CN102600064A

CN102600064A - Fulvestrant or fulvestrant derivative sustained release preparation and preparation method thereof

Info

Publication number: CN102600064A
Application number: CN2012100927244A
Authority: CN
Inventors: 卢伍党; 余惟平; 陈涛; 蔡睿
Original assignee: XIAN LIBANG PHARMACEUTICAL CO Ltd
Current assignee: XIAN LIBANG PHARMACEUTICAL CO Ltd
Priority date: 2012-03-31
Filing date: 2012-03-31
Publication date: 2012-07-25
Also published as: WO2013143300A1

Abstract

The invention relates to a long-acting fulvestrant or fulvestrant derivative sustained release preparation and preparation method of the long-acting fulvestrant or fulvestrant derivative sustained release preparation. The formula of the preparation provided by the invention comprises (1) 10mg/ml to 500mg/ml fulvestrant or fulvestrant derivative served as the active compound based on the content of preparation, (2) 3% to 80% of ketone compound or dimethyl sulfoxide served as the cosolvent based on the total weight of the preparation, (3) dispersing agent using vegetable oil or synthetic grease (ester), (4) analgesic, and (5) optional antioxidant.

Description

Fulvestrant or derivatives thereof slow releasing preparation and preparation method thereof

Technical field

The invention belongs to field of pharmaceutical preparations, relate to fulvestrant or derivatives thereof slow releasing preparation and preparation method thereof, specially refer to the prescription and the method for preparing of one type of breast cancer treatment medicine fulvestrant or derivatives thereof slow releasing preparation.

Background technology

According to statistics; The patient with breast cancer in the whole world annual nearly 1,000,000 is made a definite diagnosis at present; Account for 20% of the newly-increased malignant tumor of women, its sickness rate accounts for the 7-10% of the various malignant tumor of whole body, is one of a kind of women's of having a strong impact on physical and mental health even life-threatening modal malignant tumor.For decades recently, China's breast cancer incidence is and significantly increases trend year by year, and the patient is main with the women between 40-60 year, before and after menopause mainly, and presents rejuvenation trend.Present medical findings confirms; In the intravital cancerous cell of most patient with breast cancers high level estrogen receptor (ER) is arranged all; The secreted estrogen of body can stimulate the quick growth of this quasi-cancer cell of patient, and the height of body inner estrogen level has the positive relation with growth of tumor, thereby; Perhaps seeking various medicines suppresses ER level in the body through distinct methods, becomes one of main Therapeutic Method of such patient.

Fulvestrant or derivatives thereof (fulvestrant) is one type of new estrogen receptor antagon, and commonly used clinically is fulvestrant oiliness slow releasing preparation at present.The chemistry of fulvestrant is called 7-α-[9-(4,4,5,5,5-five fluorine penta sulfinyl) nonyl] female body-1,3,5-(10)-triolefin-3, and the 17-beta-diol, molecular formula is C ₃₂H ₄₇F ₅O ₃S is off-white powder, and its main biological activity has: (1) can combine with ER is competitive, and binding ability and estradiol are close, and (2) can excite receptor generation form to change, and retardance receptor ER combines with estrogenic, reduces concentration and cell growth inhibiting.Therefore, such medicine can be reduced the ER protein expression in the human breast cancer cell, does not change to have had neoplastic state, does not influence new generation, and growth of tumor is minimized, thereby produces the continued treatment effect.Zoopery finds, this medicine does not have estrogen action or the estrogenic antagonist of tamoxifen and to endometrial PAA, thereby related reactions obviously reduces, particularly in the danger that increases aspect the onset of endometrial cancer rate.

Azone (Azone), chemistry 1-dodecyl-aza-cycloheptane alkane by name-2-ketone, N-lauryl azepan-2-ketone, N-lauryl caprolactam or a word used for translation ketone, molecular formula is C ₁₈H ₃₅NO, structural formula such as figure below:

Azone can make keratodermatitis and lipid interact, and increases the flowability of active substance lipid in the horny layer gap, reduces the diffusional resistance of medicine in horny layer, plays the very strong short effect of oozing.Azone has the branch of aqueous and oiliness; The aqueous azone is that the oil-soluble azone becomes the efficient water soluble product through modification, and the two all has tangible transdermal effect, and clinical preceding safety evaluatio shows; Through per os, intraperitoneal injection mode, azone rat, the toxic LD of chmice acute ₅₀All more than 4g/kg, in addition evidence azones such as inferior anxious poison, skin and the damaged skin zest of animal, sensitization, teratogenesis nontoxic, have no side effect, nonirritant.The summary of data-searching at present result shows that clinically, azone is used for external preparation mainly as penetrating agent and antibacterial, also relate to orthopaedics, gynecological, department of pediatrics and department of dermatologry etc., use very extensive.Patent search result shows that azone can be used as the main solvent of avilamycin/ivermectin, is used for the exploitation of animal anthelmintic class injection; Experimental result shows that as avilamycin/ivermectin primary solvent, vegetable oil is that the injection zest of dispersant is little with azone; Do not form drug precipitation, close than drug effect compared with similar products, but the persistent period is longer; Reach that (New Tech. Development General Co., Beijing Agriculture Univ.'s Wang Yuwan etc. is studied and applied for a patent it, proprietary term: a kind of is the injection that contains avilamycin/ivermectin of cosolvent with benzyl benzoate or azone, number of patent application: 00129846.1 more than 45 days; Apply for unauthorized).Up to the present, azone does not have untoward reaction case report in clinical use.The present invention carries out the exploitation of slow releasing preparation with the azone compounds as the cosolvent of fulvestrant or derivatives thereof.

Dimethyl sulfoxide (dimethyl sulfoxide; DMSO) be a kind of organic compounds containing sulfur, molecular formula is C ₂H ₆OS, room temperature down be the transparency liquid of special odor, have most of materials such as high polarity, high boiling point, Heat stability is good,, ethanol mixed with water, propanol, benzene and chloroform, are described as " alembroth ".Nineteen fifty-three, DMSO begins to be applied to medical circle as a kind of commercial organic solvent; 1961, DMSO was first as the Organoprotective agent in the organ transplantation process; Nineteen sixty-five, in the DMSO zoopery, catching sight of it in American scholar possibly exert an influence to crystalline lens, subsequently for the safety of DMSO clinical practice; Each national scientific research personnel has carried out a large amount of experiments, and result of study shows that DMSO does not have tangible toxicity, does not find in people and the primate study that crystalline lens produces change; 1978, FDA has ratified DMSO can be used to treat interstitial cystitis, 2007; Research worker finds that DMSO can reduce the intracranial pressure of closed trauma of head; In the same year, FDA has ratified the research that DMSO can be used for alleviating the cerebral tissue swelling due to the closed injury of brain again, therefore; DMSO is present one of medicine of outbalance clinically, and the present invention mainly is that dimethyl sulfoxide is that the cosolvent of fulvestrant or derivatives thereof carries out the exploitation of slow releasing preparation.

Summary of the invention

The object of the invention is to provide the fulvestrant or derivatives thereof slow releasing preparation prescription crowd who can be used for treating breast carcinoma, and the object of the invention is to provide fulvestrant or derivatives thereof slow releasing preparation prescription crowd and method for preparing; The object of the invention is to provide the rat pharmacokinetics characteristic of fulvestrant sustained-release preparation.

Slow releasing preparation of the present invention comprises following composition:

1) reactive compound fulvestrant or derivatives thereof (10mg/ml-500mg/ml), 2) cosolvent (3%-80%), 3) dispersant: the oils and fats of vegetable oil or synthetic (ester), 4) analgesics, 5) antioxidant (optional).

Concrete, the composition that is comprised in every milliliter of preparation of the present invention is following:

Reactive compound fulvestrant or derivatives thereof basic structure is following among the present invention:

Said fulvestrant or derivatives thereof substituent group can be: 1) R ₁And R ₂Can be simultaneously-OH; 2) R ₁And R ₂Also can be one for-H ,-O-CO-R ,-CO-R perhaps-O-R, another is necessary for-OH.The or derivatives thereof of fulvestrant described in the prescription can be top wherein a kind of, two or more mixture.

Cosolvent can be selected from the present invention's prescription: dimethyl sulfoxide, acetone, butanone, N; N dimethyl formamide, N, the N dimethyl acetylamide,, one of N-N-methyl-2-2-pyrrolidone N-, N-ethyl-2-pyrrolidone, oil-soluble azone, water solublity azone and corresponding azone homologue (the azone analog that contains the different length carbochain) or their mixture.Be preferably: dimethyl sulfoxide, acetone, N, N dimethyl formamide, N, N dimethyl acetylamide, oil-soluble azone, N-N-methyl-2-2-pyrrolidone N-, N-ethyl-2-pyrrolidone.Most preferably be: dimethyl sulfoxide, oil-soluble azone, N-N-methyl-2-2-pyrrolidone N-.

