CN102319220B - Preparation method of oral sustained controlled-release particle system - Google Patents
Preparation method of oral sustained controlled-release particle system Download PDFInfo
- Publication number
- CN102319220B CN102319220B CN 201110292960 CN201110292960A CN102319220B CN 102319220 B CN102319220 B CN 102319220B CN 201110292960 CN201110292960 CN 201110292960 CN 201110292960 A CN201110292960 A CN 201110292960A CN 102319220 B CN102319220 B CN 102319220B
- Authority
- CN
- China
- Prior art keywords
- release
- slow
- curve
- pill
- preparation
- 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.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- 238000013270 controlled release Methods 0.000 title abstract description 21
- 239000002245 particle Substances 0.000 title abstract description 18
- 230000002459 sustained effect Effects 0.000 title abstract 4
- 239000002775 capsule Substances 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 19
- 239000000463 material Substances 0.000 claims abstract description 3
- 239000008188 pellet Substances 0.000 claims abstract description 3
- 239000006187 pill Substances 0.000 claims description 26
- 238000000576 coating method Methods 0.000 claims description 16
- 229960001193 diclofenac sodium Drugs 0.000 claims description 16
- JGMJQSFLQWGYMQ-UHFFFAOYSA-M sodium;2,6-dichloro-n-phenylaniline;acetate Chemical compound [Na+].CC([O-])=O.ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 JGMJQSFLQWGYMQ-UHFFFAOYSA-M 0.000 claims description 16
- 230000001186 cumulative effect Effects 0.000 claims description 13
- 239000011248 coating agent Substances 0.000 claims description 12
- 239000002671 adjuvant Substances 0.000 claims description 11
- 238000007789 sealing Methods 0.000 claims description 11
- 238000002156 mixing Methods 0.000 claims description 9
- 239000012530 fluid Substances 0.000 claims description 8
- 239000000243 solution Substances 0.000 claims description 8
- 229940093429 polyethylene glycol 6000 Drugs 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 5
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 235000010603 pastilles Nutrition 0.000 claims description 4
- 239000003361 porogen Substances 0.000 claims description 4
- -1 hydroxypropyl Chemical group 0.000 claims description 3
- 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 description 2
- 239000002994 raw material Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 19
- 230000006399 behavior Effects 0.000 abstract description 13
- 238000013461 design Methods 0.000 abstract description 11
- 238000004519 manufacturing process Methods 0.000 abstract description 10
- 238000011161 development Methods 0.000 abstract description 3
- 238000012377 drug delivery Methods 0.000 abstract 2
- 238000005070 sampling Methods 0.000 abstract 1
- 239000008187 granular material Substances 0.000 description 31
- 229940028937 divalproex sodium Drugs 0.000 description 18
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 18
- 229940079593 drug Drugs 0.000 description 11
- 239000003826 tablet Substances 0.000 description 11
- 239000000203 mixture Substances 0.000 description 10
- 239000003405 delayed action preparation Substances 0.000 description 9
- 238000000338 in vitro Methods 0.000 description 9
- BZKPWHYZMXOIDC-UHFFFAOYSA-N acetazolamide Chemical compound CC(=O)NC1=NN=C(S(N)(=O)=O)S1 BZKPWHYZMXOIDC-UHFFFAOYSA-N 0.000 description 8
- 229960000571 acetazolamide Drugs 0.000 description 8
- 239000007939 sustained release tablet Substances 0.000 description 7
- WTJXVDPDEQKTCV-UHFFFAOYSA-N 4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide;hydron;chloride Chemical compound Cl.C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2C1CC1C(N(C)C)C(=O)C(C(N)=O)=C(O)C1(O)C2=O WTJXVDPDEQKTCV-UHFFFAOYSA-N 0.000 description 6
- QNVKOSLOVOTXKF-UHFFFAOYSA-N 4-[(2-amino-3,5-dibromophenyl)methylamino]cyclohexan-1-ol;hydron;chloride Chemical compound Cl.NC1=C(Br)C=C(Br)C=C1CNC1CCC(O)CC1 QNVKOSLOVOTXKF-UHFFFAOYSA-N 0.000 description 6
- 229960000985 ambroxol hydrochloride Drugs 0.000 description 6
- 229960002421 minocycline hydrochloride Drugs 0.000 description 6
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 4
- 239000008108 microcrystalline cellulose Substances 0.000 description 4
- 229940016286 microcrystalline cellulose Drugs 0.000 description 4
- 238000013268 sustained release Methods 0.000 description 4
- 239000012730 sustained-release form Substances 0.000 description 4
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 3
- 239000004141 Sodium laurylsulphate Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000002547 new drug Substances 0.000 description 3
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 230000003321 amplification Effects 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 231100001274 therapeutic index Toxicity 0.000 description 2
