CN103156804A - Oxybutynin transdermal gel and preparation method thereof - Google Patents
Oxybutynin transdermal gel and preparation method thereof Download PDFInfo
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- CN103156804A CN103156804A CN2011104142559A CN201110414255A CN103156804A CN 103156804 A CN103156804 A CN 103156804A CN 2011104142559 A CN2011104142559 A CN 2011104142559A CN 201110414255 A CN201110414255 A CN 201110414255A CN 103156804 A CN103156804 A CN 103156804A
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Abstract
The invention relates to a transdermal gel of oxybutynin or a pharmaceutically acceptable salt thereof used for treating overactive bladder with the symptoms of frequent urination, urgent urination and urinary incontinence, and a preparation method of the transdermal gel. The transdermal gel comprises oxybutynin or the pharmaceutically acceptable salt thereof, a gel matrix hydroxypropyl methylcellulose, a pH value regulator, a humectants and a solvent of anhydrous ethyl alcohol and water.
Description
Technical field
The invention belongs to pharmaceutical composition or formulation art, be specifically related to a kind of overactive bladder (Overactive Bladder that is used for the treatment of take frequent micturition, urgent micturition and incontinence as symptom, OAB) oxibutynin or transdermal gel of its pharmaceutically acceptable salt and preparation method thereof, this transdermal gel are mainly by oxibutynin or its pharmaceutically acceptable salt, gel-type vehicle, pH value regulator, wetting agent and solvent composition.
Background technology
OAB is a kind of syndrome take symptoms of urgency as feature, and this symptom is a kind of burst, the strong desire of urinating, and is difficult to be suppressed and postpone to urinate by subjective, and this symptom is often with frequent micturition and nocturia symptom, can with or without urge incontinence; Can show as the detrusor over-activity on urodynamics, also can be the urethra-vesical dysfunction of other form.Frequent micturition refers to that patient's conscious every day of number of micturitions is too frequent.On the basis of subjective sensation, adult's number of micturitions reaches: in the daytime 〉=8 times, night 〉=2 time are thought of as frequent micturition during each urine amount＜200ml.Nocturia refers to above, main suit that urinate because of the urine meaning at patient 〉=2 time/night; Urge incontinence refer to accompany with urgent micturition or urgent micturition after the urinary incontinence phenomenon that occurs immediately.
According to statistics, the total incidence of overactive bladder is 16.6%, and increases with the growth at age.The women is apparently higher than the male, and adult female's total incidence is 16.8%, and the male is 7%.But cause the incidence rate of unstable bladder up to 50%～80% because of benign prostate hyperplasia (BPH) bladder outlet obstruction (BOO) (BOO) that occurs together in the male.In recent years, this sick sickness rate of China also constantly increased.Investigation in China Beijing area shows, the sickness rate of male uracratia is 12.1%, the women is 46.5%, and wherein more than 50 years old, the incidence rate of male's urge incontinence is that total incidence rate of women's mixed urinary incontinence and urge incontinence more than 16.4%, 18 years old is up to 40.4%.
Overactive bladder is topmost is also that the most basic means are Drug therapys.Anticholinergic agents is still the modal medicine for the treatment of OAB at present, and its main mechanism is: 1. by the antagonism m receptor, suppress detrusor contractions, improve the bladder sensation function and suppress the possibility that detrusor instability (di) shrinks; 2. to the high selectivity effect of bladder, this characteristic is that said medicine is as the Main Basis of first-line treatment medicine.At present this type of medicine is commonly used mainly contains oxibutynin, tolterodine and trospium chloride, oxibutynin is M3 cholinoceptor blocking agent and calcium antagonists, oral is that the N-desethyloxybutynin (DEO) of identical pharmacologically active is arranged with prototype by the rapid metabolism of liver CYP3A4 enzyme, this Metabolites Concentration is approximately 4 ~ 10 times of prototype medicine, still keeps the pharmacology of oxibutynin.Oxibutynin is to use clinically more M cholinoceptor blocking agent, is that the 3rd the A level in the ICI assessing drug actions recommended medicine.
In U.S.'s listing, three of listing during the last ten years certainly in 1975 for ditropan XL, and its clinical efficacy has obtained effective confirmation, and its oral formulations is accepted extensively by people.But meanwhile, its xerostomia, constipation, the untoward reaction such as nauseating, dizzy also more and more come into one's own.Therefore, on the basis that keeps this product Clinical efficacy, utilize the preparation means to reduce its untoward reaction and become and become more and more important.
After the oxibutynin oral administration, mainly through the metabolism of cytochrome P 450 Enzyme system, particularly through the CYP3A4 metabolism, metabolite comprises the phenyl ring cyclohexyl glycolic acid of parmacodynamics-less activity and the N-desethyloxybutynin (DEO) of pharmacologically active is arranged.Its untoward reaction (common adverse reactions is xerostomia) is also mainly caused by DEO, because CYP3A4 mainly is distributed in liver and intestinal wall, only has a small amount of CYP3A4 in skin, therefore, ditropan XL is developed as percutaneous drug administration preparation, to obviously reduce the generation of metabolite DEO, thereby avoid or alleviate its untoward reaction.
CN1288376 discloses the transdermal therapeutic system (TTS) of the oxibutynin that a kind of a couple of days is administered once, it is characterized in that this TTS comprises the base material that contains oxibutynin of self-adhesive layer form, wherein this base material is comprised of the oxibutynin of (first) acrylate copolymer that contains ammonium, at least a citric acid three ester that is up to 33% weight and 5-26% weight.
CN1182358 discloses a kind of compositions for the alkalescent medicine transdermal penetration and method.Said composition contains matrix patch, and described matrix patch contains the alkalescent medicine of effective dose, the penetration enhancer that substantially is comprised of triacetin of effective dose and the polymeric layer that preferably contains the pressure sensitive adhesive binding agent.Preferred medicine is oxibutynin and acid-addition salts thereof.
The characteristics of above-mentioned technology are all to have utilized only to contain a small amount of CYP3A4 in skin, thereby have reduced the generation of metabolite DEO, avoid or have alleviated the untoward reaction that is caused by DEO.But percutaneous plaster is a closed system, and breathability is relatively poor, thereby after long-time administration, the incidence rate of the irritative responses such as skin erythema and pruritus is higher.The oxybutynin transdermal paster of U.S.'s water gloomy (Watson) company exploitation is with regard to the market of progressively fading out because pressure sensitive adhesive causes allergic reaction.
