CN1112179C - Sustained release and implantation type doxorubicin medicine and method for preparing same - Google Patents
Sustained release and implantation type doxorubicin medicine and method for preparing same Download PDFInfo
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- CN1112179C CN1112179C CN97107079A CN97107079A CN1112179C CN 1112179 C CN1112179 C CN 1112179C CN 97107079 A CN97107079 A CN 97107079A CN 97107079 A CN97107079 A CN 97107079A CN 1112179 C CN1112179 C CN 1112179C
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- sustained release
- amycin
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Abstract
The present invention discloses a sustained release and implantation type doxorubicin medicine and a preparation method thereof. The doxorubicin medicine of the present invention is composed of doxorubicin, 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 doxorubicin can be basically eliminated by keeping local long acting medication. The dosage of the doxorubicin only needs to be about 5% of the normal chemotherapy dosage. The doxorubicin medicine of the present invention is prepared by that the doxorubicin and other constituents are mixed, and a mould with a specific shape to shape the mixture.
Description
The present invention relates to a kind of antitumor drug novel formulation, the novel form of a kind of amycin and preparation method thereof of more specifically saying so.
Amycin is an antitumor chemotherapeutics commonly used, is applicable to acute leukemia (lymphatic and granulocytic), He Jiejin and malignant lymphoma, breast carcinoma, lung bronchogenic carcinoma (not breaking up cellule type and non-cellule type), ovarian cancer, soft tissue sarcoma, osteogenic sarcoma, rhabdomyosarcoma, Ewing sarcoma, nephroblastoma, neuroblastoma, bladder cancer, thyroid carcinoma, carcinoma of prostate, incidence scale cancer, carcinoma of testis, gastric cancer, hepatocarcinoma etc.
The toxic and side effects of amycin mainly contains bone marrow depression, digestive tract reaction and cardiac toxicity etc., and clinical therapeutic dose commonly used is close with toxic dose.
But common amycin is intravenously administrable only, and plasma protein structure rate is very low.Enter in the body and be distributed in rapidly in the heart, kidney,liver,spleen, the lung tissue, but can not see through blood brain barrier.Mainly at intrahepatic metabolism, through bile excretion, 50% discharges with the active amycin metabolite of tool adriamycinol with constant former medicine, 23%, only 5～10% drains from urine in 6 hours.The clearance curve of amycin is heterogenetic, its three-phase T
1/2Be respectively 0.5,3 and 40～50 hour.
The purpose of this invention is to provide a kind of sustained release and implantation type doxorubicin medicine and preparation method thereof, after the amycin 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 in amplitude, 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 doxorubicin medicine, it is a kind ofly to be implanted into agent by containing the body that the following weight proportion raw material makes,
Amycin 10～80%
Polymer 20～85%
Blocker 0～10%
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,
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, paraffin, higher fatty acids, high fatty alcohol,
C, tristerin, Lac;
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, amycin 15～70%
Organosilicon polymer 29～80%
Blocker 0～5%
Porogen 0.5～10%
Or
B, amycin 15～65%
Polylactic acid 34～80%
Blocker 0～5%
Porogen 0.5～10%
The preferable weight proportion of each raw material components is:
A, amycin 20～50%
Organosilicon polymer 45～75%
Blocker 0.1～2%
Porogen 1～5%
Or
B, amycin 20～45%
Polylactic acid 50～75%
Blocker 0.1～2%
Porogen 0.5～4%
The preferable weight proportion of each raw material components is:
A, amycin 25～40%
Organosilicon polymer 60～75%
Or
B, amycin 25～45%
Polylactic acid 55～75%
The preferable weight proportion of each raw material components is:
A, amycin 25～40%
Polydimethylsiloxane 59～72%
Glyceryl tristearate 1～6%
Or
B, amycin 25～45%
The copolymer 50～70% of lactic acid and glycolic
NaCl 5～11％
A kind of preparation method of sustained release and implantation type doxorubicin 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 doxorubicin 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 doxorubicin medicine is to adopt the emblem ball method of forming of filming, preparation medicine emblem ball earlier, after film, then by proportioning combination forming in mould.
A kind of preparation method of sustained release and implantation type doxorubicin 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, and is good with the human-body biological compatibility, has no adverse reaction after inserting human body, stable to antibacterial, and 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 amycin all can be controlled or delay to organosilicon polymer and lactic acid polymer effectively, can be controlled at release time in 2 days to 6 months scopes (the effective local concentration of medicine).
Organosilicon polymer and lactic acid polymer in prescription as excipient, framework material and slow release material, play a part bonding setting and slow release, make the amycin 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 amycin 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 amycin 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 amycin, the pelletize of 0.5g glyceryl tristearate, particle diameter is controlled at φ 0.2-0.5mm scope, and gradation will contain in the 5g silicone rubber input coating pan again, and forming with the amycin microsphere is kernel, silicone rubber is the microcapsule of peplos, in 50 ℃ of following dry solidifications 4 hours, drops into and contains the uniform mixing of 5g silicone rubber, 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 82～85%.
Embodiment 2
On clean work station, earlier 15g 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 amycin again, discharging is mixed in mixing thoroughly behind the 0.5g sodium chloride.Put into mould, slowly be heated to 80 ℃, 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 98～99.5%.
