KR20050057245A - Methods of treatment of male erectile dysfunction - Google Patents

Abstract

The invention provides methods for the treatment of erectile dysfunction in a patient suffering from a co-morbid condition comprising placing in the fossa navicularis of the patient an erection- inducing amount of a semi-solid vasoactive prostaglandin composition.

Description

How to treat male erectile dysfunction {METHODS OF TREATMENT OF MALE ERECTILE DYSFUNCTION}

The present invention relates to a method of treating erectile dysfunction in a patient with a co-morbid condition.

The term "impotence" is used to indicate that a man is incapable of reaching and maintaining an erection of the penis sufficient to enable satisfactory sexual intercourse. The term "erectile dysfunction" is proposed as a more accurate term used to "show that a man is incapable of reaching the erection of the penis as part of the overall extensive procedure of male sexual function". In this regard, see Droller, M.J. Etc, Impotence. Consensus Development Conference Statement, National Institutes of Health (1993).

Erectile dysfunction can be derived from psychological causes (psychological erectile dysfunction) or organic causes, or a combination of these. Examples of organic causes include physiological, neurological, vascular and hormonal abnormalities or a combination thereof.

Normal physiological aspects of erection include stimulation of nerves that signal to relax certain muscles. These muscles limit blood flow through the arteries in the penis upon contraction. In relaxation, these muscles significantly increase blood flow. This increased blood flow congestes the blood in three groups of erectile tissue in the penis, making the penis less relaxed. Congested erectile tissue and the muscle structure of the penis weaken adjacent veins, limiting the blood flow released from the penis. Restriction of blood flow from the penis increases and sustains erections.

A deficiency of some hormones, such as testosterone, or an increase in other hormones, such as prolactin, can cause erectile dysfunction. Various drugs, such as diuretics, antihypertensives, anticonvulsants, anesthetics, alcohols and psychotropic drugs, can cause erectile dysfunction as a side effect. See, for example, Murray, F. T. et al., Amer. J. Medical Sci. 309: 99-109 (1995).

In addition, damage to nerves and blood vessels can also provide an organic cause for erectile dysfunction. Several aspects can be involved in the development of the disease. For example, diabetes, which damages both nerves and blood vessels, can cause erectile dysfunction. A significant proportion of all diabetic male patients suffer from erectile dysfunction. Diabetes is one of the common risk factors for erectile dysfunction (ED), but the pathological theory of ED during diabetes progression is not fully understood (Sullivan, ME et al., Alterations in endothelin B receptor sites in cavernosal tissue of diabetic rabbits: potential) relevance to the pathogenesis of erectile dysfunction, J. Urol. 1997 158 (5): 1966-72). Diabetic ED may be one aspect of vascular disease associated with diabetes (Sairam, K. et al., Prevalence of undiagnosed diabetes mellitus in male erectile dysfunction.BJU Int. 2001 88 (1): 68-71; Sullivan, ME et al., Nitric oxide and penile erection: is erectile dysfunction another manifestion of vascular disease? Cardiovasc Res. 1999 Aug 15; 43 (3): 658-65).

Microvascular disease is one of the hallmarks of diabetes. Many studies have revealed a relationship between diabetes, erectile dysfunction and endothelial cell dysfunction (De angelis, L. et al., Erectile and endothelial dysfunction in Type II diabetes: a possible link. Diabetologia. 2001 44 (9): 1155- 60; Burchardt, T. et al., Reduction of endothelial and smooth muscle density in the corpora cavernosa of the streptozotocin induced diabetic rat.J. Urol. 2000 164 (5): 1907-11; Hopfner, RL & Gopalakrishnan, V., Endothelin : emerging role in diabetic vascular complications.Diabetologia, 1999 42 (12): 1383-94). Other studies have shown that erectile dysfunction is prominent among patients with cardiovascular disease or diabetes, and the presence of cardiovascular disease has been shown to increase the risk of erectile dysfunction (Sasayama, S. et al., Men's Health Study. Epidemiology of Erectile Dysfunction and Cardiovascular Disease, Circ. J., 2000; 67: 656-659).

Radical retropubic prostatectomy (RPP) has been proposed as a standard treatment for tracheal / sample limited prostate cancer for decades, but even after this procedure, the likelihood of erectile dysfunction in the selected series is high, at about 90%. Technology and experience have been reported to be influential variables influencing outcomes (Zippe, CD et al., Management of erectile dysfunction following radical prostatectomy, Current Urology Reports, 2: 495-503 (2001)). Age is also a cause. Approximately 50-70% of young men recover sexual performance after neuro-conservative radical prostatectomy, but their recovery is less than 10% in patients older than 70 years (Catalona, WJ et al., Nerve-sparing radical) prostatectomy: evaluation of results after 250 patients, J. Urol. 1990; 143: 538-43; discussion 44; Quinlan, D. M et al., Sexual function following radical prostatectomy: influence of preservation of neurovascular bundles, J. Urol. 1991; 145: 998-1002).

Therefore, in most men, treatment for erectile dysfunction is necessary to enable sexual activity after radical prostatectomy. Although treatment methods using vacuum compression devices, intravascular injection of vasoactive drugs, and transurethral vasodilators have been reported to have a response rate of 50% to 70%, there is a shortage of about 50% a year due to lack of long-term adaptability. have.

Proposed methods for treating erectile dysfunction include external devices, sexual intercourse therapy, surgical implantation of internal interstitial prostheses, direct injection of drugs into the penis and topically applied drug therapy. None of these methods works entirely.

External devices include compression bars (see US Pat. No. 2,818,855) and externally attached vacuum erecting aids. Some specialists consider externally attached erectile aids to be a top priority for treatment, but some patients avoid using these devices. In this regard, reference may be made to O'Keefe, M. et al., Medical Clinics of North America 79: 415-434 (1995).

Symptomatic intercourse therapy was first reported to be effective by Masters and Johnson, but subsequent studies have not shown very good results. Sex therapy is not considered to be an interesting alternative to patients. In this regard, Vickers, M.A. Et al., J. Urology 149: 1258-1261 (1993).

Surgically implanted mechanical devices such as hinged or solid rods and inflatable, spring driven or hydraulically driven insertion prostheses have been in use for some time. Several penile insertion prostheses are disclosed which are flexible plastic components of constant strength. However, such implant prostheses remain rigid and may cause discomfort to the patient. Another type of penile insertion prosthesis includes a surgically mounted pump to form a high pressure liquid in an elastic silicone mantle. In order to insert such complex devices, it is necessary to insert several components in the patient's body, for example liquid containing reservoirs, pumps, several valves, connecting pipes, etc., in addition to the components inserted directly into the penis. Other penile prostheses use alternating magnetic field sources that vary in frequency from 50 to 1000 Hz to affect external elastic sources and internal components mounted within the penis. These components sense the magnetic field and erect the penis by moving the liquid in the internal reservoir from the reservoir into an elastic mantle disposed on the penile corpus cavernosum. Thus there are several literatures on insertion prostheses comprising permanent magnets which act as seesaws under the influence of a magnetic field and move the liquid from the reservoir to the pump and back into the elastic mantle to act as an internal component which senses the alternating magnetic field generated by an external magnetic field source. It is disclosed through. However, while such implant prostheses may provide strength suitable for sexual intercourse, it has been reported that patients and their partners do not meet expectations when using such penile prostheses. For one patient, PGE ₁ (Keogh, EJ and Earle, CM, Int. J. Impotence Res., 4: 113, 1992) or MUSE® (Chew, KK) as an attempt to alleviate dissatisfaction with the use of penile prostheses. & Stuckey, BGA, Int. J. Impotence Res., 12: 195-196, 2000).

Methods of administering erectile and stimulating drugs are disclosed in US Pat. No. 4,127,118 to La Torre. The patent publication discloses a method for treating male impotence by injecting and promoting an erection by injecting an appropriate vasodilator, specifically a sympathetic blocker or smooth muscle relaxant, into the penis.

More recently, US Pat. No. 4,801,587 to Voss et al. Discloses a method of treating an impotence by applying ointment. This ointment consists of a vasodilator papaverine, hydralazine, sodium nitroprusside, phenoxybenzamine or phentolamine and a carrier which aids in the absorption of the main drug through the skin. US Pat. No. 5,256,652 to El-Rashidy discloses an aqueous topical application composition consisting of papaverine and hydroxypropyl-β-cyclodextrin.

In view of the biochemical, physiological and clinical efficacy of cyclic guanosine 3 ', 5'-monophosphate specific phosphodiesterase (cGMP-specific PDE) inhibitors, the inhibitors are used for smooth muscle, kidney, hemostasis, and stimulation. And / or various disease states that require regulation of endocrine function. A type of isozyme, specifically type 5 cGMP-specific phosphodiesterase (PDE5), is a major cGMP hydrolase in vascular smooth muscle and has also been reported for its intracavernosal expression. Thus, PDE5 is a notable goal in the treatment of sexual dysfunction. Sildenafil, a selective inhibitor of PDE5, is marketed under the trade name VIAGRA®. Sildenafil has had notable commercial success but has drawbacks due to its significant side effects, including facial burning (10% incidence). The use of sildenafil is restricted in patients with visible abnormalities and hypertension due to harmful side effects, and most severely in patients using organic nitrates (Welds et al., Amer. J. of Cardiology, 83 (5A). ), pp. 21 (C) -28 (C) (1999). The use of sildenafil in patients administering organic nitrates can result in clinically pronounced blood pressure drops, putting the patient at risk. Thus, the packaging label of sildenafil may include it regularly or together with organic nitrates (e.g. nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, erytrityl tetranitrate) and any other form of nitric acid donor. Strict contraindications are stated for intermittent use, because sildenafil increases the coercive effect of nitrates. In this regard, C.R. Conti et al., Amer. J. of Cardiology, 83 (5A), pp. 29C-34C (1999). Thus, although sildenafil is readily available, there remains a need to find improved drugs useful for treating sexual dysfunction in patients with comorbid morbidity, such as hypertension.

One method was to find other oral phosphodiesterase-5 inhibitors of greater selectivity that presumably lack the undesirable side effects of sildenafil. In this regard, reference may be made to US Pat. No. 6,451,807. Two examples of such phosphodiesterase-5 inhibitors for oral administration are vardenafil (Levitra ^™ ) and tadalafil (Cialis ^™ ). Early evidence suggests that the two phosphodiesterase-5 inhibitors are associated with ancillary treatment in patients with angina who are receiving nitrate therapy (contraindications) and in patients with hypertension who are receiving alpha blockers. It is similar in function to sildenafil. In this regard, Greser, U. & Gleiter, CH, Erectile dysfunction: Comparison of efficacy and side effects of the PDE-5 inhibitors sildenafil, vardenafil and tadalafil. Review of the literature, European J. Med. Res., 2002, 7: 435-446.

However, this approach to finding inhibitors with superior specificity does not necessarily solve the problem of lack of therapeutic responsiveness in the majority of erectile dysfunction patients, another problem with oral phosphodiesterase-5 inhibitor therapy. . As another example, another class of drugs that act against another therapeutic target may need to be investigated to treat erectile dysfunction in patients who are not responsive to oral phosphodiesterase-5 inhibitor therapy. In addition, it is an alternative to treat patients with additional morbidity, such as patients with angina who are treated with hypertension or nitrate treated with alpha blockers, who are contraindicated or warned of phosphodiesterase-5 inhibitor therapy. It is desirable to provide a method of treatment.

Prostaglandin E ₁ is a derivative of prostannic acid, a lipid acid with 20 carbon atoms, represented by the formula:

In addition, the compound is, for example, Chinoin Pharmaceutical and Chemical Works Ltd. (Hungary, Budapest) under the trade name "Alprostadil USP" and Pharmacia & Upjohn under the trade name "Caverject". Prostaglandin E ₁ complexed with alpha-cyclodextrin under the trade name alprostatil alfadex at Ono Pharmaceuticals (Japan) and from Schwarz Pharma (Germany) under the trade names "Edex®" or "Viradex®" As an injectable form.

As one of the commercially available formulations (MUSE®, Vivus, Menlo Park, CA), alprostadil is attached to the urethra using an attachment with a hollow tube of 3.2 cm in length and 3.5 mm in diameter In the form of pellets (Padma-Nathan, H. et al., N. Engl. J. Med., 336: 1-7 (1997), in particular see FIG. 1). In the home remedies section of the Padma-Nathan et al study, 32.7% of patients receiving MUSE® (10.8% of donors) had penile pain and 5.1% of patients experienced minor urethral trauma, whereas The percentages were 3.3% and 1.0%, respectively. The frequency of reporting these adverse events was different in subsequent studies: MUSE® caused penile pain in 17-23.6% of patients, compared with 1.7% with placebo and minor urinary bleeding in 4.8% of patients. (Peterson, CA et al., J. Urol., 159: 1523-1528 (1998)). In a study of European residents, 31% of patients with MUSE® reported pain or burning in the penis, urinary bleeding in 4.8%, and severe testicular pain in 2.9% (Porst, H. , Int. J. Impot.Res., 9: 187-192 (1997)). The percentage of patients who are responsive to MUSE® therapy, ie, those who have experienced one or more erections deemed sufficient for sexual intercourse, is 43% (Porst, 1997), 65.9% (Padma-Nathan et al., 1997). And 70.5% (Peterson et al., 1998), but published literature suggests that it is more appropriate to report a 30-40% percentage of patients reactive in the latter two studies. (Benson, G., J. Urol., 159: 1527-1528 (1998)).

Urinary administration of 1 mg of prostaglandin E ₁ preparations using phosphatidylcholine liposomes in 1 ml of polyoxyethylene glycol has been reported to be less effective than intraspenic injection of prostaglandin E ₁ (Englehardt, PF et al., British J. Urology, 81: 441-444, 1998). ED patients who received the liposome formulation did not achieve full penile strength, and only six of the 25 patients achieved an erection suitable for vaginal insertion. In contrast, intracavernosal injection of prostaglandin E ₁ achieved erection with sufficient or complete intensity for vaginal insertion in 23 of 25 identical ED patients. By the above-mentioned document is a rogue gyeongyo efficacy, prostaglandin E ₁ of prostaglandin E ₁ was first proposed that caused by being spread to the corpus callosum (corpus cavernosum) after being diffused into the corpus cavernosum.

