MXPA00011316A - Compositions comprising organic mono- or dinitrate for treating impotence - Google Patents

Abstract

Pharmaceutical compositions in topical or parenteral form containing specific organic mono- or dinitrates, some of them novel compounds, are effective in treating male impotence and erectile dysfunction through topical or intracavernosal administration to the penis. Methods of treatment utilizing the mono- or dinitrate-containing compositions are also disclosed.

Description

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COMPOSITIONS COMPRISING MONONITHRATE OR ORGANIC DINITRATE FOR THE TREATMENT OF IMPOTENCE BACKGROUND OF THE INVENTION 1. FIELD OF THE INVENTION This invention relates to methods and compositions for the treatment of male impotence and erectile dysfunction. 2. DESCRIPTION OF THE PREVIOUS TECHNIQUE The erection process is generally a selective vasodilatation of the spongy tissue of the penis and of the corpora cavernosa and reductions of the exit, which causes a blood accumulation, intra-cavernous pressure rise, and consequently an erection . Conventional pharmaceutical therapies for impotence or erectile dysfunction primarily include local administration of vascular smooth muscle relaxants, for example, papaverine or prostaglandin El or α-adrenoceptor antagonists such as, for example, phentine, which results in erection of the penis due to an elevation of the arterial blood supply, distention of sinusoids and possible restriction of the venous outlet. Thus, intracavernous injection of vasoactive drugs offers impotent patients a form of therapeutic management and allows one of the tests for differential diagnosis between vasculogenic and other etiologies of impotence. Papaverine and prostaglandin El are also used in the evaluation of the pharmacological response of erectile tissues of the penis under experimental conditions (see Chen et al., J. Urol. 147: 1124-1128, 1992). Other pharmaceutical treatments for impotence have been practiced in the prior art. These treatments include the systemic administration of male hormone preparations such as methyltestosterone and testosterone esters, as well as the administration of several naturally occurring plant extracts which are considered to have aphrodisiac properties, such as yohimbine, ginseng, strychnine and Similar. Non-pharmacological therapeutic modalities for impotence include the surgical implant of a penile prosthesis and the use of tourniquet-type devices that fit closely around the penis and restrict the flow of blood through the superficial veins and the deepest dorsal vein. to prolong the erection. All of the aforementioned prior art treatment methods suffer from obvious and severe disadvantages. The injection of papaverine and other vasoactive drugs has varying success and a variable duration of response, and repeated injections into the penis can be painful and traumatic. In some patients these agents cause what is known as priapism (undesirable sustained erection), which can cause structural damage to the organ. The administration of methyltestosterone or testosterone esters can cause toxic effects or inhibit the endogenous formation of testosterone and spermatogenesis. Aphrodisiac substances administered orally have marginal and erratic efficacy and some have important side effects. The use of surgical implants or tourniquet type devices can cause significant problems of infection and trauma and cause discomfort to both men and women. Several recent studies have shown the mandatory function of nitric oxide for the erection process (see for example Rajfer et al., N. Enq. J. Med. 326: 90-94, 1992). Rajfer concluded that stimulation of the local nerve causes the production of NO, which increases blood flow in the arteries of the penis and relaxes the cavernous spaces. When these cavernous spaces are full they compress the venous outlet of the corpora cavernosa causing an erectile response. The administration of exogenous NO donors can therefore be useful to promote erections. Several patents have been granted regarding the use of nitriglycerin (NTG) and linsidomine applied topically or through intracavernous injection to treat impotence and erectile dysfunction.

