CN101804037B - Acyclovir dispersible tablet and preparation method thereof - Google Patents
Acyclovir dispersible tablet and preparation method thereof Download PDFInfo
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- CN101804037B CN101804037B CN200910078071.2A CN200910078071A CN101804037B CN 101804037 B CN101804037 B CN 101804037B CN 200910078071 A CN200910078071 A CN 200910078071A CN 101804037 B CN101804037 B CN 101804037B
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Abstract
The invention provides an acyclovir dispersible tablet and a preparation method thereof. The acyclovir dispersible tablet contains a main ingredient of acyclovir and auxiliary ingredients of a disintegrating agent, a bulking agent, a flavoring agent and the like. The acyclovir dispersible tablet has the advantages of being capable of forming a uniform injectable suspension when meeting water, improving the patient adaptability and increasing the selection of doctors and patients on clinical medicines, and has the characteristics of convenient taking, rapid absorption, high bioavailability and the like.
Description
Technical field
The present invention relates to a kind of Acyclovir dispersible tablet and preparation method thereof, belong to technical field of medicine.
Background technology
Acyclovir is a kind of antiviral agents, external to tool inhibitory action such as herpes simplex virus, varicella zoster virus, cytomegaloviruses.
Dispersible tablet is the novel troche that day by day causes that people pay close attention to.Dispersible tablet preparation technology is simple, and in tablet input water, disintegrate forms uniform suspension rapidly, and finished product both can have been put in water oral after dispersion, also can swallow, chew or take containing sucking.Dispersible tablet is the dosage form that " national pharmaceutical preparation new product development guide " recommends exploitation.2005 editions two of China's pharmacopeia have also been recorded dispersible tablet.
The diseases of viral infection such as herpes simplex encephalitis, the infection of genital herpes virus, Mucocutaneous herpes simplex infections, chickenpox, varicella zoster virus infection and cytomegalovirus (CMV) infection have become the major disease of serious threat human health.Acyclovir is the synthetic ucleosides antiviral agents with purine parent nucleus of Glaxo Wellcome company of Britain, can enter host cell, be phosphorylated and become active form ACV-TP ester, become viral dna polymerase inhibitor and substrate, suppress viral DNA and synthesize and copy, but do not affect normal cell.1981, this medicine was first in Britain's listing, and to the various herpesviruss of skin and ophthalmology, particularly single bleb I, II type virus, the diseases such as the chronic hepatitis of cytomegalovirus and the hepatitis B antigen positive are effective.Stronger 10 times than the effect of first generation antiviral agents iodouracil desoxyriboside as second filial generation antiviral agents, stronger 160 times than vidarabine effect, start the milestone of a treatment virus drugs, have that antiviral spectrum is wide, effect is strong, selectivity is high, safety, oral administration biaavailability is compared with high, is the choice drug that is used for the treatment of clinically herpes simplex infections at present.Acyclovir is in the cell of viral infection, be converted into again diphosphonic acid fat and triphosphoric acid fat by the close eyelash kinases of viral deoxynucleoside thymus and cell kinase phosphorylation, and acyclovir triphosphoric acid fat can disturb the polymerase of DNA, disturb, suppress viral DNA and synthesize, thereby obtain antivirus action.Acyclovir can effectively be treated the diseases of viral infection such as herpes simplex encephalitis, the infection of genital herpes virus, Mucocutaneous herpes simplex infections, chickenpox, varicella zoster virus infection and cytomegalovirus (CMV) infection.The advantages such as this medical instrument is effective in cure definite, easy to use, safe and reliable, and untoward reaction is lighter are clinically one of choice drugs of antiviral therapy clinically at present.
Summary of the invention
The object of this invention is to provide a kind of Acyclovir dispersible tablet and preparation method thereof.
Dispersible tablet is taking convenience not only, and drops in water disintegrate rapidly and form uniform suspension, and fineness of dispersion is less than 710 μ m.Medicine total body surface area increases, and absorbs quickening, bioavailability raising.Acyclovir raw material is white crystalline powder, and odorless is tasteless.In glacial acetic acid or hot water, dissolve, soluble,very slightly in water dissolves in diluted sodium hydroxide solution, is particularly suitable for research and development for dispersible tablet, is conducive to the raising of bioavailability.Dispersible tablet is particularly suitable for the clothes for patients of old and dysphagia and uses.
The new dosage form that Acyclovir dispersible tablet is taken as safe and effective antiviral agents and special convenient for patients.
Acyclovir dispersible tablet of the present invention is made up of the supplementary material medicine of following weight portion:
Acyclovir 100, lactose 22, microcrystalline Cellulose 60, low-substituted hydroxypropyl cellulose 15, PVP K30 1-2, magnesium stearate 1, aspartame 1.5.
