CN107157957A - Progesterone sustained-release micro-spheres and nanoparticle, its preparation method and progesterone are slow-release injected - Google Patents
Progesterone sustained-release micro-spheres and nanoparticle, its preparation method and progesterone are slow-release injected Download PDFInfo
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- CN107157957A CN107157957A CN201710378984.0A CN201710378984A CN107157957A CN 107157957 A CN107157957 A CN 107157957A CN 201710378984 A CN201710378984 A CN 201710378984A CN 107157957 A CN107157957 A CN 107157957A
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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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
- A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
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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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
Abstract
The invention provides a kind of progesterone sustained-release micro-spheres and nanoparticle, its preparation method and progesterone are slow-release injected, the preparation that the present invention is provided includes progesterone and biodegradable polymer PLGA, PLA, PCL, PGA etc.；Process aspect is respectively adopted that emulsion-solvent evaporation method prepares progesterone microballoon and nanometer emulsified method prepares progesterone nanoparticle.Microspherulite diameter prepared by the present invention is in 10 20 μ ms, drugloading rate 30% 40%, and envelop rate is more than 90%；Nanoparticle particle diameter is in the range of 100 400nm, and drugloading rate can reach 10% 20%, and envelop rate is 80% 90%.Progesterone listing preparation needs multiple frequent drug administration, and the slow-release injected In vitro-in vivo correlation that the present invention is provided is good, has reached the slow release effect of more than one week, can increase the compliance of patient medication, has improved the quality of living.
Description
Technical field
The present invention relates to pharmaceutical technology field, more particularly to a kind of progesterone sustained-release micro-spheres and preparation method thereof, progesterone
Slow release nano-particle and preparation method thereof and progesterone are slow-release injected.
Background technology
Habitual abortion refers to recurring the spontaneous abortion of >=3 times, and its predisposing factors is not completely clear and definite, to patient
Psychology brings huge injury.Recurrent miscarriage predisposing factors is various, and complex, its mainly have immune factor, heredity with
And endocrine disturbance etc., therefore bring certain difficulty to clinical treatment.Shown according to related practical studies, with this disease
Patient body among luteal phase defect for 24%-68%.For the generation of corpus luteum defects, being considered researcher more by
GuRH-A (Gonadotropin-releasing is used in most test tube baby cycles
Hormone agonist, GnRHa) falling tone section is carried out, GnRha causes hypophysis to suppress so that pituitary function is recovered relative and postponed,
Cause First Trimester luteal function defect.Clinical practice test-tube baby etc. manually helps pregnant technology 30 for many years, luteal phase medicine
Supportive treatment is gradually acknowledged as being advantageous for a kind of intervention means of pregnancy outcome.
Progesterone (Progesterone, can abbreviation PRG), also known as progesterone, are white or slightly yellow crystalline powder, fusing point
127~131 DEG C, odorless is stable in the air, there is dextrorotation photosensitiveness, water insoluble, is dissolved in ethanol, ether, chloroform, acetone, dioxy
Six rings and the concentrated sulfuric acid.The chemical name of progesterone is：DELTA4-pregn-3,20-dione, molecular formula：C21H30O2, molecular weight：
314.47, structural formula is as follows：
Progesterone can make increment phase inner membrance transform into secretory phase inner membrance, for the fertilization implantation of ovum, implantation and embryo at initial stage
The nutritional support of tire provides convenience.Progesterone can make among cell that Na ion concentration is significantly raised, make muscle fibre excitability
It is decreased obviously, and muscle fibre is substantially relaxed, and then significantly reduce uterine contraction, finally embryo is proceeded among uterus
Grow；Corpus luteum hormone is mainly reflected in inducing endometrial to the positive role of gestation to be changed to the secretory phase, increased inner membrance
Receptivity is in favor of fertilization egg implantation, and acts on uterus part, promotes blood vessel and smooth muscle to relax through factors such as nitric oxides
Open and suppress uterine contraction.
Clinically progesterone application forms mainly have oral capsule, gel suppository, the oily solubility preparation of intramuscular injection etc., wherein, corpus luteum
Ketone oral preparation drug administration is convenient and swift, and patient is easy to receive, but oral progesterone can rapidly be destroyed in intestines and stomach and liver, difficult
To play supplement and therapeutic action.Because progesterone solubility is extremely low, and first pass effect is serious, and oral administration biaavailability is only
10%.Oral formulations improve progesterone solubility often through increase surfactant concentration, it is impossible to fundamentally solve yellow
The problem of body ketone first pass effect is strong, bioavilability is low；Daily dosage still needs to can be only achieved very much curative effect greatly, causes secondary work
With larger.Therefore, oil solution intramuscular injection, price also relative moderate are clinically generally used.
But, existing progesterone injection is oil solution injection, need to be injected daily, long term injections (about 12 weeks).Oil
Solution easily causes patient uncomfortable when injecting, such as pain, local red and swollen, allergy symptom, indivedual pathology reports even point out flesh
Meat injection progesterone can induce acute eosinophilic pneumonia.And finish progesterone long half time, generally want time several weeks
It can recover.Long-term high frequency time injection also results in injection site and produces the other symptoms such as scleroma, is unfavorable for injection site tissue and is good for
Health.Patient is pregnant woman, daily injection progesterone it is extremely inconvenient, and progesterone injection exist oil solvent easily cause muscle it is hardened,
The problems such as pain.
The content of the invention
In view of this, the application provide a kind of progesterone sustained-release micro-spheres and preparation method thereof, progesterone slow release nano-particle and
Its preparation method and progesterone are slow-release injected, and the progesterone sustained-release micro-spheres and nanoparticle that the present invention is provided can be used as intramuscular injection
Agent, drugloading rate is high, and the inside and outside sustained release time is long, and injection excitant is small, good patient compliance.
