CN102266300B - Gefitinib dispersible tablet and preparation method and application thereof - Google Patents
Gefitinib dispersible tablet and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a gefitinib dispersible tablet, a preparation method and an application thereof. The gefitinib dispersible tablet of the invention comprises the following components by weight: 10-65% of gefitinib, 1-30% of fillers, 10-50% of disintegrants, 1-60% of acidifiers, 0.1-20% of adhesives, and 0.1-30% of lubricants and glidants. According to the invention, gefitinib is wrapped by the acidifier or gefitinib and the acidifier are wrapped with each other so as to reach the embedding effect. Compared with commercially available common tablets, the gefitinib dispersible tablet of the invention does not contain surfactants, has good dissolvability, dispersibility and disintegrability, and can be disintegrated completely within one minute. The gefitinib dispersible tablet prepared by the method of the invention has a high dissolution rate, good bioavailability, rapid distribution in vivo, and stable quality, and the preparation method is simple and practical, and is applicable to industrial production.
Description
Technical field
The present invention relates to medical technical field, be specifically related to a kind of gefitinib dispersible tablet and its preparation method and application.
Background technology
The Chinese Third National coroner's inquest of China's Ministry of Public Health issue shows according in April, 2008, malignant tumor accounts for the first place of the city cause of death, and pulmonary carcinoma is the first place of Death Causes of Tumor, accounts for 22.7% of whole mortality of malignant tumors sums, and being obvious ascendant trend, Past 30 Years has risen 46.5%.Britain name oncologist R.Peto prophesy: if can not get timely control, will above 1,000,000, become the first in the world pulmonary carcinoma big country to the annual pulmonary carcinoma number of China in 2025.
The molecular targeted therapy of tumor (Molecular targeted therapy) is as target spot with the specific molecular in the tumor cell, utilize the biological function of this target spot of molecular targeted agents energy specific inhibition, thereby the malignant behaviors from molecular level reversing tumor cell, reaching the purpose that suppresses tumor growth, is the field that has vigor most in recent years, receives much attention.Molecular targeted agents mainly contains EGF-R ELISA (EGFR) family group inhibitor etc.
Gefitinib (gefitinib, C
22H
24CIFN
4O
3) be the selectivity epidermal growth factor recipient tyrosine kinase inhibitor, chemistry N-(3-chloro-4-fluorophenyl) by name-7-methoxyl group-6-(3-morpholine propoxyl group) quinazoline-4-amine.Gefitinib can be blocked EGFR and send proliferation signal to lung carcinoma cell, thereby suppresses cancer development, and survival is high, and toleration is better, and most of untoward reaction are slight and reversible, and the patient who stops to treat because of adverse effect only has 1%.
In August, 2002, gefitinib at first goes on the market in Japan as nonsmall-cell lung cancer first-line treatment medicine, and commodity are called Iressa (Iressa, ZD1839).In May, 2003, FDA (Food and Drug Adminstration) approval gefitinib becomes three line single therapy medicines through the invalid patients with advanced NSCLC of platinum kind anti-cancer drugs and Docetaxel chemotherapy.Be applied at present the treatment of advanced Non-small cell lung by state's approvals such as Australia, Japan, Argentina, Singapore and Korea S.On July 1st, 2009, drug administration of European Union official approval gefitinib is for the local late period of adult's EGFR gene mutation or the treatment of Metastatic Nsclc one line, two wires and three lines.On February 28th, 2005, Chinese food Drug Administration approval gefitinib is used for the treatment of local late period or the Metastatic Nsclc (NSCLC) that previously receives chemotherapy.Behind this indication, in November, 2010, Iressa is got permission again to be used for the treatment of epidermal growth factor recipient tyrosine kinase (EGFR TK) gene in China and is had the local late period of sensitizing mutation or Metastatic Nsclc patient's first-line treatment.The clinical research result shows at present, and Iressa is to east ethnic group (Asia is artificially main), women, non smoker, alveolar cell carcinoma or adenocarcinoma patient's the higher curative effect that has.
