CN101143127A - Phentolamine external-applied preparation and its preparation method - Google Patents
Phentolamine external-applied preparation and its preparation method Download PDFInfo
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- CN101143127A CN101143127A CNA2007100474347A CN200710047434A CN101143127A CN 101143127 A CN101143127 A CN 101143127A CN A2007100474347 A CNA2007100474347 A CN A2007100474347A CN 200710047434 A CN200710047434 A CN 200710047434A CN 101143127 A CN101143127 A CN 101143127A
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Abstract
The invention belongs to the western medicine preparation field and concretely relates to an efficient and quick effective external preparation of phentolamine which considers the volatile oil of natural plant and the extracted finished product of the volatile oil of the natural plant as a percutaneous sorbefacient and the preparation method of the external preparation. The invention selects the percutaneous sorbefacient of the natural volatile oil to prepare an external percutaneous preparation of the phentolamine of the invention by considering the phentolamine as the only curative active matter of the preparation and adding the necessary medicinal auxiliary materials. The animal experiment testifies that the invention can keep the drug usability and synchronously reduce the medicament dosage greatly and reduce the side effect to the whole body and the use cost. Compared with the prior art, the preparation can improve the percutaneous absorption of the drug dosage of the phentolamine very obviously and shortens the latent period of effecting, and the preparation has good medicament safety and can provide the patient with more satisfying curative effect.
Description
Technical field
The invention belongs to the Western medicine preparation field, relate to Phentolamine external-applied preparation, be specifically related to a kind of with natural plant volatile oil and to extract highly finished product be efficient, quick-acting Phentolamine external-applied preparations of Percutaneous absorption enhancer and preparation method thereof.
Background technology
(erectile dysfunction ED) is a kind of common, important sexual dysfunction to erection disturbance.The epidemiologic data prompting, the generation of male ED is more general, and exists confidential relation with diseases such as age increase and dyslipidemia, hypertension, coronary artery pathological changes and diabetes.The whole world has 1.52 hundred million male to suffer from ED approximately at present, and along with the human society aging, predicting the whole world in 2025 will have 3.22 hundred million male to be subjected to the puzzlement of this sexual dysfunction.
Phentolamine is non-selective adrenergic blocker, can reduce peripheral vascular resistance, increases the peripheral vessels blood flow.When the treatment male erectile dysfunction, this medicine can act on the α receptor on the erectile tissue, and diastole small artery and blood capillary increase the cavernous body of penis blood supply, promotes and strengthen erection function.The Vasomax (oral of phentolamine mesylate) of U.S. Schering Corp development in the listing of part South American nations, is used for the treatment of male erectile dysfunction.But have certain first pass effect owing to phentolamine is oral, drug effect and bioavailability are subjected to bigger influence; Especially, act on whole body after the drug absorption, can produce relevant side effect, for example nasal obstruction, dizzy, feel sick, vomiting, hypotension, reflex tachycardia, arrhythmia etc.Except that oral administration, the administering mode that phentolamine is commonly used at present also has mouth paster and corpus cavernosum injection.Though mouth paster can to a certain degree be avoided gastrointestinal tract and liver first-pass effect, also belongs to the whole body administration, can't avoid systemic side effects.Adopt the administering mode of corpus cavernosum injection, medicine can directly act on local target tissue, can avoid the side effect of general, but, because the pain and the inconvenience of drug administration by injection, the compliance extreme difference of patient's medication, and side effect such as injection site spongy body fibrosis may take place, be not suitable for repeatedly medication repeatedly.
Phentolamine can be avoided the systemic side effects of medicine and the misery that local injection brought by the partial transdermal administration of genitals, is a kind of desirable medication of development in recent years.But because the particularity of this disease of ED, for the medicine of treatment ED, if make the patient obtain satisfactory therapeutic effects, except guarantee drug safety, effectively, whether can bring into play curative effect fast and just seem very important.But because the barrier action of skin and the physicochemical property of phentolamine, common Percutaneously administrable preparation is difficult to reach satisfactory therapeutic effects, for this reason, needs to add Percutaneous absorption enhancer in the preparation to quicken the speed and the degree of medicine transdermal.At present, the patent of disclosed relevant Phentolamine external-applied preparation comprises: KR20010045152, WO0108659, WO9965303, EP0346297, CA1320442, CN1113757, CN1380061, CN2497789, CN1383820, CN1579390, CN1579392.Prior art is still coming with some shortcomings aspect the dosage form of effectiveness, safety and the preparation of promoter.Patent CN1113757 all adopts propylene glycol as solvent, plays the absorption facilitation simultaneously.Yet the external concentration of propylene glycol generally is no more than 30%, and excessive concentration can produce local excitation and anaphylaxis.All select for use dimethyl sulfoxide (DMSO) as Percutaneous absorption enhancer among patent WO0108659 and the CA1320442, it has stench, and long-term or a large amount of uses can cause the serious zest of skin, even causes hepatic injury and neurotoxicity.The dosage form that patent CN1380061 and CN2497789 adopt is a transdermal patch, and its shortcoming is that production cost is higher, the more important thing is that patch lacks pliability, and its skin with medicine-feeding parts such as penis and scrotum can't closely contact, and influences therapeutic effect to a certain extent; On the other hand, because the use gross area of paster needs 70cm
2, patch still can not be thrown off during use, and user may not accommodate inconvenience, poor compliance because of foreign body sensation causes.Patent CN1383820 has introduced the phentolamine ointment, relative patch, and the ointment medication is comparatively convenient, and coating evenly reduces foreign body sensation, and patient Geng Yi accepts.But identical with CN1380061, two patents have all selected for use laurocapram as Percutaneous absorption enhancer.Though laurocapram is widely used in preparation capable of permeating skin, but its transdermal enhancing effect for phentolamine mesylate is more limited, be not enough to bring into play at short notice the therapeutical effect of medicine, onset time reached more than 45 minutes, was difficult to satisfy the needs of ED patient's quick acting.In addition, patent KR20010045152, WO9965303, EP0346297 and CN1113757 have introduced the compound external-use preparation that contains phentolamine respectively, include the medicine more than 2 kinds, the prescription more complicated.The more important thing is that in above-mentioned patent, phentolamine plays auxiliary treatment, and do not relate to the absorption enhancer problem.In general, the effect and the onset time of phentolamine Percutaneously administrable preparation are still not fully up to expectations at present.Therefore, efficient, the quick-acting Phentolamine external-applied preparation of development has very high potential applicability in clinical practice.
