CN113694017B - Fulvestrant injection preparation and preparation method thereof - Google Patents
Fulvestrant injection preparation and preparation method thereof Download PDFInfo
- Publication number
- CN113694017B CN113694017B CN202010393661.0A CN202010393661A CN113694017B CN 113694017 B CN113694017 B CN 113694017B CN 202010393661 A CN202010393661 A CN 202010393661A CN 113694017 B CN113694017 B CN 113694017B
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- China
- Prior art keywords
- fulvestrant
- injection
- preparation
- albumin
- water
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- VWUXBMIQPBEWFH-WCCTWKNTSA-N Fulvestrant Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 title claims abstract description 120
- 229960002258 fulvestrant Drugs 0.000 title claims abstract description 120
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Classifications
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- 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
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- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/32—Antioestrogens
Abstract
The invention belongs to the technical field of medicines, and provides a fulvestrant injection preparation and a preparation method thereof. The injection preparation of the invention does not contain oily substances and organic solvents, has low viscosity, is easy to filter, has simple and feasible preparation process, reduces the production cost of the medicine, and simultaneously has excellent stability, safety and good bioavailability.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a fulvestrant injection preparation and a preparation method thereof.
Background
Breast cancer is a cancerous disease in which breast gland epithelial cells undergo genetic mutation under the action of various oncogenes, so that the cells lose normal characteristics, abnormally proliferate and unordered squeeze and erode and destroy surrounding normal tissues. The breast cancer has the characteristics of strong invasiveness, difficult healing and slow disease progression. The statistics report of cancer in 2018 shows that the new incidence of breast cancer in 2014 China is about 27.89 ten thousand, which accounts for 16.51% of all malignant tumors of females, and the first place of malignant tumors of females is located. According to the international cancer research institutes report of the world health organization, the incidence rate and the death rate of female breast cancer in China are at a lower level in the world, but the incidence rate of female breast cancer accounts for 11.2% of the number of the incidence of female breast cancer in the world, and the incidence rate of female breast cancer death rate is as high as 9.2% in the United states, so that the prevention and control situation is not optimistic.
The chinese anticancer association indicates that although the incidence of chinese breast cancer is lower than in western countries, young patients are relatively more frequent due to the huge population base of our country, which is the leading world. Especially, the incidence rate of cities such as Beijing, shanghai and Tianjin is close to the level of developed countries in Europe and America, the average age of breast cancer diagnosis in China is 45-55 years old, 10-20 years old compared with western females, and patients under 35 years old account for about 10% to 15%. Meanwhile, china is one of countries with the highest rate of increase of the incidence rate of breast cancer, the rate of increase of the incidence rate of breast cancer is 3% each year, and the burden of preventing and treating cancers is still continuously increasing.
Fulvestrant, unlike Tamoxifen (TAM) and aromatase inhibitors aromatase inhibitors, AIs), is a novel estrogen receptor (estrogen receptor, ER) antagonist with novel mechanism of action that can act as an antitumor effect by blocking and degrading ER, reducing ER expression levels. Fulvestrant injection was developed by the pharmaceutical company aslicon and approved for sale in the united states in 2002, in europe and in 2010, respectively, under the trade name of fushide (specification: 0.25g;5 ml), approved for recurrence after or during anti-estrogen co-therapy, or for postmenopausal (including natural and artificial menopause) estrogen receptor positive locally advanced or metastatic breast cancer progressing in anti-estrogen therapy.
Commercially available fulvestrant injection and FushidePrescription composition: fulvestrant, ethanol (96% v/v), benzyl alcohol, benzyl benzoate and castor oil, and the benzyl benzoate has stimulation to eyes, skin, mucous membrane and upper respiratory tract in the preparation process according to the prescription, and protective articles such as masks, gloves and eyeshields are needed to be worn during operation, but the medical device still has potential threat to operators. Whereas fulvestrant also has a number of disadvantages for administration as an intramuscular injection, for example, the injection site response, including transient pain and inflammation, is that of an oil needle +.>One of the most common drug-related events reported is Bross, P.F.FDA Drug Approval Summaries:Fulvestrant [ J]The Oncololist 2002,7 (6): 477-480. If frequent administration is carried out, only events such as nerves, tissue injury, allergy and the like are increased continuously, and the safety of medication and the compliance of patients are affected.
