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CN108159055A - Treat long-acting delivery system, preparation method and the application of breast cancer - Google Patents

Treat long-acting delivery system, preparation method and the application of breast cancer Download PDF

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Publication number
CN108159055A
CN108159055A CN201810007971.7A CN201810007971A CN108159055A CN 108159055 A CN108159055 A CN 108159055A CN 201810007971 A CN201810007971 A CN 201810007971A CN 108159055 A CN108159055 A CN 108159055A
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oil
lecithin
ethyl
delivery system
phosphatide
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陈涛
顾相应
卢伍党
马鹏程
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XI'AN LIBANG MEDICINE SCIENCE AND TECHNOLOGY Co Ltd
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XI'AN LIBANG MEDICINE SCIENCE AND TECHNOLOGY Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Oil, Petroleum & Natural Gas (AREA)
  • Dermatology (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

The present invention provides a kind of using phosphatide as the long-acting delivery system of the fulvestrant of slow-release material or derivatives thereof and preparation method and application.The present invention mainly elaborates a kind of prescription of high concentration fulvestrant or derivatives thereof and preparation scheme；Wherein, the main ingredient is fulvestrant or derivatives thereof；The slow-release material is different types of phosphatide or the mixture of phosphatide and variety classes vegetable oil；The solvent is using ethyl alcohol, ethyl lactate, 1, one of 2 propylene glycol, ethyl acetate etc., mixture more than the two or the two, the analgestic is benzyl alcohol, lidocaine, procaine, Ropivacaine etc., the prescription viscosity is between 20 45mPa.s, a concentration of 60 300mg/ml of the prescription, the prescription antioxidant are：Ve, lipoic acid etc., wherein phosphatide, which have, increases intersolubility and slow-releasing and controlled-releasing action, such preparation are prepared in a manner of being sterile filtered.

Description

Treat long-acting delivery system, preparation method and the application of breast cancer
Technical field
The invention belongs to pharmaceutical science fields, and in particular to a kind of long-acting delivery system of fulvestrant or derivatives thereof, its Preparation method and application.
Background technology
Breast cancer is one of the most common malignant tumors in women, and latest survey report shows that breast cancer has become to women The disease of health threat maximum, the first place of incidence Yue Ju big cities female tumor.Fulvestrant parenteral solution be by A kind of intramuscular injection of AstraZeneca companies research and development is used to treat the drug of breast cancer.In April, 2002 by U.S. FDA for the first time Approval listing is mainly used to treat post menopausal (including the natural menopause and artificial menopause) estrogen being in progress in anti-estrogen therapy The Locally Advanced or metastatic breast cancer of receptor positive.
Fulvestrant is a kind of steroidal antiestrogen drug, and chemical constitution is similar with estradiol, is 17 beta estradiols Alkylamine analog, can by occupy estrogen receptor (ER) antagonising oestrogen act on, and inhibit one as caused by estrogen Series of cell correlated process.A kind of ER antagonists of " pure ", without partial estrogen sample stirring effect, it by combination, It blocks and lowers ER so as to inhibit estrogen receptor access, can be with ER competitive bindings, the affinity with ER is close to estrogen 100 times of tamoxifen are that uniquely can be widely used for clinical antiestrogen after tamoxifen effect failure, due to this Medicine is endocrinotherapy, the adverse reaction that chemotherapy will not be caused common, therefore with preferable patient compliance.
At present, the formula of AstraZeneca companies clinically FASLODEX is：250mg fulvestrants, ethyl alcohol (10%), Benzyl alcohol (10%), Ergol (15%) and castor oil are settled to 5ml.There are two types of clinical dosing regimens, the first is 250mg/ times/30 days, i.e. monthly patient core's intramuscular injection 5ml said preparations；Second is 500mg/ times/30 days, i.e., 15 days every Patient core's intramuscular injection 5ml said preparations, we would know that from Astrazeneca AB's FDA declaration materials, rabbit irritation test It shows, local intramuscular delivery 1ml, musculature can just be restored after animal 45 days, and clinical investigations result is equally shown, patient muscle Said preparation 5ml is injected in deep, and the reflection of patient's local anomaly is than more serious, under the influence of this factor, finds that irritation is smaller to pass Medicine system becomes even more important.
In disclosed patent, CN1222292C grinds patent for fulvestrant original, discloses a kind of containing can pharmaceutically connect The pharmaceutical preparation of alcohol, non-aqueous ester solvent and ricinoleate ester received.Wherein disclosed FASLODEX formulas can be seen that：1st, make Make solvent with a high proportion of ethyl alcohol (10%), caused local irritation is big.2nd, Ergol (15%) has been used to make Solubilizer：It is well known that Ergol is respectively provided with stronger irritation to skin, eyes and mucous membrane；3rd, high concentration has been used Benzyl alcohol (10%)：But it is with stronger haemocylolysis, and is easily formed the scleroma for being difficult to absorb, if high concentration muscle Injection, these side effects will be apparent upon；4th, single injection volume is big；By the administration of 500g dosage (EMA and FDA in 2015 Approval), then it needs once to carry out intramuscular injection at two positions.There are muscular irritation, scleroma, injection pains etc. by FASLODEX in summary Apparent and serious adverse reaction, brings larger pain to patient after injection.
In addition, the research for having many researchs to be dedicated to fulvestrant formulations at present, this is tieed up including microball preparation, improved fluorine Group's oily preparation, emulsion etc. are all to substitute solvent and dispersant finding, as Tetrahydrofurfuryl polyethylene glycol ether, polyethylene glycol, Medium chain triglyceride and poloxamer etc., the problems such as to solve low drug solubility, stability and irritation；But ensureing curative effect Under the premise of, it does not have clear improvement for the adverse reaction involved by fulvestrant clinic.
2012, applicant declared the fulvestrant preparation (patent No. CN using ethyl lactate as carrier 102600073B), a kind of fulvestrant or derivatives thereof oily preparation and preparation method thereof (patent No. CN 102600065B), Fulvestrant or derivatives thereof sustained release preparation and preparation method thereof (102600064 A of patent No. CN) has very fulvestrant The relevant auxiliary materials of good dissolving award protection, including ethyl lactate, ethyl acetate, propylene glycol, dimethylformamide, dimethyl second Amide, dimethyl sulfoxide (DMSO), Tetrahydrofurfuryl polyethylene glycol ether etc., such auxiliary material have significantly in terms of fulvestrant solubility is increased Improvement, it is possible to reduce administered volume to a certain extent, indication can improve clinical compliance to a certain extent, however, The castor oil of high-content is one big difficult in terms of irritation is improved, and how to ensure the long-acting delivery system of good fulvestrant Slow releasing function is one big difficult again, and the application has done the research of comparison system in this regard.
Invention content
Therefore, the purpose of the present invention is to overcome the defects in the prior art, provides a kind of fulvestrant or derivatives thereof Long-acting delivery system, preparation method and application.
Before technical scheme of the present invention is illustrated, it is as follows to define term used herein：
Term " lecithin E80 " refers to：Purity is not less than 80% egg yolk lecithin；
Term " lecithin PC-98T " refers to：High-purity egg yolk lecithin, wherein phosphatidylcholine content are not less than 98%；
Term " lecithin PC-96T " refers to：High-purity egg yolk lecithin, wherein phosphatidylcholine content are not less than 96%；
Term " Ve " refers to " vitamin E ".
To achieve the above object, the first aspect of the present invention provides a kind of long-acting delivery system for treating breast cancer, institute Delivery system is stated to include：Main ingredient, solvent, analgestic, antioxidant and slow-release material；
Wherein, the long-acting delivery system viscosity is 20-45mPa.s, the slow-release material for phosphatide and/or phosphatide with The mixture of oil, the main ingredient are such as with one or more in I compound represented of following formula；
Wherein, R1 and R2 can be identical or different, and is each independently selected from：
H and
Ester formed by C1-C30 linear chain or branch chain aliphatic acid, the ester are preferably palmitate, laurate and/or certain herbaceous plants with big flowers acid Ester.