Summary of the invention
The purpose of this invention is to provide a kind of efficient, quick-acting, safe Phentolamine external-applied preparation.Be specifically related to that a kind of to contain natural plant volatile oil and extract highly finished product be Phentolamine external-applied preparation of Percutaneous absorption enhancer and preparation method thereof.Preparation of the present invention is used for the treatment of male erectile dysfunction, efficient, quick-acting, safety.
Phentolamine externally applied transdermal preparation of the present invention, phentolamine by safe and effective amount is active constituents of medicine and Percutaneous absorption enhancer, and necessary adjuvant is formed on the pharmaceutics, wherein, described Percutaneous absorption enhancer be natural plant volatile oil and extract highly finished product or its with pharmaceutics on the associating Percutaneous absorption enhancer of other Percutaneous absorption enhancers of using always, the consumption of described Percutaneous absorption enhancer is 0.1～10% (w/v) or 0.1～10% (v/v); Described active constituents of medicine is phentolamine mesylate, phentolamine hydrochloride or phentolamine free alkali, and in phentolamine mesylate, the concentration of described active constituents of medicine is 0.1～20% (w/v), and preferred concentration is 1～10% (w/v).
The present invention is according to the demand of male ED patient treatment and the physicochemical property of phentolamine, select natural volatile oil Percutaneous absorption enhancer for use, with the phentolamine is active substance unique, the performance therapeutical effect in the preparation, add with medicament and go up necessary adjuvant, prepare externally applied transdermal preparation of the present invention by the conventional method of above-mentioned amount ranges by this area, described preparation is solution-type or emulsion-type spray, varnish, ointment and gel.
Percutaneous absorption enhancer of the present invention can be made up of one or more natural plant volatile oils and highly finished product thereof; It also can be the associating penetration enhancer that penetration enhancer commonly used on volatile oil and highly finished product thereof and other pharmaceuticss is formed.
Natural plant volatile oil of the present invention and highly finished product thereof are selected from: Oleum Eucalypti, Oleum menthae, sweetgum oil, Oleum Terebinthinae, Oleum Caryophylli, Oleum Cinnamomi, cananga oil, Herba Schizonepetae oil, orange blossom oil, Oleum Anisi Stellati, Rhizoma Chuanxiong oil, Oleum Viticis Negundo, Fructus Citri Limoniae oil, Radix Angelicae Sinensis volatile oil, Rhizoma Alpiniae Officinarum oil, menthol, Mentholum, ledum terpenes, Borneolum Syntheticum, d-limonene, eugenol, nerolidol and/or eucalyptol.Preferred Oleum Eucalypti, Oleum menthae, sweetgum oil, Oleum Terebinthinae, Oleum Caryophylli, menthol, Mentholum and/or Borneolum Syntheticum.Its consumption of described natural plant volatile oil and highly finished product thereof be 0.1-10% (v/v, w/v), preferable amount be 1-5% (v/v, w/v).
Described other Percutaneous absorption enhancers are selected from: decyl methyl sulfoxide, laurocapram, N-Methyl pyrrolidone, oleic acid, lauryl alcohol, ethanol, propylene glycol, carbamide, lecithin, sodium lauryl sulphate, one or more in tween or the poloxamer.Wherein the consumption of decyl methyl sulfoxide is 1-5% (v/v), the consumption of laurocapram is 1-10% (v/v), the consumption of N-Methyl pyrrolidone is 0.5-15% (w/v), oleic consumption is 1-15% (v/v), the consumption of lauryl alcohol is 1-15% (v/v), the consumption of ethanol and propylene glycol is 5-20% (v/v), the consumption of carbamide is 1-10% (w/v), the consumption of lecithin is 0.1-5% (w/v), the consumption of sodium lauryl sulphate is 0.5-10% (w/v), the consumption of tween is 0.5-8% (v/v), and the consumption of poloxamer is 0.1-5% (w/v).
Comprising of described tween: tween 20, Tween-40, Tween-60, Tween-65, tween 80, tween 85.
Comprising of described poloxamer: poloxamer-188, poloxamer-407.
Externally applied transdermal preparation of the present invention also contains adjuvant necessary on other pharmaceutics.Wherein, other adjuvant of containing of spray comprises: emulsifying agent, cosolvent, pH regulator agent, wetting agent and/or antiseptic; Other adjuvant that ointment contains comprises: emulsifiable paste matrix adjuvant, antioxidant, pH regulator agent, wetting agent and/or antiseptic; Other adjuvant that gel contains comprises: gel-type vehicle adjuvant, pH regulator agent, wetting agent and/or antiseptic.
Described wetting agent is selected from: glycerol, hyaluronic acid, propylene glycol, one or more in the sorbitol.Wherein, the consumption of glycerol is 5～30% (v/v), and hyaluronic consumption is 1～40% (w/v), and the consumption of propylene glycol is 5～15% (v/v), and the consumption of sorbitol is 5～20% (v/v).By adding wetting agent, keep agents area moistening relatively, for drug transdermal provides advantage.
Externally applied transdermal preparation of the present invention is considered the character of medicine and the physiology acceptability of skin, adds the pH regulator agent to increase stability of drug, reduces skin irritation, and the pH value of preparation is adjusted to 3.5～7.0 scopes.The pH regulator agent of being adopted is selected from: triethanolamine, sodium hydroxide, potassium hydroxide, hydrochloric acid, sulphuric acid, phosphoric acid, one or more in the glacial acetic acid.
Described antiseptic is selected from: methyl hydroxybenzoate, ethyl ester, propyl ester, butyl ester, chlorobutanol, sodium benzoate, sorbic acid, potassium sorbate, calcium sorbate, benzyl alcohol, phenethanol, chlorhexidine acetate, benzalkonium bromide, benzalkonium chloride, thimerosal, o-phenyl phenol, one or more in the chlorocresol.Preparation of the present invention requires antiseptic not influence the physicochemical property of preparation, does not produce or only produce the skin irritation that clinical permission is accepted in scope of restraining fungi.
