CN1935264B - HPMC-polyhydric alcohol composite auxiliary material for slow-release tablet - Google Patents
HPMC-polyhydric alcohol composite auxiliary material for slow-release tablet Download PDFInfo
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- CN1935264B CN1935264B CN 200510105312 CN200510105312A CN1935264B CN 1935264 B CN1935264 B CN 1935264B CN 200510105312 CN200510105312 CN 200510105312 CN 200510105312 A CN200510105312 A CN 200510105312A CN 1935264 B CN1935264 B CN 1935264B
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Abstract
The present invention relates to a compound of HPMC-polyalcohol for gel skeleton slow release tablet. It is characterized by that the HPM and polyalcohol are mixed and made into a suspension, then the solvent is dried by means of spray-drier so as to obtain the invented new compound auxiliary material for preparing slowly-controlled release preparation.
Description
Invention field
The present invention relates to a kind of HPMC-polyhydric alcohol NEW TYPE OF COMPOSITE adjuvant that is used for sustained-release preparation, be specially adapted to the preparation of slow-release tablet, overcome the defective of HPMC as slow-release material.
Background technology
HPMC is a white or milky is fibrous or the graininess flowing powder, odorless, tasteless, and dissolving forms colloid solution clear and bright or that milky has viscosity in water, is insoluble to ethanol chloroform and ether, dissolves in the mixed solvent of methanol and chloromethanes.Content according to methoxyl group and hydroxypropyl is different, and HPMC can be divided into different grades, and various grades are divided into multiple viscosity specification again, wherein one of HPMC the most widely purposes be preparation gel slow-release tablet.
Meeting water surface with the hydrogel matrix tablet of HPMC preparation and form the hydrophilic gel layer, is the essential condition of control drug release.The factor that influences drug releasing rate comprises that (the Higuchi rate of release that discharges and the inverse of HPMC hydration rate are good linear relationship to the grade of HPMC, and viscosity is high more, and linear relationship is good more from the HPMC skeleton.The content of hydrophilic group propoxyl is the principal element of decision HPMC hydration rate) and the viscosity of HPMC (speed that medicine discharges from HPMC reduces along with the increase of viscosity.The hydrogel layer viscosity that high viscosity HPMC forms is big, thereby medicine descends by gel layer speed, and the corrosion speed of gel layer is also slack-off.)
Often adopting traditional wet granulation technology in the middle of the process of preparation slow releasing tablet, is that the powder mixes of medicine and adjuvant is evenly added liquid adhesive and prepares particulate method in the back.This method relies on the effect of binding agent to make and produces adhesion between powder particle.Because the granule of wet granulation has advantages such as good looking appearance, good fluidity, wearability are strong, compression molding is good, is the method that is most widely used in medical industry.
Get in the process in preparation hydrogel slow releasing tablet, with the alcoholic solution of the finite concentration ethanol water of binding agent such as HPMC or ethanol water or polyvidone as wetting agent.But because HPMC is for meeting the sticking macromolecular material of waterishlogging, therefore, in the process that adopts aqueous binding agent or wetting agent to granulate, owing to excite the viscosity of HPMC in the material, thus produce the agglomerating situation of bonding in the process that quick stirring is granulated.Not only this agglomerating bulky grain can not separate in the process that stirs fast, but stirs solid more, final dry and become the very big granule of hardness more.This granule is difficult to leak down from screen cloth in the process of granulating of sieving, thereby cause sieving back prescription reality variation has taken place: the local loose particles that adhesive distribution is less, and powder is more, sieves easily; The more local granule of binding agent is hard, and particle shape is better, is difficult to sieve.Therefore, carry out suitability for industrialized production process in have this following problem:
At first, screening back prescription composition changes.Because the equipment and instrument scale that research of laboratory lab scale and amplification are produced is different, therefore, the amount that adds binding agent aborning can't increase according to lab scale experiment geometric ratio fully, and granulation situation and soft material situation and lab scale experiment are not quite similar.Therefore, particulate actual prescription of gained and lab scale relatively have tangible difference, thereby cause obtaining aborning and identical granule during lab scale is tested, and then cause release behavior generation obvious variation behind the tabletting.In the face of this situation, manufacturer can only readjust prescription on original basis, be equivalent to the research of writing out a prescription again, causes bigger waste on commercial production.
