CN1245956C - Method for producing oral administration delay-control release medicine micro balls - Google Patents

Method for producing oral administration delay-control release medicine micro balls Download PDF

Info

Publication number
CN1245956C
CN1245956C CN 200410068840 CN200410068840A CN1245956C CN 1245956 C CN1245956 C CN 1245956C CN 200410068840 CN200410068840 CN 200410068840 CN 200410068840 A CN200410068840 A CN 200410068840A CN 1245956 C CN1245956 C CN 1245956C
Authority
CN
China
Prior art keywords
verapamil hydrochloride
delay
controlled release
spray drying
microgranule
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CN 200410068840
Other languages
Chinese (zh)
Other versions
CN1586460A (en
Inventor
谭丰苹
丁富新
蒋国强
刘铮
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tsinghua University
Original Assignee
Tsinghua University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Tsinghua University filed Critical Tsinghua University
Priority to CN 200410068840 priority Critical patent/CN1245956C/en
Publication of CN1586460A publication Critical patent/CN1586460A/en
Application granted granted Critical
Publication of CN1245956C publication Critical patent/CN1245956C/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Images

Landscapes

  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

The present invention provides a preparation method of an oral administration delay-control release medicine micro ball, which belongs to the field of medical preparation. The method is characterized in that medicine and suitable auxiliary materials are dissolved or suspended and mixed in a microencapsulated material solution with the functions of slow release and control release, medicine micro particles are prepared by a spray drying method, and the medicine micro particles are coated to prepare the delay-control release medicine micro ball. The present invention can be prepared into various oral administration preparations by suitable preparation methods. The oral administration delay-control release medicine micro ball has the characteristic that the medicine is not immediately released after entering a human body but is stably and continuously released at a prearranged speed rate after a period of preset delay time, and the purpose of control release administration by selecting time can be obtained. A medicine releasing technology which is synchronous with physiological rhythm is used by aiming at some diseases with diurnal rhythmicity, a speed control release system is combined with a medicine releasing system by time selecting control, and an optimal therapeutic effect and minimal adverse reaction are achieved.

