CN103860521A - Icotinib hydrochloride capsule composition and preparation method thereof - Google Patents
Icotinib hydrochloride capsule composition and preparation method thereof Download PDFInfo
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- CN103860521A CN103860521A CN201410078528.0A CN201410078528A CN103860521A CN 103860521 A CN103860521 A CN 103860521A CN 201410078528 A CN201410078528 A CN 201410078528A CN 103860521 A CN103860521 A CN 103860521A
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- hydrochloric acid
- acid conmana
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Abstract
The invention provides an icotinib hydrochloride capsule composition and a preparation method thereof. The composition mainly comprises icotinib hydrochloride, a carrier, an organic solvent, a surfactant, superfine silica powder, starch, and the like. The preparation method of the composition mainly comprises the following steps of adding prescription amount of the carrier into the organic solvent, heating to 60 DEG C, then, adding the icotinib hydrochloride to dissolve the carrier, drying for 4 hours in vacuum at 40 DEG C, carrying out gas-flow pulverization, adding the superfine silica powder and the starch for uniformly mixing, and packaging in capsules to obtain the icotinib hydrochloride capsule composition. The icotinib hydrochloride capsule preparation prepared from the icotinib hydrochloride capsule composition disclosed by the invention is well absorbed by being taken orally, and is high in dissolution rate, high in bioavailability and capable of remarkably restraining tumor volume growth. The preparation process disclosed by the invention is simple, low in cost and suitable for industrial production.
Description
Invention field
The present invention relates to chemical pharmacy field, be specifically related to a kind of hydrochloric acid Conmana capsule composition and preparation method thereof.
Background of invention
Show according to the Chinese Third National coroner's inquest that in April, 2008, China's Ministry of Public Health was issued, malignant tumor accounts for the first place of the city cause of death, and the first place that pulmonary carcinoma is 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 exceed 1,000,000 to the annual pulmonary carcinoma number of China in 2025, and become the first in the world pulmonary carcinoma big country.
The molecular targeted therapy (Molecular targeted therapy) of tumor is using the specific molecular in tumor cell as target spot, utilize the biological function of this target spot of molecular targeted agents energy specific inhibition, thereby from the malignant behaviors of molecular level reversing tumor cell, reaching the object 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.
170 kilodaltons (kDa) membrane bound protein that EGF-R ELISA (EGFR) is expressed for surface epithelial cell.EGFR belongs to the growth factor receptors family of protein tyrosine kinase.EGFR is the protein that growth promotes oncogene erbBErbB or erbBl, and it be a member of the ERBB family of family's proto-oncogene (protooncogenes), it is believed that in the generation of the many cancers of the mankind with in developing and plays a crucial role.Especially in breast carcinoma, bladder cancer, pulmonary carcinoma and glioblastoma, observed the expression that EGFR strengthens.Relevant transmembrane receptor, i.e. EGFR, HER-2/neu (erbB2), HER-3 (erbB3) and HER-4 (erbB4) in four kinds of structures of ERBB family coding of oncogene.Clinically, the amplification of ERBB oncogene and/or receptor overexpression in existing report tumor are relevant with patient's poor prognosis to disease palindromia, and to the relevant (L.Harris etc. of response of therapy, 1999, Int.J.Biol.Markers, 14:8-15 and J.Mendelsohn and J.Baselga, 2000, Oncogene, 19:6550-6565).
The combination activation signal Signal Transduction Pathways of EGF or TGF-α and EGFR and cause cell proliferation.Dimerization, conformation change and the internalization of EGFR molecule plays signal in transfer cell, causes cell cycle regulation.Affect growth factor receptor function and regulate or cause the hereditism of receptor and/or part overexpression to change, cause cell proliferation.In addition, determine that EGFR is at (the M.-J.Oh etc. that work aspect the enhancing of cell differentiation, cell mobility, protein secreting, neovascularization, invasion, transfer and the drug resistance of cancerous cell to chemotherapeutant and lonizing radiation, 2000, Clin.Cancer Res., 6:4760-4763).
