CN1193759C - Sustained release and implantation type cis-platinum medicine and method for preparing same - Google Patents
Sustained release and implantation type cis-platinum medicine and method for preparing same Download PDFInfo
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- CN1193759C CN1193759C CNB971070784A CN97107078A CN1193759C CN 1193759 C CN1193759 C CN 1193759C CN B971070784 A CNB971070784 A CN B971070784A CN 97107078 A CN97107078 A CN 97107078A CN 1193759 C CN1193759 C CN 1193759C
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- cisplatin
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Abstract
The present invention discloses a sustained release and implantation type cisplatin medicine and a preparing method thereof. The medicine of the present invention is composed of cisplatin, a polymer, a retarding agent and a pore forming agent and is a medicine stick or a medicine grain which can be implanted into focal regions of the human body. By the slow release of the medicine, the systemic toxicity and side effects of the cisplatin can be basically eliminated by keeping local long acting medication. The dosage of the cisplatin is only required to be about 5% of the normal chemotherapy dosage. The cisplatin medicine of the present invention is prepared by mixing the cisplatin and other constituents through a mould with a specific shape.
Description
The present invention relates to a kind of antitumor drug novel formulation, the novel form of a kind of cisplatin and preparation method thereof of more specifically saying so.
Cisplatin is an antitumor chemotherapeutics commonly used, bladder cancer, ovarian cancer, carcinoma of testis there are curative effect preferably, breast carcinoma, cervical cancer, carcinoma of endometrium, adrenal gland's canceroderm, gastric cancer, pulmonary carcinoma, carcinoma of prostate, incidence scale cancer and child's neuroblastoma, osteosarcoma, ovarian germ cell tumor all had certain curative effect.The untoward reaction of cisplatin mainly contains Toxicity of Kidney, gastrointestinal toxicity, bone marrow depression, ototoxicity, neurotoxicity etc., and therapeutic dose is close with toxic dose.
Common cisplatin only can be by vein, tremulous pulse or intracavitary administration.Absorb rapidly after the administration and be distributed in each tissue of whole body: kidney, liver, ovary, uterus, skin, bone equal size are more, and less in spleen, pancreas, intestinal, the heart, muscle, the brain, the tumor tissue non-selectivity distributes.Major part and plasma protein combination, it is 25-49 minute that metabolism is two-phase T1/2 α, T1/2 β is 58-73 hour.
The purpose of this invention is to provide a kind of sustained release and implantation type cis-platinum medicine and preparation method thereof, after the cisplatin slow releasing pharmaceutical implants, can improve tumor locus active drug concentration and prolong drug and cancerous cell action time, the total dosage of clinical chemotherapy is descended significantly, eliminate the general toxic and side effects of existing embolic chemotherapy substantially.
The objective of the invention is to be achieved through the following technical solutions.
A kind of sustained release and implantation type cis-platinum medicine, it is a kind ofly to be implanted into agent by containing the body that the following weight proportion raw material makes,
Cisplatin 10～90%
Polymer 10～85%
Blocker 0～20%
Porogen 0～20%
Polymer is meant biological degradation polyalcohol or non-biodegradation polymer,
Blocker is meant lyophobic dust,
Porogen is meant water miscible low molecule or macromolecular compound.
Biological degradation polyalcohol is to be selected from lactide acid polymer etc., as
A, polylactic acid, its molecular weight peak value scope is measured as 8000～45000 by GPC,
The copolymer of b, lactic acid and glycolic, its molecular weight peak value scope GPC is measured as 6000～50000,
C, (a) and mixture (b), its weight ratio is 15/85～90/10,
D, chitin, gelatin, extra large bath acid sodium, glucosan, polyvidone.
The non-biodegradation polymer is to be selected from organosilicon polymer,
As polydimethylsiloxane, poly-ethylene methacrylic radical siloxane;
Blocker is selected from
A, stearic acid, magnesium stearate, calcium stearate,
B, higher fatty acids, high fatty alcohol,
C, tristerin;
Porogen is selected from
A, sodium chloride, potassium chloride,
B, gelatin, carboxymethyl cellulose, propyl methocel,
C, Polyethylene Glycol, low molecular polyethylene alcohol.
Body is implanted into medicine rod or the medicine grain that agent is meant that internal lesions position is implanted.
