CN103989628A - Etoricoxib gel preparation and preparation method thereof - Google Patents
Etoricoxib gel preparation and preparation method thereof Download PDFInfo
- Publication number
- CN103989628A CN103989628A CN201410213170.8A CN201410213170A CN103989628A CN 103989628 A CN103989628 A CN 103989628A CN 201410213170 A CN201410213170 A CN 201410213170A CN 103989628 A CN103989628 A CN 103989628A
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- China
- Prior art keywords
- etoricoxib
- preparation
- gel
- gel preparation
- carbomer
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- MNJVRJDLRVPLFE-UHFFFAOYSA-N etoricoxib Chemical compound C1=NC(C)=CC=C1C1=NC=C(Cl)C=C1C1=CC=C(S(C)(=O)=O)C=C1 MNJVRJDLRVPLFE-UHFFFAOYSA-N 0.000 title claims abstract description 52
- 229960004945 etoricoxib Drugs 0.000 title claims abstract description 51
- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims abstract description 21
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 16
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229960000281 trometamol Drugs 0.000 claims abstract description 14
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims abstract description 11
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000003756 stirring Methods 0.000 claims description 30
- 239000000243 solution Substances 0.000 claims description 16
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- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 229960000540 polacrilin potassium Drugs 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- WVWZXTJUCNEUAE-UHFFFAOYSA-M potassium;1,2-bis(ethenyl)benzene;2-methylprop-2-enoate Chemical compound [K+].CC(=C)C([O-])=O.C=CC1=CC=CC=C1C=C WVWZXTJUCNEUAE-UHFFFAOYSA-M 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229950008679 protamine sulfate Drugs 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- BTURAGWYSMTVOW-UHFFFAOYSA-M sodium dodecanoate Chemical compound [Na+].CCCCCCCCCCCC([O-])=O BTURAGWYSMTVOW-UHFFFAOYSA-M 0.000 description 1
- 229940082004 sodium laurate Drugs 0.000 description 1
- MWZFQMUXPSUDJQ-KVVVOXFISA-M sodium;[(z)-octadec-9-enyl] sulfate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCCOS([O-])(=O)=O MWZFQMUXPSUDJQ-KVVVOXFISA-M 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- PHYFQTYBJUILEZ-IUPFWZBJSA-N triolein Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CCCCCCCC)COC(=O)CCCCCCC\C=C/CCCCCCCC PHYFQTYBJUILEZ-IUPFWZBJSA-N 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention provides an etoricoxib gel preparation and a preparation method thereof. The gel preparation comprises the following components in percentage by weight: 0.3 to 10% of etoricoxib, 0.3 to 25% of carbomer 940, 0.1 to 30% of tromethamine, 1 to 45% of ethyl alcohol, 5 to 50% of propylene glycol, 0.5 to 5% of polyethylene glycol 400, 0.05 to 0.8% of edetate disodium, 1.0 to 10% of triethanolamine, and the balance of pure water. According to the preparation method, tromethamine is used to dissolve etoricoxib so as to solve the problem that etoricoxib is hardly dissolved in water; the skin penetrability of etoricoxib is improved and the transdermal absorption rate of etoricoxib is increased, and local external application of the gel preparation can obviously improve the treatment effect on arthritis or rheumatoid arthritis; simultaneously, a new administration route is provided for patients. The gel preparation is in a form of semi-solid gel with good transdermal absorption effect etoricoxib is completely dissolved and dispersed in the gel preparation, and thereby the pain of the patient can be relieved favorably. The preparation method is simple in process, and the preparation is stable and reliable in quality.
Description
Invention field
The present invention relates to pharmaceutical preparation of a kind for the treatment of of arthritis and preparation method thereof, belong to the medication of orthopaedics class disease, be specifically related to a kind of Etoricoxib gel and preparation method thereof.
