CN102048678A - Transdermal absorption preparation of oxybutynin as well as preparation method and medication application thereof - Google Patents
Transdermal absorption preparation of oxybutynin as well as preparation method and medication application thereof Download PDFInfo
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- CN102048678A CN102048678A CN2009102103336A CN200910210333A CN102048678A CN 102048678 A CN102048678 A CN 102048678A CN 2009102103336 A CN2009102103336 A CN 2009102103336A CN 200910210333 A CN200910210333 A CN 200910210333A CN 102048678 A CN102048678 A CN 102048678A
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Abstract
The invention provides a transdermal absorption preparation containing oxybutynin, which comprises gels, ointment and cream and aims at reducing the adverse reaction rate of the oxybutynin and lightening the serious adverse reaction degree, wherein when the content of the oxybutynin in the transdermal absorption preparation is 0.1-30 percent by weight, the content of the oxybutynin in the transdermal absorption preparation is preferentially to be 8-12 percent by weight. The invention also discloses the requirements of the transdermal absorption preparation in the aspects of formula compatibility and proportioning, as well as a preparation method and medication application of the transdermal absorption preparation.
Description
Technical field:
The present invention relates to field of pharmaceutical preparations, relate to a kind of cutaneous permeable agent that contains oxibutynin, and preparation method thereof with its application in medicine.
Background technology:
Oxibutynin (Oxybutynin, 4-(Diethylamino) but-2-yn-1-yl cyclohexyl (hydroxy) phenylacetate), chemical name: 4-(diethylamino) fourth-2-alkynes-1-basic ring hexyl (hydroxyl) phenylacetate, molecular formula C
22H
31NO
3, molecular weight 357.49, CAS accession number 5633-20-5, molecular structure is as follows:
The oxibutynin alternative acts on detrusor of bladder, reduce intravesical pressure, the increase capacity, reduce the not bladder contraction of autonomy, have stronger smooth muscle spasmolysis effect and anticholinergic effect, analgesic activity is also arranged, can alleviate urgent micturition, frequent micturition and urinary incontinence etc., be used for unrestraint and the backflowing property neurogenic bladder dysfunction patient and the relevant remission of urinating, as urgent micturition, frequent micturition, urinary incontinence, nocturia and the enuresis etc.The oral post-absorption of oxibutynin is complete rapidly, and onset time is 30～60 minutes, acts on the peak at 3～6 hours, sustainable 6～10 hours of spasmolysis.This product mainly is distributed in brain, lung, kidney and liver, and behind liver metabolism, mainly through homaluria.The anticholinergic activity of oxibutynin has promoted its clinical practice, but also caused following side effect, comprised the similar symptoms that anticholinergic agents produced such as xerostomia, hypohidrosis, blurred vision, cardiopalmus, drowsiness, dizzy, nauseating, vomiting, constipation, sexual impotence, inhibition lactogenic.
Oxibutynin not only can produce first pass effect during with oral preparation drug administration, and bioavailability is reduced, and the patient often has gastrointestinal reaction, has limited the extensive use of medicine, and the serious adverse continuation that limited the patient is sometimes used.
To sum up reach the coordinate indexing document, invented the administration combination formula and the relevant dosage form of oxibutynin externally applied transdermal absorption aspect, be used for reducing the incidence rate of oxibutynin side reaction and the order of severity of reduction serious adverse reaction.
The accompanying drawing summary:
Fig. 1: oral administration plasma drug level curve is the total oxibutynin concentration curve of blood plasma figure after the drug metabolism behind the oral routine dose 5mg oxibutynin.
Fig. 2: after using cutaneous permeable agent of the present invention, drug plasma total concentration time graph variation diagram.
Fig. 3, transdermal administration dosage form of the present invention untoward reaction and oral untoward reaction comparative study, the comparative study of adverse reaction rate and untoward reaction degree in various degree.
Summary of the invention:
The oxibutynin alternative acts on detrusor of bladder, reduce intravesical pressure, the increase capacity, reduce the not bladder contraction of autonomy, have stronger smooth muscle spasmolysis effect and anticholinergic effect, analgesic activity is also arranged, can alleviate urgent micturition, frequent micturition and urinary incontinence etc., be used for unrestraint and the backflowing property neurogenic bladder dysfunction patient and the relevant remission of urinating, as urgent micturition, frequent micturition, urinary incontinence, nocturia and the enuresis etc.Have weak point during the oxibutynin oral preparation drug administration, not only can produce first pass effect, bioavailability is reduced, and the patient often has gastrointestinal reaction, limited the extensive use of medicine, the serious adverse continuation that limited the patient is sometimes used.
The purpose of this invention is to provide a kind of cutaneous permeable agent that contains oxibutynin, utilize transdermal drag delivery, medicine percutaneous skin is absorbed to be entered in the body, and the detrusor of bladder part of can going directly, overcome the deficiency on oral administration way, the present invention also provides the preparation method that contains the oxybutynin transdermal absorbent and its medicinal application.