The present invention provides a kind of progesterone sustained-release micro-spheres, and it is by the material system including progesterone and first polymer material
Into the first polymer material is in Poly(D,L-lactide-co-glycolide, PLA, polycaprolactone and polyglycolic acid
It is one or more；The molecular weight of the first polymer material is 4000~40000 dalton；The progesterone accounts for sustained-release micro-spheres
The 30%~40% of gross mass；
The particle diameter of the progesterone sustained-release micro-spheres is 10~20 μm.
The present invention provides a kind of progesterone slow release nano-particle, and it is by the material system including progesterone and second polymer material
Into the second polymer material is in Poly(D,L-lactide-co-glycolide, PLA, polycaprolactone and polyglycolic acid
It is one or more；The molecular weight of the second polymer material is 6000~60000 dalton；The progesterone accounts for slow release nanometer
The 10%~20% of grain gross mass；
The particle diameter of the progesterone slow release nano-particle is 100~400nm.
To solve the deficiency in progesterone clinical practice formulation, the present inventor has invented through numerous studies and noted available for muscle
The progesterone control-release microsphere and nanoparticle penetrated, medicine are embedded in the good polymer of biodegradable, histocompatbility, in vivo
Sustainable outside to be sustained more than one week, security is stronger, and excitant is small, improves patient's compliance.
To achieve the above object, the invention provides following multiple embodiments.
In one embodiment, injection progesterone control-release microsphere of the invention includes progesterone, and biodegradable
Pharmaceutical polymerses Poly(D,L-lactide-co-glycolide (PLGA), PLA (PLA), polycaprolactone (PCL) and polyglycolic acid
(PGA) one or more in, preferably PLGA, its feature of environmental protection and injection application in terms of best results.Consider material
The degradation cycle of material, the short polymeric material PLGA of present invention first choice degradation time, it is one that can make long-acting injection dosage period
Zhou Yici.For ease of distinguishing, polymeric material in microballoon is referred to as first polymer material.
Wherein, progesterone and first polymer material charged material weight ratio can be 1：1.5-2；Progesterone accounts for microballoon gross weight 30-
40%.In the present invention, the molecular weight of the first polymer material is 4000~40000 dalton；Specifically, the poly- breast
The molecular weight of acid-co-glycolic acid can be 10000-40000 dalton；The molecular weight of PLA can be 10000-20000
Dalton；The molecular weight of polycaprolactone can be 4000-40000 dalton；The molecular weight of polyglycolic acid can be 8000-20000 roads
Er Dun.In some embodiments of the invention, the molecular weight of the Poly(D,L-lactide-co-glycolide is 12000-30000 roads
Er Dun.
In the present invention, the end-blocking mode of the first polymer material can be blocked and hydroxy-end capped for carboxy blocking, ester
In one or more；Specifically, the PLGA is carboxy blocking, ester end-blocking or hydroxy-end capped；The PCL be carboxy blocking,
Ester is blocked or hydroxy-end capped；The PLA is carboxy blocking, ester end-blocking or hydroxy-end capped.
In a preferred embodiment of the invention, lactic acid and hydroxyacetic acid rub in the Poly(D,L-lactide-co-glycolide
You are than being (50~85)：(15~50).The lactic acid of the PLGA and the mol ratio of hydroxyacetic acid are preferably 50：50、75：25 or
85：15, more preferably 50：50 or 75：25；Molecular weight be 10000-40000 dalton, one week sustained release drugs 90% with
On.
In one embodiment, injection progesterone controlled-release nano of the invention includes progesterone, and biodegradable
Pharmaceutical polymerses PLGA, PCL, PLA, PGA etc. in one or more polymeric materials mixing, preferably PLGA.
In the present invention, progesterone and second polymer material charged material weight ratio can be 1：1.5-2；Progesterone accounts for nanoparticle gross weight 10-
20%.
In the present invention, the molecular weight of the second polymer material is 6000~60000 dalton；Specifically, it is described
The molecular weight of Poly(D,L-lactide-co-glycolide can be 10000-60000 dalton；The molecular weight of PLA can be 20000-
30000 dalton；The molecular weight of polycaprolactone can be 6000-50000 dalton；The molecular weight of polyglycolic acid can be 10000-
30000 dalton.In some embodiments of the invention, the molecular weight of the Poly(D,L-lactide-co-glycolide is 10000-
40000 dalton.
In the present invention, the end-blocking mode of the second polymer material can be blocked and hydroxy-end capped for carboxy blocking, ester
In one or more；Specifically, the PLGA is carboxy blocking, ester end-blocking or hydroxy-end capped；The PCL be carboxy blocking,
Ester is blocked or hydroxy-end capped；The PLA is carboxy blocking, ester end-blocking or hydroxy-end capped.
In a preferred embodiment of the invention, lactic acid and hydroxyacetic acid rub in the Poly(D,L-lactide-co-glycolide
You are than being (50~85)：(15~50).The lactic acid of the PLGA and the mol ratio of hydroxyacetic acid are preferably 50：50、75：25 or
85：15；Molecular weight is 10000-40000 dalton, one week sustained release drugs more than 90%.
In the above-described embodiment, in progesterone suspension,sterile control-release microsphere of the invention, the lactic acid and hydroxyl of the PLGA
Acetic acid mol ratio concretely 50：50、75：25.In the above-described embodiment, progesterone suspension,sterile controlled-release nano of the invention
In, the lactic acid and glycolic acid molar ratio of the PLGA can be 85：15、75：25.
In the above-described embodiment, the drugloading rate of progesterone suspension,sterile control-release microsphere of the invention can be 30%-40%, excellent
Elect 32%-40% as；The nanoparticle drugloading rate is 10%-20%.In an embodiment of the present invention, described progesterone sustained release
The specific surface area of microballoon is 440~500m2/kg。
In the above-described embodiment, the size controlling of progesterone suspension,sterile control-release microsphere of the invention is in 5-20 μ ms
It is interior, preferably 10 μm -20 μm, more preferably 11-15 μm；The nanoparticle size controlling is in 100nm-400nm, preferably 200-300nm.
