CN101288643A - Gel composition containing tacrolimu and its preparation method and medicinal application - Google Patents
Gel composition containing tacrolimu and its preparation method and medicinal application Download PDFInfo
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- CN101288643A CN101288643A CNA2008101288044A CN200810128804A CN101288643A CN 101288643 A CN101288643 A CN 101288643A CN A2008101288044 A CNA2008101288044 A CN A2008101288044A CN 200810128804 A CN200810128804 A CN 200810128804A CN 101288643 A CN101288643 A CN 101288643A
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Abstract
The invention relates to a gel composition containing tacrolimus, which contains the tacrolimus and ingredients of a matrix, wherein, the ingredients of the matrix contain one or more of liquid polyethylene glycol, glycerin and propylene glycol, the content of the tacrolimus in the gel is 0.01 percent to 0.5 percent, and the weight ratio of the tacrolimus to one or more of the liquid polyethylene glycol, the glycerin and the propylene glycol is 1: (50 to 3000). The invention further relates to a preparation method of the gel composition of the tacrolimus and the application of the gel composition in the preparation of drugs for the treatment of atopic dermatitis, vitiligo, psoriasis, hormone-dependent dermatitis, intractable neurodermatitis, lupus erythematosus, alopecia areata and other diseases.
Description
Technical field
The invention belongs to the pharmaceutical technology field, relate to a kind of gel compositions that contains the external preparation for skin of tacrolimus, and preparation method thereof with its application in medicine.
Background technology
Tacrolimus (Tacrolimus), chemical name are 17-pi-allyl-1,14-dihydroxy-12-[2-(4-hydroxyl-3-methoxyl group cyclohexyl)-1-methyl ethylene]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-two oxa-s-4-aza-tricycle [22.3.1.0
4,9]-28 carbon-18-alkene-2,3,10, the 16-tetraketone, monohydrate, molecular structural formula is as follows:
Tacrolimus is a kind of medicine with immunosuppressant and antimicrobial acivity, and the water solublity extreme difference can be used for treating and/or preventing following disease and situation: transplanted the rejection that produces by organ or tissue; Graft versus host disease by the bone marrow transplantation generation; Autoimmune disease; The infection that causes by pathogenic microorganism.Tacrolimus uses by oral, injection, gone on the market use also have tacrolimus ointment (trade name: Pood that), be used for the treatment of or prevent disease and symptoms such as atopic dermatitis, vitiligo, psoriasis, steroid-dependent dermatitis, intractable neurodermatitis, lupus erythematosus, alopecia areata.
Chinese patent application publication number CN1059468A discloses a kind of ointment machin its preparation method that contains tacrolimus.Tacrolimus ointment (trade name: Pood that) is butyrous semi-solid external preparation, and stiff is greasy, and smearing property is poor, pollution clothes and the bad smell of mineral oils is arranged easily, and be not easy to clean.
Based on above deficiency, provide a kind of aqueous, easily smear, the tacrolimus preparation for external application to skin of easy cleaning, no bad abnormal smells from the patient, be very necessary and significant.
Summary of the invention
The purpose of this invention is to provide a kind of gel (comprising emulsion agent) that contains the external preparation for skin of tacrolimus, this external preparation is an aqueous, can well overcome the gram of the deficiency of oiliness ointment.The present invention also provides the preparation method that contains the tacrolimus gel and its medicinal application.
Should be noted that ointment, gel are in " all on the books and description in Chinese pharmacopoeia (the 2005 editions two ones) rules of preparations.Gel is meant that medicine and the adjuvant that can form gel make the glop or the semi-solid preparation of homogeneous, suspendible or emulsion type, and wherein the emulsion type gel agent is called emulsion agent again.Gel of the present invention is meant that tacrolimus and the adjuvant that can form gel make the glop or the semi-solid preparation of homogeneous, suspendible or emulsion type, wherein emulsion type gel agent emulsion agent again.
In addition, will be clear that, tacrolimus of the present invention, also comprise the clathrate (as the clathrate of HP-) of salt, derivant, modified compound, cyclodextrin and the derivant thereof of tacrolimus etc., in these chemical compounds, the main body chemical constitution that should have tacrolimus, they all are the chemical compounds that identical pharmacological action is arranged with tacrolimus.
Because tacrolimus is the material that is insoluble in water, and tacrolimus gel of the present invention is an aqueous, therefore, solving the dissolubility of tacrolimus in gel is crucial for improving the quality of products, as stability, aesthetic appearance, product qualities such as efficient stripping property, the inventor finds by lot of experiments, adopt the good cosolvent of water solublity to realize tacrolimus dissolving fully in gel, this cosolvent will satisfy the requirement of three aspects, the one, can dissolve tacrolimus preferably, the 2nd, can dissolve mutually with water, the 3rd, can dissolve mutually between the cosolvent, based on above consideration, the present invention selects liquid polyethylene glycol for use, glycerol, propylene glycol or their combination in any are as the cosolvent or the gel-type vehicle of tacrolimus gel of the present invention.
A kind of gel compositions that contains tacrolimus, contain tacrolimus and substrate composition, contain liquid polyethylene glycol in its mesostroma composition, in glycerol and the propylene glycol one or more, in order to reach excellent curative, can reduce side effect again and save drug resource, the content of tacrolimus in gel is 0.01%～0.5%, for example the content of tacrolimus in gel is 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.2%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.3%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.4%, 0.41%, 0.42%, 0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%, 0.49%, 0.5%, or the like.
