CN103006608A - Drug composition containing gefitinib - Google Patents
Drug composition containing gefitinib Download PDFInfo
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- CN103006608A CN103006608A CN201210566665XA CN201210566665A CN103006608A CN 103006608 A CN103006608 A CN 103006608A CN 201210566665X A CN201210566665X A CN 201210566665XA CN 201210566665 A CN201210566665 A CN 201210566665A CN 103006608 A CN103006608 A CN 103006608A
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- 239000005411 L01XE02 - Gefitinib Substances 0.000 title claims abstract description 168
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 title claims abstract description 166
- 229960002584 gefitinib Drugs 0.000 title claims abstract description 142
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a drug composition containing gefitinib, in particular to a tablet comprising the gefitinib. The tablet containing the gefitinib is made of the gefitinib with the particle size distribution as follows: D(0.1) is equal to 2-6mm, D(0.5) is equal to 11-20mm, and D(0.9) is equal to 35-50mm. According to the drug composition, active ingredients can be released continuously and stably, and the drug composition has a good treatment effect on the local advanced lung cancer or metastatic non-small cell lung cancer subjected to the chemotherapy in the past.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition that contains gefitinib, this pharmaceutical composition is specially the tablet that contains gefitinib, and this gefitinib tablet is sustainable, release of active ingredients is brought into play drug effect reposefully, belongs to field of pharmaceutical preparations.
Background technology
Gefitinib (chemical name: N-(3-chloro-4-fluorophenyl)-7-methoxyl group-6-(3-morpholine propoxyl group) quinazoline-4-amine), be a kind of selectivity EGF-R ELISA (EGFR) tyrosine kinase inhibitor, be applicable to epidermal growth factor recipient tyrosine kinase (EGFR TK) gene and have the local late period of sensitizing mutation or Metastatic Nsclc (NSCLC) patient's three lines, two wires even first-line treatment.
Gefitinib sheet (trade name " Iressa ", Iressa) at first develops (often being called former grinding) by Britain AstraZeneca pharmaceutical Co. Ltd, its effective percentage in asian ancestry crowd was higher by the three line medicines listing of the U.S., Japan's approval conduct treatment nonsmall-cell lung cancer in 2003.Studies show that subsequently, its curative effect and EGFR sudden change are closely related, and obtain the listing of European Union drugs administration approved on July 1st, 2009 and be target therapeutic agent, be used for local late period or Metastatic Nsclc one line, two wires and the treatment of three lines of adult's EGFR gene mutation.In December, 2004, " Iressa " enters China, be used for local late period or Metastatic Nsclc that the past receives chemotherapy, in the end of the year 2010, " Iressa " got permission again to be used for the treatment of the epidermal growth factor recipient tyrosine kinase gene in China and had the local late period of sensitizing mutation or Metastatic Nsclc patient's first-line treatment.
At present, worldwide only has AstraZeneca pharmaceutical Co. Ltd and India NATCO Pharma company this kind of production and sales, because (AstraZeneca produces the gefitinib sheet to Iressa, together lower) expensive (about 600 yuan/sheet), the have to gefitinib sheet of the relatively cheap India NATCO Pharma company of choice for use of many patients, but find the non-constant of In Vitro Dissolution of the gefitinib tablet that India NATCO Pharma company produces by comparative study.
Behind the solid preparation oral administration, the absorption of medicine depend on medicine from preparation stripping or release, medicine under physiological condition dissolving and permeate at gastrointestinal.Because the stripping of medicine has material impact to absorption, therefore, the dissolution in vitro test can be predicted behavior in its body to a certain extent.Gefitinib is in BCS(biological agent categorizing system) in belong to low-solubility-high osmosis medicine, the stripping of such medicine is the rate-limiting step of drug absorption, has preferably inside and outside dependency; Namely can indirectly reflect the drug disposition dispose procedure by the stripping curve of measuring in the external different medium; Therefore, the In Vitro Dissolution of gefitinib preparation in different dissolution mediums can be used as the important indicator of estimating curative effect of medication.
