Improved Methods and Compositions for Treating Male Erectile Dysfunction

专利摘要:
(a) prostaglandin vasodilators; (b) 15-hydroxyprostaglandin dehydrogenase inhibitor; And (c) administration of a pharmaceutical composition in the form of suppositories containing a substrate which is solid at room temperature and which releases components (a) and (b) upon insertion into the urethra or urinary tract is effective in treating male erectile dysfunction.
公开号:KR20010021625A
申请号:KR1020007000183
申请日:1998-07-09
公开日:2001-03-15
发明作者:게리 더블유. 닐
申请人:추후보정；안드로솔루션스, 인크.；
IPC主号:

专利说明:

Improved Methods and Compositions for Treating Male Erectile Dysfunction
Background of the Invention
Field of Invention
The present invention relates to a method of treating erectile dysfunction in men.
The invention further relates to pharmaceutical compositions useful for the treatment of erectile dysfunction in men.
<Review of Background>
Lack of men's ability to engage in sexual intercourse or inability to intercourse is often a joke. However, many men suffer from this problem. Impotence is generally characterized by a lack of erectile maintenance and is commonly referred to as erectile dysfunction. Erectile dysfunction affects men regardless of age, place of birth, or early biblical experience.
The term "erectile dysfunction" in the context of the present invention refers to any disorder of the fascia associated with the cavernous tissue of the penis which causes impotence and erectile dysfunction. Impotence is estimated to affect at least 10 million men in the United States alone. Impotence occurs due to the breakdown of any of the physiological or psychological factors that balance the flow of blood from and into the penis, thereby maintaining sufficient blood retention that causes tight expansion of the penis and the catheter. . In the present invention, the term "erectile dysfunction" is used in the broadest sense, meaning a lack of ability to erect when desired.
Treatment for erectile dysfunction includes sexual psychotherapy, hormonal therapy, administration of vasodilators such as nitroglycerin and α-adrenergic blockers (hereinafter referred to as "α-blockers"), surgical operations of the vessels, insertion of prosthetic prostheses, The use of external aids, such as a ring to tighten the penis to change the flow of blood through the penis or a penis support to the penis (Robert J. Krause, et al.). , N. Eng. J. Med., Vol. 321, No 24, Dec 14. 1984). Many patients treat their impotence by injecting vasoactive agents directly into the corpus cavernosum (see earlier in 1st Symposium International Sur L'Erection Pharmacologique, 17-19 Nov. 1989, Paris, P. 2; Virag). , Angiology, vol. 35, pp. 79-87, (1984); and US Pat. Nos. 4,127,118, 4,766,889, and 4,857,059, which are incorporated herein by reference). The most commonly used drugs include α-blockers such as phenoxybenzamine and phentolamine; Muscle relaxants such as papaverine; Prostaglandins having vascular functional functions such as prostaglandin E _1, and the like. In addition, the binding of such drugs with different receptors has a therapeutic effect. The amount of papaverine injected into the cavernous body generally ranges from about 7.5 to 160 mg. While the amount of phentolamine is about 0.1 to 10 mg and the amount of prostaglandin E ₁ is in the range of about 2.5 to 50 μg. (Kurkle et al., Urol. Clin. Of America, vol. 15, No. 4, pp. 625-629 (1988) and N. Ishii et al., J. of Urol., Vol. .141, pp. 323-325 (1989). Vasofunctional intestinal peptides are known to cause erections by injecting 10-100 μg of intracavernous bodies (H. Handelsman, Diagnosis and Treatment of Impotence, US Dept. of Health Services, Agency for Health Care Policy and Research, April 1990).
However, patients often find it inconvenient to inject the vascular agent, as evidenced by mental confusion, pain, trauma, or a high rate of disconnection (S. Althouf, et al., Journal of Sex and Marital Therapy, vol. 15, No. 2, pp. 121-129 (1989)). Moreover, side effects are also known, including sustained erections, corporeal nodules and diffuse fibrosis, drug resistance, bruising and hematoma, boils and ulcers in the penile skin injections.
According to U.S. Patent 5,270,323, oral administration of sildenafil for erection improvement was recently approved by the FDA and widely reported by the media. Sildenafil is thought to work by inhibiting the destruction of cyclic GMP in the penis by specific phosphodiesterases. Clinical trials on sildenafil are limited and it is difficult to see how effective it is in general use. It would be effective for 40% of the general number of men with erectile dysfunction. Among the general public, recent reports on the long-term stability of Sildenafil and the sudden death of those who used it have drawn attention.
U. S. Patent No. 5,731, 339 discloses oral use of phentolamine as a possible treatment for erectile dysfunction in men. According to a recent annual report by the American Urological Association, oral phentolamine is effective for only 20-30% of men suffering from mild erectile dysfunction (Goldstein, I. et al. See Abstract # 919, The Journal of Urology, V. 159 (5), May 1998, 240.).
US Pat. No. 5,718,917 discloses the use of a meatal dose of lyophilized PGE-1 for erectile dysfunction. The aforementioned U.S. Urological Association (AUA) annual report (unpublished results from discussions in The International Society on Impotence, AUA 93rd Annual Meeting, May 30, 1998) is a preliminary review without any assessment of efficacy. Only looking.
U.S. Patent 5,708,031 discloses the use of PGE-2 in the urethra in the treatment of erectile dysfunction. The administration method shown in this patent example requires a forceps of the catheter and the penis. The results described fit in the best case. Many men are unlikely to consider using catheter and penile forceps to achieve such results.
Administration of vasodilating drugs through the urethra of men for erection is disclosed in US Pat. No. 4,801,587 and EPA 0357581. Transuretic administration of testosterone is also reported (see Bulletins et Memoirs de la Societa Roumaine D'Endocrinologies, Vol. 5, pp. 434-437 (1989), S.M. Milco). Urinary administration of cocaine is also claimed to help with erection (JAMA, vol. 259, No. 21, page 3176 (1988)). Nitroglycerin coated erectile induction condoms are disclosed in US Pat. No. 4,829,991.
However, to date, there is no method for effectively and completely treating male erectile dysfunction. Therefore, there is still a need for treatment of male erectile dysfunction. There is also a need for compositions that are effective in treating male erectile dysfunction. In particular, there is a need for methods and compositions for treating impotence that have properties that reduce pain, prolonged erection, body nodules, diffuse fibrosis, and the induction of scars.
Summary of the Invention
Therefore, it is one of the objects of the present invention to provide a novel treatment for male erectile dysfunction.
It is yet another object of the present invention to provide a treatment for male erectile dysfunction, including topical, uratal, and / or urethral administration or injection of drugs into the cavernous body.
It is another object of the present invention to provide a treatment for male erectile dysfunction with a reduced tendency to cause pain or burning sensation.
It is another object of the present invention to provide a treatment for male erectile dysfunction with a sustained erectile tendency.
It is another object of the present invention to provide a treatment for male erectile dysfunction with a reduced tendency to cause somatic nodules.
It is another object of the present invention to provide a treatment for male erectile dysfunction with a reduced tendency to cause diffuse fibrosis.
It is another object of the present invention to provide a treatment for male erectile dysfunction with a reduced tendency to cause damage to the urethral cavernosa and the corpus cavernosum.
It is another object of the present invention to provide novel pharmaceutical compositions useful for treating male erectile dysfunction.
It is another object of the present invention to provide a pharmaceutical composition for treating male erectile dysfunction with a reduced tendency to cause pain or burning pain.
It is another object of the present invention to provide a pharmaceutical composition for treating male erectile dysfunction with a reduced tendency to prolong erection.
It is another object of the present invention to provide a pharmaceutical composition for treating male erectile dysfunction with a reduced tendency to cause somatic nodules.
It is another object of the present invention to provide a pharmaceutical composition for the treatment of male erectile dysfunction, which is effective topically, and / or for urethral application or injection into the cavernous body.
It is another object of the present invention to provide a pharmaceutical composition for treating male erectile dysfunction with a reduced tendency to cause diffuse fibrosis.
It is another object of the present invention to provide a pharmaceutical composition for treating male erectile dysfunction with a reduced tendency to cause damage to the urethral and cavernous bodies.
As will be described later, the above objects are (a) vasodilators found by the present inventors; And (b) a 15-hydroxyprostaglandin dehydrogenase inhibitor.
It is particularly effective in treating male erectile dysfunction even at low doses.
In a preferred embodiment, the pharmaceutical composition is in the form of a urethral suppository, which comprises: (a) a prostaglandin vasodilator; (b) a 15-hydroxyprostaglandin dehydrogenase inhibitor; And (c) a substrate which is solid at room temperature and which releases the components (a) and (b) when inserted into the urethra or into the ureter.
In a preferred embodiment, the component (c) is a substrate which is solid at room temperature but melts or dissolves when inserted into the urethra or ureter to release the components (a) and (b).
<Overview of Drawings>
Various other objects, features and ancillary advantages of the present invention will be better understood when considered in connection with the accompanying figures or corresponding parts throughout the several views, like reference numerals below.
1 is a cross-sectional view of the male urethra;
2 is a side view of one embodiment of the present urethral suppository;
3 is a side view of one embodiment of the present urethral suppository;
4 is a side view of one embodiment of the present urethral suppository;
5 is a side view of one embodiment of the present urethral suppository;
6 is a side view of one embodiment of the present urethral suppository;
7 is a cross sectional view of one embodiment of the present urethral suppository;
8 is a cross-sectional view of one embodiment of the present urethral suppository;
9 is a cross-sectional view of one embodiment of the present urethral suppository;
10 is a cross sectional view of one embodiment of the present urethral suppository;
11 shows the results of PGDH inhibition analysis of palmitic acid (◆) and oleic acid (▲);
12 shows the heart of cavernosal artery (CA) peaks as a function of time after administration of a composition according to the invention for five men (◆, ■, ▲, ×, and *) without erectile dysfunction as controls. The change in contractile blood flow is shown graphically;
FIG. 13 graphically depicts cardiac contractile blood flow changes of cavernous artery (CA) peaks as a function of time after administration of a composition according to the invention to five patients with erectile dysfunction will be;
FIG. 14 graphically shows the change in coronary artery (CA) peaks in cardiac contractile blood flow as a function of time after administration of a composition according to the invention for four patients (◆, ■, ▲, and ×);
FIG. 15 shows changes in cardiac contractile blood flow of cavernous artery (CA) peaks as a function of time after administration of a composition containing PGE-2 125mcg (◆) and a composition comprising 125mcg PGE-2 and 1.25mg (■) oleic acid. Is shown graphically;
16 is a composition containing 500 mcg of PGE-2 (◆); Composition (■) containing 500 mcg of PGE-1; And changes in cardiac contractile blood flow of cavernous artery (CA) peaks as a function of time after administration of a composition containing 125 mcg of PGE-2 and 1.25 mg of oleic acid (+);
FIG. 17 shows a composition (◆) containing 25 mcg of PGE-2 and 250 mcg of palmitic acid; FIG. Composition (■) containing 100 mcg of PGE-2 and 1 mg of palmitic acid; And a change in the cardiac contractile blood flow of the cavernous artery (CA) peak as a function of time after administration of the composition (▲) containing 125 mcg of PGE-2 and 1.25 mg of palmitic acid; And
18 is a composition containing PGE-2 125mcg (◆); Composition (■) containing 125 mcg of PGE-2 and 1.25 mg of oleic acid; And changes in cardiac contractile blood flow of cavernous artery (CA) peaks as a function of time after administration of a composition (▲) containing 125 mcg of PGE-2 and 1.25 mg of palmitic acid.
<Detailed Description of the Preferred Embodiments>
In a first embodiment, the present invention provides novel pharmaceutical compositions useful for treating male erectile dysfunction. The pharmaceutical composition comprises (a) a vasodilator; And (b) a 15-hydroxyprostaglandin dehydrogenase inhibitor.
The vasodilator may be any vasodilator as long as it is physiologically acceptable. Examples of suitable vasodilators include (a) nitroglycerin, isosorbide dinitrate, amyl nitrate, isosorbide mononitrate, erythrityl tetranitrate, and sodium nitroprus Nitro vasodilators including but not limited to sodium nitroprusside; (b) prazosin, phentolamine, phenoxybenzamine, dibenzamine, doxazosin, terazosin, trimazosin, tolazoline, tolazoline, corynthanine, Alphablocking agents including but not limited to rauwolscine, and piperoxan; (c) other adrenoreceptors, including but not limited to yohimbine, labetalol, carvedilol, terbutaline, and bucindolol. agents); (d) unspecified vasodilation, such as papaverine; And (e) polypeptide neurotransmitters such as vasodilatory intestinal peptide (VIP), calcitonin, calcitonin gene related products, VIP analogs, and cholecystokinin, and all analogs thereof, such as CCK8.
Preferably the vasodilator is prostaglandin. Suitable prostaglandins include PGE-1; PGE-2; PGA-1; PGB-1; PGD-2; PGE-M; PGF-M; PGH-2; PGI-2; 19-hydroxy-PGA-1; 19-hydroxy-PGB-1; PGA-2; PGB-2; 19-hydroxy-PGA-2; 19-hydroxy-PGB-2; PGB-3; 16,16-dimethyl-Δ ² -PGE-1 methyl ester; 15-deoxy-16-hydroxy-16-methyl-PGE-1 methyl ester; 16,16-dimethyl-PGE-2; 11-deoxy-15-methyl-PGE-1; 16-methyl-18,18,19,19-tetrahydrocarbacycline; (16RS) -15-deoxy-16-hydroxy-16-methyl-PGE-1 methyl ester; (+)-4,5-didehydro-16-phenoxy-α-tetranor-PGE-2 methyl ester; 11-deoxy-11a, 16,16-trimethyl-PGE-2; (+)-11a, 16a, b-dihydroxy-1,9-dioxo-1- (hydroxymethyl) -16-methyl-trans-prosten; 9-chloro-16-16-dimethyl-PGE-2; Arboprostil; Iloprost; CL 115,347; 16,16-dimethyl-PGE-2; 15 (S) -15-methyl-PGE-2; 9-deoxy-9-methylene-16,16-dimethyl-PGE-2, potassium salt; Carbaprostacycline; Prostaglandin D ₂ ; 19 (R) -hydroxy-PGE-2; 13,14-dihydro-PGE-1; 11β-PGE-2; 19 (R) -hydroxy-PGE-1; 11-deoxy-16,16-dimethyl-PGE-2; And any semi-synthetic or synthetic derivatives of such natural prostaglandins or derivatives or prostaglandins that can act as vasodilators or neuromodulators and are not limited to those listed above. Cyclodextrin complexes are also included to enhance the activity of the solution and to stabilize prostaglandins. Also included are racemates which are optically enhanced or purified stereoisomers of such compositions. Physiologically acceptable salts are also included. Preferably, the prostaglandins are PGE-1, PGE-2, PGD-2, and CL 115,347. Most preferably the prostaglandins are PGE-2 or PGE-1.
PGE-1, prostaglandin E ₁ is also known as alprostadil or PGE ₁ . The official chemical name of PGE-1 is 3-hydroxy-2- (3-hydroxy-1-octenyl) -5-oxocyclopentaneheptanoic acid and the structure of PGE-1 is as follows.