And, can dissolve preferably and be dispersed in the gel in order to make tacrolimus, the weight ratio of one or more in tacrolimus and liquid polyethylene glycol, glycerol and the propylene glycol is 1: (50～3000),
The weight ratio of one or more in preferred tacrolimus and liquid polyethylene glycol, glycerol and the propylene glycol is 1: (80～2900),
The weight ratio of one or more in preferred tacrolimus and liquid polyethylene glycol, glycerol and the propylene glycol is 1: (100～2800),
The weight ratio of one or more in preferred tacrolimus and liquid polyethylene glycol, glycerol and the propylene glycol is 1: (1 50～2700),
The weight ratio of one or more in preferred tacrolimus and liquid polyethylene glycol, glycerol and the propylene glycol is 1: (200～2600),
The weight ratio of one or more in preferred tacrolimus and liquid polyethylene glycol, glycerol and the propylene glycol is 1: (250～2500),
The weight ratio of one or more in preferred tacrolimus and liquid polyethylene glycol, glycerol and the propylene glycol is 1: (280～2300),
The weight ratio of one or more in preferred tacrolimus and liquid polyethylene glycol, glycerol and the propylene glycol is 1: (300～2000),
The weight ratio of one or more in preferred tacrolimus and liquid polyethylene glycol, glycerol and the propylene glycol is 1: (320～1800),
The weight ratio of one or more in preferred tacrolimus and liquid polyethylene glycol, glycerol and the propylene glycol is 1: (340～1500),
The weight ratio of one or more in preferred tacrolimus and liquid polyethylene glycol, glycerol and the propylene glycol is 1: (350～1300),
The weight ratio of one or more in preferred tacrolimus and liquid polyethylene glycol, glycerol and the propylene glycol is 1: (370～1200),
The weight ratio of one or more in preferred tacrolimus and liquid polyethylene glycol, glycerol and the propylene glycol is 1: (380～1000),
The weight ratio of one or more in preferred tacrolimus and liquid polyethylene glycol, glycerol and the propylene glycol is 1: (400～900),
The weight ratio of one or more in preferred tacrolimus and liquid polyethylene glycol, glycerol and the propylene glycol is 1: (420～800),
The weight ratio of one or more in preferred tacrolimus and liquid polyethylene glycol, glycerol and the propylene glycol is 1: (450～750),
The weight ratio of one or more in preferred tacrolimus and liquid polyethylene glycol, glycerol and the propylene glycol is 1: (460～700),
The weight ratio of one or more in preferred tacrolimus and liquid polyethylene glycol, glycerol and the propylene glycol is 1: (480～650).
Above-mentioned liquid polyethylene glycol is meant under the room temperature it is the Polyethylene Glycol of liquid condition, should understand, Polyethylene Glycol is ethylene glycol and polymers of ethylene oxide, various molecular weight and physical property are arranged, under the normal temperature and pressure, molecular weight is that 100～700 Polyethylene Glycol is a liquid, and liquid polyethylene glycol of the present invention comprises one or more in Polyethylene Glycol-200, Polyethylene Glycol-300, Polyethylene Glycol-400, Polyethylene Glycol-500, Polyethylene Glycol-600, Polyethylene Glycol-700 and the Polyethylene Glycol-800.
Gel of the present invention is meant that tacrolimus and the adjuvant that can form gel make the glop or the semi-solid preparation of homogeneous, suspendible or emulsion type, wherein emulsion type gel agent emulsion agent again.
The present invention contains the gel of tacrolimus, contain tacrolimus and gel-type vehicle as active component, gel-type vehicle one or more in containing liquid polyethylene glycol, glycerol and propylene glycol, can also contain one or more mixture that are selected from carbomer, chitosan, sucralfate, polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose, ethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, hypromellose, sodium carboxymethyl cellulose, poloxamer, gelatin, the sodium alginate with any mixed.As can be seen, these gel-type vehicles are the good pharmaceutic adjuvants of hydrophilic.
The gel that the present invention contains tacrolimus can further contain transdermal enhancer, wetting agent, pH regulator agent, solubilizing agent, antiseptic and antioxidant, stabilizing agent etc.
Wherein, transdermal enhancer can be one or more mixture with any mixed in laurocapram (Azone), propylene glycol, ethanol, menthol (claiming Mentholum again), Oleum menthae, eucalyptus oil, Borneolum Syntheticum, isopropyl alcohol, carbamide, the oleic acid;
Wetting agent be in water, sorbitol, the maltose alcohol one or more with the mixture of any mixed; Certainly, liquid polyethylene glycol, glycerol and propylene glycol also have the function of wetting agent;
The pH regulator agent is triethanolamine, diethanolamine, tromethane, ethylenediamine, diethylamine, lauryl amine, meglumine, ammonia spirit, sodium bicarbonate, sodium hydroxide or potassium hydroxide, hydrochloric acid, phosphate, citric acid and salt thereof etc.;
Solubilizing agent is tween series (as tween 80, Tween-60, Tween-40 etc.), span series (as Arlacel-60, Arlacel-40, Arlacel-85, Arlacel-20 etc.), sodium lauryl sulphate, polyoxyethylene hydrogenated Oleum Ricini, peregal (as peregal 0, peregal A etc.), dimethyl sulfoxine etc., solubilizing agent can significantly improve dissolubility and the dissolution of tacrolimus in preparation, helps Transdermal absorption;
Antiseptic and antioxidant be in ethanol, chlorocresol, thimerosal, sorbic acid, potassium sorbate, benzoic acid, sodium benzoate, chlorobutanol, benzalkonium chloride, benzalkonium bromide, methyl hydroxybenzoate, ethyl hydroxybenzoate, propylparaben, sulphite, aminothiopropionic acid, vitamin C, vitamin E, the di-tert-butyl hydroxy toluene one or more with the mixture of any mixed;
Stabilizing agent is metal-chelator disodium EDTA, ethylenediaminetetraacetic acid two calcium disodiums or oxalic acid triamine pentaacetic acid.
Should be noted that especially carbomer of the present invention comprises its various models, as Acritamer 940,910,941,934,971,974,980,981,1342,1382 etc.; Polyvinyl alcohol comprises its various models, as polyvinyl alcohol 1799,2099,2299,2499,2699,1788 etc.; Poloxamer comprises its various models, as poloxamer 188,407,124,128,108,237,338 etc.
