CN1650872A - Externally used medicine for treating sexual dysfunction - Google Patents

Abstract

The invention relates to an external drug to cure sexual dysfunction, comprising PGI[2] category and carbohydrate. When applied through penis smear administration or urethral administration. The external drug has the advantages of effective absorption, no induced systemic effect, and high efficiency and safety.

Description

The treatment of sexual dysfunctions medicine for external use

Technical field

The present invention relates to effectively to prevent and to treat the external used medicine of penile erectile function obstacle and female sexual disorder disease.

Background technology

Along with the growth of person in middle and old age's population, erection problem person's number also constantly increases naturally.And because the influence of social factor etc., the erection problem among the between twenty and fifty crowd also is on the increase.Tell that the women who lacks voluptus, lacks sexual dysfunction symptoms such as clitoris pleasant sensation, vagina drying, dyspareunia also constantly increases.Therefore, find prevention and the handicapped effective means of therapeutic, sexual life is improved, very important to the raising of quality of life.

Erection problem person among the Japanese, have 42% among the 55-59 year crowd, have 65% among the 65-69 year crowd (such as, Shirai M:Importence 2:67-93,1987), 75% (as Soh J Int J Urol 7 (Supp1 in the diabetics, 88): 110,2000), about 68% (as Burchardt M:J Urol 164 1188,2000) are arranged among the hyperpietic, because of the caused incidence rate of operation on prostate also very high (as Walsh PC:J Urol 128:492-497,1982).The factor of the main cause spiritedness aspect of erection problem, peripheral nerve obstacle, dyshormonia, peripheral circulation disorders, drug-induced side effect or the like a variety of causes, but no matter which kind of reason, the mechanism of erection problem is identical, and that is exactly the intrinsic pressure rising obstacle of cavernous body of penis.Intrinsic pressure rising when the increase of artery blood flow surpasses venous blood flow in the cavernous body of penis produces and erects.Therefore, try every possible means to increase artery blood flow to the treatment the most important.

In order to increase the spongy body blood flow, adopt injection vasodilator PGE1 (PGE in spongy body at present ₁) or the method for papaverin hydrochloride, but patient oneself adopts this method to cause phenomenons such as systemic blood pressure reduces, hemorrhage, local nerve obstacle sometimes, abnormally dangerous, and acting duration is also very short, very inconvenient (as, Shi Jingyan is of a specified duration: modern internal medicine (モ ダ Application Off イ ジ シ ア Application) 19:1135-1137,1999).Simultaneously, various vasodilators are used for when oral nearly unavailable again.Recently, sldenafil increases NO, increasing blood flow by performance phosphodiesterase 5 type inhibitory action, let it be to the greatest extent, and oral result increases, but it to 30% patient invalid (as, Goldenstein J:N Engl J Med 338:1397-1404,1998), the side effect incidence rate reaches 6-54%, sometimes the situation (McMahonCG:JUrol 164:1192-1196,2000) of cardiac sudden death can take place also.It forbids taking to nitric acid medicine user simultaneously, and the scope of application has limitation.

Therefore, people wish to develop by being applied on the penis or placing and medicine is effectively absorbed, can continue to increase the penis sponge blood flow, do not cause the safe external used medicine of systemic effect.

Prostaglandin I ₂(PGI ₂) derivant has very strong platelet condense inhibitory action and vasorelaxation action, is used for the treatment of peripheral circulation disorders etc.And, to containing prostaglandin I ₂The slow release type preparation of derivant and hydrogel matrix also have report (as, international disclose No. 98/41210 communique and the world discloses communique No. 99/33491).But, prostaglandin I ₂The effect that derivant is used for penis outward, cause to erect is also not known fully up to now.

In addition, glucide and local administration preparation are used the aspect, report if add saccharide in granulocyte colony-stimulating factor (G-CSF), can promote so G-CSF through the absorption of nasal mucosa (as, the spy opens bulletin flat 8-198772 number).But, prostaglandin I ₂Derivant and saccharide are united the preparation of use, no matter be that what dosage form is also not known so far.