While the mechanical and pharmaceutical treatment methods described above are focused on creating a suitable penile strength, even if these treatment methods are successful in achieving the appropriate strength, the satisfaction of the patient and the patient's sexual partner is not appropriate. There are many. Patients discontinue medical treatment methods that produce intensity due to painful side effects, such as intracavernosal infusions or urethral suppositories. Penile prostheses may form strength but have an erection insufficient. Specifically, a lack of erection of the penis glans is recognized to cause dissatisfaction with the patient and his sexual partner (see, eg, US Pat. No. 6,418,934 (2000) to Chew and Stuckey).

1 is an anatomical structural diagram showing a longitudinal section of a human penis.

Figure 2 is a schematic diagram showing in detail anatomically the distal end of the longitudinal section of the human penis.

3A and 3B are schematic diagrams illustrating a method of administering a topical prostaglandin E ₁ composition, and FIG. 3A illustrates a method of maintaining the conduit open by applying pressure to the glans on either side of the conduit to widen the conduit 3B illustrates a method of administration in which a medicament is dispensed through an open conduit without inserting the tip of the administration device or dosing device into the catheter.

Detailed Description of the Preferred Embodiments

It has been found in accordance with the present invention that it is advantageous to administer semisolid prostaglandins E ₁ suitable for treating erectile dysfunction in the presence of a co-morbid condition in the columnar cavities, which are natural enlargement spaces immediately adjacent to the penis catheter. The term "co-morbid" is used herein to refer to a medical condition present in a patient suffering from erectile dysfunction.

The columnar provides a limited area ideal for administering the pharmaceutical composition. This space is defined by a layered, scaly epidermis that is devoid of keratin, and thus is completely separated from the epidermis covering the glans, from the penis, and from the stratified columnar epidermis bordering the urethra. Thus, the borderline with the columnar provides increased permeability compared to the keratinized epidermis of the outer epidermis of the penis. It has been found that the composition of the present invention shows high efficiency and low incidence of local side effects when administered to the columnar.

The columnar is a natural expanded space suitable for receiving and retaining semisolid drugs. When semisolid medications, such as the compositions of the present invention, are administered to the columnar vortex, they have a higher flow impairment in the narrow outlets, conduits and urethra of the space. Disturbance to flow is proportional to the product of the cross sectional area of the path and the length of the path. Thus, semi-solid medications with appropriately selected viscosities naturally remain protected in the columnar and interior to facilitate absorption of active ingredients such as vasodilators and the like. Suitably the viscosity of the composition ranges from about 5,000 cps to about 20,000 cps, preferably from about 7,000 cps to about 13,000 cps.

Columnar is part of the natural defense system that protects the body from infection. The columnar is more immunologically protected than the adjacent sponges of the penile urethra. Thus, the attachment of semi-solid medications within the anatomical limits of the columnar means that artificially transporting contaminants, for example, directly from the penis surface into the penile urethra, does not bypass the natural barrier to disease. Since the relatively high glycogen content in the columnar and interior and the bacterial population provide a naturally low pH within the space, a composition with a relatively low pH within the acidic range, which provides a high solubility of prostaglandin E ₁ , causes excessive irritation to the tissue. It can be more easily accommodated without work.

Semi-solid compositions and penetration enhancers suitable for practicing the present invention are disclosed in detail in US Pat. Nos. 6,046,244, 6,118,020 and 6,323,241, which are incorporated herein by reference.

Referring to Figure 1, the basic structure of the human penis is shown. The columnar 110 in the penis glans 130 is a natural enlargement space of the male urethral cavity. The columnar extends far with respect to the urethral canal 128 and closely with respect to the oscillating region of the urethra 112 (also referred to as the “cavernous” region of the urethra). The vibratory region is the portion of the urethra that passes through the cavernous body 134 found within the axis 104 of the penis which is centered relative to the paired penile cavernous body. The soft urethra 114 is close to the vibrating region of the urethra and passes through the sphincter muscular muscle 140. More closely, the opening of the urethral wall 148 of the old urethral gland (Cooper Sea line) can be seen. Closer than that, the urethra passes through the prostate 160, where the openings of the ejaculation canal 156 and the prostate gland 158 can be seen within the urethral wall.

Referring to Figure 2, the detailed structure of the columnar 110 in the penis glans 130 is shown. The outer opening of the urethral canal 128 is the posterior limit with the columnar column. The glans of the glans are covered with keratinized lamellar scalp 186 (Pudney, J. and Anderson, D. J., (1995) Immunology of the human penile urethra, Amer. J. Path., 147: 155-165). The keratinized lamellar scalp 186 was divided into sharp transition lines (dotted lines) proximate to the glycogen-free keratinized lamellar scalp 184, which is characterized by a borderline with the posterior columnar.

The columnar is widened toward the base and the borderline is different for the non-keratinized layered scaly sheath 182 containing glycogen. Glycogen in the region is believed to support a bacterial group that lowers the pH of the region and to promote natural defense against infection. For this, see Holstein, A.F. Et al. (1991), Different epithelia in the distal human male urethra, Cell Tiss. Res. 264: 23-32. The exfoliated lamellar scaly shell containing glycogen is under hormonal control, increasing its area under high estrogen concentrations (Holestein et al., 1991). The proximal end with the columnar is narrow and forms a boundary with the layered columnar shell 180.

The semi-solid composition of the present invention has a viscosity that is appropriately selected so that the composition can be naturally protected in the columnar and the interior. The semi-solid composition may exhibit rheological properties of Newtonian or non-Newtonian. In a preferred embodiment, the semisolid compositions of the invention exhibit non-Newtonian rheological properties. That is, the apparent viscosity depends on the shear rate applied to the composition. As used herein, the term "shear thinning" means that the apparent viscosity (ratio of shear stress to shear rate) decreases with increasing shear rate, wherein the decrease in apparent viscosity is independent of time ( Pseudo plasticity), correlated with yield stress, which is defined as time dependent (tesotropy) or must be exceeded before starting flow (Bingham plastics and generalized Bingham). plastics). In this regard, as a whole, Harris, J. & Wilkinson, W. L., "Non-newtonian Fluid", pp. 856-858, Parker S.P. Edit, Mcgraw Hill Encyclopedia of PHysics, 2nd Edition, Mcgraw Hill, New York, 1993. Suitable viscosity ranges for the composition range from about 5,000 centipoise (cps) to about 20,000 cps, preferably from about 7,000 cps to about 13,000 cps.

In a preferred embodiment, the pharmaceutical composition of the present invention comprises at least one vasofunctional prostaglandin, preferably prostaglandin E ₁ , alkyl (N, N-disubstituted amino) esters, polysaccharide gums, lipophilic components and acid buffer systems. Include. The prostaglandins may be dissolved or substantially uniformly dispersed in the composition for topical administration, and are preferably soluble (and dissolved) in the composition for topical administration.

Vasofunctional prostaglandins are those that act as peripheral vasodilators, for example natural prostaglandins such as PGE ₁ , PGA ₁ , PGB ₁ , PGF _1α , 19-hydroxy-PGA ₁ , 19-hydroxy-PGB ₁ , PGE ₂ , PGA _2, PGB _2, 19- hydroxy -PGA _2, 19- hydroxy _{-PGB 2, PGE 3, PGF 3α} ; Semisynthetic or synthetic derivatives of natural prostaglandins, such as carboprost tromethamine, dinoprost tromethamine, dinoprostone, lipoprost, gemeprost, methenoprost, sulfprostone and thiaprost. For use in the methods of the invention, prostaglandin E ₁ and prostaglandin E ₂ are particularly preferred vascular prostaglandins.

The amount of vascular functional prostaglandin, such as prostaglandin E ₁ , in the pharmaceutical compositions of the present invention is an amount effective for treatment (causing erections), the specific vasoactive prostaglandins to be delivered, the condition to be treated, the other components of the composition, the desired The dosage depends on the dosage form (eg suppository or topical administration) and the specific type of vasofunctional prostaglandin used. The term "prostaglandin" as used herein refers to prostaglandin free acids and their pharmaceutically acceptable derivatives, such as prostaglandin E ₁ (PGE ₁ ), pharmaceutically acceptable salts and lower alkyl esters ("lower alkyl"). The term "means straight or branched chain alkyl having 1 to 4 carbon atoms). The composition generally comprises from about 0.001% to about 1% by weight, typically from about 0.05% to 1% by weight, preferably from about 0.1% to about 0.5% by weight of prostaglandin E, based on the total weight of the composition ₁ is contained. In one embodiment, prostaglandin E ₁ is present in the composition of the present invention in an amount from about 0.07% to about 0.4% by weight of the total composition weight.

Prostaglandin E ₁ is well known to those skilled in the art. Thus, there is no need to list specifically preferred amounts, and it can be easily determined by those skilled in the art in view of the factors as described above. Reference may be made to various references regarding the pharmacological activity, side effects, and standard dosage ranges of prostaglandin E ₁ . See, for example, Physician's Desk Reference, 51st Edition (1997), The Merck Index, 12th Edition, Merck & Co., New Jersey (1996), and Martindale The Extra Pharmacopoeia, 28th Edition, London, The Pharmaceutical Press. (1982).

In addition, it may be desirable to simultaneously administer one or more non-ecosanoid vasodilators, and in some cases, may have a synergistic effect. In this respect the combination of prazosin and prostaglandin E ₁ has been found to be particularly advantageous, where prostaglandin E ₁ appears to act as an activity enhancer for prazosin.

Suitable non-ecosanoid-based vasodilators include nitrates, for example nitroglycerin, isosorbide dinitrate, erytrityl tetranitrate, amyl nitrate, sodium nitroprusside, molsidomine, lincidomin chlorhydrate ( "SIN-1") and S-nitroso-N-acetyl-d, l-penicillamine ("SNAP"), amino acids such as L-arginine; Long- and short-acting α-sympathetic blockers such as phenoxybenzamine, dibenamine, phentolamine, tamsulosin and indoramine, in particular quinazoline derivatives such as alfuzosin, bunazosin, doxazosin, terrazosin, pra Chosin and Trimazosin; Vasodilatable natural herbal compositions and their biologically active extracts, such as gosyajinki-gan, winter jabori (satureja oboovata), bai-hua qian-hu, lipotab, jabaktang , Benphocetin, ginkgo biloba leaf extract, bacopa, dolo, zipenoside, sessile oil, rutacarpine, dehydroebodiamine, sweet ginseng, dansam root, sojahotang, control, ginseng and mixtures thereof (US Pat. No. 6,007,824) number); Ergot alkaloids such as ergotamine and ergotamine analogues, such as acetergamine, brasergoline, bromerguride, cynergoline, delorggotryl, disulsergin, ergonobin maleate, ergotamine tartrate, Etischelgin, liggotril, risergid, meschelgin, metergoline, mettergotamine, nisergoline, pergolide, propirergide, proterguride and terguride; Antihypertensive agents such as diazoxide, hydralazine and minoxidil; Vasodilators such as nimodepine, pinassidyl, cyclandelate, dipyridamole and isoxoxuprine; Chlorpromazine; Haloperidol; Yohimbine; Trazodone and vasoactive intestinal peptides.

When combined with angiogenic prostaglandins, piperazinyl quinazoline antihypertensives, such as prazosin, are present in an amount from about 0.1 mg to about 2.0 mg per dose, and the exact amount is specific piperazinyl quinazoline anti It depends on the efficacy of the hypertension and the type and dosage of the vasofunctional prostaglandins used. Doses and fractions of the vascular prostaglandin and piperazinyl quinazoline antihypertensive agents can be determined in a conventional manner by one skilled in the art without undue experimentation.

Compositions for topical administration may contain one or more penetration enhancers. Preferred penetration promoters for the present invention include ethanol, propylene glycol, glycerol, ethyl laurate, isopropyl palmitate, isopropyl myristate, laurocapram (Azone ^™ ), dioxolane (see US Pat. No. 4,861,764), macro Cyclic ketones, HP-101, oxazolidone and biodegradable penetration promoters (US Pat. Nos. 6,118,020 to Wong et al., US Pat. Nos. 6,118,020, Buyuktimkin et al., For example alkyl-2- (N- Substituted amino) alkanoates, alkyl-2- (N, N-disubstituted amino) alkanoates (e.g. dodecyl N, N-dimethylamino isopropionate (DDAIP)), N-substituted amino alkanol alkanos Acrylates, N, N-disubstituted amino alkanol alkanoates, acid addition salts and mixtures thereof, for example, crystalline acid addition salts of DDAIP can be prepared in the presence of a water miscible solvent such as DDAIP in hexane. In a crowd of mountains A process for preparation by low temperature mixing with one selected acid is disclosed in US Pat. No. 6,118,020, incorporated herein by reference .. Acid addition of dodecyl 2- (N, N-dimethylamino) propionate (DDAIP) The salt may be an inorganic acid addition salt or an organic acid addition salt, and representative inorganic acid addition salts include hydrochloride, bromate, sulfate, phosphate, and nitrate salts of DDAIP Examples of organic acid addition salts include acetate, benzoate, and salicylic acid. Salts, glycolates, succinates, nicotinates, tartarates, maleates, malates, palmophosphates, methanesulfates, cyclohexanesulphates, pictrates and lactates, and solvates thereof. As addition salt, DDAIP hydrogen chloride and DDAIP dihydrogen sulfate are preferable.

Penetration promoters are present in an amount sufficient to promote penetration of prostaglandin E ₁ . The specific amount depends on the specific release rate and the particular type of prostaglandin E ₁ used. Generally, penetration promoters are present in amounts ranging from about 0.5% to about 20% by weight based on the total weight of the composition. The penetration enhancer is preferably present in an amount from about 1% to about 10% by weight based on the weight of the composition. More preferably, the penetration enhancer is present in an amount from about 1% to about 5% by weight based on the weight of the composition.