Gefitinib is embarrassed soluble substance, and from causing its bioavailability low.Sell in existing market is the gefitinib ordinary tablet only, and the average absolute bioavailability only is 59%, and is expensive, and it has added surfactant, and body is had certain zest.
Summary of the invention
The object of the invention is to according to existing gefitinib ordinary tablet exist expensive, add surfactant body had the problems such as stimulation, bioavailability be low, a kind of gefitinib dispersible tablet is provided, this dispersible tablet steady quality, stripping is fast, distributes in the body rapidly, and bioavailability is high, dispersibility, disintegrative are good, can disintegrate in two minutes complete, and this product do not contain surfactant, and can reduce stimulates body.
Another purpose of the present invention is to provide the preparation method of above-mentioned gefitinib dispersible tablet.
A further object of the invention is to provide the application of above-mentioned gefitinib dispersible tablet.
Above-mentioned purpose of the present invention is achieved by the following technical programs:
Can form aqueous solution limpid or slightly lacteous or suspension homogeneous, that can pass through 710 μ m aperture sieve after the dispersible tablet disintegrate, absorption is very fast, abundant, can improve the bioavailability of some insoluble drug, and working condition is without specific (special) requirements.Because gefitinib is insoluble drug, special one-tenth tablet formulation is to improve its bioavailability.
A kind of gefitinib dispersible tablet is comprised of following component according to the percetage by weight meter: gefitinib 10 ~ 65%, filler 10 ~ 30%, disintegrating agent 10 ~ 50%, acidulant 5 ~ 60%, binding agent 0.1 ~ 20%, lubricant and fluidizer 0.1 ~ 30%.
As a kind of preferred version, described filler is any one or the multiple mixture in starch, Icing Sugar, dextrin, lactose, microcrystalline Cellulose, the sugar alcohols.
As a kind of preferred version, described disintegrating agent is one or more the mixture in carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, cross-linked carboxymethyl cellulose sodium, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, the dried starch.
As a kind of preferred version, described acidulant is one or more the mixture in citric acid, lactic acid, acetic acid, ethanedioic acid, malonic acid, succinic acid, tartaric acid, adipic acid, malic acid, ascorbic acid, caffeic acid, fumaric acid, the phosphoric acid solution.
As a kind of preferred version, described binding agent is one or more the mixture in hypromellose, sodium carboxymethyl cellulose, starch, pregelatinized Starch, polyvidone, gelatin, Polyethylene Glycol, ethanol, the water, is particularly preferably polyvidone, hypromellose, sodium carboxymethyl cellulose, water, ethanol or its mixture.
As a kind of preferred version, described lubricant is but is not limited to magnesium stearate, Pulvis Talci or its mixture that fluidizer includes but not limited to micropowder silica gel.
The preparation method of the above-mentioned gefitinib dispersible tablet of the present invention is characterized in that comprising the steps:
(1) gefitinib and pharmaceutic adjuvant are sieved respectively; Binding agent be dissolved in concentration be 85% or following alcoholic solution or aqueous solution in after, the acidulant with recipe quantity is dissolved in the solution that contains binding agent again, obtains acid solution;
(2) gefitinib with the made acid solution embedding of step (1) after with filler, disintegrating agent, fluidizer mix homogeneously, add binding agent, mix, make soft material;
(3) soft material is crossed 14 ~ 30 mesh sieves, 40 ~ 70 ℃ of dryings, moisture Control is 2 ~ 5%, 14 ~ 30 order granulate;
(4) add lubricant, mix homogeneously;
(5) tabletting is made the gefitinib dispersible tablet.
As a kind of preferred version, described in the step (2) with sour embedding be with gefitinib and acid solution by the fluid bed embedding, or gefitinib is put into colloid mill with acid solution shears, dry again.
The prescription ratio of gefitinib dispersible tablet of the present invention is not by teaching material or other reference material gained, but by a large amount of testing program gained up to specification, made dispersible tablet has carried out quality research, meets that " 2010 editions two ones of Chinese pharmacopoeia are made the requirement of quality standard by oneself about dispersible tablet and other.Dissolution obviously is better than not adding acidulant or adds surfactant after finding dispersible tablet adding acidulant in the research.