The present invention provides a kind of preparation method of progesterone sustained-release micro-spheres, comprises the following steps：
1) progesterone and first polymer material are dissolved in organic solvent, form organic phase；The first polymer material
Expect the one or more in Poly(D,L-lactide-co-glycolide, PLA, polycaprolactone and polyglycolic acid；Described first
The molecular weight of polymeric material is 4000~40000 dalton；2) by step 1) obtained organic phase pours into the water containing emulsifying agent
In solution, through high speed shearing emulsification, emulsion oil-in-water is obtained；3) by step 2) obtained emulsion oil-in-water is diluted with water
Afterwards, vacuum distillation is carried out, microsphere suspension is obtained；4) by step 3) after obtained microsphere suspension is washed with water, through solid-liquid point
From obtaining progesterone sustained-release micro-spheres.
To achieve the above object, the technical scheme of the preparation for the progesterone microballoon that some embodiments of the invention are provided is included such as
Lower step：
(1) progesterone and polymeric material such as PLGA are dissolved in a certain amount of organic solvent, form organic phase；(2) will
Organic phase in step (1) is poured into poly-vinyl alcohol solution rapidly, through high speed shearing emulsification, obtains o/w emulsions；(3) by step
(2) emulsion in is accumulated after distilled water diluting with pentaploid, and vacuum distillation removes organic solvent and solidified microsphere；(4) by step (3)
Thus obtained microsphere suspension repeatedly, is removed unnecessary polyvinyl alcohol, is collected by centrifugation with deionized water cyclic washing, freeze-dried,
Produce the progesterone sustained-release micro-spheres such as progesterone-PLGA microballoons.
The embodiment of the present invention weighs first polymer material and progesterone, is dissolved in organic solvent and forms organic phase.Its
In, the content of the first polymer material is as it was previously stated, this is no longer going to repeat them.In addition, crystalline substance of the present invention to progesterone
Type is not particularly limited.In the present invention, progesterone and first polymer material charged material weight ratio can be 1：1.5-2.
In the present invention, the organic solvent such as alcohols, hydro carbons, esters etc..Present invention preferably employs dichloromethane (DCM)
As organic solvent, its solubility to progesterone and PLGA etc. is high, and low boiling point, volatile removing.In some of the present invention
In embodiment, the organic solvent is the mixed solution of dichloromethane and phenmethylol；Specifically, the volume ratio of DCM and phenmethylol
Can be 9：1、8：2、7：3.The embodiment of the present invention has certain affinity using phenmethylol in organic phase and aqueous phase, and regulating drug exists
Diffusion rate in microballoon, so as to change distribution of the medicine in microballoon and influence release conditions.
The embodiment of the present invention pours into obtained organic phase in the aqueous solution containing emulsifying agent rapidly, high speed shear formation o/w
Emulsion.Wherein, the emulsifying agent is preferably polyvinyl alcohol (PVA), i.e., the present invention preferably using the aqueous solution containing polyvinyl alcohol as
Aqueous phase.In some embodiments of the invention, the mass concentration of polyvinyl alcohol water solution can be 0.5%-2%, preferably 1~
1.5%, most preferably 1%.The organic phase can be 1 with aqueous phase volume ratio：15~20, preferably 1：16.6.
In the present invention, emulsified by high speed shear, obtain emulsion oil-in-water.The rotating speed of the high speed shear is excellent
Elect 10000~14000rpm as；Shear time is preferably 1~2min.
Emulsification is obtained after o/w emulsions, and the embodiment of the present invention can be diluted with its 5 times of volume of water, and then vacuum distillation, volatilization has
Machine solvent, solidified microsphere, obtain microsphere suspension.Wherein, the temperature of the vacuum distillation can be 40~50 DEG C；Time can be
15min。
Obtained microsphere suspension is washed with water the embodiment of the present invention, removes unnecessary emulsifying agent PVA etc., is then centrifuged for
Collect microballoon, it is freeze-dried wait this area routine solid-liquid separation method, obtain progesterone sustained-release micro-spheres.
The present invention also provides a kind of preparation method of progesterone slow release nano-particle, comprises the following steps：
1) progesterone and second polymer material are dissolved in organic solvent, form organic phase；The second polymer material
Expect the one or more in Poly(D,L-lactide-co-glycolide, PLA, polycaprolactone and polyglycolic acid；Described second
The molecular weight of polymeric material is 6000~60000 dalton；2) by step 1) obtained organic phase pours into the water containing emulsifying agent
In solution, through high speed shearing emulsification, oil-in-water type colostric fluid is obtained；The oil-in-water type colostric fluid is subjected to high pressure homogenization, obtained
To whole emulsion；3) by step 2) after obtained whole emulsion is diluted with water, by low-temperature setting, obtain micronised suspensions；4) will step
After the rapid micronised suspensions 3) obtained are washed with water, through separation of solid and liquid, progesterone slow release nano-particle is obtained.
To achieve the above object, the technical scheme bag of the preparation for the progesterone nanoparticle that other embodiments of the invention are provided
Include following steps：
(1) progesterone and polymeric material are dissolved in the ethyl acetate and phenmethylol of recipe quantity, form organic phase；(2)
Organic phase in step (1) is poured into rapidly through high speed shearing emulsification in the aqueous solution containing emulsifying agent, o/w colostrums are obtained, just
Breast further reduces particle diameter through high pressure homogenizer, obtains whole breast；(3) diluted, stirred under ice bath with cold water by newborn eventually obtained by step (2)
3-4h solidification particulates are mixed, micronised suspensions are obtained；(4) micronised suspensions obtained by step (3) are added into cold water, excessively hollow membrane module
Organic solvent is removed, progesterone slow release nano-particle is obtained after drying.
In addition, the material for removing organic solvent can be divided in cillin bottle by the present invention, suitable freeze drying protectant is added
(lyophilized) is freeze-dried, progesterone sustained release freeze-dried powder is produced.
The present invention weighs second polymer material and progesterone, adds in organic solvent and dissolves, is used as organic phase.Wherein,
The content of the second polymer material is as it was previously stated, this is no longer going to repeat them.In addition, the present invention does not have to the crystal formation of progesterone
Have specifically limited.In the present invention, progesterone and second polymer material charged material weight ratio can be 1：1.5-2.