The fulvestrant oil needle preparation disclosed in the patent CN103083231A and the patent CN103083236A respectively adopts soybean oil for injection and corn oil for injection as excipients; fulvestrant pharmaceutical composition disclosed in patent CN103070871B and prepared from medium-chain triglycerideInstead of benzyl benzoate, to reduce the irritation of benzyl benzoate. Although soybean oil for injection, corn oil for injection and medium chain glyceride are used as a nontoxic and high-safety functional greaseThe improvement is carried out on the basis of the above, but the transient pain condition caused by the high viscosity of the oil injection is not fundamentally changed, and meanwhile, in the aspect of preparation technology, the cleaning of the residual oil agent on the pipeline brings great test.
Patent CN103221052a discloses fulvestrant compositions and methods of use, wherein fulvestrant is included with the cyclodextrin being water-soluble unsubstituted or substituted α -cyclodextrin, β -cyclodextrin or γ -cyclodextrin to make a water-soluble formulation, which solves the problem of indissolvable fulvestrant, and also solves the problems of pain, injury and the like caused by injection of oil needle agent, but also brings the problem of renal toxicity of cyclodextrin while using cyclodextrin. Although it has been reported that hydroxyhydrocarbyl-beta-cyclodextrin appears to be less toxic than unsubstituted or alkylated cyclodextrin, and may be potentially useful for intravenous injection, the toxicity problem remains to be alert.
Patent CN101108168B discloses a preparation method of fulvestrant sustained-release microspheres, which is believed to have excellent effects of round morphology, uniform particle size distribution, drug loading up to more than 7%, encapsulation rate up to more than 80% and the like. The microsphere can volatilize all residual organic solvents in the microsphere only when the microsphere completely presents a solid structure, and is not ideal in preparation processing, for example, the production process is complex, pilot scale amplification is difficult and the like, and the release behavior of the microsphere in clinic is difficult to control and the like. Thus, it would be highly desirable to provide fulvestrant for injection that can be dissolved or diluted in an aqueous vehicle.
Disclosure of Invention
In order to solve the technical problems, the invention provides the fulvestrant injection preparation and the preparation method thereof, which fundamentally solve the pain and side effects brought to patients during injection and ensure safer administration.
The specific technical scheme is as follows:
the invention provides fulvestrant injection preparation which contains fulvestrant, albumin and an antioxidant.
Preferably, the weight ratio of fulvestrant to albumin in the preparation is 1:0.5-5; further preferably, the weight ratio of fulvestrant to albumin is 1:0.5-2.5; still more preferably, the weight ratio of fulvestrant to albumin is 1:1 to 2.5.
Preferably, the weight ratio of fulvestrant to antioxidant in the preparation is 1:0.05-1.
Preferably, the albumin is selected from bovine serum albumin, recombinant human serum albumin or human serum albumin.
Preferably, the antioxidant is selected from sodium sulfite, sodium metabisulfite, reduced glutathione, vitamin C or L-cysteine.
The invention also provides a method for preparing the fulvestrant injection preparation, which comprises the following steps:
(1) Adding the prescription amount of fulvestrant into an organic solvent, and stirring until the fulvestrant is dissolved to obtain an organic phase;
(2) Adding the albumin and the antioxidant with the prescription amount into water for injection, and stirring until the albumin and the antioxidant are dissolved to be used as water phase;
(3) The organic phase and the water phase are ultrasonically stirred and mixed by a cell disruption instrument to form coarse emulsion, a high-pressure homogenizer is used to form fine emulsion, and a rotary evaporator is used to decompress and volatilize the organic solvent;
(4) Adding water for injection, filtering with 0.22 μm filter membrane, and sterilizing to obtain fulvestrant injection preparation.
Preferably, the step (3) forms a fine emulsion having an average particle size of less than 150nm by a high pressure homogenizer.