Gefitinib is insoluble drug, its dissolubility in aqueous solution is the pH dependency, namely dissolubility is larger in the lower aqueous solution of pH, almost insoluble in the water of pH value about 7, therefore, Europe, the United States measure for the In Vitro Dissolution of this product, all selecting 5% tween 80 aqueous solution is dissolution medium, the gefitinib sheet only stripping about 30% in 60 minutes of India NATCO Pharma company under this condition, dissolution does not obviously rise in the time of 90 minutes, illustrate that a large amount of gefitinibs do not discharge at all, also just can't reach treatment valid density.And Iressa is that gefitinib how to realize slightly solubility continues, Stable Release, without any document or books it is studied, discloses so far.
In addition, find in the experimental study to the Iressa on the market, its stability is unsatisfactory, obvious change has occured in the stripping curve near effect phase product, even in being very easy to the hydrochloric acid solution that discharges, dissolution also dropped to about 75% by 99% in 45 minutes, can not reach the quality standard requirement of this medicine.That is to say that the release in vivo of this medicine can not well reach the required speed for the treatment of, the decline that this can cause curative effect undoubtedly gently then prolongs the healing cycle, and is heavy then delay treatment best period so that patient lose the chance of rehabilitation.
Therefore, be badly in need of providing a kind of and can continue, stable and discharge gefitinib fully, and have the gefitinib preparation of good stability, compliance, make the many a kind of super quality and competitive price of extensive patients, medicine is selected safely and effectively.
Summary of the invention
The tablet that the purpose of this invention is to provide a kind of gefitinib of super quality and competitive price, said preparation have that drug release continues, stable and characteristics completely, have good bioavailability and stability.
For solving the technical problem of present existence, the present invention adopts following technical scheme:
The invention provides a kind of pharmaceutical composition that contains gefitinib, this pharmaceutical composition is the gefitinib tablet, this gefitinib tablet contains the gefitinib of effective therapeutic dose, gefitinib total amount in the sheet is as 100%, the particle size distribution of this gefitinib is: D (0.1)=2 ~ 6 μ m, D (0.5)=11 ~ 20 μ m, D (0.9)=35 ~ 50 μ m.
D represents the diameter of powder granule, D(0.1) can be written as D10 again, corresponding particle diameter when the cumulative particle sizes percentile that refers to a sample reaches 10%.To be particle diameter account for 90% greater than its granule to its physical significance, accounts for 10% less than its granule.In like manner, D(0.5) physical significance is to account for 50% less than its granule; D(0.9) physical significance is to account for 90% less than its granule.Therefore, the particle size distribution of the gefitinib that gefitinib tablet of the present invention contains can be interpreted as, the granularity of 90% gefitinib is less than 50um and greater than 35um, and the granularity of 50% gefitinib is less than 20um and greater than 11um, and the granularity of 10% gefitinib is less than 6um and greater than 2um.
In 10 years of the clinical practice of gefitinib sheet, be widely used in previously accepting the treatment of chemotherapeutical local advanced lung cancer or Metastatic Nsclc, especially to patient's total effective rate for the treatment of non-small cell gland pulmonary carcinoma and gene mutation up to 50%, particularly in the Asia, curative effect is more remarkable, and effective percentage reaches more than 70%.And it is also few to the preparation research of gefitinib both at home and abroad, in the worldwide, the Britain AstraZeneca pharmaceutical Co. Ltd that only has of having gone on the market at present produces gefitinib sheet (Iressa), and the Counterfeit Item gefitinib sheet of India NATCO Pharma production (this kind is only sold in India at present).The imitated gefitinib sheet of India NATCO Pharma company wherein, its quality and curative effect all do not obtain authoritative department and numerous clinicians' approval, and occur clinically Iressa is replaced to the case that occurs Relapse rate even deterioration behind India's gefitinib sheet.This phenomenon illustrates to a certain extent makes the preparation not a duck soup that quality is steady, curative effect is good and be convenient to take with gefitinib.
The Iressa research and development time were once done pharmacological evaluation, the gefitinib rate of release is investigated the impact of drug effect, thereby obtained the present commercially available Iressa of drug effect the best, and therefore, the present invention studies take the stripping curve of Iressa as standard.
In order to make gefitinib tablet of the present invention reach the effect suitable with the Iressa rate of release in tween 80 aqueous medium of 5%, the inventor tested several different methods, such as adding disintegrating agent, solubilizing agent and with raw material micronization etc. in prescription.Found that to add quick disintegration rate little on the impact of the dissolution rate of gefitinib, particularly after 30 minutes; The solubilizing agent effect of different cultivars and consumption is also very limited; Only have after the micronization processes gefitinib sheet stripping of (the about 10 μ m of granularity) very fast, can reach more than 50% in 10 minutes, prominent release problem (clinical manifestation is the too fast mistake that absorbs the drug but produced, toxic and side effects increases), therefore, the method for conventional solution insoluble drug stripping problem all can not make the gefitinib sheet reach lasting, steadily and the requirement that discharges fully.
