Summary of the invention
The object of the invention is to overcome above-mentioned deficiency, Transdermal absorption, water content are high, persistent and bland indomethacin Hydrophillia Babu agent to provide one to be easy to.Furthermore, the object of the invention is research indomethacin aqueous cataplasma, make it in preparation and storage, have good steady dissolution, demonstrate high-moisture and long moisture retention, to ensure the sustained release of medicine and to improve the Transdermal absorption performance of medicine.
First aspect of the present invention is to provide a kind of indomethacin cataplasm, comprises backing (conventional non-woven fabrics or stretch fabric etc.), mastic and anti-mucosa, wherein:
In mastic, the content of indomethacin is preferably 0.1-3wt%, is more preferably 0.2-2wt%, is more preferably 0.2-1.5wt%, is more preferably 0.3-1wt%;
In mastic, the weight of crotamiton is preferably the 0.1-6 of indomethacin doubly, is more preferably 0.2-4 doubly, is more preferably 0.5-3 doubly, is more preferably 1-2.5 doubly, is more preferably 1.5-2 doubly;
In mastic, the weight of N-Methyl pyrrolidone is preferably the 1-15 of indomethacin doubly, is more preferably 1.5-10 doubly, is more preferably 1.5-9 doubly, is more preferably 2-8 doubly, is more preferably 3.5-6 doubly, is more preferably 4-5.2 doubly.
In a kind of preferred embodiment in the present invention first, described cataplasma is made up of backing (conventional non-woven fabrics or stretch fabric etc.), mastic and anti-mucosa, described mastic constituent comprises indomethacin, solvent and aqueous gel substrate, hydrophilic transdermal absorbable preparation is prepared into through cataplasma moulding process, wherein, described solvent comprises crotamiton and N-Methyl pyrrolidone; Wherein:
In mastic, the content of indomethacin is preferably 0.1-3wt%, is more preferably 0.2-2wt%, is more preferably 0.2-1.5wt%, is more preferably 0.3-1wt%;
In mastic, the weight of crotamiton is preferably the 0.1-6 of indomethacin doubly, is more preferably 0.2-4 doubly, is more preferably 0.5-3 doubly, is more preferably 1-2.5 doubly, is more preferably 1.5-2 doubly;
In mastic, the weight of N-Methyl pyrrolidone is preferably the 1-15 of indomethacin doubly, is more preferably 1.5-10 doubly, is more preferably 1.5-9 doubly, is more preferably 2-8 doubly, is more preferably 3.5-6 doubly, is more preferably 4-5.2 doubly; Surplus is aqueous gel substrate.
Preferably, the constituent of the above-mentioned any aqueous gel substrate of the present invention comprises and preferably consists of: hydrophilic basis material 0.1-40wt%, more preferably 0.5-30wt%, more preferably 5-25wt%, more preferably 10-20wt%;
Cross-linking agent 0.01-2wt%, more preferably 0.02-1wt%, more preferably 0.05-0.8wt%, more preferably 0.1-0.6wt%, more preferably 0.3-0.5wt%;
Cross-linking regulator 0.01-4wt%, more preferably 0.02-2wt%, more preferably 0.08-1.5wt%, more preferably 0.12-1wt%, more preferably 0.3-0.7wt%;
Wetting agent 10-60wt%, more preferably 19-50wt%, more preferably 20-50wt%, more preferably 25-42wt%, more preferably 30-38wt%;
Transdermal penetration enhancer 0.05-45wt%, more preferably 0.1-30wt%, more preferably 2-25wt%, more preferably 5-20wt%, more preferably 10-16wt%;
Water 10-85wt%, more preferably 20-80wt%, more preferably 30-68wt%, more preferably 38-56wt%, more preferably 45-50wt%.
But described hydrophilic basis material hydrophilic high molecular material, wherein, hydrophilic high molecular material can be selected from 1) cellulose and its derivates, as carboxymethyl cellulose, carboxymethyl cellulose salt, methylcellulose, ethyl cellulose, hydroxypropyl emthylcellulose, hydroxyethyl-cellulose etc.; 2) synthesized polymer material, as polyvinyl alcohol, carbomer, polyacrylic acid, polyacrylate or ester, poly acrylic acid-poly sodium acrylate copolymer (as NP-700), poly acrylic acid-poly sodium acrylate copolymer (as NP-600), poly acrylic acid-poly sodium acrylate copolymer (as NP-800), polyvinylpyrrolidone (PVP), polybutene, carboxylic polrvinyl; 3) other comes from the hydrophilic colloid of organism, polysaccharide, polypeptide or its hydrophilic derivatives, and as gelatin, arabic gum, alginate, alginic acid, alginate, chitosan etc., described hydrophilic high molecular material can be one or more in above-mentioned substance; Described salt can be potassium salt, sodium salt, calcium salt etc.