Preferably, the amount of organic solvent used is determined by a person skilled in the art based on practical technical experience, to ensure a complete and sufficient degree of dissolution of fulvestrant, and not excessive to reduce the subsequent work of spin-evaporating the solvent, the concentration of fulvestrant in the organic phase being 2-10% in g/mL. It is further preferred that the concentration of fulvestrant in the organic phase is 5% in g/mL.
Preferably, the organic solvent can be selected from absolute ethanol, tertiary butanol and ethyl acetate; further preferably, the organic solvent is selected from ethanol or tert-butanol; still further preferably, the organic solvent is selected from ethanol.
Preferably, the high-pressure homogenizer in the step (3) has a homogenizing pressure of 30000 to 40000psi; further preferably, the high-pressure homogenizer homogenizes at a pressure of 36000 to 40000psi.
Preferably, the high-speed shearing speed in the step (3) is 9000-15000 rpm; further preferably, the high-speed shearing speed is 13000 to 15000rpm.
Preferably, in the step (3), the steps are homogeneously repeated for 2 to 6 cycles; it is further preferable that the cycle is homogeneously repeated for 4 to 6 cycles.
Preferably, the temperature required for rotary evaporation in the step (4) is 20-40 ℃.
Preferably, the pressure in the rotary evaporation in the step (4) is 0.04-0.1 Mpa; it is more preferable that the pressure during rotary evaporation is 0.06 to 0.08MPa.
The fulvestrant injection preparation of the invention can be prepared into a freeze-dried preparation by adding freeze-drying excipient, and the freeze-drying process can be a conventional freeze-drying process in the field.
Preferably, the weight ratio of fulvestrant to freeze-drying excipient is 1:0.005-0.03.
Preferably, the lyophilization excipient is selected from mannitol, glycine, dextran, xylitol or povidone.
Preferably, the prepared freeze-dried preparation and the re-dissolving solvent can be selected from physiological saline and glucose injection.
An injectable fulvestrant formulation of the invention may be used for locally advanced or metastatic breast cancer which recurs after or during anti-oestrogen adjuvant therapy or which is positive for the oestrogen receptor following menopause (including natural menopause and artificial menopause) progressing in anti-oestrogen therapy.
The dosage of fulvestrant injection prepared according to the present invention in liquid form or further prepared as a formulation in the form of a freeze-dried powder injection may vary with the particular mode of administration (e.g. intramuscular, intravenous intralesional injection or other route of administration known to those skilled in the art), and in any given case the most suitable route will depend on a variety of factors (e.g. severity of disease, progress of disease, etc.), the fulvestrant injection formulation of the present invention is preferably administered intravenously or intramuscularly.
The fulvestrant injection preparation and the preparation method of the invention have the following advantages:
(1) The fulvestrant injection preparation prepared by the invention does not contain any oily substances, so that the pain and side effects brought to patients during injection are fundamentally solved, the administration is safer, and the compliance of the patients is improved;
(3) The fulvestrant injection preparation prepared by the invention does not use surfactant such as tween 80 and the like to enhance the stability of the preparation, and overcomes the serious anaphylactic defect caused by the surfactant;
(4) The fulvestrant injection preparation prepared by the invention has average particle size smaller than 150nm, is easy to filter and reduces cost;
(5) The fulvestrant injection preparation prepared by the invention selects and uses the albumin with low concentration on the premise of ensuring the stability of the preparation, avoids adverse reactions of high-concentration protein on sensitization of human bodies, liquid retention and the like, and simultaneously reduces the dosage of the albumin and directly reduces the production cost.
Drawings
FIG. 1 is a graph showing changes in blood concentration of fulvestrant in rabbits after intramuscular injection.
Detailed Description
The present invention is further illustrated and explained below by way of examples, but the present invention is not limited to the following examples and production methods, and various modifications may be made without departing from the intention described herein and below, and are also included in the scope of the present invention.