Second, tablet weight variation is big. because soft material is more sticking, binding agent can't be in the process of granulating uniform distribution, granule differs greatly, the Density Distribution inequality, the tabletting tablet weight variation is big. and according to of the requirement of Chinese Pharmacopoeia version in 2005, often cause the result defective about tablet weight variation. for manufacturer, sheet is heavily defective to cause occurring useless sheet, and the quality of product also has been subjected to influence.
The 3rd, the alcoholic solution of employing polyvidone is granulated and can be avoided water to excite the problem of HPMC viscosity, but because PVP itself belongs to hydrophilic substance, can improve the release of medicine, therefore how many direct release behaviors that influence medicine that add binding agent, in the middle of process of the test, face dilemma: from granulate considering, still consider that from the release behavior of medicine PVP's is good forever.In addition, lab scale test is with to amplify the equipment of producing different, instrument scale difference, so the use amount of binding agent is different with ratio, therefore, the release that adopts PVP to granulate inevitably to have influence on medicine and in process of production popularization exists all difficulties.
In view of some above reasons, there is bibliographical information to adopt technique of direct powder compression to prepare the HPMC slow releasing tablet.The 34th the 10th phase of volume of " Chinese Pharmaceutical Journal " October in 1999, the hydrogel matrix slow releasing tablet of aspirin adopts pressed powder prepared sustained-release matrix tablets in " research of aspirin HPMC matrix tablet drug release factor "; Mention the preparation of adopting direct powder compression to write out a prescription in " Chinese Pharmaceutical Journal " calendar year 2001 JIUYUE the 36th volume the 9th phase " development and the release influence factor of hydroxypropyl emthylcellulose-carbopol slow release hydrogel matrix tablet " literary composition.Mention employing technique of direct powder compression in volume the 6th phase " the drug release Study on influencing factors of the doxofylline HPMC matrix tablet " literary composition " Shenyang Pharmaceutical University's journal " June the 17th in 2000.Adopt the described method of above-mentioned document to test, find that there is following problem in the HPMC direct powder compression:
At first, particulate flowability is poor.The size of measuring the angle of repose of finding mixed-powder angle of repose and prescription through powder are formed closely related.In the prescription of gel rubber sustained-release, two filleies through being usually used in regulating drug release rate are respectively lactose and calcium hydrogen phosphate.HPMC is little as the slow particle diameter of controlled-release material own, thereby mobile relatively poor, though the flowability of calcium hydrogen phosphate better, and the flowability of common 200 purpose lactose monohydrates is poor; Consider the content of prescription Chinese medicine and the character of drug powder, HPMC generally spent greater than 40 with the angle of repose that other compositions that comprise principal agent mix the mixture of back gained.For common rotary tablet machine, particulate flowability is most important.Find through overtesting, adopt ZP-19 type tablet machine, if then cause sheet heavy unstable in the punch die greater than 40 degree particulate angle of repose owing to powder has little time to be filled into.
The second, because content of powder is many, increase in addition and specific surface area is long-pending, therefore, a spot of lubricant and fluidizer are difficult to play effect, for example, adopt magnesium stearate 1% as lubricant, puckery dashing and unilateral coarse situation still occur.In suitability for industrialized production, puckery dashing not only damaged drift and punch die easily, and causes wearing and tearing for the track of rotary tablet machine.The appearance character of slice, thin piece is stable also most important for product quality, coarsely unilaterally causes wearing and tearing easily and causes sheet heavily to descend.
The 3rd, because the restriction of working condition, the production security of full pressed powder is relatively poor.A large amount of airborne dusts in the tablet manufacturing workshop, powder has higher energy, and friction produces and accumulation static under dry environment, might cause that static is a large amount of to be discharged and set off an explosion.
The 4th, full pressed powder is unfavorable to labor protection.As everyone knows, the solid workshop exists a large amount of respirable dusts that workshop workman healthy caused huge threat.Respirable dust can't be discharged and the initiation respiratory tract disease from pulmonary.
Because HPMC self adopts pressed powder can not fully overcome the problem that HPMC exists.The present invention, combines two kinds of complementary compositions of characteristics based on the adjuvant collocating principle in order to solve the problem that exists in HPMC wet granulation and the pressed powder, overcomes the problem that HPMC may occur as slow controlled-release material.