Summary of the invention

The purpose of this invention is to provide the treatment of sexual dysfunctions medicine for external use, it by be applied on the penis or in the urethra administration form effective absorption, do not cause systemic effect, not only very effectively but also as safe as a house.

Inventors of the present invention are according to above-mentioned practical situation, and the medicine of the effect for the treatment of each sexual dysfunction such as erection problem is brought into play in research and development by penis or the direct administration of urethra.Found that prostaglandin I ₂Although it is invalid substantially when being used for position such as penis that class is separately outer, if but and saccharide until urethra fabulous absorption is arranged all from penile surface when using together, have tangible blood flow increase effect, can be used as the medicine for external use that is used to prevent and treat each sexual dysfunction such as erection problem.

In other words, the present invention is to provide and contain prostaglandin I ₂The treatment of sexual dysfunctions external used medicine of class and saccharide.

Treatment of sexual dysfunctions external used medicine of the present invention, so be the local topical preparation because of external is applied to penis, female sexual organ or urethra etc., it is absorbed well by the skin and the mucosa of glans penis, penis etc., and blood flow is increased, and causes erection.Therefore, use this preparation, have low aggressivity, very safe, the penile erectile function obstacle and the female sexual disorder disease that can be used for the treatment of the male can make the sexual dysfunction patient's who comprises the old people sexual life be tending towards normally, thereby improve their quality of life.

Brief description of drawings

Fig. 1 is the illustraton of model (A: injector type, B: cover the formula cylinder type) that is used for the cartridge syringe of administration in the urethra.

1: infusion appliance the slot type cartridge case arranged, 2: the built-in tube of the preparation of syringe, 3: insert with pipe 4: lid, 5: the scale of expression dosage.

After using for the glans penis position is coated with, passes Fig. 2 the variation diagram of surface temperature in time.

Fig. 3 is a variation diagram of passing surface temperature in the urethra after the injection administration in time.

The specific embodiment

Prostaglandin I among the present invention ₂Class comprises prostaglandin I ₂(prostacyclin), prostaglandin I ₂Sodium (prostacyclin sodium) and other various prostaglandin Is ₂Derivant.As prostaglandin I ₂Derivant, preferred especially 4, in the 8--the metaphenylene prostaglandin I ₂Derivant (such as, special fair 2-12226 number bulletin, special fair 2-57548 number bulletin, special fair 1-53672 number bulletin etc.), specifically can enumerate Beraprost, limaprost, iloprost, clinprost, ataprost, western prostatitis element (シ Port ロ シ チ Application) but, receive prostalene (Na Network サ Port ロ ス テ Application), taprostene, cicaprost, pimilprost, CH169, SM-10902 and their salt.Wherein, from the angle of penile blood flow increase effect and erection initiation effect, preferred especially Beraprost ((+)-(1R ^*, 2R ^*, 3aS ^*, 8bS ^*)-2,3,3a, 8b-tetrahydrochysene-2-hydroxyl-1-[(E)-(3S ^*)-3-hydroxy-4-methyl-1-octene-6-alkynyl]-1H-encircles penta [b] benzofuran-5-sodium butyrate).

Here said prostaglandin I ₂Derivant can be synthetic by conventional method (spy opens clear 58-124778 communique, special fair 6-62564 communique etc.), also can extract to make with extra care and get from the preparation of market sale.

Saccharide among the present invention can be enumerated polysaccharides such as three saccharides such as disaccharides, Raffinose, starch, dextrin, alpha-cyclodextrin, glucosan, amylopectin (pullulan), cellulose, arabic gum, Tragacanth, agar such as monosaccharides such as glucose, dextrose, galactose, fructose, mannose, xylose, maltose, lactose, sucrose (comprising white sugar and water Mel etc.), trehalose.Wherein, from the angle of penile blood flow increase effect and erection initiation effect, preferred glucose, fructose (particularly D (-) fructose), sucrose, cellulose.

