MXPA97007038A - The use of a vasoactive agent in the preparation of compositions to prevent erectile dysfunction, and equipment for my - Google Patents

Abstract

The use of a vasoactive agent to prepare compositions for preventing erectile dysfunction, particularly vasculogenic impotence, in a male subject, by periodically administering said composition over a period of 24 hours, the composition and dosage regimen is selected in a manner that a regularly increased blood flow to the penis is achieved, preventing in turn the arterial occlusion and vascular deterioration of the vascular fibers of the vessels and collagen fibers of the cavern tissue

Description

THE USE OF A VASQ AGENT IN THE PREPARATION OF COMPOSITIONS TO AVOID ERECTILE DYSFUNCTION, AND EQUIPMENT FOR THE RUSSIAN FIELD OF THE INVENTION This invention relates, in general terms, to the use of a vasoactive agent to prevent erectile dysfunction, particularly vasculogenic impotence.

BACKGROUND OF THE INVENTION Impotence is the consistent inability to achieve or sustain an erection of sufficient rigidity for the sexual act. Recently it has been estimated that approximately million American men are impotent (R. Shabsigh et al., "Evaluation of Erectile Impotence," Urology 32: 83-90 (1988); U.L. Furlow, "Prevalence of Impotence in the United States," Med. Flspects Huro. Sex 19; 13-6 (1985)). It is recognized that impotence is a condition dependent on age, with an incidence of 1.9% at 40 years of age and 25% at 65 years of age (fl.C. Kinsey et al., "Age and Sexual O? Tlet"). , "in Sexual Behavior in the Human Male, AC Kinsey et al., eds., Philadelphia, Pennsylvania: W.B. Saunders, 218-262 (1948)). In 1985 in the United States, impotence reached more than several hundred thousand external visits to physicians (National Center for Health Statistics, National Hospital Discharge Survey, 1985, Betheeda, Maryland, Department of Health and Human Services, 1989 DHHS publication No. 87-1751). Depending on the nature and cause of the problem, treatments include psycho-sexual therapy, hormone therapy, administration of vasodilators such as nitroglycerin and a-blockers (a-blockers), oral administration of other pharmaceutical agents, vascular surgery, implanted penile prostheses, Vacuum constriction devices and external aids such as penile splints to support the penis or penile constriction rings to alter the flow of blood through the penis. Several causes of impotence have been identified, including vasculogenic, neurogenic, endocrinological and psychogenic. Also, impotence can be a side effect of different classes of therapeutic drugs, or it can be associated with different diseases, including diabetes, multiple sclerosis and falsiform cell anemia. Impotence that originates from any of these causes can be exacerbated by additional factors such as cigarette smoking, poor diet, or the like. Vasculogenic impotence occurs, either as a result of arterial occlusion - the obstruction of adequate blood flow necessary for erection to the arteries of the penis - or as a result of a cavernovenous leak, that is, excess effusion into the vein. As Krane and others have explained, "Medical Progress: Impotence," The Ne England Journal of Medicine 321 (24) .1628-1639 (1989), it is believed that the alteration in blood flow to and from the penis is the most common organic cause of impotence. The present invention renders erectile dysfunction treatment unnecessary in several cases, since a method that substantially prevents the occurrence of vasculogenic impotence is now provided. The method includes the periodic administration of a vasoactive agent, as will be described below, within the context of a predetermined dosage regimen effective to provide increased blood flow to the penis regularly. The invention additionally relates to equipment that can be used in conjunction with the novel prophylactic method BRIEF DESCRIPTION OF THE INVENTION Therefore, a primary object of the present invention is to handle the need in the art, mentioned above, to provide a novel method to avoid the occurrence of erectile dysfunction. Another object of the invention is to provide a method for preventing erectile dysfunction which includes administering to a patient, within the context of a predetermined dosage regimen, a selected vasoactive agent. Another object of the invention is to provide such a method in which the vasoactive agent is administered transurethrically. Another object of the invention is to provide a method in which erectile dysfunction is vasculogenic impotence. A further object of the invention is to provide a method in which the vasoactive agent is administered in conjunction with a transurethral penetration enhancer. Another object of the invention is to provide equipment that a patient can use to perform the aforementioned method. Objects, advantages and additional novel features of the invention will be set forth in part in the description that follows, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention. In a first aspect of the invention, a vasoactive agent is administered to a patient in the context of a predetermined dosage regimen, when the drug is periodically administered over a period of 24 hours. The drug is preferably administered traneurethrally. It has now been found that the regular administration of said agent, preferably transurethrically, is effective to substantially prevent vasculogenic impotence. Although it is not desired to be bound by theory, it is proposed that the periodic administration of a vasoactive drug, regularly increasing blood flow to the penis, not only prevents arterial occlusion but also avoids the vascular deterioration of the muscle fibers of the vessels and collagen fibers of the cavernous tissue. It has also been found that the administration of vasoactive agents in this manner can be effected at doses that are lower than those that are normally necessary with said drugs, that is, when they are used for their previously known indications. In another aspect of the invention, a device is provided to assist a patient in the administration of the drug. In general terms, the equipment includes the following components: the drug to be administered; a device for administering the drug, for example a transurethral delivery device; a sealed container that houses the drug and the device before use; and written indications for the administration of the drug. The kit may include a means for administering the drug at different doses, or may include different drugs.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a view of separate parts of a modality of the transurethral therapeutic device that can be used in conjunction with the present method.