In the nanoparticle preparation method of the invention described above, the organic solvent such as alcohols, hydro carbons, esters etc..In this hair
In some bright embodiments, the organic solvent is the mixed solution of ethyl acetate and phenmethylol；Specifically, ethyl acetate and benzene
The volume ratio of methanol can be 4：1.Present invention preferably employs ethyl acetate and phenmethylol mixed solvent, by polymeric material and corpus luteum
Ketone obtains organic phase in 30~40 DEG C of stirring in water bath after dissolving.
During nanoparticle is prepared, the embodiment of the present invention pours into rapidly obtained organic phase containing the water-soluble of emulsifying agent
In liquid, high speed shear formation o/w colostric fluids；The colostric fluid is subjected to high pressure homogenization, whole emulsion is obtained.Wherein, breast used
Agent is preferably PLURONICS F87；Also assistant for emulsifying agent can be used as using phenmethylol.Poloxamer (Poloxamer) is polyoxy second
Alkene polyoxypropylene ether block copolymers, trade name Pluronic (Pluronic), belong to macromolecule nonionic surfactant.
PLURONICS F87 is also referred to as F68, is a kind of oil-water emulsifiers.In some embodiments of the invention, PLURONICS F87 is in water
Mass concentration in phase is 2%-5%；Mass concentration of the phenmethylol in aqueous phase is 1%-5%.In addition, described containing emulsifying agent
Can also be comprising ethyl acetate etc., collectively as aqueous phase in the aqueous solution.Specifically, the profit phase volume ratio can be 1：8.
In some embodiments of the invention, the rotating speed of the high speed shear can be 10000rpm；Shear time can be
5min.In some embodiments of the invention, the pressure of the high pressure homogenization can be 600bar；Homogeneous number of times is 5-7 times.
Obtain after breast eventually, the embodiment of the present invention is diluted with cold water, by the low-temperature setting mode stirred under ice bath, solidify micro-
Grain obtains micronised suspensions；The excessively hollow membrane module of cold water is added, organic solvent is removed, is drying to obtain progesterone slow release nanometer
Grain.The drying can be using freeze-drying, specifically, lyophilized technique may include：- 40 DEG C of pre-freezes four hours, vacuumize, -40 DEG C
Two hours are maintained, two hours rise to -20 DEG C of three hours of maintenance, and a hour rises to -10 DEG C of two hours of maintenance, two
Hour rises to 0 DEG C of two hour of maintenance, and two hours rise to 20 DEG C of two hours of maintenance.
Or, the material for removing organic solvent is added into freeze drying protectant, it is freeze-dried, obtain freeze-dried powder.Described jelly
Dry protective agent may be selected from lactose, maltose, glucose, trehalose, glycerine, mannitol, sorbierite, sodium chloride, phosphate, poly-
One or more in vinylpyrrolidone (PVP), sodium carboxymethylcellulose (CMC-Na), polyethylene glycol and albumin, preferably
For mannitol.
The profile rounding of progesterone suspension,sterile control-release microsphere and progesterone nanoparticle of the present invention, size distribution is equal
Even, drugloading rate and envelop rate are high, inside and outside sustained release more than one week, add up release more than 90%, and release stable homogeneous, can
Long period maintains effective blood drug concentration, is administered once as long as can maintaining treatment in one week, injection excitant is small, patient's compliance
It is good.
The progesterone durative action preparation of the present invention is technically respectively adopted emulsification-evaporation method and prepares progesterone microballoon and receive
Rice milk method prepares progesterone nanoparticle, realizes the controlled release of medicine in micron and Nano grade respectively.It is high using biodegradable
Molecular material packaging medicine is made after the administration of microsphere for injection preparation, and medicine passes through the diffusion in microballoon and polymer backbone
Corrosion control release, reaches the long-acting purpose being steadily sustained.But microspherulite diameter is larger, certain excitant can be produced during drug administration by injection
(excitant is not obvious), therefore develop progesterone nanometer formulation.Nanoparticle can reach faster for microballoon
Required blood concentration, and discharge more steady.Nanoparticle injection excitant is small, but drugloading rate is lower with respect to microballoon.
Experiment shows that two kinds of preparations can maintain effective blood drug concentration in vivo, reaches the slow release effect of one week and the above,
The compliance of patient can be thus improved, curative effect is improved.
The present invention also provides that a kind of progesterone is slow-release injected, and it includes progesterone particle and solvent for injection；The Huang
Body ketone particle is progesterone sustained-release micro-spheres or progesterone slow release nano-particle described above.
The slow-release injected progesterone that the present invention is provided is microspheric or nanoparticle progesterone durative action preparation, the durative action preparation
(gather including progesterone and biodegradable polymer PLGA (Vicryl Rapide), PLA (PLA), PCL in oneself
Ester), PGA (polyglycolic acid) etc.；Process aspect is respectively adopted emulsification-evaporation method and prepares progesterone microballoon and nanometer emulsified method
Prepare progesterone nanoparticle.
The slow-release injected use intramuscular injection of progesterone that the present invention is provided, with solvent for injection.In the present invention, note
Penetrating can float drug suspension with solvent, so that administration is uniform, smooth.The solvent for injection is that conventional microsphere for injection is answered
Solvent, it may include water for injection, pH value regulator, osmotic pressure regulator and stabilizer, such as comprising sodium carboxymethylcellulose (CMC-
Na one kind), in mannitol or its mixture.In a particular embodiment of the present invention, the composition of the solvent for injection includes
Anhydrous citric acid, ADSP, polysorbate 20, CMC-Na, sodium chloride and water for injection.
The present invention is by particle diameter, drugloading rate, envelop rate, release in vitro, Internal pharmacokinetics etc. to progesterone long-acting injection
Characterized, as a result shown, the prepared microspherulite diameter of the present invention is in 5-20 μ ms, and drugloading rate 30%-40%, envelop rate exists
More than 90%；Nanoparticle particle diameter is in the range of 100-400nm, and drugloading rate can reach 10%-20%, and envelop rate is in 80%-90%.
