CN103585103A - Sex hormone micro-nano human body injection emulsion containing TPGS, and preparation method thereof - Google Patents
Sex hormone micro-nano human body injection emulsion containing TPGS, and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the field of bioscience and bio-pharmaceutical technology, and specifically relates to a sex hormone micro-nano human body injection emulsion containing TPGS, and a preparation method thereof. Particle size of 90% particles in the sex hormone micro-nano human body injection emulsion is no more than 200nm, and average particle size of the sex hormone micro-nano human body injection emulsion is no more than 180nm, and sex hormone and TPGS are the effective components of the sex hormone micro-nano human body injection emulsion. Beneficial effects of the sex hormone micro-nano human body injection emulsion are that: the sex hormone micro-nano human body injection emulsion contains no obvious lipid components, and is capable of reducing occurrence rate of hyperlipidaemia and microorganism infection; tween is replaced by TPGS, so that influences on intravenous injection caused by antihypertensive effect and slight hemolysis effect of tween are avoided, and cardiovascular diseases induced by tween are avoided; and TPGS comprises hydrophilic PEG chains and hydrophobic vitamin E chains, and the hydrophobic vitamin E chains are capable of inserting into hydrophobic layers of sex hormone, so as to obtain sex hormone preparations coated by PEG, and increase stability of sex hormone.
Description
Technical field
The invention belongs to life sciences and biological pharmacy technical field, be specifically related to a kind of micro-nano human injection's Emulsion of gonadal hormone containing TPGS and preparation method thereof.
Background technology
Gonadal hormone sex hormone refers to the gonad by human body, and Placenta Hominis, adrenal cortex reticular zone etc. are organized synthetic steroid hormone; There is the effects such as the sexual organ of promotion maturation, secondary sexual characteristics growth and maintenance function.Human body ovary is mainly secreted two kinds of gonadal hormone---estrogen and progestogen, and testis is mainly secreted and be take testosterone as main androgen.
Gonadal hormone is endocrine cell manufacture, and human endocrine cell has gregarious and loose firmly two kinds.Gregarious formation endocrine gland organ, as hypophysis cerebri, thyroid, parathyroid gland, adrenal gland, islets of langerhans, ovary and testis; Loose live as the gut hormone cell in gastrointestinal mucosa, hypothalamus secretion peptide hormone cell etc.Gonadal hormone is a class steroid hormone of gonad secretion, and human health is played an important role.Common gonadal hormone includes clomiphene, cortisone acetate, danazol, dehydroepiandrosterone, ethinylestradiol, finasteride, fludrocortisone, depomedroxy progesterone acetate, megestrol, methyltestosterone, norethindrone, norgestrel, estradiol, progesterone, stanozolol, diethylstilbestrol, testosterone and tibolone etc.; Wherein progestogen and testosterone are modal gonadal hormone.Progestogen are mainly formed in rear ovulation or corpus luteum stage by ovary, and fraction is synthetic in period of pregnancy by adrenal gland and Placenta Hominis.
The clinical manifestation of Progesterone Secretion deficiency mainly contains premenstrual tension syndrome and menoxenia.At present, the use approach of progestogen mainly, by vagina, rectum and intramuscular injection, makes people maintain the physiological level of progesterone, but still can not reach at short notice level in blood luteal phase; Therefore address this problem the formula that need to improve progesterone medicine.
Testosterone is endogenous androgen, and endogenous androgen is the important indicator of maintaining male genitals's normal growth, develop and maintain secondary sex characteristics.Endogenous androgen directly affects reaching maturity of prostate, seminal vesicle, penis and scrotum etc.The reason that in blood plasma, testosterone concentration reduces mainly contains the toxicity damage of operation, chemotherapy, spinal cord injury, myocardial infarction, serious burn, ethanol or heavy metal.Yet oral testosterone curative effect of medication is poor, it is short that intestinal is injected testosterone medicine timeliness outward; Therefore, how to improve the timeliness of curative effect of medication and increase medicine; It is a prior art difficult problem urgently to be resolved hurrily.
In prior art, using the vein agent exploitation of fat-soluble medicine is difficult, as the vein agent of progesterone and testosterone.In order to address this problem, generally the fat-soluble medicine that is insoluble in water is used to one or more surfactants, make the forms such as Emulsion, micelle.In prior art, conventional surfactant is tween, but tween has blood pressure lowering and slight haemolysis, in intravenous fluid, is cautious use of.In addition, the lipid impurity content in intravenous injection is large, causes safety, the poor stability of injection, and malpractice easily occurs.In view of the above problems, improving one's methods in the urgent need to a kind of progesterone, testosterone and/or other gonadal hormone dosage forms.How changing formula, dosage form, thereby reduce to greatest extent side effect, solve the problems such as absorption is fast, weak curative effect, is currently available technology problem demanding prompt solution.