Example 1
Prescription:
the preparation method comprises the following steps:
(1) Under the condition of room temperature, adding prescription amount of fulvestrant into 200mL of absolute ethyl alcohol, stirring until the fulvestrant is completely dissolved, and filling nitrogen for protection to prepare a fulvestrant solution with the concentration of 5% serving as an organic phase;
(2) Adding the prescription amount of bovine serum albumin and reduced glutathione into the water for injection at room temperature, stirring until the bovine serum albumin and the reduced glutathione are completely dissolved, and preparing a 5% bovine serum albumin solution serving as a water phase;
(3) Mixing the organic phase and the water phase together, mixing by a 400W ultrasonic cell disruption instrument, homogenizing for 30s, and emulsifying to form coarse emulsion;
(4) Homogenizing the prepared coarse emulsion by a high-pressure homogenizer under 36000psi homogenizing pressure, wherein the high-speed shearing speed is 15000rpm, and homogenizing and repeating for 4 cycles to obtain fine emulsion;
(5) The prepared fine emulsion is poured into a round bottom flask, and is subjected to rotary evaporation by a rotary evaporator under the conditions of 0.07Mpa and 30 ℃ water bath, the organic solvent in the emulsion is volatilized, the water for injection at room temperature is added to 1000mL in total volume, and finally the mixture is filtered by a PES filter membrane of 0.22 micron, so that the injection with the fulvestrant concentration of 10mg/mL is obtained.
Example 2
Prescription:
the preparation method comprises the following steps:
(1) Adding prescription amount of fulvestrant into 400mL of tertiary butanol at room temperature, stirring until the fulvestrant is completely dissolved, and filling nitrogen for protection to prepare 2.5% fulvestrant solution serving as an organic phase;
(2) Adding prescription amount of human serum albumin and sodium sulfite into room temperature water for injection, stirring until the mixture is completely dissolved, and preparing 5% human serum albumin solution serving as a water phase;
(3) Mixing the organic phase and the water phase together, mixing by a 400W ultrasonic cell disruption instrument, homogenizing for 1min, and emulsifying to form coarse emulsion;
(4) Homogenizing the prepared coarse emulsion by a high-pressure homogenizer under 40000psi homogenizing pressure at high-speed shearing speed of 9000rpm, and homogenizing and repeating for 5 cycles to obtain fine emulsion;
(5) The prepared fine emulsion is poured into a round bottom flask, and is subjected to rotary evaporation by a rotary evaporator under the conditions of 0.08mpa and 35 ℃ water bath, the organic solvent in the emulsion is volatilized, the room temperature water for injection is added to the total volume of 500mL, and finally the mixture is filtered by a PES filter membrane of 0.22 micron, so that the injection with the fulvestrant concentration of 20mg/mL is obtained.
Example 3
Prescription:
the preparation method comprises the following steps:
(1) Under the condition of room temperature, adding the prescription amount of fulvestrant into 150mL of ethyl acetate, stirring until the fulvestrant is completely dissolved, and filling nitrogen for protection to prepare 6.7% fulvestrant solution serving as an organic phase;
(2) Adding the prescription amount of bovine serum albumin and sodium metabisulfite into the water for injection at room temperature, stirring until the bovine serum albumin is completely dissolved, and preparing a 5% bovine serum albumin solution serving as a water phase;
(3) Mixing the organic phase and the water phase together, mixing by a 400W ultrasonic cell disruption instrument, homogenizing for 2min, and emulsifying to form coarse emulsion;
(4) Homogenizing the prepared coarse emulsion by a high-pressure homogenizer under 30000psi homogenizing pressure at high-speed shearing speed of 1300rpm, and homogenizing and repeating for 3 cycles to obtain fine emulsion;
(5) The prepared fine emulsion is poured into a round bottom flask, and is subjected to rotary evaporation by a rotary evaporator under the conditions of 0.06mpa and 25 ℃ water bath, the organic solvent in the emulsion is volatilized, the water for injection at room temperature is added to the total volume of 250mL, and finally the mixture is filtered by a PES filter membrane of 0.22 micron, so that the injection with the fulvestrant concentration of 40mg/mL is obtained.
