CN1562042A - Method for preparing long acting progestogen injection implant agent and use - Google Patents

Abstract

A slowly-releasing gestrinone injection for treating endometriosis by subcutaneous injecting or intramuscular injecting is prepared from biodegradable polymer PLGA or PLA as skeleton and gestrinon (R2323) as active component by solvent evaporation method.

Description

Long-acting progestogen injection implants preparation method and application

Technical field

The present invention relates to a kind of long-acting progestogen injection implants and its production and application.

Background technology

Progestogen were the progestogen of moderate strength as gestrinone (Gestrinone, R2323, dl-18-methyl-norgestrienone, 18-first norgestrienone) originally, had stronger gestation and estrogen antagonist activity.Experiment showed, that this product has anti-implantation, the antiearly pregnancy effect is in the early stage ovulation inhibitory action that still has for oral use of menstrual cycle.Its anti-implantation, antiearly pregnancy effect and change cervical mucus denseness, the growth of interference endometrium influences the ovum speed of service and antagonism inner membrance progesterone receptor is relevant.Clinical former as visiting pill or postcoital contraceptive.

In recent years clinical research both at home and abroad finds that oral gestrinone still has the treatment endometriosis, the effect of diseases such as hysteromyoma, and curative effect is reliable, as document ^1.Clin Exp Obstel Gynecol 1996,23 (4): 198-204, ^2.Chinese medicine magazine (Taibei) 1996,58 (2): 89-96, ^3.Gynecol ObstelInvest 1997,43 (3): 192-194) and ^4.J Med Assoc Thai 1999,82 (1): 9-14 has report.

Present clinical progestogen only are that tablet is a kind of as the gestrinone dosage form, dosage 1.5mg, 2.5mg.Be used for the endometriosis treatment, oral weekly secondary, each 2.5mg, 6 months course of treatment.Frequent drug administration is brought inconvenience to the patient, forgets medication and brings harmful effect to treatment.It should be noted that more progestogen such as gestrinone are oral, through liver, kidney metabolism and drainage, life-time service, to the human body Liver and kidney have certain infringement (Chen Xinqian chief editor, new pharmacology, the 15 edition, the People's Health Publisher, P597).

Summary of the invention

The technical issues that need to address of the present invention are to disclose a kind of long-acting progestogen injection implants and its production and application, to overcome that frequent drug administration that existing dosage form exists is brought inconvenience to the patient and to the defective of human liver renal damage.

Technical scheme of the present invention

Long-acting progestogen injection implants of the present invention is a kind of in microgranule, microsphere, nanoparticle or the nanosphere; comprise treatment effective amount of actives progestogen and as the biological degradation polyalcohol of framework material; microsphere is that diameter is 10～120 microns a circular entity, and the preferred weight percent content of progestogen is 1～70%.

Said progestogen comprise gestrinone, gestodene (Gestrodene), nomegestrol (Nomegestrol), promegestone (Promegestone), norethindrone (Norgestrol), megestrol (Megestrol), norgestrel (Norgestrel), levonorgestrel (Levonorgestrel), Desogestrel (Desogestrol), norgestimate (Norgestimate), Norethisteroneoxime (NorehisteroneOxime), a kind of in quingestrone (Quingestanod) or the anorethindrane dipropionate (Anordrin) etc., preferred gestrinone.

Said biological degradation polyalcohol comprises one or more of polylactide-co-glycolide, polylactic acid, polyglycolic acid, polycaprolactone, poly-anhydride, poly butyric ester-hydroxyl pentanoate copolymer, polypropylene glucosan or polylactic acid-polyglycol, preferred molecular weight range is from 5,000 to 1,000,000 polymer, the part by weight of wherein said polylactide-co-glycolide monomer polymerization is between 95: 5～5: 95, molecular weight is 10,000-500,000, the polylactic acid molecule amount is 5,000-300,000.

The invention still further relates to the long-acting progestogen of treatment effective dose and the pharmaceutical composition of good biocompatibility and degradable carrier formation, also method such as the mold pressing that can adopt this area to know altogether in above-mentioned preparation, casting, extruding, methods such as stand film are made as tablet membrane, stick, pill etc. use for subcutaneous implantation.

Said degradable carrier comprises a kind of or its mixture in polylactide-co-glycolide, poly-DL-lactic acid or the poly-anhydride etc., and preferred long-acting progestogen at the content (w/w) of injection implants are: 1～70%;

Preparation of the present invention can be used for the treatment of diseases such as endometriosis and hysteromyoma effectively.

The preparation method of the long-acting progestogen micro-balloon injection of the present invention comprises the steps:

The organic solvent that will contain progestogen and biological degradation polyalcohol is poured the aqueous solution that contains suspending agent into, make emulsion, under 5～40 ℃ temperature conditions, fling to organic solvent, method through routine is collected microsphere from this suspension then, canned behind sterilization of employing gamma-radiation or the sterile working, be long-acting progestogen ejection preparation of the present invention.

