WO2014080161A1

WO2014080161A1 - Vip and an alpha-adrenergic blocker for use in the treatment of erectile dysfunction post radical prostatectomy

Info

Publication number: WO2014080161A1
Application number: PCT/GB2013/000508
Authority: WO
Inventors: Mike WILLIE
Original assignee: Mens Health Ltd
Priority date: 2012-11-22
Filing date: 2013-11-21
Publication date: 2014-05-30
Also published as: GB201221032D0

Abstract

The present invention provides a method of treating a patient suffering from post radical prostatectomy erectile dysfunction (ED RP), in particular iatrogenic reversible erectile dysfunction post radical prostatectomy, comprising the administration of a therapeutically effective amount of a vasoactive intestinal peptide (VDP) and a therapeutically effective amount of an alpha-adrencrgic blocker. Generally the VIP is in the form of a composition having a pH of from around 6 to around 9.

Description

METHOD OF TREATMENT

The present invention relates to products, compositions, methods and uses which are useful in relation to the treatment of post radical prostatectomy erectile dysfunction (ED RP), in particular iatrogenic reversible erectile dysfunction post radical prostatectomy. According to a further aspect of the present invention, there is provided products, compositions, methods and uses which are useful in relation to the treatment of erectile dysfunction of any origin or cause. BACKGROUND TO THE INVENTION

US 5,447,912 discloses methods and compositions for inducing penile erections, in particular in a male suffering from severe atherosclerosis. The composition disclosed in this document comprise a VIP and/or peptide N-terminal histidine C-terminal methionineamide (PHM) and an alpha-adrenergic blocker.

WO 95/05188 discloses compositions for inducing penile erections comprising a vasoactive intestinal peptide (VIP) and peptide N-terminal histidine C-terminal methionineamide (PHM). Additionally this document discloses a composition VIP or PHM and an alphaadrenergic blocker. There is no suggestion that the erectile dysfunction referred to in this document post radical prostatectomy erectile dysfunction (ED RP). The compositions have a pH of about 2 to about 4.5, generally about 3.

WO 91/04039 discloses the treatment of ED through intracavernosal injection of peptide N- terminal histidine C-terminal methionineamide. Where the ED is caused by artherosclerosis, there is disclosed the administration of a combination of PHM or VIP in combination with an alpha-adrenergic blocker such as phentolamine. There is no disclosure of the treatment of ED caused by radical prostatectomy. There is no teaching of the pH of the composition.

Scientific article "Vasoactive intestinal polypeptide/phentolamine for intracavernosal injection in erectile dysfunction" (BJU International; Vol 102, pp 933 to 937 (2008) (Dinsmore & Wyllie)) discusses the use of a composition comprising 25 g VIP and 2 mg phentolamine mesylate as an intracavernosal therapy in the treatment of erectile dysfunction, in particular moderate to severe ED, including for older patients who may have advanced organic impairment (see page 935, column 2, paragraph 3). There is no teaching or suggestion of the treatment of ED caused by radical prostatectomy procedures.

Scientific article "A pilot study of the role of intracavernous injection of vasoactive intestinal peptide (VIP) and phentolamine mesylate in the treatment of erectile dysfunction" (Int J Impotence Res; Vol 8, pp223-236 (1996)) discusses the use of a composition comprising 25 μg VIP and 2 mg phentolamine mesylate as an intracavernosal therapy in the treatment of erectile dysfunction. There is no teaching or suggestion of the treatment of ED caused by radical prostatectomy procedures. Radical prostatectomy (RP) is an appropriate and potentially curative option for patients with prostate cancer where the likelihood is high that the cancer is confined to the gland and where the predicted lifespan of the patient is ten years or more. However, RP carries with it a high risk of complications. Foremost amongst these, a profound degree of sexual dysfunction almost invariably affects patients following surgery. Erectile dysfunction and reduced penile size are associated with physical and mental discomfort during sexual intimacy, less sexual enjoyment, and the perception of diminished masculinity.