Description

Oral time-delay---the preparation method of controlled release verapamil hydrochloride microsphere
Technical field
The present invention relates to medical technical field, it is to utilize spray drying to prepare oral time-delay in conjunction with art for coating in definite saying---a kind of method of controlled release verapamil hydrochloride microgranule (microcapsule or microsphere).
Background technology
Some disease of discovered in recent years demonstrates the rhythmicity characteristics, as the dyspnea of asthmatic patient outbreak be the daytime-change night, a large amount of clinical observations find that be the high-incidence season of asthma morning; The situation of hypertension and myocardial infarction morbidity is also similar.Drug-supplying system discharges and onset between in due course by the control medicine when selecting, and can prevent and treat the outbreak of diseases such as asthma and myocardial infarction.Drug-delivery preparation does not generally discharge medicine immediately when selecting after entering human body, but through the one predefined period (time lag).Time lag is the key of this technology, and the most frequently used method is the purpose that reaches time lag by substrate or outer release-controlled film in the prescription design.The release technology has obtained very big development when selecting over past ten years, from film controlled release preparation the earliest, comprise: coating capsule, coated tablet, double-deck matrix tablet, osmotic pumps, and afterwards timing plug pulse capsule, pulse patch and subcutaneous implanted pulse agent, the mode of control time lag is more and more diversified.But except the peplos osmotic pumps, drug-supplying system adopted the pulsed administration when majority was selected, promptly after delay after a while, medicine discharges suddenly with the form of pulse, can't reach the purpose of controlling administration at the time lag after date, blood drug level rises and falls very big, and " peak valley " phenomenon is arranged.When blood drug level is high (peak), may exceeds the Cmax of treatment window (the blood drug level interval that refers to medicine performance curative effect) and have side effects, even cause poisoning; When blood drug level hangs down (paddy), may be lower than effective minimum treatment concentration, so that can not manifest curative effect, limit broad research and the application in this respect of this technology.Using the preparation of microencapsulation technology delays time---and controlled-release pharmaceutical formulation has broad application prospects, the research of drug microparticles preparation method is a lot of at present, the research of relevant drug microparticles coating also has report, but does not still have the report of oral administration delay-control release medicine micro balls preparation method.
Summary of the invention
The objective of the invention is: will control administration the time and the speed controlling administration combines, adopt a kind of technology new method simple, easy and control to prepare oral time-delay---the microgranule (microcapsule or microsphere) of controlled release verapamil hydrochloride, the treatment that this will help having the cardiovascular disease of daily rhythmicity reaches optimum curative effect and minimum untoward reaction.Add excipient substance, the formulation method by suitable also can be made into various oral controlled slow-release preparations.
The invention is characterized in that it contains following steps successively:
(1) forming described mouthful by following weight percent comparison delays time---and each component of controlled release verapamil hydrochloride microsphere is prepared burden:
Verapamil hydrochloride: 2.5~7.0%
Microencapsulation material: 15~32%
Coating material: 65~80%; Adjuvant, porogen or plasticizer or wetting agent or antiplastering aid: surplus;
(2) reach process conditions according to the following steps, with spray drying method for preparation verapamil hydrochloride microgranule; Be particle diameter the verapamil hydrochloride granule of 1~90 μ m and proper auxiliary materials by the total solids content dissolving of said ratio and following feed liquid or be suspended in the microencapsulation material solution of slow/controlled release effect, be made into homogeneous or homodisperse spray drying feed liquid; Then at 75kPa~250kPa nebulizer pressure, 55 ℃~140 ℃ inlet temperatures, 45 ℃~95 ℃ outlet temperatures, the charging rate of 4~12ml/min, 2.2 spray drying granulation under the condition of the total solids content of the feed liquid of~6.0% (weight/volume) is made the verapamil hydrochloride microgranule;
(3) reach process conditions according to the following steps, the verapamil hydrochloride microgranule is carried out coating, make oral with spray drying method
Time-delay---controlled release verapamil hydrochloride microsphere:
Under the condition of high-speed stirred, the verapamil hydrochloride microgranule that step (2) is made adds in the coating material solution and is uniformly dispersed, and obtains the spray drying feed liquid; Then at 20kPa~50kPa nebulizer pressure, 55 ℃~140 ℃ inlet temperatures, 45 ℃~95 ℃ outlet temperatures, the charging rate of 4~8ml/min, 3.0 under the condition of the total solids content of the feed liquid of~12% (weight/volume), make oral time-delay with spray drying method---controlled release verapamil hydrochloride microsphere.
Feature of the present invention is that also it contains following steps successively:
(1) forming described mouthful by following weight percent comparison delays time---and each component of controlled release verapamil hydrochloride microsphere is prepared burden:
Verapamil hydrochloride: 2.5~7.0%
Microencapsulation material: 15~32%
Coating material: 65~80%;
Adjuvant, porogen or plasticizer or wetting agent or antiplastering aid: surplus;
(2) reach process conditions according to the following steps, with spray drying method for preparation verapamil hydrochloride microgranule;
Be particle diameter the verapamil hydrochloride granule of 1~90 μ m and proper auxiliary materials by the total solids content dissolving of said ratio and following feed liquid or be suspended in the microencapsulation material solution of slow/controlled release effect, be made into homogeneous or homodisperse spray drying feed liquid; Then at 20kPa~75kPa nebulizer pressure, 55 ℃~140 ℃ inlet temperatures, 45 ℃~95 ℃ outlet temperatures, the charging rate of 4~12ml/min, 5.0 spray drying granulation under the condition of the total solids content of the feed liquid of~12% (weight/volume) is made the verapamil hydrochloride microgranule;
(3) reach process conditions according to the following steps with fluid bed granulation process, the verapamil hydrochloride microgranule that step (2) is made carries out coating, makes oral time-delay---controlled release verapamil hydrochloride microsphere:
By said ratio configuration coating material solution; Again medicine carrying microgranule being placed miniature fluid bed, is 0.5mm~1mm with end spray method at nozzle diameter, and the fluidisation air quantity is 100~150m 3/ h, inlet temperature is 35~55 ℃, and temperature is 30 ℃~40 ℃ in the bed, and atomizing pressure is 150kPa~200kPa, under hydrojet speed 1.2~2.4g/min process conditions, medicine carrying microgranule is carried out coating, makes oral time-delay---controlled release verapamil hydrochloride microsphere.
The present invention can delay time in external gastrointestinal tract model---and controlled release drug, the formulation method by suitable can be made into various oral formulations.
Advantage of the present invention is: will control administration the time and the speed controlling administration combines, use time-delay---the controlled release verapamil hydrochloride microgranule (microcapsule or microsphere) of this method preparation, it is controlled to have delay time, the characteristics that the verapamil hydrochloride rate of release is controlled, and technology is simple, easy and control, can produce by batch in a large number.
Description of drawings:
Fig. 1 a is the stereoscan photograph of embodiment 1.
The stereoscan photograph of Fig. 1 b embodiment 2
The cumulative in vitro release profiles of Fig. 2 embodiment 1,2
The specific embodiment:
Below in conjunction with embodiment the present invention is further illustrated, embodiment illustrates time-delay provided by the invention by adopting different microencapsulation prescription and technology---the preparation method of controlled release verapamil hydrochloride microgranule, but not only be confined to listed
Embodiment.
Embodiment 1:
The chitosan of verapamil hydrochloride-Eudragit RS100 microsphere (VPH/CS/RS100) composition
Verapamil hydrochloride 0.2g
Chitosan 2.0g
Eudragit?RS100 4.4g
0.1mol/L acetum 100ml
Ethyl acetate 220ml
Technology
1. verapamil hydrochloride and chitosan are dissolved in the acetum of 0.1mol/L, are made into uniform solution as spray-dired feed liquid.Spray-dired operating parameter is: 140 ℃ of hot-air inlets temperature, hot blast rate 0.7m 3/ min, 95 ℃ of outlet temperatures, feed rate 12mL/min, atomisation pressure 250kPa.
2. Eudragit RS100 is dissolved in and is made into 2% solution in the ethyl acetate.Under the condition of high-speed stirred, in the chitosan microball adding solution with verapamil hydrochloride, be uniformly dispersed.With the feed liquid spray drying that obtains, operating parameter is: 80 ℃ of hot-air inlets temperature, hot blast rate 0.5m 3/ min, 65 ℃ of outlet temperatures, feed rate 8mL/min, atomisation pressure 50kPa.
The release in vitro degree is measured
Adopt the device of dissolution method (2000 editions two appendix XC second methods of Chinese Pharmacopoeia), according to drug release determination method (2000 editions two appendix XD first methods of Chinese Pharmacopoeia), with water 900ml is solvent, and rotating speed is 100r/min, and the microsphere that makes is carried out drug release determination.In each time point sampling, adopt ultraviolet spectrometry light photometry to measure trap respectively, and calculate burst size at the wavelength of 268nm.
Release in vitro result
Delay time 4h
Controlled release time 20h
Linear coefficient R of controlled release stage 2=0.9973
Embodiment 2:
Verapamil hydrochloride cellulose acetate-Eudragit RS100 microsphere (VPH/CA/RS100)
Composition
Verapamil hydrochloride 0.6g
Cellulose acetate 2.4g
PEG1500 0.06g
Eudragit?RS100 6.0g
Ethyl acetate 50ml
Ethanol 75ml
Technology
1. cellulose acetate and PEG1500 are dissolved in the ethyl acetate, are made into homogeneous solution.Under the condition of high-speed stirred, verapamil hydrochloride is joined in the ethyl acetate solution of cellulose acetate, make spray-dired feed liquid.Spray-dired operating parameter is: 55 ℃ of hot-air inlets temperature, hot blast rate 0.7m 3/ min, 45 ℃ of outlet temperatures, feed rate 4mL/min, atomisation pressure 75kPa.
2. Eudragit RS100 is dissolved in and is made into 8% solution in the ethanol.Under the condition of high-speed stirred, in the cellulose acetate microcapsule adding solution with verapamil hydrochloride, be uniformly dispersed.With the feed liquid spray drying that obtains, operating parameter is: 70 ℃ of hot-air inlets temperature, hot blast rate 0.5m 3/ min, 55 ℃ of outlet temperatures, feed rate 4mL/min, atomisation pressure 20kPa.
The release in vitro degree is measured
With embodiment 1
Release in vitro result
Delay time 4h
Controlled release time 20h
Linear coefficient R of controlled release stage 2=0.9985
Embodiment 3:
The chitosan of verapamil hydrochloride-Eudragit RS100 microsphere (VPH/CS/RS100)
Composition
Verapamil hydrochloride 0.5g
Chitosan 2.0g
Eudragit?RS100 10.0g
Triethyl citrate 0.5g
0.1mol/L acetum 50ml
Acetone 200ml
Technology
1. verapamil hydrochloride and chitosan are dissolved in the acetum of 0.1mol/L, are made into uniform solution as spray-dired feed liquid.Spray-dired operating parameter is: 140 ℃ of hot-air inlets temperature, hot blast rate 0.7m 3/ min, 95 ℃ of outlet temperatures, feed rate 12mL/min, atomisation pressure 75kPa.
2. Eudragit RS100 and triethyl citrate are dissolved in and are made into the solution that contains polymer 5% in the acetone.Medicine carrying microballoons is placed miniature fluid bed, and coating adopts end spray method, nozzle diameter 0.5mm, fluidisation air quantity 150m 3H -1, 35 ℃ of inlet temperature, temperature 30 in the bed, atomizing pressure 150kPa, hydrojet speed 2.4gmin -1
Release in vitro result
Delay time 6h
Controlled release time 8h
Linear coefficient R of controlled release stage 2=0.9987
Embodiment 4:
Verapamil hydrochloride cellulose acetate-EudragiIt RSl00 microsphere (VPH/CA/RSl00)
Composition
Verapamil hydrochloride 1.2g
Cellulose acetate 4.8g
PEG1500 0.12g
Eudragit RSl00 aqueous dispersion (polymer content 30%) 40ml
Ethyl acetate 50ml
Distilled water 80ml
Technology
L. cellulose acetate and PEG1500 are dissolved in the ethyl acetate, are made into homogeneous solution.Under the condition of high-speed stirred, verapamil hydrochloride is joined in the ethyl acetate solution of cellulose acetate, make spray-dired feed liquid.Spray-dired operating parameter is: 55 ℃ of hot-air inlets temperature, hot blast rate 0.7m 3/ min, 45 ℃ of outlet temperatures, feed rate 4mL/min, atomisation pressure 20kPa.
2. medicine carrying microballoons is placed miniature fluid bed, it is 10% coating solution that Eudragit RS100 aqueous dispersion (polymer content 30%) is diluted with water to polymer content, and coating adopts end spray method, nozzle diameter 0.5mm, fluidisation air quantity 100m 3H -1, 55 ℃ of inlet temperature, temperature is 40 ℃ in the bed, atomizing pressure 200kPa, hydrojet speed 1.2gmin -1
The release in vitro degree is measured
With embodiment 1
Release in vitro result
Delay time 6h
Controlled release time 18h
Linear coefficient R of controlled release stage 2=0.9998