Compared with prior art, the present invention has following beneficial effect:
(1) the present invention makes tablet formulation with gefitinib, and it is pioneering to belong to the whole world, can improve its bioavailability like this;
(2) the present invention granulates after adopting acidulant to process in the preparation of gefitinib dispersible tablet, and also belong to the applicant and propose first, be its unique innovative point;
(3) tablet formulation made of the present invention is compared with ordinary tablet, and stripping is rapid, and disintegrative is good, and fully disintegrate in 1 minute absorbs soon, and bioavailability is high, stable in properties;
(4) tablet formulation made of the present invention does not use surface active agent solubilization in the manufacturing process, and reducing stimulates body, has reduced the untoward reaction of medicine, has increased patient's compliance.
The specific embodiment
Further explain the present invention below in conjunction with embodiment, but embodiment does not do any type of restriction to the present invention.
Embodiment 1
Gefitinib 250g
Lactose 130g
Crospolyvinylpyrrolidone 25g
Carboxymethylstach sodium 50g
Hydroxypropyl methylcellulose 3.5g
Micropowder silica gel 15g
Magnesium stearate 7g
Water 53 g
95% ethanol 122g
Make 1000.
Preparation method:
Step 1: the gefitinib that will pulverize and pharmaceutic adjuvant are crossed respectively 120 mesh sieves, and hydroxypropyl methylcellulose is used first the hot water swelling, is stirred to dissolving, adds ethanol again, makes concentration of alcohol reach 70%.
Step 2: press recipe quantity with gefitinib, lactose, polyvinylpolypyrrolidone, micropowder silica gel mix homogeneously, add hypromellose solution described in the step 1 and make soft material.
Step 3: made soft material in the step 2 is crossed 18 mesh sieves granulate, 50 ℃ of dryings, moisture is 2.7%, 18 mesh sieve granulate.
Step 4: will make granule and magnesium stearate mix homogeneously in the step 3.
Step 5: semi-finished product detect, and determine that sheet is heavy, and tabletting namely gets the gefitinib dispersible tablet.
Embodiment 1 dispersible tablet smooth in appearance, dispersibility meet version pharmacopeia regulation in 2010, but dissolution is relatively poor.
Embodiment 2
Gefitinib 250g
Lactose 80g
Crospolyvinylpyrrolidone 14.3g
Carboxymethylstach sodium 20g
Hydroxypropyl methylcellulose 3.5g
Citric acid 100g
Micropowder silica gel 15g
Magnesium stearate 7.2g
Water 253g
95% ethanol 122g
Preparation method:
Step 1: the gefitinib that will pulverize and pharmaceutic adjuvant are crossed respectively 120 mesh sieves, and hydroxypropyl methylcellulose is used first the hot water swelling, is stirred to dissolving, adds ethanol again, makes concentration of alcohol reach 70%.Other gets above-mentioned hydroxypropyl methylcellulose solution 50g, adds 180g water, adds the citric acid mix homogeneously.
Step 2: in recipe quantity gefitinib and the step 1 citric acid solution through fluid bed acid embedding after with recipe quantity lactose, crospolyvinylpyrrolidone, carboxymethylstach sodium, micropowder silica gel mix homogeneously, add the hypromellose of residue described in the step 1 solution and make soft material.
Step 3: made soft material in the step 2 is crossed 16 mesh sieves granulate, 50 ℃ of dryings, moisture is 2.3%, 16 mesh sieve granulate.
Step 4: will make granule and magnesium stearate mix homogeneously in the step 3.
Step 5: semi-finished product detect, and determine that sheet is heavy, and tabletting namely gets the gefitinib dispersible tablet.
Embodiment 2 has added acidulant, has reduced the amount of disintegrating agent, and technique is optimized on the basis of embodiment 1, granulates after the first acidification again, finds the dispersible tablet smooth in appearance, and dissolution is better, but dispersibility is general, fully disintegrate in 3min.
Embodiment 3
Gefitinib 250g
Crospolyvinylpyrrolidone 20.9g
Carboxymethylstach sodium 50g
Hydroxypropyl methylcellulose 3.5g
Citric acid 100g
Micropowder silica gel 15g
Magnesium stearate 7.8g
Water 253g
95% ethanol 122g
Make 1000.
