CN101116663A - Percutaneously absorbable preparation for treating male sexual disfunction and method for preparing the same - Google Patents
Percutaneously absorbable preparation for treating male sexual disfunction and method for preparing the same Download PDFInfo
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- CN101116663A CN101116663A CNA2006100296646A CN200610029664A CN101116663A CN 101116663 A CN101116663 A CN 101116663A CN A2006100296646 A CNA2006100296646 A CN A2006100296646A CN 200610029664 A CN200610029664 A CN 200610029664A CN 101116663 A CN101116663 A CN 101116663A
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- papaverine
- sexual disorder
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Abstract
The invention discloses a percutaneous absorption preparation for curing male sexual dysfunction and the preparation method thereof. Calculated on the basis of total weight of the preparation, the composition at least contains 2.5 percent to 5 percent phentolamine mesylate and 2.5 percent to 5 percent papaverine hydrochloride or papaverine. The preparation adopts percutaneous administration method and completes administration through penis and scrotum skin to make phentolamine mesylate, papaverine hydrochloride or papaverine directly act on penis artery and smooth muscle so as to strengthen erection of penis, thereby being capable of effectively curing male sexual dysfunction; meanwhile, the invention avoids toxic and side effects caused by the prior cavernosum injection and oral taking medicinal preparation and is convenient in use, thereby has ideal compliance of patient.
Description
Technical field
The present invention relates to a kind of transdermal absorption formulation that is used for the treatment of male sexual disorder and preparation method thereof.
Background technology
(Erectile dysfunction ED) is meant that penis continues to reach or to keep to obtain satisfied sexual life to male sexual disorder, is the common disease of andrology.The Drug therapy of ED has had the history of decades, at different pathogeny, develops and the different a series of medicines of mechanism of action.Mainly contain the hormone replacement medicine; Oral therapeutic drug such as Phosphodiesterase V inhibitors sldenafil and adrenoceptor antagonists phentolamine; Urethra medicine Alprostadil and penis sponge interior therapeutic medicine Invicorp, papaverine etc.
Brindly in 1985 takes the lead in using phentolamine and adopts penis cavernosa injection mode therapeutic dysfunction.1997, that Geng of U.S.'s rope (Zonagen) company and spirit earlier refined (Schering-Ploug) company of preserving have developed jointly the handicapped phentolamine mesylate oral formulations of a kind of therapeutic, using dosage is 40～60mg, its commodity are called Vasomax, III clinical trial phase result shows that the clinical efficacy of this medicine is compared with placebo has the remarkable meaning of statistics.But because oral administration makes drug effect in whole body, and phentolamine mesylate is non-selective alpha-2-adrenoceptor blocker, therefore a lot of untoward reaction have been brought, mainly contain postural hypotension, tachycardia and vomiting etc., severe patient can cause priapism because of dosage is excessive, even sudden death.
Nineteen eighty-two Virag takes the lead in adopting the penis cavernosa injection mode to treat male sexual disorder with papaverine, and effective percentage is noticeable up to 68% in 125 routine ED patients.Application dose should be according to the size of the difference of the cause of disease and penis and is decided, for reducing complication, adopt constant dosage 30mg, but as undesirable escalated dose to 60～80mg, but its main adverse reaction is penile pain, fibrosis and priapism, and papaverine causes spongy body fibrosis incidence rate more than 5%.
Therefore no matter be that hormone replacement medicine, oral drugs, intracavernous injection medicine all exist certain defective.Long term injections hormone replacement medicine can cause patient's physiological metabolism to produce serious adverse effects.Oral therapeutic drug is owing to be the general administration, and the dosage of medicine is big, and toxic and side effects is obvious, uses and tends to produce headache, hypertension behind the medicine, feels sick, vomiting, priapism even cause sudden death.Intracavernous injection Drug therapy administration inconvenience, there is pain the injection site, and domestic patient generally can not accept this occupation mode, and life-time service can make injection point tissue injury and cause fibrosis.