Summary of the invention
The object of the invention is to provide a kind of micro-nano human injection's Emulsion of gonadal hormone containing TPGS, and this micro-nano human injection's Emulsion has solved the defect of current gonadal hormone medicine, has the advantages that intravenous injection safety and stability are high; Another object of the present invention is to provide the preparation method containing the micro-nano human injection's Emulsion of TPGS gonadal hormone.
The technical solution used in the present invention is: a kind of micro-nano human injection's Emulsion of gonadal hormone containing TPGS, is characterized in that: in this micro-nano human injection's Emulsion, 90% breast grain particle diameter is no more than 200nm, and the mean diameter of this breast grain is no more than 180nm; The effective ingredient of described micro-nano human injection's Emulsion is gonadal hormone and TPGS, and solvent is water; The percentage by weight of its Sex Hormones and TPGS is:
Gonadal hormone 0.001%～10%
TPGS 0.01％～20％。
The content of described gonadal hormone can be low to moderate the weight 0.001% (active component that contains 0.1 milligram in 100 grams of solution) that accounts for total composition; Also can be as high as 10%, as concentrated solution, when clinical practice, can dilute use.
Described TPGS, is a kind of watermiscible vitamin E, has another name called vitamin E polyethylene glycol succinic acid ester.TPGS is the products of different specifications of being produced by different mol ratio by the Polyethylene Glycol of vitamin e succinate and different molecular weight; In the present invention, preferred vitamin E cetomacrogol 1000 succinate is as the surfactant of gonadal hormone.
Select TPGS to replace conventional tween at present as surfactant, not only reduced production cost, reduced the content of lipid impurity; Solved the impact on intravenous injection of tween blood pressure lowering and slight haemolysis simultaneously.In addition TPGS also has following superior performance: aspect Pharmaceutical, TPGS can improve the effectiveness of absorption, bioavailability and ingredient widely.Aspect personal-care supplies, TPGS can be used as hypoallergenic, non-irritating emulsifying agent, is widely used in adjuvant and cosmetics.Aspect Animal nutrition product, TPGS provides an absorption, vitamin E product that bioavailability is high for animal.
In described micro-nano human injection's Emulsion, also include cosurfactant.Cosurfactant is selected any one or more compositions in HS15-15, alcohol ester ether, poloxamer, Polyethylene Glycol, PEP-101, phospholipid or Ovum Gallus domesticus Flavus lecithin; The addition of described cosurfactant accounts for total weight percentages of components: 0.01～10%.
In described micro-nano human injection's Emulsion, include cosolvent.Cosolvent is selected polar solvent Polyethylene Glycol or non-polar solven triglyceride, and the addition of described cosolvent accounts for total weight percentages of components and is: 0.01～5%.Cosolvent is also cosolvent, and energy assist in dissolving matter is in the dissolving of main solvent, and the kind of cosolvent and use amount are put to death the character in concrete medicine.
Described micro-nano human injection's Emulsion includes pH value regulator.PH value regulator can be selected citric acid, sorbic acid, acetic acid, sulphuric acid, and hydrochloric acid, sodium bicarbonate, sodium hydrogen phosphate, any one or a few mixture in sodium hydroxide, the addition of described pH value regulator is no more than 1% of total composition weight.
Described micro-nano human injection's Emulsion can include etc. and to ooze adjusting agent.The solution that all and blood or tear have identical osmotic pressure is called isosmotic solution, waits to ooze adjusting agent and select sodium chloride or glucose.The osmotic pressure of injection generally all should be adjusted to etc. and to ooze or higher oozing, and it is exactly that a kind of simple grade is oozed method of adjustment that freezing point reduces data method, and the weak solution that freezing point is identical all has equal osmotic pressure.When sodium chloride or glucose regulate the freezing point of injection to be-0.52 ℃, ooze with blood plasma etc.
The preparation technology who contains the micro-nano human injection's Emulsion of gonadal hormone of TPGS, is characterized in that comprising the following steps:
(1), by gonadal hormone, cosurfactant and cosolvent, mixed dissolution, in pure water, is made solution;
(2) TPGS is added in solution, stir and make its mix homogeneously, make mixed liquor;
(3) in mixed liquor, add solvent, at room temperature stir until form transparent microemulsion solution; Described solvent is any one in pure water, 5% glucose injection or 0.9%NaCl.
(4) transparent microemulsion solution is passed through to wave filter, eliminate after the microparticle material and microorganism containing in microemulsion solution, the packing of product is sealed stand-by; The model that wave filter is selected is 0.22MCM.
The preparation technology of the described micro-nano human injection's Emulsion of gonadal hormone containing TPGS, it is characterized in that cosolvent, TPGS or TPGS and cosurfactant, and gonadal hormone is mixed to form a uniform liquid, the content of its Sex Hormones is not more than 20% of this total amount of liquid, and the content of TPGS or TPGS and cosurfactant is not more than 30%.
