KR102003876B1 - A water-in-oil type emulsion composition for improving impotence - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for improving erectile dysfunction, and provides an emulsion-in-oil-induced erectile dysfunction composition comprising a surfactant having a HLB (Hydrophile-Lipophile Balance) value of 6.0 to 7.0, water, oil, and nitrite. do.

Description

Composition for improving water-in-oil erectile dysfunction of emulsion type {A WATER-IN-OIL TYPE EMULSION COMPOSITION FOR IMPROVING IMPOTENCE}

The present invention relates to a composition for improving water-in-oil erectile dysfunction of an emulsion type having excellent usability.

Erectile dysfunction is a case in which there is not enough erection for sexual activity or an erection is not maintained enough, which means that about 25% or more of sexual dysfunctions occur.

Erectile dysfunction is a common disease that occurs in about 10% of adult males and is currently reported to be about 150 million people worldwide and 2.5 to 3 million people in Korea. Erectile dysfunction is not a life-dependent disease, but it is an important factor in determining 'quality of life'.

An erectile response is the action of blood vessels initiated by the action of nerves and maintained by the complex interaction between blood vessels and the action of nerves.

An erection is a phenomenon in which the cavernous corpus is enlarged and the blood is filled and the penis is hardened. When sexual stimuli are delivered to the cavernous nerve, nitric oxide (NO) is produced at the nerve endings. Nitric oxide is involved in the expansion of blood vessels made up of smooth muscles and promotes the inflow of blood into the cavernous body.

Nitric oxide increases the concentration of cGMP in signaling molecules activate sGC (soluble guanylate cyclase) to cells and reduces the concentration of intracellular Ca ^{2 +} ions induces relaxation of smooth muscle. Increased intracellular cGMP is degraded by phosphodiesterase (PDE), which is recognized as a major target of erectile dysfunction.

Primary treatment of erectile dysfunction uses an erectile dysfunction treatment. Viagra, Levitra, Cialis and the like belong to this and act as PDE inhibitors. However, PDE inhibitors do not have a significant effect on erectile dysfunction that does not produce enough nitric oxide, and may cause side effects such as visual impairment and hot flashes.

Secondary treatment of erectile dysfunction consists of injecting drugs directly into the corpus cavernosum (ICI).

The most effective and well studied formulations used for direct injection are papaverine hydrochloride, phentolamine and alprostadil or prostaglandin E-1 (PGE-1).

Direct injection is effective, but often causes psychological anxiety, pain, injury or discomfort, as manifested by a high dropout rate in patients, and can also lead to infections, fibrosis, fibrotic nodules, hypotension and stiffness.

Phentolamine always affects sympathetic nerve control that does not cause erectile dysfunction, and PGE-1 can optionally cause expansion of arteries or nerves, including vascular congestion of the corpus cavernosa.

Prostaglandin E-1 (PGE-1) is known to be the most effective as a single agent, but it is also a major side effect, causing pain, and is prescribed in the form of BIMIX, TRIMIX to reduce the amount used.

Other methods include using a vacuum pump or reconstructing the penis with a balloon, but are not commonly used due to the possibility of physical damage and high cost.

On the other hand, there have been attempts to inject drugs that slowly release nitrogen monoxide (Nitroglycerin, SNP, etc.) through the skin or inject them into the penis, but the drug is delivered to the whole body to induce vasodilation, leading to fatal side effects such as low blood pressure. It is not widely used because it is not easy to control the sustained release of nitrogen monoxide.

The present inventors have made efforts to develop an erectile dysfunction treatment agent with minimized side effects, and have developed an emulsion type erectile dysfunction composition that can be directly applied to the penis. By applying the composition, the blood vessels of the penis can be effectively expanded. The present invention was completed by confirming.

European Patent No. 03158990

An object of the present invention is to provide a composition for improving erectile dysfunction, which is easy to use and has an excellent vasodilation effect.

