CN1208611A - Sustained release and implantation type fluorouracil medicine and method for preparing same - Google Patents
Sustained release and implantation type fluorouracil medicine and method for preparing same Download PDFInfo
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- CN1208611A CN1208611A CN 97107076 CN97107076A CN1208611A CN 1208611 A CN1208611 A CN 1208611A CN 97107076 CN97107076 CN 97107076 CN 97107076 A CN97107076 A CN 97107076A CN 1208611 A CN1208611 A CN 1208611A
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- fluorouracil
- sustained release
- medicine
- implantation type
- polymer
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Abstract
The invented medicine is composed of fluorouracil and polymer, retarding agent, pore forming agent. It features that the medicine in the form of stick or granule is interplanted in the focal position of body and is gradually released to sustain medical action on focus and it can eliminate basically the toxic side effect of fluorouracil to the whole body. The fluorouracil required is only about 5% of that used in normal chemotherapy.
Description
The present invention relates to a kind of antitumor drug novel formulation, the novel form of a kind of fluorouracil and preparation method thereof of more specifically saying so.
Fluorouracil is an antitumor chemotherapeutics commonly used, is applicable to breast carcinoma, digestive tract tumor, ovarian cancer, primary bronchogenic carcinoma of lung, malignant mole, chorionic epithelioma, incidence cancer, skin carcinoma, bladder cancer, serous cavity cancerous effusion.The untoward reaction of fluorouracil mainly damages bone marrow, and oral mucosa and digestive tract epithelium have bloody diarrhea when serious, also can cause alopecia, cerebellar ataxy, and therapeutic dose is close with toxic dose.Medicine each phase half-life in human body is tens minutes to tens hours.
The purpose of this invention is to provide a kind of sustained release and implantation type fluorouracil medicine and preparation method thereof, after the fluorouracil slow release medicine 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 fluorouracil medicine, it is a kind ofly to be implanted into agent by containing the body that the following weight proportion raw material makes,
Fluorouracil 10～98%
Polymer 2～85%
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, glyceryl stearate, 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, fluorouracil 20～80%
Organosilicon polymer 15～75%
Blocker 0～15%
Porogen 0～15%
Or
B, fluorouracil 18～80%
Lactic acid polymer 18～80%
Blocker 0.1～9%
Porogen 0～5%
The preferable weight proportion of each raw material components is:
A, fluorouracil 40～70%
Organosilicon polymer 25～55%
Blocker 0.5～4%
Porogen 0.1～2%
Or
B, fluorouracil 40～60%
Lactic acid polymer 35～55%
Blocker 0.5～4.5%
Porogen 0.5～2%
The preferable weight proportion of each raw material components is:
A, fluorouracil 40～70%
Organosilicon polymer 60～30%
Or
B, fluorouracil 50～80%
Polylactic acid 20～50%
The preferable weight proportion of each raw material components is:
A, fluorouracil 55～70%
Polydimethylsiloxane 25～40%
Glyceryl tristearate 1～6%
Or
B, fluorouracil 55～65%
Its polymers 25～35% of lactic acid and glycolic
NaCl????????????????5～11％
A kind of preparation method of sustained release and implantation type fluorouracil 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 fluorouracil 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 fluorouracil 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 fluorouracil 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, excrete then, human body is had no side effect to existing micromolecular compound in the human body is absorbed by the body, metabolism.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 fluorouracil 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 fluorouracil slow release medicinal implants 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 fluorouracil 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 fluorouracil slow release medicine is implanted into by body, and directly administration in knub position or tumor suffering from the cancer position or swollenly can forming effective drug level in rotten and keep the sufficiently long time, realizes 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
Close in purification work, with special coating pan with the 50g fluorouracil, the 2g glyceryl tristearate, pelletize, particle diameter is controlled at φ 0.1-0.5mm scope, gradation will contain in the 10g medical grade polydimethylsiloxane solution input coating pan again, and forming with the fluorouracil microglobule is kernel, and silicone rubber is the microcapsule of peplos, in 50 ℃ of following dry solidifications 4 hours, input contains the uniform mixing of 15g medical grade polydimethylsiloxane solution again, is pressed into molding in the stainless steel mould, leaves standstill to solidify 24 hours, again at 40 ℃, 0.09MPa following dry 4 hours, check, the encapsulation of sterilization back.
In 37 ℃ of constant temperature normal saline, soaked 15 days release amount about 58～72%.
Implant 5mg 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 52～64%, and blood drug level is 1.3-2.7 μ g/ml
Embodiment 2
On clean work station, first with 15g lactic acid and ethanol copolymer with mortar, molecular weight is that 32000/GPC grinds, and renders in the special rustless steel agitator behind 200 mesh sieves excessively, drops into the 30g fluorouracil again, mixes behind the 3g sodium chloride and mixes discharging thoroughly.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 82～85%
Embodiment 3
On clean work station, with the 6g polylactic acid, molecular weight is 22000/GPC with the 24g tetrahydrofuran solvent, and dissolving is poured in the special mould after adding the former medicine mix homogeneously of 20g fluorouracil again, at 5KPa, sloughs 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 50g fluorouracil, 2g potassium chloride, the poly-ethylene methacrylic radical siloxane of 1g stearic acid and 38g medical grade drops 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 10 days release amount about 75～82%.
