WO2004022064A1 - Procedes de traitement des troubles de l'erection chez l'homme - Google Patents

Procedes de traitement des troubles de l'erection chez l'homme Download PDF

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Publication number
WO2004022064A1
WO2004022064A1 PCT/US2003/027885 US0327885W WO2004022064A1 WO 2004022064 A1 WO2004022064 A1 WO 2004022064A1 US 0327885 W US0327885 W US 0327885W WO 2004022064 A1 WO2004022064 A1 WO 2004022064A1
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WIPO (PCT)
Prior art keywords
composition
accordance
prostaglandin
group
patient
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PCT/US2003/027885
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English (en)
Inventor
James L. Yeager
Nadir Büyüktimkin
Servet Büyüktimkin
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Nexmed (Holdings), Inc.
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Priority claimed from US10/236,485 external-priority patent/US7105571B2/en
Application filed by Nexmed (Holdings), Inc. filed Critical Nexmed (Holdings), Inc.
Priority to EA200500452A priority Critical patent/EA200500452A1/ru
Priority to EP03755790A priority patent/EP1534297A1/fr
Priority to JP2004534659A priority patent/JP2006512291A/ja
Priority to CA002493723A priority patent/CA2493723A1/fr
Priority to AU2003273291A priority patent/AU2003273291A1/en
Publication of WO2004022064A1 publication Critical patent/WO2004022064A1/fr
Priority to IL16627305A priority patent/IL166273A0/xx
Priority to NO20050658A priority patent/NO20050658L/no

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence

Definitions

  • This invention relates to the methods for treatment of erectile dysfunction in patients suffering from a co-morbid condition.
  • impotence has been used to signify the inability of the male to attain and maintain erection of the penis sufficient to permit satisfactory sexual intercourse.
  • erectile dysfunction has been suggested as a more precise term “to signify an inability of the male to achieve an erect penis as part of the overall multifaceted process of male sexual function.” Droller, M. J. et al. Impotence.
  • Erectile dysfunction may result from psychological causes (psychogenic erectile dysfunction) or organic causes or a combination of both.
  • Organic causes include physiological, nervous, vascular and hormonal pathologies or a combination thereof.
  • the normal physiology of an erection involves nerve impulses that signal certain muscles to relax. These muscles, when contracted, restrict blood flow through arteries in the penis. When relaxed, the muscles permit a significant increase in blood flow. The increased blood flow engorges three groups of erectile tissue within the penis with blood and the penis becomes less flaccid. The engorged erectile tissue and the muscle structure of the penis depress adjacent veins, restricting the flow of blood out of the penis. The restriction of blood flow out of the penis increases and sustains the erection.
  • Deficiencies of some hormones can cause erectile dysfunction.
  • Many drugs such diuretics, antihypertensives, anticonvulsants, narcotics, alcohol, and psychotropic drugs may cause erectile dysfunction as a side effect.
  • Damage to nerves and blood vessels may also provide an organic cause for erectile dysfunction.
  • Disease processes may involve several aspects. For example, diabetes, which causes damage to both nerves and blood vessels, can cause erectile dysfunction. A significant percent of all diabetic men will suffer from erectile dysfunction.
  • ED erectile dysfunction
  • ED in diabetes may be one aspect of vascular disease associated with diabetes (Sairam, K., et al., Prevalence of undiagnosed diabetes mellitus in male erectile dysfunction. BJU Int. 2001 88(1):68-71; Sullivan, M.E., et al. Nitric oxide and penile erection: is erectile dysfunction another manifestation of vascular disease? Cardiovasc Res. 1999 Aug 15;43(3):658-65)
  • Microvasculopathy is one of the characteristics of diabetes. Studies have suggested a link between diabetes, erectile dysfunction and endothelial cell dysfunction (De Angelis, L., et al., Erectile and endothelial dysfunction in Type LT diabetes: a possible link. Diabetologia. 2001 44(9): 1155-60; Burchardt, T., et al., Reduction of endothelial and smooth muscle density in the corpora cavemosa of the streptozotocin induced diabetic rat. J Urol. 2000 164(5): 1807-11; Hopfner, R.L., & Gopalakrishnan, V., Endothelin: emerging role in diabetic vascular complications. Diabetologia.
  • Radical retropubic prostatectomy has been the standard treatment for organ/specimen-confined prostate cancer for several decades, yet erectile dysfunction in selected series is still reported as high as 90% after this procedure, with surgical technique and experience dominant variables influencing outcome (Zippe, C.D.,et al., Management of erectile dysfunction following radical prostatectomy, Current
  • External devices include tourniquets (see U.S. Pat. No. 2,818,855) and externally applied vacuum erection aids. While some clinicians consider externally applied erection aids as a first option for treatment, some patients are unwilling to use such devices. O'Keefe, M., et al. Medical Clinics of North America 79: 415-434 (1995).
  • Surgically implanted mechanical devices such as hinged or solid rods and inflatable, spring driven or hydraulic prostheses have been used for some time.
  • penile prostheses have been described that are pliable plastic elements with constant rigidity. However, these prostheses are continuously rigid and can cause discomfort for the patient.
  • Other types of penile prostheses include surgically positioned pumps for creating high pressure of liquid in the elastic silicon mantle.
  • Implantation of these complex devices requires implanting several components into the patient's body, for example, the reservoir with liquid, pump, several valves, connecting pipes, and the like, in addition to those components implanted directly into the penis.
  • Other penile prostheses use an external source of electricity and a source of an alternating magnetic field changing with the frequency of 50 to 1000 Hz that influences the internal element located in the penis. This element senses the magnetic field and causes liquid in the inner reservoir to move from the reservoir into the elastic mantles located in the corpora cavernosa, and causes the penis to erect.
  • prostheses including a permanent magnet that makes seesaw movements under the influence of this field, which in turn causes liquid from the reservoir to pump into the elastic mantles, thus serving as an internal element sensing alternating magnetic field of the external source.
  • a permanent magnet that makes seesaw movements under the influence of this field, which in turn causes liquid from the reservoir to pump into the elastic mantles, thus serving as an internal element sensing alternating magnetic field of the external source.
  • U.S. Pat. No. 4,801,587 to Voss et al. teaches the application of an ointment to relieve impotence.
  • the ointment consists of the vasodilators papaverine, hydralazine, sodium nitroprusside, phenoxybenzamine, or phentolamine and a carrier to assist absorption of the primary agent through the skin.
  • U.S. Pat. No. 5,256,652 to El-Rashidy teaches the use of an aqueous topical composition of a vasodilator such as papaverine together with hydroxypropyl- ⁇ -cyclodextrin.
  • cGMP-specific PDE cyclic guanosine 3',5'- monophosphate specific phosphodiesterase
  • sildenafil While sildenafil has obtained significant commercial success, it has fallen short due to its significant adverse side effects, including facial flushing (10% incidence rate). Adverse side effects limit the use of sildenafil in patients suffering from visual abnormalities, hypertension, and, most significantly, by individuals who use organic nitrates (Welds et al., Amer. J. of Cardiology, 83 (5 A), pp. 21(C)-28(C) (1999)). The use of sildenafil in patients taking organic nitrates is believed to cause a clinically significant drop in blood pressure which could place the patient in danger.
  • the package label for sildenafil provides strict contraindications against its use in combination with organic nitrates (e.g., nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, erythrityl tetranitrate) and other nitric oxide donors in any form, either regularly or intermittently, because sildenafil potentiates the hypotensive effects of nitrates.
  • organic nitrates e.g., nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, erythrityl tetranitrate
  • other nitric oxide donors in any form, either regularly or intermittently, because sildenafil potentiates the hypotensive effects of nitrates.
