CN102631326A - Sustained release microsphere used for injection and preparation method and applications of sustained release microsphere - Google Patents
Sustained release microsphere used for injection and preparation method and applications of sustained release microsphere Download PDFInfo
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- CN102631326A CN102631326A CN201210140775XA CN201210140775A CN102631326A CN 102631326 A CN102631326 A CN 102631326A CN 201210140775X A CN201210140775X A CN 201210140775XA CN 201210140775 A CN201210140775 A CN 201210140775A CN 102631326 A CN102631326 A CN 102631326A
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Abstract
The invention discloses a sustained release microsphere used for injection and a preparation method and applications of the sustained release microsphere. The sustained release microsphere contains dutasteride and biodegradable polymer. The invention also relates to a pharmaceutical composition which contains effective dose of dutasteride and biodegradable polymer and at least one pharmaceutically acceptable excipient or an auxiliary material, wherein the dutasteride is contained in the microsphere basically formed by the biodegradable polymer. The invention further relates to pharmaceutical applications of the microsphere. With adoption of the microsphere, the effect time of the drug administration can be prolonged; the times of the drug administration can be reduced; and the medicinal bioavailability and the compliance of patients can be improved.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, specifically, relate to dutasteride's slow release microphere for injection, the pharmaceutical composition that comprises it, its preparation method and application thereof.
Background technology
Symptomatic benign prostatic hyperplasia (BPH) is a male gerontal patient commonly encountered diseases.BPH can cause that bladder output in various degree is obstructed, and freely causes progressivity frequent micturition and urgent micturition with quick the filling of bladder because of urinating.It is reported that in the male senile patient of China more than 60 years old, have 50% to suffer from this disease approximately, and sickness rate is up to 88% more than 70 years old, if from the statistics angle, sickness rate almost reaches 100%.
BPH is having a strong impact on people's quality of life, if untimely treatment possibly cause sexual dysfunction, causes impotence and premature ejaculation; Influence motility of sperm, cause sterility and infertility; Cause chronic nephritis, even develop into uremia; Also can cause the endocrine disturbance, symptoms such as insomnia and dreamful sleep, weak dizziness, bradyphrenia, hypomnesis; And be accompanied by the possibility of canceration.This gives male patient's human body, spirit and brings great burden economically.
Because prostate position, structure are special, surgical operation can only excise the hypertrophy of peplos internal layer, and skin does not touch.And prostate is the control switch of urinating, and is prone to the symptom of frequent micturition even incontinence behind the operation on prostate on the contrary, and prostate still can hypertrophy, can not effect a radical cure.Add surgical operation therapy human body is had bigger wound, so can not become the conventional method of prostatic hyperplasia treatment.
The dutasteride be the 2nd generations 5 the alpha-reductase depressant; Being present first kind also is unique a kind of medicine that suppresses I type and II type 5 alpha-reductases simultaneously; Research and develop by Ge Lansu company; On October 10th, 2002, in U.S.'s listing, trade name Avodart was at the commodity of European market Avolve by name by FDA Food and Drug Administration (FDA) approval
TM, be capsule, the 0.5mg/ grain, 1 of per day for adults, be generally 6 months the course of treatment.
The dutasteride is a kind of synthetic 4-azasteroid chemical compound; Its chemistry (5 α by name; 17 β)-and N-{2,5-two (trifluoromethyl) phenyl }-3-oxo-4-azepine androstane-1-alkene-17-Methanamide ((5 α, 17 β)-N-{2; 5-bis (trifluoromethyl) phenyl}-3-oxo-4-azaandrost-1-ene-17-carboxamide), molecular formula is C
27H
30F
6N
2O
2, molecular weight is 528.5, structural formula is following:
The dutasteride is a kind of white to a pale powder, 242 ° to 250 ℃ of fusing points.It is dissolved in ethanol (44mg/mL), methanol (64mg/mL) and PEG400 (3mg/mL), but water insoluble.
Dutasteride's absolute bioavailability is approximately 60% (scope at 40%-94% is floated).The maximum plasma concentration of taking simultaneously with food reduces by 10% to 15%, does not have remarkable difference clinically, therefore is suitable for after meal or taking medicine before meal usefulness.Clinical research shows that the dutasteride can improve the BPH symptom for a long time, reduces the generation of acute urinary retention, improves patient's quality of life.
Simultaneously, the dutasteride also has the effect that reduces prostate canceration risk.The dutasteride can effectively reduce prostate specific antigen in the blood (PSA) concentration, and high concentration PSA is the strong signal of prostate canceration.Through taking the dutasteride, many male can avoid the generation of prostate canceration, thus the various untoward reaction that reduced medical treatment cost and in therapeutic process, occurred.
Dutasteride's commercially available dosage form is a soft capsule for oral use, and every capsule comprises the dutasteride of 0.5mg active component, and the half-life was 5 weeks.Though showing, long half time, test can not cause savings to be poisoned.But owing to require medication every day, this is to the patient, and particularly senile patient exists compliance issues.
Therefore people still are expected for the dutasteride provides new medication, and a kind of method that reduces administration frequency particularly is provided.
Summary of the invention
The objective of the invention is particularly provides a kind of method that reduces administration frequency for the dutasteride provides new medication.In view of there is above defective in oral formulations, the inventor utilizes microencapsulation that the dutasteride is prepared into expectation can one month biodegradable microball prepn of long-acting slow release.The inventor is surprisingly found out that this microball prepn has the dependency of gratifying vivo and vitro release behavior, the present invention is based on this discovery and is accomplished.
For this reason, first aspect present invention provides a kind of microsphere, wherein comprises dutasteride and biodegradable polymer.
According to the described microsphere of the arbitrary embodiment of first aspect present invention, wherein comprise the dutasteride of 1 weight portion and the biodegradable polymer of 1～100 weight portion.In one embodiment, said microsphere comprises the dutasteride of 1 weight portion and the biodegradable polymer of 2～50 weight portions.In one embodiment, said microsphere comprises the dutasteride of 1 weight portion and the biodegradable polymer of 5～50 weight portions.In one embodiment, said microsphere comprises the dutasteride of 1 weight portion and the biodegradable polymer of 5～40 weight portions.In one embodiment, said microsphere comprises the dutasteride of 1 weight portion and the biodegradable polymer of 5～30 weight portions.In one embodiment, said microsphere comprises the dutasteride of 1 weight portion and the biodegradable polymer of 5～25 weight portions.In one embodiment, said microsphere comprises the dutasteride of 1 weight portion and the biodegradable polymer of 7.5～25 weight portions.In one embodiment, said microsphere comprises the dutasteride of 1 weight portion and the biodegradable polymer of 7.5～20 weight portions.In one embodiment, said microsphere comprises the dutasteride of 1 weight portion and the biodegradable polymer of 7.5～18 weight portions.In one embodiment, said microsphere comprises the dutasteride of 1 weight portion and the biodegradable polymer of 8～15 weight portions.