Prostaglandins E ₁ are described in Bergstrom et al., Acta Chem. Scand., Vol. 16, p. 501 (1962) and J. Biol. Chem., Vol. 238, p. 3555 (1963)] may be isolated from sheep seminal vesicle tissue. Prostaglandin E ₁ is described in Cory et al., J. Am. Chem. Soc., Vol. 91, p. 535 (1969); Corey et al., J. Am. Chem. Soc., Vol. 92, p. 2586 (1970); Shih et al., J. Am. Chem. Soc., Vol. 94, p. 3643 (1972); Shih et al., J. Am. Chem. Soc., Vol. 95, p. 1676 (1973); Schaaf et al., J. Org. Chem., Vol. 37, p. 2921 (1974); And Slates et al., Tetrahedron, vol. 30, p. 819 (1974).
PGE-2, prostaglandin E ₂ is also known as dinoprostone or PGE ₂ . The official chemical name of PGE-2 is 7- [3-hydroxy-2- (3-hydroxy-1-octenyl) -5-oxocyclopentyl] -5-heptanoic acid, and the structure of PGE-2 is as follows. .

Prostaglandin E ₂ is described in Bergstrom et al., Acta Chem. Scand., Vol. 16, p. 501 (1962), can be isolated from sheep seminal vesicle tissues according to the methods described. Prostaglandin E ₂ is described in Corey et al., J. Am. Chem. Soc., Vol 92, p. 397 (1970); Corey et al., J. Am. Chem. Soc., Vol. 92, p. 2586 (1970); Heather et al., Tetrahedron Letters, p. 2313 (1973).
Both prostaglandins E ₁ and E ₂ are commercially available from Sigma Chemical Company of St. Louis, MO. PGE-2 is also commercially available from Pharmacia & UpJohn, Kalamazoo, MI, as a PROSTIN E-2 suppository and as a PREPIDIL GEL and as Cervidil. The following company [St. Forrest Pharmaceuticals, Inc. of Louis, MO.
15-deoxy-16-hydroxy-16-methyl-PGE-1 methyl ester is also known as misoprostol and its official chemical name is (±) -methyl- (1R, 2R, 3R) -3-hydroxy Ci-2-[(E)-(4RS) -4-hydroxy-4-methyl-1-octenyl] -5-oxocyclopentaneheptanoate. 15-deoxy-16-hydroxy-16-methyl-PGE-1 methyl ester can be prepared according to the methods described in US Pat. No. 3,965,143. And this patent is incorporated herein by reference.
Enprostil is the official chemical name [1α, 2β (1E, 3R ^* ), 3α] -7- [3-hydroxy-2- (3-hydroxy-4-phenoxy-1-butenyl)- 5-oxocyclopentyl] -4,5-heptadienoic acid methyl ester. Enprosteel can be prepared according to the methods described in US Pat. No. 4,178,457, which is incorporated herein by reference.
PGI-2 is also known as prostacyclin, epoprostenol, prostaglandin I ₂ , prostaglandin X, PGI ₂ , and PGX. Prostaglandins may be prepared according to the methods described in US Pat. No. 4,539,333, which is incorporated herein by reference.
The structure of 16,16-dimethyl-PGE-2 is shown below.

The structure of 15 (S) -15-methyl-PGE-2 is as follows.

The structure of 9-deoxy-9-methylene-16,16-dimethyl-PGE-2, potassium salt is as follows.

Carbaprostacyclin has the following structure.

The structure of prostaglandin D ₂ is as follows.

The structure of 19 (R) -hydroxy-PGE-2 is as follows.

The structure of 13,14-dihydro-PGE-1 is as follows.

The structure of 11β-PGE-2 is shown below.

The structure of 19 (R) -hydroxy-PGE-1 is as follows.

The structure of 11-deoxy-16,16-dimethyl-PGE-2 is shown below.

The remaining prostaglandins include Alex Gringan z, Introduction to Medicinal Chemistry, Wiley-VCH, Inc., New York, pp. 158-159 and 641-642,1997, which are hereby incorporated by reference. And the like.
Cyclodextrin complexes of prostaglandins may be used to increase stability and efficiency. Cyclodextrin complexes can be prepared by adding an appropriate stoichiometric ratio of prostaglandin to α, β, or γcyclodextrin in aqueous solution. It is then lyophilized or used as is to provide a solid clathrate compound for mixing. Such complexes are described in Yamamura et al., J. Chromatogr., Vol. 331, pp. 383-388 (1985); Hirayama et al., Chem. Pharm. Bull., Vol. 32 pp. 4237-4240 (1984); Uekama et al., J. Pharm. Sci., Vol. 73, pp. 382-384 (1984); And Yamamura et al., J. Chromatogr., Vol. 303, pp. 165-172 (1984).
In general, the present invention provides prostaglandin E ₁ or prostaglandin E ₂ , preferably 1 to 500 μg (for urethral administration), preferably 2 μg to 200 μg (yo-dodoc administration) in an amount of 0.1 μg to 10 mg per unit dose. Case).
When other vasodilators are used, there will be an amount that exhibits the same effects as the above specified amounts of prostaglandin E ₁ and prostaglandin E ₂ .
The term "15-hydroxyprostaglandin dehydrogenase inhibitor" refers to a compound that significantly inhibits prostaglandin degrading enzyme or 15-hydroxyprostaglandin dehydrogenase (PGDH). Two forms of NAD ⁺ dependent Type I and NADP ⁺ dependent Type II are known, 15-hydroxyprostaglandindehydrogenase (PGDH). Type I is more physiologically important because it operates at orders of magnitude lower Km than type II. Type I PGDH is described in Mark et al., Biochimica et Biophysica Acta, vol. 1035, pp. 190-196 (1990); Ensor et al., J. Lipid Mediators Cell Signaling, vol. 12, pp. 313-319 (1995); And Berry et al., Biochemical Pharmacology. vol. 32, no. 19, pp. 2863-2871 (1983). The following documents (Berry et al., Tai et al., Muramatsu et al., And Mark et al., Described above) are used to determine the degree of inhibition of type I PGDH as well as assays for determining the enzymatic activity of this enzyme. It is also described.
Type II PGDH is described in Chang et al., Biochem. Biophys. Res. Commun., Vol. 99, pp. 745-751 (1981); Jarak, et al., Prostaglandins, vol. 18, pp. 241-246 (1979), and Lin et al., Biochem. Biophys. Res. Comm., Vol. 81, pp. 1227-1234 (1978).
Examples of suitable 15-hydroxyprostaglandin dehydrogenase inhibitors include glycyrrhizic acid, licorice, glycyrrhetinic acid, and various glycosides of glycyrrhetinic acid. , Carboxenolone, DHEA, spironolactone, sofalcone, indomethacin, indomethacin, sulindac, etodolac, oleic acid, palmitic acid, sulfasalazine ), And analogues thereof, and ethacrynic acid, furosemide, chlorothiazide, hydrochlorothiazide, papaverine, cis-sullac sulfide, trans-sulfac sulfide, cis- Sulindac, trans-sullindac, glutathione thiosulfonate, divalent copper cations, divalent zinc cations, selenium, nafazatrom (Bay g-6575); Lipoxygenase and cyclooxygenase-derived substrates having ω-6 hydroxyl groups such as 15-HETE, 13-HODD and HHT; Gossypol, 15 (R) -prostaglandin E-1, 15 (R) -prostaglandin E-2, including but not limited to. Antibodies that inhibit and bind to either type I or type II PGDH may be used.
Glycyrrhizin acid is also known as glycyrrhizin, glycyrrhizinic acid, and glycyrrhetinic acid glycoside. The official chemical name is 20β-carboxy-11-oxo-30-norolean-12-ene-3β-yl-2-O-β-D-glucopyranuronosyl-α-D-glucopyranosiduronic acid The structure is shown below.

