CN102764239B - Propylthiouracil sustained release pellet - Google Patents
Propylthiouracil sustained release pellet Download PDFInfo
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- CN102764239B CN102764239B CN 201210280753 CN201210280753A CN102764239B CN 102764239 B CN102764239 B CN 102764239B CN 201210280753 CN201210280753 CN 201210280753 CN 201210280753 A CN201210280753 A CN 201210280753A CN 102764239 B CN102764239 B CN 102764239B
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- KNAHARQHSZJURB-UHFFFAOYSA-N Propylthiouracile Chemical compound CCCC1=CC(=O)NC(=S)N1 KNAHARQHSZJURB-UHFFFAOYSA-N 0.000 title claims abstract description 56
- 229960002662 propylthiouracil Drugs 0.000 title claims abstract description 56
- 239000008188 pellet Substances 0.000 title claims abstract description 15
- 238000013268 sustained release Methods 0.000 title claims abstract description 12
- 239000012730 sustained-release form Substances 0.000 title claims abstract description 12
- 238000002360 preparation method Methods 0.000 claims abstract description 23
- 229920001249 ethyl cellulose Polymers 0.000 claims abstract description 20
- 235000019325 ethyl cellulose Nutrition 0.000 claims abstract description 20
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 19
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 19
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 19
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 19
- 239000001856 Ethyl cellulose Substances 0.000 claims abstract description 18
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000000463 material Substances 0.000 claims abstract description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 239000011230 binding agent Substances 0.000 claims description 10
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 8
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 7
- 239000007779 soft material Substances 0.000 claims description 6
- 229920002472 Starch Polymers 0.000 claims description 4
- 238000005563 spheronization Methods 0.000 claims description 4
- 239000008107 starch Substances 0.000 claims description 4
- 235000019698 starch Nutrition 0.000 claims description 4
- 102220487426 Actin-related protein 2/3 complex subunit 3_K15M_mutation Human genes 0.000 claims description 3
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 2
- 229920002125 Sokalan® Polymers 0.000 claims description 2
- 229960001631 carbomer Drugs 0.000 claims description 2
- 239000007921 spray Substances 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 40
- 229940079593 drug Drugs 0.000 abstract description 26
- 239000006187 pill Substances 0.000 abstract description 24
- 230000000694 effects Effects 0.000 abstract description 15
- 238000011068 loading method Methods 0.000 abstract description 9
- 238000000465 moulding Methods 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 231100000331 toxic Toxicity 0.000 abstract description 4
- 230000002588 toxic effect Effects 0.000 abstract description 4
- 230000003578 releasing effect Effects 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- 239000002671 adjuvant Substances 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 239000013558 reference substance Substances 0.000 description 6
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000000853 adhesive Substances 0.000 description 4
- 230000001070 adhesive effect Effects 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 230000001186 cumulative effect Effects 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 229960004667 ethyl cellulose Drugs 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 230000004907 flux Effects 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000003200 antithyroid agent Substances 0.000 description 2
- 229940043671 antithyroid preparations Drugs 0.000 description 2
- 230000007797 corrosion Effects 0.000 description 2
- 238000005260 corrosion Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000007599 discharging Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- -1 hydroxypropyl Chemical group 0.000 description 2
- 238000012417 linear regression Methods 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- HPJCTUJOHKGFNI-UHFFFAOYSA-N 1-propyl-2-sulfanylidenepyrimidin-4-one Chemical compound CCCN1C=CC(=O)NC1=S HPJCTUJOHKGFNI-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 206010053155 Epigastric discomfort Diseases 0.000 description 1
- 206010070840 Gastrointestinal tract irritation Diseases 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007872 degassing Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012982 microporous membrane Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 238000005453 pelletization Methods 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
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Abstract
本发明提供了一种丙硫氧嘧啶缓释微丸，它由如下重量配比的原辅料制备而成：丙硫氧嘧啶40-65份、乙基纤维素10-25份、微晶纤维素25-50份。本发明还提供了缓释微丸的制备方法和用途。本发明缓释微丸，通过对辅料种类及用量的优选，能够在保证微丸良好成型效果的同时，使其在12h内达到理想的缓释效果，有效避免了药物的峰谷现象，且微丸表面积较大，降低了药物的毒副作用；同时，本发明处方中，PTU载药量达到了65%，较大的载药量有效地降低了辅料用量，显著降低了生产成本。
The invention provides a propylthiouracil sustained-release pellet, which is prepared from the following raw and auxiliary materials in the weight ratio: 40-65 parts of propylthiouracil, 10-25 parts of ethyl cellulose, microcrystalline cellulose 25-50 servings. The invention also provides the preparation method and application of the sustained-release pellets. The sustained-release micropills of the present invention, by optimizing the type and dosage of the auxiliary materials, can achieve the ideal sustained-release effect within 12 hours while ensuring the good molding effect of the micropills, effectively avoiding the peak-valley phenomenon of the drug, and micro The surface area of the pill is larger, which reduces the toxic and side effects of the drug; at the same time, in the prescription of the present invention, the PTU drug loading reaches 65%, and the larger drug loading effectively reduces the amount of auxiliary materials and significantly reduces the production cost.