The saccharide here may be used alone, can also be two or more kinds in combination.

Treatment of sexual dysfunctions external used medicine of the present invention, preferred prostaglandin I on the effect ₂Add saccharide 1～1000mg, preferred 20～1000mg among class 1～5000 μ g.

Prostaglandin I ₂Apoplexy due to endogenous wind adds saccharide gained preparation, shown in the embodiment that puts down in writing later, with this prostaglandin I ₂The class medicine is coated with when being used for penis or being used in the urethra invalid substantially situation separately and compares, and adds that significant penile blood flow increase effect has been given play in pharmaceutical preparation behind the saccharide and erection causes effect.This shows, this preparation is effectively as the external used medicine that is used to prevent and treat the male penis erection obstacle, also can be used as to improve the external used medicine that female sexual disorder such as voluptus (excitatory state) lack (dysaphia, clitoris anaesthesia, vagina drying, urinary incontinence or dyspareunia etc.) symptom.

Swelling forms the polymer substance of gel particles and is used treatment of sexual dysfunctions of the present invention with meeting promptly that water can absorb water with gellant in the medicine for external use, as polysaccharide, protein, synthetic polymer etc.By these means, penile blood flow be can further improve and effect and erection initiation effect increased, can also have the effect of reducing friction and preserving moisture simultaneously.

The gelating agent here, alginate (as sodium salt) can have been enumerated, Thallus Laminariae (Thallus Eckloniae) extract, Sargassum extract or composition alduronic acid wherein such as fucosan, also has guar gum, plant seed stickums such as locust bean gum, also has chondroitin sulfate, hyaluronic acid or its salt, mucopolysaccharides such as dermatan sulfate, also has gelatin, albumin, casein, animal proteinums such as end collagen, also has carboxymethyl cellulose, methylcellulose, cellulose and derivants thereof such as microcrystalline Cellulose also have polyvinyl alcohol, polyacrylate (sodium polyacrylate etc.), synthetic polymers such as poly(ethylene oxide).And preferred above material mixes use more than a kind.

The use amount of this gelating agent is considered from the angle that causes erection effect, moistening effect, the resistance effect of reducing friction, and the ratio preferably approximately 0.1～50% that it accounts for the gross weight of preparation is more preferably about 5～20%.

In order to improve the stability of component, can in medicine for external use of the present invention, allocate the buffer agent of lactic acid class, phosphoric acid class, Fructus Citri Limoniae acids, tartaric acids into, expectation suitably uses these buffer agents to make pH value be adjusted into 5.5～7.5, and preferred 7.0.

In addition, effective ingredient be can in the scope that does not hinder stability, add in the external preparation of the present invention, promoter, nitric oxide generation agent, phosphodiesterase 5 type inhibitor etc. produced as hormone, estrualization agent, sperm with increasing blood flow and sexual function improving effect.This composition has Testosterone Propionate (androgen), Yohimbine Hcl alkali (estrualization agent), amino acids (lysine (sperm produces promoter), arginine (nitric oxide generation agent) etc.), ornithine sodium (ATP produces agent), sldenafil (phosphodiesterase 5 type inhibitor) etc. for instance.

Female sexual organs such as external preparation of the present invention is applicable to mainly that the glans penis, foreskin, penis cervical region, penis of penis are done, scrotum and urethra, vagina, this medicine for external use can be prepared with conventional preparations carrier, can make by the method for routine and be applicable to the skin mentioned and the arbitrary shape of mucosa affected part, as forms such as solution, powder, ointment, varnish, cream, gel, Emulsion, spray, suppositorys.