The percutaneous dosing gel disturbs except having the liver first-pass effect of avoiding and gastrointestinal tract, avoids gastrointestinal tract mucous generation zest; Keep stable blood drug level, avoid peak valley phenomenon, reduce toxic and side effects; Reduce administration number of times, improve the compliance of patient's administration; The patient who is suitable for old age, infant and unsuitable oral administration; Production technology is relatively simple, is convenient to realize also have the advantages such as medication compliance that the skin affinity is good, untoward reaction is little, can significantly improve the patient outside the characteristics of the percutaneous preparations such as suitability for industrialized production.Thereby it is a kind of more satisfactory selection that ditropan XL is developed as the percutaneous dosing gel.
CN101564377 discloses a kind of transdermal gel that is used for the treatment of overactive bladder and preparation method thereof.This transdermal gel comprises the Ketoprofen of 1-20% weight, and the carbomer of 0.5-5% weight makes the gel-type vehicle pH value be adjusted to the pH value regulator of pH5-10, the water of 1-10% weight wetting agent and remainder.
WO2005032441 discloses a kind of part oxibutynin gel, wherein oxibutynin occupies 0.5-5%, short chain alcohol is 10-80%, gel-type vehicle is 0.2-2%, gel-type vehicle is carbomer or PemulenTR-1NF, also comprises in addition the short penetrating agent of 0.5-5%, and short penetrating agent is selected from propylene glycol, propylene glycol lauric acid, IPM and methyllactic acid tetradecylic acid isopropyl alcohol also comprise the wetting agent propylene glycol in addition.
CN1708269 discloses a kind of oxibutynin gel of topical application, described topical formulations is used for mammal, provide under the curve of blood plasma of oxibutynin and its metabolite area (AUC) than being about 0.5:1 to about 5:1, to minimize the drug side effect relevant with oxybutynin therapy.This gel comprises the oxibutynin for the treatment of effective dose, gel carrier, the pH value of described preparation is about 4 to 11, wherein said oxibutynin is the oxibutynin free alkali, pharmaceutically acceptable oxibutynin salt or its mixture, and described preparation can be prepared into and be suitable for staying form to be applied topically to skin surface with non-envelope.
Above technology has solved skin irritation and anaphylaxis problem that transdermal patch causes well, and wherein, CN101564377 selects carbomer as gel-type vehicle; It is gel-type vehicle that WO2005032441 selects carbomer or PemulenTR-1NF; It is gel-type vehicle that CN1708269 selects hydroxypropyl cellulose.Prepare gel with above-mentioned gel-type vehicle, due to the factor of the physicochemical property of gel-type vehicle own, the viscosity of gel is usually larger, thereby the percutaneous rate of gel can be affected.Often need in this case to add short penetrating agent, just comprised the short penetrating agent of 0.5-5% as gel prescription in WO2005032441.The problem that can not be ignored be, the mechanism of action of short penetrating agent normally changes this body structure of skin and reaches short effect of oozing, the harmful effect that the prolonged application penetrating agent causes skin is apparent.Thereby, seek the good gel-type vehicle of a kind of safety and effectiveness and will have important clinical meaning and social benefit.Unexpectedly, oxibutynin gel of the present invention need not to add special short penetrating agent just can obtain good transdermal effect and safety.This gel appearance transparent, evenly, smooth exquisiteness is easy to extend, and with rear foreign sense, without obvious skin irritation, drug release is fast, and Transdermal absorption is good, has good stability, and uses compliance splendid, can significantly improve clinical therapeutic efficacy.
Summary of the invention
The present invention is to provide a kind of oxibutynin gel, comprise oxibutynin or its pharmaceutically acceptable salt, the gel-type vehicle hypromellose.Result of the test shows, gel of the present invention is better than the oxibutynin gel of present publication technology preparation.
Wondrous and beyond thought is that gel of the present invention is with hypromellose, it is the gel of gel-type vehicle preparation as hypromellose E4M, do not have special short penetrating agent under, the gel phase of its percutaneous rate and prior art preparation is smeared compliance better than obviously improving.
For realizing above-mentioned oxibutynin gel of the present invention, provide following embodiment.
In one embodiment, a kind of oxybutynin transdermal gel of the present invention, comprise the oxibutynin of 1%-30% or its pharmaceutically acceptable salt, the hydroxypropyl methylcellulose of 0.5%-5%, the wetting agent of 1%-20%, the ethanol of 50%-80%, He Shui, the pH value of described transdermal gel is 5.0-8.0, and described percentage ratio all is weight percentage.
The oxybutynin transdermal gel of the invention described above further comprises the pH value regulator, and its pH value regulator sodium hydroxide or triethanolamine are preferably sodium hydroxide.
the oxybutynin transdermal gel of the invention described above, the percentage by weight of oxibutynin or its pharmaceutical salts is 5%-15%, the percentage by weight of gel-type vehicle hydroxypropyl methylcellulose is for being 0.5%-3.0%, the percentage by weight of wetting agent is 2.0%-5.0%, the percentage by weight of etoh solvent is 60%-70%, pH is 5.0-6.0, wherein, preferably, oxibutynin is ditropan XL, hydroxypropyl methylcellulose is hypromellose E4M (HPMC E4M, available from Dow Chemical), hypromellose E50(HPMC E50, available from Dow Chemical) or their mixture, hypromellose E4M more preferably, wetting agent preferably glycerine or propylene glycol.
In a preferred specific embodiments, oxybutynin transdermal gel of the present invention, the oxibutynin or its pharmaceutically acceptable salt that comprise 5%-15%, be preferably the hydroxypropyl methylcellulose of ditropan XL, 0.5%-3%, the wetting agent of 2%-5%, the second alcohol and water of 60%-70%, preferred purified water, the pH value of described transdermal gel is 5.0-6.0, and described percentage ratio all is weight percentage.
In above-mentioned preferred specific embodiments, oxybutynin transdermal gel of the present invention further comprises the pH value regulator, and its pH value regulator sodium hydroxide or triethanolamine are preferably sodium hydroxide.
