CN1491647A - Composition for percutaneous treating impotence and female sexual cold and preventing sextual disease - Google Patents

Abstract

The present invention relates to water-based emulsion for percutaneously treating impotence and female's sexual apathy and preventing sexual disease, skin disease and women's disease. It consists of organic ester, sterilizer, penetration promoter, emulsifier, thickener, preservative and water. It has many functions, high effect, convenient use, stable performance, no side effect, simple production process and low cost.

Description

Transdermal composition for treating impotence and female sexual indifference and preventing and treating venereal disease

The present invention relates to a water-base cream composition for external application for curing impotence and female frigidity and preventing and curing venereal disease, which is formed from organic nitrate, bactericidal disinfectant, penetration-promoting agent, emulsifying agent, thickening agent, preservative and water.

Conventional pharmacological treatments for impotence and erectile dysfunction have primarily involved the topical administration of vascular smooth muscle relaxants such as papaverine or prostaglandin E, or α → adrenergic receptor antagonists such as phentolamine, systemic administration of male hormone preparations such as methyltestosterone and testosterone esters, and natural plant extracts (e.g., cotinine, ginseng, strychnine, epimedium, etc.) sildenafil citrate (commonly known as "viagra") produced by the united states pyroxene pharmaceutical limited company is an oral drug with greater erectile function in impotent patients.

All the above drugs have disadvantages. Papaverine and other vasoactive drugs have been injected with varying rates of success, varying durations of response, and with repeated injections into the penis causing pain and trauma. These drugs can cause an abnormal erection of the penis (an undesirably long duration of erection) in some patients, which can result in structural damage to the organs. Administration of methyltestosterone or testosterone esters may cause toxic effects or inhibit the formation of endogenous testosterone and spermatogenesis. Oral drugs for stimulating sexual desire have side effects, first pass effects and unstable effects, some have significant side effects, such as long acting time (2 hours) after meals of sildenafil citrate, and accompanying side effects of headache, flushing, runny nose, stomach ache, impaired vision, etc., and the preparation process is very complicated and the selling price is very high (about 100 yuan/capsule).

Recent medical studies have shown that the mandatory effect of nitric oxide on the erectile process, stimulating local nerves leading to NO production, will increase blood flow in the penile arteries and relax the cavernous space. When these cavernous spaces are filled, they compress the venous outlet of the cavernous body, resulting in an erectile response. Thus, administration of exogenous NO donors can be used to promote erection. As a Chinese patent CN1292691, a preparation for treating erectile dysfunction, which proposes that the nitroglycerin is matched with lanolin to treat impotence, and the maximum erection time can reach 45 minutes. CN1177294 discloses a water-based cream for external use containing nitroglycerin, a preparation method and application thereof, wherein the water-based cream for nitroglycerin is disclosed to be used for treating impotence. Both patents do not have detailed tests of the sexual response. The use of nitroglycerin is often accompanied by headache and systemic bloodpressure drop, and many patients do not respond favorably to nitroglycerin due to ultrastructural damage to smooth muscle, insufficient vein occlusion, or direct vein dilation of the inferior veins. CN1307472 discloses "composition for treating impotence comprising organic mononitrate", herein disclosed non-aqueous solvent formulation of organic nitrate, administered topically for treating impotence. WO96/34583 discloses certain organic nitrites which are effective in inducing erection when applied topically to the penis, but which irritate the skin tissue.