It has been clearly established that NTG causes relaxation of the smooth muscle of the penis and of vascular tissue, including ^ cavernous tissue. Studies using ointment formulations have shown a vasodilation and subsequent congestion. However, there is less convincing evidence that NTG administered as a 2-10% ointment or plaster applied topically results in an erection sufficient for vaginal penetration. Using an ointment of ^^ NTG at 2%, 18/26 patients showed an increase in the circumference and 7/20 patients showed a 50% increase in tumescence (Owen et al., J. Urol. 141: 546, 1939). Studies by Cavallini (J. Urol. 146: 50, 1991) showed that, using a simple blind design, with 51 patients, an elevation of the circumference of the penis and its stiffness with 10% NTG ointment. In other studies without blind, NTG plasters applied locally for several hours They resulted in relatively unsatisfactory responses in 90% of the patients in the laboratory and 60% of the patients in the home (Meyoff et al., Br. J. Urol. 69: 88, 1992). In another study, 30% of patients achieved sufficient erections for vaginal penetration at home while 71% of patients had some response (Sonksen, Biering-Sorensen, Paraplegia 30: 554, 1992). Using parts of NTG in a double-blind study, the response to the active drug was approximately 81%,. while it was 19% with placebo (Claes and Baert, Urol. Int. 4_4: 309; 1989). This was based on interviews after the test and not on patient diaries or questionnaires that could have been more accurate. The sexual response was tested only in 3 out of 5 published studies of studies evaluating the erectile response to nitrates. Statistical methods were not evaluated in most studies and only one trial reported that NTG had a response that was better than papaverine, another vasodilator or placebo. In many of these trials, headaches were frequent and it is unclear what dose of NTG is required or its duration of action. In addition, it was shown that many patients did not present a useful response to NTG. This may occur due to ultrastructural injury to the smooth muscle, failure of venous occlusion, or direct venodilation in subfunctional veins. Other factors that limit the therapeutic potential of NTG include the decrease in systemic blood pressure and headache. It has been reported in PCT application publication WO 96/34583 that certain organic nitrites, particles of dinitrites such as 1,5-pentane dinitrite, are effective in inducing erection even when applied topically to the penis, and have almost no effects undesirable collaterals caused by systemic vasodilation. However, it has been found that nitrites irritate dermal tissues and may, therefore, not be suitable for large-scale therapeutic use, f Compositions and improved pharmaceutical methods are required for the treatment of impotence, which avoid at the same time the adverse effects experienced with the treatment modalities of the prior art. COMPENDIUM OF THE INVENTION The present invention is, in summary form, the ^^ local administration (topical or intracavernous) of certain organic mononitrates and dinitrates to the penis to induce and maintain the erection with local (cavernous) selective vasodilation and few or no vasodilator effect (s) "downstream". This invention also encompasses topical and parenteral pharmaceutical compositions containing mononitrates and dinitrates for the treatment of impotence. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graph that illustrates the dose-related changes in penile volume with the passage of time caused by the topical application of 1,5-pentane dinitrate (1,5-PDN) to guinea pigs. Figure 2 is a graph illustrating the dose-related changes in penile volume over time caused by the topical application of a solution of nitroglycerin 10% (NTG) to the penis of guinea pigs. Figure 3 is a graph illustrating the topical increases in penile volume caused by the topical application of NTG and 1,5-PDN, respectively, to the penis of guinea pigs. Figure 4 is a graph illustrating changes in penile volume in guinea pigs over time after application of 5% 5-PDN (approximately 2.5 mg in 50 mg topical product) prepared in several formulations: 1) isopropyl alcohol, 2) propylene glycol, 3) KY gel and 4) petrolatum. Figure 5 is a graph illustrating the dose-related changes in penile volume over time caused by the topical application of 1,5-pentane to guinea pigs. Figure 6 is a bar graph illustrating the maximum changes in mean arterial blood pressure and cavernous pressure in anesthetized rats that received various dosages of 1,5-PDN by intracavernosal injection. Figure 7 is a bar graph illustrating the maximum changes in mean arterial blood pressure and cavernous pressure in anesthetized rats that received various dosages of NTG by intracavernosal injection. Figure 8 is a bar graph illustrating the maximum changes in mean arterial blood pressure and cavernous pressure in anesthetized rats that received various dosages of sodium nitroprusside (SNP) by cavernous injection. Figure 9 is a bar graph illustrating the maximum changes in mean arterial blood pressure