Vitro release measure is carried out using 37 DEG C of shaking bath methods, In vitro-in vivo correlation is good, reached the sustained release effect of more than one week
Really.
The clinical investigation carried out according to researcher, current clinical treatment habitual abortion and supplementary reproduction dosage are flesh
Note 20mg/day and 60mg/day.And invention formulation design dosage is 140mg/ weeks, 140mg/ branch (in terms of progesterone), one week
It is administered once.Less than clinical ordinary preparation on dosage and frequency, and this product is moved and pharmacodynamics research in follow-up medicine
As a result show, this product bioavilability and therapeutic effect are suitable with commercial preparation；And the reduction of dosage and frequency can be reduced
The incidence of side effect, improves patient compliance.
Brief description of the drawings
Fig. 1 is the plasma concentration curve figure of progesterone of embodiment of the present invention microsphere sustained-release preparation and existing product；
Fig. 2 is the plasma concentration curve figure of progesterone nanoparticle sustained release preparation of the embodiment of the present invention and existing product；
Fig. 3 is the MIcrosope image (10 × 10) of progesterone microballoon prepared by the embodiment of the present invention；
Fig. 4 is the scanning electron microscope (SEM) photograph (SEM) of progesterone microballoon prepared by the embodiment of the present invention；
Fig. 5 is the granulometry result for the progesterone sustained-release micro-spheres that embodiment 1 is prepared；
Fig. 6 is the granulometry result for the progesterone nanoparticle that embodiment 12 is prepared；
Fig. 7 is the In-vitro release curves for the progesterone sustained-release micro-spheres that embodiment 2-4 is prepared；
Fig. 8 is the In-vitro release curves for the progesterone nanoparticle that embodiment 16-18 is prepared.
Embodiment
The technical scheme in the embodiment of the present invention is clearly and completely described below, it is clear that described embodiment
Only a part of embodiment of the invention, rather than whole embodiments.Based on the embodiment in the present invention, the common skill in this area
The every other embodiment that art personnel are obtained under the premise of creative work is not made, belongs to the model that the present invention is protected
Enclose.
For a further understanding of the application, the progesterone sustained-release micro-spheres provided with reference to embodiment the application and its system
Preparation Method, nanoparticle and preparation method thereof and progesterone is slow-release injected is specifically described.
In following examples, progesterone used is crystal formation II, producer：Hubei Gedian Renfu Pharmaceutical Limited Liability Company,
Lot number：HTT151102.
The preparation of the progesterone microballoon of embodiment 1
Weigh 150mg PLGA (50/50 (molar ratio of lactic acid and hydroxyacetic acid), the dalton of molecular weight 13000, below
Embodiment represents be the same as Example 1), 75mg progesterone is dissolved in 1.5mL dichloromethane and forms organic phase.Organic phase is fallen rapidly
Enter in 25mL, 1%PVA (Kuraray) solution, 12000rpm high speed shears 2min formation o/w emulsions.It is dilute with 5 times of volume of water
After releasing, 40 DEG C of vacuum distillation 15min, volatile organic solvent solidified microsphere.Unnecessary PVA is washed with deionized in solidified microsphere
Afterwards, microballoon is collected by centrifugation, is freeze-dried, produces intramuscular injection progesterone control-release microsphere.
Wherein, freeze drying process includes：- 40 DEG C of pre-freezes four hours, vacuumize, -40 DEG C of two hours of maintenance, two small
Shi Shengzhi -20 DEG C of three hours of maintenance a, hour rises to -10 DEG C of two hours of maintenance, and two hours rise to 0 DEG C and maintain two
Hour, two hours rise to 20 DEG C of two hours of maintenance.
Prescription and related process in embodiment 1 is referring to table 1：
Prescription and related process parameters in the embodiment 1 of table 1
Embodiment 2-4 different molecular weights PLGA prepares microballoon
150mg PLGA (50/50) are weighed, molecular weight is respectively 13000,25000,30000 dalton；75mg progesterone,
It is dissolved in 1.5mL dichloromethane and forms organic phase.Organic phase is poured into rapidly in 25mL, 1%PVA solution, 12000rpm is at a high speed
Shear 2min formation o/w emulsions.After 5 times of volume of water dilutions, 40 DEG C of vacuum distillation 15min, volatile organic solvent solidified microsphere.
Solidified microsphere is washed with deionized after unnecessary PVA, microballoon is collected by centrifugation, is freeze-dried, produces intramuscular injection progesterone
Control-release microsphere.Prescription in embodiment 2-4 is referring to table 2：
Prescription in the embodiment 2-4 of table 2
It is prepared by embodiment 5-7 different theories drugloading rates microballoon
Weigh 150mg PLGA (50/50；13000) it is respectively 75mg, 90mg, 100mg that, progesterone, which is weighed, is dissolved in 1.5mL
Organic phase is formed in dichloromethane.Organic phase is poured into rapidly in 25mL, 1%PVA solution, 12000rpm high speed shear 2min shapes
Into o/w emulsions.After 5 times of volume of water dilutions, 40 DEG C of vacuum distillation 15min, volatile organic solvent solidified microsphere.By solidified microsphere
It is washed with deionized after unnecessary PVA, microballoon is collected by centrifugation, is freeze-dried, produces intramuscular injection progesterone control-release microsphere.It is real
The theoretical drugloading rate for the progesterone microballoon that a 5-7 is prepared is applied referring to table 3：
The theoretical drugloading rate for the progesterone microballoon that the embodiment 5-7 of table 3 is prepared
It is prepared by embodiment 8-11 difference organic phase microballoons
Weigh 150mg PLGA (50/50；13000), progesterone 75mg, is formed with each ratio organic solvent dissolving of prescription
Machine phase.Organic phase is poured into rapidly in 25mL, 1%PVA solution, 12000rpm high speed shears 2min formation o/w emulsions.With 5 times
After volume of water dilution, 40 DEG C of vacuum distillation 15min, volatile organic solvent solidified microsphere.Solidified microsphere is washed with deionized
After unnecessary PVA, microballoon is collected by centrifugation, is freeze-dried, produces intramuscular injection progesterone control-release microsphere.Place in embodiment 8-11
Side is referring to table 4：
Prescription in the embodiment 8-11 of table 4
Progesterone and PLGA easily dissolve in dichloromethane, and dichloromethane low boiling point, volatile removing, therefore the present invention is first
Dichloromethane is selected as organic solvent.Phenmethylol has certain affinity in organic phase and aqueous phase, can adjust medicine in microballoon
Diffusion rate, so as to change distribution of the medicine in microballoon, so as to influence release conditions.Phenmethylol addition is different, microballoon
The prominent amount of releasing is variant, it is considered to have impact on distribution of the medicine in microballoon.