In above-mentioned preferred specific embodiments, described hydroxypropyl methylcellulose is hypromellose E4M, hypromellose E50 or their mixture, hypromellose E4M more preferably, wetting agent preferably glycerine or propylene glycol.
In another preferred specific embodiments, oxibutynin gel of the present invention comprises 10% ditropan XL, 70% ethanol, and 2.0% glycerol, 1.5% hypromellose E4M, purified water, pH adjusting agent, pH value is 5.0-8.0, preferred 5.0-6.0, more preferably 5.6.
Oxibutynin gel of the present invention, described water be preferred purified water all, and its consumption is 100% to get final product for satisfying gel weight.
The present invention also provides a kind of preparation method of oxibutynin gel, it is characterized in that, get the gel matrix material hydroxypropyl methylcellulose, in water after complete swelling, the alcoholic solution that adds wetting agent, dehydrated alcohol and oxibutynin, as needs, regulate pH value to 5.0-8.0 with pH adjusting agent, mixing and get final product.
In one embodiment, the method for preparing the oxibutynin gel of the present invention, the method comprises:
A) get the gel matrix material hydroxypropyl methylcellulose, become colloid with complete swelling in purified water;
B) getting the oxibutynin of recipe quantity or its salt (preferred ditropan XL) is dissolved in and forms the oxibutynin alcoholic solution in appropriate dehydrated alcohol;
C) add wetting agent, dehydrated alcohol, oxibutynin alcoholic solution in step colloid a), stir lower mix homogeneously, form gel;
D) use pH adjusting agent, as triethanolamine or sodium hydroxide, preferred sodium hydroxide is regulated the pH value of gel to 5.0-8.0, and is preferred 5.6,
E) add the purified water of surplus to mix, get the oxibutynin gel.
In said method, the host material in step a includes but not limited to hypromellose E4M, E50, or their mixture, preferred hypromellose E4M; Wetting agent in step a includes but not limited to propylene glycol, glycerol, preferably glycerine.
Oxibutynin gel of the present invention provides 1g:150mg, 1g:100mg, and three specifications of 1g:50mg, packing specification is the 0.5g/ bag, 1g/ bag, 2mg/ bag, preferred 1g:100mg and 1g/ bag.
Oxibutynin gel of the present invention is used for the treatment of patient's bladder excessive syndrome, and its daily dose scope is preferably 50mg～150mg, be administered once every day, is used for the positions such as thigh, upper arm outward inboard, the non-air-tight state of agents area, good permeability, this gel has appearance transparent, evenly, smooth exquisiteness is easy to extend, with rear foreign sense, the characteristics such as nothing is skin irritation obviously, and drug release is fast, and Transdermal absorption is good, the use compliance is splendid, can significantly improve clinical therapeutic efficacy.
Description of drawings
Fig. 1 embodiment 2 and comparative example 1,2,3,4,5 the penetrating percentage rate time graph of the cumulative in vitro percutaneous of 24 hours.
Fig. 2 embodiment 2 and embodiment 2 place the penetrating percentage rate time graph of cumulative in vitro percutaneous of 6 months samples.
The specific embodiment
Following examples are used for further illustrating content of the present invention, but do not limit the scope of the invention.
Embodiment 1
The present embodiment is that drug content is the preparation of 1% ditropan XL gel:
| Prescription forms | Recipe quantity |
| Ditropan XL | 1g |
| Dehydrated alcohol | 70g |
| HPMC E4M | 1.5g |
| Glycerol | 2g |
| Sodium hydroxide | In right amount |
| Purified water | Add to 100g |
Preparation method: HPMC E4M crosses 80 mesh sieves, and ditropan XL is dissolved in and forms the ditropan XL alcoholic solution in 30% recipe quantity dehydrated alcohol, and NaOH is mixed with the NaOH solution of 5mol/L with purified water, standby; Get appropriate purified water, HPMC E4M is added to the water, make it be swelled into uniform colloid, the dehydrated alcohol and the ditropan XL alcoholic solution that under agitation add respectively glycerol, 70% recipe quantity, after mix homogeneously, add NaOH solution to regulate pH value to 5.6, replenish residue prescription water gaging to 100 g, after stirring, packing and get final product.
Embodiment 2:
The present embodiment is that drug content is the preparation of 10% ditropan XL gel:
| Prescription forms | Recipe quantity |
| Ditropan XL | 10g |
| Dehydrated alcohol | 70g |
| HPMC E4M | 1.5g |
| Glycerol | 2g |
| Sodium hydroxide | In right amount |
| Purified water | Add to 100g |
Preparation method: HPMC E4M crosses 80 mesh sieves, and ditropan XL is dissolved in and forms the ditropan XL alcoholic solution in 30% recipe quantity dehydrated alcohol, and NaOH is mixed with the NaOH solution of 5mol/L with purified water, standby; Get appropriate purified water, HPMC E4M is added to the water, make it be swelled into uniform colloid, the dehydrated alcohol and the ditropan XL alcoholic solution that under agitation add respectively glycerol, 70% recipe quantity, after mix homogeneously, add NaOH solution to regulate pH value to 5.6, replenish residue prescription water gaging to 100 g, after stirring, packing and get final product.
Embodiment 3:
The present embodiment is that drug content is the preparation of 30% ditropan XL gel:
| Prescription forms | Recipe quantity |
| Ditropan XL | 30g |
| Dehydrated alcohol | 50g |
| HPMC E4M | 1.5g |
| Glycerol | 2g |
| Sodium hydroxide | In right amount |
| Purified water | Add to 100g |
Preparation method:
HPMC E4M crosses 80 mesh sieves, and ditropan XL is dissolved in and forms the ditropan XL alcoholic solution in 30% recipe quantity dehydrated alcohol, and NaOH is mixed with the NaOH solution of 5mol/L with purified water, standby; Get appropriate purified water, HPMC E4M is added to the water, make it be swelled into uniform colloid, the dehydrated alcohol and the ditropan XL alcoholic solution that under agitation add respectively glycerol, 70% recipe quantity, after mix homogeneously, add NaOH solution to regulate pH value to 5.6, replenish residue prescription water gaging to 100 g, after stirring, packing and get final product.