Analgesics among the prescription crowd of the present invention can be selected from: chlorobutanol; Lignocaine (free alkali); Procaine (free alkali); Ropivacaine (free alkali); Mepivacaine (free alkali); Tetracaine (free alkali); Articaine (free alkali); Cloth caine (free alkali); Propofol; Propofol derivative; Tramadol; Lappaconitine and derivant thereof; Rotundine; Pentazocine; Bu; Fentanyl and its derivatives a kind of; Two or more mixture.Be preferably a kind of, two or more the mixture of benzyl alcohol, chlorobutanol, lignocaine (free alkali), procaine (free alkali), ropivacaine (free alkali), mepivacaine (free alkali), tetracaine (free alkali), articaine (free alkali), cloth caine (free alkali), propofol.Most preferably be benzyl alcohol, chlorobutanol, a kind of, two or more mixture of ropivacaine (free alkali).

The present invention fills a prescription, and dispersant can be selected among the crowd: 1) soybean oil; Semen Maydis oil; Olive oil; Oleum Brassicae campestris; Oleum Helianthi; Petiolus Trachycarpi oil; Oleum sesami; Oleum Hippophae; Fish oil; Seal oil; Adeps Phocae vitulinae; Shark oil; Oleum Curcumae; SEMEN COICIS oil; Oleum Bulbus Allii; Safflower oil; Fructus Zanthoxyli oil; Rhizoma Chuanxiong oil; Herba Artemisiae Annuae oil; Wintergreen oil; Radix Oenotherae erythrosepalae oil; Radix Angelicae Sinensis oil; Oil of Rhizoma Zingiberis Recens; Herba Schizonepetae oil; Fructus Forsythiae oil; Eucalyptus oil; Perilla oil; Oleum Citri Reticulatae; Oleum Viticis Negundo; Oleum Rosae Rugosae; Oleum menthae; Oil of Herba Artemisiae Scopariae; Fennel oil; Pine oil; Oleum Caryophylli; Oleum Anisi Stellati; Oleum thymi vulgaris; Oleum Cinnamomi; Oleum Folium Artemisiae Argyi; Fructus Perillae oil; Turmeric oil; Cortex Melaleucae leucadendrae oil; Essential lavender oil; Radix Aucklandiae oil; Patchouli oil; Herba Verbenae oil; Common Wormwood oil; Salvia Sclare L.oil; Rhizoma Atractylodis oil; Myrtus communis oil; Fructus Citri Limoniae oil; Fructus Aurantii Immaturus oil; Oleum Ocimi Gratissimi; Folium Perillae oil; Art (pine) pomegranate oil; Oleum Cocois; Fructus Amomi oil; Olive oil; Citronella oil; Oleum Pelargonii Graveolentis; Herba Moslae oil; Oleum Menthae Rotundifoliae; Du Shan oil; Herba Pogostemonis oil; Storax oil; Oil of Ribes nigrum L.; Fructus Schisandrae oil; Rhizoma Acori Graminei oil; Fructus Cnidii oil; Fructus Phellodendri oil; Oleum lavandula angustifolia; Oil of rosemary; Oleum bergamottae; Sandal oil; Fructus Dauci Sativae oil; Cacumen Cupressi oil; Seed oil of Herba Apii graveolentis; Herba Origani oil; Citronellal oil; Fructus Coriandri oil; Orange blossom oil; Semen Myristicae oil; Oil of Bulbus Allii Cepae; Oleum Santali albi; Flos Tagetis Erectae oil; Thyme oil; Cananga odorata oil; Glyceryl triacetate; Acetin; Benzyl benzoate; Isopropyl myristate; Tributyl citrate; Ethyl succinate; Dimethyl succinate; Alkyl (C ₁₂-C ₁₅) benzene methyl; Cognac oil; Ethyl sebacate; Triethyl citrate; The adjacent stupid dicarboxylic acid esters of tetramethylolmethane; Allyl cyclohexyl propionate; Ethyl benzoate; Benzyl phenylacetate; Ethyl caprilate; Gallic acid fourth diester; Progallin A; Propyl gallate; Methyl myristate; Iso-amyl iso-valeriate; Ethyl isovalerate; The isopentyl cetylate; Ethyl valerate; Ethyl propionate; Isoamyl propionate; Benzyl propionate; Methyl methacrylate; 2-hydroxyethyl methacry-late; Geranyl formate; Propylene carbonate; The propylene glycol carbonic ester; Diethyl malonate; The caproic acid 1-propenol-3; Ethyl hexanoate; Geranyl butyrate; Benzyl butyrate; Isoamyl butyrate; Butyl butyrate; Ethyl n-butyrate.; Cinnamyl acetate; Geranyl acetate; Benzyl acetate; Butyl acetate; Ethyl acetate; Ethyl lactate; Oleic acid and oleate analog derivative are a kind of; Two kinds or two or more with arbitrarily than carrying out blended mixture;

2) Oleum Ricini and Oleum Ricini related derivatives (mainly comprising polyoxyethylene castor oil (35,40), castor oil hydrogenated, sulfonated castor oil) any, two kinds or two or more with arbitrarily than carrying out blended mixture;

3) a kind of, two kinds or two kinds of mixture of Oleum Ricini and Oleum Ricini related derivatives (mainly comprising polyoxyethylene castor oil (35,40), castor oil hydrogenated, sulfonated castor oil) and other oils and fats (ester) type (refining back injection) type a kind of, two kinds or multiple above with arbitrarily than carrying out blended mixture, other oils and fats (ester) type includes soybean oil, Semen Maydis oil, olive oil, Oleum Brassicae campestris, Oleum Helianthi, Petiolus Trachycarpi oil, Oleum sesami, Oleum Hippophae, fish oil, seal oil, Adeps Phocae vitulinae, shark oil, Oleum Curcumae, SEMEN COICIS oil, Oleum Bulbus Allii, safflower oil, Fructus Zanthoxyli oil, Rhizoma Chuanxiong oil, Herba Artemisiae Annuae oil, wintergreen oil, Radix Oenotherae erythrosepalae oil, Radix Angelicae Sinensis oil, oil of Rhizoma Zingiberis Recens, Herba Schizonepetae oil, Fructus Forsythiae oil, eucalyptus oil, perilla oil, Oleum Citri Reticulatae, Oleum Viticis Negundo, Oleum Rosae Rugosae, Oleum menthae, oil of Herba Artemisiae Scopariae, fennel oil, pine oil, Oleum Caryophylli, Oleum Anisi Stellati, Oleum thymi vulgaris, Oleum Cinnamomi, Oleum Folium Artemisiae Argyi, Fructus Perillae oil, turmeric oil, Cortex Melaleucae leucadendrae oil, Essential lavender oil, Radix Aucklandiae oil, patchouli oil, Herba Verbenae oil, Common Wormwood oil, Salvia Sclare L.oil, Rhizoma Atractylodis oil, Myrtus communis oil, Fructus Citri Limoniae oil, Fructus Aurantii Immaturus oil, Oleum Ocimi Gratissimi, Folium Perillae oil, art (pine) pomegranate oil, Oleum Cocois, Fructus Amomi oil, olive oil, citronella oil, Oleum Pelargonii Graveolentis, Herba Moslae oil, Oleum Menthae Rotundifoliae, Du Shan oil, Herba Pogostemonis oil, Storax oil, oil of Ribes nigrum L., Fructus Schisandrae oil, Rhizoma Acori Graminei oil, Fructus Cnidii oil, Fructus Phellodendri oil, Oleum lavandula angustifolia, oil of rosemary, oleum bergamottae, sandal oil, Fructus Dauci Sativae oil, Cacumen Cupressi oil, seed oil of Herba Apii graveolentis, Herba Origani oil, citronellal oil, Fructus Coriandri oil, orange blossom oil, Semen Myristicae oil, oil of Bulbus Allii Cepae, Oleum Santali albi, Flos Tagetis Erectae oil, thyme oil, Cananga odorata oil and glyceryl triacetate, acetin, benzyl benzoate, isopropyl myristate, tributyl citrate, ethyl succinate, dimethyl succinate, alkyl (C ₁₂-C ₁₅) benzene methyl; Cognac oil; Ethyl sebacate; Triethyl citrate; The adjacent stupid dicarboxylic acid esters of tetramethylolmethane; Allyl cyclohexyl propionate; Ethyl benzoate; Benzyl phenylacetate; Ethyl caprilate; Gallic acid fourth diester; Progallin A; Propyl gallate; Methyl myristate; Iso-amyl iso-valeriate; Ethyl isovalerate; The isopentyl cetylate; Ethyl valerate; Ethyl propionate; Isoamyl propionate; Benzyl propionate; Methyl methacrylate; 2-hydroxyethyl methacry-late; Geranyl formate; Propylene carbonate; The propylene glycol carbonic ester; Diethyl malonate; The caproic acid 1-propenol-3; Ethyl hexanoate; Geranyl butyrate; Benzyl butyrate; Isoamyl butyrate; Butyl butyrate; Ethyl n-butyrate.; Cinnamyl acetate; Geranyl acetate; Benzyl acetate; Butyl acetate; Ethyl acetate; Ethyl lactate; Oleic acid and oleate analog derivative.