The present invention contains the oxybutynin transdermal absorbent and comprises gel, ointment, ointment.Oxibutynin of the present invention also comprises salt, derivant, modified compound of oxibutynin etc.Above-mentioned cutaneous permeable agent of the present invention, it focuses on oxibutynin can well reach the purpose of Transdermal absorption, and it is a lot of to influence the factor of its Transdermal absorption effect, for example the factors such as selection of the concentration of oxibutynin, choice of base, transdermal characteristic promoter.
The inventor finds by research and practice, the concentration of oxibutynin in cutaneous permeable agent is the principal element that influences its absorption, when concentration is advanced hour, transdermal usefulness weakens greatly, almost can not reach its pharmacological action, when concentration is excessive, can hinder the scribble effect of cutaneous permeable agent and disperse the area of skin to reduce, utilization rate reduces greatly, finds that absorption peak is bigger when the mass percentage content of oxibutynin in cutaneous permeable agent is 0.1%～30%.The preferred mass percentage content of oxibutynin in cutaneous permeable agent is 1%～18%; The preferred mass percentage content of oxibutynin in cutaneous permeable agent is 3%～15%; The preferred mass percentage content of oxibutynin in cutaneous permeable agent is 5%～13%; The preferred mass percentage content of oxibutynin in cutaneous permeable agent is 8%～12%.The present invention provides the gel that contains oxibutynin respectively, ointment, ointment, is described below:
The gel and the preparation method that contain oxibutynin
Gel of the present invention is meant that oxibutynin and the adjuvant that can form gel make homogeneous, suspendible or emulsion type preparation.
The Transdermal absorption system gel of the oxibutynin that the present invention contains, by gel-type vehicle, transdermal enhancer, wetting agent, pH regulator agent, solubilizing agent, compositions such as antiseptic, antioxidant and stabilizing agent.Wherein:
Mass percentage content in the Transdermal absorption system gel of oxibutynin is 0.5%～20%.
Described gel-type vehicle is selected from chitosan, sucralfate, propylene glycol, ethanol, glycerol, Polyethylene Glycol, polyvinyl alcohol, methylcellulose, ethyl cellulose, one or more in hydroxyethyl-cellulose, hydroxypropyl cellulose, hypromellose, the sodium carboxymethyl cellulose are with the mixture of any mixed.
Transdermal enhancer is ethanol, propylene glycol, isopropyl alcohol, menthol, Oleum menthae, eucalyptus oil, and one or more in Borneolum Syntheticum, carbamide, the oleic acid are with the mixture of any mixed.
Wetting agent be in water, glycerol, propylene glycol, Polyethylene Glycol, sorbitol, the maltose alcohol one or more with the mixture of any mixed;
The pH regulator agent is that in sodium bicarbonate, sodium hydroxide or potassium hydroxide, hydrochloric acid, phosphate, citric acid and the salt thereof one or more are analysed mixture with any mixed.
Solubilizing agent is one or more mixture with any mixed in tween series, span series, sodium lauryl sulphate, polyoxyethylene hydrogenated Oleum Ricini, the dimethyl sulfoxine;
Antiseptic and antioxidant are one or more mixture with any mixed in ethanol, chlorocresol, potassium sorbate, chlorobutanol, methyl hydroxybenzoate, ethyl hydroxybenzoate, propylparaben, sulphite, aminothiopropionic acid, vitamin C, vitamin E, the di-t-butyl toluene;
Stabilizing agent is that in metal-chelator disodium EDTA, ethylenediaminetetraacetic acid two calcium salts or the oxalic acid triamine pentaacetic acid one or more are with any mixture;
Transdermal gel of the present invention, the consumption of pH regulator agent in gel are that 3～10 consumption is advisable with the pH value of pH regulator gel;
Antiseptic and the antioxidant mass percentage content in gel is 0～30%, preferred 0.01～20%;
The mass percentage content of stabilizing agent in gel is 0%～0.5%, preferred 0.01～0.1%.
Transdermal gel of the present invention, contain by percentage to the quality:
Oxibutynin 0.1%～30%, preferred 8%～12%;
Gel-type vehicle 0.3%～35%, preferred 0.5%～20%;
Transdermal enhancer 0.1%～90%, preferred 50%～75%;
The pure water surplus;
Above-mentioned gel-type vehicle is selected from chitosan, sucralfate, propylene glycol, ethanol, glycerol, Polyethylene Glycol, polyvinyl alcohol, methylcellulose, ethyl cellulose, one or more in hydroxyethyl-cellulose, hydroxypropyl cellulose, hypromellose, the sodium carboxymethyl cellulose are with the mixture of any mixed.