Emulsifying agent in described spray and the varnish is selected from: sodium stearate, sodium lauryl sulphate, sucrose fatty acid ester, span, tween, carbomer, poloxamer, arabic gum, tragacanth, one or more in the lecithin.Wherein, the consumption of sodium stearate is 1～15% (w/v), the consumption of sodium lauryl sulphate is 0.5～10% (w/v), the consumption of sucrose fatty acid ester is 0.1～2% (w/v), the consumption of span is 0.1～10% (v/v), the consumption of tween is 0.5～8% (v/v), the consumption of carbomer is 0.1～1% (w/v), the consumption of poloxamer is 0.1～5% (w/v), the consumption of arabic gum is 5～15% (w/v), the consumption of tragacanth is 0.1～2% (w/v), and the consumption of lecithin is 0.1～5% (w/v); Sucrose fatty acid ester is selected from Surfhope SE Cosme C 1216, sucrose palmitate; Span is selected from Arlacel-20, Arlacel-40, Arlacel-60, Arlacel-80; Tween is selected from tween 20, Tween-40, Tween-60, Tween-65, tween 80, tween 85; Poloxamer is selected from poloxamer-188, poloxamer-407.Its effect is fully to disperse the oil-soluble composition that adds in the spray, it is disperseed with the emulsion droplet shape and uses.
Cosolvent in described spray and the varnish is selected from: ethanol, propylene glycol, glycerol, one or more in the Polyethylene Glycol.Wherein, consumption of ethanol is 1～50% (v/v), and the consumption of propylene glycol is 5～15% (v/v), and the consumption of glycerol is 5～30% (v/v), and the consumption of Polyethylene Glycol is 1～30% (v/v).Its effect is the dissolubility that increases preparation medium oil soluble components.
Emulsifiable paste matrix in the described ointment comprises: oil phase adjuvant and emulsifying agent.Described oil phase adjuvant is selected from: one or more in white vaseline, Cera Flava, liquid Paraffin, stearyl alcohol, lanoline, stearic acid, hard paraffin, the Oleum Ricini.Wherein, the consumption of white vaseline is 1～30% (w/v), mellisic consumption is 0.5～5% (w/v), the consumption of liquid Paraffin is 4～25% (w/v), the consumption of stearyl alcohol is 2～15% (w/v), and the consumption of lanoline is 3～6% (w/v), and stearic consumption is 10～20% (w/v), the consumption of hard paraffin is 2～10% (w/v), and the consumption of Oleum Ricini is 10～20% (w/v); Described emulsifying agent is selected from: stearic acid, sodium lauryl sulphate, tween, span, hexadecanol, octadecanol, glyceryl monostearate, peregal 0, polyoxyethylene nonylphenol ether.Wherein, stearic consumption is 10～25% (w/v), the consumption of sodium lauryl sulphate is 0.5～2% (w/v), the consumption of tween is 0.5～8% (w/v), the consumption of span is 0.1～10% (w/v), the consumption of hexadecanol is 5～13% (w/v), and the consumption of octadecanol is 5～13% (w/v), and the consumption of glyceryl monostearate is that the consumption of 3～15% (w/v), peregal 0 is that the consumption of 2～5% (w/v), polyoxyethylene nonylphenol ether is 1～5% (v/v).Described span be selected from Arlacel-20, Arlacel-40, Arlacel-60, Arlacel-80; The selection of tween is a tween 20, Tween-40, Tween-60, Tween-65, tween 80, tween 85.
Ointment is in storage, and the oxygen of trace may make some active component oxidation and go bad, and the present invention adds the chemical stability of antioxidant protection ointment.Antioxidant in the described ointment is selected from: vitamin E, ascorbic acid, sodium pyrosulfite, sodium sulfite, sodium sulfite, propyl gallate, cysteine, disodium edetate.Wherein, the consumption of vitamin E is 0.01～0.03% (w/v), the consumption of ascorbic acid is 0.01～0.1% (w/v), the consumption of sodium pyrosulfite is 0.1～0.5% (w/v), the consumption of sodium sulfite is 0.1～0.5% (w/v), and the consumption of sodium sulfite is 0.1% (w/v), and the consumption of propyl gallate is 0.1% (w/v), the consumption of cysteine is 0.01～0.1% (w/v), and the consumption of disodium edetate is 0.01～0.1% (w/v).
Gel-type vehicle adjuvant in the described gel is selected from: carbomer, methylcellulose, sodium carboxymethyl cellulose, hydroxypropyl emthylcellulose.Wherein, the consumption of carbomer is 0.5～3% (w/v), and the consumption of methylcellulose is 2～6% (w/v), and the consumption of sodium carboxymethyl cellulose is 2～6% (w/v), and the consumption of hydroxypropyl emthylcellulose is 2～10% (w/v).Described carbomer is selected from carbomer 934, Acritamer 940, Carbopol 941.
The using method of external preparation of the present invention is: use the phentolamine spray to be sprayed on agents area in preceding 30 minutes, or phentolamine solution or ointment or gel are applied in agents area.Agents area comprises: penis head, body of penis, the place in the scrotum or a few place.
Preparation of the present invention proves through zoopery, when keeping drug effectiveness, can reduce dosage significantly, reduces systemic side effects and use cost.Compare with the Phentolamine external-applied preparation of conventional transdermal enhancer and prior art, plant volatile oil that this preparation is natural and highly finished product thereof can improve the Transdermal absorption dose of phentolamine very significantly, shorten the incubation period of onset, and have good drug safety, can provide more satisfactory therapeutic effects for the patient.
The present invention is reasonable in design, based on the mechanism of action and the physicochemical property thereof of medicine, takes into full account ED patient's treatment needs simultaneously, has following characteristics:
1, phentolamine is the periphery promoted type medicine of treatment ED, and its action target spot is at cavernous body of penis.So the topical transdermal administration is compared with oral administration, can improve the drug level of local target site, therefore can improve therapeutic effect, shorten the incubation period of onset; GI irritation and the first pass effect of hepar that simultaneously can avoid oral administration to cause, reduce circulatory system drug concentration and due to systemic side effects.Compare with the local injection administration, can obviously improve patient's compliance, avoid the local organization fibrosis side effect that causes owing to local injection.