Be preferably: 1) soybean oil, Semen Maydis oil, olive oil, Oleum Brassicae campestris, Oleum Helianthi, Oleum sesami, ethyl lactate, glycerol trioleate, glyceryl triacetate, glyceryl monooleate, acetin, ethyl oleate, benzyl benzoate a kind of, two kinds or multiple above with arbitrarily than carrying out blended mixture;

2) Oleum Ricini, polyoxyethylene castor oil (35,40) a kind of, two kinds or multiple above with arbitrarily than carrying out blended mixture;

3) Oleum Ricini, polyoxyethylene castor oil (35,40) is a kind of or two kinds a kind of with soybean oil, Semen Maydis oil, olive oil, Oleum Brassicae campestris, Oleum Helianthi, ethyl lactate, glycerol trioleate, glyceryl triacetate, glyceryl monooleate, acetin, ethyl oleate, benzyl benzoate, two kinds or multiple above with arbitrarily than carrying out blended mixture.

Most preferably be: 1) soybean oil, Semen Maydis oil, olive oil, Oleum Brassicae campestris, Oleum Helianthi, Oleum sesami, glyceryl triacetate, ethyl oleate, benzyl benzoate a kind of, two kinds or multiple above with arbitrarily than carrying out blended mixture;

2) Oleum Ricini, polyoxyethylene castor oil (35) is a kind of or two kinds arbitrarily than carrying out blended mixture;

3) Oleum Ricini and soybean oil, Semen Maydis oil, olive oil, Oleum Brassicae campestris, Oleum Helianthi, Oleum sesami, glyceryl triacetate, ethyl oleate, benzyl benzoate a kind of, two kinds or multiple above with arbitrarily than carrying out blended mixture.

Preferably, fulvestrant or derivatives thereof prescription of the present invention is:

1)

2)

Concrete, can enumerate prescription and be:

1)

2)

3)

4)

Annotate: said miscella is meant the mixture of Oleum Ricini and soybean oil (volume ratio: 1: 1).

5)

Annotate: said miscella is meant the mixture of Oleum Ricini and Oleum sesami (volume ratio: 1: 1).

6)

Annotate: said miscella is meant the mixture of Oleum Ricini and Semen Maydis oil (volume ratio: 1: 1).

7)

8)

9)

10)

11)

12)

13)

14)

15)

16)

17)

18)

19)

20)

21)

22)

23)

24)

25)

26)

Slow releasing preparation of the present invention is the injectable drug slow releasing preparation.

The present invention also provides the method for preparing of slow releasing preparation of the present invention, may further comprise the steps:

The A formulation preparation: a kind of, two or more mixture in a certain amount of fulvestrant or derivatives thereof that precision is taken by weighing are dissolved in the cosolvent of certain volume; Ultrasonic or vortex to medicine dissolves fully; Be decided to be medicinal liquid 1; With antioxidant (optional), analgesics adds in a certain amount of dispersant (vegetable oil or synthetic oils and fats (ester) a kind of, two kinds or two or more mixture).After ultrasonic or vortex dissolves extremely fully, join in the medicinal liquid 1, utilize dispersant finally to be settled to 1ml, ultrasonic or vortex mixing is prepared required medicinal liquid;

B is aseptic subpackaged: the medicinal liquid for preparing was descended 0.45um organic membrane/nylon membrane removal of impurity, 0.22um organic membrane/nylon membrane degerming at aseptic condition; Be divided in the cillin bottle, feed degerming nitrogen, tamponade; Gland can get fulvestrant or derivatives thereof slow releasing preparation.

Also can be:

A sterile preparation preparation: in the cosolvent that is dissolved in certain volume in a certain amount of fulvestrant or derivatives thereof of precision weighing is a kind of, two or more the mixture, antioxidant (optional), analgesics; Ultrasonic or vortex to medicine dissolves fully, descends 0.45um organic membrane/nylon membrane remove impurity, 0.22um organic membrane/nylon membrane degerming in aseptic condition; Dispersant (vegetable oil or synthetic oils and fats (ester) a kind of, two kinds or two or more mixture) in 180 ℃ of dry heat sterilizations or 0.22um organic membrane/nylon membrane filtration sterilization, makes sterile preparation with aseptic pastille lactic acid ester solution and dispersant mixing;

The packing of B preparation: the sterile liquid medicine for preparing is divided in the cillin bottle, feeds degerming nitrogen, tamponade, gland can get fulvestrant or derivatives thereof slow releasing preparation.

Also can be:

The A formulation preparation: a certain amount of fulvestrant or derivatives thereof is a kind of, two or more mixture, antioxidant (optional), analgesics are dissolved in the cosolvent of certain volume; Ultrasonic or vortex hydrotropy; After treating that medicine dissolves fully, add vegetable oil (vegetable oil or synthetic oils and fats (ester) a kind of, two kinds or multiple mixture) to 1ml.Ultrasonic or vortex 30min is miscible;

B is aseptic subpackaged: the medicinal liquid for preparing was descended 0.45um organic membrane/nylon membrane removal of impurity, 0.22um organic membrane/nylon membrane degerming in aseptic condition; Be divided in the cillin bottle, feed degerming nitrogen, tamponade; Gland can get fulvestrant or derivatives thereof slow releasing preparation.

Be preferably:

Antioxidant optional described in the method for preparing of the present invention is: a kind of, two kinds or the multiple mixture of Davitin A compounds, vitamin-e ester compounds, Butylated hydroxyanisole, dibenzylatiooluene.

The present invention also provides the application of slow releasing preparation of the present invention in the medicine of preparation treatment breast carcinoma.

Fulvestrant sustained-release preparation of the present invention has following characteristics:

1, the present invention has proposed N-N-methyl-2-2-pyrrolidone N-, N-ethyl-2-pyrrolidone, azone or derivatives thereof, dimethyl sulfoxide are used for the oiliness slow releasing preparation preparation of fulvestrant or derivatives thereof as cosolvent, and carry out rat pharmacokinetics correlational study first.

2; The present invention is first with soybean oil; Semen Maydis oil; Olive oil; Oleum Brassicae campestris; Oleum Helianthi; Petiolus Trachycarpi oil; Oleum sesami; Oleum Hippophae; Fish oil; Seal oil; Adeps Phocae vitulinae; Shark oil; Oleum Curcumae; SEMEN COICIS oil; Oleum Bulbus Allii; Safflower oil; Fructus Zanthoxyli oil; Rhizoma Chuanxiong oil; Herba Artemisiae Annuae oil; Wintergreen oil; Radix Oenotherae erythrosepalae oil; Radix Angelicae Sinensis oil; Oil of Rhizoma Zingiberis Recens; Herba Schizonepetae oil; Fructus Forsythiae oil; Eucalyptus oil; Perilla oil; Oleum Citri Reticulatae; Oleum Viticis Negundo; Oleum Rosae Rugosae; Oleum menthae; Oil of Herba Artemisiae Scopariae; Fennel oil; Pine oil; Oleum Caryophylli; Oleum Anisi Stellati; Oleum thymi vulgaris; Oleum Cinnamomi; Oleum Folium Artemisiae Argyi; Fructus Perillae oil; Turmeric oil; Cortex Melaleucae leucadendrae oil; Essential lavender oil; Radix Aucklandiae oil; Patchouli oil; Herba Verbenae oil; Common Wormwood oil; Salvia Sclare L.oil; Rhizoma Atractylodis oil; Myrtus communis oil; Fructus Citri Limoniae oil; Fructus Aurantii Immaturus oil; Oleum Ocimi Gratissimi; Folium Perillae oil; Art (pine) pomegranate oil; Oleum Cocois; Fructus Amomi oil; Olive oil; Citronella oil; Oleum Pelargonii Graveolentis; Herba Moslae oil; Oleum Menthae Rotundifoliae; Du Shan oil; Herba Pogostemonis oil; Storax oil; Oil of Ribes nigrum L.; Fructus Schisandrae oil; Rhizoma Acori Graminei oil; Fructus Cnidii oil; Fructus Phellodendri oil; Oleum lavandula angustifolia; Oil of rosemary; Oleum bergamottae; Sandal oil; Fructus Dauci Sativae oil; Cacumen Cupressi oil; Seed oil of Herba Apii graveolentis; Herba Origani oil; Citronellal oil; Fructus Coriandri oil; Orange blossom oil; Semen Myristicae oil; Oil of Bulbus Allii Cepae; Oleum Santali albi; Flos Tagetis Erectae oil; Thyme oil; Cananga odorata oil; Glyceryl triacetate; Acetin; Tributyl citrate; Ethyl succinate; Dimethyl succinate; Alkyl (C ₁₂-C ₁₅) benzene methyl; Cognac oil; Ethyl sebacate; Triethyl citrate; The adjacent stupid dicarboxylic acid esters of tetramethylolmethane; Allyl cyclohexyl propionate; Ethyl benzoate; Benzyl phenylacetate; Ethyl caprilate; Gallic acid fourth diester; Progallin A; Propyl gallate; Methyl myristate; Iso-amyl iso-valeriate; Ethyl isovalerate; The isopentyl cetylate; Ethyl valerate; Ethyl propionate; Isoamyl propionate; Benzyl propionate; Methyl methacrylate; 2-hydroxyethyl methacry-late; Geranyl formate; Propylene carbonate; The propylene glycol carbonic ester; Diethyl malonate; The caproic acid 1-propenol-3; Ethyl hexanoate; Geranyl butyrate; Benzyl butyrate; Isoamyl butyrate; Butyl butyrate; Ethyl n-butyrate.; Cinnamyl acetate; Geranyl acetate; Benzyl acetate; Butyl acetate; Ethyl acetate; Ethyl lactate; Oleic acid and oleate analog derivative; The Oleum Ricini related derivatives (mainly comprises polyoxyethylene castor oil (35; 40); Castor oil hydrogenated; Sulfonated castor oil) any; Two kinds or multiple mixture are used for the preparation of fulvestrant or derivatives thereof slow releasing preparation as dispersant.