Transdermal enhancer is ethanol, propylene glycol, isopropyl alcohol, menthol, Oleum menthae, eucalyptus oil, and one or more in Borneolum Syntheticum, carbamide, the oleic acid are with the mixture of any mixed.
Optionally can contain following material: be one or more the mixture in tween series, span series, sodium lauryl sulphate, polyoxyethylene hydrogenated Oleum Ricini, the dimethyl sulfoxine with any mixed as solubilizing agent;
Optionally can contain the following material as the pH regulator agent: one or more in sodium bicarbonate, sodium hydroxide or potassium hydroxide, hydrochloric acid, phosphate, citric acid and the salt thereof are analysed mixture with any mixed.
Optionally can contain following material: one or more mixture in ethanol, chlorocresol, potassium sorbate, chlorobutanol, methyl hydroxybenzoate, ethyl hydroxybenzoate, propylparaben, sulphite, aminothiopropionic acid, vitamin C, vitamin E, the di-t-butyl toluene with any mixed as antiseptic and antioxidant.
Oxibutynin gel of the present invention can adopt following method preparation:
(1) water, ethanol, glycerol, glycerin mono-fatty acid ester are made muddy liquid, as solvent;
(2) oxibutynin is added in (1) solvent, concentration 0.1%～30%,
(3) gel-type vehicle is added in the suitable quantity of water, substrate is dissolved or swelling fully, stir, obtain blank gel-type vehicle, optionally, add the pH regulator agent and transfer pH, add antiseptic and antioxidant, add stabilizing agent;
(4) oxibutynin solution that above-mentioned (3) are obtained or muddy liquid add in the blank gel-type vehicle of (2) gained, packing.
Contain ointment of oxibutynin and preparation method thereof
Ointment of the present invention is meant oxibutynin and uniform semi-solid external preparation oil or that water-soluble base is mixed and made into.
The present invention contains the ointment of oxibutynin, comprises following technical scheme:
Oxibutynin ointment of the present invention contains active component oxibutynin and ointment base, and wherein the mass percentage content of oxibutynin is 0.1%～30%.
The preferred mass percentage content of oxibutynin in ointment is 1%～18%
The mass percentage content of preferred oxibutynin in ointment is 3%～15%
The mass percentage content of preferred oxibutynin in ointment is 5%～13%
The mass percentage content of preferred oxibutynin in ointment is 8%～12%
The mass percentage content of ointment base in ointment is 10%～90%.
Ointment base of the present invention comprises greasing base and water-soluble base, wherein greasing base is preferably stearic acid, glyceryl monostearate, polyoxyethylene monostearate, one or more the mixture in paraffin, liquid paraffin, vaseline, lanoline, hexadecanol, octadecanol, span series, Cera Flava, the Vegetable oil lipoprotein with any mixed.
One or more mixture in water-soluble base glycerol, propylene glycol, sorbitol, Polyethylene Glycol series, tween series, sodium lauryl sulphate, carbamide, peregal, ethanol, the dimethyl sulfoxine wherein with any mixed.
And, optionally can also make the following material of antiseptic and antioxidant: one or more mixture in ethanol, chlorocresol, thimerosal, 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-t-butyl toluene with any mixed;
Optionally cannot contain the following material as transdermal enhancer: laurocapram, propylene glycol, ethanol, menthol, Oleum menthae, eucalyptus oil, one or more in Borneolum Syntheticum, isopropyl alcohol, carbamide, the oleic acid are with the mixture of any mixed.
Be preferably as follows the ointment that contains oxibutynin, contain by percentage to the quality:
Stearic acid or hexadecanol or octadecanol 0%～10%,
Pure water is an amount of, and the mass percent sum is 100%
Following oxibutynin ointment technology of preparing and method further are provided:
(1) with greasing base under the temperature of room temperature to 82 ℃, fusion also stirs, and obtains blank oleaginous base;
(2) with water-soluble base under the temperature of room temperature to 82 ℃, stir and make dissolving, and stir, optionally add transdermal enhancer, antiseptic and antioxidant obtain blank aqueous matrix;
(3) oxibutynin is added in (2), stir and make dissolving or molten loosing, and mix homogeneously;
(4) (1) is mixed with (3), stir, natural cooling, packing, promptly.
Contain ointment of oxibutynin and preparation method thereof
The uniform semi-solid external preparation that the ointment of oxibutynin of the present invention is meant the oxibutynin dissolving or disperses to form in the emulsion type substrate.
Oxibutynin ointment of the present invention contains active component oxibutynin and emulsifiable paste matrix, and wherein the oxibutynin mass percentage content is 0.1%～30%.