- 238000012356 Product development Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000012362 drug development process Methods 0.000 description 1
- 238000007905 drug manufacturing Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000013265 extended release Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 229940127554 medical product Drugs 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Images
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention relates to a preparation method of an oral sustained controlled-release particle drug delivery system. The particle system comprises sustained controlled-release pellets or particles with two different release behaviors of A and B; A and B contain effective components of a same medicament, and the effective components are the same. The release curves of A and B are located at two sides of a target release curve; the slopes of Ka, Kb, and Kc of A, B and the target release curve at sampling points with the same release rate meet that Ka and Kb are within the range of Kc*(1+/-50%). The particle system is filled with proper auxiliary materials to become a capsule, or is pressed to become a tablet. The oral sustained controlled-release particle drug delivery system of the invention can effectively increase the process design space, allows the dissolving curve to approach the target release curve, reduces the development risk of the medicament, can effectively reduce differences between batches of final products, increases the consistency of the products and the internal quality of the final products, and facilitates the improvement of production stability. The invention is applicable to the imitation of products on the market and the development of new medicaments, and the operations for mass production are provided with more flexibility and maneuverability.
Description
Technical field
The invention belongs to medical technical field, relate to a kind of slow, controlled release granule, particularly relate to a kind of preparation method of drug-supplying system of oral slow, controlled release granule.
Technical background
Oral administration solid is slow, controlled release preparation is compared with conventional formulation, has the extended treatment persistent period, reduces toxic and side effects, and reduce the medication number of times, improve the advantages such as compliance of medication, be the important directions of global medical product development.At present, the kind of whole world listing reaches more than 200 kinds, more than 500 specification, and market scale reaches hundred million dollars of hundreds ofs, and keeps annual 9% growth rate.The preparation technique that preparation is slow, controlled release preparation is commonly used has film packaging technique, skeleton technology and osmotic pumps technology.The release in vitro behavior is the important indicator of oral slow, controlled release preparation optimization, is also one of most important index of production control.each is slow, controlled release preparation is with release curve table of correspondence, oral slow, the controlled release preparation dispose procedure is comparatively complicated, its release behavior will be subject to prescription and form, supplementary material, the various factors such as process conditions, in process of production due to environment, wait between adjuvant is criticized and there are differences, product quality is produced than great fluctuation process, in the quality standard of sustained-release preparation, the accumulative releasing degree span of control of sample point is wider, affect drug quality, as the diclofenac sodium slow releasing capsule 2, 6 should be respectively 25～50% of labelled amount mutually with the Cumulative release amount of 12 hours, more than 55～80% and 75%, fluctuation range is large.
Register principle according to ICH Q8: slow, controlled release preparation needs a rational technological design space (Design Space) in technological design, and state space can ensure that the release behavior in product scale amplification is consistent; The chemical drugs replacement demand technological guidance of State Food and Drug Administration principle: the excursion of the controlled adjuvant of non-release and the controlled adjuvant of release is the scope of Formulation adjuvant amount ± 10%(w/w), for the narrow medicine of therapeutic index, the excursion of the controlled adjuvant of release is ± 5%(w/w), this guideline has larger restriction to the technological design space.Keep a larger design space in drug development or production process for making, reduce the differences between batches of final products, need to design oral slow, a controlled release granule drug-supplying system.