Embodiment 4
The present embodiment is the preparation of the ditropan XL gel take HPMC E50 as substrate:
| Prescription forms | Recipe quantity |
| Ditropan XL | 10g |
| Dehydrated alcohol | 70g |
| HPMC E50 | 1.5g |
| Glycerol | 2g |
| Sodium hydroxide | In right amount |
| Purified water | Add to 100g |
Preparation method: HPMC E50 crosses 80 mesh sieves, and ditropan XL is dissolved in and forms the ditropan XL alcoholic solution in 30% recipe quantity dehydrated alcohol, and NaOH is mixed with the NaOH solution of 5mol/L with purified water, standby; Get appropriate purified water, HPMC E50 is added to the water, make it be swelled into uniform colloid, the dehydrated alcohol and the ditropan XL alcoholic solution that under agitation add respectively glycerol, 70% recipe quantity, after mix homogeneously, add NaOH solution to regulate pH value to 5.6, replenish residue prescription water gaging to 100 g, after stirring, packing and get final product.
The present embodiment is the preparation take HPMC E4M and HPMC E50 as the ditropan XL gel of substrate:
| Prescription forms | Recipe quantity |
| Ditropan XL | 10g |
| Dehydrated alcohol | 70g |
| HPMC E4M | 0.9g |
| HPMC E50 | 0.6g |
| Glycerol | 2g |
| Sodium hydroxide | In right amount |
| Purified water | Add to 100g |
Preparation method:
HPMC E4M and HPMC E50 cross 80 mesh sieves, and ditropan XL is dissolved in and forms the ditropan XL alcoholic solution in 30% recipe quantity dehydrated alcohol, and NaOH is mixed with the NaOH solution of 5mol/L with purified water, standby; Get appropriate purified water, HPMC E4M and HPMC E50 are added to the water, make it be swelled into uniform colloid, the dehydrated alcohol and the ditropan XL alcoholic solution that under agitation add respectively glycerol, 70% recipe quantity, after mix homogeneously, add NaOH solution to regulate pH value to 5.6, replenish residue prescription water gaging to 100 g, after stirring, packing and get final product.
Embodiment 6
The present embodiment is that HPMC E4M content is the preparation of 0.5% ditropan XL gel:
| Prescription forms | Recipe quantity |
| Ditropan XL | 10g |
| Dehydrated alcohol | 70g |
| HPMC E4M | 0.5g |
| Glycerol | 2g |
| Sodium hydroxide | In right amount |
| Purified water | Add to 100g |
Preparation method:
HPMC E4M crosses 80 mesh sieves, and ditropan XL is dissolved in and forms the ditropan XL alcoholic solution in 30% recipe quantity dehydrated alcohol, and NaOH is mixed with the NaOH solution of 5mol/L with purified water, standby; Get appropriate purified water, HPMC E4M is added to the water, make it be swelled into uniform colloid, the dehydrated alcohol and the ditropan XL alcoholic solution that under agitation add respectively glycerol, 70% recipe quantity, after mix homogeneously, add NaOH solution to regulate pH value to 5.6, replenish residue prescription water gaging to 100 g, after stirring, packing and get final product.
Embodiment 7
The present embodiment is that HPMC E4M content is the preparation of 5% ditropan XL gel:
| Prescription forms | Recipe quantity |
| Ditropan XL | 10g |
| Dehydrated alcohol | 70g |
| HPMC E4M | 5g |
| Glycerol | 2g |
| Sodium hydroxide | In right amount |
| Purified water | Add to 100g |
Preparation method:
HPMC E4M crosses 80 mesh sieves, and ditropan XL is dissolved in and forms the ditropan XL alcoholic solution in 30% recipe quantity dehydrated alcohol, and NaOH is mixed with the NaOH solution of 5mol/L with purified water, standby; Get appropriate purified water, HPMC E4M is added to the water, make it be swelled into uniform colloid, the dehydrated alcohol and the ditropan XL alcoholic solution that under agitation add respectively glycerol, 70% recipe quantity, after mix homogeneously, add NaOH solution to regulate pH value to 5.6, replenish residue prescription water gaging to 100 g, after stirring, packing and get final product.
Embodiment 8
The present embodiment is that glycerol content is the preparation of 1% ditropan XL gel:
| Prescription forms | Recipe quantity |
| Ditropan XL | 10g |
| Dehydrated alcohol | 70g |
| HPMC E4M | 3.0g |
| Glycerol | 1g |
| Sodium hydroxide | In right amount |
| Purified water | Add to 100g |
Preparation method:
HPMC E4M crosses 80 mesh sieves, and ditropan XL is dissolved in and forms the ditropan XL alcoholic solution in 30% recipe quantity dehydrated alcohol, and NaOH is mixed with the NaOH solution of 5mol/L with purified water, standby; Get appropriate purified water, HPMC E4M is added to the water, make it be swelled into uniform colloid, the dehydrated alcohol and the ditropan XL alcoholic solution that under agitation add respectively glycerol, 70% recipe quantity, after mix homogeneously, add NaOH solution to regulate pH value to 5.6, replenish residue prescription water gaging to 100 g, after stirring, packing and get final product.
Embodiment 9
The present embodiment is that glycerol content is the preparation of 20% ditropan XL gel:
| Prescription forms | Recipe quantity |
| Ditropan XL | 10g |
| Dehydrated alcohol | 50g |
| HPMC E4M | 1.5g |
| Glycerol | 20g |
| Sodium hydroxide | In right amount |
| Purified water | Add to 100g |
Preparation method:
HPMC E4M crosses 80 mesh sieves, and ditropan XL is dissolved in and forms the ditropan XL alcoholic solution in 30% recipe quantity dehydrated alcohol, and NaOH is mixed with the NaOH solution of 5mol/L with purified water, standby; Get appropriate purified water, HPMC E4M is added to the water, make it be swelled into uniform colloid, the dehydrated alcohol and the ditropan XL alcoholic solution that under agitation add respectively glycerol, 70% recipe quantity, after mix homogeneously, add NaOH solution to regulate pH value to 5.6, replenish residue prescription water gaging to 100 g, after stirring, packing and get final product.