Delivery system according to a first aspect of the present invention, wherein, the phosphatide is natural and/or synthetic phospholipid, has and increases Add in delivery system intersolubility between substance, control burst drug release and extend the effect of pharmaceutical release time；
Preferably, the phosphatide is selected from one or more of：Egg yolk lecithin, soybean lecithin, the phosphatidyl synthesized Choline, dioleyl lecithin, dilauroyl lecithin, two myristoyl lecithin, Dipalmitoyl Lecithin, distearyl ovum Phosphatide, 1-myristoyl-2-palmitoylphosphatidylcholine, hydrogenated soybean lecithin, dimyristoylphosphatidylethanolamine, two palmityl phosphatide Acyl ethanol amine, two myristoyl phosphatidylserines, Distearoyl Phosphatidylethanolamine, distearoylphosphatidylcholine, 1- nutmegs Acyl -2- palmityls lecithin, purifying phosphatidyl choline, Phosphatidylcholine Hydrogenated；
It is highly preferred that the phosphatide is selected from one or more of：Egg yolk lecithin, soybean lecithin, the phosphatide synthesized Phatidylcholine, dioleyl lecithin, dilauroyl lecithin, two myristoyl lecithin, Dipalmitoyl Lecithin, distearyl Lecithin, 1-myristoyl-2-palmitoylphosphatidylcholine.
Most preferably, the phosphatide is egg yolk lecithin.
Delivery system according to a first aspect of the present invention, wherein, the oil is selected from vegetable oil and/or artificial grease；
Preferably, the oil is selected from one or more of：Castor oil, rilanit special, sulfonated castor oil, polyoxyethylene Castor oil (35,40), soybean oil, corn oil, olive oil, rapeseed oil, sunflower oil, palm oil, sesame oil, Seabuckthorn Oil, fish oil, Seal oil, seal oil, shark oil, oil of zedoary turmeric, pearl barley oil, garlic oil, safflower oil, Zanthoxylum essential oil, cnidium oil, Artemisia oil, Chinese ilex It is oil, evening primrose oil, Angelica oil, oil of ginger, catnip oil, Fructus Forsythiae oil, eucalyptus oil, perilla herb oil, Oleum Citri Reticulatae, oil of negundo chastetree, attar of rose, thin Lotus oil, oil of Herba Artemisiae Scopariae, ennel oil, pine wood oil, caryophyllus oil, oil of badian, thyme oil, cinnamon oil, Blumea oil, perilla oil, Curcuma oil, cajeput oil, lavender oil, inulol, patchouli oil, verbena oil, absinthium, sage clary oil, Atractylis oil, fragrant peach Wood oil, lemon oil, Fructus Aurantii Immaturus oil, basil oil, Folium Perillae oil, art (pine) pomegranate oil, coconut oil, cardamom oil, olive oil, lemongrass Oil, geranium oil, herba elsholtziae oil, spearmint oil, Du Shan oil, Herba Pogostemonis oil, levant storax oil, oil of Ribes nigrum L, magnolia vine fruit oil, grass-leaved sweetflag Oil, selinum oil, Fructus Phellodendri oil, lavender oil, rosemary oil, bergamot oil, Oleum Ligni Santali, carrot seed oil, Cacumen Cupressi oil, celery Rapeseed oil, origanum oil, citronellal oil, coriander oil, neroli oil, mace oil, onion oil, sandalwood oil, tagetes oil, thyme Oil, Java Cananga Oil, midchain oil, middle long-chain oil, glyceryl triacetate, acetin, Ergol, myristic acid isopropyl Ester, tributyl citrate, ethyl succinate, dimethyl succinate, alkyl (C12-C15) benzene methyl, cognac oil, decanedioic acid two Ethyl ester, triethyl citrate, pentaerythrite phthalic dicarboxylic acid esters, allyl cyclohexyl propionate, ethyl benzoate, phenylacetic acid benzyl Ester, ethyl caprilate, gallic acid fourth diester, progallin A, propylgallate, methyl myristate, isovaleric acid isoamyl Ester, ethyl isovalerate, isopentyl palmitate, ethyl valerate, ethyl propionate, isoamyl propionate, benzyl propionate, methacrylic acid Methyl esters, 2-hydroxyethyl methacry-late, n-methyl-2-pyrrolidone, geranyl formate, propylene carbonate, propylene glycol carbonic acid Ester, diethyl malonate, caproic acid allyl alcohol, ethyl hexanoate, geranyl butyrate, benzyl butyrate, isoamyl butyrate, butyl butyrate, Ethyl butyrate, cinnamyl acetate, geranyl acetate, benzyl acetate, butyl acetate, ethyl acetate, oleic acid and oleate；
It is highly preferred that the oil is selected from one or more of：Ethyl oleate, Ergol, glyceryl triacetate, list One acid glyceride, midchain oil, castor oil, soybean oil, olive oil, sesame oil, corn oil；
Most preferably, the oil is selected from castor oil and/or soybean oil.
Delivery system according to a first aspect of the present invention, wherein, the solvent is selected from one or more of：Lactic acid second Ester, ethyl alcohol, 1,2-PD, ethyl acetate；Preferably ethyl lactate and/or ethyl alcohol；
The analgestic is selected from one or more of：Benzyl alcohol, anesin, lidocaine, procaine, sieve piperazine The free alkali of cacaine, totokaine, mepivacaine, Articaine, Bupivacaine etc., Propofol, propofol derivative, C16H25NO2, Lappaconitine, rotundine, pentazocine, cyclobutane, fentanyl and its derivatives；Preferably, it is described Analgestic is selected from benzyl alcohol, anesin, lidocaine, procaine, Ropivacaine, totokaine, mepivacaine, Ah 's card Cause and/or Bupivacaine；Most preferably, the analgestic is benzyl alcohol or lidocaine
The antioxidant is selected from lipoic acid and/or vitamin E.
Delivery system according to a first aspect of the present invention, wherein, each Composition Weight Parts proportioning is：
6~30 parts of main ingredient, preferably 6.25~25 parts, more preferably 6.25~20 parts；
10~60 parts of solvent, preferably 10~50 parts, more preferably 15~45 parts；
0~5 part of analgestic, preferably 0~3 part, more preferably 1~2 part；
0~1 part of antioxidant, preferably 0~0.8 part, more preferably 0.1~0.5 part；
30~75 parts of slow-release material, preferably 40~70 parts, more preferably 45~65 parts.
It is further preferred that the ratio of phosphatide and oil is 1 in the slow-release material:0~1：15.0, preferably 1：0.2~ 1：5.0, most preferably：1:0.3~1：3.0.
Delivery system according to a first aspect of the present invention, wherein, the delivery system further includes packaging material；Preferably, it is described Packaging material is selected from one or more of：Cillin bottle, ampoule, refilling type syringe, clamped bottle.
The second aspect of the present invention provides the preparation method of the delivery system described in first aspect, which can be with Include the following steps：
(1) prepared by liquid：Precision, which weighs a certain amount of main ingredient and adds in the solvent of formula ratio, extremely to be dissolved, then add formula ratio Analgestic, antioxidant to dissolving, then add formula ratio slow-release material to dissolving, mixing prepares required liquid；Finally again Designated volume is settled to grease or coordinative solvent；
(2) it is aseptic subpackaged：Aseptically, the liquid prepared is crossed into miillpore filter degerming, then sterile nitrogen is protected It is divided in cillin bottle under shield, tamponade, Zha Gai, places 2-8 DEG C of preservation；
Preferably, the method that course of dissolution is taken in the step (1) is stirring, shearing or ultrasonic；The slow-release material For phosphatide and/or oil；
It is highly preferred that in the step (2), the aperture of the miillpore filter is 0.1~1 μm, preferably 0.1~0.5 μm, Most preferably 0.2 μm.
The third aspect of the present invention provide delivery system described in first aspect prepare for deep intramuscular injection to Application in the medical product of medicine.
The fourth aspect of the present invention provide delivery system described in first aspect prepare the medicine for the treatment of breast cancer or Application in medical device product.
The pharmaceutical composition of the present invention is characterized in that, using phosphatide and/or grease as matrix, adds appropriate solvent and analgesia Agent improves drug concentration, reduces volume injected so that injection pain mitigates, and injection irritation reduces, and inflammatory reaction is small, simultaneously There is the sustained release of long period.
The present invention is achieved by following technical solution：
The present invention relates to a kind of long-acting delivery system of high concentration fulvestrant or derivatives thereof, main component includes Main ingredient, solvent, analgestic, antioxidant and slow-release material.
Slow-release material of the present invention refers to the mixture of different types of phosphatide or phosphatide and oil.