Especially, gel compositions of the present invention, contain by percentage to the quality:
Constituent content (weight %)
Tacrolimus 0.01%～0.5%, preferred 0.02%～0.3%;
Gel-type vehicle 0.3%～45%, preferred 0.5%～30%;
Antiseptic and antioxidant 0%～30%, preferred 0.01%～5%;
Transdermal enhancer 0%～25%, preferred 0.1%～15%;
PH regulator agent adjusting preparation pH value is 5～9 consumption;
In the said components, gel-type vehicle is to be selected from outside in liquid polyethylene glycol, glycerol and the propylene glycol one or more, can also contain one or more mixture with any mixed in carbomer, chitosan, sucralfate, polyvinylpyrrolidone, ethanol, polyvinyl alcohol, methylcellulose, ethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, hypromellose, sodium carboxymethyl cellulose, poloxamer, gelatin, the sodium alginate; Antiseptic and antioxidant be in ethanol, chlorocresol, thimerosal, sorbic acid, potassium sorbate, benzoic acid, sodium benzoate, chlorobutanol, benzalkonium chloride, benzalkonium bromide, methyl hydroxybenzoate, ethyl hydroxybenzoate, propylparaben, sulphite, aminothiopropionic acid, vitamin C, vitamin E, the di-tert-butyl hydroxy toluene one or more with the mixture of any mixed; Transdermal enhancer is one or more mixture with any mixed that are selected from laurocapram (Azone), propylene glycol, ethanol, menthol, eucalyptus oil, Oleum menthae, Borneolum Syntheticum, isopropyl alcohol, the oleic acid; The pH regulator agent is one or more mixture with any mixed that are selected from triethanolamine, diethanolamine, tromethane, ethylenediamine, diethylamine, lauryl amine, ammonia spirit, sodium bicarbonate, sodium hydroxide or the potassium hydroxide; Water is selected purified water usually for use, for example distilled water, deionized water or water for injection etc.
Preferably, tacrolimus gel compositions of the present invention, contain by percentage to the quality:
Constituent content (weight %)
Tacrolimus 0.02%～0.4%, preferred 0.03%～0.2%;
Carbomer or chitosan 0.5%～3%, preferred 0.6%～2%;
PH regulator agent adjusting preparation pH value is 5～9 consumption;
Wherein, the pH regulator agent is selected from one or more mixture with any mixed in triethanolamine, diethanolamine, tromethane, ethylenediamine, diethylamine, lauryl amine, ammonia spirit, sodium bicarbonate, sodium hydroxide or the potassium hydroxide; Optionally can contain following material: be selected from one or more the mixture in laurocapram (Azone), ethanol, menthol, eucalyptus oil, Oleum menthae, Borneolum Syntheticum, isopropyl alcohol, the oleic acid with any mixed as transdermal enhancer; Optionally want to contain the following material as antiseptic and antioxidant: one or more are with the mixture of any mixed in ethanol, chlorocresol, thimerosal, sorbic acid, potassium sorbate, benzoic acid, sodium benzoate, chlorobutanol, benzalkonium chloride, benzalkonium bromide, methyl hydroxybenzoate, ethyl hydroxybenzoate, propylparaben, sulphite, aminothiopropionic acid, vitamin C, vitamin E, the di-tert-butyl hydroxy toluene; Optionally want to contain following material: disodium EDTA, ethylenediaminetetraacetic acid two calcium disodiums or oxalic acid triamine pentaacetic acid as stabilizing agent.
Preferably, tacrolimus gel compositions of the present invention, contain by percentage to the quality:
Tacrolimus 0.02%～0.4%, preferred 0.03%～0.2%;
Gel-type vehicle 0.5%～3%, preferred 0.6%～2%;
Wherein, gel-type vehicle is selected from one or more mixture with any mixed in liquid polyethylene glycol, glycerol, propylene glycol, carbomer, chitosan, sucralfate, polyvinylpyrrolidone, ethanol, polyvinyl alcohol, methylcellulose, ethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, hypromellose, sodium carboxymethyl cellulose, poloxamer, gelatin, the sodium alginate; Optionally can contain following material: be selected from one or more the mixture in laurocapram (Azone), ethanol, menthol, eucalyptus oil, Oleum menthae, Borneolum Syntheticum, isopropyl alcohol, the oleic acid with any mixed as transdermal enhancer; Optionally want to contain the following material as antiseptic and antioxidant: one or more are with the mixture of any mixed in ethanol, chlorocresol, thimerosal, sorbic acid, potassium sorbate, benzoic acid, sodium benzoate, chlorobutanol, benzalkonium chloride, benzalkonium bromide, methyl hydroxybenzoate, ethyl hydroxybenzoate, propylparaben, sulphite, aminothiopropionic acid, vitamin C, vitamin E, the di-tert-butyl hydroxy toluene; Optionally want to contain following material: disodium EDTA, ethylenediaminetetraacetic acid two calcium disodiums or oxalic acid triamine pentaacetic acid as stabilizing agent.
Further, the invention provides tacrolimus gel preparation of compositions method, can adopt following method preparation usually:
(1) gel-type vehicle is added in suitable quantity of water, liquid polyethylene glycol, glycerol and the propylene glycol one or more, substrate is dissolved or swelling fully, stir, obtain blank gel-type vehicle, optionally, adding the pH regulator agent transfers pH, adds antiseptic and antioxidant, adds stabilizing agent;
(2), and look need adding solubilizing agent with one or more dissolvings in tacrolimus usefulness liquid polyethylene glycol, glycerol and the propylene glycol;
(3) in the blank gel-type vehicle that tacrolimus solution that above-mentioned (2) are obtained or muddy liquid adding (1) obtains, optionally can add transdermal enhancer, wetting agent, stir evenly packing.
In the above-mentioned preparation method, in employing liquid polyethylene glycol, glycerol and the propylene glycol one or more add blank gel-type vehicle with tacrolimus dissolving back, can not only make tacrolimus under the cosolvent effect of liquid polyethylene glycol, glycerol and/or propylene glycol, dissolve or be dispersed in the blank gel-type vehicle, improved the dissolubility of tacrolimus, and liquid polyethylene glycol, glycerol and/or propylene glycol can dissolve each other with water, gel colloid outward appearance homogeneous, clean bright, significant for the dissolution that for example improves the quality of products, trap.