Another object of the present invention is to provide the preparation method of Acyclovir dispersible tablet, and the preparation method of Acyclovir dispersible tablet of the present invention is as follows:
(a) pre-treatment: acyclovir was pulverized 100 mesh sieves, PVP K30 is dissolved in 50% ethanol, is mixed with w/v and is 50% alcoholic solution of 5% PVP K30;
(b) batching: take in proportion the microcrystalline Cellulose of acyclovir, lactose, half amount and the low-substituted hydroxypropyl cellulose mix homogeneously of half amount, obtain mixed material;
(c) granulate: in step (b) gained mixed material, add the alcoholic solution of PVP K30, mixing granulation, wet grain in 65 ± 5 ℃ dry, with 30 mesh sieve granulate;
(d) always mixed: step (c) gained granule is mixed homogeneously with the microcrystalline Cellulose of surplus, the low-substituted hydroxypropyl cellulose of surplus, magnesium stearate and the aspartame of proportional quantities;
(e) semi-finished product chemical examination, tabletting and get final product.
The supplementary material part by weight of Acyclovir dispersible tablet of the present invention and preparation method are through a large amount of strict screening tests, process certification, after stability study, just obtain, not just can directly obtain by preparation teaching material or other reference material, through screening test, process certification, stability study proved invention supplementary material ratio is reasonable, stable preparation process, finished product preparation is stable, meets the preparation guideline requirement for dispersible tablet of galenic pharmacy and State Food and Drug Administration.Supplementary material formula and preparation process screening process are as follows:
Acyclovir raw material is white crystalline powder, and odorless is tasteless.In glacial acetic acid or hot water, dissolve, soluble,very slightly in water dissolves in diluted sodium hydroxide solution.Acyclovir dissolubility in water is poor as can be seen here, and therefore, in preparation preparation process, adopting good disintegrating agent to improve its stripping property is a key in compound design.
According to the quality standard of Acyclovir dispersible tablet (" State Food and Drug Administration's national drug standards " WS
1-(X-054)-2003Z, 33-158 page) and two appendix IA of Chinese Pharmacopoeia version in 2000 in about the prescription of dispersible tablet, the starting point of known dispersible tablet recipe design is to make tablet meet after water disintegrate during short as far as possible time (being less than 3 minutes) to become very little granule (sieving by No. 2) and form uniform suspension.For this reason, think and in technical recipe design process, should note emphatically some: the high-quality disintegrating agent that (1) use in conjunction is relatively large; (2) apply suitable suspending agent; (3) adopt the stronger binding agent of hydrophilic; (4) select suitable correctives.(5) in technical process, note the fineness of raw material and the granularity of granule.
The conventional high-quality disintegrating agent of dispersible tablet preparation has carboxymethyl starch sodium (CMC-Na), low-substituted hydroxypropyl cellulose (L-HPC), crospolyvinylpyrrolidone (PVPP), microcrystalline Cellulose (MCC) etc.; Conventional suspending agent is microcrystalline Cellulose (MCC) and natural clay Magnesiumaluminumsilicate (Veegum); The binding agent that conventional hydrophilic is stronger is polyvidone (PVP), hydroxypropyl emthylcellulose (HPMC); Initial option aspartame is correctives; For meeting the requirement of dispersible tablet dispersing uniformity, when granulation, the granularity of granule should be controlled at below 30 orders.
Selection and the compound design of adjuvant in 1 formula
Adopt MCC, LS-HPC to do suspending agent and disintegrating agent, and in adopting, add and the method for additional combination take improve disintegration rate between tablet and powder make again granule as early as possible disintegrate as tiny granule and by No. 2 sieves; Usage ratio by Orthogonal Experiment and Design to the two and adding in the two with additional ratio is carried out preferably; Use the 50% Diluted Alcohol solution of the PVP of variable concentrations to do binding agent and optimize optium concentration by Orthogonal Experiment and Design; Select water solublity lactose as filler, tab is heavy to about 200mg; Preparation process Raw was pulverized 100 mesh sieves; When the wet grain of system, cross 30 mesh sieves, and with 30 mesh sieve granulate.Because the consumption of correctives in formula is very little, and several without impact on the performance of preparation, therefore, after filtering out optimum formula by orthogonal test, carry out again the selection of correctives.
We have designed orthogonal test and have carried out formula optimization accordingly, and before test, have first carried out the compatibility test of adjuvant.