Preparation method is with embodiment 2.
Implementing 3 increases crospolyvinylpyrrolidone, carboxymethylstarch sodium content, and the dispersible tablet dispersibility meets 2010 editions pharmacopeia to the requirement of dispersible tablet, and dissolution is better.
Embodiment 4
Embodiment 4 is identical with embodiment 3 prescriptions, selects different acidify embedding modes, and namely gefitinib and acidulant solution are put into colloid mill shearing, again spray drying.The indices of dispersible tablet and the made dispersible tablet there was no significant difference of embodiment 3 prescriptions.
Embodiment 5
Gefitinib 250g
Lactose 80g
Dried starch 25g
Carboxymethylstach sodium 50g
Hydroxypropyl methylcellulose 3.5g
Citric acid 100g
Micropowder silica gel 15g
Magnesium stearate 7.8g
Water 235g
95% ethanol 81g
Preparation method:
Step 1: the gefitinib that will pulverize and pharmaceutic adjuvant are crossed respectively 100 mesh sieves, and hydroxypropyl methylcellulose is used first the hot water swelling, is stirred to dissolving, adds ethanol again, makes concentration of alcohol reach 70%.Get in addition more above-mentioned hydroxypropyl methylcellulose solution 40g, add 180g water, add the citric acid mix homogeneously.
Step 2: in recipe quantity gefitinib and the step 1 citric acid solution through fluid bed acid embedding after with recipe quantity lactose, dried starch, micropowder silica gel, carboxymethylstach sodium mix homogeneously, add remaining adhesive described in the step 1 and make soft material.
Step 3: made soft material in the step 2 is crossed 14 mesh sieves granulate, 60 ℃ of dryings, moisture is 3.2%, 14 mesh sieve granulate.
Step 4: will make granule and magnesium stearate mix homogeneously in the step 3.
Step 5: semi-finished product detect, and determine that sheet is heavy, and tabletting namely gets the gefitinib dispersible tablet.
Embodiment 5 usefulness dried starch substitute crospolyvinylpyrrolidone, and all the other are constant, find that dispersibility is poor than embodiment 3.
Embodiment 6
Gefitinib 250g
Lactose 80g
Crospolyvinylpyrrolidone 25g
Carboxymethylstach sodium 50g
Starch 3.5g
Citric acid (1) 70g
Citric acid (2) 30g
Micropowder silica gel 15g
Magnesium stearate 7.8g
Water 375g
Preparation method:
Step 1: the gefitinib that will pulverize and pharmaceutic adjuvant are crossed respectively 120 mesh sieves, and starch adds water and makes starch slurry.Get the starch slurry 50g for preparing, stir adding 180g water, then add citric acid (1), mix homogeneously.
Step 2: in recipe quantity gefitinib and the step 1 the part acid solution through fluid bed acid embedding after with recipe quantity lactose, crospolyvinylpyrrolidone, carboxymethylstach sodium, micropowder silica gel, citric acid (2) mix homogeneously, add remaining starch slurry described in the step 1 and make soft material.
Step 3: made soft material in the step 2 is crossed 24 mesh sieves granulate, 60 ℃ of dryings, moisture is 3.1%, 24 mesh sieve granulate.
Step 4: will make granule and magnesium stearate mix homogeneously in the step 3.
Step 5: semi-finished product detect, and determine that sheet is heavy, and tabletting namely gets the gefitinib dispersible tablet.
Embodiment 6 starch in replace hydroxypropyl methylcellulose, all the other are constant, find that made dispersible tablet hardness descends to some extent at equal pressure condition lower sheeting, but also meet 2010 editions pharmacopeia dispersible tablet standards.
Embodiment 7
Gefitinib 250g
Lactose 80g
Crospolyvinylpyrrolidone 25g
Carboxymethylstach sodium 50g
Polyvidone 5g
Citric acid 100g
Micropowder silica gel 15g
Magnesium stearate 7.8g
Water 251g
95% ethanol 48g
Preparation method:
Step 1: the gefitinib that will pulverize and pharmaceutic adjuvant are crossed respectively 120 mesh sieves, and polyvidone is blunged to dissolving, adds ethanol again, makes concentration of alcohol reach 70%.Get povidone solution 50g, stir adding 200g water, then add the about 70g of citric acid, mix homogeneously.