Phosphatide of the present invention：
Can be：Natural and/or synthetic phospholipid, is selected from：Egg yolk lecithin, soybean lecithin, the phosphatidyl choline of synthesis, hydrogen Change Fabaceous Lecithin, dioleyl lecithin, dimyristoylphosphatidylethanolamine, dipalmitoylphosphatidylethanolamine, two nutmegs Acyl phosphatidylserine, Distearoyl Phosphatidylethanolamine, dilauroyl lecithin, two myristoyl lecithin, two palmityls Lecithin, distearoylphosphatidylcholine, distearoylphosphatidylcholine, 1-myristoyl-2-palmitoylphosphatidylcholine, purifying phosphatidyl courage At least one of alkali, Phosphatidylcholine Hydrogenated or two or more mixtures；
Preferably, Ke Yishi, egg yolk lecithin, soybean lecithin, the phosphatidyl choline of synthesis, dioleyl lecithin, two Lauroyl lecithin, two myristoyl lecithin, Dipalmitoyl Lecithin, distearoylphosphatidylcholine, distearoylphosphatidylcholine, 1- At least one of myristoyl -2- palmityl lecithin or two or more mixtures；
Each possibility is the individual embodiment of the present invention.
Phosphatide of the present invention has the function of to increase simultaneously in delivery system intersolubility between substance.
Oil of the present invention：
Can be：Vegetable oil or artificial grease, are selected from：Castor oil, rilanit special, sulfonated castor oil, polyoxyethylene castor Sesame oil (35,40), soybean oil, corn oil, olive oil, rapeseed oil, sunflower oil, palm oil, sesame oil, Seabuckthorn Oil, fish oil, sea Leopard oil, seal oil, shark oil, oil of zedoary turmeric, pearl barley oil, garlic oil, safflower oil, Zanthoxylum essential oil, cnidium oil, Artemisia oil, wintergreen, Evening primrose oil, Angelica oil, oil of ginger, catnip oil, Fructus Forsythiae oil, eucalyptus oil, perilla herb oil, Oleum Citri Reticulatae, oil of negundo chastetree, attar of rose, peppermint Oil, oil of Herba Artemisiae Scopariae, ennel oil, pine wood oil, caryophyllus oil, oil of badian, thyme oil, cinnamon oil, Blumea oil, perilla oil, ginger Butter, cajeput oil, lavender oil, inulol, patchouli oil, verbena oil, absinthium, sage clary oil, Atractylis oil, myrtle Oil, lemon oil, Fructus Aurantii Immaturus oil, basil oil, Folium Perillae oil, art (pine) pomegranate oil, coconut oil, cardamom oil, olive oil, lemongrass Oil, geranium oil, herba elsholtziae oil, spearmint oil, Du Shan oil, Herba Pogostemonis oil, levant storax oil, oil of Ribes nigrum L, magnolia vine fruit oil, grass-leaved sweetflag Oil, selinum oil, Fructus Phellodendri oil, lavender oil, rosemary oil, bergamot oil, Oleum Ligni Santali, carrot seed oil, Cacumen Cupressi oil, celery Rapeseed oil, origanum oil, citronellal oil, coriander oil, neroli oil, mace oil, onion oil, sandalwood oil, tagetes oil, thyme Oil, Java Cananga Oil, midchain oil, middle long-chain oil, glyceryl triacetate, acetin, Ergol, myristic acid isopropyl Ester, tributyl citrate, ethyl succinate, dimethyl succinate, alkyl (C12-C15) benzene methyl, cognac oil, decanedioic acid two Ethyl ester, triethyl citrate, pentaerythrite phthalic dicarboxylic acid esters, allyl cyclohexyl propionate, ethyl benzoate, phenylacetic acid benzyl Ester, ethyl caprilate, gallic acid fourth diester, progallin A, propylgallate, methyl myristate, isovaleric acid isoamyl Ester, ethyl isovalerate, isopentyl palmitate, ethyl valerate, ethyl propionate, isoamyl propionate, benzyl propionate, methacrylic acid Methyl esters, 2-hydroxyethyl methacry-late, n-methyl-2-pyrrolidone, geranyl formate, propylene carbonate, propylene glycol carbonic acid Ester, diethyl malonate, caproic acid allyl alcohol, ethyl hexanoate, geranyl butyrate, benzyl butyrate, isoamyl butyrate, butyl butyrate, Appointing in ethyl butyrate, cinnamyl acetate, geranyl acetate, benzyl acetate, butyl acetate, ethyl acetate, oleic acid and oleic acid esters One is a kind of, two or more mixture；
Preferably, Ke Yishi：Ethyl oleate, Ergol, glyceryl triacetate, single acid glyceride, midchain oil, castor Sesame oil, soybean oil, olive oil, sesame oil, corn oil are a kind of, two or more mixture；
Each possibility is the individual embodiment of the present invention.
Main ingredient of the present invention, basic structure are as follows：
Fulvestrant or derivatives thereof in the present invention：
When R1 and R2 are H, i.e. fulvestrant；
It is H when R1 with R2 differences or is not H；R1 and R2 can be that same group replaces, or different groups Substitution.Each different group substitution is the individual embodiment of the present invention.R1 or R2 preferably is selected from C1-C30 linear chain or branch chain fat Ester formed by fat acid.
Wherein, the fulvestrant ester derivant, including 3 single derivatizations of fulvestrant or fulvestrant 17 Single derivatization or fulvestrant 3 and 17 while derivatization；Simultaneously during derivatization, institute's deriveding group identical also can may be used With difference.
Further, fulvestrant or derivatives thereof can be a kind of, two or more mixture in the formulation.
Solvent of the present invention, is selected from：
One of ethyl lactate, benzyl alcohol, ethyl alcohol, benzyl alcohol, 1,2-PD, ethyl acetate etc., the two or the two with On mixture；
Preferably：The mixture of one of ethyl lactate, ethyl alcohol or the two；
Each possibility is the individual embodiment of the present invention.
Analgestic of the present invention, is selected from：
It is selected from：Benzyl alcohol, anesin, lidocaine, procaine, Ropivacaine, totokaine, mepivacaine, Ah For the free alkali of cacaine, Bupivacaine etc., Propofol, propofol derivative, C16H25NO2, lappaconitine, rotundine, Pentazocine, cyclobutane, one kind of fentanyl and its derivatives, two or more mixture；
It is preferred that：Benzyl alcohol, anesin, lidocaine, procaine, Ropivacaine, totokaine, mepivacaine, Ah For cacaine, one kind of Bupivacaine, two or more mixture；
Further preferably：Benzyl alcohol or lidocaine；
Each possibility is the individual embodiment of the present invention.
Antioxidant of the present invention, is selected from：
Lipoic acid, the mixture of Ve one or two.
Each possibility is the individual embodiment of the present invention.
In terms of formula composition ratio：
Each prescription ratio of the present invention：Fulvestrant or derivatives thereof content is 6%~30% (w/v)；Solvent content is 10 ~60% (w/v)；Analgesia agent content is 0~5% (w/v)；Antioxidant, 0.1~1% (w/v)；Slow-release material, 30~75% (w/v)；
It is preferred that fulvestrant or derivatives thereof content is 6.25%~25% (w/v)；Solvent content is 10~50% (w/ v)；Analgesia agent content is 0~3% (w/v)；Antioxidant, 0.1~0.8% (w/v)；Slow-release material, 40~70% (w/v)；
Further preferably, fulvestrant or derivatives thereof content is 6.25%~20% (w/v)；Solvent content is 15~45% (w/v)；Analgesia agent content is 1~2% (w/v)；Antioxidant, 0.1~0.5% (w/v)；Slow-release material, 45~65% (w/ v)；
Further, when making mixed solvent using only ethyl alcohol and ethyl lactate, ratio between the two is 1：0.5~1： 40；Preferably 1：2~1：15；
Further, the ratio of the slow-release material, phosphatide and vegetable oil is 1:0~15.0；The two ratio is preferably 1：0.2~1：5.0；Most preferably：1：0.3~1：3.0.
Further, the addition of the solvent is adjusted according to the aimed concn of active constituent, when active constituent is dense When spending high, correspondingly, the content of solvent in the formulation is then high, and main ingredient, which can be only achieved, to be completely dissolved without being precipitated.