The preferable weight proportion of each raw material components is:
A, cisplatin 20～80%
Organosilicon polymer 15～75%
Blocker 0～5%
Porogen 0～15%
Or
B, cisplatin 18～80%
Polylactic acid 18～78%
Blocker 0.1～3%
Porogen 0.5～5%
The preferable weight proportion of each raw material components is:
A, cisplatin 60～80%
Organosilicon polymer 18～38%
Blocker 0.1～1%
Porogen 0.6～2%
Or
B, cisplatin 60～75%
Polylactic acid 24～37%
Blocker 0.2～1.5%
Porogen 0.5～2%
The preferable weight proportion of each raw material components is:
A, cisplatin 50～75%
Organosilicon polymer 25～50%
Or
B, cisplatin 50～80%
Polylactic acid 20～50%
The preferable weight proportion of each raw material components is;
A, cisplatin 60～75%
Polydimethylsiloxane 22～38%
Glyceryl tristearate 1～6%
Or
B, cisplatin 60～80%
The copolymer 1 8～35% of lactic acid and glycolic
NaCl 2～8％
A kind of preparation method of sustained release and implantation type cis-platinum medicine is to adopt fusion method, with each component mix homogeneously, inserts melt molding in the mould, cooling and demolding by proportioning.
A kind of preparation method of sustained release and implantation type cis-platinum medicine is to adopt solvent method, in solvent, with each component mix homogeneously, inserts die for molding by proportioning, removes the back depanning of desolvating.
A kind of preparation method of sustained release and implantation type cis-platinum medicine is to adopt the microsphere method of forming of filming, preparation medicine microspheres earlier, after film, then by proportioning combination forming in mould.
A kind of preparation method of sustained release and implantation type cis-platinum medicine is to adopt the mixed-forming method, presses proportioning with each component mix homogeneously, in die for molding.
The present invention selects for use lactic acid polymer, organosilicon polymer and blocker, porogen as adjuvant.After lactic acid polymer implants, under the effect of body fluid and enzyme etc., can be biodegradable into to existing micromolecular compound in the human body is absorbed by the body, metabolism, excrete then, human body is had no side effect, medical grade silicone rubber has excellent physiological property, good with the human-body biological compatibility, have no adverse reaction after inserting human body, stable to antibacterial, good mildew resistance is arranged, and algae, mycete can not grow.Blocker means the stearic acid lyophobic dust, and porogen means water-soluble substanceses such as sodium chloride, enters in the human body and progressively all can be organized absorption after the release.
The rate of release of cisplatin all can be controlled or delay to organosilicon polymer and lactic acid polymer effectively, can be controlled at release time in 2 hours to 2 years scopes (the effective local concentration of medicine).
As excipient, framework material and slow release material play a part bonding setting and slow release in prescription for organosilicon polymer and lactic acid polymer.Make the cisplatin slow releasing pharmaceutical implant of making have required shape, intensity, toughness, multifrequency natures such as drug release feature and human body intermiscibility.
Blocker and porogen can slow down or increase the rate of release of cisplatin in prescription, regulate drug release feature, help lactic acid polymer in vivo Jie falls.
The curative effect of chemotherapy tumor depends primarily on the active drug concentration of tumor locus and the product of action time.The cisplatin slow releasing pharmaceutical is implanted into by body, and directly administration in knub position or tumor can form effective drug level and keeps the sufficiently long time in suffering from cancer position or tumor, realize local long-acting medication.One the course of treatment chemotherapy dosage can significantly reduce, the general toxic and side effects is expected to reduce significantly even eliminates substantially, most probably in the life quality that improves tumour patient, can improve the cure rate of tumor patient, reduce medical expense greatly, and can only be adopted the patients with advanced cancer of palliative treatment that new active treatment means are provided.
By the following examples, the invention will be further described.
Embodiment 1
On clean work station, with special coating pan with the 10g cisplatin, the pelletize of 2g glyceryl tristearate, particle diameter is controlled at φ 0.1-0.5mm scope, gradation will contain in the 5g medical grade polydimethylsiloxane input coating pan again, formation is kernel with the cisplatin microsphere, silicone rubber is the microcapsule of peplos, in 50 ℃ of following dry solidifications 4 hours, drops into and contains the uniform mixing of 5g polydimethylsiloxane, be pressed into molding in the stainless steel mould, leave standstill and solidified 24 hours, again at 40 ℃, 0.09MPa dry 4 hours down, check, the encapsulation of sterilization back.
In 37 ℃ of constant temperature normal saline, soaked 15 days release amount about 45～53%.
Implant 1mg medicine rod at 8 SD rat sacrum ridge intramusculars, work in the 15th day is killed, and takes out residual medicine and venous blood analysis, and the release amount is 43～54%, and blood drug level is 0.21-0.43 μ g/ml
Embodiment 2
On clean work station, earlier 5g lactic acid and ethanol copolymer (it is 31000 that molecular weight peak value GPC surveys) are ground with mortar, render in the special rustless steel agitator after crossing 200 mesh sieves, drop into the 10g cisplatin again, discharging is mixed in mixing thoroughly behind the 2g sodium chloride.Put into mould, slowly be heated to 60～120 ℃, keep 12 hours postcooling, depanning, the sterilization encapsulation of check back to room temperature.