Because of the rising trend in recent years to screen for prostate cancer, patients with the disease are increasingly youthful at the time of initial diagnosis. In 2005 almost 25% of prostate cancers were first diagnosed in men aged less than 60 years. For the same reason, prostate cancers at the time of discovery are increasingly early stage. In patients such as these, with asymptomatic, clinically localised disease, continuing good quality of life is of particular importance. Erectile dysfunction post radical prostatectomy (ED RP) is a distinct condition, limited to a clearly identifiable subset of patients, and different on clinical and pathological grounds from erectile dysfunction that occurs in the wider patient population. Erectile dysfunction in the broader population may have many systemic causes, including cardiovascular disease, drugs, diabetes and other endocrine conditions. In contrast, ED RP results directly from local surgical intervention. Recent literature reports detail the tight temporal relationship of ED RP to surgery (8-10). It is acknowledged in the literature that there is a significant risk of ED RP where peri-procedural damage occurs to the neurovascular bundles that supply the penis. These bundles pass so close to the prostate that elements are incorporated into the layers of fascia that enclose the gland. The plexus of nerve fibres, veins, arteries and adipose tissue that together comprise the neurovascular bundles varies considerably in its anatomical disposition from patient to patient. Inadvertent surgical damage to the bundles may therefore occur more easily. Secondly, because the tumour may invade more extensively than first appreciated, and because positive surgical margins are predictive of tumour recurrence, the surgeon may elect during the course of the operation to sacrifice a portion of the neurovascular bundles. Recent publications confirm that a direct and proportionate relationship exists between the extent of neurovascular preservation and the risk of ED-RP (1, 14 to 17). Attempts to improve ED RP outcomes b reconstructing sacrificed cavernous nerve using sural nerve grafting have proved unsuccessful (18).

Where a patient is suffering from ED RP, penile tissue becomes unresponsive to oral ED treatments including phosphodiesterase type 5 inhibitors (PDE5i's) such as Viagra^® Oral PDE5i's cannot modulate local blood flow if nerve-dependent generation of nitric oxide is compromised. As a result, PDE5i's fail to induce penile engorgement and erection in most patients with early stage ED RP.

Intracavernosal injections of alprostadil are known in the treatment of ED. However, this is painful and is associated with important and serious treatment limiting adverse events, including priapism. The risk-benefit ration of such treatment is generally considered to be unacceptable.

There is currently, no approved treatment options exist for ED RP.

STATEMENT OF INVENTION

According to a first aspect of the present invention there is provided a method of treating a patient suffering from post radical prostatectomy erectile dysfunction (ED RP), in particular iatrogenic reversible erectile dysfunction post radical prostatectomy, comprising the administration in a therapeutically effective amount of a physiological mediator of penile erection, generally a vasoactive intestinal peptide (VIP) and an alpha-adrenergic blocker.

Typically the method involves the sequential or combined administration in a therapeutically effective amount of a VIP and an alpha-adrenergic blocker, suitably phentolamine or phentolamine mesylate. According to a further aspect of the present invention there is provided a VIP and an alpha- adrenergic blocker for use in the treatment of post radical prostatectomy erectile dysfunction (ED RP), in particular iatrogenic reversible erectile dysfunction post radical prostatectomy. There is also provided, a pharmaceutical product comprising at least a VIP and an alpha- adrenergic blocker for use in the treatment of post radical prostatectomy erectile dysfunction (ED RP), in particular iatrogenic reversible erectile dysfunction post radical prostatectomy.

According to a further aspect of the present invention there is provided the use of a VIP and an alpha-adrenergic blocker in the manufacture of a medicament for the treatment of post radical prostatectomy erectile dysfunction (ED RP).

According to one aspect of the present invention, the VIP is in the form of a composition having a pH of 5.5 or more, generally of from around 6 to around 9; suitably from around 6.5 to around 9; typically from around 7 to around 9.

According to a further aspect of the present invention there is provided a composition comprising at least a VIP and an alpha-adrenergic blocker, wherein the pH of the composition is neutral to alkali, typically wherein the pH is above around 5.5, generally wherein the pH is between around 6 and around 9. According to one embodiment, the composition has an associated pH of from around 6.5 to around 9; typically from around 7 to around 9.

According to a further aspect of the present invention there is provided a method of treating a patient suffering from erectile dysfunction comprising the administration of the composition or compositions as described herein in a therapeutically effective amount.

According to a further aspect of the present invention there is provided the composition or compositions described herein for use in the treatment of erectile dysfunction.