Further, the solvent, benzyl alcohol both had preferable solubility property, office to fulvestrant and its derivative Again with analgesic activity, but show larger side effect at high concentrations after portion's injection；Its accounting in the formulation is 10% Below w/v；Preferably 1~5%w/v；Most preferably 2%w/v.
According to the specific content of invention, specific formula of the invention can be：
The preparation method of the present invention includes：It is prepared by liquid：Precision weighs a certain amount of fulvestrant or derivatives thereof dissolving In a certain amount of solvent, ultrasound or stirring to complete drug dissolution, then add formula ratio analgestic and antioxidant ultrasound or Then stirring adds formula ratio and delays controlled-release material, ultrasound is sheared or stirred and evenly mixed and prepares required liquid to being completely dissolved；Nothing Bacterium dispenses：Aseptically, the liquid prepared is crossed into film removing impurity, degerming and dispensed.
The fulvestrant of the present invention or derivatives thereof long-acting delivery system, packaging material is cillin bottle, ampoule, refilling type note Emitter or clamped bottle.
The long-acting delivery system form of medication of the present invention is deep intramuscular injection.
The present invention's can by the long-acting delivery system of the fulvestrant of slow-release material or derivatives thereof and preparation method of phosphatide To have but be not limited to following advantageous effect：
1st, delivery system of the invention has the precedent of liposome clinical practice, safety has preferable guarantor using phosphatide as carrier Card；
2nd, fulvestrant formulations concentration of the invention is higher, can reduce administered volume (reducing irritation indirectly) and improve patient Compliance；
3rd, fulvestrant formulations of the invention introduce other plant oil or artificial grease, and the use of castor oil is greatly reduced Amount reduces local irritation；
4th, delivery system solvent of the present invention uses the mixtures such as ethyl lactate and ethyl alcohol, benzyl alcohol, and it is high to reduce single component The irritation of concentration improves clinical compliance；
5th, for slow-release material of the present invention using variety classes phosphatide and other plant oil or artificial grease mixing, formula is adjustable Whole property is strong, and drug release controllability is strong.
6th, the irritation about fulvestrant parenteral solution, preclinical data clearly propose that recovery time is long after local administration, With the increase of clinical dosage, opposite administration time shortens, and local irritation will be clinical a great problem, and the present invention is directed to This, it is significant.
Description of the drawings
Hereinafter, carry out the embodiment that the present invention will be described in detail with reference to attached drawing, wherein：
Fig. 1 shows commercially available product compared with the rabbit muscular irritation pathological section of fulvestrant formulations of the present invention；Wherein A tables Show brine group：28 days pathological sections after injection 1ml physiological saline；B represents commercially available product (Fu Shi get) group：After injecting 1ml commercially available products 14 days pathological sections；C represents (Fu Shi get) group：28 days pathological sections after injection 1ml commercially available products；D represents 14 groups of invention formulation： 14 days pathological sections after injection 0.6ml；E represents 14 groups of invention formulation：28 days pathological sections after injection 0.6ml.
Fig. 2 shows drug-time curves in different formulations fulvestrant formulations rat body.
Specific embodiment
It is further illustrated the present invention below by specific embodiment, it should be understood, however, that, these embodiments are only It is used for specifically describing in more detail, and is not to be construed as limiting the present invention in any form.
This part carries out general description to the material and test method that are arrived used in present invention experiment.Although it is It is it is known in the art that still the present invention still uses up herein to realize many materials and operating method used in the object of the invention It may detailed description.It will be apparent to those skilled in the art that within a context, if not specified, material therefor of the present invention and behaviour It is well known in the art as method.
The reagent and instrument used in following embodiment is as follows：
Reagent：
Fulvestrant (Xian Libang Pharmaceutical Co., Ltd., lot number C068-130201)；
Fulvestrant -3- palmitates (Xi'an Li Bang Pharmaceutical Technology Co., Ltd, lot number 20150825)；
Fulvestrant -17- palmitates (Xi'an Li Bang Pharmaceutical Technology Co., Ltd, lot number 20170613)；
Fu Shi get parenteral solutions (AstraZeneca pharmaceutical Co. Ltd, lot number KV186)；
0.9% sodium chloride injection (Beijing Double-Crane Pharmaceutical Co., Ltd, lot number 1512072707)；
Ethyl alcohol (Merck, lot number K43758386235)；
Benzyl alcohol (Merck, lot number K43837887239)；
Ergol (Merck, lot number：OK43403206216)；
Lecithin PL-100M (Japanese five rosy clouds factory of Q. P. Corp., lot number EK8056)；
Lecithin E96 (Xian Libang Pharmaceutical Co., Ltd., lot number 510300-2017009)；
Lecithin E98 (Japanese Q. P. Corp., lot number AL14001)；
Ethyl lactate (Kang Yuan fragrance Co., Ltd., Factory of Henan Province, lot number 2017022208)；
Soybean oil (emerging Tieling medicine company limited company, lot number 17040102-2-02)；
Castor oil (Hunan Er-kang Pharmaceutical Co., Ltd., lot number 000220160104)；
Olive oil (Tianjin recovery fine chemistry industry research institute)；
Corn oil (Jia Li grain and oil Co., Ltd, lot number 20161016)；
Midchain oil (emerging Tieling medicine company limited company, lot number 160502-2-01)；
Anesin (Merck)；
Vitamin E (Beijing phoenix gift essence seek medical advice medicine limited company, lot number 05292724UO)；
Distearoyl lecithin (Shanghai Advanced viecle Technology Co., Ltd.)；
Two palm acid lecithins (Shanghai Advanced viecle Technology Co., Ltd.)；
Lipoic acid (Sa Si chemical technologies Co., Ltd, lot number EG200100)；
Miillpore filter (uncommon Podbielniak)；
(Xi'an Di Lepu bio-resource exploitations Co., Ltd, animal use credit number for New Zealand White Rabbit, SD rats SYXK (Shan) 2014-003).
Instrument：
Rotational viscometer (Shanghai Changji Geological Instrument Co., Ltd., model NDJ-79)
One) embodiment part：
Embodiment 1
Formula：
Preparation preparing process：
It is prepared by A liquids：Precision weighs the ethyl lactate and ethyl alcohol that a certain amount of fulvestrant is dissolved in the final quantity of needs In.Stirring is to complete drug dissolution, then adds the analgestic and antioxidant of formula ratio, stirs to being completely dissolved, and then addition is matched Side's amount slow-release material, ultrasound or stirs and evenly mixs and prepares required liquid；When whole components dissolve, time title gross weight confirms that component is waved Hair is in tolerance interval (being less than 0.5%).Above operation is carried out in room temperature.
B is aseptic subpackaged：Aseptically, the liquid prepared is crossed into 0.2um miillpore filter degermings, be then divided in pre- In filling syringe, air is discharged, compresses plating teflon piston.
Embodiment 2
Formula：
Preparation process is the same as embodiment 1.
Embodiment 3
Formula：
Preparation process is the same as embodiment 1.
Embodiment 4
Formula：
Preparation process is the same as embodiment 1.
Embodiment 5
Formula:
Preparation process is the same as embodiment 1.
Embodiment 6
Formula:
Preparation process is the same as embodiment 1.
Embodiment 7
Formula:
Preparation process is the same as embodiment 1.
Embodiment 8
Formula:
Preparation process is the same as embodiment 1.
Embodiment 9
Formula:
Preparation process is the same as embodiment 1.
Embodiment 10
Formula:
Preparation preparing process：
It is prepared by A liquids：Precision weighs a certain amount of fulvestrant, adds in the ethyl alcohol and about 2/3 formula ratio of formula ratio Ethyl lactate in.Stirring then adds the analgestic and antioxidant of formula ratio to complete drug dissolution, stirring to being completely dissolved, Then formula ratio slow-release material is added, ultrasonic mixing prepares required liquid；Finally designated volume is settled to ethyl lactate again.
B is aseptic subpackaged：Aseptically, the liquid prepared is crossed into 0.2um miillpore filter degermings, then sterile nitrogen It is divided under protection in cillin bottle/pre-encapsulated injector, tamponade, Zha Gai, places 2-8 DEG C of preservation.
Embodiment 11
Formula:
Preparation process is the same as embodiment 10.
Embodiment 12
Formula:
Preparation process is the same as embodiment 10.