In general, suitable penetration promoters can be selected from those mentioned above as well as sulfoxides, alcohols, fatty acids, fatty acid esters, polyols, amides, surfactants, terpenes, alkanones, organic acids and mixtures thereof. In this regard, see Chattaraj, S.C. And Walker, R. B., Penetration Enhancer Classification, pp. 5-20, Maibach, H.I. And Smith, H.E. (Edit), Percutaneous Penetration Enhancers, CRC Press, Inc., Boca Raton, Florida (1995) and Buyuktimkin, N., et al., Chemical Means of Transdermal Drug Delivery Systems, Interpharm Press, Inc., Buffalo Grove, Illinois (1997)] See. Examples of suitable sulfoxides include dimethyl sulfoxide, decylmethyl sulfoxide and mixtures thereof. Examples of suitable alcohols include ethanol, propanol, butanol, pentanol, hexanol, octanol, nonanol, decanol, 2-butanol, 2-pentanol, benzyl alcohol, capryl alcohol, decyl alcohol, lauryl alcohol, 2 -Lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, linolyl alcohol, linolenyl alcohol and mixtures thereof. Suitable fatty acids include valeric acid, heptanoic acid, perargonic acid, caproic acid, capric acid, lauric acid, myristic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, caprylic acid, isovaleric acid, neophene Carbonic acid, neoheptanoic acid, neononanoic acid, trimethyl hexanoic acid, neodecanoic acid, isostearic acid and mixtures thereof.

Suitable fatty acid esters are isopropyl n-butyrate, isopropyl n-hexanoate, isopropyl n-decanoate, isopropyl myristate, isopropyl palmitate, octyldecyl myristate, ethyl acetate, butyl acetate, methyl acetate , Methyl valerate, methyl propionate, diethyl sebacate, ethyl oleate, ethyl laurate and mixtures thereof. Suitable polyols include propylene glycol, polyethylene glycol, ethylene glycol, diethylene glycol, triethylene glycol, dipropylene glycol, glycerol, propanediol, sorbitol, dextran, butanediol, pentanediol, hexanetriol and mixtures thereof. have.

Suitable amides include urea, dimethylacetamide, diethyltoluamide, dimethylformamide, dimethyloctamide, dimethyldecamide, 1-alkyl-4-imidazolin-2-one, pyrrolidone derivatives, cyclic amides , Hexamethylene lauryl and its derivatives, diethanolamine, triethanolamine and mixtures thereof. Suitable pyrrolidone derivatives include 1-methyl-2-pyrrolidone, 2-pyrrolidone, 1-lauryl-2-pyrrolidone, 1-methyl-4-carboxy-2-pyrrolidone, 1- Hexyl-4-carboxy-2-pyrrolidone, 1-lauryl-4-carboxy-2-pyrrolidone, 1-decyl-thioethyl-2-pyrrolidone (HP-101), 1-methyl-4 -Methoxycarbonyl-2-pyrrolidone, 1-hexyl-4-methoxycarbonyl-2-pyrrolidone, 1-lauryl-4-methoxycarbonyl-2-pyrrolidone, N-cyclo Hexylpyrrolidone, N-methyldimethylaminopropylpyrrolidone, N-cocoalkylpyrrolidone, N-tallowalkylpyrrolidone, fatty acid ester of N- (2-hydroxymethyl) -2-pyrrolidone And mixtures thereof. Suitable cyclic amides include 1-dodecylazacycloheptan-2-one (laurocapram, Azone ^™ ), 1-geranylazacycloheptan-2-one, 1-farnesylazacycloheptan-2-one , 1-geranylgeranylazacycloheptan-2-one, 1- (3,7-dimethyloctyl) acycloheptan-2-one, 1- (3,7,11-trimethyloctyl) azacycloheptan-2 -One, 1-geranyl azacyclohexan-2-one, 1-geranyl azacyclopentane-2,5-dione, 1- farnesyl azacyclopentan-2-one, and mixtures thereof.

Suitable surfactants include anionic surfactants, cationic surfactants, nonionic surfactants, bile salts and lecithin. Suitable anionic surfactants include sodium laurate, sodium lauryl sulfate and mixtures thereof. Suitable cationic surfactants include cetyltrimethylammonium bromide, tetradecyltrimethylammonium bromide, benzalkonium chloride, octadecyltrimethylammonium chloride, cetylpyridinium chloride, dodecyltrimethylammonium chloride, hexadecyltrimethylammonium chloride and mixtures thereof Can be mentioned. Suitable nonionic surfactants include α-hydro-ω-hydroxy-poly (oxyethylene) -poly (oxypropyl) poly (oxyethylene) block copolymers, polyoxyethylene ethers, polyoxyethylene sorbitan esters, aliphatic alcohols And polyethylene glycol esters thereof and mixtures thereof. Suitable α-hydro-ω-hydroxy-poly (oxyethylene) -poly (oxypropyl) poly (oxyethylene) block copolymers include Poloxamers 231, 182 and 184 and mixtures thereof. Suitable polyoxyethylene ethers include 4-lauryl ether (BRIJ 30 ^™ ), (BRIJ 93 ^™ ), (BRIJ 96 ^™ ), 20-oleyl ether (BRIJ 99 ^™ ), and mixtures thereof. Suitable polyoxyethylene sorbitan esters include monolaurate (TWEEN20 ^™ , SPAN20 ^™ ), monopalmitate (TWEEN40 ^™ ), monostearate (TWEEN60 ^™ ) and monooleate (TWEEN80 ^™ ) and mixtures thereof. have. Suitable polyethylene glycol esters of fatty acids include 8-oxyethylene stearate ester (MYRJ45 ^™ ), (MYRJ51 ^™ ), 40-oxyethylene stearate ester (MYRJ52 ^™ ) and mixtures thereof. Examples of suitable bile salts include sodium cholate, laurocholine acid, glycolic acid and sodium salts of desoxycholine acid and mixtures thereof.

Suitable terpenes include D-limonene, α-pinene, β-eneene, α-terpinol, terpinene-4-ol, carbonol, carbon, pullegon, piperitone, mentone, menthol, geraniol, cyclohexene Oxides, limonene oxide, α-pinene oxide, cyclopentene oxide, 1,8-cineol, ylang ylang oil, anise oil, sperm oil, eucalyptus oil and mixtures thereof. Suitable alkanones include N-heptane, N-octane, N-nonane, N-undecane, N-dodecane, N-tridecane, N-tetradecane, N-hexadecane and mixtures thereof. Suitable organic acids include citric acid, succinic acid, salicylic acid, salicylates (including methyl, ethyl and propyl glycol derivatives), tartaric acid and mixtures thereof.

Natural and modified polysaccharide gums are also important components of the compositions of the present invention. Examples of suitable gums are the natural and modified galactomannan gum classes. Galactomannan gums are carbohydrate polymers containing D-galactose and D-mannose units or derivatives of such polymers. There are relatively many galactomannans, which vary in composition depending on their source. Galactoman black is characterized by a straight chain structure of (1 → 4) linked β-D-mannopyranosyl units. Single-membered α-D-mannopyranosyl units linked to the main chain (1 → 6) exist as branched chains. Galactomannan gums include guar gum and locust bean gum, guar gum found in seed endosperm of two legumes ( Cyamposis tetragonalobus and Psoraloids ), and seed endosperm of locust bean black ceratonia siliqua Found in Suitable modified polysaccharide gums include ethers of natural or substituted polysaccharide gums such as carboxymethyl ethers, ethylene glycol ethers and propylene glycol ethers. Methyl cellulose is mentioned as an example of substituted polysaccharide gum. Preferred modified galactomannan gum is modified guar gum.

Examples of other suitable gums include agar gum, carrageenan gum, gatti gum, karaya gum, ramsan gum and xanthan gum. The compositions of the present invention may contain mixtures of various gums or mixtures of gums with acidic polymers.

Gum, especially galactomannan gum, is a well known substance. In this regard, see, for example, Industrial Gums : Polysaccharides & Their Derivatives , Whistler RL and BeMiller JN (edit), 3rd edition, Academic Press (1992) and Davidson RL, Handbook of Water-Soluble Gums & Resins, McGraw-Hill, Inc. , NY (1980). Most gums are commercially available in many forms, usually in powders and ready for use in food and topical compositions. For example, locust bean gum in powder form can be found in Tic Gums, Inc. (Bellcam, MD).

When present, the polysaccharide gum is present in an amount of about 0.1 to about 5 weight percent based on the total weight of the composition, and preferably in an amount of about 0.5 to 3 weight percent. In a preferred embodiment, the polysaccharide gum is present in an amount of 2.5% by weight. The preparation of the specific composition was described in the following examples.

It is a polyacrylic acid polymer that can optionally be used in place of polysaccharide gum. Various conventional polyacrylic acid polymers are known under the common name "carbomer." Carbomers are polyacrylic acid polymers crosslinked with polyalkenyl polyethers in small amounts. It is marketed under the trade name "CARBOPOL ^™ " by BF Goodrich Company (Akron, Ohio). A particularly preferred class of carbomers is one sold under the trade name "CARBOPOL 940".

Other suitable polyacrylic acid polymers include those sold under the trade names “Pemulen ^™ ” (BF Goodrich Company) and “POLYCARBOPHIL ^™ ” (AH Robbins, Richmond, VA). Pemulen ^™ polymers are copolymers of C ₁₀ -C ₃₀ alkyl acrylates with one or more of their simple esters crosslinked with allyl ethers of acrylic acid, methacrylic acid or sucrose or pentaerythritol alkyl ethers. POLYCARBOPHIL ^™ promoter is polyacrylic acid crosslinked with divinyl glycol.

If polyacrylic acid polymers are present, they are present in about 0.5 to about 5 weight percent based on the total weight of the composition.

Another important ingredient is the lipophilic component. As used herein, the term "lipophilic component" means a reagent that is both lipophilic and hydrophilic. Those skilled in the art of pharmacy will appreciate that the lipophilic properties of a given compound, ie, "lipophilic", are commonly quantified in comparison to other compounds by using partition coefficients. According to the International Union of Pure and Applied Chemistry (IUPAC), the partition coefficient is the rate at which a substance is distributed between two phases when present in a heterogeneous system. As defined, the concentration ratio (or, strictly speaking, activity ratio) of the same molecular species between the two phases is constant at a constant temperature.

C ₁ -C ₈ aliphatic alcohols, C ₂ -C ₃₀ aliphatic esters and mixtures thereof can serve as lipophilic components. Specific examples of suitable alcohols include ethanol, n-propanol and isopropanol, and suitable esters include ethyl acetate, butyl acetate, ethyl laurate, methyl propionate, isopropyl myristate and isopropyl palmitate. . As used herein, the term "aliphatic alcohol" is meant to include polyols such as glycerol, propylene glycol and polyethylene glycol. In one embodiment, preference is given to using mixtures of alcohols and esters, in particular mixtures of ethanol and ethyl laurate.

In one embodiment, C ₂ -C ₃₀ aliphatic esters, and mixtures thereof comprising lipophilic components, comprise C ₈ -of glycerol selected from the group consisting of monoglycerides, diglycerides, triglycerides and mixtures thereof. C ₃₀ aliphatic esters. Suitable aliphatic esters include glyceryl esters of saturated fatty acids, unsaturated fatty acids and mixtures thereof and mixtures thereof. Suitable saturated fatty acids include caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid and lignoseric acid. Suitable unsaturated acids include oleic acid, linoleic acid and linolenic acid. Suitable glyceryl esters include glyceryl monooleate, triolein, trimyristin and tristearin, preferably trimyristin.

The concentration of lipophilic component required depends on other factors, such as the desired semisolid consistency and the desired skin penetration promoting effect. The concentration of the lipophilic component is suitably from 0.5% to 40% by weight based on the total weight of the composition. The topical composition preferably contains a lipophilic component at a concentration of 7% to 40% by weight based on the total weight of the composition.

When using a mixture of aliphatic alcohols and aliphatic esters, the amount of alcohol is suitably 0.5% to 10%. In one preferred embodiment, the amount of alcohol is in the range of 5% to 15% and the amount of aliphatic ester is in the range of 2% to 15% (based on the total weight of the composition). In another preferred embodiment, the amount of alcohol is in the range of 0.5% to 10% and the amount of aliphatic ester is in the range of 0% to 10% (based on the total weight of the composition).

The concentration of lipophilic component required depends on other factors, for example the desired semisolid roughness and the desired skin penetration promoting effect. Preferred topical compositions contain lipophilic components in amounts ranging from 7% to 40% by weight based on the total weight of the composition. When using a lipophilic component which is a mixture of an aliphatic alcohol and an aliphatic ester, the amount of alcohol is preferably 5% to 15%, and the amount of aliphatic ester is preferably 2% to 15% (based on the total weight of the composition).

An optional but preferred component is an emulsifier. Although not critical, suitable emulsifiers will typically exhibit a hydrophilic-lipophilic equilibrium of at least 10. Sucrose esters, specifically sucrose stearate, can be used as emulsifiers in the compositions of the present invention. When using an emulsifier, sucrose stearate is preferably used in an amount of about 2% by weight or less based on the total weight of the composition. The preferred amount of sucrose stearate emulsifier can also be expressed as the weight ratio of the emulsifier to the polysaccharide gum. The ratio of emulsifier: gum is preferably 1: 6, and in order to obtain the desired semisolid roughness and resistance to separation, the ratio is most preferably 1: 4.

Other suitable emulsifiers include polyoxyethylene sorbitan esters, long chain alcohols, preferably cetostearyl alcohol, and fatty acid glycerides. Suitable polyoxyethylene sorbitan esters include monolaurate (Tween20 ^™ , Span20 ^™ ), monopalmitate (Tween40 ^™ ), monostearate (Tween60 ^™ ) and monooleate (Tween80 ^™ ) and mixtures thereof have. Preferred fatty acid glycerides include glyceryl monooleate, triolein, trimyristin and tristearin.