The present embodiment is that ethanol content is the preparation of 50% ditropan XL gel:
| Prescription forms | Recipe quantity |
| Ditropan XL | 10g |
| Dehydrated alcohol | 50g |
| HPMC E4M | 1.5g |
| Glycerol | 2g |
| Sodium hydroxide | In right amount |
| Purified water | Add to 100g |
Preparation method:
HPMC E4M crosses 80 mesh sieves, and ditropan XL is dissolved in and forms the ditropan XL alcoholic solution in 30% recipe quantity dehydrated alcohol, and NaOH is mixed with the NaOH solution of 5mol/L with purified water, standby; Get appropriate purified water, HPMC E4M is added to the water, make it be swelled into uniform colloid, the dehydrated alcohol and the ditropan XL alcoholic solution that under agitation add respectively glycerol, 70% recipe quantity, after mix homogeneously, add NaOH solution to regulate pH value to 5.6, replenish residue prescription water gaging to 100 g, after stirring, packing and get final product.
Embodiment 11
The present embodiment is that ethanol content is the preparation of 80% ditropan XL gel:
| Prescription forms | Recipe quantity |
| Ditropan XL | 10g |
| Dehydrated alcohol | 80g |
| HPMC E4M | 1.5g |
| Glycerol | 2g |
| Sodium hydroxide | In right amount |
| Purified water | Add to 100g |
Preparation method:
HPMC E4M crosses 80 mesh sieves, and ditropan XL is dissolved in and forms the ditropan XL alcoholic solution in 30% recipe quantity dehydrated alcohol, and NaOH is mixed with the NaOH solution of 5mol/L with purified water, standby; Get appropriate purified water, HPMC E4M is added to the water, make it be swelled into uniform colloid, the dehydrated alcohol and the ditropan XL alcoholic solution that under agitation add respectively glycerol, 70% recipe quantity, after mix homogeneously, add NaOH solution to regulate pH value to 5.6, replenish residue prescription water gaging to 100 g, after stirring, packing and get final product.
The present embodiment is that pH value is the preparation of 5.0 ditropan XL gel:
| Prescription forms | Recipe quantity |
| Ditropan XL | 10g |
| Dehydrated alcohol | 70g |
| HPMC E4M | 1.5g |
| Glycerol | 2g |
| Sodium hydroxide | In right amount |
| Purified water | Add to 100g |
Preparation method:
HPMC E4M crosses 80 mesh sieves, and ditropan XL is dissolved in and forms the ditropan XL alcoholic solution in 30% recipe quantity dehydrated alcohol, and NaOH is mixed with the NaOH solution of 5mol/L with purified water, standby; Get appropriate purified water, HPMC E4M is added to the water, make it be swelled into uniform colloid, the dehydrated alcohol and the ditropan XL alcoholic solution that under agitation add respectively glycerol, 70% recipe quantity, after mix homogeneously, add NaOH solution to regulate pH value to 5.0, replenish residue prescription water gaging to 100 g, after stirring, packing and get final product.
Embodiment 13
The present embodiment is that pH value is the preparation of 8.0 ditropan XL gel:
| Prescription forms | Recipe quantity |
| Ditropan XL | 10g |
| Dehydrated alcohol | 70g |
| HPMC E4M | 1.5g |
| Glycerol | 2g |
| Sodium hydroxide | In right amount |
| Purified water | Add to 100g |
Preparation method:
HPMC E4M crosses 80 mesh sieves, and ditropan XL is dissolved in and forms the ditropan XL alcoholic solution in 30% recipe quantity dehydrated alcohol, and NaOH is mixed with the NaOH solution of 5mol/L with purified water, standby; Get appropriate purified water, HPMC E4M is added to the water, make it be swelled into uniform colloid, the dehydrated alcohol and the ditropan XL alcoholic solution that under agitation add respectively glycerol, 70% recipe quantity, after mix homogeneously, add NaOH solution to regulate pH value to 8.0, replenish residue prescription water gaging to 100 g, after stirring, packing and get final product.
The comparative example 1
This comparative example prepares the oxibutynin gel with reference to the disclosed gel prescription of CN1708269 and preparation technology take HPC as gel-type vehicle:
| Prescription forms | Recipe quantity |
| Oxibutynin | 1g |
| Dehydrated alcohol | 34g |
| HPC | 1g |
| Glycerol | 5g |
| Glyceryl monooleate | 1g |
| Sodium hydroxide | In right amount |
| Purified water | Add to 100g |
Preparation method: NaOH is mixed with the solution of 5mol/L with purified water, standby; Adopt purified water, glycerol and glyceryl monooleate dilution 95% ethanol, the percentage ratio that obtains ethanol/water/glycerol/glyceryl monooleate is 35/59/5/1 final solution.Then the oxibutynin free alkali is dissolved in above-mentioned solution, to concentration be 10mg/g (milligram/gram).Then adopt 1% hydroxypropyl cellulose to carry out gelation to the solution that obtains and process, after regulating pH value to 5.6 with NaOH solution, replenish residue recipe quantity purified water, after mix homogeneously, packing and get final product.
The comparative example 2
This comparative example is with reference to the disclosed gel of CN1708269 prescription and preparation technology, prepares drug content take HPC as gel-type vehicle and calculates by ditropan XL as 10%() the oxibutynin gel:
| Prescription forms | Recipe quantity |
| Oxibutynin | 9.07g(be equivalent to ditropan XL 10g) |
| Dehydrated alcohol | 70g |
| HPC | 1g |
| Glycerol | 5g |
| Glyceryl monooleate | 1g |
| Sodium hydroxide | In right amount |
| Purified water | Add to 100g |
Preparation method: NaOH is mixed with the solution of 5mol/L with purified water, standby; Adopt purified water, glycerol and glyceryl monooleate dilution 95% ethanol, the percentage ratio that obtains ethanol/water/glycerol/glyceryl monooleate is 35/59/5/1 final solution.Then the oxibutynin free alkali is dissolved in above-mentioned solution, to oxibutynin concentration be 10mg/g (milligram/gram).Then adopt 1% hydroxypropyl cellulose to carry out gelation to the solution that obtains and process, after regulating pH value to 5.6 with NaOH solution, replenish residue recipe quantity purified water, after mix homogeneously, packing and get final product.