The preparation of the progesterone nanoparticle of embodiment 12
PLGA (20000 is weighed with recipe quantity；50/50) ethyl acetate and phenmethylol in the mixed solvent and progesterone, are added,
Organic phase is used as after 35 DEG C of stirring in water bath dissolve.The aqueous solution is dissolved in using F68 as emulsifying agent, the phenmethylol of recipe quantity is added
And ethyl acetate is used as aqueous phase after 35 DEG C of heating stirrings are uniform.It is added in aqueous phase, obtains by organic in a shear condition
To after colostrum, after high-pressure homogeneous, plus (temperature control exists for cold water quenching<5 DEG C), stirring solidification 3-4h adds cold water and passed through
Hollow fiber film assembly removes organic solvent, after centrifugal filtration, obtains progesterone nanoparticle；Add F68 it is lyophilized after, obtain progesterone
Freeze-dried powder.
Wherein, freeze drying process includes：- 40 DEG C of pre-freezes four hours, vacuumize, -40 DEG C of two hours of maintenance, two small
Shi Shengzhi -20 DEG C of three hours of maintenance a, hour rises to -10 DEG C of two hours of maintenance, and two hours rise to 0 DEG C and maintain two
Hour, two hours rise to 20 DEG C of two hours of maintenance.
Prescription and related process in embodiment 12 is referring to table 5：
Prescription and related process parameters in the embodiment 12 of table 5
Embodiment 13-15 different emulsifiers concentration prepares progesterone nanoparticle
PLGA (20000 is weighed with recipe quantity；50/50) ethyl acetate and phenmethylol in the mixed solvent and progesterone, are added,
Organic phase is used as after 35 DEG C of stirring in water bath dissolve.The aqueous solution is dissolved in using F68 as emulsifying agent, the phenmethylol of recipe quantity is added
And ethyl acetate is used as aqueous phase after 35 DEG C of heating stirrings are uniform.It is added in aqueous phase, obtains by organic in a shear condition
To after colostrum, after high-pressure homogeneous, plus (temperature control exists for cold water quenching<5 DEG C), stirring solidification 3-4h adds cold water and passed through
Hollow fiber film assembly removes organic solvent, after centrifugal filtration, obtains progesterone nanoparticle；Add mannitol it is lyophilized after, obtain yellow
Body ketone freeze-dried powder.Prescription and related process in embodiment 13-15 is referring to table 6：
Prescription and related process parameters in the embodiment 13-15 of table 6
Emulsifier concentration mainly influences the particle diameter and particle diameter distribution of nanoparticle in the embodiment of the present invention, and emulsifier concentration is got over
Height, particle diameter is smaller, and distribution is narrower, but has limiting value.
Embodiment 16-18 difference polymeric materials prepare progesterone nanoparticle
Weigh PLGA, PLA, PCL (molecular weight is 20000, and each material is c-terminus) and corpus luteum respectively with recipe quantity
Ketone, adds ethyl acetate and phenmethylol in the mixed solvent, and organic phase is used as after 35 DEG C of stirring in water bath dissolve.It regard F68 as breast
Agent is dissolved in the aqueous solution, adds the phenmethylol and ethyl acetate of recipe quantity after 35 DEG C of heating stirrings are uniform as aqueous phase.
It is added in aqueous phase, obtains after colostrum by organic in a shear condition, after high-pressure homogeneous, plus cold water quenching (temperature control
System exists<5 DEG C), stirring solidification 3-4h adds cold water and removes organic solvent by hollow fiber film assembly, after centrifugal filtration, obtains yellow
Body ketone nanoparticle；Add mannitol it is lyophilized after, obtain progesterone freeze-dried powder.Prescription and related process in embodiment 16-18
Referring to table 7：
Prescription and related process parameters in the embodiment 16-18 of table 7
Embodiment 19-21 different technical parameters prepare progesterone nanoparticle
Weigh PLGA, PLA, PCL (molecular weight is 20000, and each material is c-terminus) and corpus luteum respectively with recipe quantity
Ketone, adds ethyl acetate and phenmethylol in the mixed solvent, and organic phase is used as after 35 DEG C of stirring in water bath dissolve.It regard F68 as breast
Agent is dissolved in the aqueous solution, adds the phenmethylol and ethyl acetate of recipe quantity after 35 DEG C of heating stirrings are uniform as aqueous phase.
It is added in aqueous phase, obtains after colostrum by organic in a shear condition, after high-pressure homogeneous, plus cold water quenching (temperature control
System exists<5 DEG C), stirring solidification 3-4h adds cold water and removes organic solvent by hollow fiber film assembly, after centrifugal filtration, obtains yellow
Body ketone nanoparticle；Add mannitol it is lyophilized after, obtain progesterone freeze-dried powder.Prescription and related process in embodiment 19-21
Referring to table 8：
Prescription and related process parameters in the embodiment 19-21 of table 8
Technological parameter is mainly high-pressure homogeneous pressure and average number of times in the embodiment of the present invention, and it influences the grain of nanoparticle
Footpath and particle diameter distribution；Homogenization pressure is bigger, number of times is more, and particle diameter is smaller, it is narrower to be distributed, but pressure is excessive or number of times is crossed and at most can
Influence stability.