The composition of the present invention comprises an acid buffer system. The acid buffer system serves to maintain or buffer the pH of the composition within a predetermined range. The term "buffer system" or "buffer" means a solute formulation (s) that stabilizes an aqueous solution against significant pH changes (or changes in hydrogen ion concentration or activity) when an acid or base is added in the aqueous solution. Thus, solute agent (s) that serve to resist changes from initial buffer pH within the ranges described above are well known. Although there are a myriad of suitable buffers, potassium phosphate monohydrate has been proven effective in the compositions of the present invention.

The final pH of the pharmaceutical composition may vary within physiologically acceptable ranges. The final pH should not irritate human skin. To the extent that these conditions are not violated, the pH can be selected to improve the stability and adjust the roughness of prostaglandin E ₁ as needed. In one embodiment, the preferred pH value is about 3 to about 7.4, more preferably about 3 to about 6.5, most preferably about 3.5 to about 6.

The remaining component of the composition is water, which must be purified. The composition contains water in the range of about 50% to about 90% based on its total weight. The specific amount of water present is not critical but can be adjusted to obtain the desired roughness and / or concentration of other components.

Prostaglandin E ₁ stabilizers, colorants, flow regulators and preservatives may be added to such an extent that they do not excessively limit prostaglandin E ₁ skin penetration or interfere with certain semisolid roughness.

Contemplated formulations of semisolid pharmaceutical compositions include creams, gels, ointments, colloidal suspensions, and the like, and include, but are not limited to, compositions suitable for use in transdermal patches and similar devices.

The aforementioned components can be combined in any order and manner to produce a stable composition comprising prostaglandin E ₁ evenly dispersed throughout the semisolid formulation. One available method for preparing such a composition is a mixture formed after dispersing the polysaccharide gum (or polyacrylic acid polymer) in a premixed water / buffer solution (hereinafter referred to as “part A”). Sufficiently homogenizing (ie mixing). If an emulsifier is present, the polysaccharide gum is dispersed after the emulsifier is added to the water / buffer solution. In order to adjust the pH value of Part A to a predetermined level, a suitable method can be used, such as adding concentrated phosphoric acid or sodium hydroxide.

Alternatively, prostaglandin E ₁ is dissolved in the lipophilic component under stirring, which may be an alcohol, an ester, or a mixture of alcohols and esters. Subsequently, penetration enhancer is added. Alternatively, if the lipophilic component comprises both alcohol and ester, after dissolving prostaglandin E ₁ in alcohol, a penetration promoter is added followed by ester. In either case, the mixture formed is referred to hereinafter as “Part B”. The final step consists in slowly adding (eg dropping) Part B with constant mixing into Part A.

As a result, the topical compositions formed have the advantageous properties as described above, such as improved penetration and bioavailability of prostaglandin E ₁ without overdose of the drug, decreased skin damage and associated inflammation, and increased in formulation design. It shows flexibility. Such compositions can be used for long-term treatment of disorders treated with peripheral vascular disease, male impotence and other prostaglandin E ₁ while not exhibiting the disadvantages of poor bioavailability and rapid chemical degradation associated with other delivery methods. The use of prostaglandin E ₁ in a composition topically administered to the skin of a patient allows the patient to be continuously administered a predetermined amount of prostaglandin E ₁ , which is undesirable when one or more doses are administered by injection. The bad effect can be prevented. By delaying the rate of release, the concentration of prostaglandin E ₁ in the patient's target tissue can be kept well within the optimal therapeutic range.

In one embodiment, the composition comprises about 0.01% to about 5% modified polysaccharide gum, based on the total weight thereof; PGE ₁ , from about 0.001% to about 1% prostaglandin selected from the group consisting of pharmaceutically acceptable salts thereof, lower alkyl esters thereof, and mixtures thereof; About 0.5% to about 10% of DDAIP or a salt thereof; About 0.5% to about 10% lower alcohol selected from the crowd consisting of ethanol, propanol, isopropanol, and mixtures thereof; About 0.5% to about 10% of an ester selected from the group consisting of ethyl laurate, isopropyl myristate, isopropyl laurate, and mixtures thereof, and acid buffers. The composition preferably further comprises up to about 2% by weight sucrose stearate.

In some cases, the composition may further comprise up to about 5% by weight emulsifier. In addition, the composition preferably further comprises up to about 2% by weight emulsifier. Suitable emulsifiers include polysorbates such as Tweens, glyceryl monooleate, triolein, trimyristin and tristearin. As an emulsifier, trimyristine is preferable.

Hereinafter, the present invention will be illustrated based on examples. The examples described below are merely illustrative of the present invention and do not limit the protection scope of the present invention. Those skilled in the art will be able to clearly see variations of the composition that do not adversely affect the efficacy of prostaglandin E ₁ , and such variations are also included in the scope of the invention. For example, additional ingredients such as colorants, antimicrobial agents, preservatives, emulsifiers, fragrances, prostaglandin E ₁ stabilizers and the like can be included in the composition as long as the composition formed retains the desirable properties as described above. have. If preservatives are present, preservatives are usually added in amounts of about 0.05 to about 0.30%. Suitable preservatives include methylparaben (methyl PABA), propylparaben (propyl PABA) and butylhydroxytoluene (BHT). Suitable fragrances and fragrances are well known in the art and it is suitable to use up to about 5% myrtenol, preferably about 2% myrtenol, based on the total weight of the composition. The composition of the present invention may further comprise a small amount, ie, from about 0.01 to about 4% by weight of local anesthetic, if necessary. Representative examples of local anesthetics include lidocaine, diclonin, dibucaine and their pharmaceutically acceptable salts and mixtures. In one preferred embodiment, the local anesthetic is about 0.5% diclonin based on the total weight of the composition.

The pharmaceutical formulation is preferably present in unit dosage form. In such formulations, the formulation is divided into unit doses containing appropriate amounts of active ingredient. The unit dosage form is a packaged preparation, for example a rigid plastic dosage device or a flexible pack, for example a package containing a limited amount of a pharmaceutical preparation.

According to another feature of the invention, a product comprising a composition for treating erectile dysfunction as described above in a suitable container, preferably in a container such as the dosing device disclosed in US Pat. No. 6,224,573, with attached instructions for use Is provided. As another example, the container may be a tube having a suitable orifice size, for example, a tube, pouch, pack, or pressurized bottle, with an end extending, which may be made of any suitable material, for example rigid plastic or flexible plastic. Can be.

Instructions for use may be in the form of pamphlets, labels affixed or bonded to the packaging of the product.

Instructions for use allow the patient to maintain the penis upright, open the catheter and open the container without introducing the tip of the container into the catheter in order to administer the composition of the present invention to the columnar of the penis of a patient suffering from erectile dysfunction. It is provided to illustrate the method of administering to the columnar vortex about 5-30 minutes prior. Reference may be made to FIGS. 3A and 3B. The printed label guidelines are functionally relevant to the compositions of the present invention as long as it describes a method for treating erectile dysfunction in accordance with the present invention. Such label guidelines are an important feature of the present invention in that the compositions must be approved for commercial use by the responsible national control authority, eg, the US Food and Drug Administration, before they are approved for a particular use. Part of this procedure consists in providing a label to be attached to the pharmaceutical composition that is finally sold. Such labels include definitions of the composition and other items such as clinical pharmacological properties, mechanisms of action, drug resistance, pharmacodynamic properties, absorption, bioavailability, contraindications, etc. Will be provided. Thus, the combination of the composition of the present invention with appropriate treatment guidelines is important for the proper use of the drug once it is marketed. Such treatment instructions will describe the method of use according to the method of treatment as described above.

The amount of active ingredient in the unit dosage formulation can vary or be adjusted in the range of 0.01 mg to 1 g depending on the particular use and the degree of efficacy of the vascular prostaglandin. For example, when the vascular prostaglandin is prostaglandin E ₁ , from about 0.05 mg to about 0.8 mg of prostaglandin E ₁ , preferably from about 0.1 mg to about 0.5 mg per unit dose, and in another example, per unit dose About 0.1 mg to about 0.3 mg of prostaglandin E ₁ is present. If desired, the composition may further contain other suitable therapeutic agents, such as piperazinyl quinazoline antihypertensives.

In the case of "on demand" treatment, the semisolid vascular prostaglandin composition should be administered to the pericardium of the penis about 2-30 minutes prior to sexual intercourse, preferably about 5-15 minutes prior to sexual intercourse. . In some cases, a regular treatment regimen may be made without necessarily being associated with the expected intercourse cycle. In this case, the semisolid vasofunctional prostaglandin composition can be administered to the columnar of the penis at least twice a week, preferably every other day or daily.

Unless otherwise noted, each composition is prepared by mixing the individual components described together in a conventional manner.

Summary of the Invention

The present invention relates to a pharmaceutical method for treating erectile dysfunction in a patient with a concomitant pathological condition, wherein the semisolid composition comprising vascular functional prostaglandins and a penetration promoter is erected in the fossa navicularis of a patient in need thereof. It provides a method comprising administering in an amount effective to induce. The pathological condition refers to one or more of erectile dysfunction that is unresponsive to diabetes, hypertension, heart disease, recovery from prostatectomy or oral phosphodiesterase-5 inhibitor therapy.

In one preferred embodiment, the present invention provides a method of treating erectile dysfunction in a patient with diabetes as a pathological condition. In another preferred embodiment, the present invention provides a method of treating erectile dysfunction in a patient with hypertension as a pathological condition. In another preferred embodiment, the present invention provides a method of treating erectile dysfunction in a patient with heart disease as a pathological condition. In another preferred embodiment, the present invention provides a method of treating erectile dysfunction in a patient recovering from prostatectomy as a pathological condition. In another preferred embodiment, the present invention provides a method of treating erectile dysfunction in a patient who is not responsive to oral phosphodiesterase-5 inhibitor therapy as a pathological condition.

An erectile dysfunction patient suffering from erectile dysfunction and not responsive to diabetes, hypertension, heart disease, prostatectomy or responsive to oral phosphodiesterase-5 inhibitor therapy, has a semi-solid vascular prostaglandin composition in the columnar of the patient. It can be treated effectively by injecting it in an amount effective to cause an erection. The composition comprises a polymer thickener selected from the group consisting of about 0.05 mg to about 0.8 mg of vasofunctional prostaglandins, a penetration accelerator, a polysaccharide gum and a polyacrylic acid polymer, aliphatic C ₁ -C ₈ alcohol, aliphatic C _8- A lipophilic component selected from the group consisting of C ₃₀ esters and mixtures thereof, and an acidic buffer system. In a preferred embodiment, the vasofunctional prostaglandin is prostaglandin E ₁ . Preferably, the semi-solid composition is packaged in unit doses, wherein the dose of prostaglandin is suitably from about 0.05 mg to about 0.8 mg per unit dose, and preferably from about 0.1 mg to about 0.5 mg per unit dose. . In another embodiment, the dose of prostaglandin E ₁ is about 0.1 mg to about 0.3 mg per unit dose.

Preferred penetration promoters are alkyl-2- (N-substituted amino) -alkanoate esters, (N-substituted amino) -alkanol alkanoates or mixtures thereof. The buffer system provides a buffer pH value range of about 3 to about 7.4 for the composition. The pH value range is preferably about 3 to about 6.5, most preferably about 3.5 to about 6. If necessary, stabilizers, preservatives and emulsifiers may be included. In some embodiments, the composition exhibits non-Newtonian rheological properties, in which case it is appropriate to include shear thinning polysaccharide gum or shear thinning polyacrylic acid polymer. . In one embodiment, the composition is thixotropic. In another embodiment, the composition has pseudo plasticity. In a preferred embodiment, the viscosity of the composition ranges from about 5,000 centipoise (cps) to about 20,000 cps, more preferably from about 7,000 cps to about 13,000 cps.

Preferred pharmaceutical compositions suitable for intratranbial administration include prostaglandin E ₁ , penetration promoters, modified polysaccharide gums, lipophilic compounds and acidic buffer systems. Penetration promoters are alkyl-2- (N-substituted amino) -alkanoates, alkyl-2- (N, N-disubstituted amino) -alkanoates, (N-substituted amino) -alkanol alkanoates, (N , N-disubstituted amino) -alkanol alkanoates, pharmaceutically acceptable salts thereof, and mixtures thereof. The lipophilic compound may be an aliphatic C ₁ -C ₈ alcohol, an aliphatic C ₈ -C ₃₀ ester or a mixture thereof. If necessary, stabilizers, preservatives and emulsifiers may be included.

In another embodiment, the present invention provides a shear thinning polymer, a lipophilic compound, and an acidic buffer system selected from the group consisting of prostaglandin E ₁ , penetration promoters, polysaccharide gums and polyacrylic acid polymers, diabetes, hypertension, heart disease. , For use in the manufacture of a medicament for treating erectile dysfunction in patients with one or more comorbid morbid conditions, such as recovery from prostatectomy or oral phosphodiesterase-5 inhibitor therapy. to provide.

The composition to be administered may take a semisolid suitable for intraosseous administration. When used as an intraosseous preparation, the composition can effectively infiltrate prostaglandins into the penis glans, thereby achieving bioavailability without the need for wasting excess prostaglandin concentration in tissues. In addition, the composition of the present invention is less damage to irritation, sensitivity and local tissue. The pharmaceutical composition of the present invention is preferably packaged in a container for single administration.

Other objects, features, advantages, embodiments, etc. of the present invention will be apparent to those skilled in the art through the following detailed description and appended claims.

Example 1 Topical Prostaglandin E _One  Composition A

Composition A was prepared as follows. Part A of the composition was prepared by dissolving 0.4 parts by weight of prostaglandin E ₁ (Alprostadil USP) in 5 parts by weight of ethyl alcohol. Then 5 parts by weight of dodecyl 2- (N, N-dimethylamino) propionate were mixed into the alcohol-prostaglandin E ₁ solution, followed by 5 parts by weight of ethyl laurate.