Embodiment 13
Formula：
Preparation preparing process：
It is prepared by A liquids：Precision weighs the solvent that a certain amount of fulvestrant is dissolved in the final quantity for equaling or exceeding needs In (ethyl lactate and/or ethyl alcohol).Stirring then adds the analgestic and antioxidant of formula ratio to complete drug dissolution, stirring or Then ultrasound adds formula ratio slow-release material to being completely dissolved, ultrasonic mixing prepares required liquid；When whole components dissolve, When the amount of ethyl lactate or ethyl alcohol is more than the final quantity needed, it is evaporated under reduced pressure to final requirement.
B is aseptic subpackaged：With embodiment 1.
Embodiment 14
Formula：
Preparation process is the same as embodiment 13.
Embodiment 15
Formula：
Preparation process is the same as embodiment 13.
Embodiment 16
Formula：
Preparation process is the same as embodiment 1.
Embodiment 17
Formula：
Preparation process is the same as embodiment 1.
Embodiment 18
Formula：
Preparation process is the same as embodiment 1.
Embodiment 19
Formula：
Preparation process is the same as embodiment 1.
Embodiment 20
Formula：
Preparation process is the same as embodiment 1.
Embodiment 21
Formula：
Preparation process is the same as embodiment 1.
Embodiment 22
Formula：
Preparation process is the same as embodiment 1.
Embodiment 23
Formula：
Preparation process is the same as embodiment 1.
Embodiment 24
Formula：
Preparation process is the same as embodiment 1.
Embodiment 25
Formula：
Preparation process is the same as embodiment 1.
Embodiment 26
Formula：
Preparation process is the same as embodiment 1.
Embodiment 27
Formula：
Preparation process is the same as embodiment 1.
Embodiment 28
Formula：
Preparation process is the same as embodiment 1.
Embodiment 29
Formula：
Preparation process is the same as embodiment 1.
Embodiment 30
Formula：
Preparation process is the same as embodiment 1.
Embodiment 31
Formula：
Preparation process is the same as embodiment 1.
Embodiment 32
Formula：
Preparation process is the same as embodiment 1.
Embodiment 33
Formula：
Preparation process is the same as embodiment 1.
Two) test example part：
1 phosphatide of test example and different solvents and the dissolubility test of vegetable oil
Precision weighs lecithin E80 1g, and ethyl lactate, ethyl alcohol, benzyl alcohol, Ergol, big is separately added into room temperature Each 5ml of soya-bean oil, castor oil, olive oil, sesame oil, corn oil, every 5 minutes, strength shaking 30 seconds was observed molten in 30 minutes Solution situation such as visually then (refers to 2015 editions four note on the use-solubility of Chinese Pharmacopoeia completely without visible particles of solute to dissolve Experiment).If dissolving is complete, continues to add lecithin to saturation state, primarily determine lecithin in different organic solvents and plant Solubility range in object oil, it is as shown in table 1 below.
The solubility test result of 1 phosphatide of table
Solvent title Phosphatide solubility (mg/ml) Dissolubility
Ethyl alcohol 1334 Easily dissolve
Ethyl lactate 1050 It is readily soluble
Benzyl alcohol 980 It is readily soluble
Soybean oil 40 It is slightly molten
Castor oil【a】 12 Slightly soluble
Corn oil 5.5 Soluble,very slightly
Olive oil 2.2 Soluble,very slightly
Sesame oil 1.0 Soluble,very slightly
【a】Plant oil viscosity is big, dissolve phosphatide after viscosity bigger, need longer dissolution time, about strength shaking 2h or Room temperature ultrasound 10min, solvent group then shake 30min.
Experimental result is shown：Under room temperature, lecithin E80 easily dissolves in ethanol, in benzyl alcohol and ethyl lactate Solubility take second place, but above-mentioned solvent to phosphatide all have preferable dissolubility, can choose as organic solvent.Lecithin E80 solubility in grease is bad；Solubility is slightly good in soybean oil, castor oil, the solubility in other measuring plants oil Take second place.Therefore lecithin solubility in vegetable oil is poor, and there may be immiscible problems for phosphatide-vegetable oil carrier.
The intersolubility experiment of 2 blank medicine-carried system of test example
1) solvent is tested with vegetable oil intersolubility：
Using ethyl alcohol, benzyl alcohol, ethyl lactate, Ergol as medicine solvent, respectively with soybean oil, castor oil, olive Olive oil, sesame oil, corn oil, fish oil, oil of zedoary turmeric, magnolia vine fruit oil, midchain oil, glyceryl triacetate progress are miscible, and observation is mutual Miscible situation, it is as shown in table 2 below.
Intersolubility result of the test between 2 Different solution of table and different vegetable oil
Title Ethyl alcohol Benzyl alcohol Ethyl lactate Ergol
Soybean oil It is unmixing It is miscible It is unmixing It is miscible
Castor oil It is miscible It is miscible It is miscible It is miscible
Olive oil It is unmixing It is miscible It is unmixing It is miscible
Sesame oil It is unmixing It is miscible It is unmixing It is miscible
Corn oil It is unmixing It is miscible It is unmixing It is miscible
Fish oil It is unmixing It is miscible It is unmixing It is miscible
Oil of zedoary turmeric It is unmixing It is miscible It is unmixing It is miscible
Magnolia vine fruit oil It is unmixing It is miscible It is unmixing It is miscible
Midchain oil It is unmixing It is miscible It is unmixing It is miscible
Glyceryl triacetate It is unmixing It is miscible It is unmixing It is miscible
Experimental result is shown：Solvent benzyl alcohol, Ergol and any vegetable oil are all miscible good；Ethyl lactate, second Alcohol is immiscible in other greases in addition to it can dissolve each other in castor oil.
2) the intersolubility experiment of blank medicine-carried system
Using ethyl alcohol, benzyl alcohol, ethyl lactate, Ergol as medicine solvent, with soybean oil, castor oil, olive oil, Sesame oil, corn oil, fish oil, oil of zedoary turmeric, magnolia vine fruit oil, midchain oil, glyceryl triacetate are mixed after adding in appropriate lecithin It is molten, mutually immiscible situation is observed, it is as shown in table 3 below.
The intersolubility result of the test of 3 blank medicine-carried system of table
It was found from the comparison of the experimental result of table 2 and table 3：A, after adding in phosphatide, ethyl lactate is with most plants oil by original Originally it is immiscible to become dissolving each other completely, and miscible with any proportion, considerably increase intersolubility.Obviously, phosphatide can increase molten Compatibility between agent and grease；B, between vehicle of ethanol, benzyl alcohol, Ergol, after the fat that phosphorates between vegetable oil, It is miscible good, solve the problems, such as that phosphatide solubility in grease is low in test example 1.In addition, it is found surprisingly that, the addition of phosphatide The viscosity of soybean oil, midchain oil, olive oil, sesame oil, corn oil can be adjusted.The viscosity of castor oil is higher in itself, therefore needs root The amount of phosphatide is determined according to the addition of solvent.
Dissolubility test of 3 fulvestrant of test example or derivatives thereof in medicine-carried system
On the basis of 2 experience of test example 1 and test example, in addition other components in preparation, investigate main ingredient and are carrying medicine body The solubility property of 2~8 DEG C of placement 48h in system.The results are shown in Table 4.
The process for preparation of preparation is as follows in table 4：The drug target of formula ratio is weighed, the solvent of formula ratio is sequentially added, closes Plug, shaking dissolving are complete；It adds dispersant dissolving or is settled to designated volume with dispersant, Zha Gai shakes up to obtain the final product.It places 2-8 DEG C of preservation, main ingredient is precipitated situation and records after observing 48h.
Steady dissolution result of the test of 4 drug of table in medicine-carried system
4 viscosity measurement of test example is tested
Experiment is investigated by external viscosity on the basis of test example 3 and tentatively filters out more excellent formula, specially：Take this hair Bright fulvestrant oily preparation (be shown in Table the formula in 4, prescription number be respectively preparation 1, preparation 10, preparation 14, preparation 15, Preparation 16, preparation 21, preparation 23 and preparation 34) and commercially available Fu Shi get (being prepared according to specification formula) each 15ml, it utilizes NDJ-79 type rotational viscometers, foundation《Chinese Pharmacopoeia 2015 editions》Third method in 0633 viscosimetry of general rule measures preparation and sticks Property size, experimental temperature be 20 DEG C, each sample is respectively tested 6 times, is averaged and is counted.Detailed results are shown in Table 5.