The comparative example 3
This comparative example is the preparation of the ditropan XL gel take polyvidone (PVPk30) as gel:
| Prescription forms | Recipe quantity |
| Ditropan XL | 10g |
| Dehydrated alcohol | 70g |
| PVPk30 | 1.5g |
| Glycerol | 2g |
| Sodium hydroxide | In right amount |
| Purified water | Add to 100g |
Preparation method: PVPk30 crosses 80 mesh sieves, and ditropan XL is dissolved in 30% recipe quantity dehydrated alcohol, and NaOH is mixed with the solution of 5mol/L with purified water, standby; Get appropriate purified water, PVPk30 is added to the water, make it be swelled into uniform colloid, the 30% recipe quantity alcoholic solution that under agitation adds respectively glycerol, 70% recipe quantity dehydrated alcohol and ditropan XL, after mix homogeneously, add NaOH solution to regulate pH value to 5.6, replenish residue prescription water gaging, after stirring, packing and get final product.
The comparative example 4
This comparative example prepares the ditropan XL gel with reference to the disclosed embodiment 2 of CN101564377 take carbomer as gel-type vehicle:
| Prescription forms | Recipe quantity |
| Ditropan XL | 10g |
| Carbomer 934 | 0.5g |
| Butanediol | 10g |
| Ethanol | 3.2g |
| Methyl parahydroxybenzoate | 0.1g |
| Propyl p-hydroxybenzoate | 0.05g |
| Triethanolamine | In right amount |
| Purified water | Add to 100g |
Preparation method: get carbomer and add the purified water swelling, regulate pH value to 5.6 with triethanolamine and get substrate; Get ditropan XL, butanediol, ethanol, methyl parahydroxybenzoate, propyl p-hydroxybenzoate and residue recipe quantity purified water dissolved substance solution; Drug solution is sneaked in substrate, after stirring, regulate pH value to 5.6 with triethanolamine, after stirring, packing and get final product.
The comparative example 5
This comparative example prepares drug content and is 10% with reference to the disclosed embodiment 2 of CN101564377 take carbomer as gel-type vehicle, ethanol content is 70% ditropan XL gel:
| Prescription forms | Recipe quantity |
| Ditropan XL | 10g |
| Carbomer 934 | 0.5g |
| Butanediol | 10g |
| Ethanol | 70g |
| Methyl parahydroxybenzoate | 0.1g |
| Propyl p-hydroxybenzoate | 0.05g |
| Triethanolamine | In right amount |
| Purified water | Add to 100g |
Preparation method: get carbomer and add the purified water swelling, regulate pH value to 5.6 with triethanolamine and get substrate; Get ditropan XL, butanediol, ethanol, methyl parahydroxybenzoate, propyl p-hydroxybenzoate and residue recipe quantity purified water dissolved substance solution; Drug solution is sneaked in substrate, after stirring, regulate pH value to 5.6 with triethanolamine, after stirring, packing and get final product.
In-vitro percutaneous penetrating test
Test 1
The in-vitro percutaneous penetrating comparative study of ditropan XL gel in embodiment 2 and comparative example 1,2,3,4 and 5.
The ditropan XL gel of tested medicine: embodiment 2 and comparative example 1,2,3,4 and 5 preparations.
Study subject: rat
Method:
1 animal skin is processed
Healthy rat is put to death, removes belly wool, peel off immediately skin of abdomen, remove subcutaneus adipose tissue and the glutinous tissue that connects, after cleaning with the normal saline of 1% benzalkonium bromide, sealing preserve and-20 ℃ of refrigerators in, standby.
In-vitro percutaneous penetrating experimental condition
Receiver media phosphate buffer (pH=4.5)
Medium volume 7mL
Rotating speed 200r/min
37 ℃ of temperature
3 in-vitro percutaneous penetrating tests
Get embodiment 2, the comparative example 1,2,3,4 and 5 samples, take respectively approximately 25mg, evenly coat keratodermatitis, add receiver media, fixture, record the setting-out time, in the sampling of setting-up time point, get approximately 1ml subsequent filtrate detection, and replenish immediately the blank receiver media of equal volume.
The mensuration of receiver media Chinese medicine content
Adopt the HPLC method to measure the content of ditropan XL, chromatographic condition is: chromatographic column: octadecylsilane chemically bonded silica is filler (Crest Premium ODS) (150 * 4.6mm, 5 μ m), detect wavelength: 210nm, flow velocity: 1.0ml/min, mobile phase: the 0.02mol/L potassium phosphate buffer (is got and is added biphosphate potassium 2.72g, add water and make in right amount dissolving, precision adds triethylamine 4ml, add water and make into 1000ml, shake up, transfer pH to 3.0 with phosphoric acid)-acetonitrile (62:38), sample size: 10 μ l; Be calculated as follows accumulation transdermal amount: Q=(C
i* V+C
i-1* V
i)/A is calculated as follows accumulation transdermal percentage rate: the x%=Q/ labelled amount.Q in formula: drug per unit area accumulation transit dose, C
i: the drug level during the i sub-sampling in accepting medium, V: receiving chamber volume, V
i: each sample volume, A: the effective infiltrating area of diffusion cell.
Result of the test
The in-vitro percutaneous penetrating result of the test of each batch sample sees Table 1
The in-vitro percutaneous penetrating comparative test result of table 1 (penetrating percentage rate X%)
| Time (hour) | 2 | 4 | 8 | 12 | 24 |
| Embodiment 2 | 2.54 | 6.54 | 13.12 | 18.89 | 32.33 |
| The comparative example 1 | 0.79 | 2.12 | 4.81 | 7.07 | 11.82 |
| The comparative example 2 | 0.53 | 1.93 | 5.03 | 7.81 | 14.49 |
| The comparative example 3 | 0.70 | 1.92 | 4.71 | 7.06 | 12.77 |
| The comparative example 4 | 0.13 | 0.52 | 1.37 | 2.56 | 4.62 |
| The comparative example 5 | 0.37 | 1.45 | 3.72 | 5.83 | 10.64 |
As shown in Table 1, press the sample of embodiment 2 preparations, its penetrating percentage rate of cumulative in vitro percutaneous of 24 hours is apparently higher than the sample by comparative example 1,2,3,4,5 preparations, be the sample of the preparation take HPMC E4M as host material, its penetrating percentage rate of cumulative in vitro percutaneous of 24 hours is apparently higher than reference CN1708269, CN101564377, with the sample of HPC, PVPk30 or carbomer preparation.