The above techniques all provide a therapeutic effect of organic esters of nitric (nitrite) acid on impotence. But most of the functions are single, only has the treatment effect on male impotence, does not mention the treatment measures on female frigidity, and does not have auxiliary functions (such as the functions of preventing and treating skin diseases, venereal diseases, gynecopathy and the like). And is generally in an oil dosage form, the drug release rate is slow (1-2 hours latency), and oil can remain on the penis or be transferred to the sexual partner to cause discomfort and uneasiness of the sexual partner. In addition, organic esters of nitric acid, which are the main active ingredients, are very complex, dangerous and costly to prepare. This is also a common problem for nitrate-based products. The nitrate is generally nitrified by alcohol (mixed acid) method, acid is dropped into the fully stirred mixed acid at-10 deg.C-0 deg.C for nitration, the reactant is poured into ice water for layering, the ester layer is washed, and then it is distilled under reduced pressure. The continuous nitration method is a method in which ester and water are continuously distilled off by reduced pressure azeotropy, and the nitration reaction proceeds to the right. Therefore, an ice salt water cooling system, a distillation reflux system and a vacuum distillation system are required to be configured, so thatthe equipment investment and the manufacturing cost are huge, and the process is complicated. Even so, there are still not the time that material spraying, burning, explosion incident take place. Even if the concentration of nitroglycerin is too high during storage and transportation, explosion can occur. U.S. Pat. No. 4,430,905 discloses a process for the production of a mixture of ethoxyacetic acid and isooctanoic acid by continuous nitration, operating at low temperatures; CN1031525 "synthetic process of isooctyl nitrate", operating at lower temperature, preparing an ice salt water cooling system and a vacuum drying system; CN1045773 production process and apparatus of isooctyl nitrate, wherein a water bath heating system is prepared by reacting at a low heat value of 50-70 ℃, and energy is additionally consumed; in the production process of organic dinitrate introduced in CN1307472, a freezing brine cooling system (so that the initial temperature reaches 0 ℃) and a vacuum concentration distillation system are required to be arranged, the reaction needs to be very careful, smoke, spray, combustion and explosion can be caused without paying attention, the rejection rate and the manufacturing cost of products are greatly improved, and a large amount of organic solvents such as dichloromethane and the like are used, so that the cost is increased, the subsequent procedures of reduced pressure distillation and purification are increased, and the environment is polluted. The production of organic mononitrate uses expensive silver nitrate as raw material and hexane for extraction, and the yield is low (7.41g of silver nitrate only gives 0.9ml of final product).

The present invention aims at providing a water-base externally used emulsifiable paste composition which is composed of organic nitrate, sterilization disinfectant, penetration enhancer, emulsifier, thickening agent and water and is used for treating impotence and female frigidity and preventing and treating venereal disease, dermatosis and gynecopathy without side effect, and a preparation method thereof.

The invention also aims to provide a simple, stable, efficient and low-cost preparation method and application of the main active component organic nitrate in the composition.

The raw materials of the invention are proportioned as follows (weight percentage)

Organic ester nitrate: 0.5 to 10 percent

And (3) sterilization and disinfection: 0.1 to 2 percent

Penetration enhancer: 5 to 15 percent of

Emulsifying agent: 0.1 to 1 percent

Thickening agent: 1 to 2 percent

An anti-corrosion agent: 0.1 to 0.5 percent

Water: 70 to 85 percent

The organic nitrate esters comprise organic mononitrate esters (such as amyl nitrate, butyl nitrate, hexyl nitrate, heptyl nitrate and isomers or derivatives thereof), organic dinitrate esters (such as 1.5-pentadinitrate, 1.4-butanedinitrate, 1.6-hexanedioate, 1.7-heptanedioate and derivatives thereof), organic trinitrate esters (such as glyceryl trinitrate), and the dosage is 0.5-10%, preferably 1-6%; the sterilizing disinfectant consists of povidone iodine (10-200mg), chlorhexidine (10-200mg), eucalyptus oil (50-500mg), polyvinylpyrrolidone (10-200mg) and benzyl alcohol (50-500mg), and the dosage is 0.1-2%, preferably 0.25-1.5%; the penetration enhancer is composed of glycerol-organic acid (such as decanoic acid, lauric acid and oleic acid) ester (3% -8%), fatty acid (such as oleic acid and stearic acid) (1% -3%), glycerol (0.5% -1%), propylene glycol (1% -3%) and the like, and the dosage is 5% -15%, preferably 8% -13%; the emulsifier is composed of span series (such as SP-80), Tween series(such as TW-80), etc., and the dosage is 0.1% -1%, preferably 0.5% -0.9%; the thickening agent comprises sodium carboxymethylcellulose, polyethylene glycol and the like, and the using amount of the thickening agent is 1-2%, preferably 1.2-1.5%; the antiseptic is composed of butylhydroxy toluene (BHT), p-hydroxybenzoate esters, PABA, etc., and is used in an amount of 0.1-0.5%, preferably 0.15-0.3%; water is supplemented to the balance.

The manufacturing process comprises the following steps: dissolving water soluble substances such as thickener, emulsifier, glycerol, propylene glycol, povidone iodine, and polyvinylpyrrolidone in water to obtain solution A; mixing oil (ester) soluble substances such as chlorhexidine, oleum Eucalypti, benzyl alcohol, organic monoglyceride, fatty acid, etc. with organic nitrate to obtain mixed solution B. Slowly adding B into A under stirring, stirring to obtain water-based cream, adding other auxiliary additives (such as antiseptic, essence, and pigment), or adding the above water-insoluble substance or ester-insoluble substance with small dosage, and stirring. If necessary, a contraceptive medicament component can be added [ see another patent of a percutaneous (or oral) contraceptive abortifacient sterilization composition].