In the process of preparation tacrolimus gel compositions of the present invention, it is the most key that in employing liquid polyethylene glycol, glycerol and the propylene glycol one or more add blank gel-type vehicle with tacrolimus dissolving back, therefore, the invention provides a kind of tacrolimus gel compositions, it is characterized in that it is prepared by following method:
(1) gel-type vehicle is added in suitable quantity of water, liquid polyethylene glycol, glycerol and the propylene glycol one or more, substrate is dissolved or swelling fully, stir, obtain blank gel-type vehicle, optionally, adding the pH regulator agent transfers pH, adds antiseptic and antioxidant, adds stabilizing agent;
(2) with tacrolimus with one or more dissolvings in liquid polyethylene glycol, glycerol and the propylene glycol, and one or more the weight ratio in tacrolimus and liquid polyethylene glycol, glycerol and the propylene glycol is 1: (50～3000);
(3) in the blank gel-type vehicle that tacrolimus solution that above-mentioned (2) are obtained or muddy liquid adding (1) obtains, optionally can add transdermal enhancer, wetting agent, stir evenly packing;
Wherein said gel-type vehicle is selected from one or more mixture with any mixed in liquid polyethylene glycol, glycerol, propylene glycol, carbomer, chitosan, sucralfate, polyvinylpyrrolidone, ethanol, polyvinyl alcohol, methylcellulose, ethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, hypromellose, sodium carboxymethyl cellulose, poloxamer, gelatin, the sodium alginate; Optionally can contain following material: be selected from one or more the mixture in laurocapram (Azone), ethanol, menthol, eucalyptus oil, Oleum menthae, Borneolum Syntheticum, isopropyl alcohol, the oleic acid with any mixed as transdermal enhancer; Optionally want to contain the following material as antiseptic and antioxidant: one or more are with the mixture of any mixed in ethanol, chlorocresol, thimerosal, sorbic acid, potassium sorbate, benzoic acid, sodium benzoate, chlorobutanol, benzalkonium chloride, benzalkonium bromide, methyl hydroxybenzoate, ethyl hydroxybenzoate, propylparaben, sulphite, aminothiopropionic acid, vitamin C, vitamin E, the di-tert-butyl hydroxy toluene; Optionally can contain following material: disodium EDTA, ethylenediaminetetraacetic acid two calcium disodiums or oxalic acid triamine pentaacetic acid as stabilizing agent.
The invention provides the gel that contains tacrolimus, and its preparation method.Further, the present invention also provides the application of above-mentioned gel aspect diseases such as preparation treatment atopic dermatitis, vitiligo, psoriasis, steroid-dependent dermatitis, intractable neurodermatitis, lupus erythematosus, alopecia areata.
The gel that the present invention contains tacrolimus uses as external preparation, and the application aspect the treatment disease has the following advantages:
1. the gel preparation of aqueous is easily smeared, easy cleaning, no bad abnormal smells from the patient.
2. the gel of tacrolimus is smeared through skin and is absorbed medicine without gastrointestinal absorption, has avoided the head of liver to cross reaction, has also avoided tacrolimus to gastrointestinal side effect and infringement.
3. its effective ingredient tacrolimus can be by the through affected part of skin, and is easy to use, rapid-action.
4. to the body not damaged, be particularly suitable for the inconvenient patient of oral administration.
5. carry and use conveniently.
The gel of further verifying tacrolimus of the present invention with following test is in stability, to the feasibility of aspects such as the zest of skin, therapeutic effect.
One. prescription and the experiment of the gel of tacrolimus aspect stable:
Get the gel of the tacrolimus of the representative preparation of the present invention, get about 10g and place the band graduated centrifuge tube, with the centrifugal 30min of 3000r/min, gel does not have lamination.
Get the gel of the tacrolimus of the representative preparation of the present invention, airtight in dress plastic flexible pipe or the aluminum pipe, reserved sample observing places 50 ℃ of dry calorstat 6h and-15 ℃ of interior 24h of refrigerator respectively, and gel does not have lamination.
At 25 ± 2 ℃, relative humidity 60 ± 5%, reserved sample observing 3 months was observed its outward appearance and was measured its content in placement in 0 day, 30 days, 60 days, 90 days.The result shows that its outward appearance and content have no significant change, and meet the requirements.
Two. the skin irritation test of tacrolimus gel:
Get 3 of rabbit respectively, 24h loses hair or feathers the about 50cm of every side before being tried in back spinal column lateral symmetry
2, erythema, edema and breakage must not appear.Behind the 24h, coat the gel of the tacrolimus of the representative preparation of 1g the present invention respectively in a side, with warm water flush away medicine, contrast behind the 24h, observe the skin irritation situation of agents area with opposite side.Observe agents area at 1h, 24h, 48h, 72h respectively, all do not have phenomenons such as redness, edema.
Three .. health examinations:
According to " Chinese pharmacopoeia (2005 editions two ones) appendix XIJ checks that microbial limit should be up to specification.
Five. the test of the gel of tacrolimus aspect the dermatitis in treatment effect:
Modelling: adopt mice to set up dermatitis-Eczema Model.Modeling method: be coated with mouse back sensitization outward with 7% dinitrochlorobenzene, excite the model that causes chronic dermatitis with 0 1% dinitrochlorobenzene repeatedly in the mouse right ear inboard after 5 days, excited 1 time every 3 days, make mice ear, thicken etc. keeps dermatitis-eczema state.
If test group: the test group mice is coated with the gel (0.03%) of tacrolimus of the present invention outside exciting back 24h, in the mouse right ear inboard, and every day 2 times, logotype 14 days.Other establishes matched group, control group mice after exciting without external used medicine.