Background of invention
Any age of rheumatoid arthritis all may fall ill, and is mainly in 30-60 year, and 45 years old the most common, and with age growth, sickness rate also increases, and women's sickness rate is apparently higher than male, and China suffers from present the number of rheumatoid arthritis in various degree and approached 200,000,000 people.According to the investigation gained for 15 years old, Shanghai City and above crowd, if disregard the disease financial burden due to DALY loss, the disease financial burden that arthritis causes for year financial burden is per capita 74.59 yuan.The disease financial burden that the arthritis of each main Types causes is respectively: Human Osteoarthritis is 778.63 yuan per capita; 1250.45 yuan per capita of rheumatoid arthritis patients; 1507.68 yuan per capita of patient with gout; 40.60 yuan per capita of patients with ankylosing spondylitis; 297.34 yuan per capita of reflection property arthritics.In conjunction with the relevant Epidemiological study result based on Regional Distribution, estimating at 1,760 ten thousand people is big city rheumatoid arthritis patients, and 3,810 ten thousand people are small and medium-sized cities rheumatoid patient, and 12,330 ten thousand people are rural area rheumatoid arthritis patients.China's rheumatism in 2005 and rheumatoid arthritis medication are about 1,100,000,000 yuan, within 2008, surpass 2,500,000,000 yuan, and 2009, along with the propelling of whole people's medical insurance, rheumatoid arthritis medicine was sold and increased by a year-on-year basis up to 41.86%, and sales volume is 38.56 hundred million yuan.Estimate that at present domestic rheumatoid arthritis surpasses 7,500,000,000 yuan by the theoretical market scale of medical market, so indomethacin uses very generally at home, indomethacin ordinary tablet discharges rapidly, action time is short.
Etoricoxib (Etoricoxib), is the effective as selective inhibitor of cyclo-oxygenase _ 2, and it has antiinflammatory, brings down a fever and ease pain character.Etoricoxib supervised approved by management is used as NSAID (non-steroidal anti-inflammatory drug) clinically.This medicine goes on the market as film-coated tablet, and commodity are by name
it is disclosed in EP O912518B1 for the first time (be also disclosed in JP1999514008, US5,861,419 and WO98/03484 in).Its structural formula is suc as formula shown in (I):
The relevant report that not yet has at present Etoricoxib gel.The invention provides a kind of new Etoricoxib gel, by adopting trometamol to dissolve Etoricoxib, thereby solve Etoricoxib not good problem of dissolubility in water, improve the penetrance of Etoricoxib to skin, the transdermal absorbance of Etoricoxib is improved, by local topical administration treatment of arthritis or Rheumatoid Arthritis, obviously improve, simultaneously for patient provides a kind of new route of administration.
Gel preparation of the present invention is the good semi-solid gel of Transdermal absorption, and Etoricoxib dissolves completely and is scattered in gel, is beneficial to patient's alleviating pain.Processing technology is simple, and the quality of the pharmaceutical preparations is reliable and stable.
Summary of the invention
The invention provides a kind of new Etoricoxib semi-solid gel, can dissolve completely and be scattered in gel, can effectively see through skin, absorb rapidly, thereby reach good curative effect.
On the one hand, the invention provides a kind of Etoricoxib gel preparation, wherein, according to percentage by weight, comprise following component:
Some embodiments therein, gel preparation of the present invention, wherein comprises following component:
Some embodiments therein, gel preparation of the present invention, wherein comprises following component:
On the other hand, the present invention relates to a kind of preparation method of Etoricoxib gel preparation of the present invention, it comprises the following steps: carbomer is put in the pure water of the total dosage 50% of prescription, soaked 24 hours; By trometamol put prescription total dosage 10% water in dissolve, standby; Etoricoxib is put in ethanol to dispersed with stirring even, add trometamol aqueous solution stirring and dissolving, clarify completely to solution, standby; Disodium edetate and remaining pure water stirring and dissolving is to without visible particle, standby; The Acritamer 940 that swelling is good is filtered through 120 objects, the propylene glycol of recipe quantity, PEG400, disodium edetate solution and Etoricoxib solution are added in carbomer, stir 15 minutes; Triethanolamine is added in carbomer substrate, stir 30 minutes, control pH at 7.0-8.5, stop stirring, fill, packing, obtains Etoricoxib gel preparation.