Example 4
Prescription:
the preparation method comprises the following steps:
(1) Under the condition of room temperature, adding prescription amount of fulvestrant into 500mL of absolute ethyl alcohol, stirring until the fulvestrant is completely dissolved, and filling nitrogen for protection to prepare 2% fulvestrant solution serving as an organic phase;
(2) Adding prescription amount of human serum albumin and vitamin C into room temperature water for injection, stirring until the mixture is completely dissolved, and preparing 5% human serum albumin solution as water phase;
(3) Mixing the organic phase and the water phase together, mixing by a 400W ultrasonic cell disruption instrument, homogenizing for 2min, and emulsifying to form coarse emulsion;
(4) Homogenizing the obtained coarse emulsion under 38000psi homogenizing pressure with high-speed shearing speed of 14000rpm, and repeating homogenizing for 5 cycles to obtain fine emulsion;
(5) The prepared fine emulsion is poured into a round bottom flask, and is subjected to rotary evaporation by a rotary evaporator under the conditions of 0.1mpa and 40 ℃ water bath, the organic solvent in the emulsion is volatilized, the water for injection at room temperature is added to the total volume of 200mL, and finally the mixture is filtered by a PES filter membrane of 0.22 micron, so that the injection with the fulvestrant concentration of 50mg/mL is obtained.
Example 5
Prescription:
the preparation method comprises the following steps:
(1) Adding prescription amount of fulvestrant into 100mL of tertiary butanol at room temperature, stirring until the fulvestrant is completely dissolved, and filling nitrogen for protection to prepare 10% fulvestrant solution serving as an organic phase;
(2) Adding the prescribed amount of recombinant human serum albumin and reduced glutathione into room-temperature water for injection, and stirring until the recombinant human serum albumin and the reduced glutathione are completely dissolved to prepare a 5% recombinant human serum albumin solution serving as a water phase;
(3) Mixing the organic phase and the water phase together, mixing by a 400W ultrasonic cell disruption instrument, homogenizing for 1min, and emulsifying to form coarse emulsion;
(4) Homogenizing the prepared coarse emulsion under 40000psi homogenizing pressure with high-pressure homogenizer at high shearing speed of 10000rpm, and homogenizing and repeating for 2 cycles to obtain fine emulsion;
(5) The prepared fine emulsion is poured into a round bottom flask, and is subjected to rotary evaporation by a rotary evaporator under the conditions of 0.08mpa and 20 ℃ water bath, the organic solvent in the emulsion is volatilized, the water for injection at room temperature is added to the total volume of 166mL, and finally the mixture is filtered by a PES filter membrane of 0.22 micron, so that the injection with the fulvestrant concentration of 60mg/mL is obtained.
Example 6
Prescription:
the preparation method comprises the following steps:
(1) Under the condition of room temperature, adding prescription amount of fulvestrant into 300mL of absolute ethyl alcohol, stirring until the fulvestrant is completely dissolved, and filling nitrogen for protection to prepare 3.3% fulvestrant solution serving as an organic phase;
(2) Adding the prescription amount of bovine serum albumin and L-cysteine into room temperature water for injection, stirring until the mixture is completely dissolved, and preparing a 5% bovine serum albumin solution serving as a water phase;
(3) Mixing the organic phase and the water phase together, mixing by a 400W ultrasonic cell disruption instrument, homogenizing for 1min, and emulsifying to form coarse emulsion;
(4) Homogenizing the prepared coarse emulsion under 36000psi homogenizing pressure by a high-pressure homogenizer at a high-speed shearing speed of 14000rpm, and homogenizing and repeating for 4 cycles to obtain fine emulsion;
(5) The prepared fine emulsion is poured into a round bottom flask, and is subjected to rotary evaporation by a rotary evaporator under the conditions of 0.05mpa and 35 ℃ water bath, the organic solvent in the emulsion is volatilized, the water for injection at room temperature is added to the total volume of 125mL, and finally the mixture is filtered by a PES filter membrane of 0.22 micron, so that the injection with the fulvestrant concentration of 80mg/mL is obtained.