Observation of curative effect: during the medication, the control group mice ear swelling, thicken, surface incrustation, epidermis thicken, and show serious, tangible dermatitis-eczema symptom, and mice tickles constantly; And the test group mice ear, thicken, dermatitis-eczema symptom that surface incrustation, epidermis thicken is slight, compared notable difference (p＜0.01) with matched group, and the number of times of mice scratching also obviously is less than matched group.The gel that tacrolimus of the present invention is described is having good effect aspect treatment dermatitis-eczema, and infringement and skin pruritus symptom can well reduce inflammation.
The specific embodiment
In implementation process of the present invention, various embodiments that those skilled in the art produce on the basis that does not depart from the scope of the present invention with spirit and modify conspicuous and be to carry out easily.Come the present invention done further specifying by the following examples, but do not represent the embodiment limitation of the present invention.
Embodiment 1. tacrolimus gel and preparations thereof
Prescription: tacrolimus 0.03g, carbomer 1g, triethanolamine 2g, propylene glycol 6g, glycerol 5g, Polyethylene Glycol-400 33g, purified water adds full 100g.
Preparation: get carbomer and add after the 35ml purified water makes its abundant swelling,, stir evenly, obtain blank gel with triethanolamine regulator solution pH value to 6.0～7.5; Other gets, and tacrolimus is molten to loose in Polyethylene Glycol-400, stir evenly the back and add propylene glycol, glycerol, stirring is dissolved in the mixed solvent of Polyethylene Glycol-400, propylene glycol and glycerol tacrolimus fully, then medicinal liquid is slowly joined in the carbomer substrate, and the limit edged stirs, add purified water at last to 100g, get the tacrolimus gel, content 0.03% is packaged in the aluminum pipe, every 20g, promptly.
Embodiment 2. tacrolimus gel and preparations thereof
Prescription: tacrolimus 0.1g, chitosan 1.2g, triethanolamine 1g, glycerol 8g, laurocapram 1g, Polyethylene Glycol-300 28g, distilled water adds to 100g.
Preparation: get chitosan and be spread on 45ml distilled water surface, make it abundant swelling after, stir evenly, add laurocapram, stir evenly, add triethanolamine again, fully stir, obtain blank gel; Other gets tacrolimus, glycerol adds in the Polyethylene Glycol-300, stirring is dissolved in the mixed solvent of Polyethylene Glycol-300 and glycerol tacrolimus fully, stir, with blank gel and tacrolimus solution mix homogeneously, adding distil water is to 100g, stir, get the tacrolimus gel, packing promptly.
Embodiment 3. tacrolimus gel and preparations thereof
Prescription: tacrolimus 0.02g, carbomer (940) 2.5g, Mentholum 2g, propylene glycol 20g, Polyethylene Glycol-400 25g, ethyl hydroxybenzoate 0.2g, triethanolamine is an amount of, and purified water is to 100g.
Preparation: get carbomer (940) and evenly be spread in an amount of purified water, make its abundant swelling after, add purified water to 50ml, stir, obtain carbomer solution, with triethanolamine regulator solution pH value to 6.0～7.5, stir evenly, obtain blank gel; Other gets tacrolimus, Mentholum, ethyl hydroxybenzoate adding Polyethylene Glycol-400 and propylene glycol, and stirring and dissolving slowly adds blank gel under constantly stirring, stir, and adds water to 100g, stirs evenly, and gets the tacrolimus gel, and packing promptly.
Embodiment 4. tacrolimus gel and preparations thereof
Prescription: tacrolimus 0.03g, sodium carboxymethyl cellulose 2.6g, glycerol 12g, ethyl hydroxybenzoate 0.2g, Polyethylene Glycol-300 25g, Polyethylene Glycol-400 15g adds purified water to 100g.
Preparation: get the recipe quantity sodium carboxymethyl cellulose and add 10g Polyethylene Glycol-300 moistening, add glycerol, stir into and add the heating of 46ml purified water behind the pasty state and sodium carboxymethyl cellulose is dissolved fully be transparent liquid; In addition take by weighing tacrolimus, ethyl hydroxybenzoate respectively, add the dissolving of 15g Polyethylene Glycol-300 and 15g Polyethylene Glycol-400, stir, solution is mixed while hot with above-mentioned substrate, stir, put coldly, pack promptly.
Embodiment 5. tacrolimus gel and preparations thereof
Prescription: tacrolimus 0.1g, sodium carboxymethyl cellulose 0.2g, chitosan 0.5g, glycerol 20g, laurocapram 1g, triethanolamine is an amount of, purified water 25g, Polyethylene Glycol-300 adds to 100g.
Preparation: get purified water 25ml, add chitosan, sodium carboxymethyl cellulose successively, make its natural peptization, stir evenly, add triethanolamine regulator solution pH value to 6.0～7.5 again, stir, obtain blank coagulant liquid, other gets tacrolimus and adds glycerol, 15g Polyethylene Glycol-300 and laurocapram, and stirring dissolves tacrolimus fully, with blank gel and tacrolimus solution mix homogeneously, add Polyethylene Glycol-300 to 100g, stir evenly, get the tacrolimus gel, packing promptly.
Embodiment 6. tacrolimus gel and preparations thereof
Prescription: tacrolimus 0.05g, carbomer (934) 1.2g, ethyl hydroxybenzoate 0.05g, Polyethylene Glycol-40045g, glycerol 5g, sodium hydroxide (or meglumine) is an amount of, adds purified water to 100g.
Preparation: get carbomer (934) and add purified water 20ml, make its natural peptization add NaOH (or meglumine) regulator solution pH value to 6.0～7.5, stir, obtain blank coagulant liquid, other gets tacrolimus and adds Polyethylene Glycol-400 and glycerol, stirring makes it to be dissolved into solution, then two kinds of solution is mixed and the adding ethyl hydroxybenzoate, stirs, add water to 100g, stir evenly, get the tacrolimus gel, packing promptly.