The viscosity of the different fulvestrant oily preparations of table 5 investigate experimental result statistics (N=6)
Formula number Pendulous frequency Average viscosity value
Commercially available Fu Shi get 6 37.0±1.1mPa.s
Preparation 1 6 22.5±1.5mPa.s
Preparation 10 6 39.0±1.0mPa.s
Preparation 14 6 35.5±1.0mPa.s
Preparation 15 6 26.0±1.0mPa.s
Preparation 16 6 20.3±1.0mPa.s
Preparation 21 6 22.0±1.5mPa.s
Preparation 23 6 40.5±1.5mPa.s
Preparation 34 6 43.5±1.5mPa.s
Experimental result is shown (table 5)：The preparation 1,21 and control formulation of the present invention compares, and viscosity is significantly relatively low, mainly The large viscosity of castor oil, other plant oil viscosity is small to be caused；The present invention preparation 15,16 due to drugloading rate it is big, solvent with Increase, slow-release material ratio reduces, and makes its viscosity significantly lower than former triturate, therefore drugloading rate and slow-release material ratio have viscosity Larger impact, and then influence drug release.It is worth noting that, from preparation 23,34 it is found that can by the addition of phosphatide come Adjust viscosity size, indicate suitable phospholipid ratio can make novel formulation of the present invention with original triturate viscosity approach, can eliminate because Preparation viscosity difference is to discharging the influence of generation in drug body.
The simple different delivery system muscle irritation experiments (blank auxiliary) of test example 5
On the basis of above-mentioned experiment, auxiliary material used is ground with original by rabbit muscle irritation experiment investigation blank auxiliary and is matched The quality of side, foundation《Medicine irritation, anaphylaxis and hemolytic investigative technique guideline》It is tested.It is white to choose New Zealand Rabbit 36, half male and half female, weight 2.5kg-3kg, adaptability are raised one week.The first shaving of all animals or so hind leg, next day press 6 groups are randomly divided into according to weight, every group 6, specific every group is shown in Table 6 successively to medicine composition.Medicine-feeding part：Left hind gives corresponding medicine Object；Administered volume is：1.0mL.2h, 12h after administration, for 24 hours, after 2d and 14d observe reaction of animals and medicine-feeding part feelings respectively Condition simultaneously keeps a record.Difference the 2nd day and the 14th day upon administration, puts to death three animals, takes quadriceps muscle of thigh respectively, longitudinally slit, Injection site stimulate the reaction is visually observed, and carries out pathological examination.Standards of grading reference guide principle is stimulated, experimental result is shown in Table 7 and table 8.
6 blank auxiliary muscle irritation experimental formula table of table
Grouping Group Accessory formula
1 Control group 0.9% sodium chloride
2 Fu Shi get -blank auxiliary Ethyl alcohol 10%, benzyl alcohol 10%, Ergol 15%, castor oil 65%
3 Preparation 10- blank auxiliaries Ethyl lactate 30%, ethyl alcohol 4%, benzyl alcohol 2%, castor oil 55%
4 Preparation 14- blank auxiliaries Ethyl lactate 30%, ethyl alcohol 4%, benzyl alcohol 2%, lecithin 30%, castor oil 26%
5 Preparation 1- blank auxiliaries Ethyl lactate 30%, ethyl alcohol 5%, benzyl alcohol 2%, lecithin 30%, soybean oil 23%
6 Preparation 23- blank auxiliaries Ethyl lactate 36%, ethyl alcohol 5%, benzyl alcohol 2%, lecithin 50%
Table 7 visually observes different time epidermis phenomenon
Naked eyes muscle is observed after 8 topography of table
From epidermis from the point of view of result, novel formulation grinds auxiliary material no significant difference (table 7) with original.But from topography result In general, the delivery system of novel formulation grinds muscle irritation better than original on TOP SCORES, and with phosphatide in prescription and greatly The addition of soya-bean oil, irritation are gradually reduced.Pathological examination result also supports above-mentioned conclusion.
The muscle irritation experiment of 6 same drug concentration difference delivery system of test example
On the basis of test example 5, main ingredient fulvestrant is added in into corresponding blank auxiliary, experimental formula is followed successively by system Agent 1, preparation 10, preparation 14, preparation 23 (Detailed composition composition is shown in Table 4), investigate different delivery systems under same main ingredient concentration Muscle irritation size.This experimental program is changed on the basis of test example 5：It is given for left hind injection site 1ml relative medicines, right hind give 0.6ml relative medicines, put to death 3 animals at 14 days and 28 days respectively, are observed and sick Reason detection.Other test methods and judgment criteria are identical with test example 5.
Experimental result is shown：After Fu Shi get parenteral solution 1ml intramuscular injections 14 days and 28 days compared with brine group, still have apparent Inflammatory reaction and prosthetic granulation tissue, it is prompted to have obvious irritation or corrosivity.10 and 23 intramuscular note of invention formulation Inflammatory reaction and prosthetic granulation tissue are shown after penetrating 1ml and 0.6ml within 14 days and 28 days, it is prompted to have slight stimulation. And preparation 14 shows slight stimulation for 14 days after intramuscular injection 0.6ml compared with brine group and commercially available group, but after 28 days completely Restore, have no apparent inflammation damnification (see attached drawing 1)；The result of preparation 1 is similar to preparation 14, and preparation 12 restores apparent.Prompting system Agent 1 and 14 irritation of preparation are ground considerably lighter relative to original.It i.e. can be apparent containing irritation when phosphatide and grease are added in medicine composition Mitigate.
The muscle irritation experiment of 7 different pharmaceutical concentration comparable delivery system of test example
On the basis of test example 5 and test example 6, the addition of main ingredient fulvestrant is adjusted, experimental formula is followed successively by system Agent 14, preparation 15, preparation 16 (Detailed composition composition is shown in Table 4)；Difference main ingredient concentration pierces muscle when investigating identical delivery system Swash the influence of property.Test method and judgment criteria are identical with test example 5.
Experimental result is shown：After difference fulvestrant formulations prescription injection of the invention, (fulvestrant is for the prescription of high concentration 12.5%) musculature of injection site is woven with compared with compareing position musculature without any difference, 10% concentration muscle groups A small amount of congested, diameter is in 0.5cm hereinafter, showing minimal irritation；8.5% concentration muscle groups are woven with hyperemia, and diameter is in 0.5cm Hereinafter, display slight stimulation；Obviously, instead high concentration fulvestrant parenteral solution irritation can be reduced；Low consistency conditions Lower irritation shows suitable with the irritation of blank auxiliary.The above analysis, the concentration level of fulvestrant is to meromyarian Meat irritation has an impact, and high concentration is more excellent, may may be related with the local anti-inflammatory effect of fulvestrant (see patent CN due to this Described in 104902904A)..
Test example 8：The fulvestrant formulations rat vivo pharmacokinetic experiment of different formulations
To sum up experimental result, formula of the present invention show more excellent effect, but in terms of drug release behavior in terms of irritation It is investigated there is still a need for further.This experiment is by investigating the fulvestrant formulations of different main ingredient concentration, different auxiliary material formula in rat Internal pharmacokinetics behavior, to study the drug release feature of inventive formulation.
1st, test method：
SD rats, female, after adaptability is raised 2-3 days, shave off lumbar vertebrae both sides position hair respectively by totally 80,200 ± 20g Hair, experiment are spare.Animal is randomly divided into 10 groups, and every group 8, there was no significant difference for weight statistics between each group, and each group is followed successively by Fu Shi get control groups, preparation 10, preparation 14, preparation 23, preparation 11, preparation 15, preparation 24, preparation 12, preparation 16 and preparation 25 (Detailed composition is shown in Table 4).Dosage is：10mg/Rat (dosage refers to Fu Shi get offering circulars).
Medicine-feeding part is：Biceps muscle of thigh deep, gently presses medicine-feeding part 2min to prevent liquid on the left of animal lumbar vertebrae after injection Outflow.Administration time is recorded after administration, respectively be administered before and be administered after 0.5h, 2h, 8h, for 24 hours, 3d, 7d, 14d, 21d, 28d, 35d right hindlimb venous blood sampling 0.5ml are in the test tube of test tube of hepari, and 3500rpm centrifugations 10min, quantitative blood plasma 0.2ml is standby Sample is analyzed.Plasma sample is detected through LC-MS-MS, and the results are shown in Table 9 for the blood concentration for surveying under different time.Further Drug-time curve is shown in attached drawing 2.