Step 2: in recipe quantity gefitinib and the step 1 the citric acid acid solution through fluid bed acid embedding after with recipe quantity lactose, crospolyvinylpyrrolidone, micropowder silica gel, residue citric acid mix homogeneously, add remaining adhesive described in the step 1 and make soft material.
Step 3: made soft material in the step 2 is crossed 18 mesh sieves granulate, 50 ℃ of dryings, moisture is 2.8%, 18 mesh sieve granulate.
Step 4: will make granule and magnesium stearate mix homogeneously in the step 3.
Step 5: semi-finished product detect, and determine that sheet is heavy, and tabletting namely gets the gefitinib dispersible tablet.
Embodiment 7 usefulness polyvidones substitute hydroxypropyl methylcellulose, and all the other are constant, find that made dispersible tablet hardness is poor than embodiment 5 at equal pressure condition lower sheeting, and good than embodiment 6, the dispersible tablet dissolution is good, and dispersibility satisfies 2010 editions pharmacopeia dispersible tablet standards.
Embodiment 8
Gefitinib 250g
Starch 80g
Crospolyvinylpyrrolidone 25g
Carboxymethylstach sodium 50g
Hydroxypropyl methylcellulose 3.5g
Citric acid 100g
Micropowder silica gel 15g
Magnesium stearate 7.8g
Water 254g
95% ethanol 122g
Make 1000.
Preparation method is with embodiment 2.
Embodiment 8 changes filler, replaces lactose with starch, and all the other are same with embodiment 3, dispersible tablet and embodiment 3 made dispersible tablet there was no significant differences, and dispersibility and dissolution are all better.
Embodiment 9
Gefitinib 250g
Icing Sugar 80g
Crospolyvinylpyrrolidone 25g
Carboxymethylstach sodium 50g
Hydroxypropyl methylcellulose 3.5g
Citric acid 100g
Micropowder silica gel 15g
Magnesium stearate 7.8g
Water 253g
95% ethanol 122g
Make 1000.
Preparation method is with implementing 2.
Embodiment 9 changes filler, replaces lactose with Icing Sugar, and all the other are same with embodiment 3, dispersible tablet and embodiment 3 made dispersible tablet there was no significant differences, and dispersibility and dissolution are all better.
Embodiment 10
Gefitinib 250g
Crospolyvinylpyrrolidone 21g
Carboxymethylstach sodium 50g
Hydroxypropyl methylcellulose 3.5g
Citric acid 100g
Micropowder silica gel 15g
Magnesium stearate 7.8g
Water 288g
95% ethanol 88g
Make 1000.
Preparation method:
Step 1: the gefitinib that will pulverize and pharmaceutic adjuvant are crossed respectively 120 mesh sieves, and hydroxypropyl methylcellulose is used first the hot water swelling, is stirred to dissolving, adds ethanol again, makes concentration of alcohol reach 50%.Get hydroxypropyl methylcellulose solution 50g, stir adding 200g water, then add citric acid, mix homogeneously.
Step 2: in recipe quantity gefitinib and the step 1 citric acid solution through fluid bed acid embedding after with recipe quantity crospolyvinylpyrrolidone, carboxymethylstach sodium, micropowder silica gel mix homogeneously, add remaining hypromellose solution described in the step 1 and make soft material.
Step 3: made soft material in the step 2 is crossed 16 mesh sieves granulate, 45 ℃ of dryings, moisture is 2.1%, 16 mesh sieve granulate.
Step 4: will make granule and magnesium stearate mix homogeneously in the step 3.
Step 5: semi-finished product detect, and determine that sheet is heavy, and tabletting namely gets the gefitinib dispersible tablet.
Embodiment 11
Gefitinib 250g
Crospolyvinylpyrrolidone 21g
Carboxymethylstach sodium 50g
Hydroxypropyl methylcellulose 3.5g
Citric acid (1) 80g
Citric acid (2) 20g
Micropowder silica gel 15g
Magnesium stearate 7.8g
Water 302g
95% ethanol 44g
Make 1000.