Cross-linking agent used can be selected from aluminium hydroxide, calcium hydroxide, dihydroxyaluminum aminoacetate, aluminum chloride, aluminium oxide, calcium chloride, aluminium citrate, synthetic aluminium silicate, dihydroxyaluminum aminoacetate, glutamic acid aluminum etc. in interior one or more.
Cross-linking regulator used can be selected from tartaric acid, citric acid, malic acid, edetic acid (EDTA), gluconic acid or its salt etc. in interior one or more, and described salt can be potassium salt, sodium salt, calcium salt etc., as EDETATE DISODIUM.
Wetting agent used is preferably polyhydric alcohol, can be selected from ethylene glycol, Polyethylene Glycol (as PEG-400, PEG-600, PEG-800), glycerol, propylene glycol, polypropylene glycol, D-glucitol, 1,3 butylene glycol, hexanediol, xylitol, liquid paraffin etc. in interior one or more.
Transdermal penetration enhancer used can be selected from laurocapram, Oleum menthae, eucalyptus oil, carbamide, dimethyl sulfoxide, propylene glycol, polyvinyl alcohol, soft phospholipid, phosphatidyl glycerol, TC, N-Methyl pyrrolidone (NMP), SA diethylester, oleic acid, oleyl alcohol, diisopropyl adipate, octyldodecanol, benzylalcohol, isopropyl myristate, lauryl alcohol, 2-octyldodecanol, ethyl 2 ethyl hexanoic acid, calcium mercaptoacetate, the last of the ten Heavenly stems monoglyceride, caprylate, the last of the ten Heavenly stems ester, decyl oleate, squalane and/or D-limonene etc. are in interior one or more.
Surfactant used can be ion-type or nonionic surfactant, and be preferably anionic surfactant, any one or a few in nonionic surfactant, can be selected from Polysorbate (as tween 80), sodium lauryl sulphate, dioctyl succinate disulfonate acid, Span, glyceryl monostearate, polyoxyethylene hydrogenated Oleum Ricini etc. in interior one or more.
In addition, described mastic can also comprise one or more in antiseptic, adhesive agent, filler, antioxidant, freshener.Wherein:
Described antiseptic can be selected from parabens (as methyl hydroxybenzoate, ethyl hydroxybenzoate etc.), benzoic acid, ethylparaben, benzalkonium chloride etc. in interior one or more.
Adhesive agent can be selected from polyvinylpyrrolidone (as PVPK30), polyacrylic acid etc. at interior one or both.
Filler can be selected from micropowder silica gel, calcium carbonate, Kaolin, Bentonite, zinc oxide, titanium dioxide etc. in interior one or more.
Antioxidant can be selected from sodium sulfite, sodium pyrosulfite, citric acid, dibenzylatiooluene, Butylated hydroxyanisole, ethylenediaminetetraacetic acid etc. in interior one or more.
Freshener can be selected from Mentholum, Camphora, menthol, Herba Menthae wet goods in interior one or more.
Second aspect of the present invention is to provide a kind of Indomethacin Compositions, comprise indomethacin, crotamiton and N-Methyl pyrrolidone, the weight of crotamiton is 0.1-6 times of indomethacin, be more preferably 0.2-4 doubly, be more preferably 0.5-3 doubly, be more preferably 1-2.5 doubly, be more preferably 1.5-2 doubly; The weight of N-Methyl pyrrolidone is 1-15 times of indomethacin, is more preferably 1.5-10 doubly, is more preferably 1.5-9 doubly, is more preferably 2-8 doubly, is more preferably 3.5-6 doubly, is more preferably 4-5.2 times.
Preferably, described Indomethacin Compositions also comprises aqueous gel substrate, wherein, in Indomethacin Compositions, the content of indomethacin is more preferably 0.2-2wt% for being preferably 0.1-3wt%(, be more preferably 0.2-1.5wt%, be more preferably 0.3-1wt%), aqueous gel substrate surplus.
Preferably, the constituent of described aqueous gel substrate comprises:
Hydrophilic basis material 0.1-40wt%, more preferably 0.5-30wt%, more preferably 5-25wt%, more preferably 10-20wt%;
Cross-linking agent 0.01-2wt%, more preferably 0.02-1wt%, more preferably 0.05-0.8wt%, more preferably 0.1-0.6wt%, more preferably 0.3-0.5wt%;
Cross-linking regulator 0.01-4wt%, more preferably 0.02-2wt%, more preferably 0.08-1.5wt%, more preferably 0.12-1wt%, more preferably 0.3-0.7wt%;
Wetting agent 10-60wt%, more preferably 19-50wt%, more preferably 20-50wt%, more preferably 25-42wt%, more preferably 30-38wt%;
Transdermal penetration enhancer 0.05-45wt%, more preferably 0.1-30wt%, more preferably 2-25wt%, more preferably 5-20wt%, more preferably 10-16wt%;
Water 10-85wt%, more preferably 20-80wt%, more preferably 30-68wt%, more preferably 38-56wt%, more preferably 45-50wt%.