The preferred mass percentage content of oxibutynin in ointment is 1%～18%
The mass percentage content of preferred oxibutynin in ointment is 3%～15%
The mass percentage content of preferred oxibutynin in ointment is 5%～13%
The mass percentage content of preferred oxibutynin in ointment is 8%～12%
Described emulsifiable paste matrix comprises oil phase and water, wherein oil phase is preferably stearic acid, glyceryl monostearate, polyoxyethylene monostearate, one or more the mixture in paraffin, liquid paraffin, vaseline, lanoline, hexadecanol, octadecanol, span series, Cera Flava, the Vegetable oil lipoprotein with any mixed.
Wherein water is preferably one or more mixture with any mixed in glycerol, propylene glycol, triethanolamine, tween series, SDS, peregal, OP emulsifying agent, ethanol, Polyethylene Glycol series, carbamide, the dimethyl sulfoxine.
And optionally can also contain the following material as transdermal enhancer: laurocapram, propylene glycol, ethanol, menthol, Oleum menthae, eucalyptus oil, one or more in Borneolum Syntheticum, isopropyl alcohol, carbamide, the oleic acid are with the mixture of any mixed.
Can also be triethanolamine as the pH regulator agent optionally, one or more in diethanolamine, guanidine carbonate, tromethane, ethylenediamine, diethylamine, lauryl amine, ammonia spirit, sodium bicarbonate, sodium hydroxide or potassium hydroxide, hydrochloric acid, phosphate, citric acid and the salt thereof be analysed mixture with any mixed.
Optionally can also make the following material of antiseptic and antioxidant: one or more mixture in ethanol, chlorocresol, thimerosal, 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-t-butyl toluene with any mixed.
The present invention preferably contains the ointment of oxibutynin, contains by percentage to the quality:
Oxibutynin 0.2%～5%,
Oil phase: stearic acid or hexadecanol or octadecanol 2%～20%,
Glycerin mono-fatty acid ester 0%～10%,
Carbopol 0.1%～5%,
Propyl p-hydroxybenzoate 0%～0.5%,
Water glycerol or propylene glycol 5%～15%,
Simethicone 0.05%～2%,
Pure water adds to 100% in right amount.
The present invention further provides the method for preparing the oxibutynin ointment, having comprised:
(1) with the solid matter in the oil-phase component under the temperature of room temperature to 88 ℃, fusion, stirring and with the liquid substance mix homogeneously, it is newly standby to obtain oil phase;
(2) with water-phase component under the temperature of room temperature to 88 ℃, stir and make dissolving, and stir, it is standby to obtain water;
(3) oxibutynin is added in (2), stir and make mix homogeneously;
(4) (1) is mixed with (3), stir, optionally add transdermal enhancer, antiseptic and antioxidant naturally cool to room temperature, packing, promptly.
The present invention aspect on above three provides gel, ointment, the ointment that contains oxibutynin respectively, and their preparation method.Further, above-mentioned gel, ointment, ointment also are provided is application aspect the overactive bladder of symptom in preparation treatment urgent micturition, incontinence and frequent micturition in preparation in the present invention; Slow at preparation treatment detrusor of bladder tension force, the application of aspects such as dysfunction.
The present invention contains the cutaneous permeable agent of oxibutynin, and the application aspect the treatment disease has the following advantages:
(1) oxibutynin is smeared and is absorbed through skin, and medicine has avoided the head of liver to cross reaction without gastrointestinal absorption, avoids or alleviated the untoward reaction of oxibutynin.
(2) its effective ingredient oxibutynin can be by the through lesion region of skin, and is easy to use, rapid-action.
(3), be particularly suitable for the inconvenient patient of oral administration to the body not damaged; Carry and use conveniently.
Embodiment:
Can produce first pass effect during the oxibutynin oral preparation drug administration, bioavailability is reduced, side reaction is many, and sometimes because of serious side reaction drug withdrawal.The invention provides the embodiment of following transdermal absorption formulation, described oxybutynin transdermal absorbent is administration combination formula and be correlated with dosage form, medicinal application etc., the present invention utilizes transdermal drag delivery, medicine percutaneous skin is absorbed to be entered in the body, avoid the oral first pass effect that causes, the detrusor of bladder part of can going directly overcomes the deficiency on oral administration way.Enlarge the range of application of medicine, reduce the incidence rate of oxibutynin side reaction and the order of severity of reduction serious adverse reaction.
Embodiment 1: oxibutynin moral gel and preparation thereof
Prescription: oxibutynin 10g
Glycerol 5g
Ethanol 75ml
Hydroxyethyl-cellulose 1g
The pure water surplus;
Preparation: water, ethanol, glycerol are made muddy liquid, as solvent; Oxibutynin is added in the solvent concentration 0.1%～30%; Gel-type vehicle is added in the suitable quantity of water, substrate is dissolved or swelling fully, stir, obtain blank gel-type vehicle, optionally, add the pH regulator agent and transfer pH to 5-7, add antiseptic and antioxidant, add stabilizing agent; Above-mentioned oxibutynin solution that obtains or muddy liquid are added in the blank gel-type vehicle of gained, make final concentration reach 10%, packing.