  • organic nitrates e.g., nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, erythrityl tetranitrate
  • Prostaglandin Ei is a derivative of prostanoic acid, a 20-carbon atom lipid acid, represented by the formula:
  • alprostadil is administered in a pellet deposited in the urethra using an applicator with a hollow stem 3.2 cm in length and 3.5 mm in diameter (Padma- Nathan, H., et al., N. Engl. J. Med., 336: 1-7 (1997), see especially Fig. 1).
  • MUSE® In the home treatment portion of the Padma-Nathan et al. study, 32.7%> of the patients (10.8%) of administrations) receiving MUSE® complained of penile pain and 5.1% experienced minor urethral trauma, compared to 3.3%> and 1.0%, respectively, of the patients receiving placebo.
  • MUSE® producing penile pain in 17-23.6% of administrations, compared to 1.7% with placebo and minor urethral bleeding reported by 4.8% of patients
  • Peterson, CA., et al., J. Urol., 159: 1523-1528 (1998) In a study on a European population, 31% MUSE® patients reporting penile pain or burning sensations, 4.8% reporting urethral bleeding, and 2.9% reporting severe testicular pain (Porst, H., Int. J. Impot. Res., 9:187-192 (1997)).
  • Intraurethral application of a preparation of 1 mg prostaglandin Ei in phosphatidylcholine liposomes in 1 ml polyoxyethylene glycol has been reported to be less effective than intracavemosal injection of prostaglandin Ei (Englehardt, P.F., et al., British J. Urology, 81: 441-444, 1998).
  • No ED patients receiving the liposomal preparation achieved complete penile rigidity, and only 6 of 25 patients achieved an erection adequate for vaginal penetration.
  • intracavemosal injection of prostaglandin E ⁇ produced erections adequate for vaginal penetration or complete rigidity in 23 of 25 of the same ED patients.
  • the authors suggested that the transurethral effect of the prostaglandin Ei probably arises by diffusion of prostaglandin Ei first into the corpus spongiosum and then into the corpus cavemosum.
  • the invention provides pharmaceutical methods for the treatment of erectile dysfunction in a patient suffering from at a co-morbid condition comprising placing in thefossa navicularis of a patient in need of such treatment an erection-inducing amount of a semi-solid composition comprising a vasoactive prostaglandin and a penetration enhancer.
  • the co-morbid condition is at least one of diabetes mellitus, hypertension, cardiac disease, recovery from prostatectomy, or erectile dysfunction unresponsive to oral phosphodiesterase-5 inhibitor therapy.
  • the present invention provides methods for the treatment of erectile dysfunction in an individual suffering from the co-morbid condition diabetes mellitus.
  • the present invention provides methods for the treatment of erectile dysfunction in an individual suffering from the co-morbid condition hypertension. In yet another preferred embodiment, the present invention provides methods for the treatment of erectile dysfunction in an individual suffering from the co-morbid condition cardiac disease. In still another preferred embodiment, the present invention provides methods for the treatment of erectile dysfunction in an individual recovering from prostatectomy. In a further preferred embodiment, the present invention provides methods for the treatment of an individual suffering from erectile dysfunction unresponsive to oral phosphodiesterase-5 inhibitor therapy.
  • a patient suffering from erectile dysfunction and at least one co-morbid condition such as diabetes mellitus, hypertension, cardiac disease, recovery from prostatectomy or erectile dysfunction unresponsive to oral phosphodiesterase-5 inhibitor therapy can be effectively treated by placing in thefossa navicularis of the patient an erection inducing amount of a semi-solid vasoactive prostaglandin composition, which contains a dose of about 0.05 mg to about 0.8 mg of a vasoactive prostaglandin, a penetration enhancer, a polymeric thickener selected from the group consisting of a polysaccharide gum and a polyacrylic acid polymer, a lipophilic component that is selected from the group consisting of an aliphatic Ci to C 8 alcohol, an aliphatic C 8 to C 30 ester, and a mixture thereof; and an acidic buffer system.
  • a semi-solid vasoactive prostaglandin composition which contains a dose of about 0.05 mg to about 0.8 mg of a vas
  • the vasoactive prostaglandin is prostaglandin Ei .
  • the semi-solid composition is packaged in a unit dose and suitably the dose of the prostaglandin E] is about 0.05 mg to about 0.8 mg per unit dose, preferably about 0.1 mg to about 0.5 mg per unit dose.
  • the dose of the prostaglandin Ei is about 0.1 mg to about 0.3 mg per unit dose.
  • a preferred penetration enhancer is an alkyl-2-(N-substituted amino)- alkanoate ester, an (N-substituted amino)-alkanol alkanoate, or a mixture of these.
  • the buffer system provides a buffered pH value for the composition in the range of about 3 to about 7.4.
  • a preferred pH value is about 3 to about 6.5, most preferably from about 3.5 to about 6.
  • stabilizers, preservatives and emulsifiers may be included.
  • the composition exhibits non-Newtonian rheological properties, suitably comprising a shear-thinning polysaccharide gum or a shear-thinning polyacrylic acid polymer.
  • the composition is thixotropic.
  • the composition is pseudoplastic.
  • the composition has a viscosity of about 5,000 centipoise (cps) to about 20,000 cps, more preferably from about 7,000 cps to about 13,000 cps.
  • a preferred pharmaceutical composition suitable for intranavicular application comprises prostaglandin Ei, a penetration enhancer, a modified polysaccharide gum, a lipophilic compound, and an acidic buffer system.
  • the penetration enhancer is selected from the group consisting of an alkyl-2-(N- substituted amino)-alkanoate, an alkyl-2-(N,N-disubstituted amino)-alkanoate, an (N- substituted amino)-alkanol alkanoate, an (N, N-disubstituted amino)-alkanol alkanoate, pharmaceutically acceptable salts thereof and mixtures thereof.
  • the lipophilic compound may be an aliphatic Ci to C alcohol, an aliphatic C 8 to C 0 ester, or a mixture of these. If desired, stabilizers, preservatives and emulsifiers may be included.
  • the present invention provides for the use of a composition comprising prostaglandin E t , a penetration enhancer, a shear-thinning polymer selected from the group consisting of a polysaccharide gum and a polyacrylic acid polymer, a lipophilic compound, and an acidic buffer system in the manufacture of a medicament for the treatment of erectile dysfunction in an individual suffering from at least one co-morbid condition such as diabetes mellitus, hypertension, cardiac disease, recovery from prostatectomy or erectile dysfunction unresponsive to oral phosphodiesterase-5 inhibitor therapy.
  • compositions to be administered can take the form of a semi-solid suitable for intranavicular application.
  • these compositions provide effective prostaglandin penetration into the glans penis and produce bioavailability without requiring a wasteful overloading prostaglandin concentration in the tissue.
  • the compositions further exhibit reduced irritation, sensitivity and damage of local tissues.
  • These pharmaceutical compositions are packaged preferably in a single dose dispenser.
  • Figure 1 is a diagram of the anatomical structure of the human penis in longitudinal section view
  • Figure 2 is a schematic diagram of the anatomical details of the distal portion of the human penis in longitudinal section.
  • Figures 3 A and 3B are schematic diagrams illustrating the method of administrating the topical prostaglandin Ei composition.
  • Figure 3A shows the method of holding the meatus open by applying pressure to the glans on either side of the meatus, thereby spreading the meatus.
  • Figure 3B shows the administration of the medication dropwise through the open meatus without inserting the tip of applicator or dispenser into the meatus.
  • a semi-solid prostaglandin Ei composition suitable for the treatment of erectile dysfunction in the presence of a co-morbid condition can be placed advantageously in a natural enlarged space immediately proximal to the penile meatus, thefossa navicularis.
  • co-morbid refers to a medical condition that is present in a patient who also suffers from erectile dysfunction.
  • Thefossa navicularis provides a restricted site that is ideally suited for the application of pharmaceutical compositions.