Degradable polymer content in organic solvent is 1～1000mg/ml;

Progestogen content in organic solvent is 1～800mg/ml;

The content of suspending agent in aqueous solution is 1～100mg/ml;

The organic solvent that contains progestogen and biological degradation polyalcohol is 1: 1～1000 (v/v) with the volume ratio that contains the aqueous solution of suspending agent.

Said organic solvent comprises dichloromethane, chloroform, one or more in ethyl acetate or the acetonitrile;

Said suspending agent comprises polyvinyl alcohol, sodium carboxymethyl cellulose (CMC-Na), polyvinylpyrrolidone (PVP) or eucolloid etc. a kind of, and eucolloid comprises gelatin, arabic gum, pectin etc.

The using method of preparation of the present invention is: the aseptic aqueous solution that will contain suspending agent injects the microspheres prepared ampoule, after the mixing jolting, can be injected in subcutaneous or intramuscular, and dosage is pressed different pharmaceutical preparation description labelled amount and handled.

In the microsphere medicine can be in vivo effective in two weeks of slow release above times, so the treatment endometriosis, symptoms such as hysteromyoma can at least at interval more than 15 days injection once, concrete dosage and medication interval can determine according to patient's concrete condition.

The medicine may command that bag covers in the microsphere discharges one period long period, and framework material can be degraded into inherent nontoxic small-molecule substance in the body automatically, is finally absorbed by body.

Medicine absorbs through peripheral blood circulation after the medication of this injection, thereby can reduce patient's medication number of times, both can make things convenient for patient treatment, reduces again that tablet is oral may to cause untoward reaction such as patient's hepatorenal damage.

The specific embodiment

Embodiment 1

Get the 20mg gestrinone, 80mg polylactide-co-glycolide (lactide: Acetic acid, hydroxy-, bimol. cyclic ester=75: 25, weight ratio), be dissolved in the 3ml dichloromethane, under vigorous stirring, under (1000rpm) it splashed in the 100ml 0.2% carboxymethyl cellulose sodium water solution, drip off the back and continue to stir 5-10 minute, reduce mixing speed then to 300rpm, in 25 ℃ of about 12h of evaporation, centrifugal, remove supernatant, precipitation is through filtration under diminished pressure, a small amount of distilled water drip washing precipitation, reduced pressure at room temperature, microsphere diameter 40～120 μ m.

Embodiment 2

Get the 20mg gestrinone, the 80mgDL-polylactic acid is dissolved in the 1ml dichloromethane, in high speed homogenizer, add 5ml 0.5%PVA aqueous solution, with 6000rpm rotating speed vigorous stirring 2min, pour in the 100ml 0.5%PVA aqueous solution,, centrifugal with 300rpm in 25 ℃ of about 12h of evaporation, remove supernatant, precipitation is through filtration under diminished pressure, a small amount of distilled water drip washing precipitation, reduced pressure at room temperature, microsphere diameter 30～80 μ m.

Embodiment 3

Get the 20mg nomegestrol, the 80mgDL-polylactic acid is dissolved in the 1.25ml ethyl acetate, in high speed homogenizer, add 10ml 0.5%PVA aqueous solution, with 8000rpm rotating speed vigorous stirring 2min, pour in the 100ml 0.5%PVA aqueous solution,, centrifugal with 300rpm in 25 ℃ of about 12h of evaporation, remove supernatant, precipitation is through filtration under diminished pressure, a small amount of distilled water drip washing precipitation, reduced pressure at room temperature, microsphere diameter 20～40 μ m.

Embodiment 4

The inhibition test of rat oestrous cycle:

Method: select the rat of oestrous cycle rule to be divided into 2 groups, show at the vaginal secretions picture of rat to give following corresponding injection the same day of metoestrus (leukocyte) respectively:

Negative control group: subcutaneous (s.c.) injection of vehicle (n=5).

The microsphere group of embodiment 2: single dose s.c. injection drug release rate is the microsphere of 0.5mg/ week/kg, microsphere gestrinone content 25% (n=5), and adopting the 0.5%CMC-Na aqueous solution is suspending agent.

After the injection, every day is the observed and recorded vaginal smear regularly, and the rat vagina sheet continues to show leukocyte, illustrate that the oestrous cycle is suppressed, as keratinocyte occurs, shows that then the oestrous cycle begins recovery, can judge the preparation duration of efficacy with the vaginal smear method.

The result: behind rat s.c. injection single dose microsphere 0.5mg/ week/kg, five rat vagina smears are respectively at 15 days, and 16 days, 16 days, 15 days, leukocyte appears all the time in 15 days, and ovum garden cell and keratinocyte appear subsequently.Illustrate that its oestrous cycle was continued to have suppressed 15 days.Negative control group is not suppressed.

