Method and compositions for treating impotence

Pharmaceutical compositions in topical or parenteral form containing organic nitrites are effective in treating male impotence and erectile dysfunction through topical or intracavernosal administration to the penis. Methods of treatment utilizing the nitrite-containing compositions are also disclosed, as are certain novel organic nitrite compounds.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
This invention relates to methods and compositions for treating male 
impotence and erectile dysfunction. 
2. Description of the Prior Art 
The process of erection is generally a selective vasodilation of the spongy 
penile tissue and corpus cavernosum and reductions in outflow, leading to 
blood pooling, elevation of intra-cavernous pressure, and therefore 
erection. 
Conventional therapies for impotence or erectile dysfunction primarily 
include local administration of vascular smooth muscle relaxants, for 
example papaverine or prostaglandin E1, or .alpha.-adrenoceptor 
antagonists, such a phentolamine, resulting in penile erection because of 
an increase in arterial inflow of blood, distension of sinusoids and 
possible restriction of venous outflow. 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 etiologic forms of impotence. Papaverine and 
prostaglandin E1 are also used in the assessment of pharmacological 
response of penile erectile tissues 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 include systemic administration of male hormonal 
preparations such as methyltestosterone and testosterone esters, as well 
as administration of various naturally occurring plant extracts believed 
to have aphrodisiac properties, such as yohimbine, ginseng, strychnine and 
the like. Non-pharmacological therapeutic modalities for impotence include 
the surgical implantation of penile prostheses and the use of 
tourniquet-like devices which fit tightly around the shaft of the penis 
and restrict the flow of blood through the surface veins and the deeper 
dorsal vein to prolong erection. 
All of the foregoing prior art treatment methods suffer from obvious and 
serious disadvantages. The injection of papaverine and other vasoactive 
drugs meets with variable success and variable duration of response, and 
repeated injections into the penis can be painful and traumatic. In some 
patients these agents cause priapism (undesirable sustained erection), 
which can lead to structural damage to the organ. The administration of 
methyltestosterone or testosterone esters may cause toxic effects or 
inhibit endogenous testosterone formation and spermatogenesis. Orally 
administered aphrodisiac substances are of marginal and erratic efficacy, 
and some have significant adverse side effects. The use of surgical 
implants or tourniquet-like devices can lead to serious problems of 
infection and trauma, and cause discomfort to both male and female 
partners. 
Several recent studies have shown the obligatory role of nitric oxide for 
the erection process (see for example Rajfer et al., N. Eng. J. Med., 
326:90-94, 1992). Stimulation of the local nerve leads to production of NO 
and vasorelaxation, leading to erection. Because of the importance of NO 
in erection, NO donors may have utility for the treatment of impotence. 
Hence, it has recently been proposed to use nitric oxide donors such as 
nitroglycerin (see U.S. Pat. No. 5,059,603) and linsidomine chlorhydrate 
(see Urology, 44:553-556, 1994) applied topically or via intracavernosal 
injection to treat impotence and erectile dysfunction. 
The use of these and other nitric oxide donors proposed in the literature 
for treatment of impotence is also less than completely satisfactory. 
Nitroglycerin, even when applied topically as an ointment, has received 
variable responses and may cause severe headaches (see Talley et al., Ann. 
Int. Med., 103:804, 1985). Of even greater concern is that systemic 
absorption of most vasoactive agents causes significant reductions in 
systemic blood pressure resulting in side effects such as 
light-headedness, increased heart rate, etc., and sometimes causing 
activation of the sympathetic nervous system leading directly to 
de-tumescence. For these reasons, the use of nitroglycerin for the 
treatment of impotence is less than ideal. 
Improved pharmaceutical compositions and methods are required for treatment 
of impotence while avoiding the serious adverse effects experienced with 
prior art treatment modalities. 
SUMMARY OF THE INVENTION 
The present invention resides, briefly stated, in the local (topical or 
intracavernosal) administration of organic nitrites to the penis to induce 
and maintain erection with selective local (cavernosal) vasodilation and 
little or no "downstream" systemic vasodilating effects. The organic 
nitrites which may be used in the present invention include those 
disclosed in co-pending parent application Ser. No. 08/213,542, filed Mar. 
15, 1994, now abandoned, as well as additional, novel organic nitrite 
compounds disclosed and described herein. The invention also comprehends 
nitrite-containing topical and parenteral pharmaceutical compositions for 
treatment of impotence.

DETAILED DESCRIPTION OF THE INVENTION 
The present invention pertains to the local administration of vasodilating 
organic nitrites to the penis, either by application of nitrite-containing 
topical pharmaceutical compositions (e.g., ointments, creams, gels, 
lotions, liquids, sprays and the like) or by intracavernosal injection of 
parenteral nitrite-containing compositions, for effective treatment of 
male impotence and erectile dysfunction in humans. 