Summary of the invention
The technical problem to be solved in the present invention: a kind of preparation method of oral slow, controlled release granule is provided, and the method can effectively improve concordance and the inherent quality of product, and can ensure the robustness of technique.
Technical scheme of the present invention:
The preparation method of a kind of oral slow, controlled release granule system, described particle system is by slow, controlled release micro pill or the granulometric composition of A, two kinds of different release behaviors of B; A, B contain the effective ingredient of same medicine, and effective ingredient is identical.
In described method, the release profiles of A, two kinds of micropills of B or granule is positioned at the both sides of target release profiles, and micropill or granule A, B and target release profiles must satisfy Ka, Kb in the scope of Kc * (1 ± 50%) at slope K a, Kb, the Kc of identical release sample point.
In described particle system, the ratio of A component is 25～75%, B component ratio 75～25%, and A, B sum are 100%.
The ratio of described A component is preferred 30～70%, the ratio of B component preferred 70～30%.
The drug content of described slow, controlled release micro pill or granule A, B should be basically identical, and content deviation is in ± 50% scope, and the particle diameter of micropill or granule is 0.3～2.0mm.
The preferred deviation of drug content of described slow, controlled release micro pill or granule A, B is in ± 20% scope.
The ratio of described micropill or granule A, B component is to be determined by the corresponding slope of the point that has identical Cumulative release amount on its release curve, described slope is the slope that has the some correspondence of identical Cumulative release amount on the release curve, and this point is Cumulative release amount one of them point between 50%～90%.
In described method, when the slope of this A and B release profiles is respectively Ka and Kb, when the slope of target release profiles was K, in this system, the ratio of A and B component was y, satisfied Kc * (1-50%)＜y＜Kc * (1+50%), wherein y=|Kb-K|:|Ka-K|.
In described system, the ratio y of A and B component satisfies: Kc * (1-30%)＜y＜Kc * (1+30%).
Described particle system adds suitable adjuvant to be filled to capsule or is pressed into tablet, capsule or tablet are comprised of instant-free part and time-delay release portion two parts, instant-free is partly fast release micropill or granule, and the time-delay release portion is two kinds of different micropills that discharge or the system of granulometric composition.
The preparation method of oral slow, controlled release granule of the present invention, by micropill or the particles filled capsule of A, two kinds of different rates of release of B or be pressed into tablet, the composition of A, two kinds of different releasing micropills of B or granule is determined by depart from objectives the up and down scope of curve of the target release profiles with respect to this kind.
The selection of target release profiles: if be new drug, trial product (pH1.0, pH4.5, pH6.8 and water) in 4 kinds of different release medium is carried out the mensuration of release curve according to slow, controlled release preparation research standard, choose the curve of release medium commonly used in pharmacopeia as aim curve; If be the sample that goes on the market, measure its release curve with former factory sample by drug release determination method in its quality standard, and take this curve as the target release profiles.
Positive beneficial effect of the present invention:
1, oral slow, controlled release preparation exploitation and imitated successful key are: requiring has certain design space on technique, with the robustness of guarantee technique.Oral pharmaceutical methods slow, controlled release granule of the present invention can strengthen the technological design space effectively, makes stripping curve near the target release profiles, reduces the development risk of medicine.
2, the present invention can effectively reduce the differences between batches of final products, improves the concordance of product and the inherent quality of final products.
3, the present invention can avoid being departed from larger product (waste product) with the target release profiles and being occurred by what the single particle system may occur in actual production process is controlled, and is conducive to improve the stability of production.
4, in the present invention, the particle diameter of A, two kinds of granules of B can be different, and suitable particle diameter difference can increase the density of hybrid particles, increase drug loading, and this preparation for large specification is most important.
5, the imitated and new drug development of the suitable product that gone on the market of the present invention realizes that easily laboratory process arrives the scale amplification of large production technology, makes large production operation have more motility and operability.
