CN104666271A - Method for preparing controlled-release medicine preparation for treatment of local advanced rectal cancer - Google Patents
Method for preparing controlled-release medicine preparation for treatment of local advanced rectal cancer Download PDFInfo
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- CN104666271A CN104666271A CN201410794272.3A CN201410794272A CN104666271A CN 104666271 A CN104666271 A CN 104666271A CN 201410794272 A CN201410794272 A CN 201410794272A CN 104666271 A CN104666271 A CN 104666271A
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Abstract
The invention relates to a method for preparing a controlled-release medicine preparation for treatment of local advanced rectal cancer. The controlled-release medicine preparation is prepared by using capecitabine as a medicinal effective ingredient and a radiosensitive colon-targeted drug carrier, is jointly applied with radiotherapy for treating local advanced rectal cancer, so that the treatment effect can be improved, and toxic and side effects are reduced.
Description
Technical field
the invention belongs to medical art, be specifically related to a kind of preparation method of the controlled-release pharmaceutical formulation for Locally Advanced rectum cancer treatment.
Background technology
colorectal cancer is one of modal malignant tumor, and the whole world is nearly close to 1,000,000 new cases every year, simultaneously at least five ten ten thousand deaths.Operative treatment is the first-selected therapy of Early rectal tumor patient, but has higher relapse rate after the treatment of rectal cancer surgery alone, and has been late period when having a considerable Finding case.
the curative effect of patients with terminal being carried out to radiation alone or chemotherapy is all undesirable, is necessary to study new Therapeutic Method, especially both therapeutic alliances.But the conjoint therapy of radiotherapy and chemotherapy can bring larger toxic and side effects to patient, clinical tolerance is not good, have impact on therapeutic effect, causes median survival time and mean survival time clinically still not high, remains at larger room for improvement.
capecitabine (trade name: xeloda) is a kind of fluorouracil carbamates antineoplastic agent, clinical in advanced breast cancer, and the treatment of knot, rectal cancer and other solid tumors, has good antitumor action and potential applicability in clinical practice.
oral colon-target positioning release medicine system, after making drug oral by several formulations technology, does not discharge at stomach and little enteral, only reaches a kind of novel controlled release system that ileocecus position or colon site could locate release.This system has the toxic and side effects of efficient target site release ability and minimizing.
segmented intestine targeted positioning release medicine is for having special meaning through the disease of large intestine drug treatment.After common oral preparation administration, some medicine will be absorbed or be degraded before arrival coton and rectal, and medicine directly can be delivered to colon by oral colon-specific drug release, and medicine can be scattered in whole colon with higher concentration.Conlon targeting adhesive pellet is on the basis of colon-site specific drug delivery system, make preparation within the scope of certain hour, adhere to colonic mucosa surface and discharge the medicine being wrapped in its inside with certain speed, reach the object improving medicine local concentration and biological effectiveness.Bioadhesive polymer as pharmaceutical carrier, have avirulence, good biocompatibility, easily with medicament mixed and good Release Performance, the feature such as cheap and easy to get, its source has synthesizes and the polytype such as natural origin.
controlled release preparation is more senior pharmaceutical carrier, through meticulous preparation and control, can realize the timing location release of medicine.There is pH sensitive carrier at present, temperature sensitive vector etc. commonly.Politef is a kind of conventional chemical products, and it there will be the change of mechanical performance after accepting roentgenization.The pharmaceutical carrier adding polytetrafluoroethylmaterial material becomes responsive to lonizing radiation, and it is after accepting radiation exposure, and due to the change of the mechanical property of materials, cracking discharges medicine.This pharmaceutical carrier to lonizing radiation sensitivity is not yet seen in report.
comprehensive the deficiencies in the prior art, this invention is intended to prepare a kind of controlled-release pharmaceutical formulation for Locally Advanced rectum cancer treatment.