2 adjuvant compatibility tests
Test method: get acyclovir raw material and various adjuvant, mix according to a certain percentage respectively, be placed in respectively under the condition of high light (4500LX), high temperature (60 ℃), high humidity (relative humidity 90 ± 5%) and place 10 days, investigate the impact of the stability of adjuvant on medicine under light, heat, wet condition, test method and investigation index are respectively in table 1, table 2:
Table 1 acyclovir mixes compatibility test proportioning with adjuvant
Table 2 acyclovir and adjuvant mixed phase capacitive result of the test
Result: very little on the impact of acyclovir content and related substance etc. under high light, high humidity, high heat condition by the visible above-mentioned each adjuvant of table 2, can be as the adjuvant of Acyclovir dispersible tablet.
3 formula screenings
3.1 Orthogonal Experiment and Design
Orthogonal experiment plan is taken into account and be the results are shown in Table 3 tables 4.
Table 3 formulation optimization four factor levels
The analysis of table 4 orthogonal experiments
3.2 preparation technology
Acyclovir raw material pulverizing is crossed 100 mesh sieves, by orthogonal array, accurately takes all supplementary materials, and wherein in microcrystalline Cellulose and low-substituted hydroxypropyl cellulose, Extra Section weighs respectively, and carries out labelling; By acyclovir raw material and all in add adjuvant mix homogeneously, add binding agent, continue mix, make suitable soft material, 30 mesh sieves granulate; By granule after 65 ℃ of oven dry, 30 mesh sieve granulate; Add all additional adjuvants by formula, fully mix; Tabletting and get final product.
3.3 orthogonal experiments analyses: we have carried out preferably the supplementary material formula of Acyclovir dispersible tablet take the dispersing uniformity (comprising disintegration and the situation of sieving) of dispersible tablet as evaluation index, the impact of the visible factor A of result and C is larger, wherein factor A has the greatest impact, and factor D affects minimum; Experiment 4,6,7,8,9 dispersing uniformity all meet the requirements and disintegration time shorter all within 2 minutes, for respectively the fill a prescription key property of gained preparation of overall merit, we are to the mobility of particle in its preparation preparation process, and integrated survey has been carried out in the hardness of compressibility, made tablet, friability, stripping etc.
3.4 tablet key propertys are evaluated: the results are shown in Table 5
Table 5 tablet key property evaluation result
Conclusion: as seen from the above table, the dissolution of respectively filling a prescription all conforms with the regulations (20 minutes dissolution > 80%), without too large difference.Conform with the regulations as prerequisite take dispersing uniformity, the indices such as formula 7 mobility of particles, compressibility and outward appearance in blocks, hardness, friability, dissolution all conform with the regulations, therefore we to select to fill a prescription 7 be A
3b
1c
3for optimization formula.
The selection of 3.5 correctivess
According to the formulation characteristic of dispersible tablet, be the compliance that increases clinical patients medication, we make tablet as correctives by formula 7 so that the A Siba of different amounts is sweet, give a mark by 5 volunteers' mouthfeel experiment, determine optimum amount, the results are shown in Table 6.
The selection of correctives in table 6 Acyclovir dispersible tablet formula
As seen from the experiment, select the aspartame of formula ratio 1.5% can obtain good mouthfeel as correctives.
4 preparation stability evaluations
For further evaluating the preparation stability of definite Recipe, we by definite Recipe from new system for 500 samples, and carry out influence factor's test according to medicine stability test guideline (two appendix of Chinese Pharmacopoeia version in 2000), method for respectively by exposedly test sample being placed in high temperature (60 ℃), high humidity (is placed 10 days under relative humidity (90% ± 5%), strong illumination (4500lx ± 500lx) condition, in the 0th day, 5 days and sampling in 10 days, the situation of change of investigating indices, result of the test refers to table 7.
Table 7 acyclovir slice influence factor result of the test
Conclusion: through test, the Acyclovir dispersible tablet of developing with the Recipe of determining is all more stable to high temperature (60 ℃), high humidity (RH92.5% ± 5%) and high light (4500 ± 500Lx).
5, scale-up and preliminary quality evaluation
According to definite formula and process conditions, my company has carried out the scale-up of six batches 10,000, and yield rate is in table 8.And according to " State Food and Drug Administration's national drug standards " WS1-(X-054)-2003Z, the quality standard of 33-158 page Acyclovir dispersible tablet has carried out quality evaluation to test specimen, the results are shown in Table 9.
