CN103006608B - Drug composition containing gefitinib - Google Patents
Drug composition containing gefitinib Download PDFInfo
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- CN103006608B CN103006608B CN201210566665.XA CN201210566665A CN103006608B CN 103006608 B CN103006608 B CN 103006608B CN 201210566665 A CN201210566665 A CN 201210566665A CN 103006608 B CN103006608 B CN 103006608B
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- 239000005411 L01XE02 - Gefitinib Substances 0.000 title claims abstract description 167
- 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 165
- 229960002584 gefitinib Drugs 0.000 title claims abstract description 141
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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-(the chloro-4-fluorophenyl of 3-)-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 there is the local late period of sensitizing mutation or Metastatic Nsclc (NSCLC) patient's three lines, even first-line treatment of two wires.
Gefitinib sheet (trade name " Iressa ", Iressa) first develop (being often called former grinding) by AstraZeneca pharmaceutical Co. Ltd of Britain, within 2003, gone on the market as three line medicines for the treatment of nonsmall-cell lung cancer by the U.S., Japan's approval, its effective percentage in asian ancestry crowd is higher.Research subsequently shows, its curative effect and EGFR sudden change are closely related, and the drugs administration approved listing of 1 Huo European Union was target therapeutic agent July in 2009, for local late period or Metastatic Nsclc one line, two wires and the treatment of three lines of the EGFR gene mutation of being grown up.In December, 2004, " Iressa " enters China, for the local late period or the Metastatic Nsclc that previously receive chemotherapy, in the end of the year 2010, " Iressa " got permission to be again used for the treatment of 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 NATCO Pharma company of India this kind of production and sales, due to Iressa, (AstraZeneca produces gefitinib sheet, lower same) expensive (approximately 600 yuan/sheet), the have to gefitinib sheet of the relatively cheap NATCO Pharma company of India of choice for use of many patients, but find the non-constant of In Vitro Dissolution of the gefitinib tablet that NATCO Pharma company of India produces by comparative study.
After solid preparation oral administration, the absorption of medicine is depended on the dissolving under physiological condition of the stripping of medicine from preparation or release, medicine and is permeated at gastrointestinal.Because the stripping of medicine has material impact to absorbing, therefore, 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 good inside and outside dependency; By the stripping curve measured in external different medium drug release process in antimer indirectly; Therefore, the In Vitro Dissolution of gefitinib preparation in different dissolution mediums can be used as the important indicator of evaluating curative effect of medication.
Gefitinib is insoluble drug, its dissolubility in aqueous solution is pH dependency, in the lower aqueous solution of pH, dissolubility is larger, almost insoluble in the water of pH value 7 left and right, therefore, Europe, the United States measure for the In Vitro Dissolution of this product, all selecting 5% tween 80 aqueous solution is dissolution medium, only stripping 30% left and right of the gefitinib sheet 60 minutes of NATCO Pharma company of India under this condition, 90 minutes time, dissolution does not obviously rise, illustrate that a large amount of gefitinibs do not discharge at all, also just cannot 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, is disclosed so far.
In addition, experimental study at the Iressa on market is found, its stability is unsatisfactory, there is obvious change in the stripping curve that approaches effect phase product, even in the very easy hydrochloric acid solution discharging, within 45 minutes, dissolution also drops to 75% left and right by 99%, can not reach the quality standard requirement of this medicine.That is to say, the release in vivo of this medicine can not well reach the required speed for the treatment of, and this can cause the decline of curative effect undoubtedly, gently extends the healing cycle, heavy delay treatment best period so that patient lose the chance of rehabilitation.
Therefore, urgent need provides one can continue, stablize and discharge gefitinib completely, and has the gefitinib preparation of good stability, compliance, makes the many a kind of super quality and competitive price of extensive patients, medicine selection safely and effectively.
Summary of the invention
The object of this invention is to provide a kind of tablet of gefitinib of super quality and competitive price, said preparation has that drug release continues, stable and feature completely, has good bioavailability and stability.
For solving the technical problem of current existence, the present invention adopts following technical scheme:
The invention provides a kind of pharmaceutical composition that contains gefitinib, this pharmaceutical composition is gefitinib tablet, this gefitinib tablet is containing the gefitinib of effective therapeutic dose, take the gefitinib total amount in sheet 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 again D10, corresponding particle diameter when the cumulative particle sizes percentile that refers to a sample reaches 10%.Its physical significance is that the granule that particle diameter is greater than it accounts for 90%, and the granule that is less than it accounts for 10%.In like manner, D(0.5) physical significance be that the granule that is less than it accounts for 50%; D(0.9) physical significance is that the granule that is less than it accounts for 90%.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 is greater than 35um, and the granularity of 50% gefitinib is less than 20um and is greater than 11um, and the granularity of 10% gefitinib is less than 6um and is 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 Asia, curative effect is more remarkable, and effective percentage reaches more than 70%.And both at home and abroad to the preparation research of gefitinib few, in worldwide, the AstraZeneca pharmaceutical Co. Ltd of Britain 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 wherein imitated gefitinib sheet of India NATCO Pharma company, its quality and curative effect all do not obtain authoritative department and numerous clinicians' approval, and occur the case that Relapse rate even worsens after occurring that clinically Iressa is replaced to India's gefitinib sheet.This phenomenon illustrates to a certain extent makes by gefitinib the preparation not a duck soup that quality is steady, curative effect is good and be convenient to take.