The present invention is by adopting trometamol to dissolve Etoricoxib, thereby solve Etoricoxib insoluble problem in water, improve the penetrance of Etoricoxib to skin, the transdermal absorbance of Etoricoxib is improved, by local topical administration treatment of arthritis or Rheumatoid Arthritis, obviously improve, simultaneously for patient provides a kind of new route of administration.
Gel preparation of the present invention is the good semi-solid gel of Transdermal absorption, and Etoricoxib dissolves completely and is scattered in gel, is beneficial to patient's alleviating pain.Processing technology is simple, and the quality of the pharmaceutical preparations is reliable and stable.
Excipient of the present invention comprises, but be not limited to, 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 FMC Corporation manufactures.
Pharmaceutical composition of the present invention can also optionally contain disintegrating agent.Disintegrating agent can be a kind of 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, with such as the mixture of hydroxypropyl cellulose and hydroxypropyl emthylcellulose is filmed, contain 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.Commercially available film for Colorcon provide for preparation mixture of powders
The present invention can also add sweeting agent and/or fumet.
The specific embodiment
Below in conjunction with embodiment, further explain the present invention, but embodiment does not limit in any form to the present invention.
Embodiment 1
Process for preparation
Carbomer is put in the purified water of the total dosage 50% of prescription, soaked 24 hours.By trometamol put prescription total dosage 10% water in dissolve, standby.Etoricoxib is put in ethanol to dispersed with stirring even, add trometamol aqueous solution stirring and dissolving, clarify completely to solution, standby.Disodium edetate and remaining purified water stirring and dissolving is to without visible particle, standby; The Acritamer 940 that swelling is good is filtered through 120 objects, the propylene glycol of recipe quantity, PEG400, disodium edetate solution and Etoricoxib solution are added in carbomer.Stir 15 minutes; Triethanolamine is added in carbomer substrate, stir 30 minutes, control pH at 7.3-8.5, stop stirring, fill, packing, obtains Etoricoxib gel.
Embodiment 2
Etoricoxib raw material is mixed with to Etoricoxib gel by following prescription:
Carbomer is put in the purified water of the total dosage 50% of prescription, soaked 24 hours.By trometamol put prescription total dosage 10% water in dissolve, standby.Etoricoxib is put in ethanol to dispersed with stirring even, add trometamol aqueous solution stirring and dissolving, clarify completely to solution, standby.Disodium edetate and remaining purified water stirring and dissolving is to without visible particle, standby; The Acritamer 940 that swelling is good is filtered through 120 objects, the propylene glycol of recipe quantity, PEG400, disodium edetate solution and Etoricoxib solution are added in carbomer.Stir 15 minutes; Triethanolamine is added in carbomer substrate, stir 30 minutes, control pH at 7.3-8.5, stop stirring, fill, packing, obtains Etoricoxib gel.
Embodiment 3
Etoricoxib raw material is mixed with to Etoricoxib gel by following prescription:
Carbomer is put in the purified water of the total dosage 50% of prescription, soaked 24 hours.By trometamol put prescription total dosage 10% water in dissolve, standby.Etoricoxib is put in ethanol to dispersed with stirring even, add trometamol aqueous solution stirring and dissolving, clarify completely to solution, standby.Disodium edetate and remaining purified water stirring and dissolving is to without visible particle, standby; The Acritamer 940 that swelling is good is filtered through 120 objects, the propylene glycol of recipe quantity, PEG400, disodium edetate solution and Etoricoxib solution are added in carbomer.Stir 15 minutes; Triethanolamine is added in carbomer substrate, stir 30 minutes, control pH at 7.3-8.5, stop stirring, fill, packing, obtains Etoricoxib gel.