Hydrochloric acid Conmana (Icotinib Hydrochloride) is oral EGFR tyrosine kinase inhibitor, reaches Pharmaceutical (Beta) exploitation by Chinese shellfish, by CFDA approval listing, is mainly used in treating nonsmall-cell lung cancer in June, 2011.Preclinical study demonstration, hydrochloric acid Conmana is a kind of efficient specific epidermal growth factor recipient tyrosine kinase inhibitor (EGFR-TKI).In to 85 kinds of kinase whose examinations, hydrochloric acid Conmana forcefully selectivity suppresses EGFR and 3 mutants thereof, but to remaining 81 kinds of kinases all without obvious inhibitory action.
Two recent I/II a clinical trial phases are studied for curative effect and the safety of hydrochloric acid Conmana treatment advanced Non-small cell lung (NSCLC).This medicine is compared with erlotinid hydrochloride with external two medicine Ji Feiteni that gone on the market at present, similar at aspects such as chemical constitution, molecular mechanisms of action, curative effects, but has better safety.
Existing market sell is hydrochloric acid Conmana ordinary tablet.The applicant, by repetition test, obtains a kind of new hydrochloric acid Conmana capsule composition pharmaceutical formulation, and preparation process is simple, convenient oral, better tolerance, and steady quality, dissolution is high, and bioavailability is high, is convenient to suitability for industrialized production.
Summary of the invention
The invention provides a kind of new hydrochloric acid Conmana capsule composition, preparation process is simple, convenient oral, better tolerance, and steady quality, dissolution is high, and bioavailability is high, is convenient to suitability for industrialized production, selects for patient provides more preparation.
On the one hand, the invention provides a kind of hydrochloric acid Conmana capsule composition, comprise hydrochloric acid Conmana, carrier, wherein, also comprise organic solvent, surfactant, micropowder silica gel, starch in described compositions, compositions composition is mainly:
Some embodiments therein, hydrochloric acid Conmana capsule composition of the present invention, wherein said carrier is selected from glyceryl monostearate, polyethylene glycol 6000, hexadecanol, octadecanol one or more, described organic solvent is selected from ethanol, methanol, acetone one or more, and described surfactant is selected from sodium lauryl sulphate, Tween 80, lecithin one or more.
In another embodiment, hydrochloric acid Conmana capsule composition of the present invention, it comprises following component:
In another embodiment, hydrochloric acid Conmana capsule composition of the present invention, it comprises following component:
In another embodiment, hydrochloric acid Conmana capsule composition of the present invention, it comprises following component:
In another embodiment, hydrochloric acid Conmana capsule composition of the present invention, it comprises following component:
Some embodiments therein, hydrochloric acid Conmana capsule composition of the present invention, wherein, in described compositions, hydrochloric acid Conmana with vehicle weight ratio is: hydrochloric acid Conmana: carrier is 1: 0.3～1: 5.
On the other hand, the present invention relates to the preparation method of hydrochloric acid Conmana capsule composition of the present invention, it comprises following steps: first carrier is added in organic solvent, be heated to 60 DEG C, add hydrochloric acid Conmana or add again surfactant it is dissolved 40 DEG C of vacuum dryings 4 hours, comminution by gas stream, grinding particle size, at 1～80 μ m, adds micropowder silica gel, starch evenly to mix, capsulation.
The prescription ratio of hydrochloric acid Conmana capsule composition of the present invention is not by teaching material or other reference material gained, but by the testing program gained conforming with the regulations in a large number, made capsule preparations has carried out quality research, meets " Chinese Pharmacopoeia " 2010 editions two and make by oneself about capsule and other requirement of quality standard.The dissolution of finding technical solution of the present invention in research is high, steady quality.