Summary of the invention
In preparation gel slow-release tablet, often use the water-soluble polyol lactose as porogen, but 200 purpose polyhydric alcohol flowabilities are not good, angle of repose is greater than 40 degree. and the consumption of two kinds of compositions of polyhydric alcohol and HPMC in prescription can reach more than 50% of whole recipe quantity, thereby these two kinds of compositions cause whole particle mobile poor. and the beat all discovery of the present invention can obtain two kinds of bad adjuvants of flowability through the processing of suitable combination and special process the graininess HPMC-polyhydric alcohol NEW TYPE OF COMPOSITE adjuvant of good fluidity. and this adjuvant improves the flowability of HPMC, can be used for direct compression, the change of component of sieving of not only having avoided wet granulation to cause, granular size is uneven and tablet weight variation that cause is big and use PVP to granulate to the interference of release behavior, and has avoided puckery the dashing that the powder flowbility difference causes in the direct powder compression process, sheet is heavy unstable, outward appearance is coarse, the problem that dust is too much.
The prepared HPMC-polyhydric alcohol compound of the present invention has following characteristics:
(1) HPMC and polyhydric alcohol form finely dispersed granule with physics mode.
(2) the particulate method characteristics of preparation are earlier HPMC and polyhydric alcohol be uniformly dispersed in suitable solvent and obtain behind the spray drying solvent flashing of back.
(3) mass ratio of HPMC and polyhydric alcohol is between 1: 0.1～1: 10.
(4) spray drying prepares the viscosity that the employed solvent of HPMC-polyhydric alcohol composite does not excite polyhydric alcohol and HPMC.
HPMC of the present invention is high viscosity HPMC, and viscosity can be used for slow-release material more than 2000mPa*s.Its model is selected from the HPMC K 4M (viscosity is at 2000mPa*s) that DOW Chemical is produced, HPMC K 15M (viscosity is at 5000mPa*s), HPMC K 100M (viscosity is at 10000mPa*s), the combination of one or more of HPMC E4 M (viscosity is at 6000mPa*s).
Polyhydric alcohol of the present invention includes but not limited to following polyhydric alcohol: the combination of one or more in lactose, sucrose, glucose, fructose, sorbitol, mannitol, the xylitol.
Disperse the dispersion solvent of HPMC to be selected from: one or more of ethanol, acetone, propanol, chloroform.These solvents do not dissolve HPMC and polyhydric alcohol, do not excite the viscosity of HPMC, can rapid evaporation in spray-dired process.The ratio of HPMC and the polyhydric alcohol solid content in suspension is 10%～30%.If solid content is lower than 10%, the particulate formability of gained is bad so; If solid content is higher than 30%, cause the obstruction of nozzle so easily.
The optimum ratio of HPMC of the present invention and polyhydric alcohol is 1/0.1～1/10.The ratio of polyhydric alcohol and HPMC changes according to the water solublity of crude drug.Be higher than 1/0.1 release that also needs to add big weight polyalcohol raising medicine from the effect HPMC of slow releasing tablet and the ratio of polyhydric alcohol, be lower than 1/10 and then do not have due slow-releasing and controlled-releasing action.
Preparation technology of the present invention is characterised in that: HPMC and polyhydric alcohol are dispersed in the solvent, obtain the suspension of HPMC and polyhydric alcohol, the gained suspension enters spray drying device and granulates under the state that stirs, the speed and the exsiccant temperature of control rotation, obtain the granule of particle diameter between the 40-100 order, reclaim solvent, collecting granules gets final product.
With HPMC with comprise that the polyhydric alcohol preparation of lactose becomes the problems that the HPMC-polyhydric alcohol compound can avoid pressed powder and wet granulation to exist:
(1) avoids the wet granulation difficulty of sieving.
(2) avoid the wet granulation sheet heavy unstable.
(3) avoid wet granulation release behavior instability.
(4) flowability problem of avoiding pressed powder to exist.
(5) avoid the puckery problem of dashing of pressed powder.
(6) avoid the heavy problem of unstable of sheet.
The specific embodiment
Following examples are used to illustrate the present invention but are not limited to the present invention.
Embodiment 1
HPMC-lactose complex prescription
Preparation technology:
HPMC K4M CR and lactose are dispersed in the recipe quantity solvent, get suspension, suspension enters spray drying device and granulates under the state that stirs, the speed of control control rotation is 115 degrees centigrade of 300Hz and exsiccant temperature, high and dry, obtain the granule of particle diameter between the 40-100 order, reclaim solvent, collecting granules gets final product.