  • the space is lined by a non-keratinized stratified squamous epithelium and is thereby distinguished from the surface skin covering the glans and the rest of the penis and from the stratified columnar epithelium of the lining of the urethra proper.
  • the lining of thefossa navicularis thus provides enhanced permeability compared to the keratinized epithelium of the surface skin of the outside of the penis. It has been found that the administration of the composition of the present invention in thefossa navicularis has high efficacy and low incidence of local side effects.
  • Thefossa navicularis is a natural expanded chamber suitably adapted to receive and retain semisolid medicaments.
  • a semi-solid medicament such as the composition of the present invention, when placed in thefossa has higher impedance to flow at narrowed exits of this space, the meatus and the urethra.
  • the impedance to flow is proportional to the product of the cross sectional area of the path and the path length.
  • a semi-solid medication of suitably chosen viscosity is naturally retained within thefossa, facilitating the absorption of active agents such as vasodilators and the like.
  • Viscosity of the composition suitably ranges from about 5,000 cps to about 20,000 cps, preferably from about 7,000 cps to about 13,000 cps.
  • the fossa navicularis is part of the natural defense system that protects the body against infection.
  • the fossa navicularis is a more immunologically protected site than the adjacent pars spongiosa region of the penile urethra proper.
  • Depositing a semisolid medicament within the anatomical limits of thefossa navicularis thus does not circumvent the natural barriers to disease by artificially transporting contaminants, e.g., from the surface of the penis, directly into the penile urethra proper.
  • the relatively high glycogen content and bacterial flora within thefossa navicularis provides a naturally lower pH within the space, so that relatively lower pH compositions in the acidic range that provide for enhanced solubility of prostaglandin Ei can be more easily tolerated without excessive irritation of the tissues.
  • Semi-solid compositions and penetration enhancers suitable for the practice of the present invention are described in detail in U.S. patents 6,046,244, 6,118,020 and 6,323,241, the teachings of which are incorporated herein by reference.
  • the fossa navicularis 110 in the glans penis 130 is a natural enlargement of the lumen of the male urethra.
  • Thefossa navicularis extends distally to the urethral meatus 128 and proximally to the pendulous region of the urethra 112 (also termed "pars spongiosa" region of the urethra), the portion of the urethra that passes through the corpus spongiosum 134 which is found within the shaft 104 of the penis medial to the paired corpora cavernosa 138.
  • the bulbar urethra 114 is proximal to the pendulous region of the urethra, and passes through the bulbospongiosus muscle 140. More proximally, the opening 148 in the wall of the urethra of the bulbourethral glands (Cowper's glands) can be seen. More proximally, the urethra passes through the prostate gland 160, where openings of ejaculatory duct 156 and of the prostate utricle 158 are visible in the wall of the urethra. Referring to Figure 2, the detailed structure of the fossa navicularis 110 within the glans penis 130 is illustrated.
  • the external opening of the urethral meatus 128 is the distal limit of the fossa navicularis.
  • the external skin of the glans is covered by a keratinized stratified squamous epithelium 186 (Pudney, J., and Anderson, D.J., (1995) Immunobiology of the human penile urethra, Amer. J. Path., 147: 155-165) that is marked by proximally by a sharp transition (dashed line) to the nonkeratinized stratified squamous epithelium without glycogen 184 that is characteristic of the lining of the distal fossa navicularis.
  • Thefossa navicularis widens proximally and the lining changes to a nonkeratinized stratified squamous epithelium with glycogen 182.
  • the glycogen in this region is believed to support a bacterial flora that lowers the pH of the region and contributes to a natural defense against infection.
  • This nonkeratinized stratified squamous epithelium with glycogen is under hormonal control, and increases in extent under increased estrogen levels (Holstein, et al., 1991).
  • the proximal fossa navicularis narrows in width, and is lined by a stratified columnar epithelium 180.
  • the semi-solid composition has a suitably chosen viscosity such that the composition is naturally retained within thefossa navicularis.
  • the semi-solid composition can exhibit Newtonian or non-Newtonian rheological characteristics.
  • the semi-solid composition of the present invention exhibits non-Newtonian rheological characteristics, i.e. in which the apparent viscosity is dependent on the shear rate applied to the composition.
  • the composition has "shear-thinning" rheological properties.
  • shear- thinning refers to a reduction in apparent viscosity (the ratio of shear stress to the shear rate) with increasing shear rate, whether the reduction in apparent viscosity is time independent (pseudoplastic), time dependent (thixotropic) or associated with a yield stress, defined as a stress that must be exceeded before flow starts, (Bingham plastics and generalized Bingham plastics). See, generally, Harris, J., & Wilkinson, W.L., "Non-newtonian Fluid," pp.856-858 in Parker, S.P., ed., McGraw-Hill Encyclopedia of Physics, Second Edition, McGraw-Hill, New York, 1993.
  • a suitable viscosity range of the composition is from about 5,000 centipoise (cps) to about 20,000 cps, preferably from about 7,000 cps to about 13,000 cps.
  • the pharmaceutical composition comprises at least one vasoactive prostaglandin, preferably prostaglandin Ei, an alkyl (N, N- disubstituted amino) ester, a polysaccharide gum, a lipophilic component, and an acid buffer system.
  • the prostaglandin can be dissolved or substantially uniformly dispersed in the topical composition, preferably soluble (and dissolved) in the topical composition.
  • Vasoactive prostaglandins are those that act as peripheral vasodilators, including naturally occurring prostaglandins such as PGEi, PGAi, PGBi, PGF ] ⁇ , 19- hydroxy-PGA,, 19-hydroxy-PGB,, PGE 2 , PGA 2 , PGB 2 , 19-hydroxy-PGA 2 , 19- hydroxy-PGB 2 , PGE 3 , PGF 3 ⁇ ; semisynthetic or synthetic derivatives of natural prostaglandins, including carboprost tromethamine, dinoprost tromethamine, dinoprostone, lipoprost, gemeprost, metenoprost, sulprostone and tiaprost.
  • naturally occurring prostaglandins such as PGEi, PGAi, PGBi, PGF ] ⁇ , 19- hydroxy-PGA,, 19-hydroxy-PGB, PGE 2 , PGA 2 , PGB 2 , 19-hydroxy-PGA 2
  • Prostaglandin Ei and prostaglandin E 2 are particularly preferred vasoactive prostaglandins for use in conjunction with the present method.
  • the quantity of vasoactive prostaglandin, such as prostaglandin E ) ; in the pharmaceutical compositions of the present invention is a therapeutically effective (i.e., erection inducing) amount and necessarily varies according to the particular vasoactive prostaglandin to be delivered, the indication to be treated, the surface area of the skin and mucous membrane over which the formulation is to be placed, the other components of the composition, the desired dose, the dosage form (e.g., suppository or topical), and the particular form of the vasoactive prostaglandin used.
  • prostaglandin refers to the prostaglandin free acid and pharmaceutically acceptable derivatives thereof, including e.g., prostaglandin E ⁇ (PGE ⁇ ), pharmaceutically acceptable salts and lower alkyl esters thereof (the term “lower alkyl” as used herein means straight chain or branched chain alkyl containing one to four carbon atoms).
  • the composition generally contains about 0.001 weight percent to 1 weight percent prostaglandin Ei, typically contains about 0.05 weight percent to 1 weight percent prostaglandin Ei, preferably about 0.1 weight percent to 0.5 weight percent, based on the total weight of the composition.
  • prostaglandin Ei is present in the composition in an amount of about 0.07 weight percent of the total composition to about 0.4 weight percent of the total composition.