Part B was prepared with a pH 5.5 water / buffer solution as starting material. The water / buffer solution was prepared by adding a sufficient amount of potassium phosphate monohydrate to purified water to form a 0.1 M solution. The pH of the water / buffer solution was adjusted to 5.5 using strong base solution (1N sodium hydroxide) and strong acid (1N phosphoric acid). The buffer solution constitutes about 80 parts of the total composition. All parts described in the examples are parts by weight.

0.5 parts by weight of ethyl laurate was added to the buffer solution. The locust bean gum (powder form) was then dispersed in a buffer solution and homogenized using a homogenizer. The components are listed in Table 1 below.

The composition formed was an electrodepositable semisolid formulation suitable for application to the skin without the need for use of auxiliary devices such as patches and adhesive strips. The composition was apparently homogeneous and resistant to separation.

Additional Composition Examples B-H were prepared in the same manner using the components listed in Table 1 below. As mentioned above, in other embodiments, such as composition H, the composition may comprise a modified polysaccharide gum, suitably a modified galactomannan gum, for example guar gum. As another example, polyacrylic acid polymers may be used in place of polysaccharide gums.

Composition A was evaluated for skin penetration using snake skin as a barrier model. Snake skin was obtained from the Animal Care Unit at the University of Kansas. The head and tail were removed, the skin was randomly divided into specimens and then immersed to hydrate.

The sample was then evaluated using a Franz type diffusion cell (surface area 1.8 cm ² ). Specifically, the skin test piece was mounted on top of a receptor cell of a vertical diffusion cell assembly with a small magnetic rod inserted and filled with isotonic buffer. Seals were placed on top of the skin fragments followed by donor cells. Two cells were fixed together. A known amount of the formulation is applied to the bottom of a small stoppered bottle (0.5 grams by weight) that fits into the donor cell so as to be uniformly distributed. This disease was placed on the skin in the donor cell. To reduce evaporation of the components, the donor cell and the bottle were taped together with a water resistant adhesive band. These cells were transferred to a stirred bath (32 degrees Celsius). Samples were withdrawn from the cell every hour for 4 hours and analyzed for concentrations of prostaglandin E ₁ , with changes in concentration suggesting penetration. Test results data using several skin samples were obtained and averaged. The use of snake skin in evaluating drug penetration is described in detail in US Pat. No. 4,771,004 to Higuchi, which is incorporated herein by reference.

Prostaglandin E ₁ penetrated rapidly at a relatively delayed rate for 4 hours. The penetration study results are shown in Table 2 below.

Example 2: Topical Prostaglandin E _One  Composition B

Composition B was prepared using the ingredients listed in Table 1 below. Composition B contained a greater amount of prostaglandin E ₁ than composition A. Despite this increased drug usage, Composition B showed similar semisolid roughness and homogeneous appearance. The penetration of prostaglandin E ₁ was measured according to the procedure described in Example 1. Composition B provided a mode of delivery of prostaglandin E _{1 which} is relatively fast and delayed. The results are shown in Table 2 below.

Example 3: Topical Prostaglandin E _One  Composition C

Composition C was prepared using the ingredients listed in Table 1 below. Composition C contained a greater amount of prostaglandin E ₁ than Composition A or B. This increased drug usage had little or no effect on roughness or appearance and exhibited roughly equivalent roughness and appearance as Compositions A and B. The penetration of prostaglandin E ₁ was likewise measured according to the procedure described in Example 1. Test results showed that composition C provided a relatively fast and delayed delivery of prostaglandin E ₁ . The results are shown in Table 2 below.

Example 4: Topical Prostaglandin E _One  Composition D

Composition D was prepared using the ingredients listed in Table 1 below. Likewise, the concentration of prostaglandin E ₁ was increased without substantially affecting favorable roughness and separation resistance. In this case too, the penetration of prostaglandin E ₁ was measured according to the procedure described in Example 1. The results are shown in Table 2 below.

Example 5: Topical Prostaglandin E _One  Composition E

Composition E was prepared using the components listed in Table 1 below. In order to evaluate the reproducibility of the compositions according to the invention, the formulation of composition D was again applied to composition E. Reproducibility was substantially demonstrated by the preferred semisolid roughness and separation resistance of composition E. Similarly, the penetration of prostaglandin E ₁ was measured by the procedure described in Example 1. The mode of delivery of prostaglandin E ₁ from composition E was relatively fast and delayed. The results are shown in Table 2 below.

Example 6: Topical Prostaglandin E _One  Composition F

In composition F, the concentration of prostaglandin E ₁ was increased again. Specific components are listed in Table 1 below. Desirable roughness and separation resistance did not decrease. The results of the penetration analysis are shown in Table 2 below.

Example 7: Topical Prostaglandin E _One  Composition G

Composition G was prepared using the ingredients listed in Table 1 below. In the case of composition G, the procedure was repeated according to the formulation F, except that the ester component (ethyl laurate) was omitted and the concentration of ethanol was increased to the corresponding amount. The composition formed was also an electrodepositable semisolid with a homogeneous appearance and resistance to separation. Penetration analysis results are shown in Table 2 below. Although still preferred, the results of this example show the relative advantages of the compositions of the invention made from lipophilic components comprising both ester and alcohol components.

Table 1: Topical Prostaglandin E ₁ Compositions

Ingredient (% by weight) A B C D E F G H I Prehydrated Locust Bean Gum 3 3 3 3 3 3 3 - - Prehydrated Modified Guar Gum - - - - - - - 3 2.5 Water / buffer (pH 5.5) 81 81 81 81 81 81 81 81 86.8 Sucrose Stearate 0.5 0.5 0.5 0.5 0.5 0.5 0.5 - - Prostaglandin E ₁ 0.1 0.2 0.3 0.4 0.4 0.5 0.4 0.3 0.2 DDAIP 5 5 5 5 5 5 5 2.5 - DDAIP HCl - - - - - - - - 2.5 ethanol 5 5 5 5 5 5 10 5 5 Ethyl laurate 5 5 5 5 5 5 - 3 3

Example 8: Comparison of Penetration Aspects

Table 2 below shows the cumulative amount of prostaglandin E ₁ penetrated every hour for 4 hours for the compositions of each example according to the invention. This data demonstrates that the prostaglandin E ₁ drug can be transdermally delivered according to the present invention.

Table 2: Prostaglandin E ₁ Cumulative Penetration (μg / cm ² )

time A B C D E F G One 1.96 3.37 5.47 7.20 7.09 10.38 3.03 2 5.49 9.72 18.06 21.26 16.6 25.03 8.17 3 11.25 18.18 30.34 35.53 28.24 42.18 12.93 4 13.98 23.48 38.49 47.98 41.1 52.13 18.71

In order to further evaluate the efficacy of the composition according to the present invention, the composition of the comparative example was prepared. Comparative Example 1 (Comparative Example 1) was prepared using the same prescription as Compositions D and E, except that no DDAIP penetration promoter was used. In Comparative Example 2 (Comparative Example 2), although DDAIP was not used, the amount of ethanol was increased correspondingly. Specific components are listed in Table 3 below.

Table 3: Comparative Example

Ingredients (parts by weight) Comparative Composition 1 Comparative Composition 2 Prehydrated Locust Bean Gum 3 3 Water / buffer (pH 5.5) 86 81 Sucrose Stearate 0.5 0.5 Prostaglandin E ₁ 0.4 0.4 ethanol 5 10 Ethyl laurate 5 5

The penetration of prostaglandin E ₁ was evaluated according to the procedure described in Example 1. The results are shown in Table 4 below.

Table 4: Cumulative Prostaglandin E ₁ Penetration Amount (μg / cm ² ) of Comparative Example

time Comparative Composition 1 Comparative Composition 2 One 2.64 1.55 2 4.46 3.69 3 6.59 6.63 4 9.67 11.05

Example 9: Single Double-Blind and Open Label Clinical Trials

The safety and efficacy of a topical composition containing 0.4% by weight of prostaglandin E ₁ (prostaglandin E ₁ or alprostadyl) (composition D in Example 4 and Table 1 above) was administered to a total of 143 men at three test sites. Was evaluated. The study consisted of an open label portion and a crossover portion using a double blind placebo control.

The double-blind placebo control portion of this study was introduced and completed for 64 men (Table 5 below). 79 men completed the study by introducing them into the open label portion of the study (Table 5 below). A review of the clinical study results is summarized below.

Inclusion Criteria

1.Men, ages 21-70 years (including marginal ages)

2. Men with a history of erectile dysfunction, defined as inability to achieve and maintain an erection of sufficient intensity for sexual intercourse due to mental, neurological or vascular factors. This includes patients with some degree of erection sufficient for sexual intercourse, but not always, which is a complaint in mild to moderate levels of erectile dysfunction male patients in typical onset of aging. Diagnosis of erectile dysfunction is based on clinical history and physical examination.

Exclusion Criteria

1. A history of urethral stenosis or obstruction.

2. Historical, physical or screening studies, in the light of investigators' opinions that may affect the results of the study, indicate that existing heart, liver and / or renal function impairments (eg, erectile dysfunction of hormonal causes). Or concomitant results of congestive heart injury, unstable anxiety or recent acute myocardial infarction, uncontrolled diabetes mellitus.

3. History of penile trauma, including penile surgery, such as penile transplantation, prostatectomy, prostate cancer, paralysis, or quadriplegia.

4. Symptoms that may provide predisposition to sustained erection, such as sickle cell anemia, multiple myeloma, or leukemia.

5. High blood pressure (seated diastolic blood pressure> 90 or systolic blood pressure> 150) requiring treatment other than angiotensin converting enzyme inhibitor (ACE inhibitor).

6. Have a sexually transmitted disease as confirmed by physical examination.

7. If a cavernous injection or external erection device was used within 4 weeks prior to introduction into this study.

8. Peyronie's Disease or other palpable fibrous wounds or scars on the penis, evidence of abnormal curvature during erection, and excitability or abnormality of the penile skin or cavernous mucosa.

9. Combination of drugs known to interfere with sexual activity, such as antidepressants, some antihypertensives, sedative hormones and allergic drugs.

10. Experienced survey treatment within 30 days prior to introduction into this study.

11. You are incapable or unwilling to give consent.

The patient group consisted of men aged 49-70 years.

Table 5.

Patient registration by study part

Patients enrolled in the study part

part One 2 3 Sum Double blind 30 34 0 64 Opening label 32 8 39 79

Six-digit scale scales were used to assess clinical efficacy by patient history and patient evaluation questionnaire paper before and after drug treatment (Table 6). In the double-blind portion of this study, each patient received one placebo and one active drug in a crossover manner with a 5-7 day washout period. In the open label portion, the patient was administered one active drug. Provided for clinical use are packages in single dose containers each containing 250 mg (net weight) of cream and 1 mg of prostaglandin E ₁ .

Efficacy response rates were determined as the ratio of the total number of males to the number of males who achieved an erection sufficient for sexual intercourse. Judgment as success is when the number is 8-10 after administration or when the patient must have had sexual intercourse.

Statistical analysis was used to compare the values before and after the reaction using a paired t-test. In the double-blind and open label sections of this study, all numerical differences between before and after dosing for each patient group were found to be statistically significant (P <0.001). In addition, there were statistically valid results between the active and placebo groups per study part.

Table 6.

Six-scale rating scale for assessing the degree of erectile dysfunction in men

Rating Justice 0 Severe impotence with no function at all 2 Severe impotence with very weak function 4 Severe impotence with some functions 6 Normal impotence 8 Not impotence but slight loss of function 10 Fully functional and no impotence

Table 7.

Number of patients by impotence level

Severe impotence Mild to moderate No impotence Sum Double blind 39 25 0 64 Opening label 63 16 0 79 Sum 102 41 0 143

Topical prostaglandin E ₁ compositions have been found to be safe and effective in men with moderate to severe impotence. The efficiency was 64.7% (66/102 patients) in severe impotence men and 100% (41/41 patients) in normal impotence men. The longitudinal clinical efficiency for this study was 74.8% (107/143 patients) as described in Table 8 below.

Table 8.

Comprehensive Clinical Efficiency

Double blind part Open label part Total Total Efficiency Placebo 4.7% (3/64) - 4.7% (3/64) Active agent 87.5% (56/64) P <0.001 64.6% (51/79) 74.8% (107/143) P <0.001

Prostaglandin E ₁ topical compositions have been found to be very effective (100%) in moderate levels of impotence. The average impotence group is the most common class and is estimated to account for 70% of all cases of complaints of erectile dysfunction. In addition, the composition was very effective in the severe impotence study group (64.7%).

Only three of the 64 patients studied in the double-blind portion of this study (4.7%) had a placebo efficacy response. This is well below the expected rate of about 10% reported in other clinical studies. This low rate is thought to be due to the fact that the majority (63%) of patients enrolled in the double-blind portion of the study had severe impotence ratings. Although 17 of 64 patients (26.6%) had improved results in placebo treatment, only 3 of these patients had improved results (8 or 10 on the rating scale) sufficient to be evaluated as effective.

Table 9.

Clinical efficiency by impotence grade study

part One 2 3 Total efficiency Severe impotence Double blind 85.7% (24/28) 63.6% (7/11) No registered patient 79.5% (31/39) Opening label 72.2% (13/18) 33.3% (2/6) 51.3% (20/39) 55.6% (35/63) Mild to moderate impotence Double blind 100% (2/2) 100% (23/23) No registered patient 100% (25/25) Opening label 100% (14/14) 100% (2/2) No registered patient 100% (16/16)

Open label efficiency is lower than double blind efficiency (Table 9). This is mainly due to the relatively large number of severe impotence men registered in the open label area compared to the double-blind part of this study (Table 8). Of the men enrolled in the open label portion of this study, 79.7% (63/79) were rated as severely impotent, whereas only 60.9% (39/64) were severe erections in men enrolled in the double-blind portion It was evaluated as incapable. The efficiency is thought to be lower in the severe impotence group because it is defined as having little or no function in men in this group. Indeed, it is thought that it is more difficult to move up the impotence rating from grade 0, 2 or 4 to grade 8 or 10. While most severe impotence men showed a marked improvement, 36 men (36/102 or 35.3%) did not show a markedly improved effect to classify as efficient.