Embodiment 2: oxibutynin moral gel and preparation thereof
Prescription: oxibutynin 10g
Glyceryl monooleate 1g
Glycerol 5g
Ethanol 35ml
Propylene glycol 1g
Hydroxyethyl-cellulose 1g
Pure water adds to 100g
Preparation: water, ethanol, glycerol, glycerin mono-fatty acid ester are made muddy liquid, as solvent; Oxibutynin is added in the solvent concentration 0.1%～30%; Gel-type vehicle is added in the suitable quantity of water, substrate is dissolved or swelling fully, stir, obtain blank gel-type vehicle, optionally, add the pH regulator agent and transfer pH to 5-7, add antiseptic and antioxidant, add stabilizing agent; Above-mentioned oxibutynin solution that obtains or muddy liquid are added in the blank gel-type vehicle of gained, make final concentration reach 10%, packing.
Prescription: oxibutynin 10g
Carbomer 1g
Sodium hydroxide 1g
Propylene glycol 10g
Glycerol 5g
Ethanol 35ml
Pure water adds to 100g
Preparation: get carbomer and add after the 35ml purified water makes its abundant swelling, stir, the ripple nurse solution that obtains going to school with sodium hydrate regulator solution pH value to 6.0～7.0, stirs evenly, and obtains blank gel; Other gets, and oxibutynin is molten to loose in ethanol, stirs evenly the back and adds propylene glycol, glycerol, stirs, and then medicinal liquid is slowly joined in the ripple nurse substrate of going to school, the limit edged stirs, and adds purified water at last to 100g, gets the oxibutynin gel, be packaged in the bag, every 100g, promptly.
Prescription: oxibutynin 10g
Chitosan 1.5g
Sodium hydroxide 1g
Glycerol 8g
Laurocapram 2g
Ethanol 35ml
Distilled water adds to 100g
Preparation: get oxibutynin, glycerol adding 35ml ethanol, stir, add the dilution of 50ml dissolved in distilled water, chitosan is spread on liquid surface, make it abundant swelling after, stir evenly, add laurocapram, stir evenly, add sodium hydroxide again, regulator solution pH value to 6.0～7.0, fully stir, distilled water adds to 100g, stirs, get the oxibutynin gel, packing obtains.
Prescription; Oxibutynin 10g
Sodium Tvlose 1g
Glycerol 35g
Ethanol 35ml
Sodium citrate 1g
Pure water is to 100g
Preparation: get purified water 25ml, add chitosan, sodium carboxymethyl cellulose successively, make its natural peptization, stir evenly, add sodium citrate regulator solution pH value to 6.0～7.0 again, stir, obtain blank coagulant liquid, other gets oxibutynin and adds glycerol, ethanol, stirs evenly, obtain blank coagulant liquid, with blank gel and oxibutynin solution mix homogeneously, add water to 100g, stir evenly, get the oxibutynin gel, packing promptly.
Prescription: oxibutynin 10g
Methylcellulose 1g
Tert-butyl alcohol 0.1g
Glycerol 35g
Add pure water to 100g
Preparation: get methylcellulose and evenly be spread on 50ml purified water surface, after making its natural swelling, stir, other gets, and oxibutynin grinds in glycerol and molten loosing in wherein, add methocel solution, stir evenly, add the solution of the tert-butyl alcohol in suitable quantity of water again, stir, add water to 100g, stir evenly, get the oxibutynin gel, packing promptly.
Prescription: oxibutynin 10g
Hydroxyethyl-cellulose 1g
Isopropyl alcohol 5g
Propylparaben 0.1g
Sodium bicarbonate 1g
Add pure water to 100g
Preparation: get oxibutynin, isopropyl alcohol, hydroxyethyl-cellulose dispersed with stirring in distilled water, under agitation be heated to into clarifying viscous solution, treat to add when temperature is reduced to 40 ℃ propylparaben, manganese hydrogen sodium regulating solution pH value to 6.0～7.0, stir, add water to 100g, stir evenly, get the oxibutynin gel, packing promptly.
Embodiment 8. oxibutynin gel and preparations thereof
Prescription: oxibutynin 10g
Ethyl cellulose 1g
Propylene glycol 35g
Glycerol 5g
Sodium bicarbonate 1g
Adding distil water is to 100g
Prepare: ethyl cellulose is mixed with 1% solution propylene glycol, glycerite with NaOH solution adjusting pH to 6.5～7 in right amount with distilled water, with both mix homogeneously, adds oxibutynin again, stir the companion evenly, get the oxibutynin gel, packing promptly.
