CN103784395B - A kind of sufentanil gel preparation and preparation method thereof - Google Patents
A kind of sufentanil gel preparation and preparation method thereof Download PDFInfo
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- CN103784395B CN103784395B CN201410065108.9A CN201410065108A CN103784395B CN 103784395 B CN103784395 B CN 103784395B CN 201410065108 A CN201410065108 A CN 201410065108A CN 103784395 B CN103784395 B CN 103784395B
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- sufentanil
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Abstract
The invention provides a kind of sufentanil gel preparation and preparation method thereof, gel preparation of the present invention comprises following component according to percentage by weight: sufentanil 0.05-0.25%, Acritamer 940 0.3-1.5%, trometamol 0.1-1.2%, ethanol 1-10%, propylene glycol 5-15%, Macrogol 4000 .5-2.0%, disodium edetate 0.005-0.015%, triethanolamine 1.0-2.5%.The present invention dissolves sufentanil by adopting trometamol, thus solve sufentanil free alkali insoluble problem in water, improve sufentanil to the penetrance of skin, the transdermal absorbance of sufentanil is improved, significantly improved, simultaneously for patient provides a kind of new route of administration by local topical administration treatment local pain curative effect.Gel preparation of the present invention is the good semi-solid gel of Transdermal absorption, and sufentanil 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.
Description
Invention field
The present invention relates to chemical pharmacy field, be specifically related to a kind of sufentanil gel preparation and preparation method thereof.
Background of invention
Sufentanil (Sufentanil) chemistry is by name: N-(4-(methoxyl methyl)-1-(2-(2-thienyl) ethyl)-4-piperidyl)-N-hydrocinnamamide, it is a kind of potent opium kind analgesics, also be a species specificity μ-receptor stimulating agent simultaneously, stronger than fentanyl (fentanyl) 7 ~ 10 times to the affinity of μ-receptor.The analgesic effect of this product is stronger than fentanyl several times, and has good hemodynamic stability, can ensure that enough myocardial oxygens should simultaneously.Just maximum drug effect can be played in a few minutes after intravenously administrable.In pharmaceutical research result, important one side is cardiovascular stability, and electroencephalogram reaction and fentanyl roughly the same, do not exist the side effect such as immunosuppressant, haemolysis or histamine release simultaneously.
Chinese Pharmacopoeia (version in 2005) has recorded sufentanil citrate injection.Existing document is less to other dosage forms report.The present invention dissolves sufentanil by adopting trometamol, thus solve the sufentanil free alkali problem that dissolubility is not good in water, improve sufentanil to the penetrance of skin, the transdermal absorbance of sufentanil is improved, significantly improved, simultaneously for patient provides a kind of new route of administration by local topical administration treatment local pain curative effect.
Gel preparation of the present invention is the good semi-solid gel of Transdermal absorption, and sufentanil 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 sufentanil semi-solid gel, can dissolve completely and be scattered in gel, effectively through skin, can absorbing rapidly, thus reach good curative effect.
On the one hand, the invention provides a kind of sufentanil gel preparation, wherein, comprise following component according to percentage by weight:
On the other hand, the present invention relates to a kind of preparation method of sufentanil gel preparation, it comprises the following steps: put by carbomer in the pure water of the total dosage 50% of prescription, soaks 24 hours; Trometamol is put in the water of the total dosage 10% of prescription and dissolve, for subsequent use; Sufentanil is put dispersed with stirring in ethanol even, add trometamol aqueous solution stirring and dissolving, clarify completely to solution, for subsequent use; By disodium edetate and remaining pure water stirring and dissolving to without visible particle, for subsequent use; Swelling good Acritamer 940 is filtered through 120 objects, the propylene glycol of recipe quantity, PEG400, disodium edetate solution and sufentanil solution are added in carbomer, stir 15 minutes; Added by triethanolamine in carbomer substrate, stir 30 minutes, control pH is at 7.0-8.5, and stop stirring, fill, packaging, obtains sufentanil gel preparation.
The present invention dissolves sufentanil by adopting trometamol, thus solve sufentanil (free alkali) insoluble problem in water, improve sufentanil to the penetrance of skin, the transdermal absorbance of sufentanil is improved, significantly improved, simultaneously for patient provides a kind of new route of administration by local topical administration treatment local pain curative effect.