in conscious rats receiving intravenous NTG (30 μg) and 1,5-PDN (30 to 2000 μg). Ethanol (EtOH) was used to solubilize the nitrate compounds and effects on blood pressure were shown. Figure 10 is a graph comparing the vascular relaxation effects of 1,5-PDN and 1,5-pentane dinitrite in various molar constitutions as determined by stress reduction in aortic segments of pre-contracted phenylephrine. Figure 11 is a graph comparing the vascular relaxation effects of 1,5-PDN and NTG at various molar concentrations in accordance with that determined by reduction of tension in rat aortic segments pre-contracted with phenylephrine. Figure 12 is a graph comparing blood levels of total radioactivity and 1,5-PDN after a single oral administration (5.2 mg / kg) of 14C-1.5 PDN. Figure 13 is a graph comparing blood levels of total radioactivity and 1,5-PDN after a single subcutaneous dose (5.0 mg / kg) of 14C-1.5 PDN.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the local administration of certain monoditrates and organic dinitrates vasodilators to the penis, either by application of topical pharmaceutical compositions containing nitrate (for example, ointment, creams, gels, lotions, liquids, sprays and the like) or by intracavernous injection of parenteral nitrate containing compositions, for the effective treatment of male impotence and erectile dysfunction in humans. It has been found that the use of certain organic mononitrates and dinitrates never used in the prior art to treat impotence and related conditions, and some of which are novel compounds, provide unexpected therapeutic advantages compared to vasodilating agents that were used for them. purposes in the art, including closely related vasodilators such as nitroglycerin (NTG). Among the unexpected advantages are mainly an increase in the degree of tumescence achieved and a substantial decrease in systemic vasodilator effects, resulting in a much lower drop in systemic blood pressure compared to what occurs with NTG and vasodilators. of nitrate the prior art. The combination of these effects makes these mononitrates and organic dinitrates more effective and safer than other vasodilators previously used to induce or maintain an erection. The organic nitrates of the present invention may also exhibit a lesser tendency towards the provocation of side effects such as severe headaches that may be caused by nitroglycerin due to a reduced systemic action. It is not known why the topical application of mononitrates and organic dinitrates of the invention causes a greater increase in penis volume than NTG. It is speculated that the differences in activity can be related to more efficient generation of NO by the dinitrates in the corpora cavernosa or the different kinetic characteristics of penetration of the two agents, which does not allow a significant peripheral vasodilatation that can result in de-excitation. The mononitrate and dinitrate compounds used in the present invention are also less volatile, more chemically stable and less irritating in the case of Topical application on the skin than organic mononitrates disclosed, for example, in PCT application W096 / 34538. Topical pharmaceutical compositions containing one or a mixture of organic mononitrates and dinitrates for their use in the present invention preferably contain at least one active nitrate ingredient in a sufficient concentration to provide about 0.1 to 40 mg of active nitrate ingredient per dose (eg, by application of about 50 to 800 mg of topical composition) , in a pharmaceutically acceptable topical vehicle. Said vehicle may take the form of an ointment, gel, cream, lotion, liquid, spray, or any other form known to those skilled in the art of formulation and pharmaceutical agents. The vehicles employed in the topical compositions may contain any conventional solvent, emollient, humectant, surfactant, opacifying agent and colorant, penetration enhancers as well as other additives commonly employed in topical vehicles. The inactive ingredients in the topical compositions should be chemically compatible with the active nitrate ingredients and with low irritation potential such that the compositions can be safely applied to the sensitive areas of the penis. Useful topical vehicles for formulating compositions containing mononitrate and dinitrate include, for example, ointment, gel, cream bases containing white petrolatum, paraffin wax, caprylic / capric diglyceryl succinate, diisopropyl adipate and / or ethoxydiglycol. Examples of topical carriers suitable for use with the organic nitrates of the present invention are presented in U.S. Patent No. 5,059,603, the disclosures of which are incorporated herein by reference. The organic nitrates of the present invention can also be incorporated into tapes and patches for application to the penis. Drug release ribbons and patches can be prepared in accordance with the technology widely employed for slow release transdermal vehicles containing cardiovascular drugs (eg, antiangin). Various different transdermal products that organic nitrates may employ in accordance with the present invention