Description
Technical field
The present invention relates to a kind of propylthiouracil slow-release micro-pill, and its production and use.
Background technology
(Propylthiouracil is the Thiourea antithyroid drug PTU) to propylthiouracil, and soluble,very slightly in water dissolves in sodium hydroxide test solution or ammonia solution; In the blood half-life 1-2 hour, dosing interval was generally 6 ~ 8h, needed long-term prescription, and the patient uses inconvenience.Moreover; the general formulation of existing propylthiouracil, because this medicine discharges rapidly, there is peak valley phenomenon in blood drug level; regular meeting causes erythra (as skin allergy), GI irritation multiple toxicities such as (as nauseating, vomiting, epigastric discomforts), has influenced patient's level orthobiosis.
Slow releasing preparation, biological half-life that can prolong drug reduces administration number of times, and has avoided the peak valley phenomenon of medicine, makes blood drug level remain on comparison steadily in the lasting effective range, and the safety that can improve medicine reduces toxic and side effects.
Current at propylthiouracil, the report of existing relevant slow releasing preparation, as number of patent application: 200410022206.0, in this patent application, adopt two kinds of slow-release auxiliary material of hydroxypropyl emthylcellulose and ethyl cellulose, propylthiouracil has been prepared slow releasing tablet, effectively prolonged the half-life of propylthiouracil, wherein, be determined by experiment comparatively desirable slow releasing preparation proportioning: hydroxypropyl emthylcellulose: water soluble starch: lactose: ethyl cellulose=2:3:1:2.But in the slow releasing preparation that this patent application provides, propylthiouracil content is about 37 ~ 46%, and the said preparation drug loading is lower, is unfavorable for the saving of adjuvant, makes production cost strengthen, and simultaneously, the each dosage of patient is also relatively large.
Sustained-release pellet preparation is the wherein a kind of of slow releasing preparation, and it can promote drug absorption so that medicine and gastrointestinal tract mucous contact area increase, and can reduce or eliminate medicine to the gastrointestinal zest simultaneously.But the quality of micropill mainly can be write out a prescription and the influence of moulding process two aspect factors after the molding of micropill and the molding, usually has mutual influence again between the various factors simultaneously.(Zheng Lin, etc., the quality research of preparation slow-release micro-pill, Chinese antibiotic magazine, 2012 37 4 phases of volume)
At present, yet there are no the relevant report that propylthiouracil is prepared slow-release micro-pill.
Summary of the invention
The object of the present invention is to provide the propylthiouracil slow-release micro-pill that a kind of supplementary product consumption is few, drug loading is high.
The invention provides a kind of propylthiouracil slow-release micro-pill, it is prepared from by the supplementary material of following weight proportion:
Propylthiouracil 40-65 part, ethyl cellulose 10-25 part, microcrystalline Cellulose 25-50 part, suitable amount of adhesive.
Further, it is prepared from by the supplementary material of following weight proportion:
65 parts of propylthiouracils, 10 parts of ethyl celluloses, 25 parts of microcrystalline Cellulose, suitable amount of adhesive.
Further, described binding agent is HPMC, carbomer or starch.
Further, described binder dosage is the 0.4-0.6 weight portion.
Further preferably, it is prepared from by the supplementary material of following weight proportion:
65 parts of propylthiouracils, 10 parts of ethyl celluloses, 25 parts of microcrystalline Cellulose, HPMC K15M0.4-0.6 part.
The present invention also provides the preparation method of above-mentioned propylthiouracil slow-release micro-pill, and it comprises following operating procedure:
(1) takes by weighing supplementary material by the prescription proportioning;
(2) get recipe quantity PTU, microcrystalline Cellulose, ethyl cellulose, cross 100 mesh sieves respectively, mix homogeneously sprays into the mixture of suitable amount of adhesive and water again, prepares soft material, again by extrude-spheronization prepares micropill.