Embodiment 7. tacrolimus gel and preparations thereof
Prescription: tacrolimus 0.03g, methylcellulose 1.6g, ethyl hydroxybenzoate 0.03g, propylene glycol 4g, Polyethylene Glycol-400 35g, sodium lauryl sulphate 1g adds purified water to 100g.
The preparation: get methylcellulose and evenly be spread on 45ml purified water surface, make its natural swelling after, stir, obtain blank coagulant liquid; Other gets the solution of tacrolimus in propylene glycol and Polyethylene Glycol-400 mixed solvent, adds blank coagulant liquid, stirs evenly, add ethyl hydroxybenzoate and the sodium lauryl sulphate solution in suitable quantity of water again, stir, add water to 100g, stir evenly, get the tacrolimus gel, packing promptly.
Embodiment 8. tacrolimus gel and preparations thereof
Prescription: tacrolimus 0.05g, hydroxyethyl-cellulose 2g, propylene glycol 6g, Polyethylene Glycol-400 50g, propylparaben 0.06g, disodiumedetate 0.02g adds purified water to 100g.
Preparation: get hydroxyethyl-cellulose dispersed with stirring in distilled water, under agitation be heated to into clarifying viscous solution, treat to add propylparaben and disodiumedetate when temperature is reduced to 40 ℃, stir, obtain blank coagulant liquid; Other gets in tacrolimus adding propylene glycol and Polyethylene Glycol-400 mixed solvent, stirs to make the blank coagulant liquid of dissolving back adding fully, adds water to 100g, stirs evenly, and gets the tacrolimus gel, and packing promptly.
Embodiment 9. tacrolimus gel and preparations thereof
Prescription: tacrolimus 0.1g, carbomer (940) 1g, Tween-80 0.2g, Borneolum Syntheticum 1g, propylene glycol 5g, Polyethylene Glycol-400 33g, ethyl hydroxybenzoate 0.1g, triethanolamine 1.4g, distilled water add to 100g in right amount.
Preparation: get carbomer and mix with ethyl hydroxybenzoate and 40mL distilled water, triethanolamine adds above-mentioned mixed liquor after being dissolved in the 10mL distilled water, the Borneolum Syntheticum that adds propylene glycol, Tween-80, porphyrize after stirring evenly again, last under agitation with in the solution adding matrix solution of tacrolimus in Polyethylene Glycol-400, stir evenly, get the tacrolimus gel, packing promptly.
Embodiment 10. tacrolimus gel and preparations thereof
Prescription: tacrolimus 0.03g, carbomer (940) 1g, triethanolamine 1.2g, glycerol 8g, Polyethylene Glycol-600 20g, polyoxyethylene hydrogenated Oleum Ricini 5g, sodium sulfite 0.05g, disodiumedetate 0.05g, laurocapram 1ml, adding distil water is to 100g.
Preparation: get the recipe quantity sodium sulfite, disodiumedetate is dissolved in the suitable quantity of water, add after recipe quantity polyoxyethylene hydrogenated Oleum Ricini, laurocapram stir, stir and add the recipe quantity carbomer down, it is even to continue to be stirred to swelling; Other gets recipe quantity tacrolimus stirring and dissolving in glycerol and Polyethylene Glycol-600 mixed solvent, the water that adds surplus, stir tacrolimus solution, this solution is joined in the carbomer swelling thing, stir evenly, add the recipe quantity triethanolamine, stir, get the tacrolimus gel, packing promptly.
Embodiment 11. tacrolimus gel and preparations thereof
Prescription: tacrolimus 0.3g, carbomer (971) 1g, hypromellose 0.4g, glycerol 3g, propylene glycol 20g, laurocapram 2ml, tween 80 0.5g, diethylamine is an amount of, adds purified water to 100g.
Preparation: carbomer (971) and hypromellose are mixed with 5% and 6% solution in right amount with purified water respectively, carbomer solution is regulated pH to 5.5～7 with diethylamine, with both mix homogeneously, add the solution of tacrolimus in glycerol and mixed with propylene glycol solvent again, stir and add laurocapram down and be dissolved with the tween 80 aqueous solution, stir, get the tacrolimus gel, packing promptly.
Embodiment 12. tacrolimus emulsion agent and preparations thereof
Prescription: tacrolimus 0.2g, stearic acid 4g, peregal 0.5g, hexadecanol 2g, liquid Paraffin 4g, laurocapram 2.5g, Borneolum Syntheticum 0.5g, carbomer (940) 1g, ethyl hydroxybenzoate 1g, ethanol 3mL, glycerol 10g, Polyethylene Glycol-400 10g, purified water adds to 100g.
Preparation: carbomer (940) is dispersed in natural swelling 48～72h in an amount of purified water, treats carbomer (940) complete swelling, and it is standby behind the transparence gel that solution is.Other gets Borneolum Syntheticum and is dissolved in the ethanol, and is standby.Tacrolimus is dissolved in the mixed solvent of glycerol and Polyethylene Glycol-400.In addition stearic acid, peregal, hexadecanol, liquid Paraffin, ethyl hydroxybenzoate etc. are heated to 80 ℃, filter, merge, in mulser, stir more than the 3h with tacrolimus solution, treat that temperature reduces to about 70 ℃, add and to give heat, continue to stir, treat that temperature reduces to about 50 ℃ to 60 ℃ carbomer (940) gel, add laurocapram, Borneolum Syntheticum solution etc. again, after waiting to be stirred to condensation, be distributed into every pipe 20g, seal and get final product.
Embodiment 13. tacrolimus emulsion agent and preparations thereof
Prescription: tacrolimus 0.1g, Polyethylene Glycol-400 25g, propylene glycol 7g, carbomer (940) 1g, triethanolamine is an amount of, laurocapram 2g, glycerol 8g, distilled water adds to 100g.
Preparation: take by weighing the recipe quantity carbomer, add an amount of distilled water, place, make its complete swelling after, add glycerol, triethanolamine, laurocapram successively and stir, regulate pH to 6.5～7.5, obtain blank coagulant liquid, standby; After other gets tacrolimus and adds in Polyethylene Glycol-400 and the propylene glycol dissolving fully, this liquid is slowly added during blank coagulant liquid mixes, the limit edged stirs, and packing promptly.
