and preparation method thereof |
| CN102600065A (en) * | 2012-03-31 | 2012-07-25 | 加拿大力邦制药有限公司 | Fulvestrant or fulvestrant derivative oily preparation and preparation method thereof |
| WO2013143300A1 (en) * | 2012-03-31 | 2013-10-03 | 西安力邦制药有限公司 | Sustained-release preparation of fulvestrant or derivatives thereof and preparation method therefor |
| WO2013143299A1 (en) * | 2012-03-31 | 2013-10-03 | 利邦德制药有限公司 | Lactate-based fulvestrant or fulvestrant derivative oily preparation and preparation method thereof |
| CN102600073A (en) * | 2012-03-31 | 2012-07-25 | 加拿大力邦制药有限公司 | Lactate-based fulvestrant or fulvestrant derivative oily preparation and preparation method of oily preparation |
| CN102600073B (en) * | 2012-03-31 | 2014-01-01 | 莱普德制药有限公司 | Lactate-based fulvestrant or fulvestrant derivative oily preparation and preparation method of oily preparation |
| CN102600065B (en) * | 2012-03-31 | 2014-08-13 | 莱普德制药有限公司 | Fulvestrant or fulvestrant derivative oily preparation and preparation method thereof |
| US10568890B2 (en) | 2012-03-31 | 2020-02-25 | Xi'an Libang Pharmaceutical Co., Ltd | Lactate-based fulvestrant or fulvestrant derivative oily preparation and preparation method thereof |
| CN111481559A (en) * | 2019-01-25 | 2020-08-04 | 江苏恒瑞医药股份有限公司 | High-concentration fulvestrant composition and preparation method thereof |
| CN111481559B (en) * | 2019-01-25 | 2021-10-08 | 江苏恒瑞医药股份有限公司 | High-concentration fulvestrant composition and preparation method thereof |
| CN113260353A (en) * | 2019-12-11 | 2021-08-13 | 上海博志研新药物技术有限公司 | Fulvestrant pharmaceutical composition, preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| MXPA04000028A (en) | 2004-05-21 |
| HUP0400115A3 (en) | 2005-11-28 |
| IL159576A0 (en) | 2004-06-01 |
| PL367624A1 (en) | 2005-03-07 |
| IS7097A (en) | 2004-01-05 |
| JP2004534093A (en) | 2004-11-11 |
| WO2003006064A1 (en) | 2003-01-23 |
| CA2453111A1 (en) | 2003-01-23 |
| BR0210898A (en) | 2004-06-22 |
| HUP0400115A2 (en) | 2004-06-28 |
| CO5560585A2 (en) | 2005-09-30 |
| EP1406662A1 (en) | 2004-04-14 |
| AR037138A1 (en) | 2004-10-27 |
| NO20040047L (en) | 2004-02-23 |
| RU2004102393A (en) | 2005-03-27 |
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