Example 7
Prescription:
the preparation method comprises the following steps:
(1) Under the condition of room temperature, adding prescription amount of fulvestrant into 100mL of absolute ethyl alcohol, stirring until the fulvestrant is completely dissolved, and filling nitrogen for protection to prepare 10% fulvestrant solution serving as an organic phase;
(2) Adding prescription amount of human serum albumin and vitamin E into room temperature water for injection, stirring until the mixture is completely dissolved, and preparing 5% human serum albumin solution as water phase;
(3) Mixing the organic phase and the water phase together, mixing by a 400W ultrasonic cell disruption instrument, homogenizing for 30s, and emulsifying to form coarse emulsion;
(4) Homogenizing the prepared coarse emulsion by a high-pressure homogenizer under 40000psi homogenizing pressure, and homogenizing at high-speed shearing speed of 15000rpm for 6 cycles to obtain fine emulsion;
(5) Pouring the prepared fine emulsion into a round bottom flask, rotationally evaporating by a rotary evaporator under the conditions of 0.04Mpa and 20 ℃ water bath, volatilizing the organic solvent in the emulsion, and supplementing the water for injection at room temperature to 100mL to obtain a solution preparation with the fulvestrant concentration of 100 mg/mL;
(6) Adding 0.1g of freeze-drying excipient mannitol into the prepared solution preparation, filtering by a PES (polyether sulfone) filter membrane of 0.22 microns, filling into a penicillin bottle, performing half-pressing on a brominated freeze-drying rubber plug, transferring into a CHRIST freeze dryer, and pre-freezing: cooling to-40deg.C, and maintaining for 1-2 hr; sublimation: vacuumizing to 15-20Pa, slowly heating to 20 ℃, and sublimating and drying for 10h; and (3) drying: heating to 20-25 ℃, preserving heat for 6h, resolving and drying, backfilling nitrogen to normal pressure after freeze-drying is finished, pressing the plugs, and capping to obtain the fulvestrant freeze-dried preparation.
Comparative example 1
Prescription:
the preparation method comprises the following steps: taking prescription amount of fulvestrant, ethanol (95%), benzyl alcohol and medium chain triglyceride, stirring and mixing at room temperature until fulvestrant is completely dissolved, adding castor oil to a final volume (10 ml), and stirring and mixing uniformly. Filtering the mixed solution for 1-2 times by a 0.2 micrometer filter to achieve the aim of sterilization, subpackaging the sample into injection vials or prefilled injection devices under the aseptic condition, and visually inspecting to obtain the product.
Comparative example 2
Prescription:
the preparation method comprises the following steps: weighing 96% ethanol and benzyl alcohol with a prescription amount, mixing, adding fulvestrant with a prescription amount, stirring, and dissolving; adding the prescribed amount of benzyl benzoate, stirring and uniformly mixing; adding the soybean oil for injection with the prescription amount to prepare the preparation solution into the final weight, and stirring and uniformly mixing; 5g of activated carbon is added, stirred for 30min at 25 ℃, filtered through a 0.45 micron filter membrane to remove carbon, and then filtered through a 0.22 micron filter membrane to sterilize. Filling the filtrate into 5ml ampoule bottle under aseptic condition, filling volume of 5.25ml, covering with aseptic nitrogen, and sealing. The preparation (50 mg/mL) was obtained.
Test example 1 irritation test of fulvestrant preparation
The fulvestrant injection preparations prepared in examples 1 to 6 and the fulvestrant freeze-dried preparation prepared in example 7 were subjected to experiments after re-dissolution of glucose injection.
Irritation refers to a reversible inflammatory response to the site of administration after administration of a non-oral formulation, and is referred to as corrosiveness if irreversible tissue damage occurs at the site of administration. The irritation test is to observe whether the blood vessel, muscle, skin, mucosa, etc. of animal is in contact with the test substance to cause local reaction such as red swelling, congestion, exudation, denaturation or necrosis. Therefore, referring to the technical guidelines for drug irritation, allergy and hemolytic studies issued by the national drug administration of the 2014 national drug administration, rabbits were selected as the irritation test animals, 3 animals per group were treated with physiological saline as a control, and the administration was respectively injected into the left and right quadriceps femoris muscle of the rabbits by a peer left and right self-contrast method, and local reactions after administration were observed, such as congestion, redness, and the like. The local stimulation response of the injection was observed by a section examination 48 hours after administration, and a local histopathological examination was performed, and the corresponding response level was calculated as shown in table 1. The total muscle irritation response level was calculated according to table 1, the average value was calculated, and the irritation level was determined according to table 2. The results of the irritation of fulvestrant formulations are given in table 3. If the difference between the highest and lowest of the quadriceps response levels is greater than 2, the animals should be retested.