Therefore, the pharmaceutical preparation of seeking the treatment male sexual disorder of a kind of determined curative effect, safe in utilization, convenient drug administration is the main contents that the present invention need solve.
Summary of the invention
The technical issues that need to address of the present invention are to disclose a kind of drug transdermal absorbable preparation for the treatment of male sexual disorder, to overcome the shortcoming that existing pharmaceutical preparation exists.
The preparation method that a kind of this drug transdermal absorbable preparation is provided is another technical problem that the present invention need solve.
Inventive concept of the present invention is such:
Phentolamine mesylate, chemical name is: 3-{[(4,5-dihydro-1H-imidazoles-2-yl) methyl] (4-tolyl) amino } the phenol mesylate.Molecular formula: C
17H
19N
3OCH
4O
3S molecular weight: 377.46.Belonging to the imidazolines medicine, is a kind of low selectivity alpha-2-adrenoceptor blocking agent, α capable of blocking
1And α
2Receptor, suppress the α sample effect of epinephrine and norepinephrine, sympathetic nerve (adrenergic nerve) tension force is reduced, cause arteria penis and smooth muscle expansion (being that smooth muscle tone reduces), the cavernous sinus blood flow is increased, tunica albuginea smooth muscle pressurized, the retardance venous return, thus make erection.
Papaverin hydrochloride, chemical name is: 1-[(3,4-Dimethoxyphenyl) methyl]-6,7-dimethoxy-isoquinoline hydrochlorate.Molecular formula: C
20H
21NO
4HCl molecular weight: 375.85.Be vascular smooth muscle relaxant, increase the concentration of cAMP in the cell, promote the smooth muscle loosening in penis small artery and blood sinus crack, cause erection by activated adenyl cyclase.
Use phentolamine mesylate treatment ED can not make the patient reach enough erections separately, through verification experimental verification, it is the compound recipe component that the present invention selects with phentolamine mesylate and papaverin hydrochloride or papaverine, because phentolamine has the different mechanism of action with papaverin hydrochloride or papaverine to arteria penis and smooth muscle, two components produce synergism, curative effect strengthens, and effect is remarkable.This preparation capable of permeating skin is easy to use, the patient can medication or interruption of the administration voluntarily at any time on penis and skin of scrotum, patient dependence is greatly improved, and overcome fibrosis and priapism that general untoward reaction that oral formulations such as phentolamine mesylate cause and corpus cavernosum injection agent such as papaverin hydrochloride or papaverine cause, untoward reaction reduces greatly.
The component of the transdermal absorption formulation of treatment male sexual disorder of the present invention and weight concentration are:
Phentolamine mesylate 2.5-5%, papaverin hydrochloride or papaverine 2.5-5%, Percutaneous absorption enhancer 1-10%, wetting agent 5-20%, gel-type vehicle 0.5-10%, solvent surplus;
The Percutaneous absorption enhancer of being addressed is selected from one or more in azone, pyrrolidone, sodium laurylsulfate, oleic acid, Mentholum, menthol, Oleum menthae, Borneolum Syntheticum, Rhizoma Chuanxiong, Elettaria cardamomum (L.) Maton, cinnamyl alcohol or the eucalyptus oil.It mainly acts on is the cuticular diffusional resistance of modulation, quickens drug osmotic and passes skin.
The wetting agent of being addressed be selected from glycerol, propylene glycol and or Polyethylene Glycol in a kind of, can reduce the volatilization of moisture in the gel-type vehicle, in use make horny layer keep moistening.
The gel-type vehicle of being addressed is selected from one or more in natural gum, hydroxypropyl cellulose, carbopol, sodium carboxymethyl cellulose, polyvinylpyrrolidone, sodium alginate, methylcellulose, hydroxypropyl methylcellulose, polyvinyl alcohol or the chitosan.The formed macromolecule network of gel-type vehicle has certain compliance, demonstrates flexibility and viscoelastic semi-solid property, utilizes the release of its character control medicine, carries out transdermal administration by its adhesiveness to skin.
The solvent of being addressed is a kind of in ethanol-water system or the isopropyl alcohol-aqueous systems, and volume ratio is 1: 9～5: 5.