Iressa research and development time were once done pharmacological evaluation, 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 Iressa rate of release in tween 80 aqueous medium of 5%, inventor tested several different methods, such as adding disintegrating agent, solubilizing agent and by raw material micronization etc. in prescription.Found that and add quick disintegration rate on the dissolution rate impact of gefitinib not quite, particularly after 30 minutes; The solubilizing agent effect of different cultivars and consumption is also very limited; Only have that after micronization processes, (granularity approximately 10 μ gefitinib sheet stripping m) is very fast, within 10 minutes, can reach more than 50%, 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 gefitinib sheet reach requirement lasting, that steadily and completely discharge.
Through great many of experiments and analysis, applicant finds that the granularity of gefitinib has appreciable impact to the stripping of its tablet, this impact not thinner (granularity is less) as conventional insoluble drug is better, but relevant with varigrained distribution within the specific limits,, 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 gefitinib total amount as 100%, lower same) 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, are tested also and cannot be drawn by limited number of time in conjunction with general knowledge known in this field in state of the art.
For making the gefitinib release in gefitinib tablet of the present invention more steady, the particle size distribution of gefitinib used 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, now, 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 closely similar compared with Iressa, f
2value is up to 87.
Experimental study by the Iressa on market is found, its less stable, approach the stripping curve of effect duration product and have notable difference compared with new production product, entirety 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, this can cause the decline of curative effect undoubtedly, gently extends the healing cycle, heavy delay treatment best period so that patient lose the chance of rehabilitation.For this reason, applicant has carried out the long-time stability investigation of 24 months to gefitinib tablet of the present invention, and its content of result, related substance and stripping curve all do not have significant change, have good stability, and can ensure the therapeutic effect of sufferer.
In gefitinib tablet of the present invention, also contain the pharmaceutic adjuvant of this area routine dose, 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.It is poor that gefitinib is met light stability, therefore in the excipient substance of gefitinib tablet of the present invention, preferably contain film coating pre-mix dose, the particularly film coating pre-mix dose of stomach dissolution type, this stomach dissolved film coating pre-mix dose composition comprises 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 mannitol, preferably a kind of in lactose, microcrystalline Cellulose or its combination; Described disintegrating agent is selected from one or more in cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, low-substituted hydroxypropyl methylcellulose, carboxymethyl starch sodium, preferably 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:
(1) getting gefitinib mixs homogeneously with filler, disintegrating agent, solubilizing agent;
(2) binding agent is dissolved in to wetting agent, joins (1) soft material processed in gained mixture of step, granulate, dry;
(3) lubricant is joined to step (2) in the dry granule of gained, mix, tabletting obtains label;
(4) film coating pre-mix dose is added water and is made into coating solution, to step (3) the label of gained carry out coating, obtain described gefitinib tablet.
The preparation method of above-mentioned gefitinib sheet is further:
(1) getting gefitinib and lactose, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose and sodium lauryl sulphate mixes;
(2) by the water-soluble PVP K30 binding agent of making, join (1) soft material processed in gained mixture of step, granulate, dry, granulate;
(3) get magnesium stearate and join step (2) in the dry granule of gained, mix, tabletting obtains label;
(4) stomach dissolved film coating pre-mix dose is added water and is made into coating solution, to step (3) the label of gained carry out coating, obtain gefitinib tablet of the present invention.
The present invention also provides described gefitinib tablet to treat the application in the medicine of previously accepting chemotherapeutical local advanced lung cancer or Metastatic Nsclc in preparation.
Inventor further verifies the impact of gefitinib particle size distribution on the stripping of gefitinib tablet by experiment.
Reiterate: following experiment is the exemplary experiment in numerous tests in development process of the present invention, do not contained with limit all experiments that invention people does for the present invention, object is only to set forth the impact of gefitinib particle size distribution on gefitinib tablet of the present invention stripping by those data.
One, gefitinib tablet formulation screening of the present invention
1, test sample: prepare gefitinib sheet by preparation method described in write out a prescription in table 1, table 2 1-9 and description.