TABLE 1 muscle stimulation response grading criteria
| Stimulus response | Reaction grade |
| No obvious change | 0 |
| Mild hyperemia, and is in the range of 0.5X1.0 cm or less | 1 |
| Moderate congestion, ranging from 0.5X1.0 cm or more | 2 |
| Severe hyperemia with muscle degeneration | 3 |
| Necrosis and brown denaturation | 4 |
| Occurrence of extensive necrosis | 5 |
Table 2 average score and grade
| Average score | Grade |
| 0.0～0.4 | Without any means for |
| 0.5～1.4 | Slight |
| 1.5～2.4 | Mild and mild |
| 2.5～3.4 | Moderate degree |
| 3.5～4.4 | Heavy weight |
| 4.5 or more | Severe severity of |
TABLE 3 irritation results for fulvestrant formulations
Table 3 shows that fulvestrant injection prepared according to the preparation process of the invention has no irritation to rabbits after intramuscular injection.
Test example 2 viscometry of fulvestrant injection formulation
Adopting an MCR302 Anton Paar rheometer, configuring a CP50-1 conical plate rotor and a flat plate temperature control of a Peltier temperature control P-PTD200, and controlling a test temperature to be 4 ℃,25 ℃ and 40 ℃; test conditions: shear rate of 1-100 s -1 ，1s -1 1 point, 100 points in total, the taking time of the point is linearly decreased by 10-1 s, and the total test is 550s. The fulvestrant injection preparations prepared in examples 1 to 6, the fulvestrant freeze-dried preparation prepared in example 7, the fulvestrant injection preparation prepared in comparative examples 1 and 2 and the fulvestrant injection preparation prepared in example 7 are subjected to viscosity test after being re-dissolved by glucose injection, and the results are counted as follows:
TABLE 4 viscosity statistics of fulvestrant injection formulations
Note that: the above examples and comparative examples are typical of newtonian fluids, i.e., the viscosity does not change with changes in shear rate, but the viscosity decreases significantly with increasing temperature.
The viscosity of the injection formulations of examples 1-7 prepared according to the preparation process of the invention is obviously lower than that of the formulations of comparative examples 1 and 2 by comparing the viscosity results of the fulvestrant formulations of Table 4. When the preparation is administrated by intramuscular injection, the preparation has low viscosity and short administration time, and the compliance of patients is improved.
Test example 3 blood concentration measurement
Fulvestrant injection preparations prepared in examples 1 and 7 were selected and represent fulvestrant injection preparations of the present invention. In order to examine the conditions of the blood concentration changes of fulvestrant injection preparations prepared in example 1, comparative example 1 and comparative example 2 and fulvestrant freeze-dried preparation prepared in example 7 in vivo, healthy adult rabbits are specially selected as experimental animals, 6 rabbits are sterilized and selected to be subjected to intramuscular injection at a plurality of places on the outer thigh muscle of the rabbits (the administration dose is calculated according to the equivalent dose ratio of body surface area between human and animals, and the administration dose of the rabbits is about 23 mg/kg), blood is taken 1, 3, 5, 7, 14 and 21 days after biochemical treatment is carried out on blood samples, and the blood concentration changes of the fulvestrant in the rabbits after intramuscular injection are detected by a high performance liquid chromatograph, as shown in figure 1.
The results of the blood concentration of the fulvestrant injected into the muscle show that the blood concentration of the preparation prepared in the embodiment 1 and 7 of the invention is smoother, the preparation is released uniformly, the blood concentration change range is small, the maintenance time is long, the blood concentration change range of the comparative example 1 and 2 is large, the maintenance time is short, and the administration period is short. The fulvestrant injection preparation prepared by the invention is more suitable for preparing medicines and is used for treatment.
Test example 4 stability measurement of fulvestrant formulation
Taking fulvestrant injection preparations prepared in examples 1-6, re-dissolving fulvestrant freeze-dried preparation prepared in example 7 by glucose injection, placing the fulvestrant injection preparation prepared in comparative examples 1 and 2 and the fulvestrant injection preparation prepared in comparative examples 1 and 2 in a constant temperature and humidity box with the temperature of 40+/-2 ℃ and the RH of 75+/-5%, sampling and detecting the fulvestrant injection preparation at the time of 0 day, 1 month, 3 months and 6 months respectively, and observing the conditions of related substances and content changes of the fulvestrant injection preparation.