The preparation method of the drug transdermal absorbable preparation of being addressed comprises the steps:
1. take by weighing phentolamine mesylate, papaverin hydrochloride or papaverine according to the above ratio, add in the dicyandiamide solution and dissolve.
2. in above-mentioned dicyandiamide solution, add wetting agent, Percutaneous absorption enhancer successively, stir it is uniformly dispersed, add gel-type vehicle, swelling, make after stirring evenly.
The transdermal administration mode is adopted in the pharmaceutical preparation that the present invention makes, through penis, skin of scrotum administration, make phentolamine mesylate and papaverin hydrochloride or papaverine can directly act on arteria penis and smooth muscle, impel erection, effectively treat male sexual disorder, avoided corpus cavernosum injection, the caused toxic and side effects of oral formulations simultaneously, easy to use, patient dependence is good.
The specific embodiment
Embodiment 1
The preparation of drug transdermal absorbable preparation
In isopropyl alcohol-water (40: 60, volume ratio) adds the papaverin hydrochloride of isopropyl alcohol-water gross weight 3% and the phentolamine mesylate of isopropyl alcohol-water gross weight 5% in, dissolving, add the glycerol of isopropyl alcohol-water gross weight 10%, the azone of isopropyl alcohol-water gross weight 2% successively, the hydroxypropyl methylcellulose that adds isopropyl alcohol-water gross weight 1% after being uniformly dispersed, swelling stirs evenly and makes drug transdermal absorption gel.
Embodiment 2
The preparation of drug transdermal absorbable preparation
Add the papaverin hydrochloride of isopropyl alcohol-water gross weight 5% and the phentolamine mesylate of isopropyl alcohol-water gross weight 2.5% in dicyandiamide solution isopropyl alcohol-water (30: 70), dissolving, add the Polyethylene Glycol of isopropyl alcohol-water gross weight 8%, the Oleum menthae of isopropyl alcohol-water gross weight 2% successively, add 5% sodium alginate after being uniformly dispersed, swelling stirs evenly and makes drug transdermal absorption gel.
Embodiment 3
The preparation of drug transdermal absorbable preparation
Add the papaverin hydrochloride of isopropyl alcohol-water gross weight 5% and the phentolamine mesylate of isopropyl alcohol-water gross weight 5% in the dicyandiamide solution alcohol-water (30: 70), dissolving, add the propylene glycol of isopropyl alcohol-water gross weight 10%, the oleic acid of isopropyl alcohol-water gross weight 10% successively, the hydroxypropyl methylcellulose that adds isopropyl alcohol-water gross weight 2% after being uniformly dispersed, swelling stirs evenly and makes drug transdermal absorption gel.
Embodiment 4
The nude mouse skin test of passing through inside is tested
Test model: nude mice (about 8 week ages), peel off skin of back immediately after drawing neck to put to death, carefully reject subcutaneous fat and adhesion thing, clean with normal saline, wipe away do standby.
Test method: adopt vertical Franz diffusion cell, with the smooth joint portion that places diffusion cell of skin, stratum corneum side is to supply pool, and skin corium is towards accepting the pond, 37 ℃ of constant temperature, and accepting medium is water, ultrasonic degas before using.Investigated gel preparation.Stirrer rotating speed 300r min
-1, carry out HPLC from accepting to take a sample in the pond after 1 hour and analyze.
Experimental result is as shown in table 1, is compound percutaneous gel, 1 hour papaverine and the phentolamine cumulative in vitro transit dose maximum of dicyandiamide solution preparation with isopropyl alcohol-water.
Table 1 transdermal test in vitro result of the test
| The preparation capable of permeating skin of different solvents system | Phentolamine 1h skin accumulation infiltration capacity/μ g cm -2 | Papaverine 1h skin accumulation infiltration capacity/μ gcm -2 |
| Water-ethanol-water isopropyl alcohol-water | 3.87 131.69 248.53 | 2.34 51.46 99.64 |
Embodiment 5
Pharmacodynamics test in the body
Animal model: emasculated male SD rat (250-300g)
Experimental technique: the SD rat lain on the back to be fixed on the plank, fasten trunk with belt, with the Transdermal absorption gel coating of preparation in the penis place and near, observe the physiological reaction of administration about 1 hour, be contrast with the preparation capable of permeating skin that only contains phentolamine or papaverine.