Containing the micro-nano human injection's Emulsion of gonadal hormone of TPGS, microemulsion Thermodynamically stable, is under the effect of surfactant, to form emulsion by two kinds of immiscible solvents, in microvesicle after nucleation, coalescent, reunion, heat treatment nanoparticle; Can not cause any solvent being separated in time course.
Micro-nano human injection's Emulsion can at room temperature be prepared, and product is a transparent liquid, sometimes slightly muddy; The granule that micro-nano human injection's Emulsion forms is small evenly, the filter aseptic filtration that can be 0.22mcm by aperture at an easy rate; In addition, the pain when hydrophilic particulate that includes medicine can fully reduce injection, can rapid dispersion when it is injected by vein in blood flow and tunica vasculose.In addition because it does not contain obvious lipid components, there is the risk that reduces hyperlipemia and infected by microbes.
Beneficial effect of the present invention: 1, do not contain obvious lipid components, there is the risk that reduces hyperlipemia and infected by microbes; 2, select TPGS to replace tween, solved the impact on intravenous injection of tween blood pressure lowering and slight haemolysis, and the cardiovascular disease of avoiding tween to cause; 3, utilize TPGS to have hydrophilic PEG chain and hydrophobic vitamin E chain, the hydrophobic chain of vitamin E can insert the hydrophobic layer of gonadal hormone, to form the gonadal hormone preparation of PEG parcel, has improved the stability of gonadal hormone; 4, the surfactant using TPGS (vitamin E) as gonadal hormone is not only conducive to medicine performance curative effect, and has increased the safety and stability of medicine; 5, to have curative effect high for micro-nano human injection's Emulsion, short treating period, the feature of good stability.
Ratio between related reagent is weight portion herein.
The specific embodiment
The concrete instrument and the material that in this experiment, relate to are as follows:
(1) experimental apparatus: the laboratory high-shear emulsion machine FSL-1 of Shanghai Farfly Energy Technology Co., Ltd.
(2) experiment material: TPGS 1000 or TPGS are produced by Wuhan English Na Shi Pharmaceutical.
(3) experimental technique
By the specific embodiment, technical scheme of the present invention is described further below.
Embodiment 1
Get the median chain triglyceride (miglyol 812) of 0.7 gram and the progesterone of 100 milligrams, under normal pressure, be heated to 45 degree, mixed dissolution; The TPGS 1000 of getting 5 grams adds wherein, continues to stir until dissolve completely.The pure water of 244.2 grams is dropwise added in above-mentioned solute, stir until form transparent microemulsion solution; Recently this microemulsion solution is passed through to 0.22M C M wave filter, to eliminate microparticle material and microorganism; Packing of product sealing is stand-by.
By ion, test result analyzed:
By concentration, be that 5% glucose injection joins among the solution that 25 milliliters of embodiment 1 prepare, to the last volume is 100 milliliters.In the water-bath of 50 degree, stir; The gross weight of the micro-nano emulsion formulation preparing due to embodiment 1 is 250 grams, wherein contains 100 milligrams of progesterone, so this adds 100 ml solns of 5% glucose injection to contain 10 milligrams of progesterone.Extract 5mL diluent and join among 25mL water, this solution is similarly heated to 50 degree stirring, then after cool to room temperature, packs analysis cell into.By Horiba LB-550 granulometer test particle size, analysis result is this particle average out to 150nm.
2, stability test
It is higher that micro-nano human injection's Emulsion can be made into curative effect, and the course for the treatment of is shorter, the better steroidal drug of stability, the assay of said preparation, rare bibliographical information.
Precision takes the sample that 3ml embodiment 1 makes, with buffer, be diluted to mensuration concentration, room temperature places 0,2,4,8h, dual-wavelength spectrophotometry, record trap and be respectively 0.613,0.614,0.614,0.615, that is: join solution trap in 8h almost unchanged, meet the quality of the pharmaceutical preparations and control requirement.
Embodiment 2
Get the median chain triglyceride (miglyol 812) of 0.7 gram and the progesterone of 100 milligrams, under normal pressure, be heated to 45 degree, mixed dissolution; The TPGS 1000 of getting 5 grams adds wherein, continues to stir until dissolve completely.244.2 grams of glucose injections are dropwise added in above-mentioned solute, stir until form transparent microemulsion solution; Recently this microemulsion solution is passed through to 0.22M C M wave filter, to eliminate microparticle material and microorganism; Packing of product sealing is stand-by.
By ion, test result analyzed:
By concentration, be that 5% glucose injection joins among the solution that 25 milliliters of embodiment 2 prepare, to the last volume is 100 milliliters.In the water-bath of 50 degree, stir; The gross weight of the micro-nano emulsion formulation preparing due to embodiment 2 is 250 grams, wherein contains 100 milligrams of progesterone, so this adds 100 ml solns of 5% glucose injection to contain 10 milligrams of progesterone.Extract 5mL diluent and join among 25mL water, this solution is similarly heated to 50 degree stirring, then after cool to room temperature, packs analysis cell into.By Horiba LB-550 granulometer test particle size, analysis result is this particle average out to 160nm.