According to the described microsphere of the arbitrary embodiment of first aspect present invention; Wherein said biodegradable polymer is that molecular weight is 5000～500000 daltonian biodegradable polymer, for example is selected from the biodegradable polymer of following molecular weight ranges: 5000～100000 dalton, 5000～80000 dalton, 5000～75000 dalton, 5000～50000 dalton, 7500～50000 dalton, 10000～50000 dalton, 10000～40000 dalton.
According to the described microsphere of the arbitrary embodiment of first aspect present invention, wherein said biodegradable polymer is to be selected from polylactide-co-glycolide, polylactide, polylactic-co-glycolic acid, polyglycolic acid, to gather β-carboxyl butyrate, poe, polycaprolactone, gather in anhydride, poly phosphate, polyphosphazene, polybutylcyanoacrylate, the polyamide one or more.In one embodiment, two kinds of monomeric mole ratios that constitute said biodegradable polymer are 15: 85～85: 15, preferred 20: 80～80: 20, and preferred 25: 75～75: 25.In an especially preferred embodiment, described biodegradable polymer is a polylactic-co-glycolic acid; Preferably, its molecular weight ranges is 5000～100000 dalton, preferred 5000～80000 dalton, preferred 5000～75000 dalton, preferred 5000～50000 dalton, preferred 7500～50000 dalton, preferred 10000～50000 dalton; Preferably, its two kinds of monomeric mole ratios are 15: 85～85: 15, preferred 20: 80～80: 20, and preferred 25: 75～75: 25.
According to the described microsphere of the arbitrary embodiment of first aspect present invention, wherein also comprise second reactive compound.In one embodiment, this second reactive compound is a α-Zu Zhiji.In one embodiment, this second reactive compound is tamsulosin (tamsulosin).
According to the described microsphere of the arbitrary embodiment of first aspect present invention, wherein comprise the dutasteride of 1 weight portion and the polylactic-co-glycolic acid of 7.5～18 weight portions.In one embodiment, wherein the molecular weight ranges of polylactic-co-glycolic acid is 5000～50000 dalton, preferred 7500～50000 dalton, preferred 10000～50000 dalton.In one embodiment, wherein two of polylactic-co-glycolic acid kinds of monomeric mole ratios are 15: 85～85: 15, preferred 20: 80～80: 20, and preferred 25: 75～75: 25.In one embodiment, the mean diameter of this microsphere is 10-200um, preferred 20-120um.In one embodiment, the medicine encapsulation ratio of this microsphere is 70-95%, preferred 75-90%, preferred 78-89%.
According to the described microsphere of the arbitrary embodiment of first aspect present invention, wherein also comprise acceptable excipient of pharmacy or adjuvant.
Second aspect present invention provides a kind of pharmaceutical composition, wherein comprises the dutasteride and the biodegradable polymer of effective dose, and acceptable excipient of at least a pharmacy or adjuvant.In one embodiment, said dutasteride is contained in basically in the microsphere (the for example described microsphere of first aspect present invention) that is formed by said biodegradable polymer.
Second aspect present invention also provides a kind of pharmaceutical composition, wherein comprises the described microsphere of first aspect present invention of effective dose, and acceptable excipient of at least a pharmacy or adjuvant.
According to the pharmaceutical composition of second aspect present invention, it is injectable liquid preparation; Or a kind of solid preparation, this solid preparation face with before available injection solution for example after the dissolve/dilute such as water, sodium chloride solution, glucose solution, Ringers solution, can be used for drug administration by injection.
Pharmaceutical composition according to second aspect present invention; Acceptable excipient of wherein said pharmacy or adjuvant are injectable excipient or adjuvant, include but not limited to: water, sodium chloride, mannitol, lactose, sucrose, sorbitol, fructose, glycerol, propylene glycol, molecular weight are the Polyethylene Glycol of 200-1000 (preferred 200-600) etc.
According to the pharmaceutical composition of second aspect present invention, it is injectable single dose dosage form.In one embodiment, the dutasteride who comprises 5～100mg in this single dose dosage form.In one embodiment, the dutasteride who comprises 5～50mg in this single dose dosage form.In one embodiment, the dutasteride who comprises 5～25mg in this single dose dosage form.In one embodiment, the dutasteride who comprises 5～20mg in this single dose dosage form.For realizing 10～30 days slow release purpose, the dutasteride who comprises 5～50mg or 5～25mg in this single dose dosage form is preferred.
Third aspect present invention provides the purposes of the said microsphere of first aspect present invention in the depot drug product of preparation treatment prostatic hyperplasia.
Fourth aspect present invention provides the method for preparing the said microsphere of first aspect present invention, and this method is emulsifying dispersion-intra-liquid desiccation method or spray drying method.In one embodiment, said emulsifying dispersion-intra-liquid desiccation method comprises that oil/water and milk divides arching pushing or oil/oily emulsifying dispersion method.
According to the method for fourth aspect present invention, it is an emulsifying dispersion-intra-liquid desiccation method, and may further comprise the steps:
A) with after biological degradation polyalcohol and medicine dissolution are in suitable organic solvent, process decentralized photo;
B) decentralized photo is splashed in the continuous phase that is added with emulsifying agent of continuous stirring, organic solvent volatilizees gradually, separates out microsphere;
C) the microsphere suspension is through centrifugalize;
D) make microsphere through drying under reduced pressure or lyophilization; With optional
E) the microsphere sterilized powder is suspended in pharmacy and can accepts in the solution, shakes up to get final product.
According to the method for fourth aspect present invention, wherein the step b) mixing speed is 400～10000rpm.
According to the method for fourth aspect present invention, wherein emulsifying dispersion-intra-liquid desiccation method comprises that oil/water and milk divides arching pushing or oil/oily emulsifying dispersion method.