Wherein, soybean oil (injection) is that the injectable of unique approval in China's pharmaceutic adjuvant is used the oiliness pharmaceutic adjuvant.

3, the present invention with oil-soluble azone, dimethyl sulfoxide as solvent application in the preparation of fulvestrant or derivatives thereof slow releasing preparation; Oil-soluble azone, dimethyl sulfoxide not only can dissolved substances, and can suppress the growth of antibacterial, help the preparation quality Control during Production; Reduce the generation of bacterial endotoxin in the preparation; At last, oil-soluble azone, dimethyl sulfoxide are compared with ethanol, and the zest of skin and tissue is obviously alleviated (result is verified for animal local injection administration irritant experiment); Therefore; Adopt oil-soluble azone, dimethyl sulfoxide as cosolvent, can reduce fulvestrant sustained-release preparation adverse reaction rate in use, improve the clinical use compliance of patient.

4, the present invention is through external medicine dissolution property screening experiment, and external different solvents compatibility is tested, and external viscosity is observed screening experiment; The stable screening experiment of external medicine low temperature (4 ℃); Animal local injection administration irritant experiment, the experiment of animal body internal dynamics, analysis-by-synthesis preparation recipe.

5, dispersant adopts soybean oil, Oleum sesami, olive oil and the Oleum Ricini of lower content to adopt the dispersant Oleum Ricini to compare with the mixture of other vegetable oil with present commercially available fulvestrant kind in the slow releasing preparation; Mobile omiting; Better along pin property, the fulvestrant kind of selling on institute's formulated and the market is compared and is convenient to inject.

6, the experiment of animal pharmacokinetics shows: the P of Rats K curvilinear characteristic of fulvestrant sustained-release preparation of the present invention shows that such preparation presents the good slow release effect; Fulvestrant Oily preparation of the present invention has rapid-action; Continue blood drug level higher (comparing), the characteristics of effective blood drug concentration longer duration in the animal body with business-like fulvestrant preparation (50mg/ml).

7, fulvestrant sustained-release preparation of the present invention is (when reducing by half dosed administration according to body weight; Azone is that cosolvent, soybean oil are dispersant) time P of Rats K curvilinear characteristic close with business-like fulvestrant preparation (50mg/ml); But preparation medicine fulvestrant use amount is the half the of business-like fulvestrant preparation, can reduce the patient treatment cost by significance.

8, various different fulvestrant preparations of the present invention can according to conventional method pharmaceutically, utilize conventional instrument preparation by those skilled in the art.

Description of drawings

Fig. 1: blood drug level is change curve (dimethyl sulfoxide is the fulvestrant preparation of cosolvent) in time

Fig. 2: blood drug level is change curve (azone is the fulvestrant preparation of cosolvent) in time

Fig. 3: blood drug level is change curve (dimethyl sulfoxide is the fulvestrant preparation of cosolvent) in time

Fig. 4: blood drug level is change curve (azone is the fulvestrant preparation of cosolvent) in time

The specific embodiment

Further specify the present invention through following experimental example and instance, but not as restriction the present invention

The dissolubility test of experimental example 1 fulvestrant

Experimental apparatus and medicine

The vortex appearance, ultrasonic washing unit, magnetic agitation appearance, high performance liquid chromatograph, manual pipettor of different size and supporting suction nozzle, suction nozzle box, 7ml cillin bottle, supporting bottle stopper, aluminium lid.

The fulvestrant crude drug, Xian Libang Pharmaceutical Co., Ltd.'s pharmacy two factories provide lot number: 080701; 1,3 butanediol, Chemical Reagent Co., Ltd., Sinopharm Group, lot number: F20090805, import packing; Glycerin, Ziguang Guhan Amino-acid Co., Ltd., Shantou, lot number 060306; Semen Maydis oil, North China pharmacy Kang Xin company limited, lot number: 081002; Oleum Helianthi, Shanghai Standard Food Co., Ltd., lot number: 20091113; The injection soybean oil, Xian Libang Pharmaceutical Co., Ltd.'s pharmacy one factory provides; Olive oil, the injection level, in bulk; Oleum Brassicae campestris, oil prodution industry company limited in Xi'an is good, lot number: 20091113; Oleum sesami, the fragrant positive food industry company limited in Xi'an, lot number: 20110701; Dehydrated alcohol, Xi'an San Pu chemical reagent company limited, lot number: 110105; The oil-soluble azone, source chemical industry company limited is thought by Xi'an Communications University; The N-N-methyl-2-2-pyrrolidone N-, Chemical Reagent Co., Ltd., Sinopharm Group.

Get 15 of 7ml cillin bottles; It is an amount of that precision takes by weighing the fulvestrant crude drug respectively, adds Oleum Brassicae campestris, olive oil, soybean oil, Oleum Helianthi, Semen Maydis oil, Oleum sesami, glycerin, 1,3 butanediol, oil-soluble azone, acetone, dimethyl sulfoxide, ethyl oleate, benzyl benzoate, glyceryl triacetate, N-N-methyl-2-2-pyrrolidone N-0.07-1ml respectively; Observe the medicine dissolution situation; If dissolving fully, then continue medicine and be added into (dissolubility＞200mg/ml alternative stops to add medicine, and experiment meets the requirements to the dissolubility of fulvestrant crude drug) till the saturation; Charge into nitrogen; The airtight placement of lucifuge 2-3 days to dissolving-deposition reaches balance, prepares as diluent with dehydrated alcohol and treats test agent, and the content in the test agent is treated in the high performance liquid chromatogram detection; Calculate the dissolubility of fulvestrant crude drug in different solvents, result such as table 1.

The dissolubility (25 ℃) of table 1 fulvestrant crude drug in different solvents

Remarks: fulvestrant crude drug dissolution velocity in azone is slower, but the mild heat hydrotropy, but the time is unsuitable long, and temperature is influential to fulvestrant stability.

Experimental result shows: the dissolubility of fulvestrant in oil-soluble azone, N-N-methyl-2-2-pyrrolidone N-, dimethyl sulfoxide, acetone better (＞200mg/ml); 1; Certain dissolubility (31.78mg/ml) is arranged in 3 butanediols, and dissolubility is all less than 4mg/ml in other solvent.Therefore; The dissolubility of oil-soluble azone, acetone, dimethyl sulfoxide, N-N-methyl-2-2-pyrrolidone N-satisfies the requirement as cosolvent in the fulvestrant sustained-release preparation; The data-searching result shows that acetone toxicity is apparently higher than the oil-soluble azone, and the N-N-methyl-2-2-pyrrolidone N-has slight zest (about adjustment pH value to 7; Reduce in the preparation N-N-methyl-2-2-pyrrolidone N-content and can to a certain degree alleviate its zest) tissues such as skins; Therefore, preferred oil dissolubility azone of the present invention, dimethyl sulfoxide are as the cosolvent in the fulvestrant sustained-release preparation, and the less important cosolvent of N-N-methyl-2-2-pyrrolidone N-is considered.

Experimental example 2 external different solvents compatibility tests

Above-mentioned different solvents is divided into oil-based solvent and non-oil-dissolving solvent, and precision is measured each 0.5ml of different solutions respectively, mixes each other in twos; Vortex 5 minutes static 10 minutes, is observed mutual miscible situation of different solvents and record; Observe next day again and examine once, the result is following:

Miscible situation statistics between two kinds of different solvents of table 2

Remarks: two kinds of solvents are respectively measured 0.5ml, and are miscible each other, and the miscible situation of static observation, experimental temperature are room temperature, and miscella is the mixture of soybean oil and Oleum Ricini, and N-Methyl pyrrolidone is claimed the N-N-methyl-2-2-pyrrolidone N-again.

Experimental result shows: oil-soluble azone, N-N-methyl-2-2-pyrrolidone N-can select different oil solutions as dispersant, and dimethyl sulfoxide only can select Oleum Ricini and miscella as dispersant.

Experimental example 3 external different auxiliary material compatibility tests

With reference to experimental example 1,2 experimental results; Be cosolvent with oil-soluble azone, dimethyl sulfoxide, N-N-methyl-2-2-pyrrolidone N-respectively; Benzyl benzoate, ethyl oleate, glyceryl triacetate, soybean oil, Oleum Ricini are dispersant; Benzyl alcohol, chlorobutanol are that analgesics carries out the test of different auxiliary material compatibility, and the result is as shown in table 3.