are described by Curtis Black, "Transder to Drug Delivery", U.S. Pharmacist, November 1982 pages 49-75, the disclosure of which is incorporated herein by reference. In addition, example patents that refer to administration systems include US Patent Nos. 4,191,015; 3,742,951; 4,191,015; 3,742,951 and 4,262,003 disclosing the use of penetration enhancers to control administration rates, these disclosures are incorporated herein by reference. In addition, topical nitrate-containing compositions, particularly in the form of ointments or gels, can be applied to the inside of a condom, for example, a latex condom, which can be applied to the penis in a conventional manner. This mode of administration serves the dual purpose of promoting erection and providing a barrier (contraceptive barrier and against the transmission of diseases during sexual intercourse) Alternatively, 5 devices such as condoms and rings for the penis may be impregnated with compositions containing nitrate in order to achieve a comparable effect Parenteral vehicles for compositions containing • nitrate in accordance with the present invention include solutions or dispersions of one or a mixture of mononitrates and organic dinitrates in a pharmaceutically acceptable parenteral vehicle. Such vehicles may include non-aqueous solvents or diluents, for example, methanol, benzyl alcohol or propylene glycol, and may include solvents, diluents or stabilizers, glycerin, povidone, lecithin, sorbitan monooleate or trioleate, Polysorbate ^ 80, peanut oil, castor oil, and other triglycerides. Lipid emulsion vehicles can also be used. The parenteral composition must have a sufficient concentration of nitrate active ingredient to provide approximately .01-1.0 mg of mononitrate or dinitrate per injectable dose, said dose should be from about 0.1 to 0.5 ml of parenteral composition. Examples of organic nitrates useful in the method of The present invention is presented in Table 1. Analytical purity by mass spectroscopy with gas chromatography of each is also presented. Many of these organic nitrates are novel compounds, never previously synthesized, as we could determine through extensive literature research and computerized databases. TABLE 1 SUMMARY OF ANALOGUES OF 1,5-PENTANE DINITRATE Compound Structure Purification (%) 2-Pentane Nitrate 96.7 Dinitrate of 1.5-99.5 O, NO-, ONC. pentane Dinitrate of 1,3-C, O > ONO I 99.6 butane Dinitrate of 1.6- O, NO. OR NOT . 98.3 hexane Dinitrate of 1,7- .ONC 96.2 heptane isoamyl nitro ONO. 100.0 isobutyl nitrate. 99 8 neopentyl nitrate x and ONO; 100 0 2-methyl-100 nitrate. 0 l-propen-3 2-methyl-100.0 nitrate 2-propen-4 nitrate of l-penten-5 O, NO. 93.3 100.0 cyclopentyl nitrate 1,4- O.NC dinitrate. 97.6 cyclohexyl O, NO,, 0NC 1-pentane 99.5 nitrate The following examples are presented to further illustrate the compositions and methods of the present invention and the organic mononitrate and dinitrate compounds which can be effectively employed, inter alia, in practice. of the novel method. These examples should not however be considered as providing compounds, compositions, formulations or methods of administration that should be practiced exclusively for the purpose of complying with the present invention. EXAMPLE 1 Preparation of 1,5-pentane dinitrate 90% HNO3 (30 ml) was added dropwise to a stirred solution of 1,5-pentane (10 g) in H20 (25 ml). The reaction mixture was cooled (0 ° C), concentrated H2SO4 (20 ml) was added dropwise and the solution was warmed to room temperature slowly with constant stirring (3 hours). The top layer was decanted, dissolved in CH2CI2 (70 ml), washed with H20 (75 ml) and saturated NaHCO 3 (3 x 75 ml), dried (Na2SO < RTI ID = 0.0 > anhydrous < / RTI >) and concentrated in vacuo. The residue was then diluted in vacuo to give the product (1,5-PDN) as a colorless liquid. The remaining dinitrates and certain monitrates useful in the practice of the present invention can be prepared by synthesis analogous to those raised above for 1,5-PDN. Thus, for example, 1,4-butane dinitrite can be prepared using an aqueous solution of 1,4-butanediol, etc. mononitrates that could not be synthesized using the method of example 1 were synthesized as shown in example 2. EXAMPLE 2 Preparation of 2-Methyl-l-Propen-3-Nitrate 7.41 grams of silver nitrate were weighed into a round-bottomed flask of 100 mL. 8 L of acetonitrile was added and the solution was stirred until the silver nitrate solution was dissolved. To the silver nitrate solution were added 4 mL of 5 3-bromo-2-methylpropene in 21 mL of acetonitrile. A yellow precipitate formed immediately at the time of addition. The reaction mixture was stirred for 30 minutes after the addition, then filtered. Thirty mL of water was added to the filtrate, and then the mixture was extracted with three 30 mL portions of hexane. The hexane layers were combined and dried in sodium sulfate. The solvent was removed under reduced pressure and the crude reaction material was purified by fractional distillation to provide 0.9 mL of final product, 2-methyl-1-propen-3-nitrate. EXAMPLE 3 ^ Topical application