According to an aspect of the present invention, an emulsion type water-in-oil erectile dysfunction improvement composition including a surfactant having a HLB (Hydrophile-Lipophile Balance) value of 6.0 to 7.0, water, oil, and nitrite is provided.

In one embodiment, the nitrite may be sodium nitrite, potassium nitrite or calcium nitrite.

In one embodiment, the concentration of the nitrite may be 200 to 800mM.

In one embodiment, the oil may be selected from the group consisting of natural oils, mineral oils, white mineral oils, and synthetic oils.

In one embodiment, the water and oil may be included in a weight ratio of 35:65 to 45:55.

In one embodiment, the surfactant may be included 1.0 to 2.0% by volume relative to the total volume of the composition.

In one embodiment, the composition may further comprise a transdermal penetration enhancer.

In one embodiment, the composition may further comprise one or more adjuvants selected from the group consisting of diluents, excipients, buffers, antimicrobial preservatives, antioxidants, tonicity modifiers, preservatives, thickeners and viscosity modifiers.

In one embodiment, the average particle diameter of the emulsion particles of the composition may be less than 1000 nm.

The composition for improving erectile dysfunction of the present invention can effectively expand blood vessels of the penis without causing pain or discomfort associated with use.

The composition for improving erectile dysfunction of the present invention may result in only local erectile phenomena without causing systemic phenomena depending on the application.

It is to be understood that the effects of the present invention are not limited to the above effects, and include all effects deduced from the configuration of the invention described in the detailed description or claims of the present invention.

1 is a measurement of the amount of nitrogen monoxide generated according to the concentration of nitrite.
Figure 2 measures the change in the particle diameter of the emulsion according to the HBL value of the surfactant.
3 is a measurement of the change in the particle diameter of the emulsion according to the surfactant, water, oil composition ratio.
Figure 4 is applied to the penis of the composition of one embodiment of the present invention and observed changes in appearance.
Figure 5 is applied to the penis of the composition of one embodiment of the present invention and confirmed the concentration of nitric oxide in the blood.

The terminology used herein is to select general terms that are currently widely used as possible in consideration of the functions in the present invention, but may vary according to the intention or precedent of the person skilled in the art, the emergence of new technologies and the like. In addition, in certain cases, there is also a term arbitrarily selected by the applicant, in which case the meaning will be described in detail in the description of the invention. Therefore, the terms used in the present invention should be defined based on the meanings of the terms and the contents throughout the present invention, rather than the names of the simple terms.

Unless defined otherwise, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art. Terms such as those defined in the commonly used dictionaries should be construed as having meanings consistent with the meanings in the context of the related art, and are not construed in ideal or excessively formal meanings unless expressly defined in this application. Do not.

The numerical range includes the numerical values defined in the range. All maximum numerical limits given throughout this specification include all lower numerical limits as if the lower numerical limits were clearly written. All minimum numerical limits given throughout this specification include all higher numerical limitations as if the higher numerical limit were clearly written. All numerical limits given throughout this specification will include all better numerical ranges within the broader numerical ranges, as if narrower numerical limits are clearly written.

Hereinafter, examples of the present invention will be described in detail, but the present invention is not limited by the following examples.

According to an aspect of the present invention, an emulsion type water-in-oil erectile dysfunction improvement composition including a surfactant having a HLB (Hydrophile-Lipophile Balance) value of 6.0 to 7.0, water, oil, and nitrite is provided.

Penile erection is a phenomenon in which the smooth blood vessels of the corpus cavernosum relax and increase the inflow of blood. When a sexual reaction occurs, the relaxation reaction may be caused by nitric oxide (NO), an endothelial relaxation factor secreted from vascular endothelial cells.

The nitric oxide may be biosynthesized by nitric oxide synthase (NOS) as a potent neurotransmitter of nonadenergic noncholinergic (NANC) neurons in the central and peripheral nervous systems.

The nitrogen monoxide promotes the biosynthesis of c-GMP (cyclic-GMP), a vasodilator, by activating guanylate cyclase in the corpus cavernosum. An increase enables erection.