  • Prostaglandin Ei is well known to those skilled in the art. Accordingly, it is not practical to enumerate particular preferred amounts but such can be readily determined by those skilled in the art with due consideration of the factors listed above. Reference may be had to various literature references for its pharmacological activities, side effects, and normal dosage ranges. See for example, Physician's Desk Reference, 51st Ed. (1997), The Merck Index, 12th Ed., Merck & Co., NJ. (1996), and Martindale The Extra Pharmacopoeia, 28th Ed., London, The Pharmaceutical Press (1982). Additionally, simultaneous administration of one or more non-ecosanoid vasodilators may be desirable and may in some cases exhibit a synergistic effect. The combination of prazosin with prostaglandin Ei has been found to be particularly advantageous in this regard; the latter drug appears to act as a potentiator for prazosin.
  • Suitable non-ecosanoid vasodilators include, but are not limited to: nitrates such as nitro glycerin, isosorbide dinitrate, erythrityl tetranitrate, amyl nitrate, sodium nitroprusside, molsidomine, linsidomine chlorhydrate ("SIN-1") and S-nitroso-N- acetyl-d,l-penicillamine (“SNAP”); amino acids such as L-arginine; long and short acting ⁇ -adrenergic blockers such as phenoxybenzamine, dibenamine, phentolamine, tamsulosin and indoramin, especially quinazoline derivatives such as alfuzosin, bunazosin, doxazosin, terazosin, prazosin, and trimazosin; vasodilative natural herbal compositions and bioactive extracts thereof, such as gosyajinki-gan, Sa
  • ergot alkaloids such as ergotamine and ergotamine analogs, e.g., acetergamine, brazergoline, bromerguride, cianergoline, delorgotrile, disulergine, ergonovine maleate, ergotamine tartrate, etisulergine, lergotrile, lysergide, mesulergine, metergoline, metergotamine, nicergoline, pergolide, propisergide, proterguride and terguride; antihypertensive agents such as diazoxide, hydralazine and minoxidil; vasodilators such as nimodepine, pinacidil, cyclandelate, dipyridamole and isoxsuprine; chlorpromazine; haloperidol; yohimbine; trazodone and vasoactive intestinal peptides.
  • ergot alkaloids such as ergotamine and ergot
  • a piperazinyl quinazoline antihypertensive such as prazosin
  • a piperazinyl quinazoline antihypertensive is present in the amount of about 0.1 mg to about 2.0 mg per unit dose, depending on the potency of the particular piperazinyl quinazoline antihypertensive and the type and dose of vasoactive prostaglandin used.
  • the dose and the proportion of vasoactive prostaglandin and the piperazinyl quinazoline antihypertensive can be routinely determined by one of ordinary skill without undo experimentation.
  • the topical composition can contain one or more penetration enhancers.
  • penetration enhancers for the present invention are ethanol, propylene glycol, glycerol, ethyl laurate, isopropyl palmitate, isopropyl myristate, laurocapram (AzoneTM ), dioxolanes (described in U.S. Patent No. 4,861,764), macrocyclic ketones, HP-101, oxazolidones and biodegradable penetration enhancers (described in U.S. Patents Nos. 4,980,378 and 5,082,866 to Wong et al. and U.S. Patent Number 6,118,020 to B ⁇ y ⁇ ktimkin et al.
  • alkyl-2-(N- substituted amino) alkanoates such as alkyl-2-(N- substituted amino) alkanoates, alkyl-2-(N, N-disubstituted amino) alkanoates (e.g., dodecyl N,N- dimethylamino isoproprionate (DDAIP)), N-substituted amino alkanol alkanoates), N, N-disubstituted amino alkanol alkanoates, acid addition salts and mixtures thereof.
  • DDAIP dodecyl N,N- dimethylamino isoproprionate
  • N-substituted amino alkanol alkanoates N, N-disubstituted amino alkanol alkanoates
  • acid addition salts and mixtures thereof acid addition salts and mixtures thereof.
  • Acid addition salts of dodecyl 2-(N,N-dimethylamino)-propionate can be inorganic as well as organic.
  • Representative inorganic acid addition salts include the hydrochloric, hydrobromic, sulfuric, phosphoric, nitric acid addition salts of DDALP, and their solvates.
  • Exemplary organic acid addition salts include acetic, benzoic, salicylic, glycolic, succinic, nicotinic, tartaric, maleic, malic, palmoic, methanesulfonic, cyclohexanesulfamic, picric, and lactic acid addition salts, as well as their respective solvates.
  • Preferred among the inorganic acid addition salts are DDAIP hydrogen chloride, and DDAIP dihydrogen sulfate.
  • the penetration enhancer is present in an amount sufficient to enhance the penetration of the prostaglandin Ej.
  • the specific amount varies necessarily according to the desired release rate and the specific form of prostaglandin Ei used.
  • the penetration enhancer is present in an amount ranging from about 0.5 weight percent to about 20 weight percent, based on the total weight of the composition.
  • the penetration enhancer is present in an amount ranging from about 1 weight percent to about 10 weight percent of the composition. More preferably, the penetration enhancer is present in an amount ranging from about 1 weight percent to about 5 weight percent of the composition.
  • suitable penetration enhancers can be chosen from those listed above as well as sulfoxides, alcohols, fatty acids, fatty acid esters, polyols, amides, surfactants, terpenes, alkanones, organic acids and mixtures thereof.
  • Suitable sulfoxides include dimethylsulfoxide, decylmethylsulfoxide and mixtures thereof.
  • Suitable alcohols include ethanol, propanol, butanol, pentanol, hexanol, octanol, nonanol, decanol, 2-butanol, 2-pentanol, benzyl alcohol, caprylic alcohol, decyl alcohol, lauryl alcohol, 2-lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, olcyl alcohol, linolyl alcohol, linolenyl alcohol and mixtures thereof.
  • Suitable fatty acids include valeric, heptanoic, pelargonic, caproic, capric, lauric, myristic, stearic, oleic, linoleic, linolenic, caprylic, isovaleric, neopentanoic, neoheptanoic, neononanoic, trimethyl hexanoic, neodecanoic and isostearic acids and mixtures thereof.
  • Suitable fatty acid esters include isopropyl n-butyrate, isopropyl n-hexanoate, isopropyl n-decanoate, isopropyl myristate, isopropyl palmitate, octyldodecyl myristate, ethyl acetate, butyl acetate, methyl acetate, methylvalerate, methylpropionate, diethyl sebacate, ethyl oleate, ethyl laurate and mixtures thereof.
  • Suitable polyols include propylene glycol, polyethylene glycol, ethylene glycol, diethylene glycol, triethylene glycol, dipropylene glycol, glycerol, propanediol, sorbitol, dextrans, butanediol, pentanediol, hexanetriol and mixtures thereof.
  • Suitable amides include urea, dimethylacetamide, diethyltoluamide, dimethylformamide, dimethyloctamide, dimethyldecamide, l-alkyl-4-imidazolin-2- one, pyrrolidone derivatives, cyclic amides, hexamethylenelauramide and its derivatives, diethanolamine, triethanolamine and mixtures thereof.
  • Suitable pyrrolidone derivatives include l-methyl-2-pyrrolidone, 2-pyrrolidone, l-lauryl-2- pyrrolidone, l-methyl-4-carboxy-2-pyrrolidone, l-hexyl-4-carboxy-2-pyrrolidone, 1- lauryl-4-carboxy-2-pyrrolidone, l-decyl-thioethyl-2-pyrrolidone (HP-101), 1 -methyl- 4-methoxycarbonyl-2-pyrrolidone, 1 -hexyl-4-methoxycarbonyl-2-pyrrolidone, 1 - lauryl-4-methoxycarbonyl-2 -pyrrolidone, N-cyclohexylpyrrolidone, N- dimethylaminopropylpyrrolidone, N-cocoalkypyrrolidone, N-tallowalkypyrrolidone, fatty acid esters of N-(
  • Suitable cyclic amides include l-dodecylazacycloheptane-2-one (laurocapram, AzoneTM), l-geranylazacycloheptan-2-one, l-farnesylazacycloheptan-2-one, 1- geranylgeranylazacycloheptan-2-one, 1 -(3 ,7-dimethyloctyl)azacycloheptan-2-one, 1 - (3,7,1 l-trimethyloctyl)azacycloheptan-2-one, l-geranylazacyclohexane-2-one, 1- geranylazacyclopentan-2,5-dione, l-farnesylazacyclopentan-2-one and mixtures thereof.