DETAILED DESCRIPTION OF THE INVENTION Before describing the present invention in detail, it is understood that this invention is not limited to particular drugs or drug delivery systems, since these may vary. It is also understood that the terminology used herein is for the purpose of describing particular modalities only, and is not intended to be limiting. It should be noted that, as used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural references, unless the context clearly dictates otherwise. Thus, for example, the reference to "a vasoactive agent" includes a mixture of two or more such drugs, the reference to "a transurethral penetration enhancer" includes mixtures of two or more enhancers, and the like. In the description and claim of the present invention, the following terminology will be used in accordance with the definitions indicated below. The term "drug" or "pharmacologically active agent", as used herein, means a compound or composition of which, when administered to an organism (human or animal) induces a desired pharmacological and / or physiological effect per action. local and / or general. As indicated above, the pharmacologically active algents used in conjunction with the present invention are vasoactive agents. The terms "transurethral" or "intraurethral" as used to specify the mode of administration of the vasoactive are used interchangeably to refer to the release of the drug in the urethra so that the drug contacts and passes through the wall of the urethra. urethra and enters the bloodstream. With "transdermal" release of drug, the applicant uses the term in its conventional sense, that is, to indicate release of a drug by passing through the skin and into the bloodstream. With "transmucosal" release of drug, the applicant refers to the release of a drug by the passage of a drug through the mucosal tissue into the blood stream. Aspects of the invention that are described in the context of "transurethral" drug release, unless otherwise specified, can also be applied to transdermal or transmucosal release. That is, it should be assumed that the compositions, systems, and methods of the invention, unless explicitly stated otherwise, are equally applicable with any of these three modes of drug delivery. "Increase in penetration", as used herein, refers to an increase in the permeability of the skin or mucosal tissue to the selected pharmacologically active agent, that is, so that the rate at which the drug penetrates to is increased. through the skin or mucous tissue. The "transurethral penetration enhancers" increase the permeability of the urethral wall to the drugs administered as described herein. "Vehicles" or "excipients", as used herein, refer to carriers materials suitable for transurethral administration of drugs, and include any material known in the art, for example, any liquid, gel, solvent, liquid diluent, solubilizer or similar that it is not toxic and that it does not interact with other components of the composition in a harmful way. An "effective" amount of a pharmacologically active drug or agent means a non-toxic but sufficient amount of the drug or agent to provide the desired effect. To carry out the method of the invention, a selected vasoactive agent is periodically administered over a period of 24 hours. Suitable vasoactive agents include, but are not limited to: nitrates such as nitroerin, isosorbide dinitrate, erythrityl tetranitrate, amyl nitrate, sodium nitroprusside, oleidomine, linsidornine hydrochloride ("SIN-1") and S-nitroso- N-acetyl-d, l-penicillamine ("SNAP"); long-acting and short-acting blockers such as phenoxybenzin ina, dibena ina, doxazosin, terazosin, phentolamine, tolazoline, prazosin, trirnazosin, alfuzosin, tamsulosin and indora ina; ergot alkaloids such as ergota ina and ergota ina analogs, for example acetergarnin, brazergoline, brogreide, cyanorgoline, delorgotril, dysulergine, ergonovine maleate, ergotamine tartrate, etisulergine, lergotril, lysergide, esulergine, metergoline, metergota ia , nicergoline, pergolide, propispergide, proterguride and terguride; antihypertensive agents such as diazoxide, hydralazine and minoxidil; vasodilators such as ni odepina, pinacidil, cycllandelate, dipyridamole and isoxsuprine; chloropornazine, haloperidol; yohimbine; trazodone; Naturally occurring prostaglandins such as PGEi, PGAi, PGBi, PGFia, 19-hydroxy-PGAi, 19-hydroxy-PGB? , PGE2, PGA2, PGB2, 19-hydroxy-PGA2, -19-hydroxy-PGB2, PGE3, PGF30; semisynthetic or synthetic derivatives of natural prostaglandins, including carboprost tromethamine, dinoprot tromethamine, dinoproetone, lipoprost, geraeprost, metenoprost, sulprostone and tiaprost; and vasoactive intestinal peptides. Prazosin, prostaglandin Ei and prostaglandin E2 are particularly preferred vasoactive agents to be used in conjunction with the present method. Additionally, simultaneous administration of two or more vasoactive agents may be convenient and may in some cases exhibit a synergistic effect. It has been found that the combination of prazosin with prostaglandin Ei is particularly advantageous to this respect; this last drug seems to act as a penetration enhancer for prozosin, that is, it increases the rate at which prazosin penetrates through the skin or mucosal tissue and enters the bloodstream. The vasoactive agent will typically be administered in a pharmaceutical composition containing one or more selected carriers or excipients, as indicated above. Examples of suitable vehicles for use herein include water, silicone, waxes, petroleum jelly, polyethylene glycol, propylene glycol, liposomes, sugars such as mannitol and lactose, and a variety of other materials. The composition may also include one or more penetration enhancers, i.e., compounds that act to increase the rate at which the selected drug penetrates through the skin or mucosal tissue. Examples of suitable penetration enhancers include dimethyl sulfoxide (DMSO), dimethylformamide (DMF), N, N-dimethylacetamide (DMA), decylmethyl sulfoxide (CioMSO), polyethylene glycol monolaurate (PEGML), glycerol monolaurate, lecithin and the azacycloheptan Substituted 2-Ones, particularly 1-n-dodecylcyclazacycloheptan-2-one (available under the brand name Azone * from Nelson Research to Development Co., Irvine, California), alcohols or the like. The amount of vasoactive agent administered is selected to provide increased blood flow to the penis regularly, so that arterial occlusion is prevented, as well as vascular deterioration of the muscle fibers of the vessels and collagen fibers of the cavernous tissue. Each individual dose is selected, in general, to produce tumescence, that