Further, the w/v of described binding agent and water is (1-3): 100.
Further, the w/v of described binding agent and water is 1:100.
Further, the concrete operations of described extruding-spheronization are as follows:
Get soft material, 18 mesh sieves are extruded and are made wet granular excessively, put in the centrifugal granulator pot body, and adjusting a pot body rotating speed is 250rmin
-1, air blast flux is 12 * 20Lmin
-1, round as a ball 5min after the gained micropill drying, sieves, and selects 18-24 order micropill, namely.
The present invention also provides the purposes of above-mentioned propylthiouracil slow-release micro-pill in the preparation antithyroid drug.
Slow-release micro-pill of the present invention, preferred by to supplementary product kind and consumption can be when guaranteeing the good molding effect of micropill, make it in 12h, reach desirable slow release effect, effectively avoided the peak valley phenomenon of medicine, and the micropill surface area is bigger, has reduced the toxic and side effects of medicine; Simultaneously, in the present invention's prescription, the PTU drug loading has reached 65%, and bigger drug loading has reduced supplementary product consumption effectively, has significantly reduced production cost.
Description of drawings
Fig. 1 different prescription release curve and ideal curve comparison diagram
Fig. 2 best prescription release curve and ideal curve comparison diagram
Release curve under Fig. 3 different rotating speeds condition
Release curve in four kinds of different pH value of Fig. 4
The specific embodiment
The preparation of embodiment 1 propylthiouracil slow-release micro-pill
(1) take by weighing supplementary material by the prescription proportioning:
Propylthiouracil (PTU) 65g, ethyl cellulose 10g, microcrystalline Cellulose 25g;
(2) get recipe quantity PTU, microcrystalline Cellulose, ethyl cellulose, cross 100 mesh sieves, mix homogeneously respectively; add an amount of 1%HPMC K15M aqueous solution (about 40-60ml), the preparation soft material, 18 mesh sieves are extruded and are made wet granular excessively; put in the centrifugal granulator pot body, adjusting pot body rotating speed is 250rmin
-1, air blast flux is 12 * 20Lmin
-1, round as a ball 5min after the gained micropill drying, sieves, and selects 18-24 order micropill, namely.
The screening of embodiment 2 slow-release micro-pill prescriptions of the present invention
1 material
1.1 instrument
BZJ-360 coating pelletizing machine (good granulation drying equipment of Changzhou company limited); RCZ-8B medicament dissolution instrument (Radio Factory of Tianjin Univ.), standard test sieve (Shangyu, Zhejiang Province county yarn sieve factory), RCZ-5A type intellectual drug digestion instrument (Precision Instrument Factory, Tianjin Univ.); UV1102 UV-detector (Shanghai Techcomp Instrument Ltd.)
1.2 reagent
Propylthiouracil crude drug (Hubei people's livelihood pharmaceutcal corporation, Ltd, lot number 081307, content 98.8%), ethyl cellulose, propylthiouracil reference substance (Nat'l Pharmaceutical ﹠ Biological Products Control Institute, lot number 100803-201002).
2 methods and result
2.1PTU the preparation of slow-release micro-pill
Get recipe quantity PTU, microcrystalline Cellulose, ethyl cellulose, cross 100 mesh sieves, mix homogeneously respectively; add adhesive (1%HPMC K15M aqueous solution) and prepare soft material in right amount; cross 18 mesh sieves and extrude and make the strip wet granular, put in the centrifugal granulator pot body, adjusting a pot body rotating speed is 250rmin
-1, air blast flux is 12 * 20Lmin
-1, round as a ball 5min, 50 ℃ of vacuum drying 2h sieve and select 18-24 order micropill, namely.
2.2 the mensuration of release
2.2.1 detection wavelength determination
Compound concentration is about 5.0 μ gmL
-1PTU reference substance aqueous solution and blank adjuvant aqueous solution are got subsequent filtrate after the filtration, in the interscan of 200 ~ 400nm wave-length coverage, reference substance solution has absorption maximum at the 274nm place according to spectrophotography, and blank adjuvant is interference measurement not, determine that therefore detecting wavelength is 274nm.