Glycyrrhizinic acid is commercially available from Sigma Chemical Company of St. Louis, MO.
Glycyrrhitin acid is a glycyrrhizinic acid which is not bonded to a glycosyl group and its structure is as follows.

Glycyrrhenic acid may be obtained from an extract of licorice.
Carbenoxolone is also known as 3β-hydroxy-11-oxo-20β-olin-12-ene-29-ionic acid hydrogen butanedioate and its structure is shown below.

Carbenoxolone can be synthesized as described in US Pat. No. 3,070,623, which is incorporated herein by reference.
Licorice is also known as sweet root liquorice and glycyrrhiza and is described in the following article by Mercy Index, 10 ^th edition, 4368. Sweet root, Glaciliza glabra L. variant of Typica Regel & Heather (Spanish Licorice) or G. Glabra L. variant of Waldst. & Kit. Regel & Heather (Russia) Roots and dried rhizomes of other varieties of Glycyrisa glabra, which produce licorice, or yellow and sweet wood, Leguminosaw, distributed in southern Europe, Central Asia 6 to 14% glycyrrhizine Glycosides of hetinic acid), asparagine, sugars, resins. "
Licorice is a raw material made from dried rhizomes or roots and contains many compounds that are not themselves proven. Simple water soluble extracts of commercially available dried licorice root preparations can be prepared as follows. Two grams of this dried licorice root is mixed with 10 mls of distilled water, stirred until completely mixed at room temperature and filtered to remove particulate matter. Such simple water soluble extracts of licorice are effective at inhibiting PGDH and can be used in the present invention.
Spyronolactone is also known as Aldactone A or Verospiron. The full chemical name of the spyronolactone is 17-hydroxy-7-mercapto-3-oxo-17α-pregn-4-ene-21-carboxylic and γ-lactone, It is 7-acetate and its structure is as follows.

Spyronolactone is commercially available from Sigma Chemical Company of St. Louis. Mo.
The formal chemical name of Sofalcone is [5-[(3-methyl-2-butenyl) oxy] -2- [3- [4 [(3-methyl-2-butenyl) oxy] phenyl] -1-oxo- 2-propenyl] phenoxy] acetic acid and the chemical formula is shown below.

Sofalcone may be prepared as described in US Pat. No. 4,085,135, which is incorporated herein by reference.
The official chemical name of DHEA is 3-hydroxyandrost-5-en-17-one or dehydroepiandrosterone or prasterone, and its structure is as follows.

DHEA may be prepared by the methods described in H. Hosoda et al., J. Org. Chem., Vol. 38, p. 4209 (1973), incorporated herein by reference.
Sulphasalazine is also known as 2-hydroxy-5 [[4-[(2-pyridinylamino) sulfonyl] phneyl] azo] benzoic acid and has the following structure.

Many sulfasalized analogs are described in Berry et al., Biochemical Pharmacology, vol. 32, pp. 2863-2871 (1983). Examples of sulfasalazine analogs that can be used as PGDH inhibitors in the present compounds are as follows.



Etodolak is also known as 1,8-diethyl-1,3,4,9, -tetrahydropyrano- [3,4-b] indole-1-acetic acid. Etodolac may be prepared as described in US Pat. No. 3,843,681, which is incorporated herein by reference.
Indomethacin is also known as 1- (4-chlorobenzoyl) -5-methoxy-2-methyl-1H-indole-3-acetic acid. Indomethacin may be prepared as described in US Pat. No. 3,161,654, which is incorporated herein by reference.
Sullindac is also known as 5-fluoro-2-methyl-1-[[4- (methylsulfinyl) phenyl] methylene] -1H-indene-3-acetic acid. Sullindac may be prepared as described in US Pat. Nos. 3,654,349 and 3,647,858, which are incorporated herein by reference.
The structure of 15 (R) -prostaglandin E-1 is as follows.

The structure of 15 (R) -15-methyl prostaglandin E-2 is as follows.