According to a further aspect of the present invention there is provided the use of the composition or compositions described herein in the manufacture of a medicament for the treatment of erectile dysfunction. According to one embodiment, the method or use involves the administration of one or more of testosterone and a PDE5i compound.

According to one embodiment, the pharmaceutical product comprises one or more of testosterone and a PDE5i compound.

According to a further aspect of the present invention, there is provided a kit of parts for use in the treatment of post radical prostatectomy erectile dysfunction (ED RP), in particular iatrogenic erectile dysfunction post radical prostatectomy, said kit of parts comprising a VIP, an alpha-adrenergic blocker and an injecting device, typically a syringe. The kit of parts may include one or more of testosterone and a PDE5i compound.

Definitions

The term "reversible" within the context of post radical prostatectomy erectile dysfunction is meant to refer to a condition wherein the cavernosal nerves have not been severed or resected by the surgeon during the radical prostatectomy surgery.

A PDE5i compound is used to refer to a phosphodiesterase type 5 inhibitor. Such compounds block the degradative action of phosphodiesterase typ 5 on cyclic GMP in the smooth muscle cells lining blood vessels. Such compounds are known in the treatment of erectile dysfunction.

By an "effective" amount or "therapeutically effective amount" is meant an amount of one or more active substances which, within the scope of sound medical judgment, is sufficient to provide a desired effect without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

All numerical values provided incorporate 10% less than and 10% more than the numerical value provided.

Method of Treatment

According to a first aspect of the present invention there is provided a method of treating a patient suffering from post radical prostatectomy erectile dysfunction (ED RP), in particular iatrogenic reversible erectile dysfunction post radical prostatectomy, comprising the administration of a therapeutically effective amount of a vasoactive intestinal peptide (VIP) and a therapeutically effective amount of an alpha-adrenergic blocker.

ED RP is a surgically induced condition that affects the great majority of men who have recently undergone surgery for prostate cancer. ED RP represents a narrow, distinct subset of the general condition of erectile dysfunction. ED RP results directly from surgical intervention and this contrasts with the broader population of men with predominantly organic ED where systemic cardiovascular, metabolic and endocrine causes prevail. Many patients with ED RP show a profound degree of sexual dysfunction after surgery, yet a gradual but progressive improvement of the disorder during the months that follow. In general, the majority of men suffering from ED RP experience some lessening in symptoms 1 year from surgery. This represents an additional important aspect in which ED RP patients differ from the general ED patient population. In the general population, loss of sexual function for organic reasons is irreversible. For an unselected mix of patients undergoing surgery during the 1990s, only 20% or so of patients had recovered sexual potency at 1 to 2 years after surgery (Hu JC et al. Predicting quality of life after radical prostatectomy: results from CaPSURE. J Urol 2004: 171: 703-8). In contrast, recent surgical series and comparative trials of advanced nerve-sparing techniques indicate that substantial recovery of sexual function may occur within the first 6 months post RP in patients with good prognostic indicators (Rogers CG et al. Age Stratified functional outcomes after laparascopic radical prostatectomy. J Urol 2006; 176:2448-52) (Haffner MC et al. Health related quality of life outcomes afteranatomic retropubic radical prostatectomy in the phosphodiesterase type 5 era: impact of neurovascular bundle preservation. Urology 2005: 66: 371-6) (Litwin MS et al. Quality of life after surgery, external beam irradiation, or brachytherapy for early stage prostate cancer. Cancer 2007; 109: 2239-47).

Possible treatments of ED RP are greatly restricted; in particular patients suffering from ED RP are unresponsive to oral ED treatment such as PDE5i's. The sooner ED RP is treated, the better the long term medical prognosis. However, the effectiveness of such oral therapies is particularly poor during the first few months immediately following surgery. This is of particular relevance as it has been found that prompt initiation of RP ED following prostate surgery may improve ultimate recovery of sexual function. As such, clear clinical and pathological differences distinguish patients with ED RP from the general population of patients with ED. Patients suffering from ED RP represent a medically plausible subset of the population of patients suffering from ED. ED RP represents a distinct and unambiguous patient subset.

It should be noted that ED RP is not by caused or associated with atherosclerosis.