Carrier of the present invention comprises, but be not limited to, micropowder silica gel, starch etc., also comprise ion-exchanger, aluminum, aluminium stearate, lecithin, serum albumin, as human albumin, buffer substance is as phosphate, glycine, sorbic acid, potassium sorbate, the partial glycerol ester admixture of saturated vegetable fatty acid, water, salt or electrolyte, as protamine sulfate, sodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloid silicon, magnesium trisilicate, polyvinylpyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-blocking-up polymer, lanoline, sugar, as lactose, dextrose plus saccharose, starch is as corn starch and potato starch, the derivant of cellulose and it is as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate, natural gum powder, Fructus Hordei Germinatus, gelatin, Pulvis Talci, adjuvant is as cocoa butter and suppository wax, oily as Oleum Arachidis hypogaeae semen, Oleum Gossypii semen, safflower oil, Oleum Sesami, olive oil, Semen Maydis oil and Oleum Glycines, glycols compound, as propylene glycol and Polyethylene Glycol, esters is as ethyl oleate and ethyl laurate, agar, buffer agent is as magnesium hydroxide and aluminium hydroxide, alginic acid, pyrogen-free water, Deng oozing salt, Lin Ge (family name) solution, ethanol, phosphate buffer solution, and other nontoxic proper lubrication agent are as sodium laurylsulfate and magnesium stearate, coloring agent, releasing agent, coating dress material, sweeting agent, flavoring agent and spice, antiseptic and antioxidant.
Pharmaceutical composition of the present invention can also optionally contain one or more diluent.The example of diluent comprises mannitol, sorbitol, biphosphate calcium dihydrate, microcrystalline Cellulose and efflorescence cellulose.Preferred diluent is microcrystalline Cellulose.Microcrystalline Cellulose can be obtained from several suppliers, comprises Avicel PH101, Avicel PH102, Avicel PH103, Avicel PH105 and Avicel PH200 that FMCCorporation manufactures.
Pharmaceutical composition of the present invention can also optionally contain disintegrating agent.Disintegrating agent can be the one in several modified starches, modified cellulose polymer or polycarboxylic acids, such as crosslinked Carboxymethyl cellulose sodium, Explotab, polacrilin potassium and calcium carboxymethylcellulose (CMCCalcium).In one embodiment, disintegrating agent is croscarmellose sodium.Croscarmellose sodium NF type A obtains with trade name " Ac-di-sol " on market.
Pharmaceutical composition of the present invention can also optionally contain one or more surfactants or wetting agent.Surfactant can be anion, cation or neutral surface active agent.Anion surfactant comprises sodium lauryl sulfate, dodecyl sodium sulfate, oleyl sodium sulfate and the sodium laurate mixing with stearate and Talcum.Cationic surfactant comprises benzalkonium chloride and alkyl trimethyl ammonium bromide.Neutral surface active agent comprises glycerol list olein, polyoxyethylene sorbitan fatty acid ester, polyvinyl alcohol and anhydro sorbitol fat.The embodiment of wetting agent comprises poloxamer, polyoxyethylene alkyl ether, castor oil derivatives and polyoxyethylene 8 stearate fat.
The present invention can also optionally join antioxidant in preparation, thereby gives its chemical stability.Antioxidant is selected from the extract of a-tocopherol, Y-tocopherol, S-tocopherol, tocopherol enrichment natural origin, sodium or calcium salt, the Vitamin C acyl cetylate of L-AA and it, amass wealth by heavy taxation propyl propionate, amass wealth by heavy taxation misery ester, amass wealth by heavy taxation sour dodecyl ester, Yoshinox BHT (BHT) and butylated hydroxyanisol (BHA).In one embodiment, antioxidant is BHT or BHA.