2, the percutaneous permeability at human body penis and scrotum position is better than other position skin, and it has abundant vascularity, helps medicine at this position drug administration and better absorbs and local distribution, reaches satisfied treatment ED effect.
3, more known other penetration enhancer of volatile oil Percutaneous absorption enhancer of preparation application of the present invention can increase the transdermal dose and the speed of phentolamine more significantly, reaches efficient, quick-acting purposes, improves patient's treatment satisfaction.Simultaneously, dosage be can reduce significantly, side effect and use cost reduced.
The specific embodiment:
The present invention specifies natural plant volatile oil and extracts highly finished product as Percutaneous absorption enhancer and use thereof by following description and embodiment.Wherein said is nonrestrictive, does not limit claim scope of the present invention.
Embodiment 1
The 5mL Oleum Eucalypti is added in the 35mL tween 80, stir, standby.Get an amount of distilled water, add the 5g phentolamine mesylate, the 100mL propylene glycol, 150mL glycerol, the 0.2g chlorhexidine acetate, stirring is dissolved it fully.This solution is slowly injected the mixed solution of Oleum Eucalypti and tween, and adding distil water is to 1000mL, clarified after the stirring, the solution of homogeneous, regulates pH to 3.5～4.5 with hydrochloric acid, filters, and is sub-packed in the special-purpose spray bottle, promptly gets external spraying agent.
Embodiment 2
Get Oleum Caryophylli 10mL and add oleic acid 10mL, be preheated to 55 ℃ as oil phase behind the mix homogeneously, standby; To disperse glycerol adding 60mL, tragacanth 10g, ethyl hydroxybenzoate 1g in the lecithin 6g adding 100mL distilled water, stirring makes dissolving, is heated to 55 ℃, and continues to stir, slowly add simultaneously oil phase, high speed homogenization made colostrum in 8 minutes, and colostrum is crossed high pressure dispersing emulsification machine circulation 6 times, added phentolamine mesylate 5g under the stirring at low speed, adding distil water is to 1000mL, filter, be sub-packed in special-purpose spray bottle, promptly get described external spraying agent.
Embodiment 3
Get an amount of distilled water, add the 50mL tween 80, after the abundant dissolving, add Peppermint Oil 50 mL, ultrasonic emulsification 5 minutes adds glycerol 150mL, chlorhexidine acetate 0.2g, and phentolamine mesylate 1g fully dissolves the back adding distil water to 1000mL, mixing.Regulating pH with hydrochloric acid is 3.5～4.5, is sub-packed in the special-purpose spray bottle, promptly gets described external spraying agent.
Embodiment 4
Get an amount of distilled water, add the 50mL tween 80, after the abundant dissolving, add Oleum Eucalypti 50mL, ultrasonic emulsification 5 minutes adds glycerol 150mL, chlorhexidine acetate 0.2g, and phentolamine mesylate 1g fully dissolves the back adding distil water to 1000mL, mixing.Regulating pH with hydrochloric acid is 3.5～4.5, is sub-packed in the special-purpose spray bottle, promptly gets described external spraying agent.
Embodiment 5
Get 15mg poloxamer 188 and be scattered in an amount of distilled water, add Oleum menthae 100mL, hyaluronic acid 50g, sorbic acid 1g.Earlier dispersion and emulsion 3～4 minutes in tissue mashing machine is made colostrum.Add phentolamine mesylate 50g, adding distil water is to 1000mL, mixing.Regulating pH with phosphoric acid is 3.5～4.5, through the emulsifying of high speed dispersing emulsification machine to oil droplet size less than 5 μ m, be sub-packed in the special-purpose spray bottle, promptly get described external spraying agent.
Embodiment 6
Get Peppermint Oil 50 mL, be dissolved in the 80mL propylene glycol, and add chlorocresol 2g, dissolving post-heating to 55 is ℃ as oil phase, and is standby.Other gets an amount of distilled water, adds the 50mL tween 80, dissolving post-heating to 55 ℃, and continue to stir, slowly adding oil phase simultaneously, high speed homogenization made colostrum in 6 minutes.Colostrum is crossed high pressure dispersing emulsification machine circulation 4 times, add phentolamine mesylate 100g under the stirring at low speed, distilled water is added to 1000mL in the dissolving back, regulates pH to 3.5～4.5 with glacial acetic acid, is sub-packed in after the filtration in the special-purpose spray bottle, promptly gets described external spraying agent.
Embodiment 7
Get arabic gum 50g, tragacanth 2g is scattered in the 60mL distilled water, adds Fructus Citri Limoniae oil 10mL, and high speed homogenization made colostrum in 8 minutes.Stir adding benzalkonium bromide 1g down, glycerol 200mL, and add distilled water to 1000mL, by high pressure dispersing emulsification machine circulation 6 times.Low temperature stirs and adds phentolamine mesylate 10g down, and fully pH to 3.5～4.5 are regulated with glacial acetic acid in the dissolving back, are sub-packed in after the filtration in the special-purpose spray bottle, promptly get described external spraying agent.
Embodiment 8
Get Mentholum 10g, add 100mL ethanol and make its dissolving, and add sucrose monolaurate 1g, the 1.5g Arlacel-80 is heated to 55 ℃ as oil phase, and is standby.Other gets the 100mL distilled water, add the 1g tween 80, dissolving post-heating to 55 ℃, slowly add oil phase under stirring, high speed homogenization made colostrum in 10 minutes, added 200mL glycerol, 0.1g thimerosal, by high pressure dispersing emulsification machine circulation 6 times, under stirring at low speed, add phentolamine mesylate 100g, and adding distil water is to 1000mL.Regulate pH to 3.5～4.5 with hydrochloric acid, be sub-packed in after the filtration and promptly get described external spraying agent in the special-purpose spray bottle.