is, penile congestion, but not necessarily rigidity. The appropriate doses of the selected drugs will be apparent to those skilled in the art or may be deduced from the literature in combination with the teaching of the present disclosure. However, it should be noted that the selected drug is preferably administered 2 to 6 times in a 24 hour period. Generally, a lower dose of vasoactive agent will be required than is typically necessary for the usual indication of said drug, that is, as an antihypertensive or similar agent. For example, for prozosin administration of 100 to 400 ug / os, preferably 1 to 10 rng per day, preferably 0.5 to 5 mg per day. For other drugs, 25% to 50% of the daily dosage indicated for use as an antihypertensive agent is generally appropriate. See Physicians / Des Reference *, 48a. Edition, Medical Economics Data Production Company (Montvale, Ne? Jersey, 1994). Transurethral administration of the drug is preferred, although it is not essential. As explained in co-pending patent application No. 07 / 514,397, entitled "Treatment of Erectile Dysfunction" (published internationally as UO91 / 16021), the description of which is incorporated herein by reference, the transurethral administration of a Drug can be carried out in different ways. For example, the drug can be introduced into the urethra from a flexible tube, compressed container, pump or aerosol spray. The drug can also be contained in coatings, pellets or suppositories that are absorbed, fused or biologically eroded in the urethra. In certain embodiments, the drug is included in a coating on the outer surface of a penile insert. A preferred drug delivery device for administering a transurethral drug is shown in Figure 1. In Figure 1, a transurethral drug delivery device in 10 is generally shown. The device comprises a transurethral inserter 11 having a readily graspable segment 12 having symmetrically opposed concave surfaces 13 and 14 adapted to be held by two fingers . The drug is contained within axis 15, which is directed to fit within the urethra. A longitudinal plunger, the tip of which is seen at 16, is slidably insertable into the longitudinal bore contained within the shaft 15. To extrude the drug into the urethra, the shaft 15 is inserted into the urethra, and the tip of the plunger 16 is pushed towards the segment 12. The inserter 11 is then removed. Before being used, and during storage, the device is capped with an elongated lid 17 that fits snugly over the flange 18 at the proximal end of the shaft 15. The lid 17 is provided with a series of parallel ridges 19 to facilitate clamping the lid and removing the inserter 11. Although the configuration shown in Fig. 1 is a preferred configuration, other inserter / container configurations and any mechanism by the which a predetermined amount of drug can be introduced from the inserter to a predetermined depth in the urethra, is suitable for use with this injection. Examples of other such devices are described and illustrated in UO91 / 16021, previously incorporated by reference. The devices can be manufactured either under sterile conditions, thereby eliminating the need for sterilization after manufacture, or they can be manufactured under non-sterile conditions and subsequently sterilized by any suitable technique, for example, radiation sterilization. The devices can be manufactured by methods known in the art, typical for forming and coating plastics, including extrusion molding, heat forming, dip coating, and the like. The vasoactive agent can also be administered topically, transdermally, or by any other available and effective means. Transdermal administration of the drug is well known to those skilled in the art, and includes the release of a pharmaceutical agent by the percutaneous passage of a drug into the general circulation of the patient. See Transder to Drug Delivery: Developmental Issues and Research Initiatives, Hadgraft and Guy (eds.), Marcel Dekker, Inc., (1989); Controlled Drug Delivery: Fundamentals and Applications, Robinson and Lee (eds.), Marcel Dekker Inc., (1987); and Transdermal Delivery of Drugs, Vols. 1-3, Kydonieus and Berner (eds.), CRC Press, (1987). A variety of types of transdermal patches can be used in the method described herein. For example, a simple adhesive patch prepared from a backing material and an acrylate adhesive can be used. The adhesive layer is formulated so that the drug, and any vehicle or speaker to be used, is contained therein. Alternatively, a hydrogel matrix patch in which the drug, water, and typically, hydroxyl polymers are used to form a hydrogel which is then incorporated into a transdermal patch between the backing layer and the adhesive layer can be used. As will be appreciated by those skilled in the art, a variety of other types of patch configurations may also be used, including liquid reservoir patches, foam matrix patches, and the like. See, for example, US Patents. Nos. 3,598,122, 4,649,075 and 5,120,544, the descriptions of which are incorporated herein by reference. Other components can also be incorporated into said transdermal patches. For example, the compositions and / or transdermal patches can be formulated with one or more preservatives or bacteriostatic agents, for example, methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, benzalkonium chloride, or the like. The invention also encompasses equipment for patients to carry out the aforementioned prophylactic method. The kit contains the drug to be administered, a device for administering the drug, preferably transurethrically (eg, as shown in Figure 1), a sealed container housing the drug and the device before use, and written instructions for administer the drug. The kit may include means for administering the drug at different doses, or may include different drugs, or a combination thereof. (That is, if the drug as initially administered is not effective, increasing doses of the drug may be used, or alternative drugs may be administered). Accordingly, the method of the invention provides an effective prophylactic therapy, in which the occurrence of erectile dysfunction, particularly vasculogenic impotence, is substantially prevented in the majority of patients. It should be understood that while the invention has been described in conjunction with the specific preferred embodiments thereof, the foregoing description as well as the following examples are intended to illustrate, and not to limit, the scope of the invention. Other aspects, advantages and modifications within the scope of the invention will be apparent to those skilled in the art to which the invention pertains.