2, stability test
It is higher that micro-nano human injection's Emulsion can be made into curative effect, and the course for the treatment of is shorter, the better steroidal drug of stability, the assay of said preparation, rare bibliographical information.
Precision takes the sample that 4ml embodiment 2 makes, with buffer, be diluted to mensuration concentration, room temperature places 0,2,4,8h, dual-wavelength spectrophotometry, record trap and be respectively 0.614,0.615,0.614,0.616, that is: join solution trap in 8h almost unchanged, meet the quality of the pharmaceutical preparations and control requirement.
Embodiment 3
Get the median chain triglyceride (miglyol 812) of 0.7 gram and the progesterone of 100 milligrams, under normal pressure, be heated to 45 degree, mixed dissolution; The TPGS 1000 of getting 5 grams adds wherein, continues to stir until dissolve completely.244.2 grams of brine injections (0.9%NaCl aqueous solution) are dropwise added in above-mentioned solute, stir until form transparent microemulsion solution; Recently this microemulsion solution is passed through to 0.22M C M wave filter, to eliminate microparticle material and microorganism; Packing of product sealing is stand-by.
By ion, test result analyzed:
By concentration, be that 5% glucose injection joins among the solution that 25 milliliters of embodiment 3 prepare, to the last volume is 100 milliliters.In the water-bath of 50 degree, stir; The gross weight of the micro-nano emulsion formulation preparing due to embodiment 3 is 250 grams, wherein contains 100 milligrams of progesterone, so this adds 100 ml solns of 5% glucose injection to contain 10 milligrams of progesterone.Extract 5mL diluent and join among 25mL water, this solution is similarly heated to 50 degree stirring, then after cool to room temperature, packs analysis cell into.By Horiba LB-550 granulometer test particle size, analysis result is this particle average out to 170nm.
2, stability test
It is higher that micro-nano human injection's Emulsion can be made into curative effect, and the course for the treatment of is shorter, the better steroidal drug of stability, the assay of said preparation, rare bibliographical information.
Precision takes the sample that 5ml embodiment 3 makes, with buffer, be diluted to mensuration concentration, room temperature places 0,2,4,8h, dual-wavelength spectrophotometry, record trap and be respectively 0.616,0.617,0.615,0.616, that is: join solution trap in 8h almost unchanged, meet the quality of the pharmaceutical preparations and control requirement.
Embodiment 4
Get the median chain triglyceride (miglyol 812) of 0.7 gram and the progesterone of 100 milligrams, under normal pressure, be heated to 45 degree, mixed dissolution; The TPGS 1000 of getting 5 grams adds wherein, continues to stir until dissolve completely.In 239.2 grams of pure water, add again the PLURONICS F87 of 5 grams; After to be dissolved, dropwise add in above-mentioned solute, stir until form transparent microemulsion solution; Recently this microemulsion solution is passed through to 0.22M C M wave filter, to eliminate microparticle material and microorganism; Packing of product sealing is stand-by.
By ion, test result analyzed:
By concentration, be that 5% glucose injection joins among the solution that 25 milliliters of embodiment 4 prepare, to the last volume is 100 milliliters.In the water-bath of 50 degree, stir; The gross weight of the micro-nano emulsion formulation preparing due to embodiment 4 is 250 grams, wherein contains 100 milligrams of progesterone, so this adds 100 ml solns of 5% glucose injection to contain 10 milligrams of progesterone.Extract 5mL diluent and join among 25mL water, this solution is similarly heated to 50 degree stirring, then after cool to room temperature, packs analysis cell into.By Horiba LB-550 granulometer test particle size, analysis result is this particle average out to 165nm.
2, stability test
It is higher that micro-nano human injection's Emulsion can be made into curative effect, and the course for the treatment of is shorter, the better steroidal drug of stability, the assay of said preparation, rare bibliographical information.
Precision takes the sample that 6ml embodiment 4 makes, with buffer, be diluted to mensuration concentration, room temperature places 0,2,4,8h, dual-wavelength spectrophotometry, record trap and be respectively 0.617,0.618,0.619,0.617, that is: join solution trap in 8h almost unchanged, meet the quality of the pharmaceutical preparations and control requirement.
Embodiment 5
Get the PEG400 of 4.0 grams and the testosterone of 100 milligrams, under normal pressure, be heated to 45 degree, mixed dissolution; The TPGS 1000 of getting 5 grams adds wherein, continues to stir until dissolve completely.240.9 grams of pure water are dropwise added in above-mentioned solute, stir until form transparent microemulsion solution; Recently this microemulsion solution is passed through to 0.22M C M wave filter, to eliminate microparticle material and microorganism; Packing of product sealing is stand-by.