Other types of 15-hydroxyprostaglandin dehydrogenase inhibitors include aliphatic or aromatic carboxylic acids and the like. Suitable carboxylic acids include, in particular, straight or branched, saturated, monounsaturated, or polyunsaturated aliphatic C ₈ -C ₃₁ carboxylic acids and the like. Particularly preferred for use as component (b) in this suppository is palmitic acid, oleic acid, elaidic acid, stearic acid, capric acid, lauric acid, myristic Free fatty acids, such as, but not limited to, acid, linoleic acid, arachidic acid, and arachadonic acid, all of which are listed below [St Louis] , Sigma Chemical Company of MO.
The 15-hydroxyprostaglandindehydrogenase inhibitor is generally present in an amount of 25 to 100, preferably 50 to 100, in units of PGDH inhibitory activity per unit dose. The amount of inhibitor corresponding to a unit of PGDH inhibitory activity can be determined in the PGDH assay table of the human penis or human placenta PGDH assay table with the specific assay tables (spectrophotonic or radiochemical or Anggard and Samuelsson) described in the Examples It may be measured by using either. Since the inhibitor shows significant absorption at 340 nm, it would be desirable to use a radiochemical assay table. On the other hand, the appropriate amount of 15-hydroxyprostaglandin dehydrogenase inhibitor can be determined by using the cavernous arterial blood flow analysis table described in the Examples.
The pharmaceutical composition will take any form suitable for administration to the penis or topically applied to the oral or glans of the urethra by injection into the cavernosal or transurethral administration. When injected into the corpus cavernosum, the pharmaceutical composition is in saline form of isotonic. Preferably the pharmaceutical composition is in a form suitable for administration of the urethra or urethra, in which case the compound is generally in the form of a solution, ointment or suppository.
Preferably, the pharmaceutical composition is in the form of suppositories. In general, suppositories contain sufficient amounts of ingredients (a) and (b) to allow administration of a single suppository to provide the desired result. Therefore, suppositories are generally (a) 0.1 μg to 10 mg of prostaglandin E ₁ , preferably 1 to 500 μg (for urethral administration), preferably 2 to 200 μg (for oral administration), or prostaglandin E ₂ 0.1㎍ to 10㎎, preferably from 1 to 500㎍ (if for transurethral administration), preferably from 2 to 200㎍ (if for administration); And (b) 25 to 100 units, preferably 50 to 100 units, of 15-hydroxyprostaglandin dehydrogenase inhibitor.
The pharmaceutical composition further constitutes a coagent. Examples of suitable coagents are:
1. ACE inhibitors including but not limited to captopril, enalapril, enalaprilat quinapril, lisinopril, and ramipril Improve the efficiency of the method and reduce organ complications such as inflammatory or fibrosis reactions;
2. Nitro vasodilators, including but not limited to nitroglycerin, isosorbide dinitrate, amyl nitrate, isosorbide mononitrate, erytrityl tetranitrate, and sodium nitroprusside Improve the efficiency of;
3. Alpha blockers, including but not limited to prazosin, phentolamine, phenoxybenzamine, dibenzamine, doxazosin, terrazosin, trimazosine, tolazoline, corintanin, lauwalsin, and piperonic acid are particularly It is desirable to increase the efficiency of the process and increase its action;
4. Other adrenoceptor preparations, including but not limited to yohimbine, labetalol, carvedilol, and vusindolol, also enhance the activity and action of the method;
5. Caffeine, aminophylline, theophylline, amrinone, milrinone, vesnarinone, vinpocetine, femobendan, cilostamide ), Forces including but not limited to enoximone, peroximone, rolipram, R020-1724, zaniprast, dipyridamole, and sildenafil Podiesterase (PDE) inhibitors are also effective in increasing the efficiency of the method and sustaining its impact;
6. Muscarinic preparations such as pilocarpine, edrophonium, and benatacol;
7. Dopamine agonists such as apomorphine and bromocriptine;
8. Ergotamine including acetergamine, bravergoline, bromerguride, clanegollone, ergonovine, ergotamine tartrate, and pergolide ergot alkaloids such as ergotamine and ergotamine analogues;
9. Naloxone, Naltrexone, Nalmefene, Nalopin, Methyl Naltrexone, CTOP, Diprenorphine, β-Funatrexamine, Naloxazine, Norbinaltormine, Natriledol, BNTX, and Opiate antagonists such as other analogs;
10. VIP, calcitonin, calcitonin gene related products, VIP analogs, and cholecystokinin and CCK8 and all its analogs and polypeptide neurotransmitters;
11. mast cell stabilizers such as chromoline, nedochromoline, ileuton, pyripost, MK-886, MK-0591, ICI-D2318, docebenone, and leukotrine receptor antagonists; And
12. Agents such as forskolin and water-soluble analogs that directly stimulate adenylate cyclase; Dibutyryl-cyclic AMPs, Dibutyryl-cyclic GMPs and guanylins improve the relaxation of cavernous tissue by increasing the amount of cyclic AMPs and cyclic GMPs.
In a second embodiment, the present invention provides a pharmaceutical composition comprising (a) prostaglandin E ₁ , prostaglandin E ₂ , or mixtures thereof; And (b) administering a 15-hydroxyprostaglandin dehydrogenase inhibitor. The method can be advantageously carried out using any of the pharmaceutical compositions of the invention mentioned above.
In this method, the pharmaceutical composition may be administered by topical administration to the urinary tract or by glacial skin or by injection into the corpus cavernosum or transurethral administration. Injection into the corpus cavernosum is described in the New England Journal of Medicine, vol. 334, by Botto I. Linet and Frances G. ogrinc, which is incorporated herein by reference. pp. 873-877 (1996.4.4). Preferably, the method comprises topical or urethral administration. Topical administration can be performed by dripping a solution of the compound directly into the urinary tract. On the other hand, suppositories can be put directly into the urinary tract. Transurethral administration is described in Herin Padam-Nathan et al., New England Journal of Medicine, vol. 336, pp. 1-7 (1997.1.2); And Wolfson V et al., Urology, vol. 42, pp. 73-75 (1993) can be carried out via their application in solution, ointment, emulsion, suppository, or any liquid form via the catheter.
Preferably the method is carried out by topical administration of suppositories. Suppositories are urethra by using devices such as those described in Herin Padham-Nathan et al., New England Journal of Medicine, vol. 336, pp. 1-7 (1997.1.2), incorporated herein by reference. It will be administered via.
In general, the pharmaceutical composition is administered 1 to 50 minutes, preferably 10 to 20 minutes before initiation of sexual intercourse. Suitably, the method is carried out by administering one of the pharmaceutical compositions mentioned above. Preferably, the method is carried out by administration of the present suppository in the urethra or topical administration of the present solution, cream, or ointment to the urinary tract.
Of course, it should also be understood that prostaglandin E ₁ or prostaglandin E ₂ need not be administered simultaneously with the 15-hydroxyprostaglandin dehydrogenase inhibitor. Rather, the 15-hydroxyprostaglandin dehydrogenase inhibitor will be administered first. Pretreatment or co-treatment with 15-hydroxyprostaglandin dehydrogenase inhibitors also reduces the burning pain associated with administration of prostaglandins. In addition, the blocking of PGDH greatly increases the uptake and efficiency of prostaglandins, requiring significantly lower doses.
Since PGDH degrades not only PGE ₁ and PGE ₂ but also most pharmacologically active prostaglandins, inhibition of PGDH may be used to bind prostaglandins or prostaglandin analogs suitable for inclusion of the compound by its vasodilating activity properties. Could be.
In a particularly preferred embodiment, the present invention provides urethral suppositories and (a) prostaglandin vasodilators; (b) a 15-hydroxyprostaglandin dehydrogenase inhibitor; And (c) has a form which is solid at room temperature and which comprises a substrate which releases component (a) and component (b) upon insertion into the urethra or oral cavity.
Prostaglandins and 15-hydroxyprostaglandin dehydrogenase inhibitors are as mentioned above.
Alternatively, the subject compounds, 0.1㎍ to 10㎎ amount per unit dose, preferably from 1 to 500㎍ (transurethral administration case), preferably between 2 and prostaglandin E ₁ in an amount of 200㎍ (administration case) May contain prostaglandin E ₂ . The 15-hydroxyprostaglandindehydrogenase inhibitor may be present in an amount of 25 to 100, preferably 50 to 100, in units of PGDH inhibitory activity, per unit dosage. The amount of inhibitor corresponding to one unit of PGDH inhibitory activity is determined using the method mentioned above.
If the 15-hydroxyprostaglandin dehydrogenase inhibitor is a fatty acid such as palmitic acid, oleic acid, eladinic acid, stearic acid, caprinic acid, lauric acid, myristic acid, linoleic acid, arachidonic acid and arachidonic acid, the fatty acid is weak. An amount from 0.1 μg to about 20 mg, preferably from about 100 μg to about 10 mg, is suitable as a suppository.
If the 15-hydroxyprostaglandin dehydrogenase inhibitor is etodolak, sulindac, or indomethacin, the suppository is in an amount of 0.1 mg to 20 mg, preferably 0.5 mg to 10 mg per unit dose of prostaglandin. 15-hydroxyprostaglandin dehydrogenase.
Component (c) (substrate or carrier drug) may comprise a substance or mixture of substances that is compatible with component (a) (prostaglandin vasodilator) and component (b) (15-hydroxyprostaglandin dehydrogenase inhibitor). And release components (a) and (b) upon insertion into the urinary tract or urethra. Examples of materials suitable for use as component (a) and component (c) releasing component (b) upon insertion of an urethral suppository include hydrogels saturated with or containing components (a) and (b). There are materials.
Examples of suitable gels include triacetin, hydroxycellulose, gels composed of water, propylene glycol, hydroxypropyl methylcellulose and other gels suitable for prostaglandins. Particularly preferred gels are described in H. Willimann et al., "Lecithin Organic Gels as Substrates for Percutaneous Transport of Drugs," J. Pharm. Sci., Vol. 81 (9), incorporated herein by reference. , pp. 871-874 (1992). This particular preparation shows extremely improved efficacy.
Gels that release one or more prostaglandins or coagents will also be used in a controlled release method (ie release under time control) to prolong the effect of the compound. For example, the components (a) and (b) may be formulated with crosslinked polyethylene oxide / urethane polymers that are well tolerated by biological tissue and that release the components (a) and (b) in a controlled release manner. Can be. Controlled release compounds are described in Controlled Release of Pesticides and Pharmaceuticals, Plenum Press, New York, 1981 to D.H. Lewis, which is incorporated herein by reference; And Controlled Release Technologies of A.F. Methods, Theory, and Applications, CRC Press. Boca Raton, 1980.
In a preferred embodiment, component (c) is compatible with component (a) (prostaglandin vasodilator) and component (b) (15-hydroxyprostaglandin dehydrogenase inhibitor), and from about 70 ° to about 100 ° F. Up to, preferably about 70 ° to about 90 ° F. is a substance or mixture of substances that results in a final compound having a melting point range.
Specific examples of materials suitable for use as component (c) include fatty acid esters such as ethyl stearate, isopropyl stearate, butyl stearate, and cetyl lactate; Fatty acid ethers such as laureth 9; Cholesterol esters such as cholesteryl oleate and cholesteryl palmitate; Fatty acid triglycerides; fatty acid; Phospholipids; Glycolipids; And sphingolipids. Ethyl stearate is a particularly preferred compound for use as component (c).
Other materials suitable for use as component (c) include polyethylene glycol (PEG). PEG is chosen so that suppositories are solid or semisolid at room temperature but dissolve or dissolve rapidly in the urethra. The use of PEG with an average molecular weight of about 1450 gave good results.
Suppositories in this embodiment further consist of one or more of the same co-reagents mentioned above.
Particularly preferred compounds contain alpha-blockers and / or PDE inhibitors. Some combinations of one compound listed above or multiple combinations of other compounds or other groups may also be used. In some instances, it may be beneficial to pretreat one or more coagents. For example, pretreatment of PGDH inhibitors prior to dealing with PGE will improve the efficiency of the method.
The urethral suppository will generally have an elliptical shape with a length to width phase ratio of about 1: 1 to about 75: 1, preferably about 5: 1 to about 20: 1. The length of the suppository can vary from about 1 mm to about 100 mm, preferably from about 2 mm to about 75 mm. The length of the suppository will be directly adjusted to the dose of prostaglandin to either the urinary tract or the urethra of the penis. When to be administered to the urethra, the length of the suppository is preferably from about 2 mm to about 60 mm, more preferably from about 5 mm to about 50 mm, most preferably from 10 mm to 40 mm. In contrast, to administer to the penis urethra, the length of the suppository is from about 50mm to about 100mm, more preferably from about 60mm to about 100mm, most preferably from about 60mm to about 80mm.
2-6 show longitudinal or side views of certain embodiments of the suppository. 7-10, on the other hand, shows cross-sectional views of certain embodiments of the suppository. Figure 2 shows a side view of suppositories with straight axes 1 and rounded vertices 2. Figure 3 shows a side view of suppository with straight axis 1 and pointed vertex 2. Figure 4 shows a side view of suppository with straight axis 1, rounded vertex 2, and a flat bottom or end 3 attached to the end of axis 1 that is distal to vertex 2; FIG. 5 shows a side view of a suppository with a straight axis 1, a sharp vertex 2, and a funnel-shaped bottom or tip 3 attached to the end of axis 1, which is the end of vertex 2. FIG. Figure 6 shows a side view of a suppository with tapered vertices 2 tapering along the entire length of axis 1; This suppository is not limited to any particular cross sectional form. As shown in Figures 7-10, the suppository may be either round, oval, rectangular, or football-shaped in cross section. Round and oval cross-sectional shapes are preferred. Figure 7 shows a cross-sectional view of a suppository having no bottom or end 3 and having axis 1 substantially circular in cross section. Figure 8 shows a cross sectional view of a suppository having no bottom or end 3 and having axis 1 substantially oval in cross section. Figure 9 shows a cross-sectional view of a suppository having a substantially circular bottom or end 3 and having axis 1 substantially circular in cross section. Figure 10 shows a cross-sectional view of a suppository having a substantially circular bottom or end 3 and having axis 1 substantially elliptical in cross section.