EXAMPLE 1 Patients with a tendency towards vasculogenic impotence, such as patients who have recently undergone radical prostatectomy, are administered 0.3 mg of prazosin hydrochloride every 4 hours for a period of 24 hours. After several days to several weeks, various penile hemodynamic parameters are measured and compared with the evaluation of corresponding parameters prior to drug therapy. These parameters will typically include maximum systolic velocity of the cavernous artery, final diastolic velocity of the cavernous artery, maximal arterial dilation, and pressure. Based on these measurements, a determination is made as to whether penile vascular sufficiency is present. Those skilled in the art will appreciate that any number of devices can be used to carry out the aforementioned measurements, provided that the desired level of accuracy is achieved. Duplex ultrasonography is the preferred method to evaluate the penile hemodynamic parameters of interest. However, other types of techniques and equipment can also be used, for example, NMR spectroscopy, pressure cuffs, cavernous body diagrams, angiography, NPT (nocturnal penile tumescence), "Rigiscans", magnetic resonance imaging (MRI), computer-facilitated tomography (CAT), pulse metrics, and the like. Examples of devices for duplex ultrasonography that can be used in conjunction with the present method include those described in the U.S. Patent. Nos. 4,334,543 per Fehr, 4,485,821 per line and 4,612,937 per Miller, the descriptions of which are incorporated by reference in the present invention. Appropriate devices are available from several manufacturers, including, for example, Advanced Technology Laboratories (Bothell, Washington) and Siemens Quantum (Issaquah, Washington). Based on the hemodynamic parameters measured using the aforementioned ultrasonography technique, a diagnosis can be made regarding penile vascular sufficiency. In general, if the measured PSV is less than about 50 cm / sec, more typically less than about 35 cm / sec, the vascular inflow is insufficient, and a diagnosis of arterial insufficiency can be made. Alternatively, or additionally, if the measured EDV is greater than 0 cm / sec, more typically greater than about cm / sec, a diagnosis of venous leakage can be made. It is expected that after the aforementioned drug therapy, the penile hemodynamic measurements that are carried out will allow to find the penile vascular sufficiency.