Gel preparation of the present invention is the good semi-solid gel of Transdermal absorption, and sufentanil 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 glyceride mixtures of saturated vegetable fatty acid, water, salt or electrolyte, as protamine sulfate, sodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal 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, cellulose and its derivant 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, glycol compound, as propylene glycol and Polyethylene Glycol, esters is as ethyl oleate and Ethyl Lauroyl acid esters, agar, buffer agent is as magnesium hydroxide and aluminium hydroxide, alginic acid, pyrogen-free water, isotonic 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 agents, sweeting agent, flavoring agent and spice, antiseptic and antioxidant.
Pharmaceutical composition of the present invention can also be optional containing one or more diluent.The example of diluent comprises mannitol, sorbitol, biphosphate calcium dihydrate, microcrystalline Cellulose and powdered cellulose.Preferred diluent is microcrystalline Cellulose.Microcrystalline Cellulose can be obtained from several supplier, comprises Avicel PH101, the Avicel PH102 of FMCCorporation manufacture, Avicel PH103, AvicelPH105 and Avicel PH200.
Pharmaceutical composition of the present invention can also be optional containing disintegrating agent.Disintegrating agent can be the one in several modified starches, modified cellulosic polymeric or polycarboxylic acids, such as croscarmellose sodium, Explotab, polacrilin potassium and calcium carboxymethylcellulose (CMCCalcium).In one embodiment, disintegrating agent is croscarmellose sodium.Croscarmellose sodium NF type A commercially obtains with trade name " Ac-di-sol ".
Pharmaceutical composition of the present invention can also be optional containing one or more surfactants or wetting agent.Surfactant can be anion, cation or neutral surface active agent.The sodium laurate that anion surfactant comprises sodium lauryl sulfate, dodecyl sodium sulfate, oleyl sodium sulfate and mixes 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 anhydrosorbitol alcohol ester.The embodiment of wetting agent comprises poloxamer, polyoxyethylene alkyl ether, castor oil derivatives and polyoxyethylene 8 stearate fat.
Antioxidant can also optionally join in preparation by the present invention, thus gives its chemical stability.Antioxidant is selected from the extract of a-tocopherol, Y-tocopherol, S-tocopherol, tocopherol enrichment natural origin, L-AA and its sodium or calcium salt, Vitamin C acyl cetylate, 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 prepared by compression method.Described tablet can carry out film with the mixture of such as hydroxypropyl cellulose and hydroxypropyl emthylcellulose, containing 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), containing titanium dioxide and/or other coloring agent, such as ferrum oxide, dyestuff and Se Dian; Or other suitable instant-free coating agent any.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
Explain the present invention further below in conjunction with embodiment, 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, soak 24 hours.Trometamol is put in the water of the total dosage 10% of prescription and dissolve, for subsequent use.Sufentanil is put dispersed with stirring in ethanol even, add trometamol aqueous solution stirring and dissolving, clarify completely to solution, for subsequent use.By disodium edetate and remaining purified water stirring and dissolving to without visible particle, for subsequent use; Swelling good Acritamer 940 is filtered through 120 objects, the propylene glycol of recipe quantity, PEG400, disodium edetate solution and sufentanil solution are added in carbomer.Stir 15 minutes; Added by triethanolamine in carbomer substrate, stir 30 minutes, control pH is at 7.3-8.5, and stop stirring, fill, packaging, obtains easypro sufentanil gel.
Embodiment 2
Sufentanil raw material is mixed with sufentanil gel by following prescription:
Carbomer is put in the purified water of the total dosage 50% of prescription, soak 24 hours.Trometamol is put in the water of the total dosage 10% of prescription and dissolve, for subsequent use.Sufentanil is put dispersed with stirring in ethanol even, add trometamol aqueous solution stirring and dissolving, clarify completely to solution, for subsequent use.By disodium edetate and remaining purified water stirring and dissolving to without visible particle, for subsequent use; Swelling good Acritamer 940 is filtered through 120 objects, the propylene glycol of recipe quantity, PEG400, disodium edetate solution and sufentanil solution are added in carbomer.Stir 15 minutes; Added by triethanolamine in carbomer substrate, stir 30 minutes, control pH is at 7.3-8.5, and stop stirring, fill, packaging, obtains sufentanil gel.