Description of drawings
Fig. 1: the release curve of diclofenac sodium micropill A, B and target sample (listing sample);
Fig. 2: the release curve of diclofenac sodium micropill A, B biased sample and target sample;
Fig. 3: the release curve of the pilot sample of divalproex sodium granule A, B and weightening finish 25%;
Fig. 4: the release curve of divalproex sodium granule A, B biased sample and 25% the pilot sample of increasing weight relatively;
Fig. 5: the release curve of acetazolamide micropill A, B and target sample (listing sample) relatively;
Fig. 6: the release curve of acetazolamide micropill A, B biased sample and target sample (listing sample) relatively;
Fig. 7: the release curve of ambroxol hydrochloride micropill A, B and target sample (listing sample) relatively;
Fig. 8: the release curve of ambroxol hydrochloride micropill A, B biased sample and target sample (listing sample) relatively;
Fig. 9: the release curve of minocycline hydrochloride micropill A, B and target sample (listing sample) relatively;
Figure 10: the release curve of minocycline hydrochloride micropill A, B biased sample and target sample (listing sample) relatively.
The specific embodiment
Further illustrate by the following examples the present invention, but not as limitation of the present invention.
Embodiment 1:
The preparation method of diclofenac sodium slow releasing capsule: the diclofenac sodium raw materials is crossed 100 mesh sieves, get HPMC10g and polyethylene glycol 6000 1.0g and add water 500ml and make solution.Getting diclofenac sodium 250g is dissolved in this solution, get fine pellet core 500g and put into fluid bed adjusting fluidized state, by fluid bed, celphere medicine-feeding (diclofenac sodium) preparation is contained pill core, fluid bed bag sealing coat, sealing coat solution is the aqueous solution (wherein containing 0.6% polyethylene glycol 6000) of 6% hydroxypropyl emthylcellulose HPMC, according to experience in the past, the coating weightening finish is 4% of pastille piller; Fluid bed bag slow release layer increase weight respectively A be 12% and B be the slow release layer of 17% two prescription (the weightening finish ratio is with respect to the pastille piller that has wrapped sealing coat), obtain the slow-release micro-pill of 2 different weightening finishes.
Sealing coat solution is the aqueous solution (wherein containing 0.6% polyethylene glycol 6000) of 6% hydroxypropyl emthylcellulose HPMC; Slow release layer coatings material is the Sulisi (Aquacoat) of the happy Kanggong of card department, and polyethylene glycol 6000 is porogen.
Learn by test, the principal element that affects the diclofenac sodium extended release capsule release is the thickness of porogen and slow release coatings, by previous experiences as can be known the consumption of porogen be that 0.6%(is with respect to the ratio of sealing coat liquor capacity), at first consider the thickness (thickness is in weightening finish) of coatings in when prescription design.The release standard of diclofenac sodium slow releasing capsule is: every Cumulative release amount at 2,6 and 12 hours is respectively more than 25～50%, 55～80% and 75% of corresponding labelled amount, all should be up to specification.
2 prescriptions slow-release micro-pill filled capsules and diclofenac sodium of the trial-production sample (being also to prepare the film-controlled slow-release capsule by coating) that goes on the market is carried out the release curve comparison, measure respectively the release curve of 2 kinds of slow-release micro-pill and listing sample, it is 75% point by Cumulative release amount on the release curve, calculate the slope K value of micropill A, B release profiles and aim curve: Ka and be 0.21, Kb is 0.16, Kc is 0.17, sees the following form 1, Fig. 1.
Table 1: the release of diclofenac sodium micropill A, B and listing sample relatively
By equation A * x%+B * (1-x%)=C; calculate mixed proportion x%, the 1-x% of micropill A, B; wherein A, B, C be micropill A, B, C in the release of same sample point, the mass ratio that mixes by calculating two kinds of granules, micropill A account for x% and are 30%, to account for (1-x%) be 70% to micropill B.
Checking: micropill A, B mix its release curve of rear mensuration according to the above ratio, compare with listing sample curve, and its release the results are shown in Table 2, Fig. 2:
Similar factors:
f 2=50log{[1+
f 2: similar factors;
:
tTime reference preparation cumulative release percentage rate;
:
tTime is subjected to test preparation cumulative release percentage rate;
n: get and count out; This equation is the logarithm transition form of variance summation.Work as f
2Value is between 50～100 the time, thinks the tablets in vitro behavior there was no significant difference of two preparations, f
2Value is more near 100, and both similarity degrees are higher; f
2Value thinks that less than 50 o'clock the tablets in vitro behavior of two preparations has significant difference.