  • Suitable surfactants include anionic surfactants, cationic surfactants, nonionic surfactants, bile salts and lecithin.
  • Suitable anionic surfactants include sodium laurate, sodium lauryl sulfate and mixtures thereof.
  • Suitable cationic surfactants include cetyltrimethylammonium bromide, tetradecyltrimethylammonium bromide, benzalkonium chloride, octadecyltrimethylammonium chloride, cetylpyridinium chloride, dodecyltrimethylammonium chloride, hexadecyltrimethylammonium chloride, and mixtures thereof.
  • Suitable nonionic surfactants include ⁇ -hydro- ⁇ - hydroxy- poly(oxyethylene)-poly(oxypropyl) poly(oxyethylene)block copolymers, polyoxyethylene ethers, polyoxyethylene sorbitan esters, polyethylene glycol esters of fatty alcohols and mixtures thereof.
  • Suitable ⁇ -hydro- ⁇ -hydroxy-poly(oxyethylene)- poly(oxypropyl) poly(oxyethylene)block copolymers include Poloxamers 231, 182, and 184 and mixtures thereof.
  • Suitable polyoxyethylene ethers include 4-lauryl ether (BRIJ 30TM), (BRIJ 93TM), (BRIJ 96TM), 20-oleyl ether (BRIJ 99TM) and mixtures thereof.
  • Suitable polyoxyethylene sorbitan esters include the monolaurate (TWEEN 20TM, SPAN 20TM) the monopalmitate (TWEEN 40TM), the monostearate (TWEEN 60TM), and the monooleate (TWEEN 80TM) and mixtures thereof.
  • Suitable polyethylene glycol esters of fatty acids include the 8-oxyethylene stearate ester (MYRJ 45TM), (MYRJ 51TM), the 40-oxyethylene stearate ester (MYRJ 52TM) and mixtures thereof.
  • Suitable bile salts include sodium cholate, sodium salts of laurocholic, glycolic and desoxycholic acids and mixtures thereof.
  • Suitable terpenes include D-limonene, ⁇ -pinene, /3-enrene, ⁇ -terpineol, terpinen-4-ol, carvol, carvone, pulegone, piperitone, menthone, menthol, geraniol, cyclohexene oxide, limonene oxide, ⁇ -pinene oxide, cyclopentene oxide, 1,8-cineole, ylang ylang oil, anise oil, chenopodium oil, eucalyptus oil and mixtures thereof.
  • Suitable alkanones include N-heptane, N-octane, N-nonane, N-decane, N-undecane, N-dodecane, N-tridecane, N-tetradecane, N-hexadecane and mixtures thereof.
  • Suitable organic acids include citric acid, succinic acid, salicylic acid, salicylates (including the methyl, ethyl and propyl glycol derivatives), tartaric acid and mixtures thereof.
  • Natural and modified polysaccharide gums are also an important ingredient of the composition. Suitable representative gums are those in the natural and modified galactomannan gum category.
  • a galactomannan gum is a carbohydrate polymer containing D-galactose and D-mannose units, or other derivatives of such a polymer.
  • the galactomannan gum is characterized by a linear structure of ⁇ -D-mannopyranosyl units linked (1— >4). Single membered ⁇ -D-manopyranosyl units, linked (l-»6) with the main chain, are present as side branches.
  • Galactomannan gums include guar gum, which is the pulverized endosperm of the seed of either of two leguminous plants ⁇ Cyamposis tetragonalobus and psoraloids) and locust bean gum, which is found in the endosperm of the seeds of the carobtree ⁇ ceratonia siliqua).
  • Suitable modified polysaccharide gums include ethers of natural or substituted polysaccharide gums, such as carboxymethyl ethers, ethylene glycol ethers and propylene glycol ethers.
  • An exemplary substituted polysaccharide gum is methylcellulose.
  • a preferred modified galactomannan gum is modified guar gum.
  • composition of the present invention may contain a mixture of various gums, or mixture of gums and acidic polymers.
  • Gums, and galactomannan gums in particular are well-known materials. See for instance, Industrial Gums: Polysaccharides & Their Derivatives, Whistler R. L. and BeMiller J.N. (eds.), 3rd Ed. Academic Press (1992) and Davidson R. L., Handbook of Water-Soluble Gums & Resins, McGraw-Hill, Inc., N.Y. (1980).
  • Most gums are commercially available in various forms, commonly a powder, and ready for use in foods and topical compositions. For example, locust bean gum in powdered form is available from Tic Gums Inc. (Belcam, MD).
  • the polysaccharide gums are present in the range from about 0.1 percent to about 5 percent, based on the total weight of the composition, with the preferred range being from 0.5 percent to 3 percent. In one preferred embodiment, 2.5 percent by weight of a polysaccharide gum is present.
  • Illustrative compositions are given in the examples, below.
  • polyacrylic acid polymer An optional alternative to the polysaccharide gum is a polyacrylic acid polymer.
  • a common variety of polyacrylic acid polymer is known generically as "carbomer.”
  • Carbomer is polyacrylic acid polymers lightly cross-linked with polyalkenyl polyether. It is commercially available from the B. F. Goodrich Company (Akron, Ohio) under the designation "CARBOPOLTM.”
  • CARBOPOL 940 A particularly preferred variety of carbomer is that designated as "CARBOPOL 940.”
  • polyacrylic acid polymers suitable for use are those commercially available under the designations "PemulenTM” (B. F. Goodrich Company) and “POLYCARBOPHILTM” (A.H. Robbins, Richmond, VA).
  • the PemulenTM polymers are copolymers of C ⁇ 0 to C 0 alkyl acrylates and one or more monomers of acrylic acid, methacrylic acid or one of their simple esters crosslinked with an allyl ether of sucrose or an allyl ether of pentaerythritol.
  • the POLYCARBOPHILTM enhancer is a polyacrylic acid cross-linked with divinyl glycol.
  • polyacrylic acid polymers are present, they represent about 0.5 percent to about 5 percent of the composition, based on its total weight.
  • lipophilic component refers to an agent that is both lipophilic and hydrophilic.
  • lipophilic nature, or “lipophilicity” of a given compound is routinely quantified for comparison to other compounds by using the partition coefficient.
  • the partition coefficient is defined by the International Union of Pure and Applied Chemistry (IUPAC) as the ratio of the distribution of a substance between two phases when the heterogeneous system (of two phases) is in equilibrium; the ratio of concentrations (or, strictly speaking, activities) of the same molecular species in the two phases is constant at constant temperature.
  • the Ci to C 8 aliphatic alcohols, the C 2 to C 30 aliphatic esters, and their mixtures can serve as lipophilic component.
  • suitable alcohols are ethanol, n-propanol and isopropanol
  • suitable esters are ethyl acetate, butyl acetate, ethyl laurate, methyl propionate, isopropyl myristate and isopropyl palmitate.
  • the term "aliphatic alcohol” includes polyols such as glycerol, propylene glycol and polyethylene glycols. In one embodiment, a mixture of alcohol and ester is preferred, and in particular, a mixture of ethanol and ethyl laurate is preferred.
  • the C 2 to C 30 aliphatic esters, and their mixtures comprising the lipophilic component include C 8 to C 30 aliphatic esters of glycerol selected from the group consisting monoglycerides, diglycerides, triglycerides, and mixtures thereof.