EXAMPLE 2 The procedure of Example 1 is repeated, except that the drug is administered every six hours instead of every four hours by adjusting the dose accordingly. The same results are expected substantially.

EXAMPLE 3 The procedure of Example 1 is repeated, except that the drug is administered every eight hours instead of every four hours adjusting the doeis accordingly. The same results are expected substantially.

EXAMPLE 4 The procedure of Example 1 is repeated, except that the drug is administered every twelve hours instead of every four hours by adjusting the dose accordingly. The same results are expected substantially.

EXAMPLE 5 The procedure of Example 1 is repeated, except that the prazoein base is replaced by prazosin hydrochloride. Substantially the same results are expected.

EXAMPLE 6 The procedure of Example 5 is repeated, except that the drug is administered every six hours instead of every four hours by adjusting the dose accordingly. The same results are expected substantially.

EXAMPLE 7 The procedure of Example 5 is repeated, except that the drug is administered every eight hours instead of every four hours adjusting the dose as a correeponde. The results are substantially improved.

EXAMPLE B The procedure of Example 5 is repeated, except that the drug is administered every twelve hours instead of every four hours, adjusting the dose accordingly. The same results are expected substantially.

EXAMPLE 9 The procedure of Example 1 is repeated, except that prostaglandin Ei is replaced by prazosin, at a dose of approximately 3.0 ug / kg of body weight. The same results are expected substantially.

EXAMPLE 10 The procedure of Example 9 is repeated, except that the drug is administered every six hours instead of every four hours by adjusting the dose co or corresponds. The same results are expected substantially.

EXAMPLE 11 The procedure of Example 9 is repeated, except that the drug is administered every eight hours instead of every four hours by adjusting the dose accordingly. Substantially the results are expected1 EXAMPLE 12 The procedure of Example 9 is repeated, except that the drug is administered every twelve hours instead of every four hours by adjusting the dose accordingly. The same results are expected substantially.