Prescription: oxibutynin 10g
Cholesterol 5g
Stearic acid or hexadecanol or octadecanol 5g
Liquid paraffin 60g
Glycerol 5g
Pure water adds to 100g
Preparation: under the temperature of room temperature to 85 ℃, fusion also stirs, and obtains blank oleaginous base with greasing base stearic acid, liquid paraffin; Water-soluble base glycerol under 85 ℃ temperature, is stirred and makes dissolving, and stir, obtain blank aqueous matrix; Oxibutynin is added in the water-soluble base, stir and make dissolving or molten loosing, and mix homogeneously; Blank oleaginous base is mixed with the oxibutynin water-soluble base, stir, natural cooling, packing, promptly.
Prescription: oxibutynin 10g
Glyceryl monostearate 20g
White vaseline 15g
Sodium lauryl sulphate 1.5g
Glycerol 10g
Distilled water adds to 100g
Preparation: oxibutynin and liquid paraffin are ground well, add glyceryl monostearate, white vaseline, be heated to 80 ℃ and make thawing, insulation; Other is soluble in water with sodium lauryl sulphate, glycerol, is heated to 80 ℃, stirs down and pours oil phase into aqueous phase, continues to be stirred to room temperature, and packing promptly.
Embodiment 11. oxibutynin emulsion agent and preparations thereof
Prescription: oxibutynin 10g
Glyceryl monostearate 10g
Carbomer 1g
Liquid Paraffin 15g
The old ketone 2.5g of Laurel nitrogen
Ethanol 15ml
Glycerol 10g
Pure 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.Standby.Other gets oxibutynin, adds ethanol and an amount of distilled water, and is evenly mixed.This liquid is slowly added in the gel-type vehicle of carbomer, the limit edged stirs, and packing promptly.
The ointment and the preparation thereof of embodiment 12. oxibutynin
Prescription: oxibutynin 10g
Oil phase: stearic acid or hexadecanol or octadecanol 20g
Glycerin mono-fatty acid ester 10g
Carbopol 5g
Oleic acid 10g
Propyl p-hydroxybenzoate 0.5g
Vaseline 10g
Water: glycerol or propylene glycol 15g
Sodium stearate 5g
Simethicone 2g
Pure water adds to 100g in right amount
Preparation: with the solid matter in the oil-phase component under the temperature of room temperature to 90 ℃, fusion, stirring and with the liquid substance mix homogeneously, it is standby to obtain oil phase; Water-phase component under the temperature of room temperature to 90 ℃, is stirred and makes dissolving, and stir, and it is standby to obtain water; With oxibutynin add water standby in, stir and to make mix homogeneously; Oxibutynin water oil phase mixes, and stirs, and naturally cools to room temperature, packing, promptly.
The ointment and the preparation thereof of embodiment 13. oxibutynin
Prescription: oxibutynin 10g
Stearic acid 12g
Vaseline 20g
Glycerol 5g
Sodium hydroxide 1g
Ethyl hydroxybenzoate 0.2g
Distilled water adds to 100g
Preparation: get stearic acid, vaseline as oil phase, other gets glycerol, sodium hydroxide, ethyl hydroxybenzoate and an amount of distilled water as water, oxibutynin adds water and closes dissolving, put in the appropriate vessel respectively with biphase, be heated to fusing or dissolving, and keep about 70 ℃ of temperature, under agitation slowly add water in the oil phase, and be stirred to by same direction and coagulate, promptly.
The ointment and the preparation thereof of embodiment 14. oxibutynin
Prescription: oxibutynin 10g
Glyceryl monostearate 3g
Stearic acid 6g
Liquid paraffin 25g
Tween 80 5g
Sodium bicarbonate 1g
Ethyl hydroxybenzoate 0.1g
Glycerol 20g
Dimethicone 0.5g
Purified water adds to 100g.
Preparation: get glyceryl monostearate, stearic acid, liquid paraffin, span and be heated to 80～90 ℃, insulation, standby as oil phase; Other gets tween 80 and an amount of purified water, is heated to 80～90 ℃, as water A; Water A is joined in the oil phase, stir, make w/o type solution.Other gets an amount of purified water, sodium bicarbonate, glycerol, ethyl hydroxybenzoate, is heated to 80～90 ℃, as aqueous phase B; Manufactured w/o type solution is added in the aqueous phase B, and the limit edged stirs, and adds oxibutynin when waiting to be chilled to 50 ℃ of left and right sides, and the limit edged is stirred to into the stabilized uniform emulsifiable paste, and packing promptly.
Claims (13)
1. transdermal absorption formulation that contains oxibutynin, comprise gel, ointment, ointment, wherein oxibutynin be oxibutynin at pharmaceutically acceptable salt or its mixture, its mass percentage content in transdermal absorption formulation is 0.1%～30%.
2. the described cutaneous permeable agent of claim 1, wherein the mass percentage content of oxibutynin in cutaneous permeable agent is 0.5%～20%.