Discomfort observed in this study was a temporary, mild burning sensation and tingling at the application site. No systemic toxic side effects were observed. In addition, spouses included in this study did not report any cases of discomfort. None of the patients were dropped out of this study or did not have regular visits after treatment.

Example 10 Repetitive Open Label Clinical Trials

Topical compositions containing 0.4% prostaglandin E ₁ (The safety and efficacy of Composition D in Example 4 and Table 1 above were further studied in 56 men in three study sections. 56 patients with organic erectile dysfunction Male patients were enrolled in this study and completed the study: Patients were based on responses to the International Index of Erectile Dysfunction (IEF) and Sexual Encounter Profile (SEP) following pre-administration. Forty-nine patients were classified as having normal erectile dysfunction disorder, and seven patients were classified as having severe erectile dysfunction. The drug was required to be administered 3 to 10. The total efficiency was 75% in the normal erectile dysfunction patient group. Consistent with the reported total efficiency, none of the patients withdrew from the replicate study or those with extreme adverse events.

Inclusion Criteria

1.Men, ages 21-70 years (including marginal ages)

2. History of erectile dysfunction, defined as inability to achieve and maintain an erection sufficient for sexual intercourse during the previous six months due to mental, neurological or vascular factors. This includes patients with some degree of erection sufficient for sexual intercourse but not always, which is a complaint in moderately erectile dysfunction male patients of typical onset of aging. Diagnosis of erectile dysfunction is based on clinical history and physical examination.

Exclusion Criteria

1. A history of urethral stenosis or obstruction.

2. Historical, physical or screening studies, in the light of investigators' opinions that may affect the results of the study, indicate that existing heart, liver and / or renal function impairments (eg, erectile dysfunction of hormonal causes). Or concomitant results of congestive heart injury, unstable anxiety or recent acute myocardial infarction, uncontrolled diabetes mellitus.

3. History of penile trauma, including penile surgery, such as penile transplantation, prostatectomy, prostate cancer, paralysis, or quadriplegia.

4. Symptoms that may provide predisposition to sustained erection, such as sickle cell anemia, multiple myeloma, or leukemia.

5. High blood pressure (seated diastolic blood pressure> 90 or systolic blood pressure> 150) requiring treatment other than angiotensin converting enzyme inhibitor (ACE inhibitor).

6. Have a sexually transmitted disease as confirmed by physical examination.

7. If a cavernous injection or external erection device was used within 4 weeks prior to introduction into this study.

8. Peyronie's Disease or other palpable fibrous wounds or scars on the penis, evidence of abnormal curvature during erection, and excitability or abnormality of the penile skin or cavernous mucosa.

9. Combination of drugs known to interfere with sexual activity, such as antidepressants, some antihypertensives, sedative hormones and allergic drugs.

10. Experienced survey treatment within 30 days prior to introduction into this study.

11. You are incapable or unwilling to give consent.

The patient group consisted of men aged 49-70 years.

Table 10.

Patient registration by study part

Patients enrolled in the study part

One 2 3 Sum 22 13 21 56

From the patient's history and questionnaire for patient evaluation before and after drug treatment, clinical efficiency was assessed using the six tolerance rating scales (Table 12) of the International Tolerance Index (Table 11) and the Sexual Intercourse Profile (SEP) on erectile function. Evaluated. Each patient was asked to administer 10 active medications and to try to have sexual intercourse as many times as possible over a four week period after using the medication at home. The medication was packaged in a specially designed single dose dosing device.

Table 11.

International Index of Erectile Function

Rating Justice <12 No function at all and severe impotence 12-18 Almost no function and normal impotence 18-24 Slightly functional and normal impotence 24+ No obstacles

The efficiency was determined as the ratio of successful sexual intercourse to the number of sexual intercourse attempted. Success was considered to have achieved a SEP level of 8-10 after drug administration or the patient experienced satisfactory sexual intercourse. Chi Square statistics were used to compare and analyze the values before and after the reaction. There was a statistically significant difference (P <0.001) before and after dosing for each patient group receiving the active agent.

Table 12.

Sexual Intercourse Profile (SEP): Six Numerical Rating Scales to Assess Male Erectile Dysfunction

Rating Justice 0 No function at all and severe impotence 2 Almost no function and normal impotence 4 Slightly functional and normal impotence 6 Normal impotence 8 Not impotence but slight loss of function 10 Fully functional and no impotence

The efficiency was determined as the ratio of successful sexual intercourse to the number of sexual intercourse attempted. Success was considered to have achieved a SEP level of 8-10 after drug administration or the patient experienced satisfactory sexual intercourse. Chi square statistics were used to compare and analyze the pre and post reaction values. There was a statistically significant difference (p <0.001) before and after dosing.

Table 13.

Patient registration according to impotence level

Severe Mild to moderate Sum patient 7 49 56

Table 14.

Efficiency per patient group

Efficiency by the number of patients Efficiency by the number of attempts Mild to moderate 36/49 (74%) 178/239 (75%) Severe 4/7 (57%) 16/36 (44%)

As mentioned above, prostaglandin E ₁ compositions for topical administration have been found to be very effective (75%) in the normal impotence patient group. The common impotence class is the most common and is estimated to account for 70% of all cases of erectile dysfunction. The composition is less effective (44%) for the study group showing severe impotence. However, this group also showed a statistically significant difference between pre and post treatment values. All men in the severe impotence group had no erectile function prior to the study, but four out of seven (57%) had sexual intercourse over three or more of 10 drug administrations.

Discomfort observed in this study was a temporary, mild burning sensation and tingling at the application site. No systemic toxic side effects were observed. In addition, spouses included in this study did not report any cases of discomfort. None of the patients were dropped out of this study or did not have regular visits after treatment.

The results of this clinical study suggest that the method of using the prostaglandin E ₁ 0.4% topical composition according to the present invention in the treatment of moderate to severe impotence is safe and efficient.

Example 11: Phase III Clinical Study

A phase 3 clinical study was conducted using the topical composition I of Table 1 above modified to produce four test compositions with a PGE ₁ dose of 0 μg (placebo), 100 μg, 200 μg or 300 μg.

Enrolled patients were randomized to placebo, 100 μg, 200 μg, or 300 μg group after four weeks of untreated period, randomly in four treatment groups, namely the placebo, 100 μg, 200 μg or 300 μg group used in the take-home portion of the study for 12 weeks. Was assigned to one.

Inclusion criteria are as follows: Patients 21 years of age or older with no upper limit, history of erectile dysfunction with a duration of 3 months or more, IIEF erectile function scores of 25 or less, and at least 4 attempts of sexual intercourse during the untreated period. that.

Untreated endocrine disorders, significant penile pathology, history of orthostatic hypertension, fainting or early onset of symptoms (before 6 months), clinically meaningful liver or kidney disease, history of myocardial infarction (within 6 months) Patients with an allergic history of alprostadil, or patients with significant neurological disorders such as stroke, spinal cord injury, recent prescription or erectile dysfunction caused by the reception of contradictive erectile dysfunction drugs or therapies, Excluded.

Patients not excluded from this study were patients with a history of prostatectomy, patients with diabetes control, patients receiving nitrate and alpha blockers, and patients with a history of failed oral PDE5 inhibitor therapy (Sildenafil, Viagra ^TM ). It was. Population statistical characteristics and baseline of the Phase 3 treatment group are summarized in Table 15 below. A given patient may have one or more concomitant pathological conditions, with 100% or more of the patients summed up in the name of "medical history".

The Phase III clinical study is based on a study on a double-blind parallel treatment design using a randomized, placebo control, including take home studies in moderate to severe erectile dysfunction patients. In the United States, two separate studies were conducted at 85 sites. The patient group consisted of 1732 men aged 24-87 years. Of the population at the start of the study, 1410 completed the study and 18% were dropped out. Patients were randomly assigned to four concurrent treatment groups, namely, placebo, prostaglandin E ₁ doses 100 μg, 200 μg and 300 μg. Up to 25 doses per patient were volunteered for 12 weeks of treatment. The patients in this study were moderate to severe erectile dysfunction patients with IIEF erectile function levels below 25. Questions 1, 2, 3, 4, 5 and 15 of the IIEF were introduced into this study.

Population statistical characteristics of the patient group are summarized in Table 15 below. It should be noted that a patient may have one or more comorbid conditions in his history.

Table 15

Population statistical characteristics of treatment group

Average age: 59.6 years (1732 men, 23-87 years)

Age> 65 15% Baseline Erectile Function Figures 13.8 ED history> 1 year 93% Medical history diabetes 21% High blood pressure 44% heart disease 28% Nitrate and Alpha Blockers 16% Prostatectomy 12% If sildenafil treatment failed 18%

The compositions used for the four treatment groups are summarized in Table 16 below. As mentioned above, a patient may have one or more comorbid pathologies.

Table 16

Population statistical and baseline characteristics of treatment group

Placebo (N = 434) 100 μg (N = 434) 200 μg (N = 430) 300 μg (N = 434) Total PGE ₁ (N = 1732) Average age (range) 61 (31-87) 61 (35-86) 60 (24-87) 61 (23-86) 61 (31-87) Medical history High blood pressure 191 186 180 198 755 Coronary artery disease 118 107 125 135 485 diabetes 85 90 95 86 356 Prostatectomy 46 71 45 51 213 Sildenafil (low or no effect) 80 83 71 78 312

The measures used as endpoints for primary efficiency were as follows: Changes in the International Erectile Function Index (IIEF) erectile function level from baseline to final visit versus placebo; Question 2: Questions from the Sexual Intercourse Profile (SEP) was it possible to insert a penis into the partner's vagina? And SEP question 3: Did the erection last long enough to complete sexual intercourse? For Question 2 and Question 3 above, the mean values of the patients were compared with the placebo group.

The endpoints for secondary efficiency included a comprehensive assessment question (GAQ): "Improving erectile function during drug research" and figures for other areas on the IIEF. The degree of erectile dysfunction is characterized by IIEF erectile function levels as follows: severe (<11), moderate (11-16), mild to moderate (17-21), moderate (22-25) or normal (> 26).

The efficiency of the four treatment groups as measured by the change in the IIEF erectile functional area is shown in Table 17 below for the groups of patients who completed the study. The two highest doses had the greatest effect. The numerical difference compared to the placebo group was about 0.001 in all doses.

Table 17

Erectile function area

Average change from baseline to endpoint Significant difference compared to placebo Number of patients Placebo -0.7 N = 408 100 µg 1.6 (p <0.001) N = 421 200 µg 2.5 (p <0.001) N = 405 300 µg 2.4 (p <0.001) N = 417

Similarly, the response to the comprehensive assessment question, “Did you notice an improvement in erection when using study medication?” (Table 18 below) also showed a valid difference from placebo at the p <0.001 level for all doses of PGE ₁ .

Table 18

Comprehensive Assessment Question

"Did you notice an improvement in erection when using study medication?

Improved patient percentage Significant difference compared to placebo Number of patients Placebo 20 N = 394 100 µg 40 (p <0.001) N = 408 200 µg 47 (p <0.001) N = 392 300 µg 52 (p <0.001) N = 398

Response to Question 2 of the Sexual Intercourse Profile (SEP) regarding the possibility of penis insertion into the partner vagina (Table 19 below) also showed a significant difference of p ≦ 0.001 for all PGE ₁ doses compared to placebo.

Table 19

Sexual Intercourse Profile (SEP) Levels

(Possibility of inserting partner in the vagina)

Sexual success rate of patients (%) Significant difference compared to placebo Number of patients Placebo 51 N = 411 100 µg 57 (p = 0.001) N = 418 200 µg 58 (p <0.001) N = 410 300 µg 58 (p <0.001) N = 410

The response to SEP's Question 3 regarding the ability to maintain erection until assessment (Table 20 below) was significantly different from the control group for the two higher doses (p <0.001), but at 0.003 level at the 100 μg dose. The difference was shown.

Table 20

Sexual Intercourse Profile (SEP) Levels

(Ability to maintain erection until assessment)

Sexual success rate of patients (%) Significant difference compared to placebo Number of patients Placebo 30 N = 411 100 µg 39 (p = 0.003) N = 418 200 µg 42 (p <0.001) N = 410 300 µg 39 (p <0.001) N = 410

The primary and secondary efficiency endpoints are summarized in Table 21 below. Overall changes following PGE ₁ treatment showed a valid difference from the placebo control.

Table 21

Summary of key efficiency variables at the endpoint Treatment group Placebo (N = 416) 100 μg (N = 422) 200 μg (N = 412) 300 μg (N = 419) Total P value EP change EP change EP change EP change Primary efficiency endpoint IIEF, erectile function, mean change from baseline 13.3 -0.7 15.3 1.6 16.1 2.5 16.1 2.5 <0.001 SEP levels, average percentage of success per patient from baseline Question 2 (Erection Achievement Ability) 51.2 -4.5 56.6 2.9 58.2 5.1 57.5 7.2 0.002 Question 3 (ability to maintain an erection until assessment) 30.2 0.4 38.9 7.0 41.9 13.8 38.5 9.1 <0.001 Secondary Efficiency Endpoint Comprehensive assessment question,% of patients who answered “Yes” (Did medication improve erection? Yes / No) 20 40 47 52 <0.001

The percentage of patients who achieved normal IIEF levels (> 26) after treatment was 6% (placebo), 10% (100 μg), 14% (200 μg) and 16% (300 μg).

Example 12 Treatment of Erectile Dysfunction in Diabetic Patients

The results of measuring treatment efficiency in a subset of patients with a history of diabetes are summarized in Tables 22-23 below. The efficiency of the four treatment groups as measured by changes in the erectile function area of IIEF is shown in Table 22 below for a subset of diabetic patients who completed the study. The maximum effect was seen for the two highest doses. The difference in values relative to placebo was significant at p <0.05 at all doses.

