CN1615885A - Method for preparing long acting progestational hormone injection embedded agent and use - Google Patents

Method for preparing long acting progestational hormone injection embedded agent and use Download PDF

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Publication number
CN1615885A
CN1615885A CNA2003101085691A CN200310108569A CN1615885A CN 1615885 A CN1615885 A CN 1615885A CN A2003101085691 A CNA2003101085691 A CN A2003101085691A CN 200310108569 A CN200310108569 A CN 200310108569A CN 1615885 A CN1615885 A CN 1615885A
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progestogen
injection
preparation
organic solvent
implants
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CN1287798C (en
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陈庆华
潘峰
包泳初
曹霖
朱焰
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Shanghai Institute of Pharmaceutical Industry
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Shanghai Institute of Pharmaceutical Industry
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Abstract

The present invention introduces the preparation process of injection microballoon with PLGA, PLA or other biodegradable polymer as skeleton material and the progestational hormone, gestrinone, as model medicine, and through solvent evaporation. The microballoon may be injected to subcutaneous part or muscle for delayed releasing for over 15 days. The microballoon skeleton material inside body degrades gradually into small molecular matter excreted to outside the body. The gestrinone microballoon injection may be administrated conveniently and is superior to conventional tablet form, which is orally taken frequently to result in damage to liver and kidney and other negative reaction. Rat experiment shows that the preparation of the present invention may be used in treating endometriosis, etc.