During 9 intramuscular injection different formulations fulvestrant formulations of table in rat body different time points blood concentration (ng/mL) result Statistics (N=8)
2nd, experimental result
It can be seen that from table 9 and attached drawing 2：When no phosphatide adds in (formula 10,11,12), blood concentration is up to quick behind peak Decline, display drug release is not steady enough.After lecithin adds in, i.e., (formula 14,15,16), during low 8.5% concentration drug release become flat Surely, PK (8.5%) curves are discussed and formulated right preferable with original；But during 12.5% concentration, possible solvent is more, and slow-release material is few, causes to release Medicine is very fast, and AUC grinds control significantly lower than original.Whether castor oil adds in, PK curves almost indifference, display castor oil can be by Phosphatide is replaced；When respectively castor oil or lecithin, the PK curve matchings of lecithin group are better than castor oil.
In summary analysis can obtain：Fulvestrant concentration is 8.5%w/v, and lecithin PC-98T is added in delivery system With castor oil or the prescription of soybean oil, ensure while injection muscles irritation minimum with it is former grind drug release it is similar or longer when Between.
Test example 9：Drug distribution is tested in fulvestrant formulations rat body
Summary experimental result, formula of the present invention show more excellent effect in terms of irritation, and in vivo release is steady, More former triturate is excellent or close, to further appreciate that the internal behavior of invention formulation, need to investigate drug distribution situation after injection. This experiment is come by the drug distribution behavior in each organ of rat after the fulvestrant formulations intramuscular injection after investigation addition phosphatide Study the internal characteristic of inventive formulation.1st, test method
SD rats 36, female, 200-240g are randomly divided into 2 groups, and Fu Shi get parenteral solution groups, fulvestrant formula 14 is (in detail 4) thin formula is shown in Table, every group 6, animal is 3 days before experiment, ad lib, water, animal intramuscular administration, Fu Shi get parenteral solution groups 0.2ml/Rat, 2 groups of fulvestrant are 0.12ml/Rat, and the heart, liver, spleen, lung, kidney, stomach, uterus, ovary, breast are won respectively after 2h Gland physiological saline cleans blood stains, and filter paper blots, weighs quality, be separately added into 0.3ml/100mg physiological saline, be put into homogenizer In, homogenate is fitted into 2ml EP pipes, and 4000 leave heart 10min, take -70 DEG C of freezen protectives of supernatant, and standby sample is through LC-MS-MS points Analysis.Experimental data is shown in Table 10.
In 10 fulvestrant novel formulation rat body of table drug distribution experimental data statistics (N=3 it is) (single
Position：ng/mL)
Original grinds control Preparation 14
Mammary gland 21.03±5.37 54.98±8.66
Ovary 31.12±7.64 35.32±5.54
Blood 15.52±4.34 37.73±6.75
Stomach 15.98±4.62 20.57±6.23
Lung 5.50±2.24 7.68±3.16
Spleen 3.96±1.63 4.00±1.78
Kidney 2.96±1.10 16.83±2.51
Heart 1.84±0.52 5.98±1.42
Liver 1.39±1.33 1.86±1.33
Uterus 1.35±1.01 7.49±2.56
After injection in two hours, invention formulation is distributed mainly on control formulation in mammary gland, ovary, blood, but It is that concentration of the preparation 14 in these organs is apparently higher than control formulation, there is certain targeting after indication invention formulation injection Property, can be more efficient be distributed in lesion organ (mammary gland, ovary).This effect may have certain pass with the addition of phosphatide System.
Although present invention has been a degree of descriptions, it will be apparent that, do not departing from the spirit and scope of the present invention Under the conditions of, the appropriate variation of each condition can be carried out.It is appreciated that the present invention is not limited to the embodiment, and it is attributed to right It is required that range, include the equivalent replacement of each factor.

Claims (10)

1. a kind of long-acting delivery system for treating breast cancer, which is characterized in that the delivery system includes：Main ingredient, solvent, analgesia Agent, antioxidant and slow-release material；
Wherein, the long-acting delivery system viscosity is 20-45mPa.s, and the slow-release material is phosphatide and/or phosphatide and oil Mixture, the main ingredient are such as with one or more in I compound represented of following formula；
Wherein, R1 and R2 can be identical or different, and is each independently selected from：
H and
Ester formed by C1-C30 linear chain or branch chain aliphatic acid, the ester are preferably palmitate, laurate and/or certain herbaceous plants with big flowers acid esters.
2. delivery system according to claim 1, which is characterized in that the phosphatide is natural and/or synthetic phospholipid, is had Increase in delivery system intersolubility between substance, control burst drug release and extend the effect of pharmaceutical release time；
Preferably, the phosphatide is selected from one or more of：Egg yolk lecithin, soybean lecithin, synthesis phosphatidyl choline, Dioleyl lecithin, dilauroyl lecithin, two myristoyl lecithin, Dipalmitoyl Lecithin, distearoylphosphatidylcholine, 1-myristoyl-2-palmitoylphosphatidylcholine, hydrogenated soybean lecithin, dimyristoylphosphatidylethanolamine, two palmityl phosphatidyl second Hydramine, two myristoyl phosphatidylserines, Distearoyl Phosphatidylethanolamine, distearoylphosphatidylcholine, 1- myristoyls -2- Palmityl lecithin, purifying phosphatidyl choline, Phosphatidylcholine Hydrogenated；
It is highly preferred that the phosphatide is selected from one or more of：Egg yolk lecithin, soybean lecithin, the phosphatidyl courage synthesized Alkali, dioleyl lecithin, dilauroyl lecithin, two myristoyl lecithin, Dipalmitoyl Lecithin, distearyl lecithin Fat, 1-myristoyl-2-palmitoylphosphatidylcholine.
Most preferably, the phosphatide is egg yolk lecithin.
3. delivery system according to claim 1 or 2, which is characterized in that the oil is selected from vegetable oil and/or artificial oil Fat；
Preferably, the oil is selected from one or more of：Castor oil, rilanit special, sulfonated castor oil, polyoxyethylene caster Oily (35,40), soybean oil, corn oil, olive oil, rapeseed oil, sunflower oil, palm oil, sesame oil, Seabuckthorn Oil, fish oil, sea dog Oil, seal oil, shark oil, oil of zedoary turmeric, pearl barley oil, garlic oil, safflower oil, Zanthoxylum essential oil, cnidium oil, Artemisia oil, wintergreen, the moon See careless oil, Angelica oil, oil of ginger, catnip oil, Fructus Forsythiae oil, eucalyptus oil, perilla herb oil, Oleum Citri Reticulatae, oil of negundo chastetree, attar of rose, peppermint oil, Oil of Herba Artemisiae Scopariae, ennel oil, pine wood oil, caryophyllus oil, oil of badian, thyme oil, cinnamon oil, Blumea oil, perilla oil, turmeric Oil, cajeput oil, lavender oil, inulol, patchouli oil, verbena oil, absinthium, sage clary oil, Atractylis oil, myrtle Oil, lemon oil, Fructus Aurantii Immaturus oil, basil oil, Folium Perillae oil, art (pine) pomegranate oil, coconut oil, cardamom oil, olive oil, lemongrass Oil, geranium oil, herba elsholtziae oil, spearmint oil, Du Shan oil, Herba Pogostemonis oil, levant storax oil, oil of Ribes nigrum L, magnolia vine fruit oil, grass-leaved sweetflag Oil, selinum oil, Fructus Phellodendri oil, lavender oil, rosemary oil, bergamot oil, Oleum Ligni Santali, carrot seed oil, Cacumen Cupressi oil, celery Rapeseed oil, origanum oil, citronellal oil, coriander oil, neroli oil, mace oil, onion oil, sandalwood oil, tagetes oil, thyme Oil, Java Cananga Oil, glyceryl triacetate, midchain oil, middle long-chain oil, acetin, Ergol, myristic acid isopropyl Ester, tributyl citrate, ethyl succinate, dimethyl succinate, alkyl (C12-C15) benzene methyl, cognac oil, decanedioic acid two Ethyl ester, triethyl citrate, pentaerythrite phthalic dicarboxylic acid esters, allyl cyclohexyl propionate, ethyl benzoate, phenylacetic acid benzyl Ester, ethyl caprilate, gallic acid fourth diester, progallin A, propylgallate, methyl myristate, isovaleric acid isoamyl Ester, ethyl isovalerate, isopentyl palmitate, ethyl valerate, ethyl propionate, isoamyl propionate, benzyl propionate, methacrylic acid Methyl esters, 2-hydroxyethyl methacry-late, n-methyl-2-pyrrolidone, geranyl formate, propylene carbonate, propylene glycol carbonic acid Ester, diethyl malonate, caproic acid allyl alcohol, ethyl hexanoate, geranyl butyrate, benzyl butyrate, isoamyl butyrate, butyl butyrate, Ethyl butyrate, cinnamyl acetate, geranyl acetate, benzyl acetate, butyl acetate, ethyl acetate, oleic acid and oleate；
It is highly preferred that the oil is selected from one or more of：Ethyl oleate, Ergol, glyceryl triacetate, single acid Glyceride, midchain oil, castor oil, soybean oil, olive oil, sesame oil, corn oil；
Most preferably, the oil is selected from castor oil or soybean oil.