2, experimental technique: take 5%(v/v) tween 80 aqueous solution is dissolution medium, investigates the stripping curve of test sample.
Operational approach: dissolution method (two appendix X C the second methods of Chinese Pharmacopoeia version in 2010)
Rotating speed: per minute 50 turn; Sample time: 10,20,30,45,60 minutes; Need testing solution: get solution 10ml, filter, precision measures subsequent filtrate 2ml, puts in 50ml volumetric flask, adds stripping medium to scale; Reference substance solution: 10 μ g/ml; Assay method: UV method; Measure wavelength: 334nm.
3, experimental result: refer to table 1, table 2.
Table 1 gefitinib tablet disintegrant prescription screening
Table 2 gefitinib tablet solubilizing agent prescription screening
Note: f2 value > 50 is similar.
Table 1 and table 2 experimental result show, the kind of different disintegrating agents, add method and use amount larger on the disintegration rate impact of gefitinib sheet, strengthen disintegrating agent consumption and can significantly accelerate disintegration rate, but dissolution rate (stripping curve) is not almost affected, particularly after 30 minutes; Equally, the solubilizing agent of different cultivars and consumption is also very limited to improving stripping curve effect; Adopted 100 orders (tablet prepared by 150 μ gefitinib m), in any case adjust disintegrating agent kind, consumption and add method, comprise use solubilizing agent, all do not realize the object of improving dissolution rate, with Iressa comparison, f2 value, all lower than 20, cannot reach the medical effect suitable with Iressa at all.
Two, gefitinib tablet material granularity sieving of the present invention
1, test sample: the tablet of making according to embodiment 1 formulation and technology with different grain size gefitinib.
2, experimental technique: with experiment ", gefitinib tablet formulation of the present invention screening ".
3, experimental result: refer to table 3.
Table 3 gefitinib tablet material granularity sieving result
Above experimental result shows, the stripping of gefitinib and the granularity of its raw material and be distributed with substantial connection.After raw material micronization, (dissolution rate of granularity approximately 10 μ gefitinib sheet m) is obviously accelerated, and within 10 minutes, can reach more than 50%, but bring the prominent problem of releasing simultaneously; 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 within the scope of a specified particle size just can make gefitinib sheet reach lasting, stable and discharge completely object.The gefitinib tablet of the present invention wherein gefitinib of contained effective dose is to exist with the form of above-mentioned gefitinib raw material.
Three, gefitinib tablet of the present invention and the dissolution comparison of commercially available same product in different medium
1, test sample: the non-Buddhist nun's tablet that replaces described in Ji of the present invention, lot number: 100827 self-controls (formulation and technology is with embodiment 1); Iressa, lot number: HB751, purchased from AstraZeneca pharmaceutical Co. Ltd; Gefitinib sheet (India), is called for short, and prints product, lot number: 600840, and purchased 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 refers to table 4.
The dissolution of table 4 three test samples in different dissolution mediums
Can find out from above experimental result, gefitinib tablet of the present invention release profiles and Iressa is under equal conditions closely similar, and 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 is shown in 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), purchased from AstraZeneca pharmaceutical Co. Ltd;
2, experimental technique: test sample is placed in to 25 ℃ ± 2 ℃, under 60%RH ± 5% condition, places 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: refer to table 5.
Table 5 gefitinib tablet of the present invention and the comparison of Iressa stability
Above experimental result shows: gefitinib tablet long-time stability of the present invention are investigated 24 months, and its quality does not almost change, the dissolution of especially each time point; And Iressa has occurred the phenomenon that stripping curve departs from placing after 24 months, show as especially in time of 45-60 minute.Therefore, adopt the tablet quality (stability) that granularity gefitinib of the present invention is made to be better than Iressa, clinical safety, have message more secure.
In order to investigate dissolution rate of the present invention and quality stability, inventor has carried out the experiment of a large amount of repeatability, different from above-mentioned experiment, and some are the particle size ranges described in gefitinib sheet of the present invention and distribute different (comprising embodiment 1 and 2-9); Other are supplementary product kind, consumption and the technique difference (comprising embodiment 10) of this gefitinib sheet.In addition, also embodiment 1 and the made product of embodiment 2-10 have been carried out to accelerated stability experiment, because experimental technique and the interpretation of result of accelerated stability experiment are ripe techniques well known, another, 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, when 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, D (0.5)=13 ~ 16 μ m, when 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 completely, when granularity large (more than 60um), stripping is slow and not exclusively, granularity can cause burst drug release when meticulous (as being less than 10um), only the raw material with specified particle size distribution within the scope of certain particle size just can be realized continuing of gefitinib sheet, stable, discharge completely, , when the particle size distribution of gefitinib in gefitinib tablet is: D (0.1)=2 ~ 6 μ m, D (0.5)=11 ~ 20 μ m, when 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, meets clinical safety, resultful requirement.