The pharmacokinetic analysis of the progesterone durative action preparation of the present invention of embodiment 22
1st, the progesterone microballoon of the 2.52mg (in terms of progesterone) according to prepared by the method for embodiment 1, to SD rat (body weight
About 200g) back leg biceps muscle of thigh carry out intramuscular injection, and with commercially available progesterone injection (producer：Zhejiang celestial being jade pendant pharmacy
Limited company, lot number：H33020828) it is check experiment.Solvent for injection in sustained release preparation of the present invention is conventional note
Penetrate and use microballoon double solvents, composition include anhydrous citric acid, ADSP, polysorbate 20, CMC-Na, sodium chloride and
Water for injection (this solvent for injection composition refers to commercially available Risperidone (permanent moral) specification).
Blood is taken to the regular eye rear vein beard of tested rat, it is dense by the medicine for setting up progesterone in LC-MS methods measure blood plasma
Degree.0-180h blood concentration is administered referring to Fig. 1, Fig. 1 is progesterone of embodiment of the present invention microsphere sustained-release preparation and existing product
Plasma concentration curve figure.The amount of releasing of being dashed forward in long-acting injection rat body of the present invention is can be seen that from Fig. 1 medicine dynamic test results
Less than progesterone injection, blood concentration is more steady, does not there is obvious fluctuation, can reach the slow release effect of more than one week.
2nd, the progesterone nanoparticle of the 2.52mg (in terms of progesterone) according to prepared by the method for embodiment 12, to SD rats
The back leg biceps muscle of thigh of (body weight about 200g) carries out intramuscular injection, and with commercially available progesterone injection (1mL:20mg) for pair
According to experiment.Solvent for injection in sustained release preparation of the present invention is microsphere for injection double solvents, and composition includes anhydrous citric acid, anhydrous
Disodium hydrogen phosphate, polysorbate 20, CMC-Na, sodium chloride and water for injection.
Blood is taken to the regular eye rear vein beard of tested rat, it is dense by the medicine for setting up progesterone in LC-MS methods measure blood plasma
Degree.0-180h blood concentration is administered referring to Fig. 2, Fig. 2 is progesterone nanoparticle sustained release preparation of the embodiment of the present invention and existing production
The plasma concentration curve figure of product.
Pharmacokinetics comparison is carried out by the progesterone durative action preparation prepared to above two technique, nanometer emulsified method prepares length
Effect injection can be rapidly reached required blood concentration, and release profiles are more steady.Though microspheric durative action preparation is later to reach peak, release
Also it is steady, and drugloading rate is high, volume injected is small.
The progesterone durative action preparation characteristic test of embodiment 23
1st, outward appearance is detected.The progesterone microballoon that above-described embodiment 1 is prepared is respectively at Optical microscope and SEM
Lower observation, as a result referring to Fig. 3 and Fig. 4, Fig. 3 be the embodiment of the present invention prepare progesterone microballoon MIcrosope image (10 ×
10), Fig. 4 is the scanning electron microscope (SEM) photograph (SEM) of progesterone microballoon prepared by the embodiment of the present invention.From result above, the present invention
The microballoon prepared is in regular circle shapes.
2nd, particle diameter and particle diameter distribution
Progesterone-PLGA the microballoons that above-described embodiment 1 is prepared are made into suspension with distilled water and 0.1%CMC-Na,
Granulometry is carried out using hundred special laser particle analyzers.The granulometry result for the progesterone sustained-release micro-spheres that embodiment 1 is prepared is shown in
Fig. 5 and table 9, Fig. 5 are the granulometry result for the progesterone sustained-release micro-spheres that embodiment 1 is prepared.From result above, microballoon
D50 is 11.42 μm, Span 1.623, and particle diameter distribution is more uniform.
The granulometry data for the progesterone sustained-release micro-spheres that the embodiment 1 of table 9 is prepared
The progesterone nanoparticle in a certain amount of above-described embodiment 12 is taken, finite concentration is diluted to, using NICOMP380 granularities
Analyzer carries out granulometry.The granulometry result for the progesterone nanoparticle that embodiment 12 is prepared is shown in Fig. 6 and table 10, Fig. 6
The granulometry result for the progesterone nanoparticle prepared for embodiment 12.From result above, average diameter：175.4nm；PI
0.059(PI<0.1), in homogeneous normal distribution.
The granulometry data for the progesterone nanoparticle that the embodiment 12 of table 10 is prepared
3rd, drugloading rate and envelop rate.Precision measures the progesterone durative action preparation 10mg that above-described embodiment prepares and puts 25mL appearances
In measuring bottle, the vibration dissolving of 1mL acetonitriles is added, scale is put with acetonitrile constant volume, mixes, with 0.45 μm of filtering with microporous membrane.With
HPLC methods determine drugloading rate and envelop rate, and calculation formula is as follows, as a result for：Drugloading rate is 36%, and envelop rate is 90%.
The release behavior of embodiment 24
On the foundation of vitro release method, the present invention considers In vitro-in vivo correlation, using 37 degree, 100rpm/min water
Bathe shaking table method and determine release in vitro.Dissolution medium uses 0.5%SDS solution to meet sink conditions.During sampling, 2500rpm from
Heart 10min, takes supernatant sample introduction to analyze, and discards 9mL media, changes fresh medium.
The comparative determination result of embodiment 2,3,4 is referring to Fig. 7, and Fig. 7 is the progesterone sustained-release micro-spheres that embodiment 2-4 is prepared
In-vitro release curves.
From figure 7 it can be seen that the microballoon of embodiment 2 progesterone in the 24h of beginning releases 21.20%, after
Slowly discharged in time, cumulative release amount is 92.13% in week age；The microballoon of embodiment 3 corpus luteum in the 24h of beginning
Ketone releases 15.96%, is slowly discharged in the time after, and cumulative release amount is 80.65% in week age；Embodiment
4 microballoon progesterone in the 24h of beginning releases 10.58%, is slowly discharged in the time after, tires out in week age
Product burst size is 65.90%.