  • Suitable aliphatic esters include glyceryl esters of saturated fatty acids, unsaturated fatty acids and mixtures thereof.
  • Suitable saturated fatty acids include caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid and lignoceric acid.
  • Suitable unsaturated fatty acids include oleic acid, linoleic acid and linolenic acid.
  • Suitable glyceryl esters include glyceryl monooleate, triolein, trimyristin and tristearin, perferably trimyristin.
  • the concentration of lipophilic component required necessarily varies according to other factors such as the desired semi-solid consistency and the desired skin penetration promoting effects.
  • concentration of lipophilic component is in the range of 0.5 percent to 40 percent by weight based on the total weight of the composition.
  • the preferred topical composition contains lipophilic component in the range of 7 percent to 40 percent by weight based on the total weight of the composition.
  • the suitable amount of alcohol is in the range of 0.5 percent to 10 percent. In one preferred embodiment, the amount of alcohol is in the range of 5 percent to 15 percent, while that of aliphatic ester is in the range from 2 percent to 15 percent (again based on the total weight of the composition). In another preferred embodiment, the amount of alcohol is in the range of 0.5 percent to 10 percent, while that of aliphatic ester is in the range from 0 percent to 10 percent (again based on the total weight of the composition).
  • the concentration of lipophilic component required necessarily varies according to other factors such as the desired semi-solid consistency and the desired skin penetration promoting effects.
  • the preferred topical composition contains lipophilic component in the range of 7 percent to 40 percent by weight based on the total weight of the composition. Where a lipophilic component that is a mixture of aliphatic alcohol and aliphatic ester is used, the preferred amount of alcohol is in the range of 5 percent to 15 percent, while that of aliphatic ester is in the range from 2 percent to 15 percent (again based on the total weight of the composition).
  • An optional, but preferred, component is an emulsifier.
  • a suitable emulsifier generally will exhibit a hydrophilic-lipophilic balance number greater than 10.
  • Sucrose esters, and specifically sucrose stearate can serve as emulsifiers for the composition.
  • Sucrose stearate is a well-known emulsifier available from various commercial sources. When an emulsifier is used, sucrose stearate present up to about 2 percent, based on the total weight of the composition, is preferred.
  • the preferred amount of sucrose stearate emulsifier can also be expressed as a weight ratio of emulsifier to polysaccharide gum. A ratio of 1 to 6 emulsifier to gum is preferred, and a ratio of 1 to 4 is most preferred to generate the desired semi- solid consistency and separation resistance.
  • emulsifiers are also suitable including polyoxyethylene sorbitan esters, long chain alcohols, preferably cetostearyl alcohol, and fatty acid glycerides.
  • Suitable polyoxyethylene sorbitan esters include the monolaurate (Tween 20TM, Span 20TM) the monopalmitate (Tween 40TM), the monostearate (Tween 60TM), and the monooleate (Tween 80TM) and mixtures thereof.
  • Preferred fatty acid glycerides include glyceryl monooleate, triolein, trimyristin and tristearin.
  • the composition includes an acid buffer system. Acid buffer systems serve to maintain or buffer the pH of compositions within a desired range.
  • buffer system or “buffer” as used herein has reference to a solute agent or agents which, when in a water solution, stabilize such solution against a major change in pH (or hydrogen ion concentration or activity) when acids or bases are added thereto. Solute agent or agents which are thus responsible for a resistance to change in pH from a starting buffered pH value in the range indicated above are well known. While there are countless suitable buffers, potassium phosphate monohydrate has proven effective for compositions of the present invention.
  • the final pH value of the pharmaceutical composition may vary within the physiologically compatible range. Necessarily, the final pH value is not irritating to human skin. Without violating this constraint, the pH may be selected to improve prostaglandin Ej stability and to adjust consistency when required. In one embodiment, the preferred pH value is about 3 to about 7.4, more preferably about 3 to about 6.5, most preferably from about 3.5 to about 6.
  • the remaining component of the composition is water, which is necessarily purified.
  • the composition contains water in the range of about 50 to about 90 percent, based on the total weight of the composition.
  • the specific amount of water present is not critical, however, being adjustable to obtain the desired consistency and/or concentration of the other components.
  • Prostaglandin Ei stabilizers, coloring agents, rheological agents, and preservatives can be added to the extent that they do not overly limit prostaglandin Ei skin penetration or prevent the desired semi-solid consistency.
  • Contemplated dosage forms of the semi-solid pharmaceutical composition are creams, gels, ointments, colloidal suspensions and the like, also including but not limited to compositions suitable for use with transdermal patches and like devices.
  • the ingredients listed above may be combined in any order and manner that produces a stable composition comprising a prostaglandin Ei evenly dispersed throughout a semi-solid formulation.
  • One available approach to preparing such compositions involves evenly dispersing the polysaccharide gum (or polyacrylic acid polymer) in a premixed water/buffer solution and then thoroughly homogenizing (i.e.
  • Part A the emulsifier is added to the water/buffer solution before dispersing the polysaccharide gum.
  • Any suitable method of adjusting the pH value of Part A to the desired level may be used, for example, by adding concentrated phosphoric acid or sodium hydroxide.
  • the prostaglandin E] is dissolved with agitation in the lipophilic component, which itself may be a mixture of alcohols, esters, or alcohol with ester.
  • the penetration enhancer is added.
  • the lipophilic component includes both an alcohol and an ester
  • the prostaglandin Ei can be dissolved in the alcohol before adding the penetration enhancer followed by the ester. In either case, the resulting mixture will be referred to as "Part B.”
  • the final step involves slow addition (e.g. dropwise) of Part B into Part A under constant mixing.
  • the resulting topical composition when compared to exhibits the advantageous properties described above, including improved prostaglandin Ei permeation and bioavailability without drug overloading, reduced skin damage and related inflammation, and increased flexibility in design of dosage forms.
  • These compositions can be used for prolonged treatment of peripheral vascular disease, male impotency and other disorders treated by prostaglandin Ei, while avoiding the low bioavailability and rapid chemical decomposition associated with other delivery methods.
  • Application of prostaglandin Ei in a topical composition to the skin of a patient allows a predetermined amount of prostaglandin Ei to be administered continuously to the patient and avoids undesirable effects present with a single or multiple administrations of larger dosages by injection. By maintaining a sustained dosage rate, the prostaglandin Ei level in the patient's target tissue can be better maintained within the optimal therapeutic range.
  • a composition comprises about 0.01 percent to about 5 percent modified polysaccharide gum; about 0.001 percent to about 1 percent of a prostaglandin selected from the group consisting of PGEi , pharmaceutically acceptable salts thereof, lower alkyl esters thereof and mixtures thereof; about 0.5 percent to about 10 percent DDAIP or salts thereof; about 0.5 percent to about 10 percent of a lower alcohol selected from the group consisting of ethanol, propanol, isopropanol and mixtures thereof; about 0.5 percent to about 10 percent on an ester selected from the group consisting of ethyl laurate, isopropyl myristate, isopropyl laurate and mixtures thereof; based on the weight of the composition, and an acid buffer.
  • the composition also comprises up to about 2 percent sucrose stearate.
  • the composition also comprises up to about 5 percent emulsifier.
  • the composition also comprises up to about 2 percent emulsifier.
  • Suitable emulsifiers include polysorbates such as Tweens, glyceryl monooleate, triolein, trimyristin and tristearin.
  • a preferred emulsifier is trimyristin.
  • Suitable preservatives include methylparabens (methyl PABA), propylparabens (propyl PABA) and butylhydroxy toluene (BHT).
  • Suitable perfumes and fragrances are known in the art; a suitable fragrance is up to about 5 percent myrtenol, preferably about 2 percent myrtenol, based on the total weight of the composition.