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 preparation method 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 some progestogen still have the treatment endometriosis as gestrinone, the effect of diseases such as hysteromyoma, curative effect reliable ( 1.Clin Exp Obstel Gynecol1996,23 (4): 198-204), ( 2.Chinese medicine magazine (Taibei) 1996,58 (2): 89-96), ( 3.Gynecol Obstel Invest 1997,43 (3): 192-194), ( 4.J Med Assoc Thai 1999,82 (1): 9-14).
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.Forget medication and bring 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 preparation method and the application that disclose a kind of long-acting progestogen injection implants, to overcome the defective that frequent drug administration that existing dosage form exists is brought inconvenience and the human body Liver and kidney had certain infringement to the patient.
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 the 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 polylactide-co-glycolide, polylactic acid, polyglycolic acid, pla-pcl, poly-anhydride, poly butyric ester-hydroxyl pentanoate copolymer, polypropylene glucosan, one or more of polylactic acid-polyglycol, preferred molecular weight range from 5,000 to 1,000,000 polymer, wherein said polylactide-co-glycolide monomer polymerization ratio 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 above-mentioned preparation of treatment effective dose and the pharmaceutical composition of good biocompatibility and degradable carrier formation, above-mentioned preparation is adopted method well known in the art, can be prepared into subcutaneous easily or intramuscular dose, subcutaneous implant such as tablet, membrane, stick, pill.
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:
Progestogen and biological degradation polyalcohol are dissolved in the organic solvent, after high-speed stirred, pour in the aqueous solution that contains suspending agent that is stirring, make under the temperature conditions that emulsion places 5～40 ℃, fling to organic solvent, from this mixture, adopt conventional method to collect microsphere then, be long-acting progestogen ejection preparation of the present invention.
Degradable polymer content in organic solvent is 1～500mg/ml;
Said organic solvent comprises dichloromethane, chloroform, ethyl acetate, ether or one or more;
Said suspending agent comprises polyvinyl alcohol, CMC, and PVP, eucolloid, as gelatin, arabic gum etc. a kind of, the content of suspending agent in aqueous solution is 1～50mg/ml;
The organic solvent that contains progestogen and biological degradation polyalcohol is 1: 1～500 (v/v) with the volume ratio that contains the aqueous solution of suspending agent.
The using method of preparation of the present invention is: the aseptic aqueous solution that will contain suspending agent injects microspheres prepared, after the mixing jolting, can be injected at subcutaneous or intramuscular, and dosage is pressed different pharmaceutical preparation description labelled amount and handled.
The treatment endometriosis, symptoms such as hysteromyoma can need the patient of above-mentioned treatment at minimum 15 days more than the interval.
Interior bag covers the medicine may command and 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.
Above time of slow releasing pharmaceutical two weeks in vivo after the medication of this injection.Can reduce patient's medication number of times, both can make things convenient for patient treatment, reduce 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), be dissolved in the 3ml dichloromethane, under vigorous stirring, under (1000rpm) it is 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, in 25 ℃ of about 12h of evaporation to 300rpm, centrifugal, remove supernatant, precipitation is through filtration under diminished pressure, and a small amount of distilled water drip washing precipitates, reduced pressure at room temperature, microsphere diameter 40～120 μ m.
Embodiment 2
Get the 20mg gestrinone, the 80mg 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
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 1: single dose s.c. injection drug release rate is the microsphere of 0.5mg/ week/kg, particle diameter 40～120 μ m, microsphere gestrinone content 25% (n=5).
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 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 4
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.Inhibition 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, particle diameter 30～80 μ m, 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
Group ????1 ????2 ?????3 ?????4 ????5 ?????6 ????7 ?????8 ????9 ????10 ???11 ???12
Empty to group ??5.45 ????4.45 ?????5.22 ?????4.95 ???6.29 ?????7.00 ????2.82 ?????3.02 ????7.69 ????3.88 Meansigma methods ???SD The P value
??5.01 ????4.42 ?????5.14 ?????5.04 ???4.72 ?????5.27 ????2.83 ?????3.02 ????6.89 ????2.88
??1.69 ????2.36 ?????2.21 ?????2.56 ???2.07 ?????2.90 ????2.16 ?????1.64 ????3.32 ????2.05
The medicine front volume ?46.14 ???46.42 ????59.30 ?????63.87 ??61.46 ???106.98 ???17.24 ????14.96 ??175.91 ???22.91 ??61.52 ???48.59
??2.82 ????3.78 ?????6.21 ??????3.72 ???5.29 ?????7.19 ????5.94 ?????5.22 ????4.87 ????5.99
??2.89 ????4.36 ?????6.21 ??????4.99 ???4.99 ?????6.78 ????5.14 ?????5.09 ????5.76 ????5.37
??1.09 ????4.36 ?????1.62 ??????1.00 ???3.36 ?????2.89 ????2.94 ?????2.05 ????1.19 ????1.94
Volume behind the medicine ??8.88 ???71.86 ????62.47 ?????18.56 ???88.69 ???140.88 ???89.94 ????54.47 ???33.38 ???62.40 ??63.15 ???38.56
Volume factor ??0.19 ????1.55 ?????1.05 ??????0.29 ????1.44 ?????1.32 ????5.22 ????3.64 ????0.19 ????2.72 ???1.76 ????1.64
Body weight 246.60 ??249.30 ???251.10 ????266.60 ??215.00 ???276.70 ??267.60 ??240.40 ??274.40 ??258.50 ?254.62 ???18.51
The R2323 group ??5.71 ????5.99 ?????5.08 ??????5.69 ????6.40 ?????5.44 ????6.10 ????3.90 ????4.60 ????4.79 Meansigma methods ????SD The P value
??5.38 ????5.99 ?????5.09 ??????5.49 ????5.69 ?????3.53 ????6.18 ????3.90 ????6.34 ????5.12
??0.97 ????2.60 ?????1.50 ??????0.80 ????1.73 ?????2.64 ????2.30 ????1.68 ????2.44 ????0.57
The medicine front volume ?29.80 ???93.29 ????38.79 ?????24.99 ???63.00 ????50.70 ???86.71 ???25.55 ???71.16 ???13.98 ??49.80 ???27.67
??4.15 ????4.45 ?????5.78 ??????4.58 ????3.83 ?????3.48 ????4.59 ????3.63 ????5.92 ????3.13
??4.15 ????3.35 ?????5.12 ??????4.88 ????4.18 ?????3.45 ????4.58 ????3.60 ????5.32 ????4.20
??0.23 ????0.85 ?????1.27 ??????0.80 ????0.76 ?????0.73 ????0.50 ????0.63 ????2.63 ????0.54
Volume behind the medicine ??3.96 ???12.67 ????37.58 ?????17.88 ???12.17 ?????8.76 ???10.51 ????8.23 ???82.83 ????7.10 ??20.17 ???23.93
Volume factor ??0.13 ????0.14 ?????0.97 ??????0.72 ????0.19 ?????0.17 ????0.12 ????0.32 ????1.16 ????0.51 ??0.44 ????0.38 ?0.0238029
Body weight 202.30 ??226.40 ???228.20 ????233.20 ??250.40 ???256.50 ??238.20 ??223.60 ??258.80 ??226.70 ?234.43 ???17.21