In one preferred embodiment, the suppository has rounded or pointed vertices to facilitate entry into the urethra (see FIGS. 2-5). On the other hand, suppositories will taper over all or at least a substantial portion of their length (see FIG. 6). The bottom of the suppository will be widened or funneled to provide a built-in end such that the depth of insertion is determined by the length from the suppository's vertex to the beginning of the flare (see FIGS. 4 and 5). On the other hand, the bottom of the suppository may be attached to a piece of gold leaf, plastic, or paper, or to the inside of the apex of the condom to fix the depth of insertion.
The suppository generally has a cross section with a maximum dimension of from about 0.1 mm to about 25 mm, preferably from about 1 mm to about 10 mm, in particular from about 2 mm to about 6 mm, depending on the portion of the suppository intended for insertion into the urethra. . Although there is no major limitation on the minimum cross-sectional dimension along the portion of the suppository to be inserted into the urethra, in practice, the suppository is thick enough to have sufficient structural strength to allow suppository insertion into the urethra without breaking or significantly bending. Should be
As mentioned above, the suppository has a wider or funnel shape. The widened or flared portion of the suppository will generally have a minimum dimension of at least about 5 mm, preferably at least about 10 mm. Although there is no major limit to the maximum cross-sectional dimension of the swollen or flared portion of the suppository, in practice it is larger than is required to prevent the insertion of the suppository into the urethra beyond the point where the widened or flared portion begins. Or it is unnecessary to make a gap.
In general, suppositories will contain sufficient amounts of (a) and (b) such that administration of a single suppository provides the desired result. Therefore, one suppository is generally (a) 0.1 μg to 1.0 mg of prostaglandin E ₁ , preferably 1 μg to 500 μg (for urethral administration), preferably 2 μg to 200 μg (for urinary administration), prostaglandin 0.1 μg to 1.0 mg of E ₂ , preferably 1 μg to 500 μg (for urethral administration), preferably 2 μg to 200 μg (for urinary administration); And (b) 25 to 100 units, preferably 50 to 100 units, of the 15-hydroxyprostaglandin dehydrogenase inhibitor.
In a particularly preferred embodiment, the present suppository contains oleic acid of from 1 to 20㎎ each ㎎ of prostaglandin E ₂ (that is, oleic acid: the weight ratio of prostaglandin E 1 _2: 1 to 20: 1). In another particularly preferred embodiment, the suppository contains prostaglandin E ₂ and palmitic acid at a weight ratio of 1: 1-20: 1 of palmitic acid: prostaglandin E ₂ .
In a preferred embodiment, the suppository is characterized by having a pH of 3 to 7, preferably 4 to 6. Such suppositories will be prepared by simply adding a sufficient amount of a pharmaceutically acceptable acid or base (eg HCl or NaOH to apply the pH to the desired value). On the other hand, pure lactic acid ˜0.5 microliter will be added to ˜30 mg suppository to form a solid formulation that releases lactic acid while melting and lowers the pH of the urethra to about 3.5-4.5. In a particularly preferred embodiment, each unit dose of residual powder will be added to 0.01 to 0.5 ml of a 0.01 molar aqueous solution of pharmaceutically acceptable citrate (eg sodium citrate, which has a preferred pH). For example, 0.5 ml of 0.01 mol sodium citrate at pH 4.5 is lyophilized and the powder residue is added to a unit dose of prostaglandin E ₂ in ethyl stearate. When this dose is inserted into the urethra, the lyophilized citrate will melt and buffer the urethra's pH to about pH 4.5. This will improve the activity of prostaglandin E _{2 as} the small ethyl stearate grains dissolve.
In a second embodiment, the present invention provides a method of treating male erectile dysfunction by administering the suppository to a patient in need thereof. The present invention will be carried out by either urethral administration or urinary tract administration of the suppository.
As shown in Fig. 1, the male penis consists of three parts: the urinary tract, the urethra, and the columnar. As used herein, the term "urethral administration" refers to the administration of drugs to the urethra and the urethra surrounded by caustic or stratified columnar epithelium. As used herein, the term "urea administration" refers to drug administration to the opening of the penis (shown in Figure 1) and / or to the urethra with the columnar, surrounded by stratified lamellar epithelium. Udodoc administration is therefore essentially the same as topical administration in terms of the difficulty of administering an effective transdermal dose. Conventionally, urinary doses of vasodilative prostaglandins are generally required to be 10 to 20 times (or more) greater than transurethral administrations due to the difficulty of passing denser epithelium. However, the present suppositories show an improvement in making the urinary tract administration feasible and effective even when using the same amount as the effective dose in urethral administration.
Udodoc administration is preferred over urethral administration for many reasons. Urethral administration is generally easier to perform than urethral administration and will be the only possible means of administration in patients with narrowed and damaged urethra. The depth of insertion of suppositories in urinary administration is generally between 2 mm and 60 mm, depending on the degree of bulge of the penis and individual differences as measured from the external inlet of the penis. In contrast, the depth of insertion of suppositories during transurethral administration is generally at least 50 mm, as measured from the external inlet of the penis, depending on the degree of inflation and individual differences in the administration of the penis. Urethral or transurethral administration is readily accomplished by the selection of suppositories having an appropriate length axis and a widened or flared bottom and the insertion of the suppository to the depth of its widened or flared bottom.
In fact, these compounds could be applied directly to the outer skin of the penis glans for erection. Such a regimen requires increasing the dose of prostaglandin E-1 or E-2 to 250 mcg-2.5 mg with the corresponding dose of inhibitor.
In general, suppositories are inserted into the urethra for 1-50 minutes, preferably 10-20 minutes, before initiating sexual intercourse. Udodoc administration may be later in the manifestation of the effect of the active agent, and therefore, it may be desirable to be performed earlier than urethral administration.
Such suppositories in which component (c) is dissolved or dissolved in the urethra are simply inserted into the urethra. Such suppositories which release components (a) and (b) into the urethra but which do not dissolve or dissolve in the urethra are preferably inserted into the urethra to a depth that leaves a portion of the suppository protruding from the urethra, It is left in the urethra until the desired result is achieved, and then removed from the urethra by the protruding part.
Of course, it should also be understood that prostaglandin E ₁ or prostaglandin E ₂ need not be administered simultaneously with the 15-hydroxyprostaglandin dehydrogenase inhibitor. Rather, the 15-hydroxyprostaglandindehydrogenase inhibitor will be administered first in the first suppository and then treated with prostaglandin in the second suppository. Pretreatment or co-treatment of the 15-hydroxyprostaglandin dehydrogenase inhibitor reduces the burning pain associated with administration of prostaglandin. In addition, blocking of PGDH significantly improves the absorption and effectiveness of prostaglandins and results in a significant reduction in the dosage required.
The suppositories will be made by standard methods known in the art, including but not limited to extrusion, casting, and injection molding. For example, the suppositories form familiar compounds containing appropriate relative amounts of components (a), (b), and (c) at temperatures above the melting point of component (c) under sterile conditions and then extruded. It can be prepared by forming a suppository of a desired shape by casting, casting, or injection molding.
The suppositories and methods provide a number of advantages when comparing male erectile dysfunction with traditional compounds and methods. In particular, the suppositories and methods are:
1. Eliminates the need for a device to administer the active agent;
2. Much less prostaglandin doses can be used than those traditionally used with the urethral dosing device;
3. The composition can be prepared in a very simplified process;
4. Reduce the exposure of prostaglandins to reduce the effects of light, heat and moisture during the manufacturing process;
5. Reduces irritation to the urethra / urea than conventional methods;
6. Allows the use of physiological concentrations of naturally occurring prostaglandins and free fatty acids; And
7. Allow for treatment of patients with abnormal urethral dissection; And
8. Allow use of urinary doses of prostaglandins that are significantly smaller than previously seen.
Other features of the invention will be further clarified by the following examples, but the invention is not limited to these examples.
I. PGDH Activity
A. Preparation of the urethral mucosa of the pig penis: The penis immediately after the slaughter of sexually mature pigs is obtained from a nearby slaughterhouse. Wash it immediately with tap water and then with ice-cold saline. Separate the urethra from the urethral cavernous body corresponding to the part from the columnar vortex to the membrane-like part of the urethra. This part is called the penis urethra, and the corresponding length of the urethra is measured in millimeters and recorded. Also record the weight of the urethra. The mucosa is homogenized with four doses of ice-cold 100 mM potassium phosphate buffer (pH 7.4) containing 1 mM EDTA and 1 mM dithiothreitol. Then, the supernatant fraction obtained by centrifugation at 15,000 g for 15 minutes is used as the enzyme source of the penile mucosa.
B. Determination of 15-hydroxyprostaglandin dehydrogenase (PGDH) activity:
Spectroscopic Analysis:
As a substrate, prostaglandin E ₁ is incubated with the urethral mucosa of the swine penis previously prepared. This reaction mixture is added to 2.0 ml of the total volume of the same buffer used for preparing the urethral mucosa of the pig penis described above.
Prostaglandin E ₁ (50 microM) and NAD (300 microM) are used as substrates. This reaction is initiated by adding prostaglandin E ₁ . Incubate at 37 ° C and terminate by adding 0.5 mL of 2NaOH. Oxidation of prostaglandins is assessed by monitoring the reduction of NAD ⁺ at 340 nanometers with a spectrophotometer. The reaction time is adjusted to oxidize 50 to 80% of the initial amount of prostaglandin.
Radiochemical measurements: (5,6,8,11,12,14,15 (n) ^-3 H) -prostaglandin E ₂ (inactive, 171 Ci, mmol: manufactured by Dupont de Nemours) used as a specific substrate Except that the same reaction conditions as in spectroscopic analysis are used. Other tritiated prostaglandin substrates can be used for this assay. Methanol precipitation (75% volume / volume) is done to terminate the reaction; Thereafter, water is added to dilute the methanol to 10 volume percent. Soluble phase extraction is performed using an octadecyl 18-C silica cartridge (JTBaker, Deventer, Holland). The prostaglandins are then eluted from the cartridge with 4 ml of anhydrous methanol and dried over a dry argon stream. The dried extract is run on 20 × 20, 60 A silica plates using an organic phase of ethyl acetate / acetic acid / isooctane / water (11: 2: 5: 10). Rated prostaglandin E _2, 15- keto-prostaglandin E ₂ and the 13,14- dihydro-15-keto-prostaglandin E ₂ moves with each record impression. After locating the compounds using a phosphomolybdic spray, the amount of each of prostaglandin E ₂ and 15-keto-prostaglandin E ₂ is determined by radiometric method. 1 mU is defined as the amount of enzyme that oxidizes 1 nanomole of prostaglandin E ₂ or E ₁ per minute at pH 7.4, 37 ° C. The level of PGDH mU per mm of penile urethra in pigs is calculated by dividing the total mU by the mm of urethra used to prepare the enzyme.
II. Determination of PGDH Inhibitor Activity
In this specification, one unit of PGDH inhibitor activity is defined as the amount of inhibitor such that one percent of the amount of prostaglandin present, as measured using any of the assays described below, is not oxidized. The PGDH may be human placental PGDH as described below or the porcine penis PGDH described above. In the case of porcine penis PGDH, enzyme activity and inhibition rate are preferably measured according to the method described immediately below. In the case of human placental PGDH, enzyme activity and inhibition rate are preferably determined according to the methods described in Anggard, E. and Samuelsson, B. (1966) Ark. Kem. 25,293-340.
Spectrophotometric: Using the spectrophotometric system described above for PGDH activity, the inhibitor is added to the reaction mixture and preincubated for 15 minutes at 37 ° C. prior to the addition of prostaglandin E ₁ . At the end of the reaction, the amount of degraded prostaglandin E ₁ is calculated and compared with the reaction without inhibitor. Inhibition rate is defined as B / AX 100:
A = nmole of oxidized prostaglandins without inhibitors; And
B = nmole of oxidized prostaglandins with inhibitor.
For example, if A = 50 nmoles and B = 25 nmoles with inhibitor C, inhibitor C shows 25/50 X 100 or 50% inhibition in this assay.
Radiochemical Measurement: The assay for inhibition is done with or without addition of the inhibitors listed above in the measurement of the radiochemical activity of PGDH. Certain inhibitors are added to the reaction mixture prior to addition of prostaglandin E ₂ to be analyzed and measured as described above. The amount of oxidized prostaglandins is determined by calculating as described above for the spectroscopic analysis of inhibitor activity.
III. Human placental PGDH activity