The preferred mass percentage content of oxibutynin in cutaneous permeable agent is 1%～18%
The preferred mass percentage content of oxibutynin in cutaneous permeable agent is 3%～15%
The preferred mass percentage content of oxibutynin in cutaneous permeable agent is 5%～13%
The preferred mass percentage content of oxibutynin in cutaneous permeable agent is 8%～12%
3. Transdermal absorption system gel that contains oxibutynin, by gel-type vehicle, transdermal enhancer, wetting agent, pH regulator agent, solubilizing agent, compositions such as antiseptic, antioxidant and stabilizing agent.Wherein: the mass percentage content in the Transdermal absorption system gel of oxibutynin is 0.5%～20%.
Described gel-type vehicle is selected from chitosan, sucralfate, propylene glycol, ethanol, glycerol, Polyethylene Glycol, polyvinyl alcohol, methylcellulose, ethyl cellulose, one or more in hydroxyethyl-cellulose, hydroxypropyl cellulose, hypromellose, the sodium carboxymethyl cellulose are with the mixture of any mixed.
Transdermal enhancer is ethanol, propylene glycol, isopropyl alcohol, menthol, Oleum menthae, eucalyptus oil, and one or more in Borneolum Syntheticum, carbamide, the oleic acid are with the mixture of any mixed.
Wetting agent be in water, glycerol, propylene glycol, Polyethylene Glycol, sorbitol, the maltose alcohol one or more with the mixture of any mixed;
The pH regulator agent is that in sodium bicarbonate, sodium hydroxide or potassium hydroxide, hydrochloric acid, phosphate, citric acid and the salt thereof one or more are analysed mixture with any mixed.
Solubilizing agent is one or more mixture with any mixed in tween series, span series, sodium lauryl sulphate, polyoxyethylene hydrogenated Oleum Ricini, the dimethyl sulfoxine;
Antiseptic and antioxidant are one or more mixture with any mixed in ethanol, chlorocresol, potassium sorbate, chlorobutanol, methyl hydroxybenzoate, ethyl hydroxybenzoate, propylparaben, sulphite, aminothiopropionic acid, vitamin C, vitamin E, the di-t-butyl toluene;
Stabilizing agent is that in metal-chelator disodium EDTA, ethylenediaminetetraacetic acid two calcium salts or the oxalic acid triamine pentaacetic acid one or more are with any mixture.
4. the described transdermal gel of claim 3, the consumption of pH regulator agent in gel are that 3～10 consumption is advisable with the pH value of pH regulator gel; Antiseptic and the antioxidant mass percentage content in gel is 0～30%, preferred 0.01～20%; The mass percentage content of stabilizing agent in gel is 0%～0.5%, preferred 0.01～0.1%.
5. gel that contains oxibutynin, contain by percentage to the quality:
Oxibutynin 0.1%～30%, preferred 8%～12%
Gel-type vehicle 0.3%～35%, preferred 0.5%～20%
Transdermal enhancer 0.1%～90%, preferred 0.5%～75%
The pure water surplus
Described gel-type vehicle is selected from chitosan, sucralfate, propylene glycol, ethanol, glycerol, Polyethylene Glycol, polyvinyl alcohol, methylcellulose, ethyl cellulose, one or more in hydroxyethyl-cellulose, hydroxypropyl cellulose, hypromellose, the sodium carboxymethyl cellulose are with the mixture of any mixed.
Transdermal enhancer is ethanol, propylene glycol, isopropyl alcohol, menthol, Oleum menthae, eucalyptus oil, and one or more in Borneolum Syntheticum, carbamide, the oleic acid are with the mixture of any mixed.
6. prepare the method for described any one the oxibutynin gel of claim 3 to 5, it comprises:
(1) water, ethanol, glycerol, glycerin mono-fatty acid ester are made muddy liquid, as solvent;
(2) oxibutynin is added in (1) solvent, concentration 0.1%～30%,
(3) gel-type vehicle is added in the suitable quantity of water, substrate is dissolved or swelling fully, stir, obtain blank gel-type vehicle, optionally, add the pH regulator agent and transfer pH, add antiseptic and antioxidant, add stabilizing agent;
(4) oxibutynin solution that above-mentioned (3) are obtained or muddy liquid add in the blank gel-type vehicle of (2) gained, packing.
7. an ointment that contains oxibutynin contains active component oxibutynin and ointment base, and wherein the mass percentage content of oxibutynin is 0.1%～30%, and the mass percentage content of ointment base is 10%～90%.
Described ointment base comprises fat substrate and water-soluble base, wherein greasing base is preferably stearic acid, glyceryl monostearate, polyoxyethylene monostearate, one or more the mixture in paraffin, liquid paraffin, vaseline, lanoline, hexadecanol, octadecanol, span series, Cera Flava, the Vegetable oil lipoprotein with any mixed.
One or more mixture in water-soluble base glycerol, propylene glycol, sorbitol, Polyethylene Glycol series, tween series, sodium lauryl sulphate, carbamide, peregal, ethanol, the dimethyl sulfoxine wherein with any mixed.