of nitrates in guinea pigs Test procedure Sixteen outbred Hartley guinea pigs 20 males were weighed and placed in the treatment groups as follows: N Treatment agent Dose 4 dinitrate 1.5 -pentane 3 μL 4 1,5-pentane dinitrate 10 μL 25 4 1,5-pentane dinitrate 50 μL 4 normal saline 30 μL The animals were placed in dorsal recumbency and kept in this position by restrictive means. The penis was extracted from the foreskin. Care was taken not to manipulate the penis. Length and diameter measurements were taken using digital calipers. The measurement of length was taken from the foreskin to the tip of the glans when the penis was extended. The diameter was measured at a distance of 0.5 cm from the tip of the glans. The appropriate amount of test material was applied with a Wiretrol® pipette on the base of the exposed penis. Once the application is finished, a timer is activated. The measurements were taken 0,1,2,5,10 and 15 minutes after the application or until the observation of a demissence. Results The data collected during this study are shown graphically in figure 1. The reduction in the data indicates that the 1,5-pentane dinitrate was significantly more effective than the saline control to increase the volume of the penis, and that it was observed a response related to the dose with 1,5-PDN. The same procedure was followed to apply topically a series of several other nitrate and dinitrate compounds (in pure form) to the penis of guinea pigs. A summary of the activity of the nitrate compound series appears in Table 2, with the values of area under the curve and peak effect for each compound compared to 1,5-PDN. TABLE 2 Compound AUC% 1,5- • PDN Peak effect (9- change) 1.5-pentane dinitrate 442 100 38.7 1,4-butane dinitrate 403 91 35.5 1,6-hexane dinitrate 349 79 31.8 1,7-heptane dinitrate 460 104 39.3 isoamyl nitrate 309 70 40.3 neopentyl nitrate 376 85 45.2 isobutyl 367 83 38.1 cyclopentyl nitrate 380 86 31.8 2-pentane nitrate 323 73 36.0 l-penten-5 nitrate 309 70 35.4 2-methyl-2-305 nitrate 69 32.6 butene-4 dinitrate 1,4- 225 51 27.9 cliclohexyl 1-pentane nitrate 234 53 25.9 1-methyl-265 60 nitrate 28.6 l-propene-3 Compound% 1 , 5-PDN Effect time Peak (minutes) 1,5-pentane dinitrate 100 5 1,4-butane dinitrate 92 2 1,6-hexane dinitrate 82 5 1,7-heptane dinitrate 102 5 isoamyl nitrate 104 2 neopentyl nitrate 117 2 isobutyl 98 2 cyclopentyl nitrate 82 10 2-pentane nitrate 93 5 l-pentene-5-nitrate 91 2 2-methyl-2- 84-buten-4-dinitrate 1,4-nitrate 72 2 cyclohexyl nitrate 1-pentane 67 2 nitrite 1-methyl- 74 5 l-propene-3 ato All the compounds listed above showed area values under the curve not less than 50% of the area under the curve of 1,5-PDN, organic nitrate compounds which have area values under the topical activity curve in this animal model equal to at least about 50% of the area value under the 1.5-PDN curve can be considered as potent erection stimulators and can be used in the present invention.

EXAMPLE 4 Topical application of nitroglycerin in guinea pigs P Test procedure The same test procedure as in Example 5 3 was followed, but by applying a 10% solution of NTG on the penis in various dosage amounts. Twelve guinea pigs of the male Hartley breed were placed in treatment groups in accordance with ^^ next: W 10 N Treatment agent Dose 4 10% nitroglycerin solution 3 μL 4 10% nitroglycerin solution 10 μL 4 10% nitroglycerin solution 30 μL Results 15 The data collected during this study are presented graphically in Figure 2. The data indicate that NTG t ^ had a minimal effect on penile volume compared to 1,5-PDN. This difference is illustrated in Figure 3 which shows the highest effect of 1,5-PDN in a erection production, in accordance with that reflected by peak changes in penile volume. EXAMPLE 5 Intracavernosal Injection of Dinitrates in Rats Description of Rat Model 25 Rats were anesthetized with a long-acting barbiturate (Inactin) and a catheter was inserted into the left femoral artery for measurement of systemic blood pressure. The area of the penis is exposed and a needle is inserted into the cavernous body area (right cane) for the measurement of the intratrevernous pressure and for the intracavernous injection of drug. The determination of rat "erection" is carried out through the measurement of cavernous pressure. In humans and ^ animals the pressure is initially very low (approximately 5-10 mm Hg), and during the erection, up to 60-90% of the systemic blood pressure rises (depending on the species and needle placement). Test procedure Three groups of laboratory rats (n = 4-7 in each group) 15 received a catheter in accordance with what was described above and the baseline blood pressure and cavernous blood pressure values were determined. The test animals received intracavernous NTG injections or other donor NO organic solution in ethanol in various 20 molar concentrations. The three groups received, respectively, NTRG (group 1); 1,5-pentane dinitrate or ethanol placebo (group 2); and placebo of ethanol or sodium nitroprusside (Group 3) . The maximum changes in arterial and cavernous blood pressure were determined for each animal.