Through great many of experiments and analysis, the granularity that the applicant finds gefitinib has appreciable impact to the stripping of its tablet, this impact is not that thinner (granularity is less) as conventional insoluble drug is better, but relevant with varigrained distribution within the specific limits, namely, when the particle size distribution of gefitinib is: D (0.1)=2 ~ 6 μ m, D (0.5)=11 ~ 20 μ m, D (0.9)=35 ~ 50 μ m(is take the gefitinib total amount as 100%, together lower) time, the stripping curve of gefitinib tablet of the present invention is similar to Iressa, f
2Value (similar factors) is not less than 60.This particle size range and concrete distribution situation without any open or instruction, also can't draw by the limited number of time test in conjunction with general knowledge known in this field in state of the art.
For making the gefitinib release in the gefitinib tablet of the present invention more steady, the particle size distribution of used gefitinib is preferably: D (0.1)=2 ~ 5 μ m, D (0.5)=11 ~ 18 μ m, D (0.9)=35 ~ 45 μ m; More preferably: D (0.1)=3 ~ 4 μ m, D (0.5)=13 ~ 16 μ m, D (0.9)=37 ~ 43 μ m, at this moment, the stripping curve of gefitinib tablet of the present invention and the f of Iressa
2Value is not less than 75.
In a preferred embodiment, select particle size distribution to be: D (0.1)=3 μ m, D (0.5)=13 μ m, the gefitinib tablet of the present invention that the gefitinib of D (0.9)=40 μ m makes, its stripping curve is compared closely similar with Iressa, f
2Value is up to 87.
Find by the experimental study to the Iressa on the market, its less stable, near effect duration product stripping curve with than the new production product notable difference is arranged, whole stripping is slowed down, and total dissolution reduces, based on the principle of inside and outside dependency, can infer that the release in vivo of this medicine can not well reach the required speed for the treatment of, the decline that this can cause curative effect undoubtedly gently then prolongs the healing cycle, and is heavy then delay treatment best period so that patient lose the chance of rehabilitation.For this reason, the applicant has carried out 24 months investigation of long-time stability to gefitinib tablet of the present invention, and its content, related substance and stripping curve all do not have significant change as a result, have good stability, and can ensure the therapeutic effect of sufferer.
The pharmaceutic adjuvant that also contains this area routine dose in the gefitinib tablet of the present invention, this pharmaceutic adjuvant are the tablet adjuvant of this area routine, and this tablet comprises filler, disintegrating agent, binding agent, solubilizing agent, wetting agent, lubricant with adjuvant.It is poor that gefitinib is met light stability, therefore preferably contain film coating pre-mix dose in the excipient substance of gefitinib tablet of the present invention, the film coating pre-mix dose of stomach dissolution type particularly, this stomach dissolved film coating pre-mix dose form and comprise polyvinyl alcohol, Liquid Macrogol, titanium dioxide, yellow ferric oxide and red ferric oxide.
Described filler is selected from one or more in lactose, microcrystalline Cellulose and the mannitol, a kind of or its combination in preferred lactose, the microcrystalline Cellulose; Described disintegrating agent is selected from one or more in cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, low-substituted hydroxypropyl methylcellulose, the carboxymethyl starch sodium, preferred cross-linking sodium carboxymethyl cellulose; Described solubilizing agent be selected from sodium lauryl sulphate, tween 80, stearic acid sodium sulfonate one or more, preferably sodium dodecyl sulfate.
The present invention also provides the preparation method of above-mentioned gefitinib sheet, and the method comprises:
⑴ get gefitinib and filler, disintegrating agent, solubilizing agent mix homogeneously;
⑵ be dissolved in wetting agent with binding agent, joins soft material processed in the step ⑴ gained mixture, granulation, drying;
⑶ join lubricant in the dried granule of step ⑵ gained, mixing, and tabletting gets label;
⑷ add water with film coating pre-mix dose and be made into coating solution, and the label of step ⑶ gained is carried out coating, gets described gefitinib tablet.