The felodipine sustained-release tablets of employing HPMC-lactose spray-dried granules direct compression and employing HPMC and the every every index with the employing wet granulation of lactose powder direct compression compare (n=50)
Prescription
| Supplementary material | mg/unit |
| Felodipine | 2.5 |
| The HPMC-polyhydric alcohol compound | 100 |
| Lactose | 20 |
| PVP K 30 | 8 |
| Magnesium stearate | 2 |
| TOTAL | 132.5mg |
Technology:
1 with supplementary material mix homogeneously in the three-dimensional blender machine.
2ZP-19 rotary tablet machine tabletting.
Heavy and the hardness of 3 detection lugs.
4 testing results such as following table.
Conclusion: adopt HPMC-lactose spray-dried granules direct compression and compare with wet granulation with HPMC and lactose powder direct compression, tablet weight variation has significant difference (p＜0.01); Adopt HPMC-lactose spray-dried granules direct compression and with HPMC and lactose powder direct compression by significant difference (p＜0.01).
Embodiment 2
HPMC-lactose complex prescription
Preparation technology:
HPMC K4M CR and lactose are dispersed in the recipe quantity solvent, get suspension, suspension enters spray drying device and granulates under the state that stirs, the speed of control control rotation is 115 degrees centigrade of 300Hz and exsiccant temperature, high and dry, obtain the granule of particle diameter between the 40-100 order, reclaim solvent, collecting granules gets final product.
The felodipine sustained-release tablets of employing HPMC-lactose spray-dried granules direct compression and employing HPMC and the every every index with the employing wet granulation of lactose powder direct compression compare (n=50)
Conclusion: adopt HPMC-lactose spray-dried granules direct compression and compare with wet granulation with HPMC and lactose powder direct compression, tablet weight variation has significant difference (p＜0.01); Adopt HPMC-lactose spray-dried granules direct compression and with HPMC and lactose powder direct compression by significant difference (p＜0.01).
Embodiment 3
HPMC-lactose complex prescription
Preparation technology:
HPMC K4M CR and lactose are dispersed in the recipe quantity solvent, get suspension, suspension enters spray drying device and granulates under the state that stirs, the speed of control control rotation is 115 degrees centigrade of 300Hz and exsiccant temperature, high and dry, obtain the granule of particle diameter between the 40-100 order, reclaim solvent, collecting granules gets final product.
The felodipine sustained-release tablets of employing HPMC-lactose spray-dried granules direct compression and employing HPMC and the every every index with the employing wet granulation of lactose powder direct compression compare (n=50)
Conclusion: adopt HPMC-lactose spray-dried granules direct compression and compare with wet granulation with HPMC and lactose powder direct compression, tablet weight variation has significant difference (p＜0.01); Adopt HPMC-lactose spray-dried granules direct compression and with HPMC and lactose powder direct compression by significant difference (p＜0.01).
Embodiment 4
HPMC-sorbitol complex prescription
Preparation technology:
HPMC K100M CR and sorbitol are dispersed in the recipe quantity solvent, get suspension, suspension enters spray drying device and granulates under the state that stirs, the speed of control control rotation is 125 degrees centigrade of 300Hz and exsiccant temperature, high and dry, obtain the granule of particle diameter between the 40-100 order, reclaim solvent, collecting granules gets final product.
The piribedil slow releasing tablet of employing HPMC-sorbitol spray-dried granules direct compression and employing HPMC and the every every index with the employing wet granulation of lactose powder direct compression compare (n=50)
Conclusion: adopt HPMC-sorbitol spray-dried granules direct compression and compare with wet granulation with HPMC and sorbitol powder direct compression, tablet weight variation has significant difference (p＜0.01); Adopt HPMC-sorbitol spray-dried granules direct compression and with HPMC and sorbitol powder direct compression by significant difference (p＜0.01).
Embodiment 5
HPMC-mannitol complex prescription
Preparation technology:
HPMC K15M CR and mannitol are dispersed in the recipe quantity solvent, get suspension, suspension enters spray drying device and granulates under the state that stirs, the speed of control control rotation is 110 degrees centigrade of 300Hz and exsiccant temperature, high and dry, obtain the granule of particle diameter between the 40-100 order, reclaim solvent, collecting granules gets final product.