Respectively implant 5mg medicine rod at 8 SD rat sacrum ridge intramusculars, work in the 15th day is killed, and takes out residual medicine analysis, and the release amount is 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 | ?20 ?27 ?21 ?28 | ?28 ?38 ?28 ?45 | ?34 ?48 ?34 ?51 | ?41 ?57 ?43 ?69 | ????52 ????65 ????52 ????78 | ????59 ????71 ????61 | ?64 ?78 ?67 | ?68 ?83 ?71 |
Different embodiment degree characteristic 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 | ????3.5????2.7????2.6????3.2????2.7????2.2????2.8????2.1 ????4.2????3.7????3.2????2.8????2.8 | ????72％ ????81％ |
Claims (11)
1, a kind of sustained release and implantation type fluorouracil 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,
Fluorouracil 10～98%
Polymer 2～85%
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.
2, a kind of sustained release and implantation type fluorouracil medicine according to claim 1 is characterized in that
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, glyceryl stearate, Lac;
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 fluorouracil 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 fluorouracil medicine according to claim 2 is characterized in that the preferable weight proportion of each raw material components is:
A, fluorouracil 20～80%
Organosilicon polymer 15～75%
Blocker 0～15%
Porogen 0～15%
Or
B, fluorouracil 18～80%
Lactic acid polymer 18～80%
Blocker 0.1～9%
Porogen 0～5%
5, a kind of sustained release and implantation type fluorouracil medicine according to claim 2 is characterized in that the preferable weight proportion of each raw material components is:
A, fluorouracil 40～70%
Organosilicon polymer 25～55%
Blocker 0.5～4%
Porogen 0.1～2%
Or
B, fluorouracil 40～60%
Lactic acid polymer 35～55%
Blocker 0.5～4.5%
Porogen 0.5～2%
6, a kind of sustained release and implantation type fluorouracil medicine according to claim 2 is characterized in that the preferable weight proportion of each raw material components is:
A, fluorouracil 40～70%
Organosilicon polymer 60～30%
Or
B, fluorouracil 50～80%
Polylactic acid 20～50%
7, a kind of sustained release and implantation type fluorouracil medicine according to claim 2 is characterized in that the preferable weight proportion of each raw material components is:
A, fluorouracil 55～70%
Polydimethylsiloxane 25～40%
Glyceryl tristearate 1～6%
Or
B, fluorouracil 55～65%
Its polymers 25～35% of lactic acid and glycolic
NaCl????????????????5～11％
8, a kind of preparation method of sustained release and implantation type fluorouracil medicine is characterized in that by proportioning each component mix homogeneously is inserted melt molding in the mould, cooling and demolding.
9, a kind of preparation method of sustained release and implantation type fluorouracil medicine is characterized in that in solvent, with each component mix homogeneously, inserts die for molding by proportioning, removes the back depanning of desolvating.
10, a kind of preparation method of sustained release and implantation type fluorouracil medicine is characterized in that preparation medicine microspheres earlier, after film, then by proportioning combination forming in mould.
11, a kind of preparation method of sustained release and implantation type fluorouracil medicine is characterized in that by proportioning with each component mix homogeneously, in die for molding.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN97107076A CN1106836C (en) | 1997-08-15 | 1997-08-15 | Sustained release and implantation type fluorouracil medicine and method for preparing same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN97107076A CN1106836C (en) | 1997-08-15 | 1997-08-15 | Sustained release and implantation type fluorouracil medicine and method for preparing same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1208611A true CN1208611A (en) | 1999-02-24 |
| CN1106836C CN1106836C (en) | 2003-04-30 |
Family
ID=5169265
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN97107076A Ceased CN1106836C (en) | 1997-08-15 | 1997-08-15 | Sustained release and implantation type fluorouracil medicine and method for preparing same |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1106836C (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102319230A (en) * | 2011-08-12 | 2012-01-18 | 西安交通大学 | Implantable 5-fluorouracil slowly released and controlled-drug delivery system and preparation method thereof |
| CN113209050A (en) * | 2021-05-14 | 2021-08-06 | 浙江恒冀制药有限责任公司 | Long-acting in vivo skin-embedded or implanted sustained-release preparation based on biocompatible polymer |
-
1997
- 1997-08-15 CN CN97107076A patent/CN1106836C/en not_active Ceased
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102319230A (en) * | 2011-08-12 | 2012-01-18 | 西安交通大学 | Implantable 5-fluorouracil slowly released and controlled-drug delivery system and preparation method thereof |
| CN113209050A (en) * | 2021-05-14 | 2021-08-06 | 浙江恒冀制药有限责任公司 | Long-acting in vivo skin-embedded or implanted sustained-release preparation based on biocompatible polymer |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1106836C (en) | 2003-04-30 |
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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: 20051226 Decision number of declaring invalidation: 7931 |