Generally the ED RP condition to be treated is reversible. According to a further embodiment, the ED RP condition to be treated is irreversible.

The method of treatment induces a penile response, generally inducing a penile erection sufficient for vaginal penetration. The method of the present invention involves the administration of a therapeutically effective amount of a vasoactive intestinal peptide (VIP) and a therapeutically effective amount of an alpha-adrenergic blocker.

The active agents may be administered simultaneously or sequentially. According to one embodiment, the active agents are administered simultaneously.

Typically the method of the present invention involves the administration of a composition comprising a therapeutically effective amount of a vasoactive intestinal peptide (VIP) and a therapeutically effective amount of an alpha-adrenergic blocker.

According to one embodiment, the method of the present invention is used to treat a patient within 6 months of radical prostatectomy surgery. As noted above, the sooner ED RP is treated, the better the long term medical prognosis. Suitably the method of the present invention is used to treat patients within 4 months of radical prostatectomy surgery, typically within 3 months, occasionally within two months of radical prostatectomy surgery.

According to a further aspect of the present invention there is provided a method of treating a patient suffering from erectile dysfunction comprising the administration of a composition in a therapeutically effective amount, said composition comprising at least a VIP and an alpha- adrenergic blocker, wherein the pH of the composition is neutral to alkali, typically wherein the pH is above around 5.5, generally wherein the pH is between around 6 and around 9. According to one embodiment, the composition has an associated pH of from around 6.5 to around 9; typically from around 7 to around 9.

In such embodiments, the erectile dysfunction may have any cause or origin including neurogenic, psychogenic, arteriogenic, atherosclerotic, drug or medication induced. The ED may be a side effect of a medical condition including diabetes, depression and anxiety. According to one embodiment, the ED is ED-RP.

The composition is generally suitable for intracavernosal injection.

The active agents may be administered to the patient by injection to or around the penis, generally by intracavernosal injection.

The total volume administered is generally 0.1 to 0.5 ml.

The method generally involves the administration of 10 to 25 μg of VIP and 200 μg to 2 mg of alpha adrenergic blocker.

The active agents may be administered simultaneously or sequentially. Where the active agents are administered sequentially, the administration of all of the active agents is generally within 10 minutes, typically within 5 minutes. Where the active agents are administered sequentially, generally the VIP composition has been buffered to a pH of above 5, typically 6 to 9. According to one embodiment, the composition has an associated pH of from around 6.5 to around 9; typically from around 7 to around 9. According to one embodiment, the composition comprising the alpha-adrenergic blocker has been buffered to a pH of above 5, typically 6 to 9. According to one embodiment, the composition has an associated pH of from around 6.5 to around 9; typically from around 7 to around 9. According to one embodiment, the method may include the administration of further active agents. Such administration may be simultaneous or sequential. Suitable active agents include testosterone and or a PDE5L In one embodiment, the method may include use of a vacuum erection device.

During and/or following administration of the active agents, the penis is generally constricted at its base. The method may include the steps of administering the active agents, during or prior to sexual stimulation.

Typically, within 1 to 15 minutes of administration of the active agents, an erectile response is induced. Generally, the erectile response is sufficient for vaginal penetration.

The method of the present invention may be undertaken whenever required. The active agents may be administered up to three times daily.

The duration of the course of treatment depends on the severity of the condition to be treated. In particular, the extent of the damage to the neurovascular bundles that supply the penis.

Where the damage to the neurovascular bundles is moderate and the ED RP is reversible, a course of treatment will generally last up to six months. However this can be extended where required. Typically a course of treatment has a duration of 3 to 6 months.

According to one embodiment, the patient will undergo a single course of treatment of 3 to 6 months in any one year.

Where the ED is moderate, for example where the patient has suffered from the ED condition for 6 months to a year, the patient may undergo a course of treatment lasting 1 to 3 months. This course of treatment may be repeatable if the patient presents again with symptoms of an ED condition. Where the damage to the neurovascular bundles is severe, including cases where the ED RP may be irreversible, the course of treatment may be ongoing, generally lasting up to several years. Where the ED is severe, for example where the patient has suffered from the ED condition for more than 18 months, the patient may undergo a course of treatment lasting up to several years.