Results The mean changes in arterial and cavernous blood pressure of the four test groups are shown in Figures 6-8, respectively. As reflected in Figure 7, the nitroglycerin injection caused relatively small dose-dependent increases in intracavernous pressure, and simultaneously caused almost equivalent ("downstream") systemic reductions in arterial blood pressure (ie, more than 30 mmHg in the tiniest dose used). In contrast, as shown in Figures 6-8, the injection of either organic dinitrate or sodium nitroprusside caused greater changes in mean intracavernous pressure in the test animals while having little or no effect on blood pressure. systemic However, sodium nitroprusside does not penetrate through the skin quickly and can produce toxic cyanide metabolites. Therefore, sodium nitroprusside can not be used as a transcutaneous drug for the treatment of penile dysfunction. EXAMPLE 6 Intravenous injection of NTG versus 1,5-pentane dinitrate in rats Test procedure Rats (n = 3) with permanent catheters in the femoral artery for blood pressure and vein measurements for drug administration received a dose of NTG (30 μg) and 6 doses of 1,5-PDN (30 μg - 2000 μg) or vehicle (ethanol) in the conscious state. Changes in mean arterial blood pressure (diastolic blood pressure + 1/3 (systolic-diastolic blood pressure)) were evaluated after each dose of nitrate. Approximately 0.5 hours to 1 hour separated the administration of each drug and dose. Results Mean changes in mean blood pressure of NTG and 1, 5-PDN appear in Figure 9. NTG resulted in a decrease of approximately 25% in blood pressure while the same dose of 1,5-PDN caused only a reduction of approximately 8% in terms of blood pressure. Higher doses of 1,5-PDN resulted in an average 12-14% decrease in blood pressure. These findings are surprising given the similarity in muscle relaxation between the two drugs. EXAMPLE 7 Vascular Reactivity Aortic menses (2-3 mm wide) from Sprague-Dawley rats were isolated and placed in a tissue bath. The vessels were pre-contracted with small amounts of phenylephrine. A transducer connected to a recording device was used to evaluate the voltage changes. As seen in Figure 10, there was no difference in vascular relaxation, power or efficacy, between 1,5-PDN and 1,5-pentane dinitrite. In a similar experiment, no appreciable difference was observed in vascular relaxation induced by NTG and 1,5-PDN (FIG. 11). EXAMPLE 8 Human experience Two 5% formulations of 1,5-PDN in petrolatum and KY-JELLY®, respectively, were tested one week apart in a male human patient. At home he observed that the petrolatum formulation provided a full erection within several minutes after the topical application of approximately 10-20 mg of drug to the penis. The KY-JELLY® formulation resulted in a less dramatic erection in approximately the same period of time. No headache was associated with the application of any of the drugs, which indicates that little downstream systemic vasodilation occurred. The following studies were carried out to define the pharmacokinetic parameters of 1,5-PDN and its metabolites in rats, including blood levels after dosing by various routes and metabolic effects. EXAMPLE 9 Test procedure Ten male rats were fasted for 16-18 hours and then received a dose of 5 mg / kg of 1C-1,5-PDN orally (in corn oil) or subcutaneously (in PEG) 400). Blood samples were collected through the tail vein and combined at predetermined times up to 24 hours after dose administration. An aliquot of each combined sample was removed, which was analyzed to determine the total radioactivity, the rest was extracted with acetonitrile and analyzed by HPLC to quantify 1,5-PDN and metabolites. Results Blood kinetic data for total radioactivity and 1,5-PDN are shown graphically in Figures 12 and 13 for oral administration and subcutaneous administration, respectively. The data show that levels of 1,5-PDN in the blood are less than 0.1% of total radioactivity levels after oral dosing and 3.4% of total radioactivity levels after subcutaneous administration. These data indicate that 1,5-PDN is metabolized very rapidly in vivo and that the systemic exposure to the compound is minimal. The lack of significant systemic exposure indicates that the effects of 1, 5-PDN are probably local, and not systemic. EXAMPLE 10 Test procedure Ten rats (five males and five females) were fasted for 16-17 hours before IV administration, oral or ^ dermal 5 mg / kg of i4C-1, 5-PDN. The rats were placed in Roth metabolism cages to allow collection separated from 14C volatile urine, feces, and substance trapped in ethanolamine / 2-ethoxyethanol at predetermined intervals up to 168 hours after administration, animals were