It has been discovered that the use of organic nitrites in the treatment of 
impotence and related conditions yields unexpected therapeutic advantages 
in comparison with vasodilating agents used for the same purposes in the 
prior art, including closely related vasodilators such as nitroglycerin. 
Chief among these unexpected advantages are an increase in the degree of 
tumescence achieved and substantial absence of systemic vasodilating 
effects, resulting in a smaller drop in systemic blood pressure than 
occurs with prior art vasodilators. The combination of these effects 
renders the organic nitrites more effective and safer than other 
vasodilators previously used to induce or maintain erection. The organic 
nitrites also are far less prone to causation of adverse side effects such 
as the severe headaches that can be caused by nitroglycerin, because of 
the smaller effect on the rest of the body. 
Topical pharmaceutical compositions containing one or a mixture of organic 
nitrites for use in the present invention preferably contain at least one 
active nitrite ingredient in a concentration sufficient to supply from 
about 0.1-20 mg of active nitrite ingredients per dose (e.g., per 
application of about 50 to 500 mg of topical composition), in a 
pharmaceutically acceptable topical carrier or vehicle. Such vehicle can 
be in the form of an ointment, gel, cream, lotion, liquid, spray, or any 
other form known to those skilled in the pharmaceutical and formulation 
arts. The vehicles used in the topical compositions may contain any 
conventional solvents, emollients, humectants, surfactants, opacifying and 
coloring agents, penetration enhancers, and other additives commonly used 
in topical vehicles. The inactive ingredients in the topical compositions 
should be chemically compatible with the active nitrite ingredients and of 
low irritation potential so that the compositions can be safely applied to 
the sensitive areas of the penis. 
Topical carriers useful for formulating nitrite-containing compositions 
include, for example, ointment, gel and 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 nitrites of 
the present invention are set forth in U.S. Pat. No. 5,059,603, the 
disclosures of which are incorporated herein by reference. 
The organic nitrites may also be incorporated into tapes and patches to be 
applied to the penis. These drug-releasing tapes and patches may be 
prepared in accordance with the technology widely utilized for 
slow-release transdermal vehicles containing cardiovascular (e.g., 
anti-anginal) drugs. 
A number of different transdermal products which can employ the organic 
nitrites in accordance with the invention are described by Curtis Black, 
"Transdermal Drug Delivery", U.S. pharmacist, Nov. 1982, pp. 49-75, which 
disclosure is hereby incorporated by reference. Additionally, exemplary 
patents relating to delivery systems include U.S. Pat. Nos. 4,191,015; 
3,742,951; 4,191,015; 3,742,951 and 4,262,003 which disclose using 
penetration enhancers to control delivery rates, which disclosures are 
hereby incorporated by reference. 
Moreover, the topical nitrite-containing compositions, particularly in the 
form of ointments or gels, can be coated onto the inside of a condom, for 
example, a latex condom, which can be applied to the penis in conventional 
fashion. Such mode of administration serves the dual purposes of promoting 
erection and providing a contraceptive and disease-transmission barrier 
during intercourse. Alternatively, devices such as condoms and penis rings 
can be impregnated with the nirite-containing compositions to achieve a 
comparable effect. 
Parenteral vehicles for nitrite-containing compositions in accordance with 
the invention include solutions or dispersions of one or a mixture of 
organic nitrites in a pharmaceutically acceptable parenteral carrier. Such 
carriers may include non-aqueous solvents or diluents, e.g., ethanol, 
benzyl alcohol or propylene glycol, and may also include as solvents, 
diluents or stabilizers, glycerine, povidone, lecithin, sorbitan 
monooleate or trioleate, polysorbate 80, peanut oil, castor oil, and other 
triglycerides. Lipid emulsion carriers may also be employed. The 
parenteral composition should have a sufficient concentration of active 
nitrite ingredient to provide about 0.01-0.75 mg of nitrite per injectable 
dose, said dose being about 0.1 to 0.5 ml of parenteral composition. 
Organic nitrites which can be used in the present invention include any 
organic nitrite ester, i.e., any ester of nitrous acid and an organic 
alcohol, provided that the starting alcohol is not toxic and does not 
interfere with or counteract the vasodilating effect of the nitrite. Such 
organic nitrites can include, for example, straight or branched chain 
alkyl nitrites, arylalkyl nitrites, cycloalkyl nitrites, haloalkyl or 
halocycloalkyl nitrites and heterocyclic nitrites, as well as di- and 
trinitrite analogs of the foregoing. The di- and trinitrite esters may be 
produced by reacting nitrous acid with the appropriate diols or triols or 
by forming partial esters of polyols such as pentaerythritol. Preferred 
nitrites containing alkyl groups are those in which the alkyl is C.sub.1 
-C.sub.10. 