Summary of the invention
the invention reside in the preparation method that a kind of controlled-release pharmaceutical formulation for Locally Advanced rectum cancer treatment is provided, said preparation is using capecitabine as effective ingredient, use the segmented intestine targeted location pharmaceutical carrier of lonizing radiation sensitivity, make controlled-release pharmaceutical formulation, with radiotherapy use in conjunction, be used for the treatment of Locally Advanced rectal cancer.To improve therapeutic effect, reduce toxic and side effects.
controlled-release pharmaceutical formulation for Locally Advanced rectum cancer treatment of the present invention is targeting piller, and it is respectively medicine carrying ball sandwich layer, adhesion layer, sealing coat and coatings from inside to outside, containing following component (percentage by weight):
carry pill core
capecitabine 10%-30%
filler 10%-60%
politef 10%-20%
adhesive agent 10%-30%
binding agent 5%-15%
sealing coat
wax material medicine carrying ball weighs 5%
antiplastering aid wax material weighs 2%
coatings
the heavy 5%-15% of macromolecule coating material isolation ball
the heavy 1%-30% of plasticizer macromolecule coating material
the lubrication heavy 1%-200% of adjuvant macromolecule coating material
the heavy 3%-200% of solvent macromolecule coating material.
filler choosing is as methylcellulose, ethyl cellulose.
adhesive agent is selected from gelatin, pectin, carbomer, chitosan, alginate and Bletilla glucomannan, the preferred carbomer of the present invention, chitosan, alginate and Bletilla glucomannan, more preferably carbomer, chitosan and Bletilla glucomannan.
binding agent preferred water, ethanol, PVP and HPMC.
wax material is selected from: stearic acid, stearyl alcohol, Brazil wax, Cera Flava, octadecanol, hexadecanol one or more, preferred stearic acid, octadecanol and Brazil wax, more preferably stearic acid and octadecanol.
antiplastering aid select Pulvis Talci, micropowder silica gel, sodium lauryl sulphate, Polyethylene Glycol, silicon dioxide and magnesium stearate one or more, preferably talc powder, micropowder silica gel and magnesium stearate.
coating solution is selected from crylic acid resin and is selected from Eudragit L100-55, Eudragit L100, Eudragit S100 and ethyl cellulose and is selected from Aquacoat and sulease, preferred acrylic resins class EudragitL100-55, Eudragit L100, Eudragit S100, concentration is 0.3%-3%.
plasticizer be selected from triethyl citrate, dibutyl phthalate, diethyl phthalate, Polyethylene Glycol and Oleum Ricini one or more, optimization citric acid triethyl, dibutyl phthalate, diethyl phthalate.
lubricant select Pulvis Talci, micropowder silica gel, sodium lauryl sulphate, Polyethylene Glycol, silicon dioxide and magnesium stearate one or more, preferably talc powder, sodium lauryl sulphate, silicon dioxide and magnesium stearate, more preferably Pulvis Talci and sodium lauryl sulphate.
solvent select water, ethanol, ethanol water, PVP, HPMC, CMC-Na etc. one or more, preferred water, ethanol water and PVP.
preparation method of the present invention comprises carries pill core by centrifugal granulation and extrusion spheronization method, preferred extrusion spheronization method, and sealing coat implements heat fusing coating with medicine carrying micropill surface, and enteric coating comprises coating pan processes and fluidized bed process, preferred fluidized coating method.Concrete grammar is as follows:
1. get the capecitabine of recipe quantity, politef, filler and adhesive agent and cross 120 mesh sieve mix homogeneously, add suitable amount of adhesive and prepare soft material, soft material is put extrusion mechanism for medicine carrying micropill: extruded velocity is 25-30rpm, round as a ball speed is 38-45Hz, and the round as a ball time is 10-35min.Piller will be extruded and be placed in dry 12h at 40 DEG C, baking oven;
2. then dry for preparation micropill is placed in coating pan, takes recipe quantity isolation coat wax material and antiplastering aid, adopt melt coating technique, regulate coating temperature to be 60-75 DEG C; Coating pan rotating speed 25-45r/min, repeatedly adds wax material and antiplastering aid on a small quantity, and continuous stirring and evenly mixing;
3. take recipe quantity enteric-coating material, plasticizer, antiplastering aid and solvent, adopt fluidized coating method, regulate coating parameter: rotation speed of fan 30%-60%, coating temperature is 25-55 DEG C, and inlet temperature is 30-60 DEG C, atomizing pressure 0.2-08MPa; Inclusion casing piller is placed in 40 DEG C of aging 24h of baking oven.