The placenta is one of the most abundant sources of PGDH, which contains large amounts of both type I and type II. Thus, placental PGDH can be used as a useful enzyme source in determining PGDH enzyme inhibitor activity and determining the relative amount of PGDH inhibitor and prostaglandin to be incorporated in unit doses in the present invention.
Placenta from healthy mothers with normal hard delivery were stored on ice immediately after delivery. Within 1 hour of delivery, a portion of the placenta (~ 1/2) is obtained, and then 100 units of heparin, 10 mM potassium phosphate (pH 7.4), 20% glycerol until all visible blood and mucus are removed Washed repeatedly with mother liquor of ice cold (1-5 ° C.) homogeneous buffer containing 1 mM EDTA and 1 mM dithiothreitol; The membrane was then excised to cut the tissue into small pieces. Because the placenta has so many blood vessels, it was washed with buffer as many times as possible to remove hemoglobin. Washed about 50 times. The tissue weight (188.4 grams) was measured and then homogenized for 2 minutes at high speed in a commercial mixer with 5 volumes of ice cold buffer. Following filtration through crude cotton, the homogenate is centrifuged at ˜800 g for 15 minutes, and the supernatant is continuously filtered with a glass fiber filter (holding capacity> 2.3 microns-Sigma Chemical Company -item # F-6269) and finally Crude with a 0.22 micron polyethersulfone membrane filter (Corning Costar Corporation, Cambridge, Mass.), Which is suitable for use as such or may be further purified according to the methods reported in the paper (Mak and Ensor, supra). Placenta homogenate was obtained. Alternatively, the homogenate can be taken out of the blender, ultracentrifuged at 100,000 g for 60 minutes at 0-4 ° C., and the supernatant can be used as crude homogenate.
PGDH activity was measured by the Enggard and Samuelson method (see Anggard, E and Samuelsson, B. (1966) Ark. Kem. 25,293-340). However, other suitable methods for measuring PGDH activity can be used, including the two methods described in this paper. Mother liquor (100-200 microliters) of crude placental homogenate was analyzed in 1 ml of total volume with 200 micromoles of PGE2, 50 mM potassium phosphate, 2.5 mM NAD for 45 minutes at 37 ° C. at pH 7.4. Then, 1.3 ml of 1 N NaOH was added to the ice-cold reaction mixture, and its chromophore absorbance was measured at 500 nm for 1 minute on a SPECTRONIC 20 GENESYS spectrophotometer (Spectronic Instruments, Rochester, NY). Controls were used without homogenates. Protein concentration was measured using a modified Lori method (catalog # P5656, Sigma Chemical, St. Louis, MO). Absorbance may be used directly or may be used to calculate the inactivity of the enzyme. Representative values of PGDH activity obtained were in the range of 4.85-6.25 picomolar 15-ketoprostaglandin E2 / min-ml for homogenates. This analysis shows roughly the expected amount of PGDH activity of the human penis (Roy, A.C., Adaikan, P.G., Sen, D.K., and Ratnam, S.S. (1989) British J. Urology, 64,180). It may be expected that such a test system will approach the environment to which the invention is intended.
Inhibitor activity can be determined by dissolving the compound to be tested in the assay in buffer and preincubating the homogenate with the inhibitor for 15 minutes before initiating the above assay by addition of PGE2. 11 shows an example of such data. Fatty acids were not water soluble and were dissolved in 95% ethanol and added to 25 microliters of mother liquor. This amount of alcohol has no effect on enzyme activity. Some sodium salts of fatty acids will precipitate upon the addition of NaOH. These visible deposits should be removed by filtration with a 0.22 micron filter before measuring absorbance to ensure accurate results.
It should be noted that sensitive enzyme systems may exhibit many interassay variability. In addition, you will not get exactly the same results when studying comparative inhibitors, especially with very poorly purified enzyme sources using enzymes from others. However, the crude homogenate obtained should be closer to the internal environment (both PGDH I and II present) that the actual dose of the present invention will encounter upon administration to the actual patient than the inhibitor studies using high purity PGDH. Using mixed enzyme samples from several different placenta is an advantageous way to cope with this situation. This inhibitor analysis greatly reduces the need for further testing in humans by calculating the approximate amount of inhibitor required per unit dose. The following examples list extremely simplified methods of human screening of dosage combinations to be used advantageously in combination with these methods of reducing the amount of testing required to reach the optimal dosage combination.
In general, it is desirable to incorporate in the unit dose the amount of inhibitor that shows> 50% inhibition in this assay. Therefore, to show> 50% inhibition of PGDH, the unit dose of palmitic acid should be twice or more than the molar amount of PGE2 used. The unit dose should have a molar ratio of 2 or more molar ratios of oleic acid relative to PGE2. This method can easily be used to determine the approximate amount of inhibitor required per unit dose by simply replacing the inhibitor to be tested in this assay in the appropriate solvent and by ensuring that the selected solvent does not inhibit the enzyme. If other prostaglandins are used, PGE2 should be replaced in the above analysis. When prostaglandins and other vasodilators are used, the actual weight of the inhibitor should be considered at the unit dose as derived from the use of PGE2 and oleic acid in the above assay.
IV. Titration of Inhibitor Dose with Blood Flow in Penile Arteries
Another method for determining the optimal amount of inhibitor to be used at a unit dose is to fill the inhibitor in varying amounts per unit dose in the form of suppositories. These various doses of inhibitors can then be administered to patients to assess the extent of erectile induction as well as to measure blood flow peaks during heart contraction. Using this technique, one can easily infer the appropriate dosage for any inhibitor.
These methods of determining the approximate dose of inhibitor required at the unit dose of the present invention are the only factors to be considered in the final product. For example, some mixtures of PGE-2 / ethyl stearate / and 20: 1 oleic acid are not solid at room temperature. Some mixtures of PGE-2 / ethyl stearate / and 20: 1 palmitic acid will not dissolve in the urethra at normal body temperature.
Reference Example.
An aqueous solution containing 250 μg of PGE2 and 150 μg of phentolamine hydrochloride was administered directly to the urethra of a 42 year old male with a history of erectile dysfunction. An erection within 10 minutes lasted 60 minutes.
Example 1
1.500 g of ethyl stearate, 6.25 mg of PGE2 and 62.5 mg of oleic acid were placed in a heat resistant glass test tube and heated to about 100 ° F. with periodic stirring on a heating plate. This mixture quickly melted into a clear solution. Standard experimental micropipettes (justor 1100BG with a dispensed volume available from 10.0 to 100.0 microliters, manufactured by Nichiryo and sold by Sigma (St. Louis, MO USA); and Sigma pipette tips-Catalog # B-6429 ) Was repeatedly immersed in this solution and inhaled to 37 microliters. The solution solidified rapidly at ambient room temperature (71 ° F.) and was forced out of the paperclip on top of the pipette to give a suppository. About 100 suppositories were made in two hours using this method. Subsequent weighings showed that 96% of the suppositories were 31 ± 0.5 mgs. Similar results were obtained when palmitic acid was replaced with oleic acid.
Example 2
In the urinary tract of five men with no history of erectile dysfunction, a suppository consisting of 125 μg PGE2 and 1.25 mg oleic acid in 30 mg ethyl stearate (length 18 mm, maximum diameter about 2 mm; made according to Example 1) was inserted. Changes in blood flow during cardiac contraction of cavernous artery peaks before and after insertion [doppler ultrasound device Knoll / Midas ], And the result is as shown in FIG. All five subjects experienced sufficient erection response to insertion. This length suppository delivers a urethral dose.
Example 3
A 46-year-old white male with atherosclerosis, smoking, antidepressant use, 30 years of circumcision, and multiple etiologies of erectile dysfunction in which the penile glans were excised by a wound was tested. Because of the narrowing of the urethra (from damaged tissue), the area around the tip of the penis was narrowed to about 2 mm so that the urethra could not be inserted into the catheter. The suppositories described in Example 1 were easily painlessly inserted into the urethra in the constriction. After 20 minutes, the patient experienced a clear erection, which lasted 60 minutes.
Example 4
All five men with a history of erectile dysfunction inserted the suppositories described in Example 1 into their respective urethra. Changes in cardiac contractile blood flow of cavernous artery peaks before and after insertion were measured with a device [Knoll / Midas Doppler ultrasound device]. The result is shown in FIG. All five patients experienced an erectile response sufficient for insertion over the next 30 minutes.
Example 5
The urethra of a 42 year old male with a history of erectile dysfunction was pretreated with 1 ml of an aqueous 0.9 percent (w / v) DHEA solution. After 15 minutes, an aqueous solution containing 250 μg PGE2 and 150 μg phentolamine hydrochloride was applied directly to the urethra. There was no burning pain and improved effect.
Example 6
An aqueous solution containing 0.1 ml of 10% w / v carbenoxolone was applied topically to a urea of a 42 year old male with a history of erectile dysfunction for 5 minutes, and then 500 μg of PGE2 and 500 μl of phentolamine in liposomes. Was applied. An erection after 15 minutes and lasted 90 minutes.
Example 7
Blood flow of cavernous arteries of 47-year-old white males with no history of erectile dysfunction was assessed using the Kultol / MIDAS system with the Urometrics, Inc. [ultrasonic doppler flow analyzer]. Baseline for unstimulated blood flow in the cavernous artery of the penis was 0.025 meters / second (see FIG. 14). # 12 French catheter (# 12 French catheter), the insert 4 cm in the urethra and carboxylic benok Solon (PGDH inhibitor) 150 to nanomolar and PGE ₂ to 150 nanomolar phentolamine hydrochloride (inhibitor and prostaglandin 1: 1 molar ratio) of the Prior to infusion it was injected for 15 minutes as a pretreatment. Cavernous artery blood flow increased to 0.45 meters per second over the next 15 minutes, resulting in an 18-fold increase in cavernous blood flow.
The 10: 1 molar ratio of inhibitor and PGE ₂ resulted in an increase of 0.72 meters per second in the cavernous artery and a 29-fold increase in cavernous blood flow at 15 minutes.
Example 8
A 46-year-old white male with intermittent difficulty in erection was evaluated for blood flow baseline of the cavernous artery using the Knol / Midas system. Blood flow baseline (relaxed) was not found. Pretreatment with 150 nanomoles of carbenoxolone as in Example 7 was followed by 150 nanomoles of PGE ₂ and phentolamine. After 15 minutes, the cavernous blood flow increased to 0.3 meters per second, increasing blood flow to the penis at least 12-fold. Due to the 10: 1 molar ratio of inhibitor and PGE ₂ , cavernous artery blood flow increased 0.35 meters per second, resulting in a 14-fold increase in blood flow in 15 minutes (see FIG. 14).
Example 9
A 42 year old Caucasian male with a history of erectile dysfunction was assessed using the Knol / Midas system. The baseline (relaxed) of the blood flow was 0.03 meters per second. A # 12 French catheter was placed 4 cm in the urethra and carbenoxolone 3.0 micromolar was used as a pretreatment to inhibit prostaglandin degradation. Then 0.75 micromoles of PGE ₂ and phentolamine chloride were introduced into the urethra (4: 1 molar ratio of inhibitor to PGE ₂ ). After 15 minutes, the blood flow of the cavernous body increased by 0.49 meters per second, increasing the blood flow of the cavernous artery by 16.3 times (see Fig. 14).
Example 10.
Using the Knol / Midas system, the blood flow of the cavernous (relaxed) cavernous artery was found to be 0.03 meters / second for a 42 year old Caucasian male with erectile dysfunction. 6.6 micromoles of carbenoxolone in the polyethylene glycol MW1450 suppository were placed in the urethra and dissolved for 15 minutes prior to administration of 0.83 micromoles of PGE ₂ and pentolamine (8 to 1 molar ratio of inhibitor and PGE ₂ ). The blood flow in the cavernous artery increased 0.43 meters per second over the next 15 minutes, leading to a 14-fold increase in blood flow (see Figure 14).
Example 11.
A 47-year-old man with erectile dysfunction was given a urinary suppository of 16 mm in length and 2 mm in diameter containing 125 mcg of PGE-2, and then the blood flow of the cavernous artery was measured for a long time to examine the response. On the other day, a urinary suppository containing 125 mcg of PGE-2 + 1.25 mg of oleic acid was administered as a PGDH inhibitor. As can be seen from the result shown in Fig. 15, the reaction peak and length were greatly increased by the present invention.
Example 12.
In 72-year-old man with complex erectile dysfunction of multiple etiologies: (1) 500 mgg of PGE-2 urethralally through the catheter as saline solution; (2) 500 mcg of PGE-1 pellets (within PEG 1450) commercially available; (3) Udodoc suppositories containing 125 mcg of PGE-2 + 1.25 mg of oleic acid were administered on different days. 16 shows the response to these three doses. Prostaglandins show the same excellent response as in urinary doses, although the dose is much lower.
Example 13.
A 43-year-old man with erectile dysfunction was administered a urethral suppository with palmitic acid and ethyl stearate in a 10: 1 ratio by weight as a PGDH inhibitor with varying amounts of Pmc-2 from 25 mcg to 125 mcg (see FIG. 17). PGE-2 25mcg dose showed a peak flow response equivalent to 125mcg dose. This 25 mcg urinary dose resulted in an equivalent response to the case of injection into the cavernous body showing the remarkable efficacy of this method.
Example 14.
42 year old male with erectile dysfunction (1) PGE-2 125mcg; (2) 125 mcg of PGE-2 + 1.25 mg of oleic acid; (3) 125 mcg of PGE-2 + 1.25 mg of palmitic acid were administered as a urethral suppository. The substrate was ethyl stearate. 18 shows that both the inhibitor and PGDH (at 10: 1 weight ratio) result in a dramatic improvement in response.
Obviously, the present invention is capable of numerous modifications and variations in light of the above theories. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.