Table 8 Acyclovir dispersible tablet scale-up yield rate information slip
The scale-up quality evaluation of table 9 Acyclovir dispersible tablet and with the contrast that contrasts medicine
The Acyclovir dispersible tablet that uses as seen from the above table this Recipe to produce, the quality index such as its outward appearance, weight differential, friability, disintegration, dissolution, related substance, guanine (%), content are stable, meet Acyclovir dispersible tablet quality standard, and with contrast medicine without significant difference, Acyclovir dispersible tablet pharmaceutical formulation and stable preparation process, feasible are described, are suitable for batch production.
After Acyclovir dispersible tablet preparation of the present invention completes, carry out quality research, work out the method for inspection of indices, and carry out the methodology checking of each index detection method according to the guideline of Chinese Pharmacopoeia and new drug research, all methods all meet analysis of pharmaceutical dosage forms requirement, according to these methods, the Acyclovir dispersible tablet of development are detected and are studied.
The specific embodiment
Following embodiment is for illustrating the preparation of Acyclovir dispersible tablet of the present invention, but it can not form any restriction to scope of the present invention.
Embodiment 1
Supplementary material part by weight: 100 grams of acyclovirs, 22 grams of lactose, 60 grams of microcrystalline Cellulose, 15 grams of low-substituted hydroxypropyl celluloses, 1.3 grams of PVP K30s, 1 gram of magnesium stearate, 1.5 grams of aspartames;
Preparation method: (a) pre-treatment: acyclovir was pulverized 100 mesh sieves, PVP K30 is dissolved in 50% ethanol, is mixed with w/v and is 50% alcoholic solution of 5% PVP K30;
(b) batching: take in proportion the microcrystalline Cellulose of acyclovir, lactose, half amount and the low-substituted hydroxypropyl cellulose mix homogeneously of half amount, obtain mixed material;
(c) granulate: in step (b) gained mixed material, add the alcoholic solution of PVP K30, mixing granulation, wet grain in 65 ± 5 ℃ dry, with 30 mesh sieve granulate;
(d) always mixed: step (c) gained granule is mixed homogeneously with the microcrystalline Cellulose of surplus, the low-substituted hydroxypropyl cellulose of surplus, magnesium stearate and the aspartame of proportional quantities;
(e) semi-finished product chemical examination, tabletting and get final product.
Assay: outward appearance: white tablets; Tablet weight variation: conform with the regulations; Friability: conform with the regulations; Dispersing uniformity: conform with the regulations; Dissolution: 99.12%; Guanine: 0.59%; Related substance: 0.89%; Content: 100.50%.
Claims (1)
1. Acyclovir dispersible tablet, its supplementary material weight ratio is:
Acyclovir 100, lactose 22, microcrystalline Cellulose 60, low-substituted hydroxypropyl cellulose 15, PVP K30 1-2, magnesium stearate 1, aspartame 1.5,
Described Acyclovir dispersible tablet makes through following steps:
(a) pre-treatment: acyclovir was pulverized 100 mesh sieves, PVP K30 is dissolved in 50% ethanol, is mixed with w/v and is 50% alcoholic solution of 5% PVP K30;
(b) batching: take in proportion the microcrystalline Cellulose of acyclovir, lactose, half amount and the low-substituted hydroxypropyl cellulose mix homogeneously of half amount, obtain mixed material;
(c) granulate: in step (b) gained mixed material, add the alcoholic solution of PVP K30, mixing granulation, wet grain in 65 ± 5 ℃ dry, with 30 mesh sieve granulate;
(d) always mixed: step (c) gained granule is mixed homogeneously with the microcrystalline Cellulose of surplus, the low-substituted hydroxypropyl cellulose of surplus, magnesium stearate and the aspartame of proportional quantities;
(e) semi-finished product chemical examination, tabletting and get final product.
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| CN102988313A (en) * | 2011-09-14 | 2013-03-27 | 北京以岭生物工程技术有限公司 | Anastrozole dispersible tablet and preparation method thereof |
| CN104784126B (en) * | 2014-01-16 | 2018-09-21 | 南京瑞尔医药有限公司 | A kind of preparation method of Acyclovir Tablet composition |
| CN104784127A (en) * | 2014-01-16 | 2015-07-22 | 南京瑞尔医药有限公司 | Acyclovir tablet composition |
| CN104546750A (en) * | 2014-12-25 | 2015-04-29 | 海南卫康制药(潜山)有限公司 | Acyclovir composition freeze-dried tablet and preparation method thereof |
| CN104644585B (en) * | 2015-01-28 | 2018-09-18 | 康普药业股份有限公司 | A kind of acyclovir pharmaceutical composition |
| CN109662951A (en) * | 2018-12-31 | 2019-04-23 | 辰欣药业股份有限公司 | A kind of dispersion tablet of vasilowy hydrochlaride and its preparation process of high bioavilability |
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