said preparation is oral gives Locally Advanced rectal cancer patient, coordinates lesions position radiotherapy to use.Can reach good antineoplaston effect, and side effect is lower, patient tolerance is good.Radiotherapy preferably adopts 15MV X-ray routine to irradiate, and pelvic cavity radiation accumulated dose (TD) 46 ~ 50 Gy, contract wild dosage 20 ~ 24 Gy.
the advantage of technical solution of the present invention
controlled release preparation provided by the invention is oral gives patient, compliance is better, after gastrointestinal absorption, targeting location adheres to colon, rectum position, combined radiotherapy, uses radiation exposure tumor focus, while radiotherapy, the pharmaceutical carrier adhering to focus periphery is owing to being subject to radiation exposure and disintegrate, and release anti-tumor active ingredient capecitabine, in focus local, targeting plays antitumor action.All the other medicine carrying carriers being distributed in the non-lesions position of Colon and rectum are then owing to lacking roentgenization and cannot disintegrate release, normally excreted by metabolism, the effective ingredient of performance antitumor action and lonizing radiation are farthest made to act on tumor focus, and injure normal structure as little as possible, reduce side effect.
Detailed description of the invention
further will describe the present invention in detail below.It is pointed out that following explanation is only illustrating the technical scheme that application claims is protected, any restriction not to these technical schemes.The content that protection scope of the present invention is recorded with appended claims is as the criterion.
embodiment 1
carry pill core
capecitabine 25%
ethyl cellulose 25%
politef 15%
octadecanol 12%
chitosan 23%
sealing coat
stearic acid medicine carrying ball weighs 5%
pulvis Talci stearic acid weighs 2%
coatings
especially strange S100 isolation ball weighs 5%
triethyl citrate is strange S100 aqueous dispersion body weight 9% especially
pulvis Talci is strange S100 aqueous dispersion body weight 32% especially
take recipe quantity medicine and 120 mesh sieve mix homogeneously crossed by adjuvant, add appropriate 35% alcoholic solution and prepare soft material, put extruder 32Hz and extrude bar, the round as a ball 10min of spheronizator rotating speed 43r/min, be placed in 40 DEG C of dry 12h of baking oven.Take dry medicine carrying micropill, be placed in temperature 60 C, engine speed 50r/min coating pan, repeatedly adds recipe quantity stearic acid and Pulvis Talci on a small quantity, and constantly stirs.Take recipe quantity especially strange S 100, triethyl citrate and Pulvis Talci, ethanol with 95% is solvent configuration coating solution, first triethyl citrate (addition is 8% of polymer) is dissolved during configuration coating solution, after add Pulvis Talci (addition is 30% of polymer), slowly adding especially strange S100 again makes it dissolve, and prepares coating solution.Then sealing coat piller will be wrapped put into the silo of fluidized coating machine, fluidisation machine coating parameter: temperature of charge 40 DEG C, inlet temperature 58 DEG C, rotation speed of fan 29.8Hz, atomizing pressure 0.18mPa, preheating time 5min, Coating times 35 minutes, is then placed in 40 DEG C of aging 24h of baking oven by inclusion casing piller.
measure the release of the obtained drug-loaded pellets of embodiment 1: drug-loaded pellets is placed in 0.1mol/l hydrochloric acid 2 hours, pH6.8 phosphate buffer 4 hours, sampling after pH7.8 phosphate buffer 1 hour, the Cumulative release amount of capecitabine is less than 5%; Be placed in lower 1 hour of the x-ray bombardment of Radiotherapy dosimetry, the Cumulative release amount of capecitabine is greater than 75%.