And, optionally can also make the following material of antiseptic and antioxidant: one or more mixture in ethanol, chlorocresol, thimerosal, 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-t-butyl toluene with any mixed;
Optionally cannot contain the following material as transdermal enhancer: laurocapram, propylene glycol, ethanol, menthol, Oleum menthae, eucalyptus oil, one or more in Borneolum Syntheticum, isopropyl alcohol, carbamide, the oleic acid are with the mixture of any mixed.
8. ointment that contains oxibutynin, contain by percentage to the quality:
Oxibutynin 1%～20%,
Cholesterol 0～5%,
Stearic acid or hexadecanol or octadecanol 0%～10%,
Liquid paraffin 70%～100%,
Glycerol 5%～20%,
Pure water is an amount of, and the mass percent sum is 100%
9. prepare the method for the described any oxibutynin ointment of claim 8, it comprises:
(1) with greasing base under the temperature of room temperature to 85 ℃, fusion also stirs, and obtains blank oleaginous base;
(2) with water-soluble base under the temperature of room temperature to 85 ℃, stir and make dissolving, and stir, optionally add transdermal enhancer, antiseptic and antioxidant obtain blank aqueous matrix;
(3) oxibutynin is added in (2), stir and make dissolving or molten loosing, and mix homogeneously;
(4) (1) is mixed with (3), stir, natural cooling, packing, promptly.
10. an ointment that contains oxibutynin contains active component oxibutynin and emulsifiable paste matrix, and wherein the percentage composition of oxibutynin is 0.1%～30%.
Described emulsifiable paste matrix comprises oil phase and water, wherein oil phase is preferably stearic acid, glyceryl monostearate, polyoxyethylene monostearate, one or more the mixture in paraffin, liquid paraffin, vaseline, lanoline, hexadecanol, octadecanol, span series, Cera Flava, the Vegetable oil lipoprotein with any mixed.
Wherein water is preferably one or more mixture with any mixed in glycerol, propylene glycol, triethanolamine, tween series, SDS, peregal, OP emulsifying agent, ethanol, Polyethylene Glycol series, carbamide, the dimethyl sulfoxine.
And optionally can also contain the following material as transdermal enhancer: laurocapram, propylene glycol, ethanol, menthol, Oleum menthae, eucalyptus oil, one or more in Borneolum Syntheticum, isopropyl alcohol, carbamide, the oleic acid are with the mixture of any mixed.
Can also be triethanolamine as the pH regulator agent optionally, one or more in diethanolamine, guanidine carbonate, tromethane, ethylenediamine, diethylamine, lauryl amine, ammonia spirit, sodium bicarbonate, sodium hydroxide or potassium hydroxide, hydrochloric acid, phosphate, citric acid and the salt thereof be analysed mixture with any mixed.
Optionally can also make the following material of antiseptic and antioxidant: one or more mixture in ethanol, chlorocresol, thimerosal, 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-t-butyl toluene with any mixed;
11. an ointment that contains oxibutynin contains by percentage to the quality:
Active component: oxibutynin 0.2%～15%,
Oil phase: stearic acid or hexadecanol or octadecanol 2%～20%,
Glycerin mono-fatty acid ester 0%～10%,
Carbopol 0.1%～5%,
Oleic acid 0%～10%,
Propyl p-hydroxybenzoate 0%～0.5%,
Vaseline 2%～10%,
Water glycerol or propylene glycol 5%～15%,
Sodium stearate 1%～5%,
Simethicone 0.05%～2%,
Pure water adds to 100% in right amount.
And optionally can also contain the following material as transdermal enhancer: laurocapram, propylene glycol, ethanol, menthol, Oleum menthae, eucalyptus oil, one or more in Borneolum Syntheticum, isopropyl alcohol, carbamide, the oleic acid are with the mixture of any mixed.
12. prepare the method for claim 11 oxibutynin ointment, it comprises:
(1) with the solid matter in the oil-phase component under the temperature of room temperature to 90 ℃, fusion, stirring and with the liquid substance mix homogeneously, it is newly standby to obtain oil phase;
(2) with water-phase component under the temperature of room temperature to 90 ℃, stir and make dissolving, and stir, it is standby to obtain water;
(3) oxibutynin is added in (2), stir and make mix homogeneously;
(4) (1) is mixed with (3), stir, optionally add transdermal enhancer, antiseptic and antioxidant naturally cool to room temperature, packing, promptly.
13. claim 1,2,3,4,5,7,8,10,11 described any one contain the cutaneous permeable agent of oxibutynin, application in the following areas:
(1) be application aspect the overactive bladder of symptom in preparation treatment urgent micturition, incontinence and frequent micturition;
(2) slow at preparation treatment detrusor of bladder tension force, the application of aspects such as dysfunction.
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