4. delivery system according to any one of claim 1 to 3, which is characterized in that the solvent is selected from following one kind It is or a variety of：Ethyl alcohol, ethyl lactate, 1,2-PD, ethyl acetate；Preferably ethyl alcohol and/or ethyl lactate；
The analgestic is selected from one or more of：Benzyl alcohol, anesin, lidocaine, procaine, sieve piperazine card Free alkali, Propofol, propofol derivative, C16H25NO2, the height of cause, totokaine, mepivacaine, Articaine, Bupivacaine etc. Black A prime, rotundine, pentazocine, cyclobutane, fentanyl and its derivatives；Preferably, the town Pain agent is selected from benzyl alcohol, anesin, lidocaine, procaine, Ropivacaine, totokaine, mepivacaine, Articaine And/or Bupivacaine；Most preferably, the analgestic is benzyl alcohol or lidocaine.
The antioxidant is selected from lipoic acid and/or vitamin E.
5. delivery system according to any one of claim 1 to 4, which is characterized in that each Composition Weight Parts are matched Than for：
6~30 parts of main ingredient, preferably 6.25~25 parts, more preferably 6.25~20 parts；
10~60 parts of solvent, preferably 10~50 parts, more preferably 15~45 parts；
0~5 part of analgestic, preferably 0~3 part, more preferably 1~2 part；
0~1 part of antioxidant, preferably 0~0.8 part, more preferably 0.1~0.5 part；
30~75 parts of slow-release material, preferably 40~70 parts, more preferably 45~65 parts.
6. delivery system according to any one of claim 1 to 5, which is characterized in that in the slow-release material phosphatide with The ratio of oil is 1:0~1：15.0, preferably 1：0.2~1：5.0, most preferably：1:0.3~1：3.0.
7. delivery system according to any one of claim 1 to 6, which is characterized in that the delivery system further includes packet Material；Preferably, the packaging material is selected from one or more of：Cillin bottle, ampoule, refilling type syringe, clamped bottle.
8. the preparation method of delivery system according to any one of claim 1 to 7, which is characterized in that the method packet Include following steps：
(1) prepared by liquid：Precision, which weighs a certain amount of main ingredient and adds in the solvent of formula ratio, extremely to be dissolved, then add the town of formula ratio Then pain agent, antioxidant add formula ratio slow-release material to dissolving, mixing prepares required liquid to dissolving；Finally again with oil Fat or coordinative solvent are settled to designated volume；
(2) it is aseptic subpackaged：Aseptically, the liquid prepared is crossed into miillpore filter degerming, then under sterile nitrogen protection It is divided in cillin bottle, tamponade, Zha Gai, places 2-8 DEG C of preservation；
Preferably, the method that course of dissolution is taken in the step (1) is stirring, shearing or ultrasonic；The slow-release material is phosphorus Fat and/or oil；
It is highly preferred that in the step (2), the aperture of the miillpore filter is 0.1~1 μm, preferably 0.1~0.5 μm, optimal It is selected as 0.2 μm.
9. delivery system according to any one of claim 1 to 7 is preparing the medicine for deep intramuscular injection administration Application in product.
10. the delivery system described in any one of claim 1 to 7 is in the medicine or medical device product for preparing treatment breast cancer In application.
CN201810007971.7A 2018-01-04 2018-01-04 Treat long-acting delivery system, preparation method and the application of breast cancer Pending CN108159055A (en)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111388406A (en) * 2020-03-24 2020-07-10 西安力邦医药科技有限责任公司 Fulvestrant or fulvestrant derivative injectable drug delivery storage reservoir and preparation method and application 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
CN111904928A (en) * 2019-05-07 2020-11-10 江苏恒瑞医药股份有限公司 Injectable pharmaceutical composition containing butorphanol and preparation method thereof
CN113116813A (en) * 2020-01-14 2021-07-16 中国科学院上海药物研究所 Depot ropivacaine pharmaceutical composition, preparation method and application thereof
CN113117092A (en) * 2020-01-14 2021-07-16 中国科学院上海药物研究所 Non-aqueous sustained-release drug delivery system
JP2021525278A (en) * 2018-05-24 2021-09-24 カシーヴ バイオサイエンシズ，リミテッド・ライアビリティ・カンパニー Fulvestrant prodrug
CN113597316A (en) * 2019-04-15 2021-11-02 湖州依诺唯新药物制剂有限公司 Lipid pharmaceutical preparation and application thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040175402A1 (en) * 2001-07-07 2004-09-09 Gellert Paul Richard Formulation
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
CN104224702A (en) * 2014-08-11 2014-12-24 杭州九源基因工程有限公司 Fulvestrant-containing medicine preparation
CN107362142A (en) * 2016-05-13 2017-11-21 山东新时代药业有限公司 A kind of fulvestrant lipidosome injection and preparation method thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040175402A1 (en) * 2001-07-07 2004-09-09 Gellert Paul Richard Formulation
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
CN104224702A (en) * 2014-08-11 2014-12-24 杭州九源基因工程有限公司 Fulvestrant-containing medicine preparation
CN107362142A (en) * 2016-05-13 2017-11-21 山东新时代药业有限公司 A kind of fulvestrant lipidosome injection and preparation method thereof

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2021525278A (en) * 2018-05-24 2021-09-24 カシーヴ バイオサイエンシズ，リミテッド・ライアビリティ・カンパニー Fulvestrant prodrug
JP7653092B2 (en) 2018-05-24 2025-03-28 シヴァンカ リサーチ リミテッド ライアビリティ カンパニー Fulvestrant prodrug
JP7384903B2 (en) 2018-05-24 2023-11-21 ケーアイ ファーマシューティカルズ，リミテッド・ライアビリティ・カンパニー fulvestrant prodrug
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
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
CN113597316A (en) * 2019-04-15 2021-11-02 湖州依诺唯新药物制剂有限公司 Lipid pharmaceutical preparation and application thereof
CN113597316B (en) * 2019-04-15 2023-11-24 湖州依诺唯新药物制剂有限公司 Lipid pharmaceutical formulation and use thereof
CN111904928A (en) * 2019-05-07 2020-11-10 江苏恒瑞医药股份有限公司 Injectable pharmaceutical composition containing butorphanol and preparation method thereof
CN113116813A (en) * 2020-01-14 2021-07-16 中国科学院上海药物研究所 Depot ropivacaine pharmaceutical composition, preparation method and application thereof
CN114980893A (en) * 2020-01-14 2022-08-30 中国科学院上海药物研究所 Long-acting ropivacaine pharmaceutical composition and preparation method and application thereof
CN115038464A (en) * 2020-01-14 2022-09-09 中国科学院上海药物研究所 A non-aqueous sustained-release drug delivery system
CN113117092A (en) * 2020-01-14 2021-07-16 中国科学院上海药物研究所 Non-aqueous sustained-release drug delivery system
WO2021143746A1 (en) * 2020-01-14 2021-07-22 中国科学院上海药物研究所 Non-aqueous sustained release drug delivery system
CN114980893B (en) * 2020-01-14 2023-12-29 中国科学院上海药物研究所 Long-acting ropivacaine pharmaceutical composition and preparation method and application thereof
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