Since the composition contains nitrite in the emulsified particles, it effectively penetrates into the skin upon topical application to generate nitrogen monoxide and can relax the corpus cavernosum smooth muscle through the NO-cGMP pathway.

In particular, the composition produces nano-sized emulsified particles because the ratio of water and oil and the properties of the surfactant are properly controlled, and the emulsified particles can effectively penetrate the skin tissue. The emulsified particle average diameter may be less than 1000 nm, because of the small size can be efficiently delivered nitrite.

The nitrite may be sodium nitrite, potassium nitrite or calcium nitrite, and may be used alone or in combination of two or more thereof, preferably sodium nitrite.

The sodium nitrite is sseuyimyeo the manufacture of dyes as colorless crystals made by dissolving sodium nitrate with lead, food additives, pharmaceuticals, etc., and formula NaNO _2, molecular weight of 69.0, melting point 271 ℃, has a characteristic of decomposing above 320 ℃ . Since the sodium nitrite has low biotoxicity, even when topically applied or administered, it can effectively produce nitrogen monoxide without causing any side effects.

The concentration of the nitrite may be 200 to 800mM. If the concentration of the nitrite is less than 200mM may not properly implement the vasodilation effect, if the concentration of the nitrite is more than 800mM the amount of nitrogen monoxide is no longer increased to cause a burden on the cell tissue due to inefficient and high concentration Can be.

The oil may be selected from the group consisting of natural oil, mineral oil, white mineral oil, and synthetic oil, but is not limited thereto.

The oil is a mineral oil, including white isoparaffin (isoparaffin), isohexadecane or isododecane (isododecane) having a carbon number of C8 to C16 (white mineral oil) (Marcol 52/82 Etc.), fatty alcohol ethers such as synthetic oils including polyisobutene or polyisodecene, dioctyl ether or didecyl ether Fatty esters such as natural oil, octylpalmitate, triglyceride, cococaprylate caproate, and hexyl stearate, including It may be any one or more selected from the group consisting of natural oil (natural oil) and squalane (Squalane) including, but may be appropriately changed in consideration of the characteristics of the product. .

The size of the emulsified particles may be significantly changed by the weight ratio of water and oil, and the water and oil may be included in the composition in a weight ratio of 35:65 to 45:55. If the weight ratio of water is less than 35:65 relative to oil, the diameter of the emulsified particles may be excessively increased. If the weight ratio of water is more than 45:55 relative to oil, water-in-oil emulsion may not be formed.

The HLB (Hydrophile-Lipophile Balance) value of the surfactant may be 6.0 to 7.0, and 1.0 to 2.0% by volume based on the total volume of the composition.

The HLB value of the surfactant is preferably controlled so as to minimize the diameter of the emulsified particles. The surfactant is not particularly limited as long as it is an amphiphilic substance, but if the HLB value of the surfactant is less than 6.0, the diameter of the emulsified particles may be excessively increased, and the skin penetration ability of the nitrite may be reduced. Since it is not formed, the surfactant can be appropriately selected in consideration of the HLB value and the product characteristics.

In addition, when the amount of the surfactant is less than 1.0% by volume, the diameter of the emulsified particles may be increased, so that an effect of improving erectile dysfunction may not be properly realized. When the content of the surfactant is more than 2.0% by volume, the economical efficiency may be lowered and the original quality of the product may be reduced. have.

The composition may further comprise a transdermal penetration enhancer. The percutaneous penetration enhancer is a substance that promotes the absorption of certain components into the blood vessel cells of the skin, which allows higher levels of penetration of certain components within the skin, particularly in the lower epidermis and dermis, and may result in increased permeation through the skin. It may be.

In general, penetration enhancers suitable for promoting transdermal absorption of drugs or external preparations are known. The penetration enhancers can be classified according to the mechanism of action [Sinha VR, Kaur MP, "Permeation Enhancers for Transdermal Drug Delivery", Drug Dev Ind Pharm. 2000 Nov; 26 (11): 1131-40], preferably, but not limited to, phospholipid components, liposome components and the like used in lecithin cosmetics.