Preparations carrier can be enumerated oils (lanoline, vaseline, polyethylene glycols etc.), emulsifying agent (various surfactants etc.), thickening agent (acrylic copolymer, fructose, Brazil wax, the agar end, glycerol, Magnesiumaluminumsilicate, refining gelatin, hydroxyethyl-cellulose, hydroxypropyl cellulose, propylene glycol, sodium polyacrylate etc.), sticker (sodium alginate, xanthan gum, Magnesiumaluminumsilicate etc.), dispersant (Radix Acaciae senegalis, propylene glycol alginate, CVP Carbopol ETD2050, hydroxyethyl-cellulose, methylcellulose, propylene glycol, polysorbate, Polyethylene Glycol etc.), solubilizing agent (tartaric acid, citric acid, lactic acid, the L-aspartic acid, sorbitan carboxylic esters, hydroxypropyl cellulose, polyoxyethylene hardened castor oil, liquid paraffin etc.), stabilizing agent (aminoacid or its salt etc.), absorption enhancer (sodium glycollate, edetate sodium etc.), dissolving adjuvant (polyoxyethylene hardened castor oil, polysorbate 80, Polyethylene Glycol etc.), disintegrating agent (corn starch, carboxymethyl cellulose etc.), excipient is (as lactose, white sugar, mannitol, crystalline cellulose, silicic acid), binding agent (crystalline cellulose, saccharide, dextrin), lubricant (magnesium stearate, calcium stearate, Pulvis Talci), also has antiseptic, isotonic agent, the pH regulator agent, antioxidant, buffer agent, antistaling agent, aromatic, coloring agent, fragrance etc.

The urethral bougie that is used for administration in the urethra is generally elongated pencil shape, has the shape that is fit to insert urethra, and the male is 7～14cm with length, and women's length is 5～7cm.Drug-delivery preparation can be made and be fit to be administered to endo-urethral size in the urethra of solid or semi-solid, is below the 1cm as length.If drug-delivery preparation in the liquid urethra then directly injects administration or the employing endo-urethral utensil that can insert resemble the flexible pipe in case of necessity and injects administration.

Treatment of sexual dysfunctions of the present invention is with the dosage of medicine for external use, if medicine is coated with up then each administration 0.1～5g, preferred 0.5～1.0g; If the interior administration of urethra, then each administration 0.1～5.0g, preferred 0.25～0.5g.

Below further specify with embodiment, but the present invention is not limited in these embodiment.

Embodiment

The preparation of embodiment 1 liquid preparation

Add normal saline 10ml in the powder of beraprost sodium 25 μ g, D-(-) fructose 2g, fully mix, preparation cost invention product 1.

Below use the same method and make the liquid preparation of the present invention's product 2～12 shown in the following table 1～2 and reference substance 1～3.

In addition, extracting from " DORNER sheet " (eastern beautiful Yamanouchi) that beraprost sodium uses obtains.

Table 1

(liquid preparation)

		Product of the present invention							Reference substance
												??1	??2	??3	??4	??5	??6	??7	??1	??2	??3
		Beraprost (μ g)		??25	??50	??200	??25	??50	??200	??50	??25											??50	??200
Saccharide	D-(-) fructose (g)											??2	??2	??2	??2	??2	??2
		Cellulose (g)							??2
	Sodium polyacrylate (ml)														??2	??2	??2
Normal saline (ml)			??10	??10	??10	??8	??8	??8	??10	??10	??10											??10

Table 2

(liquid preparation)

		Product of the present invention
							8	?9	?10	?11	?12
		Beraprost (μ g)		200	?200	?200						?200	?200
Saccharide	D-(-) fructose (g)						2
		Glucose (g)		2	?2
	Sucrose									2	?2
		L (+) sodium alginate (g) 150pc		0.5		?0.5							?0.5
Normal saline							10	?10	?10	?10	?10

The preparation of embodiment 2 powder agents (powder)

Add D-(-) fructose 2g among the Beraprost 200 μ g, add L (+) sodium alginate 0.5g again, fully mix then, thus preparation cost invention product 14.Below use the same method and make the powder agent of the present invention's product 13～15 as shown in table 3 below.

Table 3

(powder agent)

	Product of the present invention
				13	?14	?15
	Beraprost (μ g)	200	?200				?200
Glucose (g)				2	?2	?2
	L (+) sodium alginate (g) 150pc		?1
Sodium carboxymethyl cellulose (g)						1

Embodiment 3 clinical researches

(1) object

60～69 years old 5 people that are engaged in medical authority, do not see to play erection morning are object of study.After obtaining oral informed consent, carried out following research between year December in putting down in May, 15 to 15.