By ion, test result analyzed:
By concentration, be that 5% glucose injection joins among the solution that 25 milliliters of embodiment 5 prepare, to the last volume is 100 milliliters.In the water-bath of 50 degree, stir; The gross weight of the micro-nano emulsion formulation preparing due to embodiment 5 is 250 grams, wherein contains 100 milligrams of testosterones, so this adds 100 ml solns of 5% glucose injection to contain 10 milligrams of testosterones.Extract 5mL diluent and join among 25mL water, this solution is similarly heated to 50 degree stirring, then after cool to room temperature, packs analysis cell into.By Horiba LB-550 granulometer test particle size, analysis result is this particle average out to 155nm.
2, stability test
It is higher that micro-nano human injection's Emulsion can be made into curative effect, and the course for the treatment of is shorter, the better steroidal drug of stability, the assay of said preparation, rare bibliographical information.
Precision takes the sample that 7ml embodiment 5 makes, with buffer, be diluted to mensuration concentration, room temperature places 0,2,4,8h, dual-wavelength spectrophotometry, record trap and be respectively 0.618,0.619,0.619,0.620, that is: join solution trap in 8h almost unchanged, meet the quality of the pharmaceutical preparations and control requirement.
Embodiment 6
Get the PEG400 of 4.0 grams and the testosterone of 100 milligrams, under normal pressure, be heated to 45 degree, mixed dissolution; The TPGS 1000 of getting 5 grams adds wherein, continues to stir until dissolve completely.244.2 grams of glucose injections are dropwise added in above-mentioned solute, stir until form transparent microemulsion solution; Recently this microemulsion solution is passed through to 0.22M CM wave filter, to eliminate microparticle material and microorganism; Packing of product sealing is stand-by.
By ion, test result analyzed:
By concentration, be that 5% glucose injection joins among the solution that 25 milliliters of embodiment 6 prepare, to the last volume is 100 milliliters.In the water-bath of 50 degree, stir; The gross weight of the micro-nano emulsion formulation preparing due to embodiment 6 is 250 grams, wherein contains 100 milligrams of testosterones, so this adds 100 ml solns of 5% glucose injection to contain 10 milligrams of testosterones.Extract 5mL diluent and join among 25mL water, this solution is similarly heated to 50 degree stirring, then after cool to room temperature, packs analysis cell into.By Horiba LB-550 granulometer test particle size, analysis result is this particle average out to 160nm.
2, stability test
It is higher that micro-nano human injection's Emulsion can be made into curative effect, and the course for the treatment of is shorter, the better steroidal drug of stability, the assay of said preparation, rare bibliographical information.
Precision takes the sample that 8ml embodiment 6 makes, with buffer, be diluted to mensuration concentration, room temperature places 0,2,4,8h, dual-wavelength spectrophotometry, record trap and be respectively 0.619,0.618,0.620,0.621, that is: join solution trap in 8h almost unchanged, meet the quality of the pharmaceutical preparations and control requirement.
Embodiment 7
Get the PEG400 of 4.0 grams and the testosterone of 100 milligrams, under normal pressure, be heated to 45 degree, mixed dissolution; The TPGS 1000 of getting 5 grams adds wherein, continues to stir until dissolve completely.In 235.9 grams of pure water, add again the PLURONICS F87 of 5 grams; After to be dissolved, dropwise add in above-mentioned solute, stir until form transparent microemulsion solution; After to be dissolved, dropwise add in above-mentioned solute, stir until form transparent microemulsion solution; Recently this microemulsion solution is passed through to 0.22M C M wave filter, to eliminate microparticle material and microorganism; Packing of product sealing is stand-by.
By ion, test result analyzed:
By concentration, be that 5% glucose injection joins among the solution that 25 milliliters of embodiment 7 prepare, to the last volume is 100 milliliters.In the water-bath of 50 degree, stir; The gross weight of the micro-nano emulsion formulation preparing due to embodiment 7 is 250 grams, wherein contains 100 milligrams of testosterones, so this adds 100 ml solns of 5% glucose injection to contain 10 milligrams of testosterones.Extract 5mL diluent and join among 25mL water, this solution is similarly heated to 50 degree stirring, then after cool to room temperature, packs analysis cell into.By Horiba LB-550 granulometer test particle size, analysis result is this particle average out to 140nm.
2, stability test
It is higher that micro-nano human injection's Emulsion can be made into curative effect, and the course for the treatment of is shorter, the better steroidal drug of stability, the assay of said preparation, rare bibliographical information.
Precision takes the sample that 9ml embodiment 7 makes, with buffer, be diluted to mensuration concentration, room temperature places 0,2,4,8h, dual-wavelength spectrophotometry, record trap and be respectively 0.621,0.620,0.622,0.621, that is: join solution trap in 8h almost unchanged, meet the quality of the pharmaceutical preparations and control requirement.