  • the compositions of the present invention can also include a small amount, about 0.01 to about 4% by weight, of a topical anesthetic, if desired.
  • Typical topical anesthetics include lidocaine, dyclonine, dibucaine, pharmaceutically acceptable salts and mixtures thereof. In one preferred embodiment, the topical anesthetic is about 0.5 percent dyclonine, based on the weight of the composition.
  • the pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form is a packaged preparation, where the package containing the discrete quantities of the pharmaceutical preparation is, e.g. a rigid plastic dispenser or flexible packet.
  • Another aspect of the invention is an article of manufacture that comprises a composition for treating erectile dysfunction as described above in a suitable container, preferably in a container such as the dispenser disclosed in U.S. Patent No. 6,224,573, in combination with labeling instructions.
  • the container can be a tube with a suitable orifice size, such as an extended tip tube, pouch, packet, or squeeze bottle and made of any suitable material, for example rigid plastic or flexible plastic.
  • the labeling instructions can come in the form of a pamphlet, a label applied to or associated with the packaging of the article of manufacture.
  • the labeling instructions provide for administering a composition of the invention to thefossa navicularis of the penis of a patient suffering from erectile dysfunction, directing the patient to hold the penis upright, hold the meatus open and place the composition in thefossa navicularis without introducing the tip of the container into the meatus, about 5-30 minutes before sexual intercourse, see Figures 3A-3B.
  • Printed labeling instructions are functionally related to the composition of the invention inasmuch as such labeling instructions describe a method to treat erectile dysfunction according to the present invention.
  • the labeling instructions are an important aspect of the invention in that before a composition can be approved for any particular use, it must be approved for marketing by the responsible national regulatory agency, such as the United States Food and Drug Administration. Part of that process includes providing a label that will accompany the pharmaceutical composition which is ultimately sold. While the label will include a definition of the composition and such other items such as the clinical pharmacology, mechanism of action, drug resistance, pharmacokinetics, absorption, bioavailability, contraindications and the like, it will also provide the necessary dosage, administration and usage. Thus, the combination of the composition with the dispenser with appropriate treatment instructions is important for the proper usage of the drug once it is marketed to the patient. Such treatment instructions will describe the usage in accordance with the method of treatment set forth herein before.
  • the quantity of active component in a unit dose preparation may be varied or adjusted from 0.01 mg to 1 g according to the particular application and the potency of the vasoactive prostaglandin.
  • the vasoactive prostaglandin is prostaglandin Ei
  • about 0.05 mg to about 0.8 mg prostaglandin Ei is present per unit dose, preferably about 0.1 mg to about 0.5 mg per unit dose and in another embodiment, about 0.1 mg to about 0.3 mg per unit dose.
  • the composition can, if desired, also contain other compatible therapeutic agents, such as a piperazinyl quinazoline antihypertensive.
  • the semi-solid vasoactive prostaglandin composition should be applied to thefossa navicularis of the penis about 2-30 minutes before sexual intercourse, preferably about 5-15 minutes before sexual intercourse.
  • a regular regimen of treatment not necessarily linked to anticipated sessions of sexual intercourse can be undertaken.
  • the semi-solid vasoactive prostaglandin composition can be applied to the fossa navicularis of the penis at least twice a week, preferably every other day, or on a daily basis.
  • each composition is prepared by conventionally admixing the respective indicated components together.
  • Composition A was prepared as follows. Part A of the composition was formed by dissolving 0.4 parts by weight prostaglandin Ei (Alprostadil USP) in 5 parts by weight ethyl alcohol. Next, 5 parts by weight dodecyl 2-(N,N- dimethylamino)-propionate were mixed into the alcohol-prostaglandin Ei solution, followed by 5 parts by weight ethyl laurate.
  • prostaglandin Ei Alpharostadil USP
  • dodecyl 2-(N,N- dimethylamino)-propionate were mixed into the alcohol-prostaglandin Ei solution, followed by 5 parts by weight ethyl laurate.
  • Part B was prepared starting from a pH 5.5 water/buffer solution.
  • the water/buffer solution was prepared by adding sufficient potassium phosphate monohydride to purified water to create a 0.1 M solution.
  • the pH of the water/buffer solution was adjusted to 5.5 with a strong base solution (1 N sodium hydroxide) and a strong acid (1 N phosphoric acid).
  • the buffer solution represented about 80 parts of the total composition. All parts specified herein are parts by weight. Ethyl laurate, 0.5 parts by weight, was added to the buffer solution.
  • the locust bean gum (in powder form) was dispersed in the buffer solution and homogenized using a homogenizer. Table 1, below, contains a list of the ingredients.
  • the resulting composition was a spreadable, semi-solid preparation suitable for application to the skin without the need for supporting devices such as patches and adhesive strips.
  • the composition was both homogenous in appearance and resistant to separation.
  • compositions B - H were prepared in the same manner using the components listed in Table 1.
  • the composition may include a modified polysaccharide gum, suitably a modified galactomannan gum, such as a guar gum.
  • a polyacrylic polymer may be used instead of the polysaccharide gum.
  • Composition A was evaluated for skin penetration using shed snake skin as a model barrier.
  • Shed snake skin was obtained from the Animal Care Unit of the University of Kansas. With head and tail sections removed, the skin was randomly divided into test sections and then hydrated by soaking.
  • the samples were then evaluated using Franz-type Diffusion Cells (surface area 1.8 cm 2 ). Specifically, skin pieces were mounted on top of a receptor cell of a vertical diffusion cell assembly in which a small magnetic bar was inserted and filled with an isotonic buffer. A seal was placed on top of the skin section followed by a donor cell. The two cells were clamped together. Known amounts of the formulations were applied on the bottom of a small capped vial (weight 0.5 grams) which fits exactly to the donor cell to ensure uniform distribution. The vials were placed on the skin in the donor cell. To reduce the evaporation of the ingredients, the donor cell and vial were taped together with a water-resistant adhesive band. The cells were transferred to a stirred water bath (32 degrees Celsius).
  • Composition B contained more prostaglandin Ei than Composition A. Despite this increased drug loading, Composition B exhibited a similar semi-solid consistency and homogenous appearance. The penetration of prostaglandin Ej was measured according to the technique described in Example 1. Composition B provided a relatively fast, sustained delivery of prostaglandin Ei . The results are presented in Table 2.
  • Composition C was prepared using the ingredients listed in Table 1, below.
  • Composition B contained more prostaglandin Ei than either Composition A or B.
  • the increased drug loading had little or no effect on the consistency or appearance, which substantially matched that of Compositions A and B.
  • the penetration of prostaglandin Ei was again measured according to the technique described in Example 1. According to this test, Composition C also provided a relatively fast, sustained delivery of prostaglandin Ei .
  • Composition D was prepared using the ingredients listed in Table 1, below.
  • the level of prostaglandin Ei was again increased without substantially affecting the favorable consistency and separation resistance.
  • the penetration of prostaglandin Ei was again measured according to the technique described in Example 1. The results are presented in Table 2, below.
  • composition E was prepared using the ingredients listed in Table 1, below.
  • compositions according to the present invention were again applied for Composition E. Repeatability was substantially confirmed by Composition E's favorable, semi-solid consistency and separation resistance.
  • the penetration of prostaglandin Ei was again measured according to the technique described in Example 1.
  • the prostaglandin Ei delivery from Composition E was again relatively fast and sustained. The results are presented in Table 2, below.
  • the level of prostaglandin Ei was again increased for Composition F.
  • the specific ingredients are listed in Table 1.
  • the favorable consistency and separation resistance was undiminished.
  • the results of a penetration analysis are presented in Table 2, below.
  • composition G the recipe of Composition F was repeated except that the ester component (ethyl laurate) was omitted and the level of ethanol was increased a corresponding amount.