embodiment 2
carry pill core
capecitabine 25%
methylcellulose 30%
politef 15%
octadecanol 10%
carbomer 20%
sealing coat
octadecanol medicine carrying ball weighs 7%
pulvis Talci stearic acid weighs 2%
coatings
especially strange S100 isolation ball weighs 4%
especially strange L100 isolation ball weighs 3%
triethyl citrate coating polymer aqueous dispersion body weight 7%
pulvis Talci coating polymer aqueous dispersion body weight 31%
take recipe quantity medicine and 120 mesh sieve mix homogeneously crossed by adjuvant, add appropriate 35% alcoholic solution and prepare soft material, put extruder 32Hz and extrude bar, the round as a ball 10min of spheronizator rotating speed 43r/min, be placed in 40 DEG C of dry 12h of baking oven.Take dry medicine carrying micropill, be placed in temperature 60 C, engine speed 50r/min coating pan, repeatedly adds recipe quantity octadecanol and Pulvis Talci on a small quantity, and constantly stirs.Take recipe quantity especially strange S 100, especially strange L100, triethyl citrate and Pulvis Talci, ethanol with 95% is solvent configuration coating solution, first triethyl citrate (addition is 6% of polymer) is dissolved during configuration coating solution, after add Pulvis Talci (addition is 30% of polymer), slowly add again especially strange S 100 and especially strange L100 make it dissolve, prepare coating solution.Then sealing coat piller will be wrapped put into the silo of fluidized coating machine, fluidisation machine coating parameter: temperature of charge 40 DEG C, inlet temperature 58 DEG C, rotation speed of fan 29.8Hz, atomizing pressure 0.18mPa, preheating time 5min, Coating times 35 minutes, is then placed in 40 DEG C of aging 24h of baking oven by inclusion casing piller.
measure the release of the obtained drug-loaded pellets of embodiment 2: drug-loaded pellets is placed in 0.1mol/l hydrochloric acid 2 hours, pH6.8 phosphate buffer 4 hours, sampling after pH7.8 phosphate buffer 1 hour, the Cumulative release amount of capecitabine is less than 8%; Be placed in lower 1 hour of the x-ray bombardment of Radiotherapy dosimetry, the Cumulative release amount of capecitabine is greater than 80%.
embodiment 3 drug efficacy study
10 routine Locally Advanced rectal cancer patients are object of study, all make a definite diagnosis through pathological examination.Wherein man 4 example, female 6 example, 46 ~ 72 years old age, the median age 54 years old.Confirming that local tumor is fixing cannot row radical excision, all without metastasis such as liver, lung, bones.Be divided into two groups at random, often organize 5 examples.
method
first group of capecitabine drug-loaded pellets preparation imposing embodiment 1 and prepare, is as the criterion with capecitabine dosage, fixed dosage, 1300mg × m
-2
× d
-1
, points 2 times oral.From the 1st day of radiotherapy, continuous 1 week was 1 cycle with 2 weeks rear rests.Radiotherapy adopts 15MV X-ray routine to irradiate, and pelvic cavity radiation accumulated dose (TD) 46 ~ 50 Gy, contract wild dosage 20 ~ 24 Gy.Clinical target area is confirmed by diagnostic imaging section doctor, radiotherapy department doctor and physics Shi Gongtong.
second group of commercially available capecitabine preparation xeloda imposing same dose, combined radiotherapy adopts identical scheme.
the standard of curative effect evaluation presses the standard of curative effect evaluation of WHO solid tumor, curative effect is divided into: complete incidence graph, partial rcsponse, stable and progress, complete incidence graph and partial rcsponse are effective.Curative effect is with the front CT of contrast therapy and treat latter 1 month CT inspection, color ultrasound, barium enema examination and histodiagnosis and determine.Toxic reaction is observed by the requirement of WHO.
experimental result
in curative effect first group: complete incidence graph 4 example, partial rcsponse 1 example; Second group: complete incidence graph 1 example, partial rcsponse 1 example, stablizes 3 examples.The therapeutic effect using first group of invention formulation is obviously better than second group that adopts commercial preparation.
do not occur the acute untoward reaction such as times of defecation increases in toxic reaction first group, bone marrow depression 5 example is lighter I level; Occur the acute untoward reaction such as 2 routine times of defecation increase in second group, bone marrow depression has 1 routine I level, 2 routine II levels, 2 routine III level.First group after treatment untoward reaction obviously lighter.
content of the present invention merely illustrates some claimed specific embodiments; one of them or more described technical characteristic can be combined with arbitrary one or more technical scheme in technical scheme; these technical schemes obtained through combination also in the application's protection domain, just as these technical schemes obtained through combination in the disclosure of invention concrete record.