Embodiment 9
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Get 100g stearic acid, 100g Oleum Ricini, 100g liquid paraffin, heating in water bath makes fusing, adds sweetgum oil 60mL and keeps about 80 ℃, as oil phase; Other gets triethanolamine 8g, glycerol 40g, oxybenzene second fat 1g, sodium pyrosulfite 1g are dissolved in the 452g distilled water, be heated to synthermal, as water.Under agitation oil phase is slowly added aqueous phase, simultaneously the degassing.Constantly be stirred to and be condensed into paste, and in below 50 ℃ the time, add the phentolamine mesylate aqueous solution, wherein contain phentolamine mesylate 70g.Packing after stirring is described external such as unguentum.
Embodiment 10
Get 220g stearyl alcohol, 250g white vaseline, heating in water bath makes fusing, adds Oleum Terebinthinae 50mL, keeps about 80 ℃, as oil phase; Other gets 0.25g methyl hydroxybenzoate, 0.15g propyl hydroxybenzoate, 120g propylene glycol, sodium lauryl sulphate 15g and is dissolved in about 300mL distilled water, be heated to synthermal, as water.Under agitation oil phase is slowly added aqueous phase, simultaneously the degassing.Constantly be stirred to and be condensed into paste, and in below 50 ℃ the time, add the aqueous solution that contains ascorbic acid 0.5g and phentolamine mesylate 100g, and regulate pH to 3.5～4.5 with hydrochloric acid, the back packing that stirs is described external ointment.
Embodiment 11
Get tristerin 35g, stearic acid 120g, liquid Paraffin 60g, white vaseline 10g, lanoline 50g, heating makes its fusing, adds Oleum menthae 20mL, vitamin E 0.1g, stirs and keeps about 80 ℃, as oil phase; Other gets triethanolamine 4mL, ethyl hydroxybenzoate 1g and is dissolved in about 400mL distilled water, be heated to synthermal, as water.Under agitation oil phase is slowly added aqueous phase, simultaneously the degassing.Constantly be stirred to and be condensed into paste, and in below 50 ℃ the time, add and contain the aqueous solution of phentolamine mesylate 200g, and add distilled water to 1000g.Regulate pH to 3.5～4.5 with hydrochloric acid, the back packing that stirs is described external ointment.
Embodiment 12
Get 60g stearic acid, 60g stearyl alcohol, 16g Arlacel-80,90g liquid Paraffin, 60g white vaseline, heating makes its fusing, adds Herba Schizonepetae oil 20mL, stirs and keeps about 80 ℃, as oil phase; Other gets 44g tween 80,100g glycerol, 2 g sorbic acid and is dissolved in about 400mL distilled water, be heated to synthermal, as water.Under agitation oil phase is slowly added aqueous phase, simultaneously the degassing.Constantly be stirred to and be condensed into paste, and in below 50 ℃ the time, add and contain the aqueous solution of phentolamine mesylate 60g, and add distilled water to 1000g.Regulate pH to 3.5～4.5 with phosphoric acid, the back packing that stirs is described external ointment.
Embodiment 13
Get white vaseline 125g, liquid Paraffin 125g, hexadecanol 80g heating it is melted fully, add Oleum Eucalypti 100mL, stir and keep about 80 ℃, as oil phase; Other gets 35g peregal 0,50g glycerol, 1g ethyl hydroxybenzoate and is dissolved in about 300mL distilled water, be heated to synthermal, as water.Under agitation oil phase is slowly added aqueous phase, simultaneously the degassing.Constantly be stirred to and be condensed into paste, and in below 50 ℃ the time, add and contain the aqueous solution of phentolamine mesylate 50g, and add distilled water to 1000g.Regulate pH to 3.5～4.5 with phosphoric acid, the back packing that stirs is described external ointment.
Embodiment 14
Get 114g stearic acid, 100g Oleum Ricini, the heating of 114g liquid Paraffin is melted it fully, adds Oleum menthae 1mL, propyl gallate 1g, stir and keep about 80 ℃, as oil phase; Other gets 3mL polyoxyethylene nonylphenol ether, 160mL glycerol, 1g ethyl hydroxybenzoate, triethanolamine 8mL and is dissolved in about 300mL distilled water, be heated to synthermal, as water.Under agitation oil phase is slowly added aqueous phase, simultaneously the degassing.Constantly be stirred to and be condensed into paste, and in below 50 ℃ the time, add and contain the aqueous solution of phentolamine mesylate 80g, and add distilled water to 1000g.Packing after stirring is described external ointment.
Embodiment 15
Get the 10g Acritamer 940, the 2g tween 80 mixes in the 300mL distilled water; Other gets the 4g dissolution of sodium hydroxide in the 100mL distilled water, in the adding liquid stir clear gel substrate.In 50mL ethanol, add 1g ethyl hydroxybenzoate, 50g glycerol, 50g Mentholum, behind the mix homogeneously, add gradually in the above-mentioned gel-type vehicle.Add and contain the aqueous solution of phentolamine mesylate 100g, and add distilled water to 1000g.Packing after stirring is described exterior-applied gel.
Embodiment 16
Get sodium carboxymethyl cellulose 60g, methyl hydroxybenzoate 1.7g and be scattered in about 600mL distilled water, get clear gel substrate.Other gets 150mL glycerol, adds Oleum Eucalypti 1mL, adds gradually in the above-mentioned gel-type vehicle after stirring.Add and contain the aqueous solution of phentolamine mesylate 50g, and add distilled water to 1000g.Regulate pH to 5.0 with hydrochloric acid, the back packing that stirs is described exterior-applied gel.
Embodiment 17
Preparation with the foregoing description 3 and 4 carries out the transdermal test in vitro test
Embodiment 3 and 4 used transdermal enhancers are respectively Oleum menthae and Oleum Eucalypti, and concentration is 5% (v/v).In order to investigate the influence of transdermal enhancer to drug transdermal comprehensively, this test has also selected for use other representative penetration enhancer to contrast, and they comprise: propylene glycol (10%, v/v), and laurocapram (5%, v/v), N-Methyl pyrrolidone (5%, v/v), and sodium lauryl sulphate (5%, w/v), tween 80 (5%, v/v), and oleic acid (5%, v/v).Simultaneously in contrast with the phentolamine mesylate spray that do not add penetration enhancer.All are 0.1% (w/v) for the drug level in the reagent liquid.Animal skin is selected SD rat abdomen skin for use.Transdermal device adopts the franz diffusion cell.The mensuration of drug level adopts high performance liquid chromatography.Data draw the percutaneous rate of phentolamine mesylate under different transdermal enhancer effects by calculating.Table 1 is the phentolamine mesylate percutaneous rate under the different penetration enhancer effects.