Miscible and dissolving situation statistics between table 3 cosolvent, dispersant, the analgesics

Remarks: different solvents is respectively measured 0.5ml, and is miscible, and the miscible situation of static observation, miscella ratio are 1: 1, and experimental temperature is a room temperature, and W is a benzyl alcohol, and U is a chlorobutanol.

Experimental result shows: oil-soluble azone, N-N-methyl-2-2-pyrrolidone N-can select mixture that ethyl oleate, benzyl benzoate, glyceryl triacetate and not greasy intermixture can select ethyl oleate and benzyl benzoate and not greasy mixture, glyceryl triacetate and Oleum Ricini as dispersant, dimethyl sulfoxide as dispersant, and three kinds of cosolvents all can select benzyl alcohol and chlorobutanol as analgesics.

Carry out the blank prescription design of slow releasing preparation with reference to top experimental example experimental result, the preferred concrete blank preparation recipe of part can be:

The blank prescription statistics of the preferred slow releasing preparation of table 4 part statistics

Annotate: miscella is a kind of, two or more the mixture of Oleum Ricini and soybean oil, Oleum sesami, Oleum Helianthi, olive oil, Oleum Brassicae campestris, Semen Maydis oil.

Experimental example 4 pharmaceutical preparation vitro stability experiments (4 ℃)

Carry out 4 ℃ of steady dissolution property mensuration of fulvestrant, detailed process is that precision takes by weighing a certain amount of fulvestrant crude drug, according to preferred blank prescription in the experimental example 3; Add earlier the cosolvent dissolving, after add analgesics, dispersant successively, seal after filling nitrogen; Prepare back 2h room temperature (25 ℃) and observe the preparation clarity, will not have the deposition preparation and select, continue to observe the preparation clarity at 4-6 ℃ of preservation 2-3d; Filtering out does not have the deposition preparation, and the concrete prescription of part is following:

Table 5: the highest pastille prescription design statistics

Annotate: miscella is Oleum Ricini and soybean oil, Oleum sesami, Oleum Helianthi, olive oil, Oleum Brassicae campestris, a kind of, two or more mixture of Semen Maydis oil.

Experimental example 5 external stickiness observation experiments

Choosing representative prescription in the experimental example 4 (is specially: prescription 1,3,5,7,9,11,16,20,22,26,34,42,46,48,50,54,58,62; Add up to 18 kinds; Concrete compound method is seen table 5) and each 10ml of business-like fulvestrant preparation (preparing according to the description prescription); Utilize NDJ-1 rotary viscosimeter appearance test formulation stickiness, each sample is tested 6 times altogether, asks its meansigma methods and adds up; Utilize 5ml syringe (containing the 0.7mm syringe needle) to carry out along the pin property testing concrete outcome such as following table:

Table 6: the different prescription viscosity test results (n=6, unit: mpa/s, 20 ℃) of fulvestrant

Annotate: compare with control formulation, ^*P＜0.01, ^*P＜0.05

The result shows: representative prescription 1,3,5,7,9,11,16,42 viscositys of the present invention are compared with the contrast prescription respectively, and significant difference (P＜0.01, P＜0.05) is arranged, and invention prescription stickiness is slightly larger than the contrast prescription; Prescription 46,48,58 viscositys are compared with the contrast prescription respectively; Significant difference (P＜0.01) is arranged; Invention prescription stickiness is less than the contrast prescription; Prescription 20,22,26,34,50,54,62 and the contrast prescription no significant difference of comparing show that along pin property testing result prescription 1,2 is slightly poor along pin property.All the other each groups are better along pin property.

Experimental example 6 animal local injection administration irritant experiments

Be the basis with experimental example 3～5, design experiment administration group is specifically like table 7: 66 of female New Zealand white rabbits (or Japan large ear rabbit), body weight 2kg-2.5kg; After adaptability was raised 2-3d under the experimental situation, all animal left and right sides hind legs were all shaved hair earlier, and handle with the depilatory depilation back; At random be divided into 11 group according to body weight next day, and 6 every group, according to the grouping situation; Each treated animal left side hind leg quadriceps femoris injecting normal saline 1.2ml, right side hind leg quadriceps femoris injection relative medicine 1.2ml, 1h observation reaction of animals and medicine-feeding part situation and keeping a record after the administration; Observation reaction of animals and medicine-feeding part situation and keep a record behind the 24h, animal put to death subsequently in 48h observation reaction of animals and medicine-feeding part situation and record; Cut open and get quadriceps femoris, vertically cut perusal injection site IR; And carrying out histopathologic examination, the perusal result marks according to table 10.

Table 7 irritant experiment prescription is chosen statistics

Annotate: miscella is the mixture of soybean oil and Oleum Ricini (1: 1)

Table 8 intramuscular injection local excitation reaction standards of grading

Experimental result such as following table:

Table 9 intramuscular injection local excitation reaction appraisal result

Annotate: prescription 2-6 compares with prescription 1 respectively, ^*P＜0.05, ^*P＜0.01.

Experimental result shows: each prescription of the present invention is compared with control formulation: each organizes intramuscular injection local excitation score value all less than control formulation; Wherein, Prescription 1-9 compares with matched group; Score value has significant difference (P＜0.01, P＜0.05), and each prescription intramuscular injection local irritation of the present invention is significantly less than control formulation.

Experimental example 7 animal drug disposition dynamic experiments one

Female sd inbred rats, 110, body weight 190-210g; Adaptability was raised after 2-3 days, was divided into 11 groups at random, 10 every group; Prescription specifically designs like table 7; According to the grouping situation, outer deep each prescription solution 0.2ml of side injection of right limb gastrocnemius (respectively organize rat body weight and all calculate administration) behind every group of each rat according to 200g, the light medicine-feeding part 1-2min that presses in injection back is to prevent the medicinal liquid outflow.Writing time after the administration; Respectively with administration before, 2h, 6h, 1d, 3d, 7d, 15d, 31d after the administration, the eye socket vein is got blood 0.3ml in the test tube of heparinization, the centrifugal 10min of 3500rpm; Quantitatively get serum 0.1ml; Utilize LS-MS-MS to measure fulvestrant concentration in the blood sample, concrete numerical value such as following table, blood drug level in time change curve shown in accompanying drawing 1 (dimethyl sulfoxide is the fulvestrant preparation of cosolvent), accompanying drawing 2 (azone is the fulvestrant preparation of cosolvent).

The blood drug level of different time points statistics one ( n=10) in rat body during table 10 intramuscular injection fulvestrant preparation of the present invention

Experimental result shows: all show slow releasing function preferably after each prescription administration, after the administered intramuscular 31 days the time, surveyed blood drug level still on effective blood drug concentration, concrete outcome is following:

Prescription 1 is commercially available fulvestrant preparation, and 2h blood drug level is 6.94 ± 0.82ng/ml after the administration, and administration 72h reaches peak value, and 744h (31d) back blood drug level is 9.30 ± 2.56ng/ml, and medicine presents the good slow release effect.

Prescription 1～3,6～10 animals administer dosage of the present invention are identical with control formulation; 2h blood drug level is all above valid density after the administration; Blood drug level rises rapidly behind the 12-24h, and 24-72h reaches the peak, and the peak time of comparing with control formulation slightly shifts to an earlier date and reaches peak concentration and obviously increases; Still on valid density, prescription of the present invention presents good slow releasing function to 744h (31d) back blood drug level.

Prescription 4,5 animals administer dosage of the present invention are compared with control formulation, and administration volume same dose doubles, and the zoopery result shows; 2h blood drug level is all above valid density after the administration, and blood drug level rises rapidly behind the 12-24h, and 72h reaches the peak; Reach about the twice that peak concentration is about control formulation; 744h (31d) back blood drug level is all greater than 12ng/ml, and more than the twice for control formulation, prescription of the present invention presents good slow releasing function.

Experimental example 8 animal drug disposition dynamic experiments two

Female sd inbred rats, 90, body weight 200 ± 10g; Raise after 2-3 days, be divided into 11 groups at random, 10 every group; Prescription specifically designs like table 11, and according to the grouping situation, solution 50mg/kg is respectively write out a prescription (if rat body weight all calculates administration according to 200g according to the experimental design injection in control formulation, deep, 1～7 group of each rat right hind leg gastrocnemius outside of prescription; Medicament contg is 100mg/ml; Be administration 0.1ml), 8 groups of experimental design dosages of prescription are 25mg/kg, the light medicine-feeding part 1-2min that presses in injection back is to prevent the medicinal liquid outflow.Write down administration time after the administration; Respectively with administration before with administration after 2h, 12h, 1d, 3d, 7d, 15d, 31d, the eye socket vein is got blood 0.3ml in the test tube of heparinization, the centrifugal 10min of 3500rpm; Quantitatively get serum 0.1ml; Utilize LS-MS-MS to measure fulvestrant concentration in the blood sample, concrete numerical value such as following table, blood drug level in time change curve shown in accompanying drawing 3 (dimethyl sulfoxide is the fulvestrant preparation of cosolvent), accompanying drawing 4 (azone is the fulvestrant preparation of cosolvent).