According to the method for fourth aspect present invention, its medium oil/water and milk divides in the arching pushing, and organic solvent is one-component or its any mixture of dichloromethane, chloroform, ethyl acetate, methanol, ethanol, acetone, acetonitrile, DMSO and benzene in the decentralized photo.
According to the method for fourth aspect present invention, its medium oil/water and milk divides in the arching pushing, and the continuous phase medium is a water.
According to the method for fourth aspect present invention, its medium oil/water and milk divides in the arching pushing, and emulsifying agent is one-component or its any mixture of PVPk-30, gelatin, CMC-Na, low viscosity HPMC, HPC or PVA.
According to the method for fourth aspect present invention, wherein emulsifying agent is PVA.
According to the method for fourth aspect present invention, in its medium oil/oily emulsifying dispersion method, the decentralized photo organic solvent is acetone, acetonitrile or ethyl acetate.
According to the method for fourth aspect present invention, in its medium oil/oily emulsifying dispersion method, continuous phase is Dormant oils or vegetable oil.
According to the method for fourth aspect present invention, wherein Dormant oils is liquid paraffin or silicone oil or simethicone.
According to the method for fourth aspect present invention, wherein vegetable oil is Oleum Arachidis hypogaeae semen, Oleum Gossypii semen, Oleum Sesami, Oleum Camelliae or Oleum Glycines.
According to the method for fourth aspect present invention, in its medium oil/oily emulsifying dispersion method, emulsifying agent is the nonionic surfactant between the HLB1.5-5.
According to the method for fourth aspect present invention, described nonionic surfactant is Span80 or Span85.
According to the method for fourth aspect present invention, it adopts spray drying method for preparation, after biological degradation polyalcohol is dissolved by organic solvent; Add the dutasteride, stir and make its one-tenth settled solution, filter; The spray-dried microsphere that is prepared into of filtrating; The microsphere sterilized powder is suspended in pharmaceutical acceptable carrier, shakes up, and promptly gets.
The characteristic that arbitrary embodiment had of the arbitrary aspect of the present invention or this arbitrary aspect is equally applicable to arbitrary embodiment of other arbitrary aspect or this other arbitrary aspect; As long as they can be not conflicting; Certainly at where applicable each other, necessary words can be done suitably to modify to individual features.In addition, arbitrary technical characterictic of the arbitrary aspect of the present invention is equally applicable to the relevant art characteristic of other arbitrary aspect.
Do further to describe with characteristics to various aspects of the present invention below.
All documents that the present invention quoted from, their full content is incorporated this paper by reference into, and if the expressed implication of these documents and the present invention when inconsistent, be as the criterion with statement of the present invention.In addition; Various terms and phrase that the present invention uses have the general sense of well known to a person skilled in the art; Nonetheless; The present invention still hopes at this more detailed explanation and explanation to be done in these terms and phrase, and term of mentioning and phrase are as the criterion with the implication that the present invention was explained if any inconsistent with known implication.
As described herein, term " effective dose " is meant the dosage that can in the experimenter, realize treating and/or preventing prostatic hyperplasia property disease.
As described herein, term " pharmaceutical composition " also can be described as " compositions ", wherein comprises active component dutasteride and optional pharmaceutically acceptable carrier or excipient.
In the present invention, the dutasteride can also use the acceptable salt of its medicine, so the acceptable salt of dutasteride's medicine equally also comprises within the spirit and scope of the present invention.Term " the acceptable salt of medicine " refers in reliable medical judgment scope, be suitable for contacting with zootic tissue and over-drastic toxicity, stimulation, anaphylaxis etc. do not occur with the mankind, and with rational effect/risk than the salt that matches.The acceptable salt of medicine is well known in the art.For example, S.M.Berge etc. are at J.Pharmaceutical Sciences, and 1977, among the 66:1 the acceptable salt of medicine is described in detail.According to the present invention, wherein said dutasteride can use with the acceptable salt of its pharmacy.Though the present invention only makes an experiment through the dutasteride; But it will be apparent to those skilled in the art that; Can expect that according to the present invention dutasteride's the acceptable salt of medicine also is effective equally; Certainly, when confirming dosage, can convert, so that roughly confirm dosage as the use of salt type through gram-molecular weight.
This is according to the present invention, and term " single dose dosage form " also can be described as " form of UD " or " unit dosage form ", for example is meant the medicine that single ampoule is bottled.
This is according to the present invention; Term " effective dose "; Perhaps " effective dose " perhaps can be described as " prevention with/treatment or effective dose ", is appreciated that to dutasteride according to the invention with reasonable effect/risk of being applicable to any therapeutic treatment than sanatory q.s.But it should be understood that dutasteride's of the present invention average total consumption per day or total daily dose of single preparation course of treatment can maked decision in the medical judgment scope by those skilled in the art reliably.For any concrete experimenter, the horizontal fibrous root of concrete prevention effective dose is decided according to multiple factor, and said factor comprises experimenter's age, body weight, general health situation, sex and diet; The concrete compositions that is adopted; Make up the medicine that uses or use simultaneously with the dutasteride; And the known similar factor of medical field.
Arbitrary aspect embodiment according to the present invention; Dosage every day that said dutasteride gives experimenter's (for example mammal, like the people) becomes known for treating 0.01～100 times of dosage of disease, preferred 0.1～10 times for this medicine; Preferred 0.2～5 times, preferred 0.5～2 times.
Use like this paper, term " biodegradable polymer " is meant a kind of high molecular polymer, and it can be degraded and be absorbed by the body in the body fluid environment.
Use like this paper, term " two kinds of monomeric mole ratios " is meant that said biodegradable polymer is formed by two kinds of monomers, these two kinds of monomers in polymer shared ratio with the ratio of molar ratio computing.For example for polylactide-co-glycolide, should " two kinds of monomeric mole ratios " be meant that lactide and Acetic acid, hydroxy-, bimol. cyclic ester are with the ratio of molar ratio computing in the said polymer.And for example for polylactic-co-glycolic acid; Should " two kinds of monomeric mole ratios " be meant last monomer lactic acid and back one monomer hydroxyacetic acid (also can be described as " glycolic " in this article) in the said polymer both with the ratio of molar ratio computing; Be that expression is a lactic acid as two kinds of monomer ratios of this polymer: hydroxyacetic acid is 15: 85～85: 15 (mol/mol) under 15: 85～85: 15 the situation two kinds of monomeric mole ratios.Relate to " two kinds of monomeric mole ratios " and also have similar meaning.