Table 1
| Tested number | ?1 | ?2 | ?3 | ?4 | ?5 | ?6 | ?7 | ?8 | ?9 |
| The penetration enhancer kind | Oleum menthae | Oleum Eucalypti | Propylene glycol | Laurocapram | N-Methyl pyrrolidone | Sodium lauryl sulphate | Tween 80 | Oleic acid | Contrast |
| Percutaneous rate (μ gh -1·cm -2) | ?60.75 | ?22.49 | ?0.35 | ?7.48 | ?0.17 | ?0.72 | ?1.13 | ?0.24 | ?0.55 |
| Relative percutaneous rate | ?110.45 | ?40.90 | ?0.64 | ?13.60 | ?0.31 | ?1.31 | ?2.05 | ?0.44 | ?1 |
The result shows: under the identical situation of drug level, different types of penetration enhancer has appreciable impact to the percutaneous rate of medicine.Wherein, Oleum menthae, Oleum Eucalypti, laurocapram, sodium lauryl sulphate and tween 80 all can increase the percutaneous rate of phentolamine mesylate.The short effect optimum of Oleum menthae, Oleum Eucalypti takes second place.The percutaneous rate of two kinds of volatile oil is respectively 8.12 times and 3 times of laurocapram.Chinese patent CN1383820 has selected for use laurocapram as transdermal enhancer, can be foreshortened to 45 minutes the onset time of medicine.According to the result of this test, use the volatile oil transdermal enhancer, can further accelerate medicine and see through skin barrier, can bring into play the therapeutic effect of medicine in theory quickly.
Embodiment 18
Carry out the test of rabbit erection function with the foregoing description 3,6 and 10
Embodiment 3 and 6 used transdermal enhancers are Oleum menthae, and concentration is 5% (v/v), and drug level is respectively 0.1% (w/v) and 10% (w/v).Embodiment 10 used transdermal enhancers are Oleum Terebinthinae, and concentration is 5% (v/v), and drug level is 10% (w/v).In order to investigate the influence of other transdermal enhancer to the rabbit erection function, this test has also selected for use other representative penetration enhancer to contrast, and they comprise: laurocapram (5%, v/v), tween 80 (5%, v/v), propylene glycol (10%, v/v).Compare with the phentolamine mesylate spray (general dose group) that does not add penetration enhancer simultaneously.More than be 10% (w/v) for the drug level in the reagent liquid.In the experiment, the dosage of rabbit is 0.5mg/kg.In order to investigate the influence of dosage to the rabbit erection function, set up in test high dose group in addition, dosage is 10 mg/kg.In the test, get 6 of male and healthy rabbit, body weight 2.2～2.5kg.Medicine-feeding part is selected penis head (embodiment 3 and high dose group are because medicine liquid volume is excessive, and medicine-feeding part comprises penis and scrotum).Observe the time lag (incubation period) and the length of rabbit erection in 4 hours.Table 2 is rabbit erection function result of the tests.
Table 2
| Tested number | ?1 | ?2 | ?3 | ?4 | ?5 | ?6 | ?7 | ?8 |
| Dosage (mg/kg) | ?0.5 | ?0.5 | ?0.5 | ?0.5 | ?0.5 | ?0.5 | ?0.5 | ?10 |
| The penetration enhancer kind | Oleum menthae | Oleum menthae | Oleum Terebinthinae | Propylene glycol | Laurocapram | Tween 80 | ||
| Incubation period (min) | ?49.2±7.3 | ?32.5±6.1 | ?39.1±4.9 | ?667±5.2 | ?50.0±7.7 | ?60.8±9.2 | ?62.5±6.1 | ?35.0±7.7 |
| Erection length (mm) | ?6.5±07 | ?11.2±1.2 | ?10.2±1.5 | ?10.0±0.9 | ?9.7±0.8 | ?10.8±1.5 | ?97±1.6 | ?10.7±1.8 |
Statistical results show is a penetration enhancer with Oleum menthae (1, No. 2), Oleum Terebinthinae (No. 3), laurocapram (No. 5), and rabbit erects incubation period significantly less than the normal dose group of not adding penetration enhancer (No. 7), P＜0.05.The incubation period of high dose group (No. 8) is also significantly less than normal dose group (No. 7), P＜0.05.Result of the test shows, by increasing dosage (No. 8) or adding the time lag that suitable penetration enhancer (2,3, No. 5) all can shorten drug effect.The effect of erecing as the promotion that penetration enhancer was played with natural volatile oil is better than laurocapram, but the decline of preparation of Chinese medicine concentration (No. 1) can cause the prolongation of onset time and the reduction of erection length.The incubation period of high dose group and two kinds volatilization line of oils is close, but its dosage is 20 times of the volatilization line of oils, and simultaneously because the restriction of drug level (too high may cause local side effects), the volume of administration and coating skin area are forced to increase.Chinese patent CN1383820 has introduced the external ointment of phentolamine mesylate.It selects for use azone as penetration enhancer, gives in rabbit erects test and the about 11mg/ of drug dose (dosage converts by embodiment), and medicine-feeding part comprises penis and scrotum, and the result can make rabbit that the erection reaction took place in 45 minutes.And the present invention has used volatile oil as transdermal enhancer, can make rabbit about 30 minutes erectile response take place, and the dosage of this moment less than 1.5mg/ only, and medicine-feeding part only is the penis head.Therefore, the present invention adopts the natural volatile oil transdermal enhancer can be with lower dosage, and less administration area reaches the purpose of quick acting.