Table 2SD rat is in the body results of pharmacodynamic test
| Stiffening effect | - | + | ++ |
No physiological reaction is represented with "-"; Physiological reaction is strong and weak to be used "+, ++, +++" expression
Result of the test shows that the preparation capable of permeating skin administration that only contains phentolamine or papaverine is after 1 hour, and emasculated male SD rat penis has certain reaction that swells, but not stiffening; With phentolamine and papaverine is that the transdermal absorption formulation that the compound recipe component is prepared has significantly swell effect and stiffening effect, and does not have tangible untoward reaction.
Claims (7)
1. a transdermal absorption formulation for the treatment of male sexual disorder is characterized in that, the gross weight in preparation comprises in the component at least: phentolamine mesylate 2.5-5%, papaverin hydrochloride or papaverine 2.5-5%.
2. the transdermal absorption formulation of treatment male sexual disorder according to claim 1 is characterized in that, the gross weight in preparation also comprises, Percutaneous absorption enhancer 1-10%, wetting agent 5-20%, gel-type vehicle 0.5-10%, solvent surplus.
3. the transdermal absorption formulation of treatment male sexual disorder according to claim 2, it is characterized in that the Percutaneous absorption enhancer of being addressed is selected from one or more in azone, pyrrolidone, sodium laurylsulfate, oleic acid, Mentholum, menthol, Oleum menthae, Borneolum Syntheticum, Rhizoma Chuanxiong, Elettaria cardamomum (L.) Maton, cinnamyl alcohol or the eucalyptus oil.
4. the transdermal absorption formulation of treatment male sexual disorder according to claim 2 is characterized in that, the wetting agent of being addressed be selected from glycerol, propylene glycol and or Polyethylene Glycol in a kind of.
5. the transdermal absorption formulation of treatment male sexual disorder according to claim 2, it is characterized in that the gel-type vehicle of being addressed is selected from one or more in natural gum, hydroxypropyl cellulose, carbopol, sodium carboxymethyl cellulose, polyvinylpyrrolidone, sodium alginate, methylcellulose, hydroxypropyl methylcellulose, polyvinyl alcohol or the chitosan.
6. the transdermal absorption formulation of treatment male sexual disorder according to claim 2 is characterized in that, the solvent of being addressed is a kind of in ethanol-water system or the isopropyl alcohol-aqueous systems, and volume ratio is 1: 9～5: 5.
7. according to the preparation method of the transdermal absorption formulation of each described treatment male sexual disorder of claim 1～6, it is characterized in that, comprise the steps: to take by weighing according to the above ratio phentolamine mesylate, papaverin hydrochloride or papaverine, add in the dicyandiamide solution and dissolve, in above-mentioned dicyandiamide solution, add wetting agent, Percutaneous absorption enhancer successively, stirring is uniformly dispersed it, adds gel-type vehicle, swelling, makes after stirring evenly.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006100296646A CN101116663A (en) | 2006-08-02 | 2006-08-02 | Percutaneously absorbable preparation for treating male sexual disfunction and method for preparing the same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006100296646A CN101116663A (en) | 2006-08-02 | 2006-08-02 | Percutaneously absorbable preparation for treating male sexual disfunction and method for preparing the same |
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| Publication Number | Publication Date |
|---|---|
| CN101116663A true CN101116663A (en) | 2008-02-06 |
Family
ID=39053020
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006100296646A Pending CN101116663A (en) | 2006-08-02 | 2006-08-02 | Percutaneously absorbable preparation for treating male sexual disfunction and method for preparing the same |
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|---|---|
| CN (1) | CN101116663A (en) |
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2006
- 2006-08-02 CN CNA2006100296646A patent/CN101116663A/en active Pending
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Open date: 20080206 |