Use like this paper, term " second reactive compound " is meant the second kind of chemical compound with physiologically active that is different from reactive compound dutasteride of the present invention.Because known dutasteride can use separately or can make up use (referring to http://www.rxlist.com/avodart-drug.htm with other medicines (for example α-Zu Zhiji); Up-to-date checking the date: 10/7/2010), so microsphere of the present invention does not repel use second reactive compound.
Use like this paper, term " injectable " is meant and can injects to the curee with any approach.In one embodiment, through intramuscular or subcutaneous route injection.
In the present invention; Term " envelop rate "; Represent with %, be meant at microsphere of the present invention to prepare in the process that the active component dutasteride of being contained in the whole end-product microspheres that obtain amount accounts for the percent of the theoretical inventory of active component dutasteride in the preparation process.The assay method of the dutasteride's in the microsphere amount can adopt conventional method for example to use the HPLC method of hereinafter Test Example 1 to measure.
As described herein, microsphere of the present invention comprises the dutasteride of 1 weight portion and the biodegradable polymer of 1～100 weight portion.With regard to the object of the invention; When preparation pharmaceutical composition of the present invention; In the said composition except microsphere; Can also comprise acceptable excipient of pharmacy or adjuvant, acceptable excipient of these pharmacy or adjuvant comprise any excipient or adjuvant that is of value to the injecting drug use preparation, can also comprise biodegradable polymer as described herein.Therefore; In pharmaceutical composition of the present invention; Wherein can comprise the dutasteride of 1 weight portion and the biodegradable polymer of wideer weight range, for example can in pharmaceutical composition, add some biodegradable chemical compounds, so that produce the effect of some desirable; For example the messenger drug fluid viscosity increases, and microsphere of the present invention is beneficial to is suspended in the injection solution.
Microsphere of the present invention can be through subcutaneous injection in body, and medicine can slowly discharge through framing structure, and framing structure slowly is degraded to nontoxic small-molecule substance (carbon dioxide and water) in vivo simultaneously, finally excretes.Medicine can be kept in vivo and discharge one month.
Technical problem to be solved by this invention provides a kind of dutasteride's slow release microphere for injection.Another technical problem to be solved by this invention provides the method for preparing of dutasteride's slow release microphere for injection.Another technical problem to be solved by this invention provides the method for preparing of another kind of dutasteride's slow release microphere for injection.The slow release microphere for injection that another technical problem to be solved by this invention is the dutasteride be used to prepare the durative action preparation of treating prostatic hyperplasia.
In one embodiment of the invention, the release profiles similar factors can reach more than 60% in outer release curve of dutasteride's microsphere of the present invention and the rat body.Those skilled in the art know; Similar factors (similarity factor) is to estimate in the slow releasing preparation body-important method of external dependency; For example the match factor (fit factor) method is just adopted in the quantitative analysis of relevant similarity in the FDA guideline, and this match factorization method comprises similar factors and difference factorization method.Wherein, similar factors is recommended as the prefered method of 2 release profiles similaritys of comparison by FDA, so similar factors is used more in the evaluation index of sustained-release preparation formulation optimization.Similar factors shows that more greatly dependency is good more, and for example similar factors is being acceptable basically more than 40, and similar factors is being satisfied basically more than 50, and will be quite gratifying greater than 60.
In one embodiment of the invention, microspherulite diameter distribution of the present invention is 10～200um, preferred 20～120um.In one embodiment of the invention, the mean diameter of microsphere according to the invention is 10～200um, preferred 20～120um.
In one embodiment of the invention, dutasteride's of the present invention slow release microphere for injection adopts the preparation of emulsifying dispersion-intra-liquid desiccation method, comprises the following steps:
After biological degradation polyalcohol and medicine dissolution are in suitable organic solvent, process decentralized photo;
Decentralized photo is splashed in the continuous phase that is added with emulsifying agent of continuous stirring, organic solvent volatilizees gradually, separates out microsphere;
The microsphere suspension is through centrifugalize;
Make microsphere through drying under reduced pressure or lyophilization;
The microsphere sterilized powder is suspended in pharmacy and can accepts to shake up in the solution, promptly gets.
In one embodiment of the invention, the entrapment efficiency of method for preparing microsphere of the present invention is greater than 60%.
In one embodiment of the invention, decentralized photo is added the continuous phase that is stirring, mixing speed is a very important parameters of control microspherulite diameter, and agitator adopts rectilinear SANYE glass or rustless steel stirring paddle, and rotating speed is 400～10000rpm.The microspherulite diameter distribution of the present invention's preparation is 10～200um, and screening 20～120um particle diameter is an injectable microsphere.Microsphere suspension liquid is collected supernatant through centrifugalize, and microsphere is with distilled water repeatedly drip washing on a small quantity, and drying under reduced pressure or lyophilization get final product under room temperature.
In one embodiment of the invention, dutasteride's injectable microsphere can adopt oil/water (O/W) emulsifying-intra-liquid desiccation method preparation.Biological degradation polyalcohol is dissolved in the suitable organic solvent, adds medicine dissolution and make oil phase, oil phase splashes into that (water) makes into O/W Emulsion in the aqueous surfactant solution that is stirring.Above-mentioned organic solvent is volatilized gradually, separate out medicine carrying microballoons, centrifugalize, the washing desiccant can.
In one embodiment of the invention, the decentralized photo solvent flashing of oil/water (O/W) emulsifying-intra-liquid desiccation method can be selected one-component or its any mixture of dichloromethane, chloroform, ethyl acetate, methanol, ethanol, acetone, acetonitrile, DMSO and benzene for use.Continuous phase is medium with water, in the medium surfactant should be arranged, like one-component or its any mixture of PVPk-30, gelatin, CMC-Na, low viscosity HPMC, HPC or PVA, first-selected PVA.The surfactant addition is 0.2-8.0% for the continuous phase volume, first-selected 0.3-2.0%.Among the present invention, polymer solvent kind, the mixture of the one-component of first-selected dichloromethane or ethyl acetate or two components.Polymer concentration is that the percentage ratio that 1～50% (w/v) medicine accounts for microsphere weight is 0.2～75%, and decentralized photo and continuous phase volume ratio are 1/50～1/5, preferred 1/10～1/5.