According to one embodiment, the method of treatment is initiated within 6 months (generally 3 months) of radical prostatectomy surgery and the duration of the course of treatment is 3 to 6 months.

The patient is generally a human male although in some embodiments, an animal may be treated.

Products

Peptides are generally considered to be more stable in acidic solution that in alkali solution. The potential degradation pathways for peptides in alkali solution include base catalysed deamidation and base catalysed racemisation. In addition, oxidation of peptides is generally accelerated at higher pH. Surprisingly the composition of the present invention is more stable at neutral or alkali pH than at acidic pH. According to a further aspect of the present invention there is provided a composition comprising at least a VIP, an alpha-adrenergic blocker and one or more of testosterone and a PDE5i compound. Generally the composition comprises a VIP, an alpha-adrenergic blocker, testosterone and a PDE5i compound.

According to one embodiment, the method of the present invention involves the administration of a therapeutically effective amount of a vasoactive intestinal peptide (VIP) and a therapeutically effective amount of an alpha-adrenergic blocker.

The VIP is generally in the form of a composition having a pH of above around 5.5, generally wherein the pH is between around 6 and around 9. According to one embodiment, the composition has an associated pH of from around 6.5 to around 9; typically from around 7 to around 9.

As noted above, ED RP is a medically plausible subset of erectile dysfunction. Patients with the iatrogenic form only respond well to locally administered agents and do not require long term treatment unless extensive nerve resection was performed and/or erectile function was already seriously impaired prior to surgery.

Men who undergo radical prostatectomy have no well studied or approved treatment options for this "life limiting" post operative condition.

VIP is an endogenous non-adrenergic non-cholinergic peptide neurotransmitter. It is a physiological mediator of penile erection. The VIP may have the formula C₁₄₇H₂3₇N₄₃0₄₃S (Aviptadil). According to one embodiment, VIP is administered in a dosage range of 1 to 60

The alpha adrenergic blocker is generally phentolamine mesylate or phentolamine. The alpha adrenergic blocker acts to increase arterial blood flow to the penis. According to one embodiment, the alpha adrenergic blocker is administered in a dosage range of 100 μg to 5 mg.

The ratio of the VIP to alpha-adrenergic blocker administered according to the invention may be at least 1:4 for example at least 1:6 or 1:8. Preferably the alpha-adrenergic blocker is phentolamine mesylate or phentolamine and the ratio of VIP to alpha-adrenergic blocker is 1:4 to 1:8. Generally the composition comprises 1 to 50 μg VIP, typically 5 to 30 μg VIP, suitably 10 to 25 μg VIP.

The composition typically comprises 100 μg to 5 mg phentolamine or phentolamine mesylate, generally 200 μg to 3 mg phentolamine or phentolamine mesylate, suitably 200 g to 2 mg phentolamine or phentolamine mesylate. The composition may comprise 0.4 mg, 1 mg or 2 mg phentolamine or phentolamine mesylate.

According to one embodiment the composition comprises 25 μg VIP and 1 to 2 mg phentolamine or phentolamine mesylate.

Generally the ratio of VIP to alpha-adrenergic blocker is 1:4 to 1:8 in the product of the invention. According to one embodiment, the composition may comprise testosterone. The composition generally comprises 10 to 100 mg testosterone.

Alternatively or additionally, the composition may comprise one or more PDE5i compounds such as sildenafil, avanafil, lodenafil, mirodenafil, tadalafil, vardenafil, udenafil and zaprinast.

According to one embodiment, the composition of the present invention comprises 10 to 100 mg PDE5i compound. The method of the present invention may include administering 0.1 to 0.5 ml of composition per administration.

The composition generally has a pH of 2 to 5.5. The action associated with the composition for use in the present invention is generally independent of neuronal nitric oxide release and the generation of intracellular cGMP.

The abovementioned active agents may be administered as free or fixed combinations. Free combinations may be provided as combination packages containing all the active agents in free combinations. Fixed combinations are often injectable compositions, in particular compositions suitable for intracavernosal injection.

Generally, the active agents are administered as a fixed dose combination comprising VIP and an alpha-adrenergic blocker.