Test 2
The in-vitro percutaneous penetrating comparative study that embodiment 2 and embodiment 2 place 6 months samples.
Tested medicine: embodiment 2 and embodiment 2 place 6 months (accelerating to investigate 6 months) samples at 30 ± 2 ℃ under RH65 ± 5% condition.
Study subject: rat
Method:
1 animal skin is processed
Healthy rat is put to death, removes belly wool, peel off immediately skin of abdomen, remove subcutaneus adipose tissue and the glutinous tissue that connects, after cleaning with the normal saline of 1% benzalkonium bromide, sealing preserve and-20 ℃ of refrigerators in, standby.
In-vitro percutaneous penetrating experimental condition
Receiver media phosphate buffer (pH=4.5)
Medium volume 7mL
Rotating speed 200r/min
37 ℃ of temperature
3 in-vitro percutaneous penetrating tests
Get embodiment 2 and embodiment 2 at 30 ± 2 ℃, place 6 months (accelerating to investigate 6 months) samples under RH65 ± 5% condition, take respectively 25mg, evenly coat keratodermatitis, add receiver media, fixture, record the setting-out time, in the sampling of setting-up time point, get the 1ml subsequent filtrate and detect, and replenish immediately the blank receiver media of equal volume.
The mensuration of receiver media Chinese medicine content
Adopt the HPLC method to measure the content of ditropan XL, chromatographic condition is: chromatographic column: octadecylsilane chemically bonded silica is filler (Crest Premium ODS) (150 * 4.6mm, 5 μ m), detect wavelength: 210nm, flow velocity: 1.0ml/min, mobile phase: the 0.02mol/L potassium phosphate buffer (is got and is added biphosphate potassium 2.72g, add water and make in right amount dissolving, precision adds triethylamine 4ml, add water and make into 1000ml, shake up, transfer pH to 3.0 with phosphoric acid)-acetonitrile (62:38), sample size: 10 μ l; Be calculated as follows accumulation transdermal amount: Q=(C
i* V+C
i-1* V
i)/A is calculated as follows accumulation transdermal percentage rate: the x%=Q/ labelled amount.Q in formula: drug per unit area accumulation transit dose, C
i: the drug level during the i sub-sampling in accepting medium, V: receiving chamber volume, V
i: each sample volume, A: the effective infiltrating area of diffusion cell.
Result of the test
The in-vitro percutaneous penetrating result of the test of each batch sample sees Table 2.
The in-vitro percutaneous penetrating comparative test result of table 2 (penetrating percentage rate X%)
| Time (hour) | 2 | 4 | 8 | 12 | 24 |
| Embodiment 2 | 2.54 | 6.54 | 13.12 | 18.89 | 32.33 |
| Embodiment 2 accelerates June | 1.91 | 5.21 | 12.67 | 19.65 | 32.51 |
As shown in Table 2, press the sample of embodiment 2 preparations, after accelerating to investigate 6 months, its penetrating percentage rate of cumulative in vitro percutaneous of 24 hours is without significant change; Embodiment 2 and embodiment 2 are at 30 ± 2 ℃, place 6 months (accelerating to investigate 6 months) samples under RH65 ± 5% condition, be the sample of identical formula preparation, after accelerating to investigate 6 months, its penetrating percentage rate of cumulative in vitro percutaneous of 24 hours was compared without significant change with 0 month, showed that the gel stability that the present invention prepares is good.
The physical behavior contrast test
Test 3
Each embodiment and comparative example's ditropan XL gel physical behavior comparative study
Tested medicine: the ditropan XL gel of each embodiment and comparative example's preparation
Method:
Get the ditropan XL gel of each embodiment and comparative example preparation, observe outward appearance, mobility, and get appropriate sample, according to viscosimetry (2010 editions two appendix VI G the second methods of Chinese Pharmacopoeia), adopt NDJ-1 type Rotary Viscosimeter (Shanghai Ping Xuan scientific instrument company limited), with No. 3 rotors, rotating speed is per minute 12 to turn, and measures dynamic viscosity in the time of 20 ℃, the results are shown in Table 3.
Table 3 viscosity comparative test result
| Sample | Outward appearance | Mobility | Viscosity (mPas) |
| Embodiment 1 | Evenly, clear gel | Well | 4800 |
| Embodiment 2 | Evenly, clear gel | Well | 5020 |
| Embodiment 3 | Evenly, clear gel | Well | 4850 |
| Embodiment 4 | Evenly, clear gel | Well | 4925 |
| |
Evenly, clear gel | Well | 5200 |
| Embodiment 6 | Evenly, clear gel | Well | 2150 |
| Embodiment 7 | Evenly, clear gel | Well | 8400 |
| The comparative example 1 | Evenly, clear gel | Generally | 25500 |
| The comparative example 2 | There are little agglomerate, clear gel in the part | Generally | 10800 |
| The comparative example 3 | Evenly, clear gel | Generally | 30500 |
| The comparative example 4 | Evenly, clear gel | Well | 27000 |
| The comparative example 5 | Evenly, clear gel | Well | 9000 |
As shown in Table 3, the ditropan XL gel viscosity of embodiment 2 is starkly lower than comparative example 1,2,3,4,5 ditropan XL gel.
Test 4
Each embodiment and comparative example's ditropan XL gel and listing sample compliance, zest comparative study
Tested medicine: the ditropan XL gel of each embodiment and comparative example's preparation and listing sample
Study subject: rabbit
Method:
Get the ditropan XL gel of each embodiment and comparative example preparation, be applied in the skin surface that loses hair or feathers and process, investigate compliance and zest, the results are shown in Table 4.
Table 4 transdermal comparative test result
| Sample | Compliance | Zest |
| Embodiment 1 | Well | Nothing |
| Embodiment 2 | Well | Slightly |
| Embodiment 3 | Well | Nothing |
| Embodiment 4 | Well | Slightly |
| |
Well | Slightly |
| Embodiment 6 | Well | Nothing |
| Embodiment 7 | Well | Nothing |
| The comparative example 1 | Foreign body sensation is arranged | Nothing |
| The comparative example 2 | Foreign body sensation is arranged | Slightly |
| The comparative example 3 | Foreign body sensation is arranged | Nothing |
| The comparative example 4 | Foreign body sensation is arranged | Nothing |
| The comparative example 5 | Foreign body sensation is arranged | Slightly |
As shown in Table 4, embodiment and comparative example's ditropan XL gel and listing sample are all without obvious irritation, but the ditropan XL gel compliance of embodiment 2 is significantly better than comparative example 1,2,3,4,5 ditropan XL gel.