In the environment of 25 ℃ of room temperatures, humidity 60%, the lower part of the body is sloughed clothing and is kept peace and quiet in 5 minutes, measures penis temperature, cavernous body of penis oxygen saturation, penis hardness then.Be worth in contrast with the value before the administration, measure after the administration 1 hour, 3 hours, 6 hours, 12 hours, 24 hours, 36 hours value respectively, express changing value (changing value+average deviation).After the administration 3 hours as no change, then as invalidation, stop immediately measuring.

(2) drug administration method

1) semar technique: be coated with full glans penis, penis with each preparation of 0.5ml.

2) urethra injection method: the instrument used for injection with silicon system flexible pipe is arranged on the head as shown in Figure 1, this infusion appliance is inserted urethra, rotatable cartridge is injected preparation 1ml.

(3) metric method

1) penis variations in temperature algoscopy

Temperature raises and illustrates that blood flow increases.Therefore, we measure the penis temperature with heat determination instrument (Thermography) (FUKUTA electronics).Use this device, can on picture, indicate the position,, therefore carried out quantitative analysis, and compare before the administration at same position with the temperature at numeric representation this position.

2) penis hardness determination

The increase of penis hardness is then erected.Therefore, we (Hardness testerSD6-11, probe Mitsutoyo) are pressed in the back, left side of penis and measure hardness, represent with mm, relatively before and after the administration with durometer.

(4) result

1. the glans penis effect of smearing

A) penis variation of temperature

Fig. 2 represents, respectively reference substance 1 (Beraprost 25 μ g and normal saline), reference substance 2 (Beraprost 50 μ g and normal saline), product of the present invention 1 (Beraprost 25 μ g and fructose 2g also have normal saline), product of the present invention 2 (Beraprost 50 μ g and fructose 2g also have normal saline) is applied in the rising degree and the time experience of back penile surface temperature on penis and the glans penis.

Reference substance 1 is not seen variations in temperature fully, and reference substance 3 has temperature to raise and continues more than 48 hours.Reference substance 2 has only a little temperature to raise, and product of the present invention 2 has obvious rising and continues more than 48 hours.Simultaneously, penis hardness as shown in table 4 have continue to increase.Show that thus fructose has promoted the absorption of Beraprost.

Other preparations also are as shown in table 4, and the sucrose of the fructose of monosaccharide and glucose, disaccharides has strengthened the effect of Beraprost.The sodium alginate of gel class, sodium polyacrylate itself are not seen potentiation, but find that the preparation that has added monosaccharide, disaccharides and gel has simultaneously shown potentiation.The result of powder formulation also is same.

B) variation of penis hardness

Each preparation of table 4 demonstration is smeared the increase degree of back penis hardness.Reference substance 1,2 does not have hardness to increase substantially, but the product of the present invention 1 and 2 that has added fructose has remarkable increase.This shows that they have strengthened the erection effect of Beraprost.Cooperate the preparation that other monosaccharides use, the preparation that has added gel all to show reinforced effects equally.In addition, the result of powder formulation also is same.

Table 4

Be applied in the maximum value added and the persistent period of penis temperature behind the penis, hardness

		Variations in temperature (degree centigrade)	Temperature raises the persistent period				Hardness (mm)
								?＜12	??12-24	??24-48	?48＜
			Product of the present invention (liquid preparation)	??1	??1.9									??*	??100
??2	??3.2								??*	??130
				??3	??4.7								??*	??190
??4	??1.7								??*	??110
				??5	??3.0								??*	??130
??6	??4.8								??*	??145
				??8	??4.6								??*	??167
??9	??4.7								??*	??150
				??10	??4.8								??*	??190
??11	??4.2								??*	??140
				??12	??4.8								??*	??150
Product of the present invention (powder agent)	??13	??4.0								??*					??150
			??14	??3.8								??*	??130
	??15	??4.1								??*				??135
			Reference substance	??1	??0										??0
??2	??1.0						??*			??25
				??3	??3.1						??*			??120