Biological activity test
Embodiment 4
Experimental selection be take Franz diffusion cell as experimental provision, the Etoricoxib of take sees through the amount of in vitro little piglets skin as investigating index, observe the Transdermal absorption situation of the product (specification: 0.5%, 3mg/ props up) of embodiments of the invention 1-3, Transdermal absorption measurement result is as table 1:
Table 1 Transdermal absorption situation
| Lot number | Embodiment 1 | Embodiment 2 | Embodiment 3 |
| Transmitance % (1h) | 0.92 | 0.91 | 0.90 |
| Transmitance % (2h) | 1.30 | 1.29 | 1.28 |
| Transmitance % (4h) | 1.85 | 1.84 | 1.84 |
| Transmitance % (8h) | 2.68 | 2.68 | 2.65 |
| Transmitance % (12h) | 2.99 | 2.92 | 2.93 |
| Transmitance % (24h) | 3.78 | 3.56 | 3.59 |
From in-vitro percutaneous permeability test result, the Etoricoxib gel sample Transdermal absorption situation of embodiment 1-3 is good, and increase transmitance in time continues to increase; The transmitance meansigma methods of 24 hours is 3.60%, thereby explanation gel preparation Transdermal absorption of the present invention is effective, and the blood drug level while having increased local application, has improved curative effect, for arthritis or patient with rheumatoid arthritis provide another kind of route of administration.
Claims (4)
1. an Etoricoxib gel preparation, wherein, comprises following component according to percentage by weight:
2. gel preparation according to claim 1, wherein comprises following component:
3. gel preparation according to claim 1, wherein comprises following component:
4. a preparation method for the Etoricoxib gel preparation described in claim 1-3 any one, it comprises the following steps: carbomer is put in the pure water of the total dosage 50% of prescription, soaked 24 hours; By trometamol put prescription total dosage 10% water in dissolve, standby; Etoricoxib is put in ethanol to dispersed with stirring even, add trometamol aqueous solution stirring and dissolving, clarify completely to solution, standby; Disodium edetate and remaining pure water stirring and dissolving is to without visible particle, standby; The Acritamer 940 that swelling is good is filtered through 120 objects, the propylene glycol of recipe quantity, PEG400, disodium edetate solution and Etoricoxib solution are added in carbomer, stir 15 minutes; Triethanolamine is added in carbomer substrate, stir 30 minutes, control pH at 7.0-8.5, stop stirring, fill, packing, obtains Etoricoxib gel preparation.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108210929A (en) * | 2016-12-21 | 2018-06-29 | 北京泰德制药股份有限公司 | A kind of pharmaceutical composition containing Etoricoxib and preparation method thereof |
| CN112870156A (en) * | 2021-03-25 | 2021-06-01 | 深圳前海九华国际投资控股有限公司 | Etoricoxib in-situ gel and preparation method thereof |
| CN113181149A (en) * | 2021-06-11 | 2021-07-30 | 北京畅盛医药科技有限公司 | External skin medicinal preparation for treating gouty arthritis |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102697703A (en) * | 2012-05-28 | 2012-10-03 | 江苏中丹制药有限公司 | Piroxicam gel preparation and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102697703A (en) * | 2012-05-28 | 2012-10-03 | 江苏中丹制药有限公司 | Piroxicam gel preparation and preparation method thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108210929A (en) * | 2016-12-21 | 2018-06-29 | 北京泰德制药股份有限公司 | A kind of pharmaceutical composition containing Etoricoxib and preparation method thereof |
| CN112870156A (en) * | 2021-03-25 | 2021-06-01 | 深圳前海九华国际投资控股有限公司 | Etoricoxib in-situ gel and preparation method thereof |
| CN113181149A (en) * | 2021-06-11 | 2021-07-30 | 北京畅盛医药科技有限公司 | External skin medicinal preparation for treating gouty arthritis |
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Application publication date: 20140820 |