2.2.2 the preparation of standard curve
Configuration concentration is respectively 0.98,1.95,2.44,2.93,3.90,4.88 μ gmL
-1Series P TU reference substance solution, measure at the 274nm place according to spectrophotography in accordance with the law, carry out linear regression with trap A and concentration C, get equation of linear regression and be: (r=0.9993, n=6), the range of linearity is 0.98 μ gmL to C=0.095A+0.0533
-1~ 4.88 μ gmL
-1
2.2.3 precision and recovery test
Precision takes by weighing the about 10mg of PTU reference substance respectively, and 20mg, 50mg place the 100mL volumetric flask, add the blank adjuvant that is equivalent to recipe quantity, adding distil water is an amount of, and ultrasonic dissolution 30min is put to room temperature and added the water standardize solution, shake up, filtering with microporous membrane, precision are measured subsequent filtrate 1mL, thin up to 100 times, measure absorbance, calculate recovery rate in the 274nm place.The response rate of the basic, normal, high concentration of result is respectively 98.16%, 98.84%, 99.10%, RSD and is respectively 1.97%, 1.32%, and 0.59%.
2.2.4 stability test
Get the mixed solution that concentration under the 2.2.3 item is about 0.2mg/mL, put 37 ℃ of water-baths, respectively at 0h, 3h, 6h, 12h measures absorbance, and RSD respectively 1.77% as a result, shows that PTU is better at the 12h internal stability.
2.2.5 drug release determination method
Get this product 0.5g, according to " 2010 editions two appendix X C of Chinese pharmacopoeia drug release determination method, second method, 900mL is release medium with degassing distilled water, rotating speed is that per minute 50 changes, operation in accordance with the law is in different time points (0.5,1,2,4,8,12h) get solution 5mL respectively, filter, get after 100 times of the subsequent filtrate dilutions and to measure absorbance in 274nm wavelength place; It is an amount of that other gets propylthiouracil reference substance stock solution, measures in accordance with the law, and external standard method is calculated the burst size of different time.
2.3 prescription proportioning screening experiment
According to Pharmacopoeia of the People's Republic of China pertinent regulations, draft a desirable release profiles (data see Table 1, and curve is seen Fig. 1,2) earlier.
In order to obtain discharging comparatively desirable PTU slow-release micro-pill, the present invention determines ethyl cellulose (X in the prescription
1), PTU(X
2), microcrystalline Cellulose (X
2) be major variable, prepare micropill in accordance with the law and measure release, and compare with the desirable release profiles of setting, calculate similar factors f
2The required release profiles that reach of desirable release profiles for drafting temporarily, the cumulative release amount Q of different time points sees Table 1, experimental program and the results are shown in Table 2 and Fig. 1,2.
The cumulative release amount Q (%) of the desirable release profiles different time points of table 1
As seen from the above table, when the amount ratio between ethyl cellulose, microcrystalline Cellulose, the propylthiouracil three is 0.1:0.25:0.65, the release profiles of propylthiouracil and ideal curve are the most approximate, and drug loading maximum, greatly saved supplementary product consumption, saved cost, therefore, preferred the 11st group of prescription of the present invention is the best prescription of slow-release micro-pill.
Table 3 best prescription different time points cumulative release percentage rate
Best prescription release curve of the present invention is compared f with desirable release profiles
2=71.04%; Under this best prescription, drug release rate is comparatively even in the day part, and 0.5h only discharges in 17.77%, the 2h and only discharges 42.89%, show that slow-release micro-pill of the present invention does not have prominently to release phenomenon, and 12 hours releases is near 90%, and release is comparatively complete.
2.4 brief summary and analysis
In this experiment, the PTU consumption is bigger to the releasing effect influence, and experimental result shows that the PTU consumption is more big, and is more approaching with desirable release curve.Find that also the PTU consumption surpasses at 65% o'clock, f in the present invention's experiment
2The factor also can increase, and still, becomes ball looser, has a strong impact on the pill molding.Therefore, among the present invention, after slow-release micro-pill release and molding effect taken all factors into consideration, the PTU consumption is final in the final optimizing prescriptions adopted 65%, ethyl cellulose consumption 10%, microcrystalline Cellulose consumption 25%.
The release research of embodiment 3 slow-release micro-pill of the present invention
1 changes oar speed to the influence of drug release
Investigate the drug release behavior when the PTU slow-release micro-pill of optimizing the prescription preparation is different to change oar speed, the release curve is seen Fig. 3 as a result.
Advance f in accordance with the law
2Factor check, 50rpm and 75rpm compare, f
2=68.33%; 50rpm and 100rpm compare, f
2=68.27%; 75rpm and 100rpm compare, f
2=85.37%.The result shows, f
2The factor is changeed oar speed release rate of drugs is not had the significance influence all greater than 65%, shows that also rate of release was slower when rotating speed was 50rpm simultaneously, and for better simulated in vivo environment, the selection rotating speed is 50rpm.