Embodiment 19
Carry out skin irritation test and skin anaphylactic test with the foregoing description 6,11 and 15
The skin irritation test:
Get 6 of healthy rabbits, male and female half and half, body weight 2.2～2.5kg.4 of every tame rabbit back symmetric depilation, every 3 * 3cm.Lost hair or feathers back second day, depilation district in left side is coated with respectively with phentolamine mesylate spray medicinal liquid (embodiment 6) and phentolamine mesylate ointment (embodiment 10), and depilation district in right side is coated with phentolamine mesylate gel (embodiment 15) and blank substrate.Clean depilation district, 4 places with warm water after 4 hours, observe and find local no erythema and edema reaction.Be coated with continuously in the same manner 7 days then, observe skin condition before cleaning back 1 hour at every turn and being coated with again.The last coating is cleaned the back and was observed skin condition in 1,24,48 and 72 hour.The result shows: do not find that skin has erythema and edema reaction, confirms that three kinds of phentolamine mesylate preparations of the present invention are to the skin nonirritant.
Skin anaphylactic test:
Adopt the Buehler test method(s).Get 70 of healthy guinea pigs, male and female are regardless of, and are divided into 4 groups at random, are respectively phentolamine mesylate spray group (20), phentolamine mesylate ointment group (20), phentolamine mesylate gel group (20) and negative control group (10).After dorsal body setae is sloughed in the part, be coated with pharmaceutical preparation in the 0th, 7,14 day in test: spray (embodiment 6), ointment (embodiment 10) and gel (embodiment 15) also seal matched group use normal saline with closure plate.The 28th day in the rib abdominal part coating of prior defeathering 6 hours with local excitation.Remove behind the closure plate and to observe skin condition in 24 and 48 hours.The result shows that three kinds of preparations of the present invention are not all being observed erythema and edema during the sensitization He after the local excitation, confirms that preparation of the present invention does not have the skin hypersensitivity reaction.
Above-mentioned result of the test shows: the volatile oil penetration enhancer can promote more effectively that than the penetration enhancer of other class phentolamine mesylate sees through skin barrier, brings into play therapeutical effect fast.Added the external preparation of transdermal enhancer of the present invention, safe in utilization, even reaching 20%, concentration do not have skin irritation and anaphylaxis yet.
Claims (20)
1. phentolamine externally applied transdermal preparation, it is characterized in that described preparation is active constituents of medicine and Percutaneous absorption enhancer by the phentolamine of safe and effective amount, and necessary adjuvant is formed on the pharmaceutics, wherein, described Percutaneous absorption enhancer be selected from natural plant volatile oil and extract highly finished product or its and other pharmaceutics on the associating Percutaneous absorption enhancer of the Percutaneous absorption enhancer used always, the consumption of described Percutaneous absorption enhancer is 0.1～10%w/v or 0.1～10%v/v.
2. by the described phentolamine externally applied transdermal of claim 1 preparation, it is characterized in that described active constituents of medicine is phentolamine mesylate, phentolamine hydrochloride or phentolamine free alkali, in phentolamine mesylate, the concentration of described active constituents of medicine is 0.1～20%w/v.
3. by claim 1 or 2 described phentolamine externally applied transdermal preparations, it is characterized in that described active constituents of medicine in phentolamine mesylate, its concentration is 1～10%w/v.
4. by claim 1 or 2 described phentolamine externally applied transdermal preparations, it is characterized in that described plant volatile oil and highly finished product thereof are selected from: Oleum Eucalypti, Oleum menthae, sweetgum oil, Oleum Terebinthinae, Oleum Caryophylli, Oleum Cinnamomi, cananga oil, Herba Schizonepetae oil, orange blossom oil, Oleum Anisi Stellati, Rhizoma Chuanxiong oil, Oleum Viticis Negundo, Fructus Citri Limoniae oil, Radix Angelicae Sinensis volatile oil, Rhizoma Alpiniae Officinarum oil, menthol, Mentholum, ledum terpenes, Borneolum Syntheticum, the d-limonene, eugenol, nerolidol and/or eucalyptol, wherein, menthol, Mentholum and Borneolum Syntheticum are solid state, its consumption is 0.1～10%w/v, other is a liquid condition, and its consumption is 0.1～10%v/v.
5. by the described phentolamine externally applied transdermal of claim 4 preparation, the consumption that it is characterized in that described solid state plant volatile oil and highly finished product thereof is 1～5%w/v; The consumption of liquid condition plant volatile oil and highly finished product thereof is 1～5%v/v.
6. by claim 1 or 2 described phentolamine externally applied transdermal preparations, it is characterized in that the Percutaneous absorption enhancer on described other pharmaceuticss is selected from: one or more in decyl methyl sulfoxide, laurocapram, N-Methyl pyrrolidone, oleic acid, lauryl alcohol, ethanol, propylene glycol, carbamide, lecithin, sodium lauryl sulphate, tween and the poloxamer; Wherein, the consumption of decyl methyl sulfoxide is 1～5%v/v, the consumption of laurocapram is 1～10%v/v, the consumption of N-Methyl pyrrolidone is 0.5～15%w/v, oleic consumption is 1～15%v/v, the consumption of lauryl alcohol is 1～15%v/v, the consumption of ethanol and propylene glycol is 5～20%v/v, the consumption of carbamide is 1～10%w/v, the consumption of lecithin is 0.1～5%w/v, the consumption of sodium lauryl sulphate is 0.5～10%w/v, and the consumption of tween is 0.5～8%v/v, and the consumption of poloxamer is 0.1～5%w/v.
7. by the described phentolamine externally applied transdermal of claim 6 preparation, what it is characterized in that described tween is selected from tween 20, Tween-40, Tween-60, Tween-65, tween 80 or tween 85; Described poloxamer is selected from poloxamer-188 or poloxamer-407.
8. by the described phentolamine externally applied transdermal of claim 1 preparation, it is characterized in that described preparation is spray, varnish, ointment or gel.
9. by the described phentolamine externally applied transdermal of claim 8 preparation, it is characterized in that necessary adjuvant comprises on the pharmaceutics that described spray contains: emulsifying agent, cosolvent, pH regulator agent, wetting agent and antiseptic.
10. by the described phentolamine externally applied transdermal of claim 8 preparation, it is characterized in that necessary adjuvant comprises on the pharmaceutics that described ointment contains: emulsifiable paste matrix adjuvant, antioxidant, pH regulator agent, wetting agent and antiseptic.
11. by the described phentolamine externally applied transdermal of claim 8 preparation, it is characterized in that necessary adjuvant comprises on the pharmaceutics that described gel contains: gel-type vehicle adjuvant, pH regulator agent, wetting agent and antiseptic.