Embodiment 3
Sufentanil raw material is mixed with sufentanil gel by following prescription:
Carbomer is put in the purified water of the total dosage 50% of prescription, soak 24 hours.Trometamol is put in the water of the total dosage 10% of prescription and dissolve, for subsequent use.Sufentanil is put dispersed with stirring in ethanol even, add trometamol aqueous solution stirring and dissolving, clarify completely to solution, for subsequent use.By disodium edetate and remaining purified water stirring and dissolving to without visible particle, for subsequent use; Swelling good Acritamer 940 is filtered through 120 objects, the propylene glycol of recipe quantity, PEG400, disodium edetate solution and sufentanil solution are added in carbomer.Stir 15 minutes; Added by triethanolamine in carbomer substrate, stir 30 minutes, control pH is at 7.3-8.5, and stop stirring, fill, packaging, obtains sufentanil gel.
Biological activity test
Embodiment 4
Experimental selection with Franz diffusion cell for experimental provision, with sufentanil through the amount of in vitro little piglets skin for inspection target, observe product (specification: 0.5%, 5mg/ props up) the Transdermal absorption measurement result of embodiments of the invention 1-3 as table 1:
Table 1 Transdermal absorption situation
| Lot number | Embodiment 1 | Embodiment 2 | Embodiment 3 |
| Transmitance %(1h) | 0.80 | 0.85 | 0.82 |
| Transmitance %(2h) | 1.23 | 1.28 | 1.26 |
| Transmitance %(4h) | 1.92 | 1.95 | 1.89 |
| Transmitance %(8h) | 2.64 | 2.68 | 2.63 |
| Transmitance %(12h) | 2.87 | 2.92 | 2.89 |
| Transmitance %(24h) | 3.34 | 3.38 | 3.35 |
From Ligustrazine hydrochloride result of the test, the sufentanil gel sample Transdermal absorption situation of embodiment 1-3 is apparently higher than existing contrast medicine, and increase transmitance in time continues to increase; The transmitance meansigma methods of 24 hours is about 3.36%, thus illustrates that inventive gel preparation Transdermal absorption effect is better, adds blood drug level during local application, improves curative effect.
Claims (2)
1. a sufentanil gel preparation, wherein, composed of the following components according to percentage by weight:
2. a preparation method for sufentanil gel preparation according to claim 1, it comprises the following steps: put by carbomer in the pure water of the total dosage 50% of prescription, soaks 24 hours; Trometamol is put in the water of the total dosage 10% of prescription and dissolve, for subsequent use; Sufentanil is put dispersed with stirring in ethanol even, add trometamol aqueous solution stirring and dissolving, clarify completely to solution, for subsequent use; By disodium edetate and remaining pure water stirring and dissolving to without visible particle, for subsequent use; Swelling good Acritamer 940 is filtered through 120 objects, the propylene glycol of recipe quantity, PEG400, disodium edetate solution and sufentanil solution are added in carbomer, stir 15 minutes; Added by triethanolamine in carbomer substrate, stir 30 minutes, control pH is at 7.0-8.5, and stop stirring, fill, packaging, obtains sufentanil gel preparation.
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| CN201410065108.9A CN103784395B (en) | 2014-02-25 | 2014-02-25 | A kind of sufentanil gel preparation and preparation method thereof |
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| CN201410065108.9A CN103784395B (en) | 2014-02-25 | 2014-02-25 | A kind of sufentanil gel preparation and preparation method thereof |
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| CN103784395A CN103784395A (en) | 2014-05-14 |
| CN103784395B true CN103784395B (en) | 2015-10-28 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006047362A2 (en) * | 2004-10-21 | 2006-05-04 | Durect Corporation | Transdermal delivery systems |
| CN101083964A (en) * | 2004-11-12 | 2007-12-05 | 扎斯公司 | Instant patch for dermal drug delivery |
| CN102068405A (en) * | 2010-12-16 | 2011-05-25 | 天津工业大学 | Ketoprofen gel and preparation method thereof |
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2014
- 2014-02-25 CN CN201410065108.9A patent/CN103784395B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006047362A2 (en) * | 2004-10-21 | 2006-05-04 | Durect Corporation | Transdermal delivery systems |
| CN101083964A (en) * | 2004-11-12 | 2007-12-05 | 扎斯公司 | Instant patch for dermal drug delivery |
| CN102068405A (en) * | 2010-12-16 | 2011-05-25 | 天津工业大学 | Ketoprofen gel and preparation method thereof |
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| CN103784395A (en) | 2014-05-14 |
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