Claims (2)

1. oral time-delay---the preparation method of controlled release verapamil hydrochloride microsphere is characterized in that it contains following steps successively:
(1) described oral time-delay---each component of controlled release verapamil hydrochloride microsphere is prepared burden by following weight percent comparison composition:
Verapamil hydrochloride: 2.5~7.0%
Microencapsulation material: 15~32%
Coating material: 65~80%;
Adjuvant, porogen or plasticizer or wetting agent or antiplastering aid: surplus;
(2) reach process conditions according to the following steps, use spray drying method for preparation verapamil hydrochloride microgranule:
Be particle diameter the verapamil hydrochloride granule of 1~90 μ m and proper auxiliary materials by the total solids content dissolving of said ratio and following feed liquid or be suspended in the microencapsulation material solution of slow/controlled release effect, be made into homogeneous or homodisperse spray drying feed liquid; Then at 75kPa~250kPa nebulizer pressure, 55 ℃~140 ℃ inlet temperatures, 45 ℃~95 ℃ outlet temperatures, the charging rate of 4~12ml/min, 2.2 spray drying granulation under the condition of the total solids content of the feed liquid of~6.0% weight/volume is made the verapamil hydrochloride microgranule;
(3) reach process conditions according to the following steps, the verapamil hydrochloride microgranule carried out coating, make oral time-delay with spray drying method---controlled release verapamil hydrochloride microsphere:
Under the condition of high-speed stirred, the verapamil hydrochloride microgranule that step (2) is made adds in the coating material solution and is uniformly dispersed, and obtains the spray drying feed liquid; Then at 20kPa~50kPa nebulizer pressure, 55 ℃~140 ℃ inlet temperatures, 45 ℃~95 ℃ outlet temperatures, the charging rate of 4~8ml/min, 3.0 under the condition of the total solids content of the feed liquid of~12% weight/volume, make oral time-delay with spray drying method---controlled release verapamil hydrochloride microsphere.
2. oral time-delay---the preparation method of controlled release verapamil hydrochloride microsphere is characterized in that it contains following steps successively:
(1) forming described mouthful by following weight percent comparison delays time---and each component of controlled release verapamil hydrochloride microsphere is prepared burden:
Verapamil hydrochloride: 2.5~7.0%
Microencapsulation material: 15~32%
Coating material: 65~80%;
Adjuvant, porogen or plasticizer or wetting agent or antiplastering aid: surplus;
(2) reach process conditions according to the following steps, use spray drying method for preparation verapamil hydrochloride microgranule:
Be particle diameter the verapamil hydrochloride granule of 1~90 μ m and proper auxiliary materials by the total solids content dissolving of said ratio and following feed liquid or be suspended in the microencapsulation material solution of slow/controlled release effect, be made into homogeneous or homodisperse spray drying feed liquid; Then at 20kPa~75kPa nebulizer pressure, 55 ℃~140 ℃ inlet temperatures, 45 ℃~95 ℃ outlet temperatures, the charging rate of 4~12ml/min, 5.0 spray drying granulation under the condition of the total solids content of the feed liquid of~12% weight/volume is made the verapamil hydrochloride microgranule;
(3) reach process conditions according to the following steps with fluid bed granulation process, the verapamil hydrochloride microgranule that step (2) is made carries out coating, makes oral time-delay---controlled release verapamil hydrochloride microsphere:
By said ratio configuration coating material solution; Again medicine carrying microgranule being placed miniature fluid bed, is 0.5mm~1mm with end spray method at nozzle diameter, and the fluidisation air quantity is 100~150m 3/ h, inlet temperature is 35~55 ℃, and temperature is 30 ℃~40 ℃ in the bed, and atomizing pressure is 150kPa~200kPa, under hydrojet speed 1.2~2.4g/min process conditions, medicine carrying microgranule is carried out coating, makes oral time-delay---controlled release verapamil hydrochloride microsphere.
CN 200410068840 2004-07-09 2004-07-09 Method for producing oral administration delay-control release medicine micro balls Expired - Fee Related CN1245956C (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN 200410068840 CN1245956C (en) 2004-07-09 2004-07-09 Method for producing oral administration delay-control release medicine micro balls