Illustrative examples of organic nitrites which may be useful in the method 
of the invention are shown below. 
##STR1## 
Of the above-listed organic nitrites, the three dinitrite compounds, i.e., 
1,3-propane dinitrite, 1,5-pentane dinitrite and 1,7-heptane dinitrite are 
novel compounds. These dinitrites may be prepared by adding a solution of 
4N hydrochloric acid to a solution of sodium nitrite and the appropriate 
diol (for example, 1,7-heptane diol) in water at room temperature. After 
addition of the hydrochloric acid, the reaction mixture is cooled and 
concentrated sulfuric acid added. After complete addition of the sulfuric 
acid, the two-phased solution is stirred with cooling and then decanted. 
The top oily layer is separated, diluted (e.g., with methylene chloride) 
and washed, for example with a saturated solution of sodium bicarbonate. 
The resulting organic phase is separated, dried, filtered and concentrated 
in vacuo. The oily residue sustained is distilled under high vacuum to 
yield the desired dinitrite product. 
The following examples are presented to further illustrate the compositions 
and methods of the present invention and the novel organic nitrite 
compounds which may be effectively used, among others, in practicing the 
novel method. These examples also demonstrate the remarkable ability of 
the organic nitrite-containing compositions to induce erection in tests 
using accepted animal models while at the same time not inducing 
generalized systemic vasodilation. These examples should not be viewed, 
however, as providing compounds, compositions, formulations or methods of 
administration which must be practiced exclusively in order to come within 
the present invention. 
EXAMPLE 1 
Preparation of 1,7-Heptane Dinitrite 
A solution of 4N hydrochloric acid (38.0 ml) was added dropwise to a 
one-necked 1000 ml round-bottomed flask containing a stirred solution of 
sodium nitrite (38.0 gms, 0.551 mol) and 1,7-heptane diol (25.0 g, 0.189 
mol) in water (250 ml) at room temperature. After complete addition of the 
4N HCl, the reaction mixture was cooled (ice/water bath) and concentrated 
sulfuric acid (27 ml) was added dropwise. The funnel containing the 
sulfuric acid was loosely stoppered to avoid seepage of the nitrous acid 
generated in the reaction mixture. After complete addition of the sulfuric 
acid, the two-phased solution was stirred 10-15 minutes with cooling and 
then decanted. The top oily layer was separated, diluted with methylene 
chloride (100 ml) and washed with a saturated solution of sodium 
bicarbonate (200 ml). The organic phase was separated, dried (anhydrous 
Na.sub.2 SO.sub.4), filtered and concentrated in vacuo. The oily residue 
obtained was distilled under high vacuum to afford the product, 
1,7-heptane dinitrite, as a yellow oil (32.1 g, 89%); b.p. 
75.degree.-77.degree. C. (1.5 mm Hg). 
Elemental analysis for C.sub.7 H.sub.14 N.sub.2 O.sub.4 : 
Calculated: C-44.21%; H-7.42%; N-14.73% 
Found: C-44.48%; H-7.48%; N-14.44% 
EXAMPLE 2 
Preparation of 1,5-pentane Dinitrite 
The procedure of Example i was followed utilizing 1,5-pentane diol (20g, 
0.192 mol) in place of the 1,7-heptane diol. 
EXAMPLE 3 
Preparation of 1,3-propane Dinitrite 
The procedure of Example 1 was followed utilizing 1,3-propane diol (15 g, 
0.197 mol) in place of the 1,7-heptane diol. 
EXAMPLE 4 
Topical Composition 
A 5% topical ointment of isoamyl nitrite was prepared in a base of white 
petrolatum and paraffin wax. The composition contained about 15 mg of 
nitrite per one inch dose (300 mg) of ointment. 
EXAMPLE 5 
Parenteral Composition 
A parenteral solution of 1,7-heptane dinitrite suitable for intracavernosal 
injection was prepared with about 0.05 mg (50 .mu.g) of nitrite per 
injectable dose of 0.2 ml. 
EXAMPLE 6 
Intracavernosal Injection of Nitrites in Rats 
Description of Rat Model 
Rats are anesthetized with a long-acting barbiturate (Inactin), and a 
catheter is inserted in the left femoral artery for the measurement of 
systemic blood pressure. The penile area is exposed and a needle is 
inserted in the corpus cavernosal area (the right crus) for the 
measurement of intracavernosal pressure, and for intracavernosal injection 
of drugs. 