The design of table 11 animal drug disposition dynamic experiment two prescriptions

Annotate: miscella is the mixture of Oleum Ricini and soybean oil (1: 1).

Blood drug level statistics two (

n=10) of different time points in rat body during the different prescription fulvestrant of table 12 intramuscular injection preparation

Experimental result shows: each prescription of the present invention is compared with control formulation; Have close characteristics of pharmacokinetics, after the local administered intramuscular of rat during 31d, surveyed blood drug level and control formulation close; All on effective blood drug concentration, all show release effect preferably after the administration.

Embodiment 1

Prescription:

With 10mg fulvestrant crude drug, chlorobutanol 3mg, Vitamin E acetate (optional) 5mg, be dissolved in the dimethyl sulfoxide solvent of 0.03ml; Ultrasonic or vortex hydrotropy; Treat that medicine dissolves fully, after the solution clarification, add ethyl oleate 0.35ml; The vortex mixing adds Oleum Ricini again to 1ml.Ultrasonic or vortex 30min mixing descended 0.45um organic membrane/nylon membrane remove impurity, 0.22um organic membrane/nylon membrane degerming in aseptic condition, fed degerming nitrogen, tamponade, and gland promptly gets.

Embodiment 2

Prescription:

With 500mg fulvestrant crude drug, benzyl alcohol 50ul, Vitamin E acetate (optional) 5mg, be dissolved in the dimethyl sulfoxide solvent of 0.70ml, ultrasonic or vortex hydrotropy treats that medicine dissolves fully, after the solution clarification, adds Oleum Ricini to 1ml.Ultrasonic or vortex 30min is miscible, descended 0.45um organic membrane/nylon membrane remove impurity, 0.22um organic membrane/nylon membrane degerming in aseptic condition, feed degerming nitrogen, tamponade, gland promptly gets.

Embodiment 3

Prescription:

70mg fulvestrant crude drug, benzyl alcohol 50ul, Vitamin E acetate (optional) 5mg are dissolved in the dimethyl sulfoxide solvent of 0.10ml, and ultrasonic or vortex hydrotropy treats that medicine dissolves fully; After the solution clarification; Add ethyl oleate 0.30ml, the vortex mixing adds Oleum Ricini again to 1ml.Ultrasonic or vortex 30min is miscible, descended 0.45um organic membrane/nylon membrane remove impurity, 0.22um organic membrane/nylon membrane degerming in aseptic condition, feed degerming nitrogen, tamponade, gland promptly gets.

Embodiment 4

Prescription:

50mg fulvestrant crude drug, chlorobutanol 5mg, Vitamin E acetate (optional) 5mg are dissolved in the dimethyl sulfoxide solvent of 0.10ml; Ultrasonic or vortex hydrotropy treats that medicine dissolves fully, after the solution clarification; Add ethyl oleate 0.30ml; The vortex mixing adds miscella (one of Oleum Ricini and soybean oil, Oleum sesami, olive oil, Semen Maydis oil, Oleum Brassicae campestris or more than one mixture, ratio are 1: 1) again to 1ml.Ultrasonic or vortex 30min is miscible, descended 0.45um organic membrane/nylon membrane remove impurity, 0.22um organic membrane/nylon membrane degerming in aseptic condition, feed degerming nitrogen, tamponade, gland promptly gets.

Embodiment 5

Prescription:

140mg fulvestrant crude drug, benzyl alcohol 50ul, Vitamin E acetate (optional) 5mg are dissolved in the dimethyl sulfoxide solvent of 0.20ml; Ultrasonic or vortex hydrotropy treats that medicine dissolves fully, after the solution clarification; Add ethyl oleate 0.20ml; The vortex mixing adds miscella (one of Oleum Ricini and soybean oil, Oleum sesami, olive oil, Semen Maydis oil, Oleum Brassicae campestris or more than one mixture, ratio are 1: 1) again to 1ml.Ultrasonic or vortex 30min is miscible, descended 0.45um organic membrane/nylon membrane remove impurity, 0.22um organic membrane/nylon membrane degerming in aseptic condition, feed degerming nitrogen, tamponade, gland promptly gets.

Embodiment 6

Prescription:

10mg fulvestrant crude drug, Vitamin E acetate (optional) 5mg, chlorobutanol 3mg are dissolved in the oil-soluble azone of certain 0.10ml, and ultrasonic or vortex hydrotropy treats that medicine dissolves fully, after the solution clarification, adds soybean oil to 1ml.Ultrasonic or vortex 30min is miscible, descended 0.45um organic membrane/nylon membrane remove impurity, 0.22um organic membrane/nylon membrane degerming in aseptic condition, feed degerming nitrogen, tamponade, gland promptly gets.

Embodiment 7

Prescription:

10mg fulvestrant crude drug, Vitamin E acetate (optional) 5mg, chlorobutanol 3mg are dissolved in the oil-soluble azone of certain 0.10ml, and ultrasonic or vortex hydrotropy treats that medicine dissolves fully, after the solution clarification, adds Oleum sesami to 1ml.Ultrasonic or vortex 30min is miscible, descended 0.45um organic membrane/nylon membrane remove impurity, 0.22um organic membrane/nylon membrane degerming in aseptic condition, feed degerming nitrogen, tamponade, gland promptly gets.

Embodiment 8

Prescription:

10mg fulvestrant crude drug, Vitamin E acetate (optional) 5mg, chlorobutanol 3mg are dissolved in the oil-soluble azone of certain 0.10ml, and ultrasonic or vortex hydrotropy treats that medicine dissolves fully, after the solution clarification, adds olive oil to 1ml.Ultrasonic or vortex 30min is miscible, descended 0.45um organic membrane/nylon membrane remove impurity, 0.22um organic membrane/nylon membrane degerming in aseptic condition, feed degerming nitrogen, tamponade, gland promptly gets.

Embodiment 9

Prescription:

160mg fulvestrant crude drug, Vitamin E acetate (optional) 5mg, chlorobutanol 5mg are dissolved in the oil-soluble azone of certain 0.80ml, and ultrasonic or vortex hydrotropy treats that medicine dissolves fully, after the solution clarification, adds Oleum Ricini to 1ml.Ultrasonic or vortex 30min is miscible, descended 0.45um organic membrane/nylon membrane removal of impurity, 0.22um organic membrane/nylon membrane degerming in aseptic condition, feed degerming nitrogen, tamponade, gland promptly gets.

Embodiment 10

Prescription:

100mg fulvestrant crude drug, Vitamin E acetate (optional) 5mg, chlorobutanol 5mg are dissolved in the oil-soluble azone of certain 0.50ml, and ultrasonic or vortex hydrotropy treats that medicine dissolves fully, after the solution clarification, adds Oleum Ricini to 1ml.Ultrasonic or vortex 30min is miscible, descended 0.45um organic membrane/nylon membrane remove impurity, 0.22um organic membrane/nylon membrane degerming in aseptic condition, feed degerming nitrogen, tamponade, gland promptly gets.

Embodiment 11

Prescription:

90mg fulvestrant crude drug, Vitamin E acetate (optional) 5mg, chlorobutanol 5mg are dissolved in the oil-soluble azone of certain 0.55ml, and ultrasonic or vortex hydrotropy treats that medicine dissolves fully, after the solution clarification, adds Oleum sesami to 1ml.Ultrasonic or vortex 30min is miscible, descended 0.45um organic membrane/nylon membrane remove impurity, 0.22um organic membrane/nylon membrane degerming in aseptic condition, feed degerming nitrogen, tamponade, gland promptly gets.

Embodiment 12

Prescription:

90mg fulvestrant crude drug, Vitamin E acetate (optional) 5mg, chlorobutanol 5mg are dissolved in the oil-soluble azone of certain 0.55ml, and ultrasonic or vortex hydrotropy treats that medicine dissolves fully, after the solution clarification, adds olive oil to 1ml.Ultrasonic or vortex 30min is miscible, descended 0.45um organic membrane/nylon membrane remove impurity, 0.22um organic membrane/nylon membrane degerming in aseptic condition, feed degerming nitrogen, tamponade, gland promptly gets.

Embodiment 13

Prescription:

50mg fulvestrant crude drug, Vitamin E acetate (optional) 5mg, chlorobutanol 5mg are dissolved in the oil-soluble azone of certain 0.35ml, and ultrasonic or vortex hydrotropy treats that medicine dissolves fully, after the solution clarification, adds Oleum Ricini to 1ml.Ultrasonic or vortex 30min is miscible, descended 0.45um organic membrane/nylon membrane remove impurity, 0.22um organic membrane/nylon membrane degerming in aseptic condition, feed degerming nitrogen, tamponade, gland promptly gets.

Embodiment 14

Prescription:

40mg fulvestrant crude drug, Vitamin E acetate (optional) 5mg, chlorobutanol 5mg are dissolved in the oil-soluble azone of certain 0.30ml, and ultrasonic or vortex hydrotropy treats that medicine dissolves fully, after the solution clarification, adds olive oil to 1ml.Ultrasonic or vortex 30min is miscible, descended 0.45um organic membrane/nylon membrane remove impurity, 0.22um organic membrane/nylon membrane degerming in aseptic condition, feed degerming nitrogen, tamponade, gland promptly gets.