The active agents may be administered simultaneously, sequentially or separately. The active agents may be provided as a combination package. The combination package may contain the product of the invention together with instructions for simultaneous, separate or sequential administration of each of the active agents. For sequential administration, the active agents can be administered in any order.

Where the active agents are administered sequentially or separately, the VIP is generally in the form of a composition having an associated pH of more than 5.5, typically from about 6 to about 9. According to one embodiment, the composition has an associated pH of from around 6.5 to around 9; typically from around 7 to around 9.

Where the active agents are administered sequentially or separately each active agent may be in the form of a composition having an associated pH of more than 5.5, typically from about 6 to about 9. According to one embodiment, the composition has an associated pH of from around 6.5 to around 9; typically from around 7 to around 9.

The active agents of the product of the invention may be provided as pharmaceutical compositions additionally containing one or more pharmaceutically acceptable diluents, excipients and/or carriers. This applies to both fixed and free combinations.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, and/or compositions which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings or, as the case may be, an animal without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Such carriers are well known in the art and include buffers, fillers, extenders, binding agents, moisturizing agents, disintegrating agents, resorption accelerators, surface active agents, adsorptive carriers, lubricants and preservatives. The product of the invention is generally in the form of a liquid suitable for subcutaneous injection. Particular mention may be made of suspensions and solutions.

According to one embodiment, the composition is a solution. Solutions in aqueous propylene glycol can be employed, as well as sterile aqueous solutions of the corresponding water- soluble salts. Such aqueous solutions may be suitably buffered, if necessary, and the liquid diluent first rendered isotonic with sufficient saline or glucose. In this connection, the sterile aqueous media employed are all readily obtainable by standard techniques well-known to those skilled in the art.

According to one embodiment the composition is buffered to a pH of from about 6 to about 9. Generally the composition is in the form of a buffered aqueous solution. The amount of therapeutically active compound that is administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age and weight of the subject, the severity of the erectile dysfunction condition to be treated, the frequency of administration, and the particular compounds employed, as well as the pharmacokinetic properties of the individual treated, and thus may vary widely. One of skill in the art will appreciate that the dosage regime or therapeutically effective amount of the active agents to be administrated may need to be optimized for each individual. The pharmaceutical compositions may contain active ingredients in the range of about 0.01 to 200 mg, preferably in the range of about 0.05 to 50 mg and most preferably between about 1 and 5 mg. A daily dose of about 0.01 to 1 mg/kg body weight, preferably between about 0.01 and about 0.5 mg/kg body weight and most preferably from about 0.01 to 0.2 mg/kg body weight, may be appropriate. The product of the present invention may be administered when an erectile response is required, up to three doses per day. The agents of the invention may be administered in the form of pharmaceutically acceptable salts. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., US, 1985, p. 1418, the disclosure of which is hereby incorporated by reference; see also Stahl et al, Eds, "Handbook of Pharmaceutical Salts Properties Selection and Use ", Verlag Helvetica Chimica Acta and Wiley-VCH, 2002. The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings or, as the case may be, an animal without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The invention thus includes pharmaceutically-acceptable salts of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof for example the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases. Examples of such acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate. Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth. Also, the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others. The active agents mentioned in this specification can exist in different forms, such as free acids, free bases, esters and other prodrugs, salts and tautomers, for example, and the invention includes all variant forms of the agents. Medical Use

According to a further aspect of the present invention there is provided a VIP and an alpha- adrenergic blocker for use in the treatment of post radical prostatectomy erectile dysfunction (ED RP), in particular iatrogenic reversible erectile dysfunction post radical prostatectomy. According to a further aspect of the present invention there is provided the composition described herein for use in the treatment of erectile dysfunction wherein the pH of the composition is neutral to alkali, typically wherein the pH is above around 5.5, generally wherein the pH is between around 6 and around 9. According to one embodiment, the composition has an associated pH of from around 6.5 to around 9; typically from around 7 to around 9.

Generally the VIP and the alpha-adrenergic blocker are as described above. Typically the active agents are in the form of a composition as described above. There is also provided, a pharmaceutical product comprising at least a VIP and an alpha- adrenergic blocker for use in the treatment of post radical prostatectomy erectile dysfunction (ED RP), in particular iatrogenic reversible erectile dysfunction post radical prostatectomy.