Preparation method:
Step 1: the gefitinib that will pulverize and pharmaceutic adjuvant are crossed respectively 120 mesh sieves, and hydroxypropyl methylcellulose is used first the hot water swelling, is stirred to dissolving, adds ethanol again, makes concentration of alcohol reach 25%.Get hydroxypropyl methylcellulose solution 50g, stir adding 170g water, then add citric acid (1), mix homogeneously.
Step 2: in recipe quantity gefitinib and the step 1 citric acid solution through fluid bed acid embedding after with recipe quantity crospolyvinylpyrrolidone, carboxymethylstach sodium, micropowder silica gel, citric acid (2) mix homogeneously, add remaining hypromellose solution described in the step 1 and make soft material.
Step 3: made soft material in the step 2 is crossed 24 mesh sieves granulate, 50 ℃ of dryings, moisture is 3.2%, 24 mesh sieve granulate.
Step 4: will make granule and magnesium stearate mix homogeneously in the step 3.
Step 5: semi-finished product detect, and determine that sheet is heavy, and tabletting namely gets the gefitinib dispersible tablet.
Embodiment 10, embodiment 11 find that impact is little, because ethanol has volatility, so can select 25% dissolve with ethanol solution, convenient operation with the dissolve with ethanol of adhesive with variable concentrations.
Embodiment 12
Gefitinib 250g
Lactose 80g
Crospolyvinylpyrrolidone 25g
Carboxymethylstach sodium 50g
Hydroxypropyl methylcellulose 3.5g
Citric acid (1) 75g
Citric acid (2) 25g
Micropowder silica gel 15g
Magnesium stearate 8.3g
Water 312g
95% ethanol 44g
Preparation method is with embodiment 11.
Embodiment 12 made dispersible tablet smooth in appearance, dispersibility, dissolution are better.
Embodiment 13
Gefitinib 250g
Lactose 80g
Crospolyvinylpyrrolidone 25g
Carboxymethylstach sodium 50g
Hydroxypropyl methylcellulose 3.5g
Citric acid 50g
Micropowder silica gel 15g
Magnesium stearate 7.3g
Water 332g
95% ethanol 44g
Preparation method:
Step 1: the gefitinib that will pulverize and pharmaceutic adjuvant are crossed respectively 120 mesh sieves, and hydroxypropyl methylcellulose is used first the hot water swelling, is stirred to dissolving, adds ethanol again, makes concentration of alcohol reach 25%.Get hydroxypropyl methylcellulose solution 50g, stir adding 180g water, then add citric acid, mix homogeneously.
Step 2: in recipe quantity gefitinib and the step 1 citric acid solution through fluid bed acid embedding after with recipe quantity crospolyvinylpyrrolidone, carboxymethylstach sodium, micropowder silica gel mix homogeneously, add remaining hypromellose solution described in the step 1 and make soft material.
Step 3: made soft material in the step 2 is crossed 24 mesh sieves granulate, 50 ℃ of dryings, moisture is 3.2%, 24 mesh sieve granulate.
Step 4: will make granule and magnesium stearate mix homogeneously in the step 3.
Step 5: semi-finished product detect, and determine that sheet is heavy, and tabletting namely gets the gefitinib dispersible tablet.
Embodiment executes 13 made dispersible tablet smooth in appearance, and dissolution is better, and dispersibility is prepared poor than embodiment 12.
Embodiment 12, embodiment 13: adopt the acid of different proportion, find within the specific limits, acid content is higher, and its dissolution is better, but gefitinib at pH less than 1 o'clock, its dissolubility can descend, and it is too many to add acid, may zest be arranged to stomach, adds acid very little, may cause dispersible tablet dispersibility variation, so can select the acid of an intermediate concentration.
Embodiment 14
Gefitinib 250g
Lactose 80g
Crospolyvinylpyrrolidone 25g
Carboxymethylstach sodium 50g
Hydroxypropyl methylcellulose 3.5g
Fumaric acid 100g
Micropowder silica gel 15g
Magnesium stearate 7.8g
Water 332g
95% ethanol 44g
Preparation method is with embodiment 13.