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN 200410068840 CN1245956C (en) 2004-07-09 2004-07-09 Method for producing oral administration delay-control release medicine micro balls

Publications (2)

Publication Number Publication Date
CN1586460A CN1586460A (en) 2005-03-02
CN1245956C true CN1245956C (en) 2006-03-22

Family

ID=34604174

Family Applications (1)

Application Number Title Priority Date Filing Date
CN 200410068840 Expired - Fee Related CN1245956C (en) 2004-07-09 2004-07-09 Method for producing oral administration delay-control release medicine micro balls

Country Status (1)

Country Link
CN (1) CN1245956C (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1879606B (en) * 2006-05-02 2011-12-14 沈阳药科大学 Preparation of novel drug delivery system based on liquid spray method
CN103520115B (en) * 2013-09-27 2015-04-22 内蒙古医科大学 Verapamil hydrochloride sustained release microsphere and preparation method thereof

Also Published As

Publication number Publication date
CN1586460A (en) 2005-03-02

Similar Documents

Publication Publication Date Title
RU2240786C2 (en) Peroral medicinal formulations with sustained-release effect
EP1976489B1 (en) Multiple unit type sustained release oral formulation comprising zaltoprofen and process for the preparation thereof
CN1625390A (en) Multi-stage oral drug controlled-release system
CN1630513A (en) Hydrodynamically balancing oral drug delivery system with biphasic release
CN1923184A (en) Multiple apertures releasing osmosis pump and preparation process thereof
CN1531420A (en) Pharmaceutical formulation for efficient administration of apomorphine, 6aR-(-)-N-propyl-norepomorphine and their derivatives and pro-drugs thereof
CN1491105A (en) Novel modified released formulation
CN100350913C (en) Colonic release composition
CN1744889A (en) Controlled release pharmaceutical compositions of tamsulosin
CN1186014C (en) Multiparticulate pharmaceutical form with programmed and timed release and preparation method
JPH09194348A (en) Persistent animal growth hormone preparation and its production
CN1245956C (en) Method for producing oral administration delay-control release medicine micro balls
CN1682696A (en) Timing slow-releasing micrpill and its preparation
CN101032462A (en) Mexiletine Hydrochloride slow release reagent and preparing method thereof
CN1435261A (en) Thermosetting medical carrier composition with mucosa adsorption
CN1634116A (en) Stavudine sustained release tablet and its preparing process
CN1758903A (en) Enteric sustained-release fine particles for tamsulosin or its salt and process for producing the same
CN1919197A (en) Slow release drop pills comprising toraesmide active ingredient and method for preparing same
CN1274295C (en) Method for preparing oral slow/coutrolled release medicinal micro granule
CN1568954A (en) Mesalazine colon target releasing micro pills and preparation method thereof
CN1887278A (en) Slow released doxazosin mesilate capsule and its prepn process
CN1259040C (en) Albuterol time controlling pulse slow release oral preparation and its preparation method
CN1895250A (en) Gliquilone slow-releasing preparation
CN1234361C (en) Method for preparing medicine of levo-stephandinine
CN1543953A (en) Colon targeted fluorouracil minipills prepartion

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
C17 Cessation of patent right
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20060322

Termination date: 20120709