2 release medium pH value are to the influence of drug release
Investigate 4 kinds of different pH value release medium (pH1.0 hydrochloric acid solution, pH4.0 phosphate buffer, pH6.8 phosphate buffer, distilled water) to optimizing the influence of prescription preparation slow-release micro-pill release behavior, release profiles is seen Fig. 4 in accordance with the law.Similar factors f as a result
2All more than 70, show that pH value does not have the significance influence to the rate of release of propylthiouracil slow-release micro-pill.
3 release model matches
Adopt Single-Index Model, Higuchi equation, Ritger-Peppas model to carry out by match optimizing prescription release curve respectively, the results are shown in Table 4.Single-Index Model and Higuchi equation model are better as a result, experimentation is found, after discharging fully, the micropill skeleton keeps intact, drug release meets insoluble skeleton ball release rule, n=0.1254 in the Ritger-Peppas equation to be diffused as the master, much smaller than 0.45, prove that also drug release meets the Fick flooding mechanism.
Table 4 model fitting result (n=6)
Make suitable adjustment on the basis of best prescription of the present invention, detect the cumulative release percentage rate of contrast prescription, and compare with best prescription, the result is as follows:
Table 5
As shown in Table 5:
Prescription one: on the best prescription basis, substitute the part microcrystalline Cellulose with lactose, it is PTU consumption 65%, ethyl cellulose consumption 10%, microcrystalline Cellulose consumption 15%, lactose 10%, the initial stage of gained micropill, prominent releasing acted on obviously, may be because the pore effect of lactose makes the rate of release of medicine that obvious quickening be arranged, therefore, finally abandon in filler, adding lactose.
Prescription two: employing starch replaces microcrystalline Cellulose as filler, finds all disintegrates fast of micropill in the experiment, and prominent releasing acts on obviously.
Prescription three: adopting HPMC K is the micropill that adjuvant is replaced the preparation of skeleton material EC material, and piller is that corrosion is complete in 8 hours, and its medicine all discharges, and fails to reach 12 hours slow release effect.
Prescription four: adopting HPMC E is the micropill that adjuvant is replaced the preparation of skeleton material EC material, and piller is that corrosion is complete in 8 hours, and its medicine all discharges, and fails to reach 12 hours slow release effect.
According to The above results as can be known, when PTU is prepared into sustained-release pellet preparation, because the influence of PTU medicine and the special physicochemical property of micropill dosage form self is not to use adjuvant commonly used all can prepare release PTU slow-release micro-pill preferably; Find that by experiment sieving (ethyl cellulose: microcrystalline Cellulose: propylthiouracil=0.1:0.25:0.65) can guarantee that the PTU pellet preparations does not have to dash forward and release phenomenon, finally reach uniform slow release effect to use best prescription of the present invention.
In sum, slow-release micro-pill of the present invention, preferred by to supplementary product kind and consumption, can when guaranteeing the good molding effect of micropill, make it in 12h, reach desirable slow release effect, effectively avoid the peak valley phenomenon of medicine, and the micropill surface area is bigger, has reduced the toxic and side effects of medicine; Simultaneously, in the present invention's prescription, the PTU drug loading has reached 65%, and bigger drug loading has reduced supplementary product consumption effectively, has significantly reduced production cost.
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| US20040185097A1 (en) * | 2003-01-31 | 2004-09-23 | Glenmark Pharmaceuticals Ltd. | Controlled release modifying complex and pharmaceutical compositions thereof |
| CN1602874A (en) * | 2003-09-30 | 2005-04-06 | 厦门建发制药有限公司 | Sustained release preparation of propylthiouracil and its preparation method |
| CN1676132A (en) * | 2004-03-30 | 2005-10-05 | 贵州圣济堂制药有限公司 | Thio-oxy pyrimidine formulation and its preparing method |
| CN1957928A (en) * | 2005-09-26 | 2007-05-09 | 北京吉厚成科技有限公司 | Controlled release preparation of clinical treating medication, and fabricating method |
| CN101288659B (en) * | 2007-04-18 | 2014-06-18 | 王雷波 | Floating type pellets in stomach and preparation method thereof |
-
2012
- 2012-08-08 CN CN 201210280753 patent/CN102764239B/en not_active Expired - Fee Related
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