TABLE 5 results of accelerated stability investigation
The results of the accelerated stability investigation of fulvestrant preparations in table 5 show that the fulvestrant injection preparations in examples 1 to 7 prepared according to the invention have the content of more than 99.5%, the content of related substances is less than 0.2%, the content and the related substances are not obviously changed after accelerating for 6 months, and the content of related substances is obviously increased and the content is obviously reduced after accelerating for 6 months in comparative examples 1 and 2. The example and the comparative example show that the fulvestrant injection preparation prepared according to the invention has good stability and is suitable for clinical use.
Claims (6)
1. A fulvestrant injection formulation, characterized in that: the preparation consists of fulvestrant, albumin, an antioxidant and water for injection;
the weight ratio of fulvestrant to albumin in the preparation is 1:0.5-5;
the weight ratio of fulvestrant to antioxidant in the preparation is 1:0.05-1;
the albumin is selected from bovine serum albumin and human serum albumin;
the antioxidant is selected from sodium sulfite, sodium metabisulfite, reduced glutathione, vitamin C or L-cysteine;
the method for the fulvestrant injection preparation is characterized by comprising the following steps of:
(1) Adding the prescription amount of fulvestrant into an organic solvent, and stirring until the fulvestrant is dissolved to obtain an organic phase;
(2) Adding the albumin and the antioxidant with the prescription amount into water for injection, and stirring until the albumin and the antioxidant are dissolved to be used as water phase;
(3) The organic phase and the water phase are ultrasonically stirred and mixed by a cell disruption instrument to form coarse emulsion, a high-pressure homogenizer is used to form fine emulsion, and a rotary evaporator is used to decompress and volatilize the organic solvent;
(4) Adding water for injection, filtering with 0.22 μm filter membrane, and sterilizing to obtain fulvestrant injection preparation.
2. Fulvestrant injection formulation according to claim 1, wherein: the concentration of fulvestrant in the organic phase is 2-10%, and the unit g/mL.
3. Fulvestrant injection formulation according to claim 1, wherein: the organic solvent is selected from absolute ethyl alcohol, tertiary butyl alcohol or ethyl acetate.
4. Fulvestrant injection formulation according to claim 1, wherein: the fulvestrant injection preparation can also be added with freeze-drying excipient to prepare a freeze-drying preparation.
5. The fulvestrant injection formulation of claim 4, wherein: the weight ratio of fulvestrant to freeze-drying excipient in the preparation is 1:0.005-0.03.
6. Fulvestrant injection formulation according to claim 1, wherein: the albumin is recombinant human serum albumin.
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| CN102784109A (en) * | 2012-08-22 | 2012-11-21 | 复旦大学 | Taxane medicines albumin nanoparticle preparation for injection and preparation method thereof |
| CN104224702A (en) * | 2014-08-11 | 2014-12-24 | 杭州九源基因工程有限公司 | Fulvestrant-containing medicine preparation |
| CN104434808A (en) * | 2014-07-03 | 2015-03-25 | 石药集团中奇制药技术（石家庄）有限公司 | Therapeutic nanoparticles and preparation method thereof |
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| WO2015033302A2 (en) * | 2013-09-06 | 2015-03-12 | Salah Uddin Ahmed | Fulvestrant compositions |
| JP2019516789A (en) * | 2016-05-06 | 2019-06-20 | イーグル ファーマスーティカルズ、インク． | Fulvestrant formulation and method of use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102784109A (en) * | 2012-08-22 | 2012-11-21 | 复旦大学 | Taxane medicines albumin nanoparticle preparation for injection and preparation method thereof |
| CN104434808A (en) * | 2014-07-03 | 2015-03-25 | 石药集团中奇制药技术（石家庄）有限公司 | Therapeutic nanoparticles and preparation method thereof |
| CN104224702A (en) * | 2014-08-11 | 2014-12-24 | 杭州九源基因工程有限公司 | Fulvestrant-containing medicine preparation |
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