Embodiment 14. tacrolimus emulsion agent and preparations thereof
Prescription: tacrolimus 0.03g, propylene glycol 5g, Polyethylene Glycol-400 10g, polyvinylpyrrolidone 2.3g, methylcellulose 10g, laurocapram 1g, distilled water adds to 100g.
Preparation: take by weighing the recipe quantity tacrolimus and be dissolved in Polyethylene Glycol and the propylene glycol, in addition polyvinylpyrrolidone, methylcellulose are added the surplus distilled water, place, after making its complete swelling, add tacrolimus solution and laurocapram, stir, evenly mixed, packing promptly.
Embodiment 15. embodiment 1 to embodiment 14 prepared tacrolimus gel, emulsion agent treated the application aspect the diseases such as atopic dermatitis, vitiligo, psoriasis, steroid-dependent dermatitis, intractable neurodermatitis, lupus erythematosus, alopecia areata in preparation.
Claims (9)
1. gel compositions that contains tacrolimus, contain tacrolimus and substrate composition, contain in liquid polyethylene glycol, glycerol and the propylene glycol one or more in its mesostroma composition, the content of tacrolimus in gel is 0.01%～0.5%, and one or more the weight ratio in tacrolimus and liquid polyethylene glycol, glycerol and the propylene glycol is 1: (50～3000).
2. the gel compositions of the described tacrolimus of claim 1, wherein said liquid polyethylene glycol comprises one or more in Polyethylene Glycol-200, Polyethylene Glycol-300, Polyethylene Glycol-400, Polyethylene Glycol-500, Polyethylene Glycol-600, Polyethylene Glycol-700 and the Polyethylene Glycol-800.
The gel compositions of the described tacrolimus of 3 claim 1, the substrate composition is selected from one or more mixture with any mixed in carbomer, chitosan, sucralfate, polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose, ethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, hypromellose, sodium carboxymethyl cellulose, poloxamer, gelatin, the sodium alginate, and can further contain transdermal enhancer, wetting agent, pH regulator agent, solubilizing agent, antiseptic and antioxidant, stabilizing agent in the gel compositions.
4. the described gel compositions of claim 3, wherein:
Transdermal enhancer is selected from one or more mixture with any mixed in laurocapram, propylene glycol, ethanol, menthol, Oleum menthae, eucalyptus oil, Borneolum Syntheticum, isopropyl alcohol, carbamide, the oleic acid;
Wetting agent is selected from water, sorbitol, the maltose alcohol one or more with the mixture of any mixed;
The pH regulator agent is selected from one or more mixture with any mixed in triethanolamine, diethanolamine, tromethane, ethylenediamine, diethylamine, lauryl amine, meglumine, ammonia spirit, sodium bicarbonate, sodium hydroxide or potassium hydroxide, hydrochloric acid, phosphate, citric acid and the salt thereof;
Solubilizing agent is selected from one or more mixture with any mixed in tween series, span series, sodium lauryl sulphate, polyoxyethylene hydrogenated Oleum Ricini, peregal, the dimethyl sulfoxine;
Antiseptic and antioxidant are selected from ethanol, chlorocresol, thimerosal, sorbic acid, potassium sorbate, benzoic acid, sodium benzoate, chlorobutanol, benzalkonium chloride, benzalkonium bromide, methyl hydroxybenzoate, ethyl hydroxybenzoate, propylparaben, sulphite, aminothiopropionic acid, vitamin C, vitamin E, the di-tert-butyl hydroxy toluene one or more with the mixture of any mixed;
Stabilizing agent is selected from one or more mixture with any mixed in metal-chelator disodium EDTA, ethylenediaminetetraacetic acid two calcium disodiums or the oxalic acid triamine pentaacetic acid.
5. gel compositions that contains tacrolimus, contain by percentage to the quality:
Constituent content (weight %)
Tacrolimus 0.01%～0.5%, preferred 0.02%～0.3%;
Gel-type vehicle 0.3%～45%, preferred 0.5%～30%;
Antiseptic and antioxidant 0%～30%, preferred 0.01%～5%;
Transdermal enhancer 0%～25%, preferred 0.1%～15%;
PH regulator agent adjusting preparation pH value is 5～9 consumption;
Wherein: gel-type vehicle is selected from outside in liquid polyethylene glycol, glycerol and the propylene glycol one or more, can also contain one or more mixture with any mixed in carbomer, chitosan, sucralfate, polyvinylpyrrolidone, ethanol, polyvinyl alcohol, methylcellulose, ethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, hypromellose, sodium carboxymethyl cellulose, poloxamer, gelatin, the sodium alginate; Antiseptic and antioxidant are selected from ethanol, chlorocresol, thimerosal, sorbic acid, potassium sorbate, benzoic acid, sodium benzoate, chlorobutanol, benzalkonium chloride, benzalkonium bromide, methyl hydroxybenzoate, ethyl hydroxybenzoate, propylparaben, sulphite, aminothiopropionic acid, vitamin C, vitamin E, the di-tert-butyl hydroxy toluene one or more with the mixture of any mixed; Transdermal enhancer is selected from one or more mixture with any mixed in laurocapram, propylene glycol, ethanol, menthol, eucalyptus oil, Oleum menthae, Borneolum Syntheticum, isopropyl alcohol, the oleic acid; The pH regulator agent is selected from one or more mixture with any mixed in triethanolamine, diethanolamine, tromethane, ethylenediamine, diethylamine, lauryl amine, ammonia spirit, sodium bicarbonate, sodium hydroxide or the potassium hydroxide.