Claims (4)
1. the preparation method for the controlled-release pharmaceutical formulation of Locally Advanced rectum cancer treatment, described preparation is using capecitabine as effective ingredient, use the segmented intestine targeted location pharmaceutical carrier of lonizing radiation sensitivity, make controlled-release pharmaceutical formulation, with radiotherapy use in conjunction, be used for the treatment of Locally Advanced rectal cancer, described carrier is targeting piller, it is respectively medicine carrying ball sandwich layer, adhesion layer, sealing coat and coatings from inside to outside, it is characterized in that the concrete steps of described method are:
(1) get the capecitabine of recipe quantity, politef, filler and adhesive agent and cross 120 mesh sieve mix homogeneously, add suitable amount of adhesive and prepare soft material, soft material is put extrusion mechanism for medicine carrying micropill: extruded velocity is 25-30rpm, round as a ball speed is 38-45Hz, and the round as a ball time is 10-35min.
2. will extrude piller and be placed in dry 12h at 40 DEG C, baking oven;
(2) then dry for preparation micropill is placed in coating pan, takes recipe quantity isolation coat wax material and antiplastering aid, adopt melt coating technique, regulate coating temperature to be 60-75 DEG C; Coating pan rotating speed 25-45r/min, repeatedly adds wax material and antiplastering aid on a small quantity, and continuous stirring and evenly mixing;
(3) take recipe quantity enteric-coating material, plasticizer, antiplastering aid and solvent, adopt fluidized coating method, regulate coating parameter: rotation speed of fan 30%-60%, coating temperature is 25-55 DEG C, and inlet temperature is 30-60 DEG C, atomizing pressure 0.2-08MPa; Inclusion casing piller is placed in 40 DEG C of aging 24h of baking oven.
3. preparation method according to claim 1, is characterized in that the prescription of described targeting piller consists of (percentage by weight):
Carry pill core
Capecitabine 10%-30%
Filler 10%-60%
Politef 10%-20%
Adhesive agent 10%-30%
Binding agent 5%-15%
Sealing coat
Wax material medicine carrying ball weighs 5%
Antiplastering aid wax material weighs 2%
Coatings
The heavy 5%-15% of macromolecule coating material isolation ball
The heavy 1%-30% of plasticizer macromolecule coating material
The lubrication heavy 1%-200% of adjuvant macromolecule coating material
The heavy 3%-200% of solvent macromolecule coating material.
4. preparation method according to claim 1, it is characterized in that described radiotherapy preferably adopts 15MV X-ray routine to irradiate, pelvic cavity radiation accumulated dose (TD) 46 ~ 50 Gy, contract wild dosage 20 ~ 24 Gy.
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| CN201410794272.3A CN104666271B (en) | 2014-12-21 | 2014-12-21 | A kind of preparation method of controlled-release pharmaceutical formulation for Locally Advanced rectum cancer treatment |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113855695A (en) * | 2021-11-01 | 2021-12-31 | 上海理工大学 | Oral compound medicinal composition for releasing medicine in colon and preparation method thereof |
| CN116159037A (en) * | 2023-04-25 | 2023-05-26 | 四川省川龙动科药业有限公司 | Targeted pellet composition for preventing and treating piglet colitis and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101700227A (en) * | 2009-09-27 | 2010-05-05 | 宁夏医科大学 | Matrine colon targeted adhesive pellet and preparation method thereof |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101700227A (en) * | 2009-09-27 | 2010-05-05 | 宁夏医科大学 | Matrine colon targeted adhesive pellet and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 区英鸿 主编: "《塑料手册》", 28 February 1991, 北京：兵器工业出版社 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113855695A (en) * | 2021-11-01 | 2021-12-31 | 上海理工大学 | Oral compound medicinal composition for releasing medicine in colon and preparation method thereof |
| CN116159037A (en) * | 2023-04-25 | 2023-05-26 | 四川省川龙动科药业有限公司 | Targeted pellet composition for preventing and treating piglet colitis and preparation method thereof |
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Inventor after: Ma Baohua Inventor after: Qiao Lei Inventor after: Zhang Laixiang Inventor after: Wang Hong Inventor after: Han Shuhong Inventor after: Liang Hua Inventor before: Yao Juan Inventor before: Xu Peng Inventor before: Liu Wu Inventor before: Han Shuhong |
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Effective date of registration: 20180315 Address after: 266042 No. four, No. 127 South Road, Shandong, Qingdao Applicant after: Zhongxin Hospital, Qingdao Address before: 266000 Shandong province Qingdao City, Weihai Road No. 232 8-402 Applicant before: Yao Juan |
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