Described Indomethacin Compositions can also comprise one or more in antiseptic, adhesive agent, filler, antioxidant, freshener.
Hydrophilic basis material, cross-linking agent, cross-linking regulator, wetting agent, transdermal penetration enhancer, antiseptic, adhesive agent, filler, antioxidant, freshener etc. described in the present invention second aspect, have identical implication and weight proportion scope respectively with hydrophilic basis material, cross-linking agent, cross-linking regulator, wetting agent, transdermal penetration enhancer, antiseptic, adhesive agent, filler, antioxidant, freshener etc. described in the present invention first aspect respectively.
Applicant finds: crotamiton and N-Methyl pyrrolidone used in combination time can increase the dissolubility of indomethacin, but when crotamiton consumption is excessive, long-time placement understands variable color, less stable, and consumption is too small, and indomethacin is poorly soluble; N-Methyl pyrrolidone consumption is excessive, poor stability and easily produce stink, and the very few indomethacin of consumption is poorly soluble, and percutaneous abilities is also just deteriorated.Applicant is 0.1-6 times, preferably 0.2-4 times of indomethacin at the consumption of crotamiton through great many of experiments discovery, the consumption of N-Methyl pyrrolidone be the 1-15 of indomethacin doubly, preferably 1.5-10 times time, indomethacin dissolves completely, and good stability, and be dispersed in the medium-term and long-term not easily crystallization of aqueous gel substrate.
Indomethacin cataplasm provided by the invention take indomethacin as active component, the mixed solvent of crotamiton and N-Methyl pyrrolidone is adopted to increase the dissolubility of indomethacin, indomethacin is made to dissolve completely, and be dispersed in the medium-term and long-term not easily crystallization of aqueous gel substrate, increase the Transdermal absorption performance of indomethacin; The transdermal penetration enhancer added, wetting agent etc. ensure that indomethacin cataplasm high-moisture and long time moisture retention, increase the Transdermal absorption of medicine.The U.S. pungent cataplasma of diindyl provided by the invention can be used for the various arthralgia diseases such as rheumatic arthritis, gouty arthritis, tatanic myelitis, tenosynovitis, myalgia, pain in the lumbar region.
Detailed description of the invention
Referring to specific embodiment, the invention will be further described, to understand the present invention better.
Embodiment 1
The indomethacin cataplasm that the present embodiment provides is made up of backing, mastic and anti-mucosa, and the constituent of described mastic comprises:
First 2.0g sodium carboxymethyl cellulose is dissolved in glycerol and partial purification water, then adds 1.0g Vinlub 73 and 0.1g Tween 80, be heated to 40 DEG C, stir, obtain component A;
Get 1g Gelatin in partial purification water, expand complete post-heating to 60 DEG C, stirs to translucent colloid, obtained B component;
5.0g sodium polyacrylate part corrective, 0.06g aluminium hydroxide and 0.15g disodium edetate are dissolved in glycerol, are uniformly mixed, obtained component C;
Join in purified water by 0.12g tartaric acid, then add the indomethacin solution be dissolved in advance in crotamiton, N-Methyl pyrrolidone, mixing, stirs, obtains D component;
Get residue purified water in prefabricated tanks, add component A, B component, component C, make its fully refine and, be uniformly dispersed, then add D component, about 40-50 DEG C of insulation, mix, stir, make cream.By cream even spread, section, packaging, obtained cataplasma.
Embodiment 2
The indomethacin cataplasm that the present embodiment provides is made up of backing, mastic and anti-mucosa, and the constituent of described mastic comprises:
First 2.0g sodium carboxymethyl cellulose is dissolved in glycerol and partial purification water, then adds 1.0g Vinlub 73 and 0.1g Tween 80, be heated to 40 DEG C, stir, obtain component A;
Get 2.0g Gelatin in partial purification water, expand complete post-heating to 60 DEG C, stirs to translucent colloid, obtained B component;
6.0g sodium polyacrylate part corrective, 0.05g aluminium hydroxide and 0.15g disodium edetate are dissolved in glycerol, are uniformly mixed, obtained component C;
Join in purified water by 0.12g tartaric acid, then add the indomethacin solution be dissolved in advance in crotamiton, N-Methyl pyrrolidone, mixing, stirs, obtains D component;
Get residue purified water in prefabricated tanks, add methyl hydroxybenzoate, then add component A, B component, component C, make its fully refine and, be uniformly dispersed, then add D component, about 40-50 DEG C of insulation, mix, stir, make cream.By cream even spread, section, packaging, obtained cataplasma.