The preparation method of above-mentioned gefitinib sheet further is:
⑴ get gefitinib and lactose, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose and sodium lauryl sulphate mixing;
⑵ join soft material processed in the step ⑴ gained mixture with the water-soluble binding agent of making of PVP K30, granulation, dry, granulate;
⑶ get magnesium stearate and join in the dried granule of step ⑵ gained, mixing, and tabletting gets label;
⑷ add water with stomach dissolved film coating pre-mix dose and be made into coating solution, and the label of step ⑶ gained is carried out coating, obtains gefitinib tablet of the present invention.
The present invention also provides described gefitinib tablet preparing the application for the treatment of in the medicine of previously accepting chemotherapeutical local advanced lung cancer or Metastatic Nsclc.
The inventor verifies by experiment that further the gefitinib particle size distribution is on the impact of gefitinib tablet stripping.
Reiterate: following experiment is the exemplary experiment in numerous tests in the development process of the present invention, do not contained with limit all experiments that the invention people does for the present invention, purpose only is to set forth the gefitinib particle size distribution to the impact of gefitinib tablet of the present invention stripping with those data.
One, gefitinib tablet formulation screening of the present invention
1, test sample: prepare the gefitinib sheet by prescription 1-9 and the described preparation method of description in table 1, the table 2.
2, experimental technique: take 5%(v/v) the tween 80 aqueous solution is dissolution medium, investigates the stripping curve of test sample.
Operational approach: dissolution method (two appendix X of Chinese Pharmacopoeia version in 2010 C the second method)
Rotating speed: per minute 50 turns; Sample time: 10,20,30,45,60 minutes; Need testing solution: get solution 10ml, filter, precision is measured subsequent filtrate 2ml, puts in the 50ml volumetric flask, adds the stripping medium to scale; Reference substance solution: 10 μ g/ml; Assay method: UV method; Measure wavelength: 334nm.
3, experimental result: see table 1, table 2 for details.
Table 1 gefitinib tablet disintegrant prescription screening
Table 2 gefitinib tablet solubilizing agent prescription screening
Annotate: f2 value＞50 are similar.
Table 1 and table 2 experimental result show, kind, adding method and the use amount of different disintegrating agents is larger on the disintegration rate impact of gefitinib sheet, strengthen the disintegrating agent consumption and can significantly accelerate disintegration rate, but on almost not impact of dissolution rate (stripping curve), particularly after 30 minutes; Equally, the solubilizing agent of different cultivars and consumption is also very limited to improving the stripping curve effect; Adopted the tablet of the gefitinib preparation of 100 orders (150 μ m), in any case adjust disintegrating agent kind, consumption and adding method, comprise the use solubilizing agent, all do not realize improving the purpose of dissolution rate, compare with Iressa, the f2 value all is lower than 20, can't reach the medical effect suitable with Iressa at all.
Two, gefitinib tablet material particle filter of the present invention
1, test sample: the tablet of making according to embodiment 1 formulation and technology with the different grain size gefitinib.
2, experimental technique: with experiment ", gefitinib tablet formulation of the present invention screening ".
3, experimental result: see table 3 for details.
Table 3 gefitinib tablet material particle filter result
Above experimental result shows, the stripping of gefitinib and the granularity of its raw material and be distributed with substantial connection.The dissolution rate of the gefitinib sheet of (the about 10 μ m of granularity) is obviously accelerated behind the raw material micronization, can reach more than 50% in 10 minutes, but bring simultaneously the prominent problem of releasing; Even if recognize that particle size distribution is to importance of the present invention, can not obtain easily realizing the particle size distribution of the object of the invention, as write out a prescription 13, although f2 value＞50, but still have the prominent problem of releasing, only the suitable distribution of the different grain size in a specified particle size scope just can make the gefitinib sheet reach lasting, stable and discharge completely purpose.The gefitinib tablet of the present invention wherein gefitinib of contained effective dose is that form with above-mentioned gefitinib raw material exists.
Three, gefitinib tablet of the present invention and commercially available with the dissolution comparison of product in different medium
1, test sample: the present invention is lucky described non-for Buddhist nun's tablet, lot number: 100827 self-controls (formulation and technology is with embodiment 1); Iressa, lot number: HB751 is available from AstraZeneca pharmaceutical Co. Ltd; Gefitinib sheet (India) is called for short, the seal product, and lot number: 600840, available from NATCO PHARMA LIMITED.