Embodiment 15

Prescription:

40mg fulvestrant crude drug, Vitamin E acetate (optional) 5mg, chlorobutanol 5mg are dissolved in the oil-soluble azone of certain 0.30ml, and ultrasonic or vortex hydrotropy treats that medicine dissolves fully, after the solution clarification, adds soybean oil to 1ml.Ultrasonic or vortex 30min is miscible, descended 0.45um organic membrane/nylon membrane remove impurity, 0.22um organic membrane/nylon membrane degerming in aseptic condition, feed degerming nitrogen, tamponade, gland promptly gets.

Embodiment 16

Prescription:

60mg fulvestrant crude drug, Vitamin E acetate (optional) 5mg, chlorobutanol 5mg are dissolved in the N-N-methyl-2-2-pyrrolidone N-of certain 0.10ml; Ultrasonic or vortex 30min hydrotropy; Treat that medicine dissolves fully, after the solution clarification, add glyceryl triacetate 0.30ml; Ultrasonic or vortex mixing adds Oleum Ricini again to 1ml.Ultrasonic or vortex 10min is miscible, descended 0.45um organic membrane/nylon membrane remove impurity in aseptic condition, 0.22um organic membrane/nylon membrane degerming feeds degerming nitrogen, tamponade, gland promptly gets.

Embodiment 17

Prescription:

55mg fulvestrant crude drug, benzyl alcohol 50ul, Vitamin E acetate (optional) 5mg are dissolved in the N-N-methyl-2-2-pyrrolidone N-of certain 0.10ml; Ultrasonic or vortex 30min hydrotropy; Treat that medicine dissolves fully, after the solution clarification, add ethyl oleate 0.25ml; Ultrasonic or vortex mixing adds soybean oil again to 1ml.Ultrasonic or vortex 10min is miscible, descended 0.45um organic membrane/nylon membrane remove impurity in aseptic condition, 0.22um organic membrane/nylon membrane degerming feeds degerming nitrogen, tamponade, gland promptly gets.

Embodiment 18

Prescription:

110mg fulvestrant crude drug, benzyl alcohol 50ul, Vitamin E acetate (optional) 5mg are dissolved in the N-N-methyl-2-2-pyrrolidone N-of certain 0.20ml; Ultrasonic or vortex 30min hydrotropy; Treat that medicine dissolves fully, after the solution clarification, add ethyl oleate 0.15ml; Ultrasonic or vortex mixing adds soybean oil again to 1ml.Ultrasonic or vortex 10min is miscible, descended 0.45um organic membrane/nylon membrane remove impurity in aseptic condition, 0.22um organic membrane/nylon membrane degerming feeds degerming nitrogen, tamponade, gland promptly gets.

Embodiment 19

Prescription:

120mg fulvestrant crude drug, chlorobutanol 5mg, Vitamin E acetate (optional) 5mg are dissolved in the N-N-methyl-2-2-pyrrolidone N-of certain 0.20ml; Ultrasonic or vortex 30min hydrotropy; Treat that medicine dissolves fully, after the solution clarification, add glyceryl triacetate 0.20ml; Ultrasonic or vortex mixing adds Oleum Ricini again to 1ml.Ultrasonic or vortex 10min is miscible, descended 0.45um organic membrane/nylon membrane remove impurity in aseptic condition, 0.22um organic membrane/nylon membrane degerming feeds degerming nitrogen, tamponade, gland can get the fulvestrant Oily preparation.

Claims

1. the slow releasing preparation of a fulvestrant or derivatives thereof is characterized in that, comprises in every ml of formulation:

(a) fulvestrant or derivatives thereof 10-500mg,

(b) cosolvent 0.03-0.80ml,

(c) analgesics 3-5mg/30-50 μ l,

(d) dispersant adds to 1ml;

Wherein, said fulvestrant or derivatives thereof has following structure:

Wherein:

1) R ₁And R ₂Be simultaneously-OH;

2) R ₁And R ₂One be-H ,-O-CO-R ,-CO-R perhaps-O-R, another is necessary for-OH;

And in preparation, can use a kind of, two or more mixture in the fulvestrant or derivatives thereof.

2. preparation according to claim 1 is characterized in that, comprises in every ml of formulation:

(a) fulvestrant or derivatives thereof 10-160mg

(b) cosolvent 0.05-0.80ml

(c) analgesics 3-5mg/30-50ul

(d) dispersant adds to 1ml.

3. preparation according to claim 1 and 2; It is characterized in that; Said cosolvent is selected from: dimethyl sulfoxide, acetone, butanone, N; N dimethyl formamide, N, a kind of, two or more the mixture of N dimethyl acetylamide, N-N-methyl-2-2-pyrrolidone N-, N-ethyl-2-pyrrolidone, oil-soluble azone, water solublity azone and corresponding azone derivant and homologue (the azone analog that contains the different length carbochain).

4. preparation according to claim 1 and 2; It is characterized in that said analgesics is selected from: a kind of, two or more the mixture of benzyl alcohol, chlorobutanol, lignocaine (free alkali), procaine (free alkali), ropivacaine (free alkali), mepivacaine (free alkali), tetracaine (free alkali), articaine (free alkali), cloth caine (free alkali), propofol, propofol derivative, tramadol, lappaconitine, rotundine, pentazocine, Bu, fentanyl and its derivatives.

5. according to the said preparation of claim 1, it is characterized in that said dispersant is selected from:

1) soybean oil; Semen Maydis oil; Olive oil; Oleum Brassicae campestris; Oleum Helianthi; Petiolus Trachycarpi oil; Oleum sesami; Oleum Hippophae; Fish oil; Seal oil; Adeps Phocae vitulinae; Shark oil; Oleum Curcumae; SEMEN COICIS oil; Oleum Bulbus Allii; Safflower oil; Fructus Zanthoxyli oil; Rhizoma Chuanxiong oil; Herba Artemisiae Annuae oil; Wintergreen oil; Radix Oenotherae erythrosepalae oil; Radix Angelicae Sinensis oil; Oil of Rhizoma Zingiberis Recens; Herba Schizonepetae oil; Fructus Forsythiae oil; Eucalyptus oil; Perilla oil; Oleum Citri Reticulatae; Oleum Viticis Negundo; Oleum Rosae Rugosae; Oleum menthae; Oil of Herba Artemisiae Scopariae; Fennel oil; Pine oil; Oleum Caryophylli; Oleum Anisi Stellati; Oleum thymi vulgaris; Oleum Cinnamomi; Oleum Folium Artemisiae Argyi; Fructus Perillae oil; Turmeric oil; Cortex Melaleucae leucadendrae oil; Essential lavender oil; Radix Aucklandiae oil; Patchouli oil; Herba Verbenae oil; Common Wormwood oil; Salvia Sclare L.oil; Rhizoma Atractylodis oil; Myrtus communis oil; Fructus Citri Limoniae oil; Fructus Aurantii Immaturus oil; Oleum Ocimi Gratissimi; Folium Perillae oil; Art (pine) pomegranate oil; Oleum Cocois; Fructus Amomi oil; Olive oil; Citronella oil; Oleum Pelargonii Graveolentis; Herba Moslae oil; Oleum Menthae Rotundifoliae; Du Shan oil; Herba Pogostemonis oil; Storax oil; Oil of Ribes nigrum L.; Fructus Schisandrae oil; Rhizoma Acori Graminei oil; Fructus Cnidii oil; Fructus Phellodendri oil; Oleum lavandula angustifolia; Oil of rosemary; Oleum bergamottae; Sandal oil; Fructus Dauci Sativae oil; Cacumen Cupressi oil; Seed oil of Herba Apii graveolentis; Herba Origani oil; Citronellal oil; Fructus Coriandri oil; Orange blossom oil; Semen Myristicae oil; Oil of Bulbus Allii Cepae; Oleum Santali albi; Flos Tagetis Erectae oil; Thyme oil; Cananga odorata oil; Glyceryl triacetate; Acetin; Benzyl benzoate; Isopropyl myristate; Tributyl citrate; Ethyl succinate; Dimethyl succinate; Alkyl (C12-C15) benzene methyl; Cognac oil; Ethyl sebacate; Triethyl citrate; The adjacent stupid dicarboxylic acid esters of tetramethylolmethane; Allyl cyclohexyl propionate; Ethyl benzoate; Benzyl phenylacetate; Ethyl caprilate; Gallic acid fourth diester; Progallin A; Propyl gallate; Methyl myristate; Iso-amyl iso-valeriate; Ethyl isovalerate; The isopentyl cetylate; Ethyl valerate; Ethyl propionate; Isoamyl propionate; Benzyl propionate; Methyl methacrylate; 2-hydroxyethyl methacry-late; Geranyl formate; Propylene carbonate; The propylene glycol carbonic ester; Diethyl malonate; The caproic acid 1-propenol-3; Ethyl hexanoate; Geranyl butyrate; Benzyl butyrate; Isoamyl butyrate; Butyl butyrate; Ethyl n-butyrate.; Cinnamyl acetate; Geranyl acetate; Benzyl acetate; Butyl acetate; Ethyl acetate; Ethyl lactate; Oleic acid and oleic acid esters a kind of; Two or more mixture;