Embodiment 14 has selected a fumaric acid to replace citric acid, the every detection of dispersible tablet and embodiment 3 made dispersible tablet there was no significant differences.
Embodiment 15
Gefitinib 250
Starch 80g
Crospolyvinylpyrrolidone 25g
Carboxymethylstach sodium 50g
Hydroxypropyl methylcellulose 3.5g
Adipic acid 100g
Micropowder silica gel 15g
Magnesium stearate 7.8g
Water 332g
95% ethanol 44g
Make 1000.
Preparation method is with embodiment 13.
Embodiment 15 made dispersible tablet smooth in appearance, dispersibility meet 2010 editions pharmacopeia dispersible tablet standards, dissolution is better.
Embodiment 16
Gefitinib 250
Starch 80g
Crospolyvinylpyrrolidone 25g
Carboxymethylstach sodium 50g
Hydroxypropyl methylcellulose 3.5g
Malic acid 100g
Micropowder silica gel 15g
Magnesium stearate 7.8g
Water 332g
95% ethanol 44g
Preparation method is with embodiment 13.
Embodiment 16 made dispersible tablet smooth in appearance, dissolution are good, and dispersibility is slightly poorer than adopting citric acid, fumaric acid to do the dispersible tablet of acidulant.
The monitoring of gefitinib dispersible tablet indices:
(1) table 1 is to implement 1 prescription and preparation method, the assay of three batch samples of producing according to specific embodiments.
Table 1 gefitinib dispersible tablet assay
Can find out that the every monitoring index of gefitinib dispersible tablet all meets country to the index request of dispersible tablet, and its disintegrate is fast from 1, can disintegrate in 1min complete.
(2) table 2 is sold the dissolution comparative result of gefitinib ordinary tablet for gefitinib dispersible tablet and market.
With reference to dissolution method (2010 editions two appendix XC two methods of Chinese Pharmacopoeia).
Ordinary tablet cumulative percentage dissolution is sold relatively in table 2 gefitinib dispersible tablet and market
As can be seen from Table 2, the dissolution in vitro of gefitinib dispersible tablet in 20min obviously is better than ordinary tablet.
(3) gefitinib dispersible tablet assay
Measure with reference to high-efficient liquid phase technique (two appendix VD of Chinese Pharmacopoeia version in 2010).
Table 3 gefitinib dispersible tablet assay
| Lot number | Gefitinib dispersible tablet content (%) |
| 1010171 | 100.42 |
| 1010172 | 101.03 |
| 1010173 | 100.57 |
As can be seen from Table 3, the content of gefitinib dispersible tablet requirement up to specification.
(4) quality stability of gefitinib dispersible tablet relatively
Gefitinib dispersible tablet accelerated test: the gefitinib dispersible tablet of blister package is put under the condition of 40 ℃ ± 2 ℃ of temperature, relative humidity 75% ± 5% and placed six months, outcome quality is stable, indices such as table 4.
Six months accelerated test testing results of table 4 gefitinib dispersible tablet
| The inspection item lot number | Outward appearance | Disintegration | Dispersing uniformity | Dissolution % | Content % |
| 1010171 | Faint yellow smooth | 40” | Up to specification | 100.14 | 100.09 |
| 1010172 | Faint yellow smooth | 39” | Up to specification | 99.98 | 99.98 |
| 1010173 | Faint yellow smooth | 42” | Up to specification | 102.76 | 100.49 |
Claims (2)
1. a gefitinib dispersible tablet is characterized in that being comprised of following component according to the percetage by weight meter: gefitinib 10 ~ 65%, filler 10 ~ 30%, disintegrating agent 10 ~ 50%, acidulant 5 ~ 60%, binding agent 0.1 ~ 20%, lubricant and fluidizer 0.1 ~ 30%;
Wherein, described filler is any one or the multiple mixture in starch, Icing Sugar, dextrin, lactose, microcrystalline Cellulose, the sugar alcohols;
Described disintegrating agent is one or more the mixture in carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, cross-linked carboxymethyl cellulose sodium, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, the dried starch;
Described acidulant is one or more the mixture in citric acid, lactic acid, acetic acid, ethanedioic acid, malonic acid, succinic acid, tartaric acid, adipic acid, malic acid, ascorbic acid, caffeic acid, fumaric acid, the phosphoric acid solution;
Described binding agent is one or more the mixture in hypromellose, sodium carboxymethyl cellulose, starch, pregelatinized Starch, polyvidone, gelatin, Polyethylene Glycol, ethanol, the water;
Described lubricant and fluidizer are one or more mixture of micropowder silica gel, magnesium stearate, Pulvis Talci, Polyethylene Glycol apoplexy due to endogenous wind.