2, experimental technique:
Respectively take 5%(v/v) Tween 80 aqueous solution, 0.1mol/L hydrochloric acid solution, pH4.5 acetate buffer and 5%(v/v) tween 80 pH6.8 phosphate buffer is dissolution medium, investigates by the stripping curve of test sample.Operational approach is with experiment ", gefitinib tablet formulation of the present invention screening ".
3, experimental result: the stripping situation of three test samples in different dissolution mediums sees table 4 for details.
The dissolution of table 4 three test samples in different dissolution mediums
Can find out that from above experimental result gefitinib tablet of the present invention release profiles and Iressa under equal conditions is closely similar, the f2 value is up to 87.5.Because gefitinib has good inside and outside dependency, so be interpreted as, gefitinib tablet of the present invention has the medical effect suitable with Iressa.
Stripping curve figure sees Figure of description 1.
Four, gefitinib tablet long-term stable experiment of the present invention
1, test sample: gefitinib sheet of the present invention, lot number: 100827, self-control.Iressa, lot number: HB751(date of manufacture: 2010.05), available from AstraZeneca pharmaceutical Co. Ltd;
2, experimental technique: test sample is placed 25 ℃ ± 2 ℃, under 60%RH ± 5% condition, placed 24 months, measure its content, related substance and stripping situation during respectively at 0,6,12,18,24 month.The content of gefitinib and the mensuration of related substance operate according to quality standard, and dissolution determination method is with experiment ", gefitinib tablet formulation of the present invention screening ".
3, experimental result: see table 5 for details.
Table 5 gefitinib tablet of the present invention and Iressa stability are relatively
Above experimental result shows: gefitinib tablet long-time stability of the present invention are investigated 24 months, and its quality does not almost change, especially the dissolution of each time point; And Iressa the phenomenon that stripping curve departs from occurred after placing 24 months, shows as especially in time of 45-60 minute.Therefore, the tablet quality (stability) that adopts granularity gefitinib of the present invention to make is better than Iressa, clinical safety, has message more secure.
In order to investigate dissolution rate of the present invention and quality stability, the inventor has carried out the experiment of a large amount of repeatability, and different from above-mentioned experiment is that some are the described particle size ranges of gefitinib sheet of the present invention and distribute different (comprising embodiment 1 and 2-9); Other are supplementary product kind, consumption and the technique different (comprising embodiment 10) of this gefitinib sheet.In addition, also embodiment 1 and the made product of embodiment 2-10 have been carried out the accelerated stability experiment, experimental technique and the interpretation of result of testing because of accelerated stability are ripe techniques well known, and in addition, because length is limit, data owe to give temporarily.
Experimental result show following some:
1, gefitinib tablet of the present invention adopts particle size distribution to be: D (0.1)=2 ~ 6 μ m, D (0.5)=11 ~ 20 μ m, during the raw material of D (0.9)=35 ~ 50 μ m, the rate of release of this tablet is similar to Iressa and more stable, particularly when adopting particle size distribution D (0.1)=3 ~ 4 μ m, when D (0.5)=13 ~ 16 μ m, the raw material of D (0.9)=37 ~ 43 μ m, the stripping curve of this tablet is more similar to Iressa.
2, select different kind adjuvants, consumption or stripping and stability that preparation technology is slightly adjusted gefitinib tablet of the present invention have no significant effect.
In sum, continuing of gefitinib sheet, stable, discharge with raw material granularity in close relations fully, stripping is slow and not exclusively during granularity large (more than 60um), granularity can cause burst drug release when meticulous (as less than 10um), only the raw material with specified particle size distribution in the certain particle size scope just can be realized continuing of gefitinib sheet, stable, discharge fully, namely, the particle size distribution of gefitinib is in the gefitinib tablet: D (0.1)=2 ~ 6 μ m, D (0.5)=11 ~ 20 μ m, during D (0.9)=35 ~ 50 μ m, the stripping curve of gefitinib tablet of the present invention is similar to Iressa, the inside and outside degree of association good according to this product, gefitinib tablet of the present invention previously accepted chemotherapeutical local advanced lung cancer for treatment or Metastatic Nsclc has good result.Meanwhile, gefitinib tablet stability of the present invention is better, satisfies clinical safety, resultful requirement.