Embodiment 5

Rat endometrium dystopy curative effect:

Method: with reference to the Jones method (Acta Endocrinol 1984,106:282-88).Set up endometriotic rat model with the surgery autoplasty, a jiao of female rats uterus is cut, migrate on the abdominal wall.All around, open the abdominal cavity once more and check the Ectopic Endometrium upgrowth situation.Transplanting place Ectopic Endometrium well-grown and yellow liquid content person is arranged is the modelling winner, carry out following processing with the animal random packet after the measurement volumes:

Negative control group: rat back s.c. every day injecting normal saline (dividing 10 groups, every group of n=3).The microsphere group of embodiment 2: the disposable s.c. injectable microsphere of rat back, dosage is 0.5mg/ week/kg, microsphere gestrinone content 25% (dividing 10 groups, every group of n=3).

At the 2nd weekend, rat is put to death in anesthesia, opens the abdominal cavity, measures the Ectopic Endometrium volume, calculates suppression ratio.

Suppression ratio %=(1-V ₂/ V ₁) * 100%

V ₁: transplant volume (mm before the treatment ²)

V ₂: volume (mm is transplanted in the treatment back ²)

It the results are shown in Table 1.

From experimental result as seen, negative control group injection forebody-afterbody integration does not increase to 63.15 from 61.52, suppression ratio is-2.65%, microsphere group injection back volume reduces to 20.17 from 49.80 respectively, suppression ratio is 59.50%, there is significant difference (p＜0.05) in both, and body weight is not seen the increase phenomenon after the medication.

Table 1, gestrinone micro-balloon injection are to rat endometrium allosteric inhibition result of the test

Claims (12)

1, a kind of progestogen injection implants is characterized in that, comprises treatment effective amount of actives progestogen and as the biological degradation polyalcohol of framework material.

2, progestin preparation according to claim 1 is characterized in that, the weight percentage of progestogen is 1～70%.

3, progestin preparation according to claim 1 is characterized in that, said preparation is a microgranule, microsphere, a kind of in nanoparticle or the nanosphere.

4, progestin preparation according to claim 3 is characterized in that, microsphere is that diameter is 10～120 microns a circular entity.

5, progestin preparation according to claim 1, it is characterized in that said progestogen comprise a kind of in gestrinone, gestodene, nomegestrol, promegestone, norethindrone, megestrol, norgestrel, levonorgestrel, Desogestrel, norgestimate, Norethisteroneoxime, quingestrone or the anorethindrane dipropionate.

6, long-acting progestogen injection implants according to claim 1, it is characterized in that, said biological degradation polyalcohol comprises polylactide-co-glycolide, polylactic acid, polyglycolic acid, polycaprolactone, poly-anhydride, poly butyric ester-hydroxyl pentanoate copolymer, polypropylene glucosan, one or more of polylactic acid-polyglycol.

7, progestin preparation according to claim 6 is characterized in that, polymer molecular weight is 5,000～1,000,000, wherein, the part by weight of polylactide-co-glycolide monomer polymerization is 95: 5～5: 95, and molecular weight is 10,000-500,000, the polylactic acid molecule amount is 5,000-300,000.

8, a kind ofly contain the pharmaceutical composition that each described preparation of claim 1～7 for the treatment of effective dose and good biocompatibility and degradable carrier constitute.

9, pharmaceutical composition according to claim 8 is characterized in that, this pharmaceutical composition is subcutaneous or intramuscular dose or subcutaneous implant.

10, according to the preparation method of each described injectable progestogen microsphere of claim 1～9, it is characterized in that comprising the steps: progestogen and biological degradation polyalcohol are dissolved in the organic solvent, pour in the aqueous solution that contains suspending agent that is stirring, make O/w emulsion, fling to organic solvent, from this suspension, adopt conventional method to collect microsphere then, be preparation of the present invention.

11, preparation method according to claim 10 is characterized in that, degradable polymer content in organic solvent is 1～1000mg/ml;

Said organic solvent comprises dichloromethane, chloroform, ethyl acetate, acetonitrile or one or more;

Said suspending agent comprises polyvinyl alcohol, sodium carboxymethyl cellulose (CMC-Na), and polyvinylpyrrolidone (PVP), eucolloid, as gelatin, arabic gum, pectin etc. a kind of, the content of suspending agent in aqueous solution is 1～100mg/ml;

The organic solvent that contains progestogen and biological degradation polyalcohol is 1: 1～1000 (v/v) with the volume ratio that contains the aqueous solution of suspending agent.

12, according to of the application of each described progestin preparation of claim 1～9 in treatment endometriosis or hysteromyoma symptom.