The result: f
2The tablets in vitro behavior there was no significant difference of=84.8, two preparations.Contrasted as can be known by release curve after mixing and aim curve, slow, the controlled release micro pill of two kinds of curves that depart from objectives can be utilized by this system, namely sample all can be applied by this system in slow release layer weightening finish 12～17% scopes, and namely the technological design space of diclofenac sodium slow releasing capsule is slow release layer weightening finish 12～17%.
The preparation of divalproex sodium slow releasing capsule: by the preparation medicine-containing particle, fluidized bed coating, the weightening finish of 20%, 25% and 30% 3 prescription that increases weight respectively during the coated slow release layer draws the divalproex sodium slow-releasing granules of 3 different weightening finishes.Divalproex sodium sustained-release tablet is listing abroad, the divalproex sodium slow releasing capsule is as new drug, its release standard formulation need to be according to the standard of Divalproex sodium sustained-release tablet, need to be in 4 kinds of release medium (pH1.0, pH4.5, pH6.8 and water) carry out the mensuration of release curve.Every Cumulative release amount at 4 hours, 12 hours, 22 hours of Divalproex sodium sustained-release tablet should be respectively more than 30%～50%, 55%～75% and 80% of labelled amount, all should be up to specification.
The Divalproex sodium sustained-release tablet of getting slow release layer weightening finish and being 25% divalproex sodium granule and abroad gone on the market uses respectively 4 kinds of media (pH1.0, pH4.5, pH6.8 and water) to carry out the release curve comparison, testing result such as following table 3.
Release by homemade divalproex sodium particulate samples and the external divalproex sodium sample that has gone on the market contrasts as can be known, coating weightening finish be 25% prescription in 4 kinds of release medium with the Divalproex sodium sustained-release tablet of external listing discharge basically identical, can be with the release standard of the Divalproex sodium sustained-release tablet release inspection method as the divalproex sodium slow releasing capsule.
Get respectively the granule of coating weightening finish 20% and 30% as experiment granule A, B, carry out the mensuration of release curve by the assay method of Divalproex sodium sustained-release tablet release, calculated the slope K value of micropill A, B and aim curve: Ka by the point of release 75% on the release curve and be 0.096, Kb is 0.065, Kc is 0.076.Referring to table 4, Fig. 3.
Table 4: the sample release of divalproex sodium granule A, B and weightening finish 25% relatively
Be that granule A, B, C are in the release of same sample point by equation A * x%+B * (1-x%)=C(A, B, C) count particles A, B mixed proportion: by the ratio of two kinds of granules calculating, granule A accounts for 60%, granule B accounts for 40%.
Checking: in measuring its release curve after this ratio hybrid particles A, B, compare with the target sample curve, see the following form 5:
The release curve of divalproex sodium granule A, B biased sample and 25% the pilot sample of increasing weight relatively, referring to Fig. 4.
The similar factors formula of use-case 1, the result: similar factors f
2The tablets in vitro behavior there was no significant difference of=82.5, two preparations.By the contrast that mixes rear release curve and aim curve as can be known, slow, the controlled release micro pill of two kinds of curves that depart from objectives can be utilized by this system, and namely sample all can be applied by this system in the scope of slow release layer weightening finish 20～30%.
The bulk density of 20% coating weightening finish is 0.85g/cm
3, the bulk density of 30% coating weightening finish is 0.83g/cm
3, the bulk density after both are mixed in proportion is 0.86g/cm
3, effectively increased the loading of capsule.
The preparation of acetazolamide slow releasing capsule: contain pill core by extruding preparation, in the adjustment prescription, the amount of the amount of solubilizing agent and microcrystalline Cellulose is controlled the burst size of acetazolamide slow releasing capsule.