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, progestogen injection implants according to claim 1 is characterized in that the weight percentage of progestogen is 1～70%.
3, progestogen according to claim 1 injection implants is characterized in that said preparation is a microgranule, microsphere, a kind of in nanoparticle or the nanosphere.
4, progestogen injection implants according to claim 3 is characterized in that microsphere is that diameter is 10～120 microns a circular entity.
5, progestogen injection implants according to claim 1 is characterized in that said progestogen comprise gestrinone, the gestodene, nomegestrol, promegestone, norethindrone, megestrol, norgestrel, levonorgestrel, Desogestrel, norgestimate, Norethisteroneoxime, a kind of in quingestrone or the anorethindrane dipropionate.
6, progestogen injection implants according to claim 1, it is characterized in that, said biological degradation polyalcohol comprises polylactide-co-glycolide, polylactic acid, polyglycolic acid, pla-pcl, poly-anhydride, poly butyric ester-hydroxyl pentanoate copolymer, polypropylene glucosan, one or more of polylactic acid-polyglycol.
7, progestogen injection implants according to claim 6 is characterized in that polymer molecular weight is 5,000～1,000,000, wherein, polylactide-co-glycolide monomer polymerization ratio is between 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 of each described progestogen of claim 1～7 for the treatment of effective dose that contain are injected the pharmaceutical composition that implants 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 such as tablet, membrane, stick, a kind of in the pill, preferred subcutaneous or intramuscular dose.
10, the preparation method of injecting implants according to each described progestogen of claim 1～8, 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 mixture, 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 1～500mg/ml;
Said organic solvent comprises dichloromethane, chloroform, ethyl acetate, ether or one or more;
Said suspending agent comprises polyvinyl alcohol, CMC, and PVP, eucolloid, as gelatin, arabic gum etc. a kind of, the content of suspending agent in aqueous solution is 1～50mg/ml;
The organic solvent that contains progestogen and biological degradation polyalcohol is 1: 1～500 (v/v) with the volume ratio that contains the aqueous solution of suspending agent.
12, according to each described progestogen injection implants application in preparation treatment endometriosis or hysteromyoma symptom medicine of claim 1～8.
CNB2003101085691A 2003-11-13 2003-11-13 Method for preparing long acting progestational hormone injection embedded agent and use Expired - Fee Related CN1287798C (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021207806A1 (en) * 2020-04-17 2021-10-21 Luiz Peracchi Edson Long-lasting reabsorbable subcutaneous implant with controlled release of pre-concentrated pharmacologically active substance in polymer for the treatment of endometriosis

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021207806A1 (en) * 2020-04-17 2021-10-21 Luiz Peracchi Edson Long-lasting reabsorbable subcutaneous implant with controlled release of pre-concentrated pharmacologically active substance in polymer for the treatment of endometriosis
EP4137126A4 (en) * 2020-04-17 2024-05-22 Peracchi Edson Luiz Long-lasting reabsorbable subcutaneous implant with controlled release of pre-concentrated pharmacologically active substance in polymer for the treatment of endometriosis

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