The felodipine sustained-release tablets of employing HPMC-mannitol spray-dried granules direct compression and employing HPMC and the every every index with the employing wet granulation of mannitol direct powder compression compare (n=50)
Conclusion: adopt HPMC-mannitol spray-dried granules direct compression and compare with wet granulation with HPMC and mannitol direct powder compression, tablet weight variation has significant difference (p＜0.01); Adopt HPMC-mannitol spray-dried granules direct compression and with HPMC and mannitol direct powder compression by significant difference (p＜0.01).
Embodiment 6
HPMC-mannitol complex prescription
Preparation technology:
HPMC E 4M CR and mannitol are dispersed in the recipe quantity solvent, get suspension, suspension enters spray drying device and granulates under the state that stirs, the speed of control control rotation is 115 degrees centigrade of 300Hz and exsiccant temperature, high and dry, obtain the granule of particle diameter between the 40-100 order, reclaim solvent, collecting granules gets final product.
The felodipine sustained-release tablets of employing HPMC-mannitol spray-dried granules direct compression and employing HPMC and the every every index with the employing wet granulation of mannitol direct powder compression compare (n=50)
Conclusion: adopt HPMC-mannitol spray-dried granules direct compression and HPMC and mannitol direct powder compression to compare with wet granulation, tablet weight variation has significant difference (p＜0.01); Adopt HPMC-mannitol spray-dried granules direct compression and with HPMC and mannitol direct powder compression by significant difference (p＜0.01).
Claims (2)
1. NEW TYPE OF COMPOSITE adjuvant that contains HPMC that is used for slow-release tablet, it is characterized in that: by viscosity more than 2000mPas HPMC and in lactose, sorbitol or the mannitol one or more according to mass ratio be 1: 0.1～1: 10 in solvent homodisperse form suspension, form granule behind the spray-dried solvent, wherein the ratio of one or more solid contents in suspension in HPMC and lactose, sorbitol or the mannitol is 10%-30%, and solvent is selected from one or more in ethanol, acetone, propanol, the chloroform.
2. the application of the described composite auxiliary material of claim 1 in the preparation slow-release tablet.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510105312 CN1935264B (en) | 2005-09-23 | 2005-09-23 | HPMC-polyhydric alcohol composite auxiliary material for slow-release tablet |
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| Application Number | Priority Date | Filing Date | Title |
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| CN 200510105312 CN1935264B (en) | 2005-09-23 | 2005-09-23 | HPMC-polyhydric alcohol composite auxiliary material for slow-release tablet |
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| Publication Number | Publication Date |
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| CN1935264A CN1935264A (en) | 2007-03-28 |
| CN1935264B true CN1935264B (en) | 2010-05-05 |
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| CN 200510105312 Expired - Fee Related CN1935264B (en) | 2005-09-23 | 2005-09-23 | HPMC-polyhydric alcohol composite auxiliary material for slow-release tablet |
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| CN110896969B (en) * | 2018-09-17 | 2021-12-14 | 中国医学科学院药用植物研究所 | Green slow-release disinfection effervescent tablet and preparation method thereof |
| CN114504580B (en) * | 2021-12-28 | 2024-04-16 | 湖南醇健制药科技有限公司 | Method for preparing ursodeoxycholic acid preparation in large scale |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1216467A (en) * | 1996-04-23 | 1999-05-12 | 詹森药业有限公司 | Immediate release PH-independent solid dosage form of cisapride |
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- 2005-09-23 CN CN 200510105312 patent/CN1935264B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1216467A (en) * | 1996-04-23 | 1999-05-12 | 詹森药业有限公司 | Immediate release PH-independent solid dosage form of cisapride |
Non-Patent Citations (4)
| Title |
|---|
| Estrada FL et. al.."Study of load capacity of Avicel PH-200 and Cellactose, twodirect compression excipients, using experimental design".Drug Dev. Ind. Pharm.vol 26 no 4.2000,vol 26(no 4),465-469. |
| Estrada FL et.al.."Study of load capacity of Avicel PH-200 and Cellactose,twodirect compression excipients,using experimental design".Drug Dev.Ind.Pharm.vol 26 no 4.2000,vol 26(no 4),465-469. * |
| Nachaegari SK et.al.."Coprocessed excipients for solid dosage forms".Pharmaceutiacl Technologyvol. 28 No.1.2004,vol. 28(No.1),52-64. * |
| NachaegariSKet.al.."Coprocessedexcipientsforsoliddosageforms".PharmaceutiaclTechnologyvol.28No.1.2004 vol. 28(No. 1) |
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