Table 22

Diabetic Erectile Function Areas

Average change from baseline to endpoint Significant difference compared to placebo Number of patients Placebo -1.2 N = 81 100 µg 2.1 (p = 0.014) N = 90 200 µg 3.7 (p <0.001) N = 94 300 µg 2.4 (p = 0.003) N = 95

Comprehensive Assessment Questions The response to “Did you notice an improvement in erection when using medications in this study?” (Table 23 below) showed a difference from placebo with p <0.001 levels for all doses of PGE ₁ .

Table 23

Diabetic Comprehensive Assessment Questions

"Did you notice an improvement in erection when using the drugs in this study?"

% Of patients improved Significant difference compared to placebo Number of patients Placebo 20 N = 76 100 µg 43 (p = 0.001) N = 69 200 µg 45 (p = 0.001) N = 92 300 µg 53 (p <0.001) N = 79

The response to Question 2 of the Sexual Intercourse Profile (SEP) regarding the possibility of penile insertion into the partner vagina (Table 24 below) showed no difference at p ≦ 0.05 at any PGE ₁ dose compared to placebo.

Table 24

diabetic

Sexual Intercourse Profile (SEP) Levels

Sexual success rate of patients Significant difference compared to placebo Number of patients Placebo 44 N = 84 100 µg 51 p = 0.209 N = 90 200 µg 64 p = 0.069 N = 95 300 µg 52 p = 0.255 N = 83

The response to SEP's Question 3 regarding the ability to maintain erection until assessment (Table 25 below) showed a valid difference from the control at a dose of 200 μg (p <0.005).

Table 25

diabetic

Sexual Intercourse Profile (SEP) levels (the ability to maintain an erection until assessment)

Sexual success rate of patients Significant difference compared to placebo Number of patients Placebo 29 N = 84 100 µg 36 p = 0.123 N = 90 200 µg 46 p = 0.002 N = 95 300 µg 33 p = 0.253 N = 83

Example 13: Treatment of Erectile Dysfunction in Patients with Prostatectomy

The results of measuring treatment efficiency in a subset of patients with a history of prostatectomy are summarized in Tables 26-29 below. The efficiency of the four treatment groups as measured by the change in erectile function area of IIEF is shown in Table 27 below for a subset of patients who completed the study. The maximum effect was seen for the two highest doses. The difference in values relative to placebo was shown to be valid at the p <0.01 level for all doses.

Table 26

Patients with prostatectomy

Erectile function area

Average change from baseline to endpoint Significant difference compared to placebo Number of patients Placebo -2.2 N = 46 100 µg 2.2 p = 0.004 N = 71 200 µg 2.4 p = 0.006 N = 44 300 µg 2.5 p = 0.003 N = 51

Comprehensive Assessment Questions The response to “Did you notice an improvement in erection when using medications in this study?” (Table 27 below) showed a valid difference from placebo with p <0.001 levels for all doses of PGE ₁ .

Table 27

Prostatectomy Patients Comprehensive Assessment Questions

"Did you notice an improvement in erection when using the drugs in this study?"

% Of patients improved Significant difference compared to placebo Number of patients Placebo 11 N = 44 100 µg 47 p <0.001 N = 70 200 µg 57 p <0.001 N = 42 300 µg 55 p <0.001 N = 51

Response to Question 2 of the Sexual Intercourse Profile (SEP) regarding the possibility of penis insertion into the partner vagina (Table 28 below) showed a valid difference at a p <0.01 level only at 300 μg of PGE ₁ dose compared to placebo.

Table 28

Patients with prostatectomy

Sexual Intercourse Profile (SEP) Levels

Sexual success rate of patients Significant difference compared to placebo Number of patients Placebo 21 N = 45 100 µg 41 p = 0.129 N = 71 200 µg 35 p = 0.155 N = 45 300 µg 36 p = 0.006 N = 51

The response to SEP's Question 3 regarding the ability to maintain erection until assessment (Table 29 below) showed a valid difference from the control group at the p = 0.056 level at a dose of 300 μg.

Table 29

Patients with prostatectomy

Sexual Intercourse Profile (SEP) levels (the ability to maintain an erection until assessment)

Sexual success rate of patients Significant difference compared to placebo Number of patients Placebo 13 N = 45 100 µg 22 p = 0.541 N = 71 200 µg 24 p = 0.511 N = 45 300 µg 24 p = 0.056 N = 51

Example 14 Erectile Dysfunction Treatment Regimen of Prostatectomy Patients

Patients in need of treatment for erectile dysfunction following radical prostatectomy or neuropreservative prostatectomy were treated with the semisolid prostaglandin composition of Example 11. Although treatment can begin at any time after prostatectomy surgery, treatment is preferably started about 1 to about 6 months after surgery. Depending on the degree of erectile dysfunction assessed using the IIEF, the composition was administered according to a regular treatment regimen that is not necessarily associated with the expected sexual intercourse cycle. Semi-solid vasoactive prostaglandin compositions delivering doses of about 100 μg to about 400 μg of prostaglandin E ₁ have been applied to the pericardium of the penis at least twice a week, every other day or daily. For "on demand" treatment, the semisolid vasculature prostaglandin composition was applied to the pericardium of the penis about 2-30 minutes prior to intercourse, preferably about 5-15 minutes. About 40-60% of treated patients reported an improvement in erection concurrent with the administration of medication after about three months of treatment.

Example 15 Treatment of Erectile Dysfunction in Erectile Dysfunction Patients Where Oral Phosphodiesterase-5 Inhibitor Therapy is Ineffective

Measurement results of treatment efficiency in a subset of patients in which oral phosphodiesterase-5 inhibitor therapy is ineffective are summarized in Tables 30-33 below. The efficiency of the four treatment groups as measured by the change in erectile function area of IIEF is shown in Table 31 below for a subset of patients who completed the study. The maximum effect was seen for the two highest doses. The difference in values relative to placebo was shown to be valid at the p <0.05 level for all doses.

Table 30

Erectile area of erectile dysfunction in which oral sildenafil treatment is ineffective

Average change from baseline to endpoint Significant difference compared to placebo Number of patients Placebo -0.4 N = 80 100 µg 1.2 p = 0.134 N = 83 200 µg 1.7 p <0.061 N = 70 300 µg 1.4 p <0.097 N = 83

Comprehensive Assessment Questions The response to “Did you notice an improvement in erection when using drugs in this study?” (Table 31 below) showed a significant difference from placebo at p <0.05 levels for 200 μg and 300 μg doses of PGE ₁ . .

Table 31

Comprehensive assessment question for patients with erectile dysfunction in which oral sildenafil treatment is ineffective

"Did you notice an improvement in erection when using the drugs in this study?"

% Of patients improved Significant difference compared to placebo Number of patients Placebo 21 N = 77 100 µg 29 p = 0.158 N = 82 200 µg 37 p = 0.025 N = 68 300 µg 45 p = 0.001 N = 73

Response to Question 2 of the Sexual Intercourse Profile (SEP) regarding the possibility of penis insertion into the partner vagina (Table 32 below) showed a difference of p ≦ 0.05 at 200 μg and 300 μg PGE ₁ compared to placebo.

Table 32

Erectile dysfunction patients with oral sildenafil treatment are ineffective

Sexual Intercourse Profile (SEP) Levels

Sexual success rate of patients Significant difference compared to placebo Number of patients Placebo 43 N = 80 100 µg 45 p = 0.181 N = 83 200 µg 45 p = 0.046 N = 70 300 µg 49 p = 0.004 N = 78

The response to SEP's Question 3 regarding the ability to maintain erection until assessment (Table 33 below) showed no significant difference from the control group.

Table 33

Erectile dysfunction patients with oral sildenafil treatment are ineffective

Sexual Intercourse Profile (SEP) levels (the ability to maintain an erection until assessment)

Sexual success rate of patients Significant difference compared to placebo Number of patients Placebo 23 N = 80 100 µg 29 p = 0.809 N = 83 200 µg 32 p = 0.112 N = 70 300 µg 30 p = 0.820 N = 78

Example 16: Treatment of Erectile Dysfunction in Hypertensive Patients

The results of measuring treatment efficiency in a subset of patients with a history of hypertension are summarized in Tables 34-37 below. The efficiency of the four treatment groups, as measured by the change in erectile function area of IIEF, is listed in Table 35 below for a subset of patients who completed the study. The maximum effect was seen for the two highest doses. Differences in placebo values were found to be effective at p <0.05 for all doses and at p <0.001 at doses of 200 μg and 300 μg.

Table 34

Erectile function area

Average change from baseline to endpoint Significant difference compared to placebo Number of patients Placebo -0.6 N = 187 100 µg One p = 0.022 N = 185 200 µg 2.9 p <0.001 N = 175 300 µg 2.0 p <0.001 N = 198

Comprehensive Assessment Questions The response to “Did you notice an improvement in erection when using medications in this study?” (Table 35 below) showed a significant difference from placebo with p <0.001 levels for all doses of PGE ₁ .

Table 35

Comprehensive Assessment Question

"Did you notice an improvement in erection when using the drugs in this study?"

% Of patients improved Significant difference compared to placebo Number of patients Placebo 20 N = 178 100 µg 37 p <0.001 N = 178 200 µg 47 p <0.001 N = 173 300 µg 49 p <0.001 N = 187

Response to Question 2 of the Sexual Intercourse Profile (SEP) regarding the possibility of penis insertion into the partner vagina (Table 36 below) showed a significant difference at a level of p ≦ 0.05 at all PGE ₁ doses compared to placebo.

Table 36

Sexual Intercourse Profile (SEP) Levels

Sexual success rate of patients Significant difference compared to placebo Number of patients Placebo 47 N = 189 100 µg 53 p = 0.038 N = 182 200 µg 59 p <0.001 N = 179 300 µg 54 p = 0.006 N = 195

The response to SEP's Question 3 regarding the ability to maintain erection until ejaculation (Table 37 below) showed a significant difference from the control only at the 200 μg dose (p = 0.001).

Table 37

Sexual Intercourse Profile (SEP) levels (the ability to maintain an erection until assessment)

Sexual success rate of patients Significant difference compared to placebo Number of patients Placebo 26 N = 189 100 µg 35 p = 0.329 N = 182 200 µg 41 p = 0.001 N = 179 300 µg 35 p = 0.34 N = 195

Example 17 Treatment of Erectile Dysfunction in Heart Disease Patients

The results of measuring treatment efficiency in a subset of patients with a history of heart disease are summarized in Tables 38-41 below. The efficiency of the four treatment groups, as measured by the change in erectile function area of IIEF, is listed in Table 38 below for a subset of patients who completed the study. The maximum effect was seen for the two highest doses. The difference in values relative to placebo was found to be significant at the p <0.05 level for all doses.

Table 38

Erectile function area

Average change from baseline to endpoint Significant difference compared to placebo Number of patients Placebo -1.7 N = 115 100 µg 1.4 p = 0.002 N = 107 200 µg 1.5 p = 0.001 N = 122 300 µg 1.9 p <0.001 N = 135

Comprehensive Assessment Questions The response to “Did you notice an improvement in erection when using drugs in this study?” (Table 39 below) showed a significant difference from placebo with p <0.005 levels for all doses of PGE ₁ .

Table 39

Comprehensive Assessment Question

"Did you notice an improvement in erection when using the drugs in this study?"

% Of patients improved Significant difference compared to placebo Number of patients Placebo 17 N = 111 100 µg 35 p <0.003 N = 104 200 µg 48 p <0.001 N = 116 300 µg 50 p <0.001 N = 126

Response to Question 2 of the Sexual Intercourse Profile (SEP) regarding the possibility of penis insertion into the partner vagina (Table 40 below) showed a valid difference at the p ≦ 0.05 level only at the 200 μg dose compared to placebo. However, the difference compared to the control at the 300 μg PGE ₁ dose was significant at p = 0.054 level.

Table 40

Sexual Intercourse Profile (SEP) Levels

Sexual success rate of patients Significant difference compared to placebo Number of patients Placebo 44 N = 117 100 µg 54 p = 0.109 N = 105 200 µg 54 p = 0.018 N = 125 300 µg 51 p = 0.054 N = 130

The response to SEP's Question 3 regarding the ability to maintain erection until assessment (Table 41 below) showed a significant difference from the control at the two higher doses (p <0.05).

Table 41

Sexual Intercourse Profile (SEP) levels (the ability to maintain an erection until assessment)

Sexual success rate of patients Significant difference compared to placebo Number of patients Placebo 23 N = 117 100 µg 33 p = 0.260 N = 105 200 µg 36 p = 0.003 N = 125 300 µg 31 p = 0.022 N = 130

Example 18 Measurement of Treatment Efficiency by Baseline Intensity in Patients with Erectile Dysfunction

Treatment efficiency compared to initial baseline intensity was analyzed separately for two studies, including the Phase 3 study. Baseline intensity was defined by IIEF erectile functional area values as follows: severe (1-10), moderate (11-18), mild to moderate (17-21), medium (23-25). The results are summarized in Tables 42-46 below.