The preferred dosage form of drug composition of the present invention is the tablet of preparing by compression method.Described tablet can carry out film with the mixture such as hydroxypropyl cellulose and hydroxypropyl emthylcellulose, contains titanium dioxide and/or other coloring agent, such as ferrum oxide, dyestuff and Se Dian in this mixture; The mixture of polyvinyl alcohol (PVA) and Polyethylene Glycol (PEG), contains titanium dioxide and/or other coloring agent, such as ferrum oxide, dyestuff and Se Dian; Or any other suitable instant-free coating agent.Coating provides taste masked and other stability to final tablet.What commercially available film provided for Colorcon is preparation mixture of powders
The present invention can also add sweeting agent and/or fumet.
Detailed description of the invention
Further explain the present invention below in conjunction with embodiment, but embodiment does not limit in any form to the present invention.
Embodiment 1
Preparation method:
1. 350g glyceryl monostearate is added in 50ml ethanol, be heated to 60 DEG C, add 125g hydrochloric acid Conmana that it is dissolved, take out, 40 DEG C of vacuum dryings 4 hours, comminution by gas stream, grinding particle size requires at 0～20 μ m.2. press recipe quantity, add micropowder silica gel, starch evenly to mix.
3. fill capsule No. 0, packaging.
Embodiment 2
Preparation method:
1. 500g glyceryl monostearate is added in 60ml ethanol, be heated to 60 DEG C, add 125g hydrochloric acid Conmana, 3.0g sodium lauryl sulphate that it is dissolved, take out, 40 DEG C of vacuum dryings 4 hours, comminution by gas stream, grinding particle size requires at 20～40 μ m.
2. add micropowder silica gel, starch evenly to mix by recipe quantity.
3. fill capsule No. 0, packaging.
Embodiment 3
Preparation method
1. 175g PEG6000 is added in 40ml acetone, be heated to 60 DEG C, add 125g hydrochloric acid Conmana that it is dissolved, 40 DEG C of vacuum dryings 4 hours, comminution by gas stream, grinding particle size requires at 60～80 μ m.
2. press recipe quantity, add micropowder silica gel, starch evenly to mix.
2. fill capsule No. 0, packaging.
Embodiment 4
Preparation method:
1. 250g hexadecanol is added in 40ml ethanol, be heated to 60 DEG C, add 125g hydrochloric acid Conmana, 5.0g lecithin that it is dissolved, take out, 40 DEG C of vacuum dryings 4 hours, comminution by gas stream, grinding particle size requires at 60～80 μ m.
2. press recipe quantity, add micropowder silica gel, starch evenly to mix.
3. fill capsule No. 0, packaging.
Biological test
(1) table 1 is the dissolution comparative result before embodiment 1-4 gained hydrochloric acid Conmana compositions encapsulating capsule.With reference to dissolution method (2010 editions two annex XC bis-methods of Chinese Pharmacopoeia).
Table 1 hydrochloric acid Conmana encapsulating capsule compares with compositions cumulative percentage dissolution (%)
As can be seen from Table 1, hydrochloric acid Conmana encapsulating capsule of the present invention uses the dissolution in vitro of compositions in 10-30min better, and in 30 minutes, just stripping is complete substantially, can greatly improve in vivo its bioavailability.
Clinical case is analyzed
Clinical case analysis of the present invention: this product (embodiment 1) clinical trial, obtain good safety, efficiency evaluation, and bioavailability is high, sustainable 24 hours drug releases in vivo, good effect.Below adopt several routine typical clinical cases to analyze:
Clinical case l: patient A, man, 30 years old, advanced Non-small cell lung used hydrochloric acid Conmana capsule under doctor advised, takes twice every day, takes continuously 28 days, and gross tumor volume has the trend of reducing.
Clinical case 2: patient B, man, 36 years old, advanced Non-small cell lung used hydrochloric acid Conmana capsule under doctor advised, takes twice every day, takes continuously 28 days, and gross tumor volume has no growth sign.
Clinical case 3: patient C, man, 45 years old, advanced Non-small cell lung used hydrochloric acid Conmana capsule under doctor advised, takes twice every day, takes continuously 6 weeks, and gross tumor volume has no growth sign.