Above result of the test shows, the ditropan XL gel of the present invention's preparation, and appearance transparent, evenly, smooth exquisiteness is easy to extend, with rear foreign sense, without obvious skin irritation, drug release is fast, and Transdermal absorption is good, uses compliance splendid, can significantly improve clinical therapeutic efficacy.
Claims (12)
1. oxybutynin transdermal gel, comprise the oxibutynin of 1%-30% or its pharmaceutically acceptable salt, the hydroxypropyl methylcellulose of 0.5%-5%, the wetting agent of 1%-20%, the ethanol of 50%-80%, and water, the pH value of described transdermal gel is 5.0-8.0, described percentage ratio all is weight percentage.
2. oxybutynin transdermal gel according to claim 1, described oxibutynin is ditropan XL.
3. oxybutynin transdermal gel according to claim 1, the percentage by weight of hydroxypropyl methylcellulose is for being 0.5%-3.0%.
4. oxybutynin transdermal gel according to claim 1, further comprise the pH value regulator.
5. oxybutynin transdermal gel according to claim 4, book pH value regulator is sodium hydroxide or triethanolamine, is preferably sodium hydroxide.
6. oxybutynin transdermal gel according to claim 1, the percentage by weight of described wetting agent is 2.0%-5.0%.
7. oxybutynin transdermal gel according to claim 1 and 2, the percentage by weight of oxibutynin or its pharmaceutical salts is 5%-15%.
8. according to claim 1 or 3 described oxybutynin transdermal gels, described hydroxypropyl methylcellulose is hypromellose E4M, hypromellose E50 or their mixture, is preferably hypromellose E4M.
9. according to claim 1 or 6 described oxybutynin transdermal gels, described wetting agent is glycerol or propylene glycol.
10. oxybutynin transdermal gel according to claim 1, the percentage by weight 60%-70% of described ethanol.
11. oxybutynin transdermal gel according to claim 1, described pH value are 5.0-7.0.
12. a method for preparing the arbitrary described oxybutynin transdermal gel of claim 1-11, the method comprises:
A) get the gel matrix material hydroxypropyl methylcellulose, become colloid with complete swelling in purified water;
B) getting the oxibutynin of recipe quantity or its salt is dissolved in and forms the oxibutynin alcoholic solution in appropriate dehydrated alcohol;
C) add wetting agent, dehydrated alcohol, oxibutynin alcoholic solution in step colloid a), stir lower mix homogeneously, form gel;
D) regulate the pH value of gel to 5.0-8.0 with pH adjusting agent triethanolamine or sodium hydroxide;
F) add the purified water of surplus to mix, get oxybutynin transdermal gel.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103908426A (en) * | 2014-03-11 | 2014-07-09 | 江苏远恒药业有限公司 | Oxybutynin hydrochloride transdermal gel formula and preparation method thereof |
| CN103936558A (en) * | 2014-04-25 | 2014-07-23 | 湘潭大学 | Preparation method of ethanol powered gel |
| CN105816853A (en) * | 2015-01-04 | 2016-08-03 | 山东国际生物科技园发展有限公司 | Modified antibacterial peptide and preparation of gel |
| CN111617029A (en) * | 2020-05-31 | 2020-09-04 | 江苏福邦药业有限公司 | Loxoprofen sodium gel and preparation method thereof |
| CN114601789A (en) * | 2022-03-29 | 2022-06-10 | 辽宁方诺生物科技有限公司 | Celecoxib gel and preparation method and application thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050287194A1 (en) * | 2004-05-07 | 2005-12-29 | Arnaud Grenier | Permeation enhancing compositions for anticholinergic agents |
| US20060177510A1 (en) * | 2001-11-06 | 2006-08-10 | Vergez Juan A | Dual controlled release osmotic device |
| CN101564377A (en) * | 2009-04-24 | 2009-10-28 | 杭州锐思医药科技有限公司 | Oxybutynin transdermal gel and the preparation method thereof |
| CN102048678A (en) * | 2009-10-30 | 2011-05-11 | 北京隆旗生物科技有限公司 | Transdermal absorption preparation of oxybutynin as well as preparation method and medication application thereof |
-
2011
- 2011-12-13 CN CN2011104142559A patent/CN103156804A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060177510A1 (en) * | 2001-11-06 | 2006-08-10 | Vergez Juan A | Dual controlled release osmotic device |
| US20050287194A1 (en) * | 2004-05-07 | 2005-12-29 | Arnaud Grenier | Permeation enhancing compositions for anticholinergic agents |
| CN101564377A (en) * | 2009-04-24 | 2009-10-28 | 杭州锐思医药科技有限公司 | Oxybutynin transdermal gel and the preparation method thereof |
| CN102048678A (en) * | 2009-10-30 | 2011-05-11 | 北京隆旗生物科技有限公司 | Transdermal absorption preparation of oxybutynin as well as preparation method and medication application thereof |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103908426A (en) * | 2014-03-11 | 2014-07-09 | 江苏远恒药业有限公司 | Oxybutynin hydrochloride transdermal gel formula and preparation method thereof |
| CN103936558A (en) * | 2014-04-25 | 2014-07-23 | 湘潭大学 | Preparation method of ethanol powered gel |
| CN103936558B (en) * | 2014-04-25 | 2015-12-09 | 湘潭大学 | A kind of preparation method of ethanol powdery gel |
| CN105816853A (en) * | 2015-01-04 | 2016-08-03 | 山东国际生物科技园发展有限公司 | Modified antibacterial peptide and preparation of gel |
| CN111617029A (en) * | 2020-05-31 | 2020-09-04 | 江苏福邦药业有限公司 | Loxoprofen sodium gel and preparation method thereof |
| CN114601789A (en) * | 2022-03-29 | 2022-06-10 | 辽宁方诺生物科技有限公司 | Celecoxib gel and preparation method and application thereof |
| CN114601789B (en) * | 2022-03-29 | 2024-03-26 | 辽宁方诺生物科技有限公司 | Celecoxib gel and preparation method and application thereof |
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