Table 42

Baseline Changes in IIEF Erectile Function Area Values at Endpoints by Baseline Accuracy (Study 1)

usually Mild to moderate middle Severe Placebo -4 -1.9 -0.4 2.5 100 µg -0.5 -0.7 2.3 4.1 200 µg One 1.1 2.9 4.9 300 µg -0.2 1.6 3.8 5.1

Table 43

Baseline variation in IIEF erectile functional area values at endpoints by baseline accuracy (Study 2)

usually Mild to moderate middle Severe Placebo -4.8 -0.7 -0.1 0.6 100 µg -1.6 0.3 1.5 4.6 200 µg -3.1 2.9 2.7 2.5 300 µg -0.4 1.2 1.5 3.4

Table 44

Success Rate of Vaginal Insertion by Baseline Erectile Dysfunction in Treatment

SEPQ2 / SEPQ1 (% Insertion Success Rate / Attempts) (Study 2)

Mild Mild to moderate usually Severe Placebo 77.7 68.3 51.2 23.1 100 µg 90.5 72.8 60.4 25.9 200 µg 83.9 82.5 62.6 25.4 300 µg 88.4 78.9 63.8 33.2

Table 45

Success rate of intercourse completion by baseline erectile dysfunction during treatment

SEPQ3 / SEPQ1 (number of trials / trials completed by assessment)% of successful patients (Study 2)

Mild Mild to moderate usually Severe Placebo 62.6 47.6 27.4 10.3 100 µg 73.5 48.6 38.2 17.3 200 µg 71.9 63.7 41.4 23.9 300 µg 75.7 61.9 37.7 15.4

Example 19: Integrated Safety Analysis

The results of the integrated safety analysis are shown in Tables 46-47 below.

Table 46

Summary of Treatment-Related Adverse Events

Treatment group PlaceboN = 434 100 µg N = 434 200 µg N = 434 300 µg N = 434 TotalN = 1732 % Of patients with one or more drug-related side effects 61 (14) 156 (36) 187 (20) 188 (42) 592 (34) Drug-related extreme side effects 0 0 0 0 0 Number of patients who abandoned because of drug-related adverse events, n (%) 1 (1) 10 (2) 14 (3) 26 (6) 51 (3) Drug-related adverse events in more than 3% of all patients Penis burning 26 (6) 76 (18) 106 (25) 101 (23) 309 (18) Penis erythema 9 (2) 33 (8) 39 (9) 49 (11) 121 (7) Genital pain 2 (0.5) 48 (11) 67 (16) 76 (18) 193 (11) Vaginal burning 7 (2) 15 (3) 30 (7) 18 (4) 70 (4)

Table 47

Summary of patients discontinued due to drug-related adverse events

Side effects case % Of patients discontinued Genital pain 15 (0.9) Penis burning 21 (1.2) Penis erythema 4 (0.2) Vaginal burning 3 (0.3) Etc 8 (0.5) Sum, n (%) 51 (3)

In general, the treatment did not cause severe side effects. Most adverse events occurred locally only at the site of application, but were weak, short-lived and well tolerated. Overall, treatment results have proven effective against a wide range of erectile dysfunction and accompanying pathological conditions.

Example 20 Alpha _One  Treatment of hypertensive patients with blockers

The results of measuring treatment effects in a subset of Chinese characters with a history of hypertension and also being treated with alpha ₁ blockers are summarized in Table 48-51 below. Because of the small sample size, there are limitations to calculating the p-value for comparing the differences.

The efficiency of the four treatment groups, as measured by the change in erectile function area of IIEF, is shown in Table 48 below for a subset of patients who completed the study. Maximum effect was seen with the 300 μg dose. The difference in values relative to placebo was not valid at p <0.05 at any dose.

Table 48

Erectile function area

Average change from baseline to endpoint Significant difference compared to placebo Number of patients Placebo -1.2 N = 27 100 µg 0.0 p <0.619 N = 24 200 µg -0.2 p <0.543 N = 26 300 µg 2.2 p <0.112 N = 25

In spite of the small sample size, the response to the comprehensive assessment question “Did you notice an improvement in erection when using the drug in this study?” (Table 49 below) from the placebo at a p <0.05 level for the 300 μg dose of PGE ₁ A valid difference was shown.

Table 49

Comprehensive Assessment Question

"Did you notice an improvement in erection when using the drugs in this study?"

% Of patients improved Significant difference compared to placebo Number of patients Placebo 11.5 N = 26 100 µg 25 p <0.474 N = 24 200 µg 28 p <0.103 N = 25 300 µg 44 p <0.033 N = 25

Response to Question 2 of the Sexual Intercourse Profile (SEP) regarding the possibility of penis insertion into the partner vagina (Table 50 below) showed no significant difference at any level at p <0.05 compared to placebo. Maximum effects were seen at doses of 200 μg and 300 μg.

Table 50

Sexual Intercourse Profile (SEP) Levels

Sexual success rate of patients Average change from baseline Significant difference compared to placebo Number of patients Placebo 52.8 -5.6 N = 28 100 µg 39.8 2.4 p <0.266 N = 24 200 µg 47.3 4.8 p <0.327 N = 26 300 µg 59.5 6.7 p <0.151 N = 26

The response to SEP's Question 3 regarding the ability to maintain erection until assessment (Table 51 below) did not show a valid difference from placebo.

Table 51

Sexual Intercourse Profile (SEP) levels (the ability to maintain an erection until assessment)

Sexual success rate of patients Average change from baseline Significant difference compared to placebo Number of patients Placebo 29.0 2.8 N = 28 100 µg 30.8 12.0 p <0.140 N = 24 200 µg 34.3 14.0 p <0.317 N = 26 300 µg 40.1 1.5 p <0.559 N = 26

Similar studies on a smaller subset of patients with a history of hypertension and being treated with nitrates did not provide useful information due to the smaller sample size (all 22 patients in all four treatment groups).

The claims should not be construed as limited to the specific order or components of the detailed description as set forth above unless intended. Accordingly, all embodiments that come within the scope and spirit of the appended claims and their equivalents are also claimed as the invention.

Claims (40)

Administering an amount of semi-solid composition causing an erection to a patient's columnar and fossa navicularis , wherein the semi-solid composition comprises: Vasoactive prostaglandins; Penetration accelerators; Polymeric thickeners selected from the group consisting of polysaccharide gums and polyacrylic acid polymers; Lipophilic components in the crowd consisting of aliphatic C ₁ -C ₈ alcohols, aliphatic C ₈ -C ₃₀ esters and mixtures thereof; And A method of treating erectile dysfunction in a patient with a co-morbid condition, comprising an acid buffer system. The method of claim 1, Wherein the blood vessel functional prostaglandin _{PGE 1, PGA 1, PGB 1} , PGF 1α, 19- hydroxy -PGA _1, 19- hydroxy _{-PGB 1, PGE 2, PGA 2} , PGB 2, 19- _{2-hydroxy--PGA} , 19-hydroxy-PGB ₂ , PGE ₃ , PGF _3α and mixtures thereof. The method of claim 1, Said vasoactive prostaglandin is prostaglandin E ₁ . The method of claim 1, Wherein said vasofunctional prostaglandin is present in an amount from 0.001% to about 1% by weight based on the total weight of the composition. The method of claim 1, Wherein said vasofunctional prostaglandin is present in an amount from about 0.07% to about 0.4% by weight based on the total weight of the composition. The method of claim 1, Wherein said semi-solid composition is packaged as a unit dose and wherein said vasofunctional prostaglandin is present in an amount from about 0.05 mg to about 0.8 mg per unit dose. The method of claim 1, The polymer thickener is a polyacrylic acid polymer. The method of claim 1, Wherein said polymer thickener is a shear-thinning polysaccharide gum. The method of claim 8, The shear thinning polysaccharide gum is galactomannan gum. The method of claim 8, Wherein said shear thinning polysaccharide gum is a modified galactomannan gum. The method of claim 10, Wherein said modified galactomannan gum is a modified guar gum. The method of claim 1, And wherein the viscosity of the composition is from about 5,000 cps to about 20,000 cps. The method of claim 1, And wherein said composition has a viscosity of about 7,000 cps to about 13,000 cps. The method of claim 1, The penetration promoter is alkyl-2- (N-substituted amino) -alkanoate, alkyl-2- (N, N-disubstituted amino) -alkanoate, (N-substituted amino) -alkanol alkanoate, ( N, N-disubstituted amino) -alkanol alkanoate, pharmaceutically acceptable salts thereof and mixtures thereof. The method of claim 1, Wherein said penetration promoter is dodecyl 2- (N, N-dimethylamino) propionate hydrochloride. The method of claim 1, Wherein said lipophilic component comprises at least one aliphatic C ₈ -C ₃₀ ester. The method of claim 1, Wherein said lipophilic component comprises at least one glyceryl ester selected from the group consisting of monoglycerides, diglycerides, triglycerides and mixtures thereof. The method of claim 1, Wherein said lipophilic component is at least one glyceryl ester selected from the group consisting of glyceryl monooleate, triolein, trimyristin, tristearin and mixtures thereof. The method of claim 1, Wherein said acidic buffer system provides said composition with a buffered pH value in the range of about 3 to about 7.4. The method of claim 1, Wherein said acidic buffer system provides said composition with a buffered pH value in the range of about 3 to about 6.5. The method of claim 1, Wherein said composition further comprises an emulsifier selected from the group consisting of sucrose esters, polyoxyethylene sorbitan esters, long chain alcohols and glyceryl esters. The method of claim 1, Wherein said emulsifier comprises at least one glyceryl ester selected from the group consisting of glyceryl monooleate, triolein, trimyristin, tristearin and mixtures thereof. The method of claim 1, Wherein said composition further comprises up to about 5% myrtenol based on the total weight of the composition. The method of claim 1, Wherein said composition further comprises a preservative. The method of claim 1, Wherein said composition further comprises a local anesthetic. The method of claim 1, Wherein said composition further comprises a fragrance. The method of claim 1, Further comprising administering the composition on demand. The method of claim 1, Further comprising administering said composition about 5 minutes to about 15 minutes prior to sexual intercourse. The method of claim 1, The semi-solid prostaglandin E ₁ composition further comprises administering at least twice a week. The method of claim 1, The method further comprises administering the semi-solid prostaglandin E ₁ composition every other day. The method of claim 1, The method further comprises daily administering the semi-solid prostaglandin E ₁ composition. The method of claim 3, wherein Wherein said composition is packaged as a unit dose and prostaglandin E ₁ is present in an amount from about 0.1 mg to about 0.5 mg per unit dose. The method of claim 3, wherein Wherein said composition is packaged as a unit dose and prostaglandin E ₁ is present in an amount from about 0.1 mg to about 0.3 mg per unit dose. The method of claim 3, wherein The composition based on the total weight of the composition, From about 0.001% to about 1% prostaglandin E ₁ ; Dodecyl 2- (N, N-dimethylamino) propionate hydrochloride about 0.5% to about 10% by weight; About 0.5% to about 10% ethyl alcohol; About 0.5% to about 10% ethyl laurate; And And from about 0.01% to about 5% by weight modified guar gum. Administering an amount of semi-solid prostaglandin E ₁ composition that causes an erection to the columnar of the patient, wherein the semi-solid composition comprises: Penetration accelerators; Shear thinning polymer thickeners selected from the group consisting of polysaccharide gums and polyacrylic acid polymers; Components in the crowd consisting of aliphatic C ₁ -C ₈ alcohols, aliphatic C ₈ -C ₃₀ esters and mixtures thereof; And A method of treating erectile dysfunction in a patient with a co-morbid condition of diabetes, comprising an acid buffer system. Administering an amount of semi-solid prostaglandin E ₁ composition that causes an erection to the columnar of the patient, wherein the semi-solid composition comprises: Penetration accelerators; Shear thinning polymer thickeners selected from the group consisting of polysaccharide gums and polyacrylic acid polymers; Components in the crowd consisting of aliphatic C ₁ -C ₈ alcohols, aliphatic C ₈ -C ₃₀ esters and mixtures thereof; And A method of treating erectile dysfunction in a patient with an accompanying pathological condition of hypertension, comprising an acid buffer system. Administering an amount of semi-solid prostaglandin E ₁ composition that causes an erection to the columnar of the patient, wherein the semi-solid composition comprises: Penetration accelerators; Shear thinning polymer thickeners selected from the group consisting of polysaccharide gums and polyacrylic acid polymers; Components in the crowd consisting of aliphatic C ₁ -C ₈ alcohols, aliphatic C ₈ -C ₃₀ esters and mixtures thereof; And A method of treating erectile dysfunction in a patient with concomitant morbidity of heart disease, comprising an acid buffer system. Administering an amount of semi-solid prostaglandin E ₁ composition that causes an erection to the columnar of the patient, wherein the semi-solid composition comprises: Penetration accelerators; Shear thinning polymer thickeners selected from the group consisting of polysaccharide gums and polyacrylic acid polymers; Components in the crowd consisting of aliphatic C ₁ -C ₈ alcohols, aliphatic C ₈ -C ₃₀ esters and mixtures thereof; And A method of treating erectile dysfunction in a patient with concomitant morbidity in the recovery phase from prostatectomy, comprising an acid buffer system. Administering an amount of semi-solid prostaglandin E ₁ composition that causes an erection to the columnar of the patient, wherein the semi-solid composition comprises: Penetration accelerators; Shear thinning polymer thickeners selected from the group consisting of polysaccharide gums and polyacrylic acid polymers; Components in the crowd consisting of aliphatic C ₁ -C ₈ alcohols, aliphatic C ₈ -C ₃₀ esters and mixtures thereof; And A method of treating a patient with erectile dysfunction that is not reactive to an oral phosphodiesterase-5 inhibitor therapy, comprising an acid buffer system. Prostaglandin E ₁ ; Alkyl-2- (N-substituted amino) -alkanoates, alkyl-2- (N, N-disubstituted amino) -alkanoates, (N-substituted amino) -alkanol alkanoates, (N, N- Penetration promoters selected from the group consisting of disubstituted amino) -alkanol alkanoates, pharmaceutically acceptable salts thereof and mixtures thereof; Polymeric thickeners selected from the group consisting of polysaccharide gums and polyacrylic acid polymers; Lipophilic components in the crowd consisting of aliphatic C ₁ -C ₈ alcohols, aliphatic C ₈ -C ₃₀ esters and mixtures thereof; And Acid buffer system, Pharmaceuticals for treating erectile dysfunction in patients with concomitant morbidity, including one or more of diabetes, hypertension, heart disease, history of prostatectomy, or erectile dysfunction that is unresponsive to oral phosphodiesterase-5 inhibitor therapy. Use for preparing the composition, And wherein said pharmaceutical composition is administered to the columnar of said patient.