2. the preparation method of the described gefitinib dispersible tablet of claim 1 is characterized in that comprising the steps:
(1) gefitinib and pharmaceutic adjuvant are sieved respectively; Binding agent be dissolved in concentration be 85% or following alcoholic solution or aqueous solution in after, the acidulant with recipe quantity is dissolved in the solution that contains binding agent again, obtains acid solution;
(2) gefitinib with the made acid solution embedding of step (1) after with filler, disintegrating agent, fluidizer mix homogeneously, add binding agent, mix, make soft material;
(3) soft material is crossed 14 ~ 30 mesh sieves, 40 ~ 70 ℃ of dryings, moisture Control is 2 ~ 5%, 14 ~ 30 order granulate;
(4) add lubricant, mix homogeneously;
(5) tabletting is made the gefitinib dispersible tablet.
3. the preparation method of gefitinib dispersible tablet according to claim 2, it is characterized in that described in the step (2) that with sour embedding be by the fluid bed embedding with gefitinib and acid solution, or gefitinib is put into colloid mill with acid solution shear, dry again.
4. gefitinib dispersible tablet claimed in claim 1 has application in the medicine of local late period of sensitizing mutation or Metastatic Nsclc at preparation treatment epidermal growth factor recipient tyrosine kinase gene.
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Cited By (1)
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|---|---|---|---|---|
| US20140031352A1 (en) * | 2012-07-24 | 2014-01-30 | Laurus Labs Private Limited | Solid forms of tyrosine kinase inhibitors, process for the preparation and their pharmaceutical composition thereof |
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| CN104586798A (en) * | 2015-01-04 | 2015-05-06 | 成都恒瑞制药有限公司 | Gefitinib dispersible tablet and preparation method thereof |
| CN106913544B (en) * | 2015-12-28 | 2019-08-30 | 山东新时代药业有限公司 | A kind of Gefitinib tablet of Fast Stripping and preparation method thereof |
| TWI750152B (en) | 2016-03-01 | 2021-12-21 | 大陸商江蘇恆瑞醫藥股份有限公司 | A pharmaceutical composition comprising pyrrolo six-member heterocyclic compound or its medicinal salt thereof |
| CN108096251B (en) * | 2016-11-24 | 2021-11-16 | 江苏恒瑞医药股份有限公司 | Gefitinib pharmaceutical composition and preparation method thereof |
| CN111035619B (en) * | 2018-10-12 | 2023-02-28 | 四川科伦药物研究院有限公司 | Gefitinib tablet and preparation method thereof |
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Cited By (1)
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| US20140031352A1 (en) * | 2012-07-24 | 2014-01-30 | Laurus Labs Private Limited | Solid forms of tyrosine kinase inhibitors, process for the preparation and their pharmaceutical composition thereof |
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Application publication date: 20111207 Assignee: Haikou Nanlu Pharm-Tech Co., Ltd. Assignor: Guangdong Pharmaceutical University Contract record no.: 2015460000003 Denomination of invention: Gefitinib dispersible tablet and preparation method and application thereof Granted publication date: 20130102 License type: Exclusive License Record date: 20150504 |
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Address after: 510220 40 Haizhuqu District, Guangdong, Guangzhou. Patentee after: Guangdong Pharmaceutical University Address before: 510006 No. 280 East Ring Road, Guangzhou City University, Guangdong Patentee before: Guangdong Pharmaceutical University |