In one embodiment of the invention, dutasteride's microsphere also can adopt oil/oil (O/O) emulsifying-intra-liquid desiccation method preparation.Adopt the O/O emulsion process to prepare microsphere, dissolve polymer and dutasteride's emulsifying decentralized photo (inner phase) organic solvent can adopt acetone, acetonitrile or ethyl acetate, and continuous phase can adopt Dormant oils, like liquid paraffin, and silicone oil or simethicone.Vegetable oil such as Oleum Arachidis hypogaeae semen, Oleum Gossypii semen, Oleum Sesami, Oleum Camelliae and Oleum Glycines.For decentralized photo can better be dispersed in the continuous phase, the latter should add low HLB value non-ionic surface active agent, and its HLB is advisable between 1.5～5.0.Preferred Span80 or Span85.The microsphere preparation can splash into decentralized photo in the continuous phase that is stirring.Said system is in a steady temperature, and under constant agitation speed, organic solvent evaporates gradually in the decentralized photo, and medicine carrying microballoons is separated out.Supernatant is gone in the suspension centrifugalize, and microsphere gets through the filter membrane decompression separation.With hexane or cyclohexane extraction repeatedly drip washing on a small quantity, remove the microsphere surface oil stain.Reduced pressure at room temperature or lyophilization and get.
In one embodiment of the invention, dutasteride's microsphere also can adopt spray drying method for preparation.When adopting spray drying to prepare microsphere, biological degradation polyalcohol adds the dutasteride after being dissolved by organic solvent, stirs to make it become settled solution, filters the spray-dried microsphere of processing of filtrating.The decentralized photo organic solvent can adopt dichloromethane, chloroform, ethyl acetate, dioxane, acetone, a kind of or any mixture in the oxolane.
In one embodiment of the invention, biological degradation polyalcohol amount molecular weight is 5000～500000 dalton in the said slow release microphere for injection.
In one embodiment of the invention, biological degradation polyalcohol is selected from polylactide-co-glycolide in the said slow release microphere for injection, polylactide, polyglycolic acid; Gather beta-hydroxy-butanoic acid ester, polylactic-co-glycolic acid, poe; Polycaprolactone gathers anhydride, poly phosphate; Polyphosphazene, polybutylcyanoacrylate, a kind of or any mixture in the polyamide.
In one embodiment of the invention, biological degradation polyalcohol is selected from polylactide-co-glycolide in the said slow release microphere for injection, polylactide or polylactic-co-glycolic acid.
In one embodiment of the invention, polylactide-co-glycolide in the said slow release microphere for injection, the molecular weight of polylactide or polylactic-co-glycolic acid are 10000～40000 dalton.
In one embodiment of the invention, polylactide-co-glycolide or polylactic-co-glycolic acid two polymerization single polymerization monomer mole ratios are 15: 85～85: 15 in the said slow release microphere for injection.
In one embodiment of the invention, polylactide-co-glycolide or polylactic-co-glycolic acid two polymerization single polymerization monomer mole ratios are 25: 75～75: 25 in the said slow release microphere for injection.
In one embodiment of the invention; The for example method for preparing of the said microsphere of the arbitrary embodiment of the present invention of preparation slow release microphere for injection is provided; It adopts the preparation of emulsifying dispersion-intra-liquid desiccation method; Comprise the following steps: to process decentralized photo with after biological degradation polyalcohol and medicine dissolution are in suitable organic solvent; Decentralized photo is splashed in the continuous phase that is added with emulsifying agent of continuous stirring, organic solvent volatilizees gradually, separates out microsphere; The microsphere suspension is through centrifugalize; Make microsphere through drying under reduced pressure or lyophilization; The microsphere sterilized powder is suspended in pharmacy and can accepts in the solution, shakes up to get final product.In one embodiment, wherein the step b) mixing speed is 400～10000rpm.In one embodiment, wherein emulsifying dispersion-intra-liquid desiccation method comprises that oil/water and milk divides arching pushing or oil/oily emulsifying dispersion method.In one embodiment, its medium oil/water and milk divides in the arching pushing, and organic solvent is one-component or its any mixture of dichloromethane, chloroform, ethyl acetate, methanol, ethanol, acetone, acetonitrile, DMSO and benzene in the decentralized photo.In one embodiment, its medium oil/water and milk divides in the arching pushing, and the continuous phase medium is a water.In one embodiment, its medium oil/water and milk divides in the arching pushing, and emulsifying agent is one-component or its any mixture of PVPk-30, gelatin, CMC-Na, low viscosity HPMC, HPC or PVA.In one embodiment, wherein emulsifying agent is PVA.In one embodiment, in its medium oil/oily emulsifying dispersion method, the decentralized photo organic solvent is acetone, acetonitrile or ethyl acetate.In one embodiment, in its medium oil/oily emulsifying dispersion method, continuous phase is Dormant oils or vegetable oil.In one embodiment, wherein Dormant oils is liquid paraffin or silicone oil or simethicone.In one embodiment, wherein vegetable oil is Oleum Arachidis hypogaeae semen, Oleum Gossypii semen, Oleum Sesami, Oleum Camelliae or Oleum Glycines.In one embodiment, in its medium oil/oily emulsifying dispersion method, emulsifying agent is the nonionic surfactant between the HLB1.5-5.In one embodiment, described nonionic surfactant is Span80 or Span85.
In one embodiment of the invention, the for example method for preparing of the said microsphere of the arbitrary embodiment of the present invention of preparation slow release microphere for injection is provided, it adopts spray drying method for preparation; Biological degradation polyalcohol adds the dutasteride after being dissolved by organic solvent, stirs to make it become settled solution; Filter; The spray-dried microsphere that is prepared into of filtrating, the microsphere sterilized powder is suspended in pharmaceutical acceptable carrier, both shook up.In one embodiment, described organic solvent is a kind of or its any mixture in dichloromethane, chloroform, two chloroethene rings, acetone, ethyl acetate, the oxolane.
In one embodiment of the invention, provide slow release microphere for injection for example the arbitrary embodiment of the present invention said microsphere be used to prepare the purposes of the durative action preparation of treating prostatic hyperplasia.
Dutasteride's slow release microphere for injection durative action preparation of the present invention can be that the microsphere sterilized powder for preparing is suspended in the 0.3-0.6% sodium carboxymethyl cellulose solution, and jolting is even, can make subcutaneous injection.This dosage form has prolonged drug treating time, has reduced the medication number of times, has improved drug bioavailability.