Prescription A prescription B
Acetazolamide 500g acetazolamide 500g
Microcrystalline Cellulose 50g microcrystalline Cellulose 125g
Sodium lauryl sulphate 0.4% sodium lauryl sulphate 0.2%
5%HPMC aqueous solution 110ml 5%HPMC aqueous solution 110ml
The micropill that respectively prepares 1000 sample sizes by prescription.
Measure respectively the release curve of A, two kinds of slow-release micro-pill of B by the release standard, calculated the slope K value of micropill A, B and aim curve: Ka by the point of release 75% on the release curve and be 0.61, Kb is 0.25, Kc is 0.35.The release curve of acetazolamide micropill A, B and target sample (listing sample) compares, referring to Fig. 5.
Be that micropill A, B, C are in the release of same sample point by equation A * x%+B * (1-x%)=C(A, B, C) calculate the ratio of two kinds of micropills: micropill A accounts for 40%, micropill B accounts for 60%.
Checking: measure its release curve after mixing in this ratio micropill A, B, compare with aim curve.Referring to Fig. 6.
The result: f
2The tablets in vitro behavior there was no significant difference of=78.3, two preparations.Contrasted as can be known by release curve after mixing and aim curve, slow, the controlled release micro pill of two kinds of curves that depart from objectives can be utilized by this system.
According to the chemical drugs replacement demand technological guidance of State Food and Drug Administration principle: the excursion of the controlled adjuvant of non-release and the controlled adjuvant of release is the scope of Formulation adjuvant amount ± 10%(w/w), for the narrow medicine of therapeutic index, the excursion of the controlled adjuvant of release is ± 5%(w/w); By the prescription of acetazolamide slow releasing capsule as can be known, in this preparation in two prescriptions the controlled microcrystalline cellulose excipients of release and the sodium lauryl sulphate excursion larger, can be by the adjusting of oral slow controlled release granule preparation method, can make the product produced and listing sample tablets in vitro behavior there was no significant difference, make difference between product reduce and improve the robustness of technique in production.
Sustained Release Ambroxol Hydrochloride Capsules
The preparation of Sustained Release Ambroxol Hydrochloride Capsules: get ambroxol hydrochloride and contain pill core by extruding preparation, fluidized bed coating sealing coat and slow release layer, 5% and 9% two different prescription (except coating weightening finish difference, other compositions are all identical) increases weight respectively during the coated slow release layer.Measure respectively the release curve of 2 kinds of slow-release micro-pill by the release standard, calculated the slope K value of micropill A, B and aim curve (for the sample that gone on the market): Ka by the point of release 75% on the release curve and be 0.60, Kb is 0.30, Kc is 0.42.
The release curve of ambroxol hydrochloride micropill A, B and target sample (listing sample) compares, referring to Fig. 7.
Be that micropill A, B, C are in the release of same sample point by equation A * x%+B * (1-x%)=C(A, B, C) calculate the ratio of two kinds of micropills: micropill A accounts for 50%, micropill B accounts for 50%.
Checking: measure its release curve after mixing in this ratio micropill A, B, compare with aim curve.Referring to Fig. 8.
The result: f
2The tablets in vitro behavior there was no significant difference of=88.4, two preparations.Contrasted as can be known by release curve after mixing and aim curve, slow, the controlled release micro pill of two kinds of curves that depart from objectives can be utilized by this system.
The minocycline hydrochloride sustained-release capsule
The preparation of minocycline hydrochloride sustained-release capsule: get minocycline hydrochloride and contain pill core by extruding preparation, fluidized bed coating sealing coat and slow release layer, 13% and 15% two different prescription (except coating weightening finish difference, other compositions are all identical) increases weight respectively during the coated slow release layer.Measure respectively the release curve of 2 kinds of slow-release micro-pill by the release standard, calculated the slope K value of micropill A, B and aim curve (for the sample that gone on the market): Ka by the point that discharges 75% on the release curve and be 0.81, Kb is 0.58, Kc is 0.71.The release curve of minocycline hydrochloride micropill A, B and target sample (listing sample) compares, referring to Fig. 9.