Embodiment 8
Get the median chain triglyceride (miglyol 812) of 0.7 gram, the Ovum Gallus domesticus Flavus lecithin of 3 grams and the progesterone of 100 milligrams, mixed dissolution; The TPGS 1000 of getting 5 grams adds wherein, continues to stir until dissolve completely.241.2 grams of pure water solution are added dropwise in the solution of MCT of progesterone, at room temperature stir until form transparent microemulsion solution; Recently this microemulsion solution is passed through to 0.22M C M wave filter, to eliminate microparticle material and microorganism; Packing of product sealing is stand-by.
By ion, test result analyzed:
By concentration, be that 5% glucose injection joins among the solution that 25 milliliters of embodiment 8 prepare, to the last volume is 100 milliliters.In the water-bath of 50 degree, stir; The gross weight of the micro-nano emulsion formulation preparing due to embodiment 8 is 250 grams, wherein contains 100 milligrams of progesterone, so this adds 100 ml solns of 5% glucose injection to contain 10 milligrams of progesterone.Extract 5mL diluent and join among 25mL water, this solution is similarly heated to 50 degree stirring, then after cool to room temperature, packs analysis cell into.By Horiba LB-550 granulometer test particle size, analysis result is this particle average out to 135nm.
2, stability test
It is higher that micro-nano human injection's Emulsion can be made into curative effect, and the course for the treatment of is shorter, the better steroidal drug of stability, the assay of said preparation, rare bibliographical information.
Precision takes the sample that 9ml embodiment 8 makes, with buffer, be diluted to mensuration concentration, room temperature places 0,2,4,8h, dual-wavelength spectrophotometry, record trap and be respectively 0.621,0.622,0.623,0.624, that is: join solution trap in 8h almost unchanged, meet the quality of the pharmaceutical preparations and control requirement.
Embodiment 9
Get the median chain triglyceride (miglyol 812) of 0.7 gram, the Ovum Gallus domesticus Flavus lecithin of 3 grams and the progesterone of 100 milligrams, mixed dissolution; The TPGS 1000 of getting 5 grams adds wherein, continues to stir until dissolve completely.241.2 gram of 5% glucose injection is added dropwise in the solution of MCT of progesterone, at room temperature stirs until form transparent microemulsion solution; Recently this microemulsion solution is passed through to 0.22M C M wave filter, to eliminate microparticle material and microorganism; Packing of product sealing is stand-by.
By ion, test result analyzed:
By concentration, be that 5% glucose injection joins among the solution that 25 milliliters of embodiment 9 prepare, to the last volume is 100 milliliters.In the water-bath of 50 degree, stir; The gross weight of the micro-nano emulsion formulation preparing due to embodiment 9 is 250 grams, wherein contains 100 milligrams of progesterone, so this adds 100 ml solns of 5% glucose injection to contain 10 milligrams of progesterone.Extract 5mL diluent and join among 25mL water, this solution is similarly heated to 50 degree stirring, then after cool to room temperature, packs analysis cell into.By Horiba LB-550 granulometer test particle size, analysis result is this particle average out to 145nm.
2, stability test
It is higher that micro-nano human injection's Emulsion can be made into curative effect, and the course for the treatment of is shorter, the better steroidal drug of stability, the assay of said preparation, rare bibliographical information.
Precision takes the sample that 10ml embodiment 9 makes, with buffer, be diluted to mensuration concentration, room temperature places 0,2,4,8h, dual-wavelength spectrophotometry, record trap and be respectively 0.623,0.624,0.624,0.625, that is: join solution trap in 8h almost unchanged, meet the quality of the pharmaceutical preparations and control requirement.
Embodiment 10
Get the median chain triglyceride (miglyol 812) of 0.7 gram, the Ovum Gallus domesticus Flavus lecithin of 3 grams and the progesterone of 100 milligrams, mixed dissolution; The TPGS 1000 of getting 5 grams adds wherein, continues to stir until dissolve completely.241.2 grams of brine injections (0.9%NaCl aqueous solution) are added dropwise in the solution of MCT of progesterone, at room temperature stir until form transparent microemulsion solution; Recently this microemulsion solution is passed through to 0.22M C M wave filter, to eliminate microparticle material and microorganism; Packing of product sealing is stand-by.
By ion, test result analyzed:
By concentration, be that 5% glucose injection joins among the solution that 25 milliliters of embodiment 10 prepare, to the last volume is 100 milliliters.In the water-bath of 50 degree, stir; The gross weight of the micro-nano emulsion formulation preparing due to embodiment 10 is 250 grams, wherein contains 100 milligrams of progesterone, so this adds 100 ml solns of 5% glucose injection to contain 10 milligrams of progesterone.Extract 5mL diluent and join among 25mL water, this solution is similarly heated to 50 degree stirring, then after cool to room temperature, packs analysis cell into.By Horiba LB-550 granulometer test particle size, analysis result is this particle average out to 150nm.