Some organic nitrate esters (especially organic dinitrate) of the invention are novel compounds, and no formal commodity is available in the market at present. They produce a greater penile volume augmentation and a smaller systemic blood pressure reduction than prior art nitroglycerin, which makes the present invention more effective and safer in inducing or maintaining erection, and less prone to side effects such as headache, flushing, runny nose, stomach pain, impaired vision, and the like. This is because organic ester dinitrate acid produces NO more efficiently in the sponge. In addition, the organic mononitrate is less volatile, chemically stable and less irritating after being applied to skin.

It has been surprisingly found that organic nitrate based compositions provide engorgement of the female clitoris and provide anatomical erection of the clitoris corpus cavernosum, thereby facilitating orgasm and vaginal tightening. Moreover, the clitoris is smaller than the male counterpart, with the dermis layer being thinner and more sensitive to tactile stimulation. Thus, the sexual intercourse of both men and women can be realized simultaneously by using one medicine.

The sterilization disinfectant comprises povidone iodine, chlorhexidine, eucalyptus oil, polyvinylpyrrolidone, benzyl alcohol and the like. The povidone iodine is the most widely used disinfectant with the international broad spectrum, low toxicity, high efficiency and safety, but the iodine is easy to volatilize after water is added, so the quality guarantee period is short, the benzyl alcohol is added to inhibit the iodine volatilization and prolong the storage time, and the polyvinylpyrrolidone is added to prolong the sterilization time of the povidone iodine and enhance the effect. Meanwhile, the polyvinylpyrrolidone has the functions of absorbing water, preserving moisture and promoting infiltration. Chlorhexidine (chlorhexidine) can be adsorbed on the surface of bacteria to change the permeability of cell wall, so that enzyme and metabolic intermediate in thallus can be escaped, bacterial respiration and glycolysis can be hindered, and thallus protein can be denatured, so that the goal of sterilization and disinfection can be achieved. Eucalyptus oil is a nontoxic broad-spectrum bactericide and insecticide and has the function of essence. The raw materials are scientifically prepared, so that the invention has good prevention and treatment effects on venereal diseases, skin diseases and gynecological diseases, has broad-spectrum sterilization and good effect, and has curative effects on protozoa, fungi, viruses and spores.

The penetration enhancer of the present invention improves the permeability of the skin by disorganizing the structure of the subcutaneous or deeper skin, increasing and optimizing the thermodynamic activity of the drug, and results in the storage of the drug in the skin. It is composed of organic glyceride, fatty acid, propanediol and glycerine. The monoglyceride is particularly suitable for promoting the rapid subcutaneous penetration of water-insoluble oil-soluble drugs. The fatty acid can generate synergistic action with the propylene glycol to enhance the penetration effect. Glycerol not only promotes penetration, but also lubricates and relieves skin irritation.

The emulsifier of the invention consists of span series or Tween series surfactants. The composition can form a stable O/W emulsifying system. Wherein the temperature-spitting emulsifier also has the function of promoting penetration.

The thickening agent of the present invention may be comprised of sodium carboxymethylcellulose or polyethylene glycol, wherein polyethylene glycol is also a penetration enhancer.

The preservative of the present invention may be added little or not due to the presence of the germicidal sterilant.

In addition, the invention provides a set of novel process for producing nitrate products. The process does not use ice brine freezing and cooling equipment, a water bath heating system, ester and water products which are continuously pumped from the system, a condensation reflux device or vacuum distillation or concentration equipment, thereby saving huge equipment investment, greatly simplifying the production process and reducing the production cost. The whole production process is carried out at normal temperature (or temperature brought by reaction heat of raw materials), and an amino-containing substance (preferably thiourea or carbamide containing 2 amino groups) is added as a stabilizer to carry out chemical reaction with a byproduct nitrous acid (a strong oxidant which can cause explosive violent reaction) in nitration reaction, thereby achieving a stable effect and preventing material spraying, combustion and explosion. The reaction formula is as follows (thiourea):