Description of drawings
Fig. 1 is the stripping curve figure of gefitinib tablet of the present invention and Iressa and India's product gefitinib sheet;
Fig. 2 is a collection of gefitinib particle size distribution figure that meets gefitinib tablet needs of the present invention.
Specific embodiments
Prescription (1000):
Gefitinib: 250.0g lactose: 163.5g
Microcrystalline Cellulose: 50.0g cross-linking sodium carboxymethyl cellulose: 20.0g
30 POVIDONE K 30 BP/USP
30: 10.0g sodium lauryl sulphate: 1.5g
Magnesium stearate: 5.0g stomach dissolved film coating pre-mix dose: 12.5g
Wherein the particle size distribution of gefitinib is: D (0.1)=3 μ m, D (0.5)=13 μ m, D (0.9)=40 μ m.
The preparation technology of embodiment 1: label: first adjuvant (that is, the material beyond the gefitinib) is crossed respectively 80 mesh sieves, for subsequent use; Get gefitinib, lactose, microcrystalline Cellulose, sodium lauryl sulphate and the cross-linking sodium carboxymethyl cellulose of recipe quantity, mixed about 15 minutes, make it even; With 30 POVIDONE K 30 BP/USP
30Water-soluble, make concentration and be 8% binder solution, join in the above-mentioned mixed-powder, stir the preparation soft material; 14 mesh sieves granule processed; Wet granular is in 60 ℃ ± 5 ℃ dryings, is lower than 2% to moisture; Dried granule adds recipe quantity magnesium stearate mixing, tabletting through 20 mesh sieve granulate.
Coating: stomach dissolved film coating pre-mix dose is added water, and to make concentration be 18% coating solution, and this coating solution is crossed 100 mesh sieves label is carried out coating, gets gefitinib tablet of the present invention.
Prescription (1000) supplementary material kind and consumption is identical with embodiment 1, and the particle size distribution of different is gefitinib is: D (0.1)=2 μ m, D (0.5)=18 μ m, D (0.9)=35 μ m.
Technique: with embodiment 2.
Prescription (1000) supplementary material kind and consumption is identical with embodiment 1, and the particle size distribution of different is gefitinib is: D (0.1)=2 μ m, D (0.5)=20 μ m, D (0.9)=35 μ m.
Technique: with embodiment 2.
Embodiment 5
Prescription (1000) supplementary material kind and consumption is identical with embodiment 1, and the particle size distribution of different is gefitinib is: D (0.1)=5 μ m, D (0.5)=11 μ m, D (0.9)=45 μ m.
Technique: with embodiment 2.
Prescription (1000) supplementary material kind and consumption is identical with embodiment 1, and the particle size distribution of different is gefitinib is: D (0.1)=3 μ m, D (0.5)=16 μ m, D (0.9)=43 μ m.
Technique: with embodiment 2.
Embodiment 7
Prescription (1000) supplementary material kind and consumption is identical with embodiment 1, and the particle size distribution of different is gefitinib is: D (0.1)=4 μ m, D (0.5)=13 μ m, D (0.9)=37 μ m.
Technique: with embodiment 2.
Embodiment 8
Prescription (1000) supplementary material kind and consumption is identical with embodiment 1, and the particle size distribution of different is gefitinib is: D (0.1)=3 μ m, D (0.5)=13 μ m, D (0.9)=37 μ m.
Technique: with embodiment 2.
Embodiment 9
Prescription (1000) supplementary material kind and consumption is identical with embodiment 1, and the particle size distribution of different is gefitinib is: D (0.1)=2 μ m, D (0.5)=11 μ m, D (0.9)=35 μ m.
Technique: with embodiment 2.
Prescription (1000):
Gefitinib: 250.0g mannitol: 125.0g
Microcrystalline Cellulose: 55.0g polyvinylpolypyrrolidone: 25.0g
Low-substituted hydroxypropyl methylcellulose: 25.0 30 POVIDONE K 30 BP/USPs
30: 8.0g
Sodium lauryl sulphate: 1.5g magnesium stearate: 5.0g
Stomach dissolved film coating pre-mix dose: 12.5g
Wherein the particle size distribution of gefitinib is: D (0.1)=3 μ m, D (0.5)=13 μ m, D (0.9)=40 μ m.