2, stability test
It is higher that micro-nano human injection's Emulsion can be made into curative effect, and the course for the treatment of is shorter, the better steroidal drug of stability, the assay of said preparation, rare bibliographical information.
Precision takes the sample that 12ml embodiment 10 makes, with buffer, be diluted to mensuration concentration, room temperature places 0,2,4,8h, dual-wavelength spectrophotometry, record trap and be respectively 0.622,0.621,0.622,0.623, that is: join solution trap in 8h almost unchanged, meet the quality of the pharmaceutical preparations and control requirement.
Embodiment 11
Get the median chain triglyceride (miglyol 812) of 0.7 gram, HS15-15 of 3 grams and the progesterone of 100 milligrams, mixed dissolution; The TPGS 1000 of getting 5 grams adds wherein, continues to stir until dissolve completely.241.2 grams of pure water are added dropwise in the solution of MCT of progesterone, at room temperature stir until form transparent microemulsion solution; Recently this microemulsion solution is passed through to 0.22M C M wave filter, to eliminate microparticle material and microorganism; Packing of product sealing is stand-by.
By ion, test result analyzed:
By concentration, be that 5% glucose injection joins among the solution that 25 milliliters of embodiment 11 prepare, to the last volume is 100 milliliters.In the water-bath of 50 degree, stir; The gross weight of the micro-nano emulsion formulation preparing due to embodiment 11 is 250 grams, wherein contains 100 milligrams of progesterone, so this adds 100 ml solns of 5% glucose injection to contain 10 milligrams of progesterone.Extract 5mL diluent and join among 25mL water, this solution is similarly heated to 50 degree stirring, then after cool to room temperature, packs analysis cell into.By Horiba LB-550 granulometer test particle size, analysis result is this particle average out to 165nm.
2, stability test
It is higher that micro-nano human injection's Emulsion can be made into curative effect, and the course for the treatment of is shorter, the better steroidal drug of stability, the assay of said preparation, rare bibliographical information.
Precision takes the sample that 15ml embodiment 11 makes, with buffer, be diluted to mensuration concentration, room temperature places 0,2,4,8h, dual-wavelength spectrophotometry, record trap and be respectively 0.625,0.626,0.625,0.627, that is: join solution trap in 8h almost unchanged, meet the quality of the pharmaceutical preparations and control requirement.
Embodiment 12
Get the median chain triglyceride (miglyol 812) of 0.7 gram, HS15-15 of 3 grams and the progesterone of 100 milligrams, mixed dissolution; The TPGS 1000 of getting 5 grams adds wherein, continues to stir until dissolve completely.241.2 grams of glucose injections (5% aqueous solution) are added dropwise in the solution of MCT of progesterone, at room temperature stir until form transparent microemulsion solution; Recently this microemulsion solution is passed through to 0.22M CM wave filter, to eliminate microparticle material and microorganism; Packing of product sealing is stand-by.
1, by ion, test result analyzed:
By concentration, be that 5% glucose injection joins among the solution that 25 milliliters of embodiment 12 prepare, to the last volume is 100 milliliters.In the water-bath of 50 degree, stir; The gross weight of the micro-nano emulsion formulation preparing due to embodiment 12 is 250 grams, wherein contains 100 milligrams of progesterone, so this adds 100 ml solns of 5% glucose injection to contain 10 milligrams of progesterone.Extract 5mL diluent and join among 25mL water, this solution is similarly heated to 50 degree stirring, then after cool to room temperature, packs analysis cell into.By Horiba LB-550 granulometer test particle size, analysis result is this particle average out to 175nm.
2, stability test
It is higher that micro-nano human injection's Emulsion can be made into curative effect, and the course for the treatment of is shorter, the better steroidal drug of stability, the assay of said preparation, rare bibliographical information.
Precision takes the sample that 5ml embodiment 12 makes, with buffer, be diluted to mensuration concentration, room temperature places 0,2,4,8h, dual-wavelength spectrophotometry, record trap and be respectively 0.618,0.617,0.618,0.619, that is: join solution trap in 8h almost unchanged, meet the quality of the pharmaceutical preparations and control requirement.
Embodiment 13
Get the median chain triglyceride (miglyol 812) of 0.7 gram, HS15-15 of 3 grams and the progesterone of 100 milligrams, mixed dissolution; The TPGS 1000 of getting 5 grams adds wherein, continues to stir until dissolve completely.241.2 grams of brine injections (0.9%NaCl aqueous solution) are added dropwise in the solution of MCT of progesterone, at room temperature stir until form transparent microemulsion solution; Recently this microemulsion solution is passed through to 0.22M C M wave filter, to eliminate microparticle material and microorganism; Packing of product sealing is stand-by.