Embodiment 2, embodiment 3, PLGA molecular weight used in the microballoon of embodiment 4 are between 10000-30000, in release process
In there is no phenomenon of burst release, can continuously discharge one week.Other embodiment has such as embodiment 2, embodiment 3, embodiment 4 is similar releases
Put characteristic；Microballoon rate of release prepared by the bigger PLGA of molecular weight is slower.
The comparative determination result of embodiment 16,17,18 is referring to Fig. 8, and Fig. 8 is that the progesterone that embodiment 16-18 is prepared is received
The In-vitro release curves of the grain of rice.
From figure 8, it is seen that the nanoparticle of embodiment 16 progesterone in the 24h of beginning releases 23.43%, after
Time in slowly discharge, in week age cumulative release amount be 90.21%；24h of the nanoparticle of embodiment 17 in beginning
Interior progesterone releases 18.33%, is slowly discharged in the time after, and cumulative release amount is 69.30% in week age；
The nanoparticle of embodiment 18 progesterone in the 24h of beginning releases 14.08%, is slowly discharged in the time after, one
Cumulative release amount is 51.00% in time-of-week.
Embodiment 16, embodiment 17, polymeric material used in the nanoparticle of embodiment 18 are PLGA (75：25；25000)、
PLA (10000), PCL (10000).Polymeric material is different, and degraded feature is different, can continuously discharge one week；Material degradation speed
Rate is PLGA>PLA>PCL.
In summary, progesterone long-acting injection of the invention can be released in one week, and release process is steady, without bright
Aobvious phenomenon of burst release, it is ensured that the therapeutic scheme being clinically administered once for one week.
Claims (10)
1. a kind of progesterone sustained-release micro-spheres, it is characterised in that be made up of the material including progesterone and first polymer material, institute
State one kind in Poly(D,L-lactide-co-glycolide, PLA, polycaprolactone and polyglycolic acid of first polymer material or
It is a variety of；The molecular weight of the first polymer material is 4000~40000 dalton；The progesterone accounts for sustained-release micro-spheres gross mass
30%~40%；
The particle diameter of the progesterone sustained-release micro-spheres is 10~20 μm.
2. progesterone sustained-release micro-spheres according to claim 1, it is characterised in that the Poly(D,L-lactide-co-glycolide
Molecular weight be 10000-40000 dalton；The molecular weight of PLA is 10000-20000 dalton；The molecule of polycaprolactone
Measure as 4000-40000 dalton；The molecular weight of polyglycolic acid is 8000-20000 dalton.
3. progesterone sustained-release micro-spheres according to claim 2, it is characterised in that the Poly(D,L-lactide-co-glycolide
The mol ratio of middle lactic acid and hydroxyacetic acid is (50~85)：(15~50).
4. according to progesterone sustained-release micro-spheres according to any one of claims 1 to 3, it is characterised in that the first polymer
The end-blocking mode of material be carboxy blocking, ester end-blocking and it is hydroxy-end capped in one or more.
5. a kind of preparation method of progesterone sustained-release micro-spheres, comprises the following steps：
1) progesterone and first polymer material are dissolved in organic solvent, form organic phase；The first polymer material choosing
One or more from Poly(D,L-lactide-co-glycolide, PLA, polycaprolactone and polyglycolic acid；First polymerization
The molecular weight of thing material is 4000~40000 dalton；
2) by step 1) obtained organic phase poured into the aqueous solution containing emulsifying agent, through high speed shearing emulsification, obtains oil-in-water type
Emulsion；
3) by step 2) after obtained emulsion oil-in-water is diluted with water, vacuum distillation is carried out, microsphere suspension is obtained；
4) by step 3) after obtained microsphere suspension is washed with water, through separation of solid and liquid, obtain progesterone sustained-release micro-spheres.
6. preparation method according to claim 5, it is characterised in that the step 2) in the aqueous solution containing emulsifying agent be poly-
Glycohol solution；The mass concentration of poly-vinyl alcohol solution is 0.5%~2%.
7. preparation method according to claim 5, it is characterised in that the step 2) rotating speed of high speed shearing is
10000~14000rpm, shear time is 1~2min.
8. a kind of progesterone slow release nano-particle, it is characterised in that be made up of the material including progesterone and second polymer material,
The one kind of the second polymer material in Poly(D,L-lactide-co-glycolide, PLA, polycaprolactone and polyglycolic acid
Or it is a variety of；The molecular weight of the second polymer material is 6000~60000 dalton；It is total that the progesterone accounts for slow release nano-particle
The 10%~20% of quality；
The particle diameter of the progesterone slow release nano-particle is 100~400nm.
9. a kind of preparation method of progesterone slow release nano-particle, comprises the following steps：
1) progesterone and second polymer material are dissolved in organic solvent, form organic phase；The second polymer material choosing
One or more from Poly(D,L-lactide-co-glycolide, PLA, polycaprolactone and polyglycolic acid；Second polymerization
The molecular weight of thing material is 6000~60000 dalton；
2) by step 1) obtained organic phase poured into the aqueous solution containing emulsifying agent, through high speed shearing emulsification, obtains oil-in-water type
Colostric fluid；The oil-in-water type colostric fluid is subjected to high pressure homogenization, whole emulsion is obtained；
3) by step 2) after obtained whole emulsion is diluted with water, by low-temperature setting, obtain micronised suspensions；
4) by step 3) after obtained micronised suspensions are washed with water, through separation of solid and liquid, obtain progesterone slow release nano-particle.
10. a kind of progesterone is slow-release injected, it is characterised in that including progesterone particle and solvent for injection；The progesterone
Particle is any one of progesterone sustained-release micro-spheres according to any one of claims 1 to 4, claim 5~7 preparation method system
Progesterone sustained-release micro-spheres, the progesterone slow release nano-particle described in claim 8 or the preparation method system described in claim 9
The progesterone slow release nano-particle obtained.
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| CN114342930A (en) * | 2022-03-01 | 2022-04-15 | 中国农业科学院植物保护研究所 | Pesticide nanocapsule and preparation method thereof |
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