Below further specify dutasteride's microsphere of the present invention and method for preparing through embodiment, release pattern and to the therapeutical effect of animal prostatic hyperplasia.
The specific embodiment:
Can further describe the present invention through following embodiment, yet scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and under the prerequisite that does not deviate from the spirit and scope of the present invention, can carry out various variations and modification to the present invention.The present invention carries out generality and/or concrete description to the material and the test method that are used in the test.Though for realizing that employed many materials of the object of the invention and operational approach are well known in the art, the present invention still does to describe in detail as far as possible at this.
A, microsphere prepare embodiment
Embodiment 1
100mg polylactic-co-glycolic acid (molecular weight 20000 dalton, two monomer mole ratios 50: 50) is dissolved in the 1ml dichloromethane, adds the 10mg dutasteride, stirring and dissolving makes into clear and bright solution.Be equipped with one and add 5%PVA (124) aqueous solution in the beaker of stirring paddle level land, constant temperature (25 ℃), the back splashes into above-mentioned polymer solution wherein in stirring down; Stir formation Emulsion with 800rpm; Add a large amount of distilled water again, keep 400rpm, make that organic solvent volatilizes gradually in the O/W Emulsion.The whole process microscopy of constantly sampling is observed multistage microsphere forming process.
Above-mentioned solution centrifugal separates, the supernatant that inclines, and microsphere is collected in decompression on filter membrane, and with distilled water repeatedly washing on a small quantity, microsphere decompression room temperature is drying to obtain.Microsphere average grain diameter 80um.
Embodiment 2
100mg polylactic-co-glycolic acid (molecular weight 10000 dalton, two monomer mole ratios 20: 80) and 8mg dutasteride are dissolved in the 0.8ml dichloromethane, and stirring and dissolving makes into settled solution.Solution is added drop-wise to gradually 600rpm stirs, contains among the liquid paraffin 25ml of 2%Span80, stir behind the 10min speed drop to 500rpm, 25 ℃ are continued down to stir 10 hours to volatilize organic solvent.After suspension is carried out centrifugalize, go supernatant, microsphere is repeatedly cleaned with normal hexane on a small quantity, at room temperature, drying under reduced pressure promptly gets.Microsphere average grain diameter 120um.
Embodiment 3
Take by weighing dutasteride 500mg, tamsulosin 200mg and polylactic-co-glycolic acid (molecular weight 50000 dalton; Two monomer mole ratios 80: 20) 7.5g; Be dissolved in the 15mL dichloromethane, produce supercritical gas Hangzhoupro dissolving agent process, the organic solvent that has dissolved medicine and macromolecular material is expanded with the CO2 supercritical fluids system; Dissolved chemical compound is hypersaturated state in the organic solvent, thereby forms microsphere.Remove and desolvate, promptly get.Microsphere average grain diameter 50um.
Embodiment 4
Take by weighing dutasteride 278mg and polylactic-co-glycolic acid (molecular weight 20000 dalton, two monomer mole ratios 25: 75) 5g, being dissolved in 10mL has in the dichloromethane, under stirring condition, fully dissolves after-filtration, adopts spray drying method to make microsphere.Microsphere average grain diameter 40um.
Embodiment 5
Get dutasteride 40mg; Polylactic-co-glycolic acid (molecular weight 20000 dalton, two monomer mole ratios 75: 25) 300mg is dissolved in the acetone of 1mL, under the 800rpm stirring condition, splashes in the 10% span Oleum Glycines of 20mL; After stirring 4h; The centrifugalize microsphere, with centrifugal again behind the normal hexane cyclic washing, thus obtained microsphere is through reduced pressure volatilization organic solvent.The microsphere of this method preparation, envelop rate can reach 81%, and particle diameter is about 20um.
Embodiment 6
800mg polylactic-co-glycolic acid (molecular weight 20000 dalton, two monomer mole ratios 50: 50) is dissolved in the 2.5ml acetonitrile, adds the 100mg dutasteride, stirring and dissolving is as the O1 phase.In the 30ml liquid Paraffin, add 1.5% Span85, behind the mix homogeneously as the O2 phase.Under the 3000rpm rotating speed, O1 is splashed among the O2, make into O1/O2 Emulsion.The control system temperature, it is dried that organic solvent is evaporated to gradually, makes suspension carry out centrifugalize and remove supernatant, and microsphere promptly gets in reduced pressure at room temperature with hexane repeatedly washing on a small quantity.Microsphere average grain diameter 80um.
The entrapment efficiency of above embodiment 1-6 thus obtained microsphere is between 78～89%, and for example the entrapment efficiency of embodiment 1 is about 86%, the entrapment efficiency of embodiment 4 is about 78%, the entrapment efficiency of embodiment 2 is about 89%, the entrapment efficiency about 84% of embodiment 6.
Embodiment 7
Basically the method for reference implementation example 1; Different is; In different prescriptions; Only general's polylactic-co-glycolic acid wherein replaces with respectively and gathers third friendship fat-Acetic acid, hydroxy-, bimol. cyclic ester (molecular weight 20000 dalton, two monomer mole ratios 50: 50) or replace with polylactide (molecular weight 20000 dalton, two monomer mole ratios 50: 50).Microsphere average grain diameter 50～80um.The envelop rate of two kinds of microspheres is about 69% and 61% respectively.
Basically the method for reference implementation example 1, different is, in different prescriptions, only will polylactic-co-glycolic acid wherein replaces with molecular weight respectively and be 5000,75000 or 100000 polylactic-co-glycolic acid (two monomer mole ratios 50: 50).Microsphere average grain diameter 40～70um.The envelop rate of three kinds of microspheres is respectively in 57% to 71% scope.
Basically the method for reference implementation example 1, different is, in different prescriptions, only will polylactic-co-glycolic acid wherein replaces with the polylactic-co-glycolic acid (molecular weight is 20000) of two monomer mole ratios 10: 90 and 90: 10 respectively.Microsphere average grain diameter 40～70um.The envelop rate of two kinds of microspheres is respectively in 54% to 63% scope.
Basically the method for reference implementation example 1, different is in different prescriptions, to use the amount of polylactic-co-glycolic acid to be respectively 40mg, 50mg, 60mg.Thus obtained microsphere mean diameter 45～80um, the envelop rate of three kinds of microspheres are respectively in 36% to 57% scope.