The determination of rat "erection" is through the measurement of 
cavernosal pressure. In humans and animals the pressure is initially very 
low (approx. 5-10 mmHg), and during erection it rises to 60-90% of 
systemic blood pressure (depending on the species and needle placement). 
Test Procedure 
Four groups of laboratory rats (n=4-7 in each group) were catheterized as 
described above and baseline cavernosal and arterial blood pressure values 
were determined. The test animals received intracavernosal injections of 
nitroglycerin or organic nitrite in ethanol solution in varying molar 
concentrations. The four groups received, respectively, nitroglycerin 
(Group 1); 1,5-pentane dinitrite or ethanol solution as placebo (Group 2); 
1,7-heptane dinitrite or ethanol placebo (Group 3); and isoamyl nitrite or 
ethanol placebo (Group 4). 
The maximum changes in cavernosal and arterial blood pressure were 
determined for each animal. 
Results 
The mean changes in cavernosal and arterial blood pressure of the four test 
groups are reflected in FIGS. 1-4, respectively. As reflected in FIG. 1, 
injection of nitroglycerin caused relatively small, dose-dependent 
increases in intracavernosal pressure, and simultaneously caused almost 
equivalent systemic ("downstream") reductions in arterial blood pressure 
(i.e., over 30 mmHg at the highest dose used). 
By contrast, as reflected in FIGS. 2-4, injection of organic nitrites 
caused greater changes in mean intracavernosal pressure in the test 
subjects while having little or no effects on systemic blood pressure. 
EXAMPLE 7 
Topical Application of Nitrites in Guinea Pigs 
Test Procedure 
Ten male outbred Hartley guinea pigs were weighed and placed into treatment 
groups as follows: 
______________________________________ 
Group N Treatment Dose 
______________________________________ 
A1 1 1,5-pentane dinitrite 
1 .mu.L 
A2 1 1,5-pentane dinitrite 
5 .mu.L 
A3 1 1,5-pentane dinitrite 
20 .mu.L 
B1 1 1,7-heptane dinitrite 
1 .mu.L 
B2 1 1,7-heptane dinitrite 
5 .mu.L 
B3 1 1,7-heptane dinitrite 
20 .mu.L 
C1 4 amyl nitrite 5 .mu.L 
C2 4 amyl nitrite 20 .mu.L 
D1 4 nitroglycerin (2%) 
1 mg 
D2 4 nitroglycerin (2%) 
4 mg 
______________________________________ 
The animals were placed in dorsal recumbency and held in place by 
restraints. The penis was extruded from the prepuce. Care was taken to not 
manipulate the penis. Length and diameter measurements were made using 
digital calipers. The length measurement was taken from the prepuce to the 
tip of the glans when the penis was extended. The diameter was taken 0.5 
cm proximally from the tip of the glans. 
The appropriate amount of test material was applied with a Wiretrol.TM. 
pipette to the base of the exposed penis. When application was complete, a 
timer was started. Measurements were taken at 0, 1, 2, 5, 10 and 15 
minutes after application or until detumescence was observed. 
Results 
Data collected during this study are graphically represented in FIGS. 5-13. 
Inspection of the data indicates that all three of the nitrite compounds 
were effective at a topical dose of 20 .mu.L. At the 20 .mu.L dose amyl 
nitrite was slightly more effective than the dinitrite compounds. At the 5 
.mu.L dose the data indicate that the 1,5-pentane dinitrite was clearly 
more effective than the other two compounds (FIGS. 5-6). Due to its poor 
response at the 5 .mu.L dose, amyl nitrite was not evaluated at 1 .mu.L. 
At the 1 .mu.L dose 1,5-pentane dinitrite was more effective than the 
1,7-heptane dinitrite. 
The penis of the guinea pig is classified as mucocutaneous tissue. The 
glans is covered primarily with keratinized scales. During erection a 
pouch at the tip of the glans is everted. This pouch contains two horny 
styles. In all nitrite-treated animals, the eversion of the pouch was 
observed. This indicated that for the amyl nitrite, 1,5-pentane dinitrite 
and 1,7-heptane dinitrite, a true erection was produced. 
It is believed that the organic nitrites are particularly well-suited for 
treatment of male impotence and erectile dysfunction because of their 
ability to provide local cavernosal vasodilation with little systemic 
vasodilation. They also have the valuable attribute for topical purposes 
of rapid penetration upon local application. 
It has thus been shown that there are provided compositions and methods 
which achieve the various objects of the invention and which are well 
adapted to meet the conditions of practical use. 
As various possible embodiments might be made of the above invention, and 
as various changes might be made in the embodiments set forth above, it is 
to be understood that all matters herein described are to be interpreted 
as illustrative and not in a limiting sense. 
What is claimed as new and desired to be protected by Letters Patent is set 
forth in the following claims.