thus, the invention can carry out nitration esterification reaction under extremely wide and mild conditions. The reaction temperature is-10-80 ℃, the proportion of the mixed acid is not strict, only a kettle type reactor with a stirrer is needed, the temperature is adjusted by adjusting the speed of dripping the raw materials, and the temperature is generally adjusted without a jacket. The waste acid liquid can be recycled, and the environmental pollution is reduced. The process flow is as follows: mixing sulfuric acid, nitric acid and water, adding a stabilizer, finally dropwise adding corresponding organic alcohol to react for 1-3 hours, carrying out static quantity layering, taking an upper ester layer, washing with water and alkali, then washing with water to ensure that the pH value of the ester layer is approximately equal to 7, and dehydrating and drying to obtain the colorless transparent organic nitrate ester, wherein the purity and the yield are over 97 percent. The process has wide application, is suitable for various nitrate products, such as nitrate, dinitrate, trinitrate and the like, also expands the application of the products (explosives, medicines, high-energy fuels, cetane number improvers and the like), simplifies the production process, greatly reduces the manufacturing cost, and is energy-saving and environment-friendly.

The composition can be made into various dosage forms, such as ointment, gel, lotion, spray and the like, can be directly sprayed (coated) on the penis or coated on theinner side (or the inner side and the outer side) of the condom so as to simultaneously act on both men and women, and can promote erection, prevent contraception and prevent diseases. The preferred formulation of the present invention is a water-based cream, which releases the drug rapidly (the time for the pure active substance to reach the peak of action is only 2-5 minutes), and no oil remains on the penis or is transferred to the sexual partner to cause uneasiness and discomfort, so that the present invention can be used without the knowledge of the sexual partner. The invention can sustain erection for about one hour. Animal experiments show that the peak value of the penis volume increase of the animal is more than 2 times of that of the nitroglycerin preparation group. The composition does not irritate skin.

The following examples are presented to further illustrate the compositions of the present invention and the methods of making organic esters of nitric acid as the active ingredient, but are not to be construed as providing compounds, compositions, formulations or methods of administration which are necessarily exclusive for use within the scope of the present invention.

Example 1

Preparation of 1, 4-butanedinitrate

35ml of 98% concentrated sulfuric acid and 15ml of 95% fuming nitric acid are mixed, and 25ml of water is added to form a mixed acid solution. Adding 1g of thiourea into the mixed acid solution, and uniformly stirring. Finally, 10ml of 1, 4-butanediol solution is dripped under the stirring condition (after 30 minutes of dripping is finished), the reaction is carried out for 3 hours, and the mixture is kept stand and layered to obtain-14 ml of 1, 4-butanedinitrate. The upper ester layer was taken out from the separatory funnel, and washed with water → alkali (5% NaoH) → water to give an ester layer PH of 7. The ester layer was removed with a separatory funnel and dried over anhydrous sodium sulfate to give the final product 1, 4-butanedinitrate as a colorless transparent liquid. The product purity is 99%, and the yield is as follows: 97 percent. The peak effect was 35.5% change, the time to peak effect was 2 minutes, and the local activity AUC was 403.

Example 2

Preparation of an aqueous cream containing 1, 4-butanedinitrate and other ingredients

Dissolving 1.5g of polyethylene glycol 8000, 1g of Tween-80, 1g of glycerol, 2g of propylene glycol, 100mg of povidone-iodine and 100mg of polyvinylpyrrolidone in 80g of water; obtaining a solution A; uniformly mixing 120mg of chlorhexidine, 300mg of eucalyptus oil, 200mg of benzyl alcohol, 5g of glycerol monolaurate, 1g of stearic acid and 1g of oleic acid with 5g of the 1.4-butanedinitrate to obtain a mixed solution B. Slowly injecting the mixed solution B into the solution A under stirring at a rotating speed of 3000R/min, and uniformly stirring to obtain the water-based cream. Then 0.2g of Butyl Hydroxy Toluene (BHT) is added into the mixture, and if necessary, a small amount of essence and pigment are added into the mixture, and the mixture is stirred uniformly, so that the final product is obtained.

The final product, water-based cream 0.5ml, is applied to penis and glans of a man (35 years old, mild cold feeling), rubbed evenly, and completely erected within 2 minutes, and the love time reaches 60 minutes/time in the same day, after 10 hours, a fatigue-strengthening test is carried out, and the operation is repeated, and the love time can still reach 45 minutes/time. Erection for sexual intercourse can be achieved within 20 minutes after ejaculation, love is continued for 20 minutes, and then the test is terminated in advance due to lower body pain of women. On the third day, the above operations were repeated for a period of 70 minutes/time. According to the introduction feeling of a male, the penis swelling degree is increased, and the sensibility to touch is slightly reduced in the middle of making love, so that ejaculation is not needed to be impulsed, and the making love time is prolonged; the female is felt that the clitoris has a cool feeling, the clitoris has good congestion, can completely reach the orgasm, and has more than second orgasm, the vagina is vigorous, and the tightening degree is higher than usual. In the test process, the symptoms of headache, nausea, stomachache, runny nose, flush complexion, impaired vision and the like are not found in both parties.