Basically the method for reference implementation example 1, different is in different prescriptions, to use the amount of polylactic-co-glycolic acid to be respectively 200mg, 250mg.Thus obtained microsphere mean diameter 50～80um, the envelop rate of two kinds of microspheres in 67% to 79% scope, use the release in vitro degree of these microspheres of method investigation of hereinafter experimental example 1 respectively, and 90% above burst size needs 51-67 days as a result; It will be appreciated by those skilled in the art that it is disadvantageous that rate of release is crossed slow monitoring for clinical application.
Basically the method for reference implementation example 2, different is in different prescriptions, to use the amount of polylactic-co-glycolic acid to be respectively 40mg, 50mg, 60mg.Thus obtained microsphere mean diameter 60～100um, the envelop rate of three kinds of microspheres are respectively in 42% to 55% scope.
Basically the method for reference implementation example 2, different is in different prescriptions, to use the amount of polylactic-co-glycolic acid to be respectively 200mg, 250mg.Thus obtained microsphere mean diameter 50～90um, the envelop rate of two kinds of microspheres in 63% to 77% scope, use the release in vitro degree of these microspheres of method investigation of hereinafter experimental example 1 respectively, and 90% above burst size needs 48-64 days as a result.
Embodiment 8
Basically the method for reference implementation example 1, different is, the dutasteride is replaced with finasteride (a kind of medicine that is used for prostatic hyperplasia, its common dose are 5mg/ days), the about 60um of thus obtained microsphere mean diameter, the envelop rate of medicine is about 69%.
Embodiment 9
800mg polylactic-co-glycolic acid (molecular weight 20000 dalton, two monomer mole ratios 50: 50) is dissolved in the 2.5ml acetonitrile, adds the 200mg finasteride, stirring and dissolving is as the O1 phase.In the 30ml liquid Paraffin, add 1.5% Span85, behind the mix homogeneously as the O2 phase.Under the 3000rpm rotating speed, O1 is splashed among the O2, make into O1/O2 Emulsion.The control system temperature, it is dried that organic solvent is evaporated to gradually, makes suspension carry out centrifugalize and remove supernatant, and microsphere promptly gets in reduced pressure at room temperature with hexane repeatedly washing on a small quantity.Microsphere average grain diameter 75um, the envelop rate of medicine is about 62%.
Embodiment 10
160mg polylactic-co-glycolic acid (molecular weight 20000 dalton, two monomer mole ratios 50: 50) is dissolved in the 0.6ml dichloromethane, adds the 40mg finasteride, stirring and dissolving makes into clear and bright solution.Be equipped with one and add 5%PVA (05-88) aqueous solution in the beaker of stirring paddle level land, constant temperature (25 ℃), the back splashes into above-mentioned polymer solution wherein in stirring down; Stir formation Emulsion with 2000rpm; Add a large amount of distilled water again, keep 200rpm, make that organic solvent volatilizes gradually in the O/W Emulsion.The whole process microscopy of constantly sampling is observed multistage microsphere forming process.Above-mentioned solution centrifugal is separated, the supernatant that inclines, microsphere is collected in decompression on filter membrane, and with distilled water repeatedly washing on a small quantity, microsphere decompression room temperature is drying to obtain.Microsphere average grain diameter 85um, the envelop rate of medicine is about 66%.
B, microsphere are investigated Test Example
Experimental example 1: dutasteride's microsphere release in vitro degree test
The microsphere of laboratory sample: embodiment 1,2,3,4,5 preparations
Experiment reagent: the pH7.4 buffer that contains 0.5% sodium lauryl sulphate
Experimental apparatus: constant temperature oscillator, centrifuge, high performance liquid chromatograph (HPLC)
Experiment condition: temperature: 37 ± 5 ℃; Frequency of oscillation: 72 times/min; Centrifugal rotational speed: 1000rpm
The HPLC chromatographic condition that detects: chromatographic column: Apollo C18 chromatographic column (250mm * 4.6mm, 5 μ m), with methanol: water (80: 20) is mobile phase; Flow velocity: 1.0mL/min; Column temperature: 25 ℃; Detect wavelength: 220nm, sample size: 20 μ L.
Experimental technique: precision takes by weighing dutasteride's microsphere and (is equivalent to dutasteride 25mg in right amount; In this article, when relating to the microsphere amount, as not mentioning in addition; All be meant the amount that is equivalent to the active component dutasteride), place the 50mL triangular flask, add phosphate buffer (the containing 0.5% sodium lauryl sulphate) 50mL of pH7.4; Placing temperature is (37.0 scholar 1.0) ℃; Speed is in the constant-temperature shaking appearance of 72rpm, and the 5ml that regularly took a sample in 0,1,3,5,7,10,14,21,25,28 day replenishes medium 5mL simultaneously.The HPLC method is measured the content of medium Chinese medicine, calculating cumulative release degree.Calculate the cumulative release degree of microsphere by following formula.Every lot sample article repetitive operation 3 times.
Experimental result: see table 1.
Table 1 dutasteride continuous release microsphere release in vitro degree result of the test table
Make an experiment with the sample of same procedure to embodiment 6 preparations, the cumulative release of release in vitro degree test and the sample of embodiment 1 are basic identical.In addition, the release profiles of tamsulosin and dutasteride's curve is approaching basically in discovery embodiment 3 microspheres.In addition; The method of reference implementation example 1,2,3,4,5 prepares microsphere respectively; The difference of method is to use other five kinds of polymer manufacture respectively; The used polymer phase of corresponding with it the respectively embodiment of the use amount of each polymer with; It is identical that the molecular weight of each polymer and the used polymer of its corresponding embodiment are gone up basically, and the used polymer phase of the embodiment that two kinds of monomeric ratios of each polymer are corresponding with it basically is with (except the polymer that same monomer polymerization obtains), and used polymer is respectively in five tests: polyglycolic acid, polylactide, polyglycolic acid, poe, polycaprolactone.Though five kinds of microsphere sphere diameters that obtain are basically between 20～120um, their entrapment efficiency and is tested through the identical mode of above microsphere release in vitro degree test between 58～74%, between 3-10 days, discharges fully basically.In addition, each sample of embodiment 7 preparations is tested through the identical mode of above microsphere release in vitro degree test, all between 6-14 days, discharges fully basically.