sacrificed by exsanguination after puncture ^^ cardiac and the selected tissues were removed. The blood, plasma, harvested tissues and residual carcasses were analyzed to determine the total radioactivity. Results The main route of elimination of radioactivity administered IV, orally or dermally for both males and for females was through the air expired as 14C02 (identified by barium precipitation). The feN animals eliminated approximately 60% of the radioactivity administered as 14C02, 305 in the urine and 5% in the feces. Tissue levels of radioactivity were located between a range of 0.1 - 1 ppm and accounted for approximately 5% of the dose. The skin treated for the dermal dose group contained only 1-2% of the dose. These data demonstrate that the compound is well absorbed both orally and dermally, and is metabolized rapidly and extensively in alive, largely in C02. The elimination of radioactivity takes place mainly through respiration as 14C02. The compound seems to be handled in a very similar way both in the case of males and females. It has therefore been shown that compositions and methods are provided which achieve the various objects of the invention and which are well adapted to meet the conditions of practical use. Since various possible embodiments of the above invention can be made, and since several changes can be made to the aforementioned embodiments, it is understood that all of the material described herein should be construed as illustrative and not limiting. What is claimed as novel and what is desired to be protected by a patent is set forth in the following claims.

Claims (19)

1. CLAIMS 1. A topical pharmaceutical composition for the treatment of male impotence or erectile dysfunction, comprising: an organic mononitrate or dinitrate, said mononitrate or dinitrate is selected from the group consisting of 1.5 pentane dinitrate, dinitrate of 1, 4 butane, 1,6 hexane dinitrate, 1,7 heptane nitrate, isoamyl nitrate, isobutyl nitrate, neopentyl nitrate, cyclopentyl nitrate, 2-pentane nitrate, 1-penten-5-nitrate and 2-methyl -2-buten-4-nitrate; and a topical vehicle suitable for topical administration to the penis. The composition according to claim 1, comprising a sufficient amount of organic mononitrate or dinitrate to provide about 0.1 mg - 40 mg of nitrate per dose applied to the penis. 3. The composition according to claim 2, comprising about 15 mg of mononitrate or dinitrate per dose. 4. The composition according to claim 2, wherein said dose comprises from about 50 to 800 mg of topical composition. 5. The composition according to claim 1, comprising 1,5 pentane dinitrate. 6. A method for the treatment of male impotence or erectile dysfunction in humans by local administration to the penis of a pharmaceutical composition comprising an organic mononitrate or dinitrate in a pharmaceutically acceptable topical or parenteral vehicle, said mononitrate or dinitrate being selected within from the group consisting of 1,5-pentane dinitrate, 1,4-butane dinitrate, 1,6-hexane dinitrate, 1,7-heptane nitrate, isoamyl nitrate, isobutyl nitrate, neopentyl nitrate, cyclopentyl nitrate, nitrate of 2-pentane, l-penten-5-nitrate and 2-methyl-2-buten-4-nitrate. 7. The method according to claim 6, wherein said composition is administered by topical administration or intracavernosal injection. 8. The method according to claim 6, wherein said composition is applied topically to the penis. 9. The method according to claim 8, wherein said vehicle is a topical vehicle. The method according to claim 8, wherein said composition contains sufficient mononitrate or dinitrate to provide approximately 0.1-40 mg of dinitrate per dose applied to the penis. The method according to claim 10, wherein said composition comprises about 15 mg of mononitrate or dinitrate per dose. The method according to claim 9, wherein said dose comprises from about 50 to 800 mg of topical composition. 13. The method according to claim 6, wherein said composition is injected intrecavernosa. 14. The method according to claim 13, wherein said vehicle is a parenteral vehicle. 15. The method according to claim 14, wherein said vehicle is a non-aqueous solvent or diluent. 16. The method according to claim 15, wherein said solvent or diluent is ethanol or propylene glycol. 17. The method according to claim 13, wherein said composition comprises a sufficient amount of organic mononitrate or dinitrate to provide about 0.1 to 1.0 mg of nitrate per injectable dose. 18. The method according to claim 17, wherein said composition comprises from about 0.1 to 0.5 ml of parenteral composition. 19. The method according to claim 6, wherein said composition comprises 1,5-pentane dinitrate.