The composition may be formulated with a suitable amount of pharmaceutically acceptable vehicle or carrier to provide a suitable dosage form.

The compositions may be formulated as creams, microneedles and the like depending on the form of use, using suitable methods known in the art or by Remington's Pharmaceutical Sciences (Recent Edition, Mack Publishing Company, Easton PA). It may be formulated using the method disclosed in.

The composition may further comprise one or more adjuvants selected from the group consisting of pharmaceutically acceptable carriers, diluents, excipients, buffers, antimicrobial preservatives, antioxidants, tonicity modifiers, preservatives, thickeners and viscosity modifiers.

The carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline Cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil, but are not limited thereto.

The composition may be used in the form of a suspension, an emulsion, a syrup, an aerosol, or the like, or an external preparation.

Sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations may be used for the formulation. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate may be used.

The composition may be applied in a pharmaceutically effective amount sufficient to treat the disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level may be the type of subject and its severity, age, sex, type of disease, activity of the drug. , Sensitivity to the drug, time of administration, route of administration and rate of release, duration of treatment, factors including concurrent use of the drug, and other factors well known in the medical arts.

The composition may be applied as an individual therapeutic agent or applied in combination with other therapeutic agents and may be applied sequentially or simultaneously with conventional therapeutic agents. In consideration of all the above factors, it is important to apply an amount that can obtain the maximum effect in a minimum amount without side effects, and can be easily determined by those skilled in the art.

The preferred amount of application of the composition may vary depending on the condition and weight of the patient, the severity of the disease, the form of the drug, and the duration of time, and a suitable total daily dose may be determined by the practitioner within the correct medical judgment.

Hereinafter, with reference to the accompanying drawings will be described in detail with respect to embodiments of the present invention, it is apparent that the present invention is not limited by the following examples.

Experiment preparation

All experiments were conducted in accordance with the Experimental Animal Ethics Policy of the Konkuk University Animal Experiment Ethics Committee. The nanoemulsion which does not contain nitrogen monoxide was made into the negative control group.

A mixture of Tween 80 and Span 80 was used as a surfactant, and a water-in-oil type composition in which sodium nitrite solution and vitamin E body oil were mixed was used as an experimental group.

Experimental Example 1 Measurement of Nitric Oxide Production According to Nitrite Concentration

Figure 1 measures the change in the amount of nitrogen monoxide generated in a solution of different concentrations of nitrite.

Referring to FIG. 1, when the concentration of sodium nitrite was 100 mM or more, the amount of nitrogen monoxide generated in the solution increased rapidly. However, when the concentration of sodium nitrite exceeded 800 mM, the amount of nitrogen monoxide did not increase anymore. Decreased.

That is, by adjusting the concentration of sodium nitrite within a certain range, the effect of improving the erectile dysfunction of the composition for improving erectile dysfunction can be appropriately controlled.

Experimental Example 2 Measurement of Particle Size According to HLB Value

Figure 2 is a change in the HBL value of the surfactant, measuring the change in the particle diameter of the emulsion.

In the preparation of the oil-in-water composition of the emulsion type, a water-in-oil emulsion is formed when the HBL value of the surfactant is 7 or less, and an oil-in-water emulsion is formed when it is 9 or more.

Since sodium nitrite was dissolved in water, the diameter of the emulsion particles was measured by adjusting the HBL value to 7 or less to form an oil-in-water emulsion.

Referring to FIG. 2, when the HLB value was 6.0 or more, the average particle diameter of the emulsion particles was less than 1000 nm, and the smallest size emulsion particles were formed at 7.0.

Experimental Example 3 Measurement of Particle Size According to Surfactant / Water / Oil Ratio

Figure 3 is a change in the surfactant, water, oil composition ratio, measuring the change in the particle diameter of the emulsion.

Since the size of the emulsified particles may vary significantly depending on the composition ratio of the surfactant, water, and oil, the diameter change of the emulsified particles was measured while varying the content of the surfactant and the water / oil ratio.