Be that micropill A, B, C are in the release of same sample point by equation A * x%+B * (1-x%)=C(A, B, C) ratio of two kinds of micropills calculating: micropill A accounts for 55%, micropill B accounts for 45%.
Checking: measure its release curve after mixing in this ratio micropill A, B, compare with aim curve.Referring to Figure 10.
The result: f
2The tablets in vitro behavior there was no significant difference of=93.8, two preparations.Contrasted as can be known by release curve after mixing and aim curve, slow, the controlled release micro pill of two kinds of curves that depart from objectives can be utilized by this system.
Claims (1)
1. the preparation method of a diclofenac sodium slow releasing capsule, it is characterized in that, described method is specially: the diclofenac sodium raw materials is crossed 100 mesh sieves, getting HPMC10g and polyethylene glycol 6000 1.0g adds water 500ml and makes solution, getting diclofenac sodium 250g is dissolved in this solution, get fine pellet core 500g and put into fluid bed adjusting fluidized state, preparation contains pill core to celphere medicine-feeding diclofenac sodium by fluid bed, fluid bed bag sealing coat, sealing coat solution is the aqueous solution of 6% hydroxypropyl emthylcellulose HPMC, contain 0.6% polyethylene glycol 6000 in sealing coat solution, the coating weightening finish is 4% of pastille piller, fluid bed bag slow release layer increase weight respectively A be 12% and B be 17% two prescription, wherein weightening finish ratio is the slow release layer with respect to the pastille piller that has wrapped sealing coat, obtain the slow-release micro-pill of 2 different weightening finishes, the slope that is 75% sample point in identical burst size with the target release profiles of the release profiles of slow-release micro-pill A, slow-release micro-pill B and this sample is followed successively by 0.21,0.16,0.17, calculate the mixing quality of A and B two components than accounting for 30% for micropill A, micropill B accounts for 70%, two kinds of different slow-release micro-pill A that increase weight are mixed according to mass ratio with slow-release micro-pill B adds adjuvant to be filled to capsule, slow release layer coatings material is Aquacoat for the Sulisi of the happy Kanggong of card department, and wherein polyethylene glycol 6000 is porogen, above-mentioned slow-release micro-pill A is that basis is to be determined by slope corresponding to the point of identical Cumulative release amount on its release curve with the mixing quality ratio of slow-release micro-pill B, slope is that identical Cumulative release amount point is corresponding, and it is between 50%～90% that this point should be chosen in Cumulative release amount, the ratio y of A, B component, y=∣ Kb-K ∣: ∣ Ka-K ∣, Ka, Kb, K be burst size between 50%～90%, the slope of identical Cumulative release amount point A, B and the corresponding point of target release profiles.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110292960 CN102319220B (en) | 2011-09-30 | 2011-09-30 | Preparation method of oral sustained controlled-release particle system |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110292960 CN102319220B (en) | 2011-09-30 | 2011-09-30 | Preparation method of oral sustained controlled-release particle system |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102319220A CN102319220A (en) | 2012-01-18 |
| CN102319220B true CN102319220B (en) | 2013-06-05 |
Family
ID=45447149
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201110292960 Active CN102319220B (en) | 2011-09-30 | 2011-09-30 | Preparation method of oral sustained controlled-release particle system |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102319220B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102949377B (en) * | 2012-11-28 | 2015-05-27 | 河南中帅医药科技股份有限公司 | Acetazolamide sustained-release capsule and preparation method thereof |
| CN103054832B (en) * | 2012-12-26 | 2015-01-07 | 河南中帅医药科技股份有限公司 | Minocycline hydrochloride sustained-release capsule and preparation method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1217655A (en) * | 1996-03-08 | 1999-05-26 | 尼科梅德丹麦有限公司 | Modified release multiple-units dosage composition |