权利要求:
Claims (51)
[1" claim-type="Currently amended] (a) vasodilators; And
(b) A pharmaceutical composition comprising a 15-hydroxyprostaglandin dehydrogenase inhibitor.
[2" claim-type="Currently amended] The pharmaceutical composition of claim 1, wherein the vasodilator is prostaglandin E ₁ .
[3" claim-type="Currently amended] The pharmaceutical composition of claim 1, wherein said vasodilator is prostaglandin E ₂ .
[4" claim-type="Currently amended] The method of claim 1, wherein the 15-hydroxyprostaglandin dehydrogenase inhibitor is glycyrrhizic acid, licorice, glycyrrhetinic acid, glycosides of various glycyrrhetinic acid, carboxenolone, DHEA, Spironolactone, sofalcone, indomethacin, sulindac, etodolak, ellidinic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, oleic acid, linoleic acid, and arachidonic acid, Sulfasalazine and analogs thereof, and ethacrylic acid, purosemide, chlorothiazide, hydrochlorothiazide, papaverine, cis-sulfak sulfide, trans-sulfac sulfide, cis-sulfac, trans-sulfac, glutathione. Thiosulfonate, divalent copper cation, divalent zinc cation, selenium, napazathrom (Bayg-6575); Lipoxygenase and cyclooxygenase-derived substrates with ω-6 hydroxyl groups such as 15-HETE, 13-HODD and HHT, gossypol, 15 (R) -prostaglandin E-1, 15 (R ) -Prostaglandin E-2, 15 (R) -15-methylprostaglandin E-2.
[5" claim-type="Currently amended] The pharmaceutical composition of claim 1 in the form selected from the group consisting of solutions, ointments and suppositories.
[6" claim-type="Currently amended] The pharmaceutical composition of claim 1 which is a suppository.
[7" claim-type="Currently amended] The pharmaceutical composition of claim 1 further comprising polyethylene glycol.
[8" claim-type="Currently amended] The pharmaceutical composition according to claim 2, comprising 0.01 to 2.0 mg of the prostaglandin E ₁ and 25 to 100 units of the prostaglandin degrading enzyme inhibitor.
[9" claim-type="Currently amended] 4. A pharmaceutical composition according to claim 3, comprising 0.01 to 2.0 mg of said prostaglandin E ₂ and 50 to 100 units of said prostaglandin degrading enzyme inhibitor.
[10" claim-type="Currently amended] (a) vasodilators; And
(b) 15-hydroxyprostaglandin dehydrogenase enzyme inhibitor
A method of treating male erectile dysfunction comprising administering an effective amount of to a patient in need thereof.
[11" claim-type="Currently amended] The method of claim 10, wherein said vasodilator is prostaglandin E ₁ .
[12" claim-type="Currently amended] The method of claim 10, wherein said vasodilator is prostaglandin E ₂ .
[13" claim-type="Currently amended] The method of claim 10, wherein the 15-hydroxyprostaglandin dehydrogenase inhibitor is glycyrrhizic acid, licorice, glycyrrhetinic acid, glycosides of various glycyrrhetinic acid, carboxenolone, DHEA, Spironolactone, sofalcone, indomethacin, sulindac, etodolak, ellidinic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, oleic acid, linoleic acid, and arachidonic acid, Sulfasalazine and analogs thereof, and ethacrylic acid, purosemide, chlorothiazide, hydrochlorothiazide, papaverine, cis-sulfak sulfide, trans-sulfac sulfide, cis-sulfac, trans-sulfac, glutathione. Thiosulfonate, divalent copper cation, divalent zinc cation, selenium, napazathrom (Bayg-6575); Lipoxygenase and cyclooxygenase-derived substrates having ω-6 hydroxyl groups such as 15-HETE, 13-HODD and HHT; Gossypol, 15 (R) -prostaglandin E-1, 15 (R) -prostaglandin E-2, 15 (R) -15-methylprostaglandin E-2.
[14" claim-type="Currently amended] The method of claim 10 wherein (a) and (b) are contained in a pharmaceutical composition in the form selected from the group consisting of solutions, ointments and suppositories.
[15" claim-type="Currently amended] The method of claim 10 wherein (a) and (b) are contained in a pharmaceutical composition that is a suppository.
[16" claim-type="Currently amended] The method of claim 11, comprising administering 0.01 to 2.0 mg of the prostaglandin E ₁ and 25 to 100 units of the prostaglandin degrading enzyme inhibitor.
[17" claim-type="Currently amended] The method of claim 12, comprising administering 0.01 to 2.0 mg of the prostaglandin E ₂ and 50 to 100 units of the prostaglandin degrading enzyme inhibitor.
[18" claim-type="Currently amended] The method of claim 10, wherein the pharmaceutical composition is administered by either injection into the corpus cavernosum or urinary tract.
[19" claim-type="Currently amended] The method of claim 10, wherein said pharmaceutical composition is administered urethically.
[20" claim-type="Currently amended] The method of claim 10, wherein said pharmaceutical composition is administered topically to the urinary tract.
[21" claim-type="Currently amended] (a) prostaglandins;
(b) a 15-hydroxyprostaglandin dehydrogenase inhibitor; And
(c) a substrate that is solid at room temperature and releases the components (a) and (b) when inserted into the urethra or ureter
Pharmaceutical compositions in the form of suppositories containing.
[22" claim-type="Currently amended] The pharmaceutical composition of claim 21 wherein said component (c) melts or dissolves upon insertion into said urethra to release said components (a) and (b).
[23" claim-type="Currently amended] The pharmaceutical composition of claim 21, wherein upon insertion into the urethra the component (c) releases components (a) and (b) without melting or dissolving.
[24" claim-type="Currently amended] The method of claim 21, wherein the prostaglandin vasodilator is selected from the group consisting of prostaglandin E-1; Prostaglandin E-2; Prostaglandin A-1; Prostaglandin B-1; Prostaglandin D-2; Prostaglandin EM; Prostaglandin FM; Prostaglandin H-2; Prostaglandin I-2; 19-hydroxy-prostaglandin A-1; 19-hydroxy-prostaglandin B-1; Prostaglandin A-2; Prostaglandin B-2; 19-hydroxy-prostaglandin A-2; 19-hydroxy-prostaglandin B-2; Prostaglandin B-3; 16,16-dimethyl-Δ ² -prostaglandin E-1 methyl ester; 15-deoxy-16-hydroxy-16-methyl-prostaglandin E-1 methyl ester; 16,16-dimethyl-prostaglandin E-2; 11-deoxy-15-methyl-prostaglandin E-1; 16-methyl-18,18,19,19-tetrahydrocarbacycline; (16RS) -15-deoxy-16-hydroxy-16-methyl-prostaglandin E-1 methyl ester; (+)-4,5-didehydro-16-phenoxy-α-tetranor-prostaglandin E-2 methyl ester; 11-deoxy-11a, 16,16-trimethyl-prostaglandin E-2; (+)-11a, 16a, b-dihydroxy-1,9-dioxo-1- (hydroxymethyl) -16-methyl-trans-prosten; 9-chloro-16,16-dimethyl-prostaglandin E-2; Arboprostill; Ilofrost; CL 115,347; 16,16-dimethyl-PGE-2; 15 (S) -15-methyl-PGE-2; 9-deoxy-9-methylene-16,16-dimethyl-PGE-2, potassium salt; Carbaprostacycline; Prostaglandin D ₂ ; 19 (R) -hydroxy-PGE-2; 13,14-dihydro-PGE-1; 11β-PGE-2; 19 (R) -hydroxy-PGE-1; And 11-deoxy-16,16-dimethyl-PGE-2.
[25" claim-type="Currently amended] The pharmaceutical composition of claim 21, wherein the prostaglandin vasodilator is selected from the group consisting of prostaglandin E-1, prostaglandin E-2, and prostaglandin D-2.
[26" claim-type="Currently amended] The pharmaceutical composition of claim 21, wherein said prostaglandin vasodilator is prostaglandin E ₁ .
[27" claim-type="Currently amended] The pharmaceutical composition of claim 21, wherein said prostaglandin vasodilator is prostaglandin E ₂ .
[28" claim-type="Currently amended] The method according to claim 21, wherein the 15-hydroxyprostaglandin dehydrogenase inhibitor is selected from the group consisting of glycidyl acid, licorice, glycyrrhetinic acid, glycosides of various glycyrrhetinic acid, carboxenolone, DHEA, Spironolactone, sofalcone, indomethacin, sulindac, etodolak, ellidinic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, oleic acid, linoleic acid, and arachidonic acid, Sulfasalazine and analogs thereof, and ethacrylic acid, purosemide, chlorothiazide, hydrochlorothiazide, papaverine, cis-sulfak sulfide, trans-sulfac sulfide, cis-sulfac, trans-sulfac, glutathione. Thiosulfonate, divalent copper cation, divalent zinc cation, selenium, napazathrom (Bayg-6575); Lipoxygenase and cyclooxygenase-derived substrates with ω-6 hydroxyl groups such as 15-HETE, 13-HODD and HHT, gossypol, 15 (R) -prostaglandin E-1, 15 (R) A pharmaceutical composition selected from the group consisting of prostaglandin E-2, 15 (R) -15-methylprostaglandin E-2.
[29" claim-type="Currently amended] The method of claim 26, wherein the prostaglandin E _{1 is} 0.1 μg to 10 mg; And 25 to 100 units of said 15-hydroxyprostaglandin dehydrogenase inhibitor.
[30" claim-type="Currently amended] 27. The composition according to claim 26, wherein the prostaglandin E _{1 is} 0.1 µg to 10 mg, and caprinic acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, ellidinic acid, oleic acid, linoleic acid, and arachidonic acid. A pharmaceutical composition containing 0.1 μg to 20 mg of a 15-hydroxyprostaglandin dehydrogenase inhibitor selected from the group.
[31" claim-type="Currently amended] The pharmaceutical composition of claim 26, wherein said prostaglandin E ₁ contains 0.1 μg to 10 mg, and 0.1 mg to 20 mg of 15-hydroxyprostaglandin dehydrogenase inhibitor selected from the group consisting of etodolak, indomethacin and sulindac. Composition.
[32" claim-type="Currently amended] The pharmaceutical composition of claim 27 containing 0.1 μg to 10 mg of the prostaglandin E ₂ and 25 to 100 units of the 15-hydroxyprostaglandin dehydrogenase inhibitor.
[33" claim-type="Currently amended] 28. The composition of claim 27, wherein the prostaglandin E _{2 is} 0.1 µg to 10 mg, and caprinic acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, ellidinic acid, oleic acid, linoleic acid, and arachidonic acid. A pharmaceutical composition containing 0.1 μg to 20 mg of a 15-hydroxyprostaglandin dehydrogenase inhibitor selected from the group.
[34" claim-type="Currently amended] The pharmaceutical composition of claim 27, wherein said prostaglandin E ₂ contains 0.1 μg to 10 mg, and 0.1 mg to 20 mg of 15-hydroxyprostaglandin dehydrogenase inhibitor selected from the group consisting of etodolak, indomethacin and sulindac. Composition.
[35" claim-type="Currently amended] (a) prostaglandins;
(b) a 15-hydroxyprostaglandin dehydrogenase inhibitor; And
(c) a substrate that is solid at room temperature and releases the components (a) and (b) when inserted into the urethra or ureter
A method of treating male erectile dysfunction comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition in the form of suppositories.
[36" claim-type="Currently amended] 36. The method of claim 35 wherein said component (c) melts or dissolves upon insertion into said urethra to release said components (a) and (b).
[37" claim-type="Currently amended] 36. The method of claim 35, wherein said component (c) is released upon insertion into said urethra without dissolving or dissolving said component (c).
[38" claim-type="Currently amended] 36. The method of claim 35, wherein said prostaglandin vasodilator is selected from prostaglandin E-1; Prostaglandin E-2; Prostaglandin A-1; Prostaglandin B-1; Prostaglandin D-2; Prostaglandin EM; Prostaglandin FM; Prostaglandin H-2; Prostaglandin I-2; 19-hydroxy-prostaglandin A-1; 19-hydroxy-prostaglandin B-1; Prostaglandin A-2; Prostaglandin B-2; 19-hydroxy-prostaglandin A-2; 19-hydroxy-prostaglandin B-2; Prostaglandin B-3; 16,16-dimethyl-Δ ² -prostaglandin E-1 methyl ester; 15-deoxy-16-hydroxy-16-methyl-prostaglandin E-1 methyl ester; 16,16-dimethyl-prostaglandin E-2; 11-deoxy-15-methyl-prostaglandin E-1; 16-methyl-18,18,19,19-tetrahydrocarbacycline; (16RS) -15-deoxy-16-hydroxy-16-methyl-prostaglandin E-1 methyl ester; (+)-4,5-didehydro-16-phenoxy-α-tetranor-prostaglandin E-2 methyl ester; 11-deoxy-11a, 16,16-trimethyl-prostaglandin E-2; (+)-11a, 16a, b-dihydroxy-1,9-dioxo-1- (hydroxymethyl) -16-methyl-trans-prosten; 9-chloro-16,16-dimethyl-prostaglandin E-2; Arboprostill; Ilofrost; CL 115,347; 16,16-dimethyl-PGE-2; 15 (S) -15-methyl-PGE-2; 9-deoxy-9-methylene-16,16-dimethyl-PGE-2, potassium salt; Carbaprostacycline; Prostaglandin D ₂ ; 19 (R) -hydroxy-PGE-2; 13,14-dihydro-PGE-1; 11β-PGE-2; 19 (R) -hydroxy-PGE-1; And 11-deoxy-16,16-dimethyl-PGE-2.
[39" claim-type="Currently amended] 36. The method of claim 35, wherein said prostaglandin vasodilator is selected from the group consisting of prostaglandin E-1, prostaglandin E-2, and prostaglandin D-2.
[40" claim-type="Currently amended] 36. The method of claim 35, wherein said prostaglandin vasodilator is prostaglandin E ₁ .
[41" claim-type="Currently amended] 36. The method of claim 35, wherein said prostaglandin vasodilator is prostaglandin E ₂ .
[42" claim-type="Currently amended] 36. The method of claim 35, wherein the 15-hydroxyprostaglandindehydrogenase inhibitor is selected from the group consisting of glycidyl acid, licorice, glycyrrhetinic acid, glycosides of various glycyrrhetinic acid, carboxenolone, DHEA, Spironolactone, sofalcone, indomethacin, sulindac, etodolak, ellidinic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, oleic acid, linoleic acid, and arachidonic acid, Sulfasalazine and analogs thereof, and ethacrylic acid, purosemide, chlorothiazide, hydrochlorothiazide, papaverine, cis-sulfak sulfide, trans-sulfac sulfide, cis-sulfac, trans-sulfac, glutathione. Thiosulfonate, divalent copper cation, divalent zinc cation, selenium, napazathrom (Bayg-6575); Lipoxygenase and cyclooxygenase-derived substrates with ω-6 hydroxyl groups such as 15-HETE, 13-HODD and HHT, gossypol, 15 (R) -prostaglandin E-1, 15 (R ) -Prostaglandin E-2, 15 (R) -15-methylprostaglandin E-2.
[43" claim-type="Currently amended] The method of claim 40, wherein the pharmaceutical composition contains 0.1 μg to 10 mg of the prostaglandin E ₁ and 25 to 100 units of the 15-hydroxyprostaglandin dehydrogenase inhibitor.
[44" claim-type="Currently amended] The pharmaceutical composition of claim 40, wherein the pharmaceutical composition comprises 0.1 μg to 10 mg of prostaglandin E ₁ and capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, ellidinic acid, oleic acid, linoleic acid and A method containing from 0.1 μg to 20 mg of a 15-hydroxyprostaglandin dehydrogenase inhibitor selected from the group consisting of arachidonic acid.
[45" claim-type="Currently amended] 41. The pharmaceutical composition of claim 40, wherein the pharmaceutical composition comprises 0.1 μg to 10 mg of prostaglandin E ₁ and 15-hydroxyprostaglandin dehydrogenase inhibitor selected from the group consisting of etodolak, indomethacin and sulindac. Containing.
[46" claim-type="Currently amended] The method of claim 41, wherein the pharmaceutical composition contains 0.1 μg to 10 mg of the prostaglandin E ₂ and 25 to 100 units of the 15-hydroxyprostaglandin dehydrogenase inhibitor.
[47" claim-type="Currently amended] The pharmaceutical composition of claim 41, wherein the pharmaceutical composition comprises 0.1 μg to 10 mg of prostaglandin E ₂ and capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, ellidinic acid, oleic acid, linoleic acid and A method containing from 0.1 μg to 20 mg of a 15-hydroxyprostaglandin dehydrogenase inhibitor selected from the group consisting of arachidonic acid.
[48" claim-type="Currently amended] 42. The pharmaceutical composition of claim 41, wherein the pharmaceutical composition comprises 0.1 μg to 10 mg of prostaglandin E ₂ and 15-hydroxyprostaglandin dehydrogenase inhibitor selected from the group consisting of etodolak, indomethacin and sulindac. Containing.
[49" claim-type="Currently amended] 46. The method of claim 45, wherein said pharmaceutical composition is administered urethically.
[50" claim-type="Currently amended] 46. The method of claim 45, wherein said pharmaceutical composition is administered to the urinary tract.
[51" claim-type="Currently amended] 46. The method of claim 45, wherein said pharmaceutical composition is topically administered to glans skin.