Experimental example 2: pharmacodynamics test
Adopt dutasteride's microsphere of embodiment 1 preparation to carry out the therapeutic test of SD rat prostate hypertrophy.Experiment is divided into the testosterone propionate model group, oral group of dutasteride's suspension and dutasteride's microsphere group, and every treated animal is 6.Propanoic acid testis group adopts the administration of 2.5mg/kg subcutaneous injection, and the dutasteride adopts the 0.25mg/kg oral administration gavage; Above-mentioned two groups of administrations every day, continuous 28 days.Dutasteride's microsphere was administered once in per 28 days; The dose that adopts is 60% of an oral medication accumulated dose (0.25mg/kg*28), i.e. 0.25*28*0.6/ microsphere drug content, subcutaneous injection administration.Each is organized on 28th and puts to death animal, dissects, and observes weight of prostate, calculates prostate exponential sum prostata tissue water content, its experimental result such as following table 2.
Table 2SD rat pharmacodynamic experiment data
| Group | Body weight (g) | Prostate heavy (g) | Prostate index (%) | Tissue water content (%) |
| Propanoic acid testis group | 265.2±6.9 | 1.42±0.05 | 0.54±0.03 | 79.4±2.4 |
| Oral group of dutasteride | 460±10 | 1.59±0.07 | 0.36±0.02 | 70.1±2.02 |
| Dutasteride's microsphere group | 452±17 | 1.33±0.40 | 0.30±0.02 | 73.3±7.6 |
Above-mentioned experimental data shows that dutasteride's microsphere has the obvious suppression effect to the rat prostate hypertrophy that testosterone propionate causes.
Experimental example 3: the vivo releasing test of medicine
Adopt dutasteride's microsphere of embodiment 1 preparation to carry out absorbing in the SD rat body experiment of release degree.Dutasteride's microsphere (40mg/ only) is injected the intramuscular injection of solvent (the tween purification of aqueous solutions that contains 0.5% sodium carboxymethyl cellulose and 0.1%) suspendible tailing edge rat back leg with 1mL.3 of the sacrificed by exsanguination respectively in the 1st, 3,5,7,14,21,28 day cut residual microsphere and muscular tissue on every side thereof, measure residual dose.
Collect residual microsphere in the syringe simultaneously, the medication amount that quantitative assay is residual, the microsphere that calculates actual injection is at the intravital medicine realeasing rate of rat, medicine realeasing rate=[1-(medication amount of the content/actual injection of the residual microsphere Chinese medicine in injection site)] * 100%.The result of the interior burst size of residual quantity and body sees table 3 respectively in the body.
Table 3 dutasteride microsphere is at intravital retained percentage of rat and cumulative release degree
| Time (my god) | Residual quantity (%) in the body | Burst size (%) in the body |
| 1 | 0.854 | 0.146 |
| 3 | 0.602 | 0.398 |
| 5 | 0.450 | 0.549 |
| 7 | 0.399 | 0.600 |
| 14 | 0.287 | 0.712 |
| 21 | 0.227 | 0.772 |
| 28 | 0.001 | 0.999 |
The release profiles similar factors reaches 61.43, two release profiles in outer release curve of dutasteride's microsphere of embodiment 1 preparation and the rat body does not have significant difference, explains that dutasteride's microsphere discharges in the rat body well.In investigating in addition the external release curve of testing microsphere and rat body in the test of release profiles with above-mentioned Test Example 1 and 3 same procedure; Test with embodiment 8 thus obtained microspheres with embodiment 6; The similar factors of acetonideexample 6 microspheres is 66.2, and the similar factors of embodiment 8 microspheres is 46.2.
The above is merely preferred embodiment of the present invention, is not limited to the scope of the invention, and is all within spirit of the present invention and principle, any modification of being done, is equal to replacement, improvement etc., all should be included in protection scope of the present invention.
Claims (10)
1. a microsphere wherein comprises the dutasteride of 1 weight portion and the biodegradable polymer biodegradable polymer of 5～25 weight portions.
2. the microsphere of claim 1, wherein said biodegradable polymer is that molecular weight is 5000～500000 daltonian biodegradable polymer.
3. each microsphere of claim 1 to 2, wherein said biodegradable polymer are to be selected from polylactide-co-glycolide, polylactide, polylactic-co-glycolic acid, polyglycolic acid, to gather β-carboxyl butyrate, poe, polycaprolactone, gather in anhydride, poly phosphate, polyphosphazene, polybutylcyanoacrylate, the polyamide one or more; Preferred polylactic-co-glycolic acid.
4. each microsphere of claim 1 to 3, two kinds of monomeric mole ratios that wherein constitute said biodegradable polymer are 15: 85～85: 15.
5. each microsphere of claim 1 to 4 wherein also comprises second reactive compound, and it is α-Zu Zhiji preferably, is more preferably tamsulosin.
6. each microsphere of claim 1 to 5, its mean diameter is 10-200um.
7. a pharmaceutical composition wherein comprises dutasteride and biodegradable polymer, and acceptable excipient of at least a pharmacy or adjuvant, and said dutasteride is contained in basically in the microsphere that is formed by said biodegradable polymer.
8. pharmaceutical composition wherein comprises each the microsphere of claim 1 to 6 of effective dose and acceptable excipient of at least a pharmacy or adjuvant.
9. each the purposes of microsphere in the depot drug product of preparation treatment prostatic hyperplasia of claim 1 to 6.
10. each the method for microsphere of preparation claim 1 to 6, this method is emulsifying dispersion-intra-liquid desiccation method or spray drying method, wherein said emulsifying dispersion-intra-liquid desiccation method may further comprise the steps:
A) with after biological degradation polyalcohol and medicine dissolution are in suitable organic solvent, process decentralized photo;
B) decentralized photo is splashed in the continuous phase that is added with emulsifying agent of continuous stirring, organic solvent volatilizees gradually, separates out microsphere;
C) the microsphere suspension is through centrifugalize;
D) make microsphere through drying under reduced pressure or lyophilization; With optional
E) the microsphere sterilized powder is suspended in pharmacy and can accepts to shake up in the solution, promptly gets.
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| CN104257665A (en) * | 2014-09-01 | 2015-01-07 | 南京正大天晴制药有限公司 | Oral solid preparation of dutasteride and preparation method thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104257665A (en) * | 2014-09-01 | 2015-01-07 | 南京正大天晴制药有限公司 | Oral solid preparation of dutasteride and preparation method thereof |
| CN110996916A (en) * | 2017-08-18 | 2020-04-10 | 创技公司株式会社 | Microparticles comprising finasteride and methods of making the same |
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