Compared with the prior art, the invention has the following advantages:

1. multifunctional (can be used for treating sexual impotence, female hyposexuality, and preventing and treating STDs, dermatoses, and gynecological diseases, and can be used as lubricant, and optionally contraceptive component to achieve contraceptive function);

2. short effective time and good effect (2-5 minutes effective, erection time can reach about 1 hour, which makes women easy to reach orgasm and tighten vagina);

3. stable performance (non-volatile, non-explosive and less irritant);

4. no adverse side effects (no headache, stomach ache, flush complexion, nasal discharge, impairment of vision, and no systemic blood pressure drop);

5. the production process is simple and convenient (normal temperature esterification, no need of freezing and heating, no need of vacuum concentration, no need of organic solvent, environmental protection and energy conservation, shortening of the production period and providing reference for the production mode of other nitrate products);

6. the cost is low (the cost of 1.4-butyl dinitrate raw material is less than 16 yuan/kg based on industrial raw materials, the cost of water-based cream raw material is less than 3 yuan/kg, and the use cost of Viagra is more than 3 ten thousand times of the use cost of the invention compared with the cost of 1 g/use of Viagra which is 100 yuan based on 1g of the use amount of the invention).

Claims (6)

1. A percutaneous composition for treating impotence and female hyposexuality and preventing and treating venereal disease is prepared from organic nitrate, disinfectant, penetrant, emulsifier, thickening agent, antiseptic and water.

2. The composition according to claim 1, wherein the composition comprises (wt%): 0.5 to 10 percent of organic nitrate, 0.1 to 2 percent of disinfectant, 5 to 15 percent of penetration enhancer, 0.1 to 1 percent of emulsifier, 1 to 2 percent of thickener, 0.1 to 0.5 percent of preservative and 70 to 85 percent of water.

3. The composition of claim 2, wherein the preferred proportions of the components are (wt%), organic nitrate 1% -6%, disinfectant 0.25% -1.5%, penetration enhancer 8% -13%, emulsifier 0.5% -0.1%, thickener 1.2% -1.5%, preservative 0.15% -0.3%, and water to balance.

4. A composition according to claim 2 or 3, wherein the organic nitrate may comprise an organic ester of mononitrate, an organic ester of dinitrate, an organic ester of trinitrate, preferably an organic ester of dinitrate; the disinfectant comprises povidone iodine (10-20mg), chlorhexidine (10-200mg), oleum Eucalypti (50-500mg), polyvinylpyrrolidone (10-200mg), and benzyl alcohol (50-500 mg); the penetration enhancer is composed of glycerol-organic acid (such as decanoic acid, lauric acid and oleic acid) ester (3% -8%), fatty acid (such as oleic acid and stearic acid) (1% -3%), glycerol (0.5% -1%), propylene glycol (1% -3%) and the like; the emulsifier is composed of span series and/or Tween series surfactant, preferably Tween-80; the thickening agent is composed of sodium carboxymethylcellulose and/or polyethylene glycol, preferably polyethylene glycol; the preservative is composed of Butylated Hydroxytoluene (BHT), parabens, PABA, etc.

5. The composition as claimed in claim 4, wherein the preparation process comprises dissolving the water-soluble substance in water, mixing the oil (ester) soluble substance with the organic nitrate, slowly adding the mixture into the aqueous solution, stirring to obtain water-based cream, adding the adjuvant, and stirring.

6. The composition of claim 5, wherein the organic nitrate is prepared by a process comprising: mixing concentrated sulfuric acid, concentrated nitric acid and water, adding a small amount of amino-containing compound (preferably thiourea or carbamide with 2 amino groups), dropwise adding an organic alcohol solution at normal temperature under the condition of stirring, reacting for 1-3 hours, standing for layering, separating an ester layer from a mixed acid solution, washing with water → alkali washing → washing with water to make the pH of the ester layer equal to 7, and dehydrating and drying the ester layer (anhydrous sodium sulfate) to obtain the colorless transparent organic nitrate.