Referring to FIG. 3, when the surfactant is less than 1.0%, small sized emulsified particles are not formed, and when the surfactant is 1.5% by volume and the weight ratio of water and oil is 4: 6, the smallest sized emulsified particles are formed. It became.

If the water content is higher than the oil, the water-in-oil emulsion is not formed properly. If the water ratio is less than 3: 7, the diameter of the emulsion particles in the emulsion becomes excessively large, so that the weight ratio of water and oil is 35:65 to 45:55. It is preferable to control in a range.

Experimental Example 4 Visual Evaluation

As an experimental animal, the erection of the penis was visually evaluated in dogs. After the dog penis was exposed from the epidermis, the composition of the Example was applied to the penis and the change of the penis surface was observed.

When visually confirmed, the erectile negative response does not change the size and color of the penis and no swelling phenomenon is observed. On the other hand, erectile positive reactions increase the size of the penis and bleeding phenomenon is observed.

Referring to FIG. 4, when the external changes of the penis were observed according to the application of the composition, a positive reaction was clearly observed in the experimental group to which the composition of Example 1 was applied, whereas the control group to which the composition was excluded was excluded. In the case of penis size did not change and swelling phenomenon was not observed.

Some redness was confirmed even when the composition except for sodium nitrite was applied, but it was judged to be due to physical stimulation applied to the penis during the experiment, and when the composition of the example was applied, redness was significantly increased compared to the control.

Experimental Example 5 Evaluation of Nitric Oxide Concentration in Blood

As a test animal, blood nitric oxide levels were measured in dogs.

After the dog penis was exposed from the epidermis, the composition of the present invention (600mM sodium nitrite, water / oil weight ratio 40:60, surfactant content 1.5% by volume, surfactant HLB 7.0) was applied to the penis and blood was collected from the corpus cavernosum.

The control group coated with the composition excluding sodium nitrite was collected from the jugular vein because sufficient blood was not collected from the penis.

Referring to FIG. 5, the blood concentration of the control group coated with the composition excepting sodium nitrite was 20 μm, which was not significantly different from usual, but after applying the composition of the present invention, the blood nitric oxide concentration was 60 μm compared with the control group. Increased more than three times.

The foregoing description of the present invention is intended for illustration, and it will be understood by those skilled in the art that the present invention may be easily modified in other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are exemplary in all respects and not restrictive. For example, each component described as a single type may be implemented in a distributed manner, and similarly, components described as distributed may be implemented in a combined form.

The scope of the invention is indicated by the following claims, and it should be construed that all changes or modifications derived from the meaning and scope of the claims and their equivalents are included in the scope of the invention.

Claims (9)

A surfactant having a Hydrophile-Lipophile Balance (HLB) value of 6.0 to 7.0, water, oil, and sodium nitrite,
The surfactant is a mixture of Tween 80 and Span 80,
The oil is a vitamin E body oil,
The concentration of the sodium nitrite is a composition for improving water-in-oil erectile dysfunction of the emulsion type is 200 to 800mM. delete delete delete The method of claim 1,
The water and oil composition comprising a weight ratio of 35:65 to 45:55. The method of claim 1,
The surfactant is 1.0 to 2.0% by volume based on the total volume of the composition. According to claim 1, Terpene, Terpenoid, Essential Oil, Pyrrolidone, Fatty acid, Ester, Sulfoxide, Alcohol ( Alcohol, glycol (Glycol), glycerides (Glyceride), phospholipids (Phospholipid) and liposomes (Liposomes) composition further comprising one or more transdermal penetration enhancer selected from the group consisting of. The method of claim 1,
A composition further comprising one or more adjuvants selected from the group consisting of diluents, excipients, buffers, antimicrobial preservatives, antioxidants, tonicity modifiers, preservatives, thickeners and viscosity modifiers. The method of claim 1,
A composition having an average diameter of the emulsified particles of less than 1000 nm.

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