6. gel compositions that contains tacrolimus, contain by percentage to the quality:
Constituent content (weight %)
Tacrolimus 0.02%～0.4%, preferred 0.03%～0.2%;
Carbomer or chitosan 0.5%～3%, preferred 0.6%～2%;
PH regulator agent adjusting preparation pH value is 5～9 consumption;
Wherein: the pH regulator agent is selected from one or more mixture with any mixed in triethanolamine, diethanolamine, tromethane, ethylenediamine, diethylamine, lauryl amine, ammonia spirit, sodium bicarbonate, sodium hydroxide or the potassium hydroxide; Optionally can contain the following material as transdermal enhancer: one or more in laurocapram, ethanol, menthol, eucalyptus oil, Oleum menthae, Borneolum Syntheticum, isopropyl alcohol, the oleic acid are with the mixture of any mixed; Optionally want to contain the following material as antiseptic and antioxidant: one or more are with the mixture of any mixed in ethanol, chlorocresol, thimerosal, sorbic acid, potassium sorbate, benzoic acid, sodium benzoate, chlorobutanol, benzalkonium chloride, benzalkonium bromide, methyl hydroxybenzoate, ethyl hydroxybenzoate, propylparaben, sulphite, aminothiopropionic acid, vitamin C, vitamin E, the di-tert-butyl hydroxy toluene; Optionally want to contain following material: disodium EDTA, ethylenediaminetetraacetic acid two calcium disodiums or oxalic acid triamine pentaacetic acid as stabilizing agent.
7. gel compositions that contains tacrolimus, contain by percentage to the quality:
Constituent content (weight %)
Tacrolimus 0.02%～0.4%, preferred 0.03%～0.2%;
Gel-type vehicle 0.5%～3%, preferred 0.6%～2%;
Wherein: gel-type vehicle is selected from one or more mixture with any mixed in liquid polyethylene glycol, glycerol, propylene glycol, carbomer, chitosan, sucralfate, polyvinylpyrrolidone, ethanol, polyvinyl alcohol, methylcellulose, ethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, hypromellose, sodium carboxymethyl cellulose, poloxamer, gelatin, the sodium alginate; Optionally can contain following material: be selected from one or more the mixture in laurocapram, ethanol, menthol, eucalyptus oil, Oleum menthae, Borneolum Syntheticum, isopropyl alcohol, the oleic acid with any mixed as transdermal enhancer; Optionally want to contain the following material as antiseptic and antioxidant: one or more are with the mixture of any mixed in ethanol, chlorocresol, thimerosal, sorbic acid, potassium sorbate, benzoic acid, sodium benzoate, chlorobutanol, benzalkonium chloride, benzalkonium bromide, methyl hydroxybenzoate, ethyl hydroxybenzoate, propylparaben, sulphite, aminothiopropionic acid, vitamin C, vitamin E, the di-tert-butyl hydroxy toluene; Optionally want to contain following material: disodium EDTA, ethylenediaminetetraacetic acid two calcium disodiums or oxalic acid triamine pentaacetic acid as stabilizing agent.
8. prepare the gel method for compositions of described any one tacrolimus of claim 1 to 7, it comprises:
(1) gel-type vehicle is added in suitable quantity of water, liquid polyethylene glycol, glycerol and the propylene glycol one or more, substrate is dissolved or swelling fully, stir, obtain blank gel-type vehicle, optionally, adding the pH regulator agent transfers pH, adds antiseptic and antioxidant, adds stabilizing agent;
(2), and look need adding solubilizing agent with one or more dissolvings in tacrolimus usefulness liquid polyethylene glycol, glycerol and the propylene glycol;
(3) in the blank gel-type vehicle that tacrolimus solution that above-mentioned (2) are obtained or muddy liquid adding (1) obtains, optionally can add transdermal enhancer, wetting agent, stir evenly packing.
9. gel compositions that contains tacrolimus is characterized in that it is prepared by following method:
(1) gel-type vehicle is added in suitable quantity of water, liquid polyethylene glycol, glycerol and the propylene glycol one or more, substrate is dissolved or swelling fully, stir, obtain blank gel-type vehicle, optionally, adding the pH regulator agent transfers pH, adds antiseptic and antioxidant, adds stabilizing agent;
(2) with tacrolimus with one or more dissolvings in liquid polyethylene glycol, glycerol and the propylene glycol, and one or more the weight ratio in tacrolimus and liquid polyethylene glycol, glycerol and the propylene glycol is 1: (50～3000);
(3) in the blank gel-type vehicle that tacrolimus solution that above-mentioned (2) are obtained or muddy liquid adding (1) obtains, optionally can add transdermal enhancer, wetting agent, stir evenly packing;
Wherein: described gel-type vehicle is selected from one or more mixture with any mixed in liquid polyethylene glycol, glycerol, propylene glycol, carbomer, chitosan, sucralfate, polyvinylpyrrolidone, ethanol, polyvinyl alcohol, methylcellulose, ethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, hypromellose, sodium carboxymethyl cellulose, poloxamer, gelatin, the sodium alginate; Optionally can contain following material: be selected from one or more the mixture in laurocapram, ethanol, menthol, eucalyptus oil, Oleum menthae, Borneolum Syntheticum, isopropyl alcohol, the oleic acid with any mixed as transdermal enhancer; Optionally want to contain the following material as antiseptic and antioxidant: one or more are with the mixture of any mixed in ethanol, chlorocresol, thimerosal, sorbic acid, potassium sorbate, benzoic acid, sodium benzoate, chlorobutanol, benzalkonium chloride, benzalkonium bromide, methyl hydroxybenzoate, ethyl hydroxybenzoate, propylparaben, sulphite, aminothiopropionic acid, vitamin C, vitamin E, the di-tert-butyl hydroxy toluene; Optionally can contain following material: disodium EDTA, ethylenediaminetetraacetic acid two calcium disodiums or oxalic acid triamine pentaacetic acid as stabilizing agent.
Claim 1,5,6,7,9 described any one contain the gel compositions of tacrolimus, the application aspect diseases such as preparation treatment atopic dermatitis, vitiligo, psoriasis, steroid-dependent dermatitis, intractable neurodermatitis, lupus erythematosus, alopecia areata.
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Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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2008
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