Technique:
Label: first adjuvant (that is, the material beyond the gefitinib) is crossed respectively 80 mesh sieves, for subsequent use; Get gefitinib, mannitol, microcrystalline Cellulose, sodium lauryl sulphate, low-substituted hydroxypropyl methylcellulose and the polyvinylpolypyrrolidone of recipe quantity, mixing; With 30 POVIDONE K 30 BP/USP
30Water-soluble, making concentration is 10% binder solution, joins in the above-mentioned mixed-powder, stirs the preparation soft material; 12 mesh sieves granule processed; Wet granular is in 60 ℃ ± 5 ℃ dryings, is lower than 3% to moisture; Dried granule adds recipe quantity magnesium stearate mixing, tabletting through 24 mesh sieve granulate.
Coating: stomach dissolved film coating pre-mix dose is added water, and to make concentration be 20% coating solution, and this coating solution is crossed 80 mesh sieves label is carried out coating, gets gefitinib tablet of the present invention.
Above embodiment is intended to further specify the present invention, scope of the present invention is not limited.Those skilled in the art can not depart from improvement and the variation of category of the present invention and spirit to embodiment disclosed herein.
Claims (10)
1. pharmaceutical composition that contains gefitinib, it is characterized in that, this pharmaceutical composition is the gefitinib tablet, this tablet contains the gefitinib of effective therapeutic dose, the particle size distribution of this gefitinib is: D (0.1)=2 ~ 6 μ m, D (0.5)=11 ~ 20 μ m, D (0.9)=35 ~ 50 μ m.
2. pharmaceutical composition as claimed in claim 1 is characterized in that, the particle size distribution of described gefitinib is: D (0.1)=2 ~ 5 μ m, D (0.5)=11 ~ 18 μ m, D (0.9)=35 ~ 45 μ m.
3. pharmaceutical composition as claimed in claim 1 is characterized in that, the particle size distribution of described gefitinib is: D (0.1)=3 ~ 4 μ m, D (0.5)=13 ~ 16 μ m, D (0.9)=37 ~ 43 μ m.
4. pharmaceutical composition as claimed in claim 1 is characterized in that, the particle size distribution of described gefitinib is: D (0.1)=3 μ m, D (0.5)=13 μ m, D (0.9)=40 μ m.
5. such as each described pharmaceutical composition of claim 1-4, it is characterized in that, the pharmaceutic adjuvant that also contains this area routine dose in this pharmaceutical composition, this pharmaceutic adjuvant is the tablet adjuvant of this area routine, and this tablet comprises filler, disintegrating agent, binding agent, solubilizing agent, wetting agent, lubricant with adjuvant.
6. pharmaceutical composition as claimed in claim 5, wherein filler is selected from one or more in lactose, microcrystalline Cellulose, the mannitol.
7. pharmaceutical composition as claimed in claim 5, wherein disintegrating agent is selected from one or more in cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, low-substituted hydroxypropyl methylcellulose, the carboxymethyl starch sodium.
8. pharmaceutical composition as claimed in claim 5, wherein solubilizing agent is selected from one or more in sodium lauryl sulphate, tween 80, the stearic acid sodium sulfonate.
9. the preparation method of pharmaceutical composition claimed in claim 1, wherein, described pharmaceutical composition is the gefitinib tablet, this gefitinib tablet also contains the tablet adjuvant of this area routine, this tablet adjuvant is filler, disintegrating agent, binding agent, solubilizing agent, wetting agent, lubricant, film coating pre-mix dose, and the method comprises:
⑴ get gefitinib and filler, disintegrating agent and solubilizing agent mix homogeneously;
⑵ be dissolved in wetting agent with binding agent, joins soft material processed in the step ⑴ gained mixture, granulation, drying;
⑶ join lubricant in the dried granule of step ⑵ gained, mixing, and tabletting gets label;
⑷ add water with film coating pre-mix dose and be made into coating solution, and the label of step ⑶ gained is carried out coating, gets described gefitinib tablet.
10. pharmaceutical composition claimed in claim 1 is preparing the application for the treatment of in the medicine of previously accepting chemotherapeutical local advanced lung cancer or Metastatic Nsclc.
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Effective date of registration: 20161018 Address after: 226100 No. 688, sea route, Haimen Economic and Technological Development Zone, Jiangsu, Nantong Patentee after: Jiangsu Wangao Pharmaceutical Co., Ltd. Address before: 226100 No. 688, Hai Lu, Haimen Economic Development Zone, Jiangsu, Nantong Patentee before: Yao Junhua |