According to a further aspect of the present invention there is provided a pharmaceutical product comprising at least a VIP and an alpha-adrenergic blocker for use in the treatment of erectile dysfunction wherein the pH of the composition is neutral to alkali, typically wherein the pH is above around 5.5, generally wherein the pH is between around 6 and around 9. According to one embodiment, the composition has an associated pH of from around 6.5 to around 9; typically from around 7 to around 9.

As described above, the composition is generally suitable for intracavernosal injection.

Kit of Parts

According to a further aspect of the present invention, there is provided a kit of parts for use in the treatment of post radical prostatectomy erectile dysfunction (ED RP), in particular iatrogenic erectile dysfunction post radical prostatectomy, said kit of parts comprising a VIP, an alpha-adrenergic blocker and an injecting device, generally a syringe. According to a further aspect of the present invention, there is provided a kit of parts for use in the treatment of erectile dysfunction, said kit of parts comprising a VIP at a pH of from 6 to 9, an alpha-adrenergic blocker and an injecting device, generally a syringe.

According to a further aspect of the present invention, there is provided a kit of parts for use in the treatment of erectile dysfunction, said kit of parts comprising a VIP, an alpha- adrenergic blocker and one or more of testosterone and a PDE5i compound and an injecting device, generally a syringe.

The kit of parts may comprise the active agents in dosage units containing a particular amount of the active agent, for example, one or more ampoules or capsules. The dosage units may comprise one or more of the active agents.

Generally the kit includes instructions for use, for example the nature of administration. As described above, men afflicted by erectile dysfunction following radical prostatectomy form a distinct and unambiguous patient subset. The surgery that they have undergone clearly identifies them. Unlike the broader population of men with erectile dysfunction, the disorder of ED RP is most commonly caused by peri-surgical neuropraxia and thus is likely to improve with time. Nevertheless, treatment of ED RP in the immediate post-operative period (generally up to three months from surgery) is difficult. Generally oral treatments such as PDE5i's are ineffective. The methods and compositions of the present invention provide an effective, valuable therapeutic option to this commonly occurring problem - more than 50% of men who undergo radical prostatectomy surgery will suffer from ED RP. The severity of ED RP generally lessens in time resulting in the recovery of a spontaneous erectile function. However, the methods and compositions of the present invention provide an important therapeutic treatment until this time. In addition, the sooner the treatment of ED RP commences, the better the long term prognosis. Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith.

Throughout the description and claims of this specification, the words "comprise" and "contain" and variations of the words, for example "comprising" and "comprises", mean "including but not limited to", and are not intended to (and do not) exclude other moieties, additives, components, integers or steps. All documents referred to herein are incorporated by reference.

Further aspects and embodiments of the invention are set forth in the following description and claims. The present invention is further described by way of example only with reference to the accompanying Figures in which:

Figure 1 provides a graph showing the various treatments available for prostate cancer cases and prevalence of each treatment as recorded by the NCDB (2005).

Example 1

Experiments relating to the present invention are in the process of being conducted. In these experiments, the efficacy of compositions comprising the VIP aviptadil and phentolamine or phentolamine mesylate was tested in the treatment of erectile dysfunction. The composition is in the form of an aqueous buffered solution comprising 25 μg VIP and lmg or 2 mg phentolamine or phentolamine mesylate. 0.1 to 0.5 ml of the composition is administered via intracarvernosal injection. The patients have undergone a radical prostatectomy procedure within 6 months and the course of treatment will last 3 to 6 months. The clinical efficacy is assessed within standard intracavernosal injection protocols and data capture using validated endpoints.

The results currently generated from these experiments indicate that the composition is effective in the treatment of ED RP. Moreover, the results generated show that the composition tested is effective in situations even where patients have failed prior oral PDEi therapy or alternative intracavernosal therapy, particularly alprostadil.

Example 2

The stability of compositions comprising the VIP aviptadil and phentolamine or phentolamine mesylate was tested at different pH. The composition is in the form of an aqueous buffered solution comprising 25 g VIP and 2 mg phentolamine mesylate. The percentage degradation of the VIP aviptadil was tested after 30 days storage of the composition at standard room temperature and pressure. The results are summarized below in Table X.