| CN1546039A (en) * | 2003-12-15 | 2004-11-17 | 中国药科大学 | Sustained releasing minipills of diltiazem hydrochloride and its preparation |
| CN1559397A (en) * | 2004-03-12 | 2005-01-05 | 中国药科大学 | Chrono-slow-releasing prepn. hydrochloride verapamil |
| CN1935124A (en) * | 2006-09-30 | 2007-03-28 | 中国药科大学 | Tetramethylpyrazine phosphate slow-release micro-pill and its preparing method |
-
2011
- 2011-09-30 CN CN 201110292960 patent/CN102319220B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1217655A (en) * | 1996-03-08 | 1999-05-26 | 尼科梅德丹麦有限公司 | Modified release multiple-units dosage composition |
| CN1546039A (en) * | 2003-12-15 | 2004-11-17 | 中国药科大学 | Sustained releasing minipills of diltiazem hydrochloride and its preparation |
| CN1559397A (en) * | 2004-03-12 | 2005-01-05 | 中国药科大学 | Chrono-slow-releasing prepn. hydrochloride verapamil |
| CN1935124A (en) * | 2006-09-30 | 2007-03-28 | 中国药科大学 | Tetramethylpyrazine phosphate slow-release micro-pill and its preparing method |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102319220A (en) | 2012-01-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106063780B (en) | A kind of tetradoxin fast release micropill preparation, preparation method and applications | |
| FI97686B (en) | A method of making beads for the purpose of producing controlled release products | |
| KR920004094B1 (en) | Process for preparing sustained release pharmaceutical compositions | |
| EA017764B1 (en) | Pharmaceutical composition, method for preparation thereof and method for treating antiviral diseases using same | |
| Lafeber et al. | 3D printed furosemide and sildenafil tablets: Innovative production and quality control | |
| Mundada et al. | Formulation and optimization of controlled release powder for reconstitution for metoprolol succinate multi unit particulate formulation using risk based QbD approach | |
| CN102319220B (en) | Preparation method of oral sustained controlled-release particle system | |
| CN106511280A (en) | Ibuprofen slow-releasing dry suspension and preparation method thereof | |
| CN104523631B (en) | Preparation method of olanzapine orally disintegrating tablet for treating depression | |
| CN108014085A (en) | A kind of preparation method and applications of sabril solid composite | |
| CN109833309A (en) | Memantine is sustained microplate capsule and preparation method thereof | |
| JP6084355B2 (en) | Ambroxol-containing preparation particles | |
| Kukkar et al. | Mixing and formulation of low dose drugs: underlying problems and solutions | |
| CN104758180A (en) | Secondary filling method for compound preparation capsules | |
| KR20070063358A (en) | Combination containing stabilized coenzyme q10, multivitamins and minerals | |
| CN106902097B (en) | A pharmaceutical composition for improving bioavailability of medicine | |
| Liu et al. | Development of arsenic trioxide sustained-release pellets for reducing toxicity and improving compliance | |
| CN107028912A (en) | A kind of preparation method of Irbesartan Capsules | |
| Khalid et al. | Optimization of rofecoxib liquisolid tablets usingbox-behnken design and desirability function | |
| CN100551373C (en) | The buspirone hydrochloride slow/controlled release pellet | |
| CN105534980B (en) | The pharmaceutical composition and its preparation process of Repaglinide Metformin hydrochloride | |
| Sarangi et al. | Formulation Development and evaluation of Bilayer tablets containing Paracetamol SR and Tizanidine | |
| CN114452264B (en) | Pioglitazone hydrochloride capsule and preparation method thereof | |
| CN105497023B (en) | Saxagliptin pharmaceutical preparation | |
| CN102641253A (en) | Valsartan sustained release tablet and preparation method thereof |
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 | ||
| ASS | Succession or assignment of patent right |
Owner name: ZHONGSHUAI PHARMACEUTICAL SCIENCE AND TECHNOLOGY I Free format text: FORMER OWNER: SUN WEIDONG Effective date: 20140213 |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20140213 Address after: 18, building 7, block A, 450001 Holly Road, Gaoxin District, Henan, Zhengzhou Patentee after: ZHONGSHUAI PHARMACEUTICAL SCI & TECH INCORPORATED CO., LTD. Address before: 18 building A, block 7, Holly Street, Zhengzhou hi tech Industrial Development Zone, Henan 450001, China Patentee before: Sun Weidong |