By ion, test result analyzed:
By concentration, be that 5% glucose injection joins among the solution that 25 milliliters of embodiment 13 prepare, to the last volume is 100 milliliters.In the water-bath of 50 degree, stir; The gross weight of the micro-nano emulsion formulation preparing due to embodiment 13 is 250 grams, wherein contains 100 milligrams of progesterone, so this adds 100 ml solns of 5% glucose injection to contain 10 milligrams of progesterone.Extract 5mL diluent and join among 25mL water, this solution is similarly heated to 50 degree stirring, then after cool to room temperature, packs analysis cell into.By Horiba LB-550 granulometer test particle size, analysis result is this particle average out to 150nm.
2, stability test
It is higher that micro-nano human injection's Emulsion can be made into curative effect, and the course for the treatment of is shorter, the better steroidal drug of stability, the assay of said preparation, rare bibliographical information.
Precision takes the sample that 10ml embodiment 13 makes, with buffer, be diluted to mensuration concentration, room temperature places 0,2,4,8h, dual-wavelength spectrophotometry, record trap and be respectively 0.619,0.620,0.621,0.620, that is: join solution trap in 8h almost unchanged, meet the quality of the pharmaceutical preparations and control requirement.
Claims (9)
1. containing the micro-nano human injection's Emulsion of gonadal hormone of TPGS, it is characterized in that: in this micro-nano Emulsion, 90% breast grain particle diameter is no more than 200nm, and the mean diameter of this breast grain is no more than 180nm; The effective ingredient of described micro-nano Emulsion is gonadal hormone and TPGS, and solvent is water; The percentage by weight of its Sex Hormones and TPGS is:
Gonadal hormone 0.001%～10%
TPGS 0.01％～20％。
2. the micro-nano human injection's Emulsion of gonadal hormone containing TPGS according to claim 1, is characterized in that: the mean diameter of the micro-nano Emulsion of described gonadal hormone is 100～180nm.
3. the micro-nano human injection's Emulsion of gonadal hormone containing TPGS according to claim 1, it is characterized in that: the micro-nano Emulsion of described gonadal hormone also includes cosurfactant, cosurfactant is a kind of or any several compositions in HS15-15, alcohol ester ether, poloxamer, Polyethylene Glycol, PEP-101, phospholipid or Ovum Gallus domesticus Flavus lecithin; The addition of described cosurfactant accounts for total weight percentages of components: 0.1～10%.
4. the micro-nano human injection's Emulsion of gonadal hormone containing TPGS according to claim 1, is characterized in that: the micro-nano Emulsion of described gonadal hormone also includes cosolvent, and cosolvent is selected polar solvent Polyethylene Glycol, or non-polar solven triglyceride; The addition of described cosolvent accounts for total weight percentages of components: 0.01～5%.
5. the micro-nano human injection's Emulsion of gonadal hormone containing TPGS according to claim 1, it is characterized in that: the micro-nano Emulsion of described gonadal hormone also includes pH value regulator, pH value regulator is selected citric acid, sorbic acid, acetic acid, sulphuric acid, hydrochloric acid, sodium bicarbonate, sodium hydrogen phosphate, any one in sodium hydroxide, the addition of described pH value regulator is no more than 1% of total composition weight.
6. the micro-nano human injection's Emulsion of gonadal hormone containing TPGS according to claim 1, is characterized in that: the micro-nano Emulsion of described gonadal hormone also includes etc. and to ooze adjusting agent, waits to ooze adjusting agent and select sodium chloride or glucose.
7. described in claim 1, contain the preparation technology of the micro-nano human injection's Emulsion of gonadal hormone of TPGS, it is characterized in that: comprise the following steps:
(1), by gonadal hormone, cosurfactant and cosolvent, mixed dissolution, in pure water, is made solution;
(2) TPGS is added in solution, stir and make its mix homogeneously, make mixed liquor;
(3) in mixed liquor, add solvent, at room temperature stir until form transparent microemulsion solution.
(4) transparent microemulsion solution is passed through to wave filter, eliminate after the microparticle material and microorganism containing in microemulsion solution, the packing of product is sealed stand-by.
8. contain according to claim 7 the preparation technology of the micro-nano human injection's Emulsion of gonadal hormone of TPGS, it is characterized in that: described step 3), described solvent is any one in pure water, 5% glucose injection or 0.9%NaCl.
9. contain according to claim 7 the preparation technology of the micro-nano human injection's Emulsion of gonadal hormone of TPGS, it is characterized in that: described step 4), the model that wave filter is selected is 0.22MCM.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US10898432B2 (en) | 2015-12-18 | 2021-01-26 | Proinvet Innovations S.A. | Formulations and methods for controlling the reproductive cycle and ovulation |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US10898432B2 (en) | 2015-12-18 | 2021-01-26 | Proinvet Innovations S.A. | Formulations and methods for controlling the reproductive cycle and ovulation |
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