Surprisingly it was found that the stability of the VIP component of the composition increased at pH of from around 6 to 9. In general, the stability of peptides decreases with increasing pH and this effect was unexpected. Various modifications and variations of the described aspects of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes of carrying out the invention which are obvious to those skilled in the relevant fields are intended to be within the scope of the following claims.

Claims

1. A method of treating a patient suffering from post radical prostatectomy erectile dysfunction (ED RP), in particular iatrogenic reversible erectile dysfunction post radical prostatectomy, comprising the administration of a therapeutically effective amount of a vasoactive intestinal peptide (VIP) and a therapeutically effective amount of an alpha-adrenergic blocker.

2. The method as claimed in claim 1 wherein the VIP is buffered to a pH of from around 6 to around 9, generally from 6.5 to 9, suitably from 7 to 9.

3. The method as claimed in either one of claims 1 and 2 wherein the VIP and alpha- adrenergic blocker are administered simultaneously.

4. A method of treating a patient suffering from erectile dysfunction, comprising the administration of a therapeutically effective amount of a vasoactive intestinal peptide (VIP) and a therapeutically effective amount of an alpha-adrenergic blocker, wherein the VIP is buffered to a pH of from about 6 to about 9, generally from 6.5 to 9, suitably from 7 to 9.

5. The method as claimed in any preceding claim wherein the VIP and alpha-adrenergic blocker are administered via injection, generally intracavernosal injection.

6. The method as claimed in claim 1 wherein the method of treatment is initiated within 6 months (generally 3 months) of radical prostatectomy surgery and the duration of the course of treatment is 3 to 6 months.

7. The method as claimed in any preceding claim wherein the alpha adrenergic blocker is phentolamine mesylate or phentolamine.

8. The method as claimed in any preceding claim wherein 100 μg to 5 mg, generally 200 g to 2 mg, of the alpha adrenergic blocker is administered per dose.

9. The method as claimed in any preceding claim wherein 5 to 30 μg VIP, suitably 10 to 25 μg VIP is administered per dose.

10. The method as claimed in any preceding claim including the step of administering a composition comprising 25 μg VIP and 1 to 2 mg phentolamine or phentolamine mesylate.

11. The method as claimed in claim 10 wherein 0.1 to 0.5 ml of the composition is administered per dose.

12. The method as claimed in either one of claims 10 and 11 wherein the composition is in the form of a buffered aqueous solution.

13. The method as claimed in any preceding claim comprising the administration of a therapeutically effective amount of one or more of testosterone and a PDE5i compound.

14. The method as claimed in any preceding claim comprising the administration of a therapeutically effective amount of testosterone and a PDE5i compound.

15. A composition comprising at least a VIP and an alpha-adrenergic blocker, wherein the pH of the composition is neutral to alkali, typically wherein the pH is above around 5.5, generally wherein the pH is between around 6 and around 9, typically from 6.5 to 9, suitably from 7 to 9.

16. A composition comprising at least a VIP, an alpha-adrenergic blocker, and one or more of testosterone and a PDE5i compound.

17. A composition as claimed in either one of claims 15 and 16 for use in the treatment of erectile dysfunction.

18. A VIP and an alpha-adrenergic blocker for use in the treatment of post radical prostatectomy erectile dysfunction (ED RP), in particular iatrogenic reversible erectile dysfunction post radical prostatectomy.

19. A pharmaceutical product comprising at least a VIP and an alpha-adrenergic blocker for use in the treatment of post radical prostatectomy erectile dysfunction (ED RP), in particular iatrogenic reversible erectile dysfunction post radical prostatectomy.

20. A kit of parts for use in the treatment of post radical prostatectomy erectile dysfunction (ED RP), in particular iatrogenic erectile dysfunction post radical prostatectomy, said kit of parts comprising a VIP, an alpha-adrenergic blocker and an injecting device, generally a syringe.

21. A kit of parts for use in the treatment of erectile dysfunction, said kit of parts comprising a VIP at a pH of from 6 to 9, an alpha-adrenergic blocker and an injecting device, generally a syringe.

22. A kit of parts for use in the treatment of erectile dysfunction, said kit of parts comprising a VIP, an alpha-adrenergic blocker and one or more of testosterone and a PDE5i compound and an injecting device, generally a syringe.