Clinical case 4: patient D, man, 40 years old, advanced Non-small cell lung used hydrochloric acid Conmana capsule under doctor advised, takes twice every day, took continuously 6 weeks, and gross tumor volume has obviously and reduces.
Claims (8)
1. a hydrochloric acid Conmana capsule composition, comprises hydrochloric acid Conmana, carrier, wherein, also comprises organic solvent, surfactant, micropowder silica gel, starch in described compositions, and compositions composition is mainly:
2. hydrochloric acid Conmana capsule composition according to claim 1, wherein said carrier is selected from glyceryl monostearate, polyethylene glycol 6000, hexadecanol, octadecanol one or more, described organic solvent is selected from ethanol, methanol, acetone one or more, and described surfactant is selected from sodium lauryl sulphate, Tween 80, lecithin one or more.
3. hydrochloric acid Conmana capsule composition according to claim 1 and 2, it comprises following component:
4. hydrochloric acid Conmana capsule composition according to claim 1 and 2, it comprises following component:
5. hydrochloric acid Conmana capsule composition according to claim 1 and 2, it comprises following component:
6. hydrochloric acid Conmana capsule composition according to claim 1 and 2, it comprises following component:
7. hydrochloric acid Conmana capsule composition according to claim 1, wherein, in described compositions, hydrochloric acid Conmana with vehicle weight ratio is: hydrochloric acid Conmana: carrier is 1: 0.3～1: 5.
8. the preparation method of the hydrochloric acid Conmana capsule composition described in a claim 1-7 any one, it comprises following steps: first carrier is added in organic solvent, be heated to 60 DEG C, add hydrochloric acid Conmana or add again surfactant and make its dissolving, 40 DEG C of vacuum dryings 4 hours, comminution by gas stream, grinding particle size is at 1～80 μ m, add micropowder silica gel, starch evenly to mix, capsulation.
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| CN201410078528.0A CN103860521A (en) | 2014-03-05 | 2014-03-05 | Icotinib hydrochloride capsule composition and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106176755A (en) * | 2016-07-07 | 2016-12-07 | 杭州紫金医药科技有限公司 | Conmana is preparing the application and pharmaceutical preparation thereof prevented and treated in idiopathic pulmonary fibrosis medicine |
| CN108403661A (en) * | 2018-04-16 | 2018-08-17 | 包宝金 | A kind of medicament microcapsule preparation and preparation method thereof for treating non-small cell lung cancer |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1398590A (en) * | 2002-08-20 | 2003-02-26 | 杭州容立医药科技有限公司 | Recipe and prepn of progesterone capsule |
| CN102911179A (en) * | 2008-07-08 | 2013-02-06 | 浙江贝达药业有限公司 | Lcotinib hydrochloride crystal form, medicinal composition and application |
-
2014
- 2014-03-05 CN CN201410078528.0A patent/CN103860521A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1398590A (en) * | 2002-08-20 | 2003-02-26 | 杭州容立医药科技有限公司 | Recipe and prepn of progesterone capsule |
| CN102911179A (en) * | 2008-07-08 | 2013-02-06 | 浙江贝达药业有限公司 | Lcotinib hydrochloride crystal form, medicinal composition and application |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106176755A (en) * | 2016-07-07 | 2016-12-07 | 杭州紫金医药科技有限公司 | Conmana is preparing the application and pharmaceutical preparation thereof prevented and treated in idiopathic pulmonary fibrosis medicine |
| CN108403661A (en) * | 2018-04-16 | 2018-08-17 | 包宝金 | A kind of medicament microcapsule preparation and preparation method thereof for treating non-small cell lung cancer |
| CN108403661B (en) * | 2018-04-16 | 2020-03-10 | 吉林大学 | Medicinal microcapsule preparation for treating non-small cell lung cancer and preparation method thereof |
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