EXAMPLE 13 The procedure of Example 1 is repeated, except that prostaglandin E is replaced by prazosin, at a dose of about 5 mg. The same results are expected substantially. EXAMPLE 14 The procedure of Example 13 is repeated, except that the drug is administered every six hours instead of every four hours by adjusting the dose as a correeponde. The same results are expected substantially.

EXAMPLE 15 The procedure of Example 13 is repeated, except that the drug is administered every eight hours instead of every four hours by adjusting the dose accordingly. The same results are expected substantially.

EXAMPLE 16 The procedure of Example 13 is repeated, except that the drug is administered every twelve hours instead of every four hours by adjusting the dose accordingly. The same results are expected substantially.

Claims (20)

NOVELTY OF THE INVENTION CLAIMS

1. The use of a selected vasoactive agent to prepare compositions for preventing erectile dysfunction in a male subject, within the context of an effective dose regimen to provide a regularly increased blood flow to the penis.

2. The use of claim 1, wherein the composition comprising the vasoactive agent is administered transurethrally.

3. The use of claim 2, wherein the dose regimen comprises administering a predetermined dose of the composition comprising the vasoactive agent two to six times in a period of 24 hours.

4. The use of claim 1, wherein the erectile dysfunction is vasculogenic impotence.

5. The use of claim 2, wherein the administration of the composition is carried out by contacting the composition comprising the vasoactive agent with the male urethra at a point between the proximal portion of the navicular fossa and the distal portion. of the hanging urethra, so that the drug enters the bloodstream of the individual through the urethral wall.

6. The use of claim 5, wherein the composition is administered in a dispersant that releases the composition in the urethra at said depth at a weight ratio of the dispersant to the agent of from about 1: 1 to 50: 1, amount of said dose not exceeding the dose that retains the capacity of the urethra.

7. The use of claim 6, wherein the amount of the composition and the dispersant that are administered transurethrally is about 50 mg.

8. The use of claim 2, wherein the prepared composition contains a transurethral permeation enhancer.

9. The use of claim 1, wherein the vaeoactive agent is selected from the group consisting of antihypeedant agents, nitrates, short-acting and long-acting alpha blockers, calcium blockers, ergot alkaloids, clopromazine, haloperidol, yombine, natural and synthetic vasoactive prostaglandins and sue analogues, vasoactive intestinal peptides, dopa ina agonists, opioid antagonists, and combinations thereof.

10. The use of claim 2, wherein the vasoactive agent is selected from the group consisting of antihypertensive agents, nitrates, short-acting and long-acting alpha blockers, calcium blockers, ergot alkaloids, chloropromazine, haloperidol, yombin, natural and synthetic vasoactivae prostaglandins and their analogs, vasoactive intestinal peptides, dopamine agonists, opioid antagonists, and combinations thereof.

11. The use of claim 13, wherein the vasoactive agent is an antihypertensive agent.

12. The use of claim 14, wherein the antihypertensive agent is prazosin.

13. The use of claim 13, wherein the vasoactive agent is prostaglandin Ei.

14. The use of claim 13, wherein the composition simultaneously contains prazosin and prostaglandin Ei.

15. A device for preventing vasculogenic erectile dysfunction in a male individual, comprising: an effective vasoactive agent to increase blood flow to the penis; drug dispensing means for administering the vasoactive agent; a container for housing the agent and the drug dispensing means; and written instructions for using the agent and the drug dispensing means.

16. The kit of claim 18, wherein the vasoactive agent is selected from the group consisting of antihypertensive agents, nitrates, short-acting and long-acting alpha blockers, calcium blockers, ergot alkaloids, chloropromazine, haloperidol , yombine, natural and synthetic vasoactive prostaglandins and their analogs, vasoactive intestinal peptides, dopa agonists, opioid antagonists, and combinations thereof.

17. The kit of claim 19, wherein the vasoactive agent is an antihypertensive agent.

18. The equipment of claim 20, wherein the antihypertensive agent is prazosin.

19. The kit of claim 19, wherein the vasoactive agent is prostaglandin Ei.

20. The kit of claim 19, containing prazosin and prostaglandin Ei.