Embodiment 3
On clean work station, with 5g polylactic acid (molecular weight peak value GPC survey be 20000) dissolving, pour in the special mould after adding the former medicine mix homogeneously of 5g amycin again with the 20g tetrahydrofuran solvent, at 5KPa, slough solvent under 35 ℃, depanning, the sterilization encapsulation of check back.
In 37 ℃ of constant temperature normal saline, soaked 15 days release amount 88～93%.
Embodiment 4
On clean work station, get the 10g amycin, 0.2g sodium chloride, 0.5g stearic acid, 25g medical grade silicone rubber drop in the rustless steel blender, uniform mixing, be pressed into molding in the stainless steel mould, leave standstill and solidified depanning 24 hours, again at 40 ℃, 5～50MPa dry 2 hours down, check, the encapsulation of sterilization back.
In 37 ℃ of constant temperature normal saline, soaked 15 days release amount about 72～80%.
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 | 25 40 49 58 65 72 79 84 32 51 61 70 79 87 94 99 27 45 56 66 74 80 85 90 19 30 39 49 57 64 71 76 |
Claims (10)
1, a kind of sustained release and implantation type doxorubicin 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,
Amycin 10～80%
Polymer 20～85%
Blocker 0～10%
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 doxorubicin 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;
Porogen is selected from
A, sodium chloride, potassium chloride,
B, gelatin, carboxymethyl cellulose, propyl methocel,
C, Polyethylene Glycol, low molecular weight polyethylene alcohol.
3, a kind of sustained release and implantation type doxorubicin 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 doxorubicin medicine according to claim 1 is characterized in that the weight proportion of each raw material components is:
A, amycin 15～70%
Organosilicon polymer 29～80%
Blocker 0～5%
Porogen 0.5～10% or
B, amycin 15～65%
Polylactic acid 34～80%
Blocker 0～5%
Porogen 0.5～10%.
5, a kind of sustained release and implantation type doxorubicin medicine according to claim 1 is characterized in that the preferable weight proportion of each raw material components is:
A, amycin 20～50%
Organosilicon polymer 45～75%
Blocker 0.1～2%
Porogen 1～5%
Or
B, amycin 20～45%
Polylactic acid 50～75%
Blocker 0.1～2%
Porogen 0.5～4%.
6, a kind of sustained release and implantation type doxorubicin medicine according to claim 1 is characterized in that the preferable weight proportion of each raw material components is:
A, amycin 25～40%
Polydimethylsiloxane 59～72%
Glyceryl tristearate 1～6%
Or
B, amycin 25～45%
The copolymer 50～70% of lactic acid and glycolic
NaCl 5～11％。
7, the preparation method of described each sustained release and implantation type doxorubicin medicine of claim 1～6 is characterized in that by proportioning with each component mix homogeneously, in die for molding.
8, the preparation method of sustained release and implantation type doxorubicin medicine according to claim 7 is characterized in that by proportioning each component mix homogeneously is inserted melt molding in the mould, cooling and demolding.
9, the preparation method of sustained release and implantation type doxorubicin medicine according to claim 7 is characterized in that in solvent, with each component mix homogeneously, inserts die for molding by proportioning, removes the back depanning of desolvating.
10, the preparation method of sustained release and implantation type doxorubicin medicine, it is characterized in that: elder generation is with 10g amycin and the pelletize of 0.5g glyceryl tristearate in coating pan, Φ 0.2～0.5mm, after the 5g polydimethylsiloxane is dropped in the coating pan, forming polydimethylsiloxane is the microcapsule of peplos, drop into the uniform mixing of 5g polydimethylsiloxane behind the dry solidification again, drop into curing molding in the mould, the demoulding, drying at last.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN97107079A CN1112179C (en) | 1997-08-15 | 1997-08-15 | Sustained release and implantation type doxorubicin medicine and method for preparing same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN97107079A CN1112179C (en) | 1997-08-15 | 1997-08-15 | Sustained release and implantation type doxorubicin medicine and method for preparing same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1208613A CN1208613A (en) | 1999-02-24 |
| CN1112179C true CN1112179C (en) | 2003-06-25 |
Family
ID=5169268
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN97107079A Ceased CN1112179C (en) | 1997-08-15 | 1997-08-15 | Sustained release and implantation type doxorubicin medicine and method for preparing same |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1112179C (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102198080B (en) * | 2011-05-18 | 2012-12-05 | 山东省医疗器械研究所 | Adriamycin sustained-release medicinal rod for treating Cerebral gliomas disease and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0139286A2 (en) * | 1983-10-14 | 1985-05-02 | Sumitomo Pharmaceuticals Company, Limited | Prolonged sustained-release preparations |
-
1997
- 1997-08-15 CN CN97107079A patent/CN1112179C/en not_active Ceased
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0139286A2 (en) * | 1983-10-14 | 1985-05-02 | Sumitomo Pharmaceuticals Company, Limited | Prolonged sustained-release preparations |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1208613A (en) | 1999-02-24 |
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| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C35 | Partial or whole invalidation of patent or utility model | ||
| IW01 | Full invalidation of patent right |
Decision date of declaring invalidation: 20060104 Decision number of declaring invalidation: 7975 |