In 37 ℃ of constant temperature normal saline, soaked 15 days release amount 76～81%.
Embodiment 3
On clean work station,, pour in the special mould after adding the former medicine mix homogeneously of 10g cisplatin again 5g polylactic acid (molecular weight peak value GPC survey be 20000) dissolving with the 20g tetrahydrofuran solvent, at 5KPa, slough solvent, depanning, the sterilization encapsulation of check back under 35 ℃.
In 37 ℃ of constant temperature normal saline, soaked 15 days release amount 62～73%
Embodiment 4
On clean work station, get the 10g cisplatin, 2g potassium chloride and 4g polydimethylsiloxane drop in the rustless steel blender, uniform mixing, be pressed into molding in the stainless steel mould, leave standstill and solidified 24 hours, depanning is again at 40 ℃, 5～50MPa dry 2 hours down, check, the encapsulation of sterilization back.
In 37 ℃ of constant temperature normal saline, soaked 10 days release amount about 85～89%.
Respectively implant 1mg medicine rod at 8 SD rat sacrum ridge intramusculars, work in the 10th day is killed, and takes out residual medicine analysis, and the release amount is 80～89%.
Different embodiment drug release features relatively
| Embodiment | Cumulative release percent in 37 ℃ of normal saline (average, %) |
| 1 day 3 days 5 days 7 days 9 days 11 days 13 days 15 days | |
| 1 2 3 4 | 12 23 30 37 41 46 49 51 25 40 48 55 61 67 74 78 21 37 44 49 56 61 66 70 28 49 64 76 83 86 (10 days) |
Different embodiment drug release feature in animal body relatively
| Embodiment | Blood drug level μ g/ml (meansigma methods) | Release amount (accumulative total meansigma methods) |
| 1 day 3 days 5 days 7 days 9 days 11 days 13 days 15 days | (％) | |
| 1 4 | 0.32 0.41 0.35 0.31 0.24 0.28 0.25 0.22 0.39 0.52 0.47 0.39 0.28 | 49％ 85％ |
Claims (11)
1, a kind of sustained release and implantation type cis-platinum medicine is characterized in that it is a kind ofly to be implanted into agent by containing the body that the following weight proportion raw material makes,
Cisplatin 10～90%
Polymer 10～85%
Blocker 0～20%
Porogen 0～20%
Polymer is meant biological degradation polyalcohol or organosilicon polymer,
Blocker is selected from
A, stearic acid, magnesium stearate, calcium stearate,
B, higher fatty acids, high fatty alcohol,
C, tristerin;
Porogen is meant water miscible low molecule or macromolecular compound.
2, a kind of sustained release and implantation type cis-platinum medicine according to claim 1 is characterized in that biological degradation polyalcohol is selected from
A, polylactic acid, its molecular weight peak value scope is measured as 8000～45000 by GPC,
The copolymer of b, lactic acid and glycolic, its molecular weight peak value scope is measured as 6000～50000 by GPC,
C, (a) and mixture (b), its weight ratio is 15/85～90/10,
D, chitin, gelatin, sodium alginate, glucosan, polyvidone;
Organosilicon polymer is selected from
Polydimethylsiloxane, poly-ethylene methacrylic radical siloxane;
Blocker is selected from glyceryl tristearate;
Porogen is selected from
A, sodium chloride, potassium chloride,
B, gelatin, carboxymethyl cellulose, propyl methocel,
C, Polyethylene Glycol, low molecular polyethylene alcohol.
3, a kind of sustained release and implantation type cis-platinum medicine according to claim 1 is characterized in that body is implanted into medicine rod or medicine grain that agent is meant that internal lesions position is implanted.
4, a kind of sustained release and implantation type cis-platinum medicine according to claim 2 is characterized in that the weight proportion of each raw material components is:
A, cisplatin 20～80%
Organosilicon polymer 15～75%
Blocker 0～5%
Porogen 0～15%
Or
B, cisplatin 18～80%
Polylactic acid 18～78%
Blocker 0.1～3%
Porogen 0.5～5%
5, according to claim 2 or 4 described a kind of sustained release and implantation type cis-platinum medicines, it is characterized in that the weight proportion of each raw material components is:
A, cisplatin 60～80%
Organosilicon polymer 18～38%
Blocker 0.1～1%
Porogen 0.6～2%
Or
B, cisplatin 60～75%
Polylactic acid 24～37%
Blocker 0.2～1.5%
Porogen 0.5～2%
6, a kind of sustained release and implantation type cis-platinum medicine according to claim 2 is characterized in that the weight proportion of each raw material components is:
A, cisplatin 50～75%
Organosilicon polymer 25～50%
Or
B, cisplatin 50～80%
Polylactic acid 20～50%
7, a kind of sustained release and implantation type cis-platinum medicine according to claim 2 is characterized in that the weight proportion of each raw material components is:
A, cisplatin 60～75%
Polydimethylsiloxane 22～38%
Glyceryl tristearate 1～6%,
Or
B, cisplatin 60～80%
The copolymer 1 8～35% of lactic acid and glycolic
NaCl 2～8％。
8, the preparation method of described each sustained release and implantation type cis-platinum medicine of claim 1～7 is characterized in that by proportioning with each component mix homogeneously, in die for molding.