2) in Oleum Ricini, polyoxyethylene castor oil (35,40), castor oil hydrogenated, the sulfonated castor oil a kind of, two kinds or multiple above with arbitrarily than carrying out blended mixture;

3) in Oleum Ricini, polyoxyethylene castor oil (35,40), castor oil hydrogenated, the sulfonated castor oil a kind of, two kinds or multiple mixture are a kind of with other oils and fats (ester) type (refining back injection), two kinds or multiple above with arbitrarily than carrying out blended mixture, other oils and fats (ester) class is soybean oil, Semen Maydis oil, olive oil, Oleum Brassicae campestris, Oleum Helianthi, Petiolus Trachycarpi oil, Oleum sesami, Oleum Hippophae, fish oil, seal oil, Adeps Phocae vitulinae, shark oil, Oleum Curcumae, SEMEN COICIS oil, Oleum Bulbus Allii, safflower oil, Fructus Zanthoxyli oil, Rhizoma Chuanxiong oil, Herba Artemisiae Annuae oil, wintergreen oil, Radix Oenotherae erythrosepalae oil, Radix Angelicae Sinensis oil, oil of Rhizoma Zingiberis Recens, Herba Schizonepetae oil, Fructus Forsythiae oil, eucalyptus oil, perilla oil, Oleum Citri Reticulatae, Oleum Viticis Negundo, Oleum Rosae Rugosae, Oleum menthae, oil of Herba Artemisiae Scopariae, fennel oil, pine oil, Oleum Caryophylli, Oleum Anisi Stellati, Oleum thymi vulgaris, Oleum Cinnamomi, Oleum Folium Artemisiae Argyi, Fructus Perillae oil, turmeric oil, Cortex Melaleucae leucadendrae oil, Essential lavender oil, Radix Aucklandiae oil, patchouli oil, Herba Verbenae oil, Common Wormwood oil, Salvia Sclare L.oil, Rhizoma Atractylodis oil, Myrtus communis oil, Fructus Citri Limoniae oil, Fructus Aurantii Immaturus oil, Oleum Ocimi Gratissimi, Folium Perillae oil, art (pine) pomegranate oil, Oleum Cocois, Fructus Amomi oil, olive oil, citronella oil, Oleum Pelargonii Graveolentis, Herba Moslae oil, Oleum Menthae Rotundifoliae, Du Shan oil, Herba Pogostemonis oil, Storax oil, oil of Ribes nigrum L., Fructus Schisandrae oil, Rhizoma Acori Graminei oil, Fructus Cnidii oil, Fructus Phellodendri oil, Oleum lavandula angustifolia, oil of rosemary, oleum bergamottae, sandal oil, Fructus Dauci Sativae oil, Cacumen Cupressi oil, seed oil of Herba Apii graveolentis, Herba Origani oil, citronellal oil, Fructus Coriandri oil, orange blossom oil, Semen Myristicae oil, oil of Bulbus Allii Cepae, Oleum Santali albi, Flos Tagetis Erectae oil, thyme oil, Cananga odorata oil, glyceryl triacetate, acetin, benzyl benzoate, isopropyl myristate, tributyl citrate, ethyl succinate, dimethyl succinate, alkyl (C ₁₂-C ₁₅) benzene methyl; Cognac oil; Ethyl sebacate; Triethyl citrate; The adjacent stupid dicarboxylic acid esters of tetramethylolmethane; Allyl cyclohexyl propionate; Ethyl benzoate; Benzyl phenylacetate; Ethyl caprilate; Gallic acid fourth diester; Progallin A; Propyl gallate; Methyl myristate; Iso-amyl iso-valeriate; Ethyl isovalerate; The isopentyl cetylate; Ethyl valerate; Ethyl propionate; Isoamyl propionate; Benzyl propionate; Methyl methacrylate; 2-hydroxyethyl methacry-late; Geranyl formate; Propylene carbonate; The propylene glycol carbonic ester; Diethyl malonate; The caproic acid 1-propenol-3; Ethyl hexanoate; Geranyl butyrate; Benzyl butyrate; Isoamyl butyrate; Butyl butyrate; Ethyl n-butyrate.; Cinnamyl acetate; Geranyl acetate; Benzyl acetate; Butyl acetate; Ethyl acetate; Ethyl lactate; Oleic acid and oleic acid esters.

6. according to the said preparation of claim 2～5, it is characterized in that the blank preparation combination of slow release is specially:

Wherein, said miscella is meant the mixture of one of Oleum Ricini and soybean oil, Oleum sesami, Semen Maydis oil, olive oil, Oleum Brassicae campestris, Oleum Helianthi.

7. preparation according to claim 1 is characterized in that, comprises in every milliliter of said preparation:

(a) fulvestrant 10mg,

(b) dimethyl sulfoxide 0.03ml,

(c) chlorobutanol 3mg,

(d) benzyl benzoate 0.37ml

(e) Oleum Ricini adds to 1ml.

8. preparation according to claim 1 is characterized in that, comprises in every milliliter of said preparation:

(a) fulvestrant 500mg,

(b) dimethyl sulfoxide 0.70ml,

(c) benzyl alcohol 50 μ l,

(d) Oleum Ricini adds to 1ml.

9. preparation according to claim 1 is characterized in that, comprises in every milliliter of said preparation:

(a) fulvestrant 70mg,

(b) dimethyl sulfoxide 0.10ml,

(c) benzyl alcohol 50 μ l,

(d) ethyl oleate 0.3ml

(e) Oleum Ricini adds to 1ml.

10. preparation according to claim 1 is characterized in that, comprises in every milliliter of said preparation:

(a) fulvestrant 60mg,

(b) dimethyl sulfoxide 0.10ml,

(c) chlorobutanol 50 μ l,

(d) ethyl oleate 0.30ml,

(e) miscella adds to 1ml,

Said miscella is meant the mixture of Oleum Ricini and soybean oil.

11. preparation according to claim 1 is characterized in that, comprises in every milliliter of said preparation:

(a) fulvestrant 60mg,

(b) dimethyl sulfoxide 0.10ml,

(c) chlorobutanol 5mg,

(d) ethyl oleate 0.30ml,

(e) miscella adds to 1ml,

Said miscella is meant the mixture of Oleum Ricini and Oleum sesami.

12. root is characterized in that according to the method for preparing of the said preparation of claim 1, comprises following step:

The A formulation preparation: a kind of, two or more mixture in a certain amount of fulvestrant or derivatives thereof that precision is taken by weighing are dissolved in the cosolvent of certain volume; Ultrasonic or vortex to medicine dissolves fully; Be decided to be medicinal liquid 1; To choose antioxidant wantonly, analgesics adds in a certain amount of dispersant (vegetable oil or synthetic oils and fats (ester) a kind of, two kinds or two or more mixture).After ultrasonic or vortex dissolves extremely fully, add medicinal liquid 1, utilize dispersant finally to be settled to 1ml, ultrasonic or vortex mixing is prepared required medicinal liquid;

B is aseptic subpackaged: the medicinal liquid for preparing descended 0.45um organic membrane/nylon membrane remove impurity, 0.22um organic membrane/nylon membrane degerming at aseptic condition, was divided in the cillin bottle, fed degerming nitrogen, and tamponade, gland gets final product.

13. the method for preparing according to the said preparation of claim 1 is characterized in that, comprises following step:

A sterile preparation preparation: in the cosolvent that is dissolved in certain volume in a certain amount of fulvestrant or derivatives thereof of precision weighing is a kind of, two or more mixture, optional antioxidant, the analgesics; Ultrasonic or vortex to medicine dissolves fully, descends 0.45um organic membrane/nylon membrane remove impurity, 0.22um organic membrane/nylon membrane degerming in aseptic condition; Dispersant (vegetable oil or synthetic oils and fats (ester) a kind of, two kinds or two or more mixture) in 180 ℃ of dry heat sterilizations or 0.22um organic membrane/nylon membrane filtration sterilization, makes sterile preparation with aseptic pastille lactic acid ester solution and dispersant mixing;

The packing of B preparation: the sterile liquid medicine for preparing is divided in the cillin bottle, feeds degerming nitrogen, tamponade, gland gets final product.

14. the method for preparing according to the said preparation of claim 1 is characterized in that, comprises following step:

A formulation preparation: a certain amount of fulvestrant or derivatives thereof, optional antioxidant, analgesics are dissolved in the cosolvent of certain volume; Ultrasonic or vortex hydrotropy; After treating that medicine dissolves fully; Add vegetable oil (vegetable oil or synthetic oils and fats (ester) a kind of, two kinds or multiple mixture) to 1ml, ultrasonic or vortex 30min is miscible;

B is aseptic subpackaged: the medicinal liquid for preparing descended 0.45um organic membrane/nylon membrane remove impurity, 0.22um organic membrane/nylon membrane degerming in aseptic condition, was divided in the cillin bottle, fed degerming nitrogen, and tamponade, gland gets final product.