Embodiment 3
The indomethacin cataplasm that the present embodiment provides is made up of backing, mastic and anti-mucosa, and the constituent of described mastic comprises:
First 2.0g sodium carboxymethyl cellulose is dissolved in glycerol and partial purification water, then adds 1.0g carboxylic polrvinyl, 0.3g polyoxyethylene hydrogenated Oleum Ricini and 0.1g Tween 80, be heated to 40 DEG C, stir, obtain component A.
Get 1.0g Gelatin in partial purification water, expand complete post-heating to 60 DEG C, stirs to translucent colloid, obtained B component;
6.0g sodium polyacrylate part corrective, 0.05g aluminium hydroxide and 0.15g disodium edetate are dissolved in glycerol, are uniformly mixed, obtained component C;
Join in purified water by 0.12g tartaric acid, then add the indomethacin solution be dissolved in advance in crotamiton, N-Methyl pyrrolidone, mixing, stirs, obtains D component;
Get residue purified water in prefabricated tanks, add component A, B component, component C, make its fully refine and, be uniformly dispersed, then add D component, about 40-50 DEG C of insulation, mix, stir, make mastic.By mastic even spread, section, packaging, obtained cataplasma.
1, stability test
Prepare cataplasma according to embodiment 1 and example 3, by cataplasma respectively with aluminium plastic packaging bag sealing, be placed on 40 DEG C, preserve in 75% calorstat, measure indomethacin content in the 0-6 month, result is as shown in table 1, and in June, indomethacin content is basicly stable.(temperature 30 DEG C, relative humidity are 60%) places 24 months at ambient temperature, respectively at sampling in 0,1,2,3,24 month, measure indomethacin content, result is as shown in table 2, indomethacin stable content in 24 months, do not occur that crystal is separated out, illustrate that indomethacin of the present invention has good stability.
Indomethacin relative amount under table 1 high temperature (40 DEG C)
| Sample time | 0 | January | March | June |
| Embodiment 1 | 100.00% | 98.12% | 94.26% | 93.58% |
| Embodiment 3 | 100.00% | 97.70% | 95.14% | 93.83% |
Indomethacin relative amount under table 2 room temperature (30 DEG C, relative humidity 60%)
| Sample time | 0 | 1 month | 2 months | 3 months | 24 months |
| Embodiment 1 | 100.00% | 98.14% | 98.64% | 98.13% | 96.56% |
| Embodiment 3 | 100.00% | 99.27% | 99.85% | 98.74% | 97.98% |
2, Ligustrazine hydrochloride test
Adopt improved Franz diffusing cells method, be fixed on by mouse skin on diffusion cell, corium is towards receiving chamber, and stratum corneum side, to supply chamber, adds appropriate phosphate buffered solution in receiving chamber.Cataplasma obtained for embodiment 1 is affixed on skin, opens constant temperature (32 ± 1) DEG C water-bath circulation and magnetic stirring apparatus (300rmin-1) different time points 2,4,6,8,12,24h sampling, utilize high phase liquid chromatography for measuring indomethacin content, Q is unit area Percutaneous permeability, the results are shown in Table 3.
Table 3 Ligustrazine hydrochloride result of the test
| Transdermal time (h) | 2 | 4 | 6 | 8 | 12 | 24 |
| Q(μg·cm-2) | 19.30 | 40.98 | 54.62 | 72.54 | 136.13 | 230.69 |
As shown in Table 3, the percutaneous rate of the indomethacin cataplasm that the embodiment of the present invention 1 is obtained is 9.79 μ gcm-2h-1, illustrate that indomethacin cataplasm percutaneous abilities provided by the invention is good.
3, irritation test
Get 24 SD rats, male and female half and half, body weight is about 160-180g, is equally divided into three groups, and skin of abdomen is shaved removed with being shaved a mao machine.First group of rat applies ointment or plaster in epilating area (2 × 3) cm2the obtained indomethacin cataplasm of embodiment 1, divest after 24, second group of blank cataplasma of tester of applying ointment or plaster in epilating area, divests after 24, after divesting after 3rd group of successive administration 14d, observe when divesting, divesting 24h, divest 48h after, 7 divest 2h after to lose hair or feathers district's irriate situation.All there is not the anaphylaxis such as erythema and edema in the skin that result shows the depilation district of three groups of rats, illustrate that this cataplasma is to no skin irritation, safety is good.
In sum, indomethacin Hydrophillia Babu agent provided by the invention has good stability, water content is high, moisture retention is strong, Transdermal absorption performance good, to no skin irritation.
Be described in detail specific embodiments of the invention above, but it is just as example, the present invention is not restricted to specific embodiment described above.To those skilled in the art, any equivalent modifications that the present invention is carried out and substituting also all among category of the present invention.Therefore, equalization conversion done without departing from the spirit and scope of the invention and amendment, all should contain within the scope of the invention.