9, the preparation method of sustained release and implantation type cis-platinum medicine according to claim 8 is characterized in that by proportioning each component mix homogeneously is inserted melt molding in the mould, cooling and demolding.
10, the preparation method of sustained release and implantation type cis-platinum medicine according to claim 8 is characterized in that in solvent, with each component mix homogeneously, inserts die for molding by proportioning, removes the back depanning of desolvating.
11, the preparation method of the described sustained release and implantation type cis-platinum medicine of claim 7, it is characterized in that: elder generation is with the cisplatin and the glyceryl tristearate pelletize of proportional quantity in coating pan, Φ 0.1～0.5mm, back gradation drops into the medical grade polydimethylsiloxane of proportional quantity in the coating pan, forming polydimethylsiloxane is the microcapsule of peplos, drop into the polydimethylsiloxane uniform mixing of remaining proportional quantity behind the dry solidification again, throw curing molding in the mould, the demoulding, drying at last.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB971070784A CN1193759C (en) | 1997-08-15 | 1997-08-15 | Sustained release and implantation type cis-platinum medicine and method for preparing same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB971070784A CN1193759C (en) | 1997-08-15 | 1997-08-15 | Sustained release and implantation type cis-platinum medicine and method for preparing same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1208616A CN1208616A (en) | 1999-02-24 |
| CN1193759C true CN1193759C (en) | 2005-03-23 |
Family
ID=5169267
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB971070784A Expired - Lifetime CN1193759C (en) | 1997-08-15 | 1997-08-15 | Sustained release and implantation type cis-platinum medicine and method for preparing same |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1193759C (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100416242B1 (en) * | 1999-12-22 | 2004-01-31 | 주식회사 삼양사 | Liquid composition of biodegradable block copolymer for drug delivery and process for the preparation thereof |
| CN100500219C (en) * | 2005-04-06 | 2009-06-17 | 山东蓝金生物工程有限公司 | Anti tumour medicinal composition containing platinum compound |
| CN111991418A (en) * | 2020-08-29 | 2020-11-27 | 吴国斌 | Medicine carrying system of chitosan carrier and preparation method thereof |
-
1997
- 1997-08-15 CN CNB971070784A patent/CN1193759C/en not_active Expired - Lifetime
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| Publication number | Publication date |
|---|---|
| CN1208616A (en) | 1999-02-24 |
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Owner name: HU'NAN QIU ZEYOU PATENT STRATEGIC PLANNING CO., LT Free format text: FORMER OWNER: QIU ZEYOU Effective date: 20101029 |
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Free format text: CORRECT: ADDRESS; FROM: 410011 28/F, SHUNTIANCHENG, NO.59, SECTION 2 OF FURONG MIDDLE ROAD, CHANGSHA CITY, HU'NAN PROVINCE TO: 410205 JUXING INDUSTRY BASE, NO.8, LUJING ROAD, CHANGSHA HIGH-TECH. DEVELOPMENT ZONE, YUELU DISTRICT, CHANGSHA CITY, HU'NAN PROVINCE |
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| TR01 | Transfer of patent right |
Effective date of registration: 20101105 Address after: Dalian Lu, Baohe Industrial District of Hefei City, Anhui Province, No. 16 230051 Patentee after: Anhui Fengyuan people Pharmaceutical Co. Ltd. Address before: 307, room 193, electronic city, No. 230001, Tunxi Road, Hefei, Anhui Patentee before: Zhongren Science and Technology Co., Ltd., Anhui Prov. |
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Effective date of registration: 20170104 Address after: Hefei City, Anhui Province, 230088 Lake Road No. 1429 Patentee after: Hefei China Science and Technology Co., Ltd. Address before: Dalian Lu, Baohe Industrial District of Hefei City, Anhui Province, No. 16 230051 Patentee before: Anhui Fengyuan people Pharmaceutical Co. Ltd. |
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| CX01 | Expiry of patent term |
Granted publication date: 20050323 |
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| CX01 | Expiry of patent term |