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同族专利:

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公开号 | 公开日

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AU8473498A|1999-02-08|

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CA2295595A1|1999-01-21|

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US20020128314A1|2002-09-12|

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NO20000085L|2000-03-01|

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EP1005336A4|2001-01-17|

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JP2001509480A|2001-07-24|

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US6414027B1|2002-07-02|

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US6559184B2|2003-05-06|

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NO20000085D0|2000-01-07|

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WO1999002147A1|1999-01-21|

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EP1005336A1|2000-06-07|

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AU742787B2|2002-01-10|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
1997-07-09|Priority to US08/890,445

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1997-07-09|Priority to US8/890,445

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1997-12-19|Priority to US6829497P

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1997-12-19|Priority to US60/068,294

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1998-07-09|Application filed by 추후보정, 안드로솔루션스, 인크.

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1998-07-09|Priority to PCT/US1998/013439

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2001-03-15|Publication of KR20010021625A

优先权:

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申请号 | 申请日 | 专利标题

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US08/890,445|US6103765A|1997-07-09|1997-07-09|Methods for treating male erectile dysfunction|

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US8/890,445|1997-07-09|

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US6829497P| true| 1997-12-19|1997-12-19|

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US60/068,294|1997-12-19|

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PCT/US1998/013439|WO1999002147A1|1997-07-09|1998-07-09|Improved methods and compositions for treating male erectile dysfunction|