Accompanying drawing explanation
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 (, the material beyond gefitinib) is crossed respectively to 80 mesh sieves, for subsequent use; Get gefitinib, lactose, microcrystalline Cellulose, sodium lauryl sulphate and the cross-linking sodium carboxymethyl cellulose of recipe quantity, mix approximately 15 minutes, make it even; By 30 POVIDONE K 30 BP/USP
30water-soluble, make concentration and be 8% binder solution, join in above-mentioned mixed-powder, stir, prepare soft material; 14 mesh sieve granule processed; Wet granular in 60 ℃ ± 5 ℃ dry, to moisture lower than 2%; Dry granule, through 20 mesh sieve granulate, adds recipe quantity magnesium stearate to mix, tabletting.
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 to coating, obtains gefitinib tablet of the present invention.
Prescription (1000) supplementary material kind and consumption are 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 are 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 are 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 are 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 are 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 are 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 are 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 (, the material beyond gefitinib) is crossed respectively to 80 mesh sieves, for subsequent use; Gefitinib, mannitol, microcrystalline Cellulose, sodium lauryl sulphate, low-substituted hydroxypropyl methylcellulose and the polyvinylpolypyrrolidone of getting recipe quantity, mix; By 30 POVIDONE K 30 BP/USP
30water-soluble, making concentration is 10% binder solution, joins in above-mentioned mixed-powder, stirs, and prepares soft material; 12 mesh sieve granule processed; Wet granular in 60 ℃ ± 5 ℃ dry, to moisture lower than 3%; Dry granule, through 24 mesh sieve granulate, adds recipe quantity magnesium stearate to mix, tabletting.
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 to coating, obtains gefitinib tablet of the present invention.
Above embodiment is intended to further illustrate 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 (8)
1. a pharmaceutical composition that contains gefitinib, it is characterized in that, this pharmaceutical composition is gefitinib tablet, this tablet is containing the gefitinib of effective therapeutic dose, the particle size distribution of this gefitinib is: D (0.1)=2～5 μ m, D (0.5)=11～18 μ m, D (0.9)=35～45 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)=3～4 μ m, D (0.5)=13～16 μ m, D (0.9)=37～43 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 μ m, D (0.5)=13 μ m, D (0.9)=40 μ m.
4. the pharmaceutical composition as described in claim 1-3 any one, it is characterized in that, in this pharmaceutical composition, also contain the pharmaceutic adjuvant of this area routine dose, 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.
5. pharmaceutical composition as claimed in claim 4, wherein filler is selected from one or more in lactose, microcrystalline Cellulose, mannitol.
6. pharmaceutical composition as claimed in claim 4, wherein disintegrating agent is selected from one or more in cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, low-substituted hydroxypropyl methylcellulose, carboxymethyl starch sodium.
7. pharmaceutical composition as claimed in claim 4, wherein solubilizing agent is selected from one or more in sodium lauryl sulphate, tween 80, stearic acid sodium sulfonate.
8. the preparation method of pharmaceutical composition claimed in claim 1, wherein, described pharmaceutical composition is 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:
(1) getting gefitinib mixs homogeneously with filler, disintegrating agent and solubilizing agent;
(2) binding agent is dissolved in to wetting agent, joins (1) soft material processed in gained mixture of step, granulate, dry;
(3) lubricant is joined to step (2) in the dry granule of gained, mix, tabletting obtains label;
(4) film coating pre-mix dose is added water and is made into coating solution, to step (3) the label of gained carry out coating, obtain described gefitinib tablet.
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| CN104800175A (en) * | 2015-04-20 | 2015-07-29 | 珠海润都制药股份有限公司 | Gefitinib tablet preparation method |
| CN104887638A (en) * | 2015-06-19 | 2015-09-09 | 山东省药学科学院 | Preparation method of gefitinib tablets |
| CN106913541A (en) * | 2015-12-25 | 2017-07-04 | 山东新时代药业有限公司 | A kind of Gefitinib tablet and preparation method thereof |
| CN108721243B (en) * | 2017-04-25 | 2022-07-08 | 正大天晴药业集团股份有限公司 | Crizotinib pharmaceutical composition and preparation method thereof |
| CN107961224B (en) * | 2017-12-06 | 2021-05-04 | 齐鲁制药(海南)有限公司 | Acertinib tablet and preparation method thereof |
| CN110013468B (en) * | 2018-01-09 | 2022-02-18 | 北京福元医药股份有限公司 | AZD9291 deuterated derivative pharmaceutical preparation |
| CN115887406B (en) * | 2022-12-24 | 2024-02-13 | 山东理工职业学院 | Preparation method of crizotinib capsule |
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