12. by the described phentolamine externally applied transdermal of claim 9～11 preparation, it is characterized in that described wetting agent is selected from: one or more in glycerol, hyaluronic acid, propylene glycol or the sorbitol, wherein, the consumption of glycerol is 5～30%v/v, hyaluronic consumption is 1～25%w/v, the consumption of propylene glycol is 5～15%v/v, and the consumption of sorbitol is 5～20%v/v.
13., it is characterized in that described antiseptic is selected from: one or more in methyl hydroxybenzoate, ethyl hydroxybenzoate, propyl hydroxybenzoate, butyl hydroxybenzoate, chlorobutanol, sodium benzoate, sorbic acid, potassium sorbate, calcium sorbate, benzyl alcohol, phenethanol, chlorhexidine acetate, benzalkonium bromide, benzalkonium chloride, thimerosal, o-phenyl phenol or the chlorocresol by the described phentolamine externally applied transdermal of claim 9～11 preparation.
14., it is characterized in that described pH regulator agent is selected from: one or more in triethanolamine, sodium hydroxide, potassium hydroxide, hydrochloric acid, sulphuric acid, phosphoric acid, the glacial acetic acid by the described phentolamine externally applied transdermal of claim 9～11 preparation; Regulate pH regulator to 3.5～7 of preparation.
15., it is characterized in that described emulsifying agent is selected from: one or more in sodium stearate, sodium lauryl sulphate, sucrose fatty acid ester, span, tween, carbomer, poloxamer, arabic gum, tragacanth or the lecithin by the described phentolamine externally applied transdermal of claim 9 preparation; Wherein the consumption of sodium stearate is 1～15%w/v, the consumption of sodium lauryl sulphate is 0.5～10%w/v, the consumption of sucrose fatty acid ester is 0.1～2%w/v, the consumption of span is 0.1～10%v/v, and the consumption of tween is 0.5～8%v/v, and the consumption of carbomer is 0.1～1%w/v, the consumption of poloxamer is 0.1～5%w/v, the consumption of arabic gum is 5～15%w/v, and the consumption of tragacanth is 0.1～2%w/v, and the consumption of lecithin is 0.1～5%w/v.
16., it is characterized in that wherein sucrose fatty acid ester is selected from Surfhope SE Cosme C 1216 or sucrose palmitate by the described phentolamine externally applied transdermal of claim 15 preparation; Span is selected from Arlacel-20, Arlacel-40, Arlacel-60 or Arlacel-80; Tween is selected from tween 20, Tween-40, Tween-60, Tween-65, tween 80 or tween 85; Poloxamer is selected from poloxamer-188 or poloxamer-407.
17., it is characterized in that described cosolvent is selected from: one or more in ethanol, propylene glycol, glycerol or the Polyethylene Glycol by the described phentolamine externally applied transdermal of claim 9 preparation; Wherein, consumption of ethanol is 1～50%v/v, and the consumption of propylene glycol is 5～15%v/v, and the consumption of glycerol is 5～30%v/v, and the consumption of Polyethylene Glycol is 1～30%v/v.
18., it is characterized in that described emulsifiable paste matrix accessory package oil scraper phase adjuvant and emulsifying agent by the described phentolamine externally applied transdermal of claim 10 preparation; Wherein, described oil phase adjuvant is selected from: one or more in white vaseline, Cera Flava, liquid Paraffin, stearyl alcohol, lanoline, stearic acid, hard paraffin or the Oleum Ricini, the consumption of white vaseline is 1～30%w/v, mellisic consumption is 0.5～5%w/v, the consumption of liquid Paraffin is 4～25%w/v, the consumption of stearyl alcohol is 2～15%w/v, the consumption of lanoline is 3～6%w/v, stearic consumption is 10～20%w/v, the consumption of hard paraffin is 2～10%w/v, and the consumption of Oleum Ricini is 10～20%w/v; Described emulsifying agent is selected from stearic acid, sodium lauryl sulphate, tween, span, hexadecanol, octadecanol, glyceryl monostearate, paregal O or polyoxyethylene nonylphenol ether, wherein, stearic consumption is 10～25%w/v, the consumption of sodium lauryl sulphate is 0.5～2%w/v, the consumption of tween is 0.5～8%w/v, the consumption of span is 0.1～10%w/v, the consumption of hexadecanol is 5～13%w/v, the consumption of octadecanol is 5～13%w/v, and the consumption of glyceryl monostearate is 3～15%w/v, the consumption of paregal O is 2～5%w/v, the consumption of polyoxyethylene nonylphenol ether is 1～5%v/v; Described span is selected from Arlacel-20, Arlacel-40, Arlacel-60 or Arlacel-80; Described tween is selected from tween 20, Tween-40, Tween-60, Tween-65, tween 80 or tween 85.
19., it is characterized in that described antioxidant is selected from: vitamin E, ascorbic acid, sodium pyrosulfite, sodium sulfite, sodium sulfite, propyl gallate, cysteine or disodium edetate by the described phentolamine externally applied transdermal of claim 10 preparation; Wherein, the consumption of vitamin E is 0.01～0.03%w/v, the consumption of ascorbic acid is 0.01～0.1%w/v, the consumption of sodium pyrosulfite is 0.1～0.5%w/v, the consumption of sodium sulfite is 0.1～0.5%w/v, and the consumption of sodium sulfite is 0.1%w/v, and the consumption of propyl gallate is 0.1%w/v, the consumption of cysteine is 0.01～0.1%w/v, and the consumption of disodium edetate is 0.01～0.1%w/v.
20., it is characterized in that described gel-type vehicle adjuvant is selected from: carbomer, methylcellulose or sodium carboxymethyl cellulose by the described phentolamine externally applied transdermal of claim 11 preparation; Wherein, the consumption of carbomer is 0.5～3%w/v, and the consumption of methylcellulose is 2～6%w/v, and the consumption of sodium carboxymethyl cellulose is 2～6%w/v; Described carbomer is selected from carbomer 934, Acritamer 940 or Carbopol 941.
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| CN101361725A (en) | 2009-02-11 |
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