2. inject the effect of administration in the urethra

Fig. 3 represents variations in temperature degree and the time duration after the injection administration in reference substance 1 and 2, product of the present invention 1 and 2 urethras.Product 1 of the present invention and 2 temperature raise, hardness increases, and show that saccharide has promoted the absorption of Beraprost by mucous membrane of urethra.As shown in table 5, other preparations have shown the absorption facilitation effect of saccharide too.

Table 5

Penis temperature after injecting in the urethra, the maximum rising value and the persistent period of hardness

		Variations in temperature (degree centigrade)	The temperature rise time				Hardness (mm)
								?＜12	??12-24	???24-48	?48＜
			Product of the present invention (liquid preparation)	??1	??0.8							??*			??85
??2	??2.3								??*	??120
				??3	??4.9								??*	??180
??4	??1.0						??*			??100
				??5	??2.5								??*	??100
??6	??4.6								??*	??150
				??7	??2.5						??*
??8	??3.7								??*	??155
				??9	??4.2								??*	??155
??10	??3.8								??*	??130
				??11	??3.5								??*	??130
??12	??3.5								??*	??120
				Reference substance	??1	??0									??0
??2	??0.3								??0
					??3	??2.6					??*			??100

Embodiment plays the research of erection 3 mornings

(1) method

Rising morning erects is the good index that expression has erectile ability.Therefore, we choose and do not see the 4 routine objects that play erection morning, as shown in table 6 product of the present invention are applied on the glans penis, and whether research erection takes place to rise morning.

(2) result

That table 6 shows is exactly the result who this time studies.Use reference substance 1～3 that Beraprost and normal saline be made into, or do not have and play erection morning, even or have, number of times is also seldom.And use product of the present invention generation high-frequency erection.

Table 6

		Erect early morning and routine number occurs
			Product of the present invention	1	1/4
2	2/4
		3		4/4
7	4/4
		9		3/4
11	3/4
		Reference substance		1	0/4
2	0/4
			3	2/4

Embodiment 4 stability of formulation

Product of the present invention shown in the table 7 is 4 degrees centigrade of stored refrigerated, after the 2nd week, 1 month, after 2 months, be applied in the glans penis position, comparative effectiveness after 4 months.As shown in table 7, even the present invention's product still are stable through long preservation, drug effect is constant.

Table 7

	The stored refrigerated time
							Take out immediately	2 weeks	1 month	2 months	4 months
Product 3 of the present invention	?4.7	?4.4	?4.4	?4.1	?4.2
						Product 9 of the present invention	?4.0	?4.1	?4.2	?4.0	?3.8
Product 12 of the present invention	?4.8	?4.4	?4.4	?4.3	?4.3
						Reference substance 3	?3.0	?1.8	?1.0	?1.1	?0.4

Claims (7)

1. the treatment of sexual dysfunctions external used medicine contains prostacyclin I2 class and saccharide.

2. the treatment of sexual dysfunctions external used medicine of putting down in writing as claim 1, saccharide wherein is selected from glucose, fructose and sucrose.

3. as claim 1 or 2 treatment of sexual dysfunctions of being put down in writing external used medicines, prostacyclin I2 class wherein is a beraprost sodium.

4. as any one treatment of sexual dysfunctions of being put down in writing external used medicine of claim 1～3, also contain gelating agent.

5. as any one treatment of sexual dysfunctions of being put down in writing external used medicine of claim 1～4, also contain nitric oxide and produce agent.

6. as any one treatment of sexual dysfunctions of being put down in writing external used medicine of claim 1～5, to carrying out administration in penis, female sexual organ or the urethra.

7. as any one treatment of sexual dysfunctions of being put down in writing external used medicine of claim 1～6, be the medicine of prevention or treatment penile erectile function obstacle or female sexual disorder disease.