  • the resulting composition was also a spreadable, semi-solid having a homogenous appearance and resistance to separation.
  • the results of a penetration analysis are presented in Table 2, below. While still favorable, these results reflect the relative benefit to compositions of the present invention from a lipophilic compound that includes both an ester component and an alcohol component.
  • Table 1 Topical Prostaglandin Ei Compositions Ingredient (wt%) A B C D E F H prehydrated locust bean gum 3 3 3 3 3 3 3 3 - - prehydrated modified guar gum - - - - - - 3 2.5 water/buffer (pH 5.5) 81 81 81 81 81 81 81 81 86.8 sucrose stearate 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 - - prostaglandin Ei 0.1 0.2 0.3 0.4 0.4 0.5 0.4 0.3 0.2
  • Table 2 shows the cumulative amount of prostaglandin Ei penetrating each hour for 4 hours for each example composition according to the present invention.
  • compositions according the present invention were prepared.
  • a first comparative example (Comparative Example 1) was prepared with the same recipe as Compositions D and E except that the DDAIP penetration enhancer was omitted.
  • Comparative Example 2 For a second comparative example (Comparative Example 2), the DDAIP was again omitted, but the level of ethanol was increased a corresponding amount.
  • the specific ingredients used are listed in Table 3, below. Table 3: Comparative Examples
  • Comparative Comparative Ingredient (parts by weight) Composition 1 Composition 2 prehydrated locust bean gum 3 3 water/buffer (pH 5.5) 86 81 sucrose stearate 0.5 0.5 prostaglandin E 0.4 0.4
  • prostaglandin Ej The penetration of prostaglandin Ej was evaluated according to the technique described in Example 1. The results are presented in Table 4, below.
  • prostaglandin Ei prostaglandin Ej or alprostadil topical composition
  • composition D of Example 4 and Table 1, above The safety and efficacy of a 0.4%> weight prostaglandin Ei (prostaglandin Ej or alprostadil) topical composition (composition D of Example 4 and Table 1, above) was evaluated in a total of 143 men at three study sites.
  • This study consisted of a double-blind, placebo controlled and cross-over portion and an open-label portion.
  • the double-blind placebo controlled portion of the study was entered and completed by 64 men (Table 5, below). Seventy-nine (79) men entered and completed the open-label portion of the study (Table 5, below). Summarized below are discussions on the results of the clinical studies.
  • erectile dysfunction defined as the inability to achieve and maintain an erection of sufficient rigidity for sexual intercourse due to psychogenic, neurogenic or vasculogenic causes during the previous 6 months. This includes patients who may still have some erections sufficient for intercourse but not consistently, which is the typical complaint of the age onset, mild to moderate impotent man. The diagnosis of erectile dysfunction was based on medical history and physical examination.
  • Exclusion Criteria History of urethral stricture or obstruction.
  • penile surgery including penile implant, prostatectomy or cancer of the prostate, penile trauma including paraplegia or quadriplegia.
  • priapism any condition which might predispose towards priapism, such as sickle cell anemia, multiple myeloma, or leukemia. 5. Hypertension, (sitting diastolic pressure >90 or systolic >150) requiring treatment with other than angiotensin converting enzyme inhibitors (ACE inhibitors).
  • ACE inhibitors angiotensin converting enzyme inhibitors
  • Peyronie's Disease or any palpable fibrous scar or plaque on the penis evidence of curvature during tumescence and rigidity stimulation or an anomaly of the penis skin or mucosa of the glans.
  • Any concomitant medication which are known to interfere with sexual activity such as antidepressants, some antihypertensives, sedatives hormones and some allergy medications.
  • Clinical efficacy was evaluated from patient history and patient evaluation questionnaires both before and after medication using a six-point classification scale (Table 6). Each patient was given one (1) placebo and one (1) active dose in a crossover manner with a 5 to 7 day wash-off period in the double-blind portion of the study. In the open-label portion the patients were given only one (1) active dose.
  • the clinical supply was packaged in single-dose containers each containing 250 mg (net weight) of cream and 1 mg prostaglandin Ei.
  • the efficacy response rate was determined as the number of men that had erections sufficient for intercourse out of the total number of men. To be considered a success, a score of 8 to 10 must be achieved after administration of the dose or the patient must have had intercourse.
  • Statistical analysis compared before and after response scores using a paired t- test. A statistically significant difference (P ⁇ 0.001) between all before and after dosing scores was found for each group of patients receiving active medication whether in the double-blind portion of the study or the open label portion of the study. Also, a statistical significance was seen between the active and placebo groups per study site.
  • the topical prostaglandin Ei composition was found to be safe and effective in impotent men with the moderate to severe impotence.
  • the efficacy rate was 64.7%) (66/102 patients) in severely impotent men and 100% (41/41 patients) in mild to moderately impotent men.
  • the overall clinical efficacy rate for the study is 74.8% (107/143 patients) as shown in Table 8, below.
  • the prostaglandin Ei topical composition was extremely effective (100%) in the mild to moderate impotent patient population.
  • the mild to moderate impotence class is the most prevalent class and is estimated to represent 70%> of all erectile dysfunction complaints.
  • the product was also very effective (64.7%) in the severely impotent study population.
  • the open label efficacy rate was lower than the double-blind efficacy rate (Table 9). This was primarily due to the enrollment of a relatively high number of severely impotent men in the open-label portion of the study as compared to the double-blind portion. (Table 8) Of the men enrolled in the open label portion of the study, 79.7%o (63/79) were assessed as severely impotent while only 60.9%> (39/64) were assessed as severely impotent on entering the double-blind portion. The efficacy rate among the severely impotent population is expected to be lower because by definition these men have little or no function. Practically, it is expected to be more difficult to move the impotence classification from 0, 2 or 4 up to 8 or 10. While most of the severely impotent men showed significant improvement, 36 men (36/102 or 35.3%) did not have sufficient improvement to be classified as efficacious.
  • composition D of Example 4 and Table 1, above The safety and efficacy of a 0.4%> prostaglandin Ei topical composition (composition D of Example 4 and Table 1, above) was evaluated in an additional study of a total of 56 men at three study sites.
  • UEF International Index of Erectile Dysfunction
  • SEP Sexual Encounter Profile
  • Forty-nine (49) patients were classified as having mild to moderate erectile dysfunction and 7 patients were classified as having severe erectile dysfunction.
  • Each patient was asked to use from 3 to 10 doses of medication over a four week period in a multiple use, in-home study. The overall efficacy rate for the mild to moderate group was 75%. The results of this study were consistent with the combined overall efficacy rate reported above in Example 9. None of the patients dropped out of this multiple
  • erectile dysfunction which is defined as the inability to achieve and maintain an erection of sufficient rigidity for sexual intercourse due to psychogenic, neurogenic or vasculogenic, causes during the previous 6 months. This includes patients who may still have some erections sufficient for intercourse but not consistently, which is the typical complaint of the age onset, mild to moderate impotent man. The diagnosis of erectile dysfunction based on medical history and physical examination.
  • Exclusion Criteria History of urethral stricture or obstruction.
  • penile surgery including penile implant, prostatectomy or cancer of the prostate, penile trauma including paraplegia or quadriplegia.
  • priapism any condition which might predispose towards priapism, such as sickle cell anemia, multiple myeloma, or leukemia. 5. Hypertension, (sitting diastolic pressure >90 or systolic >150) requiring treatment with other than angiotensin converting enzyme inhibitors (ACE inhibitors).
  • ACE inhibitors angiotensin converting enzyme inhibitors
  • Any concomitant medication which are known to interfere with sexual activity such as antidepressants, some antihypertensives, sedatives hormones and some allergy medications.
  • the patient population in this study consisted of men in the age range of 49-
  • the efficacy response rate was determined as the number of intercourse successes out of the total number of intercourse attempts. To be considered a success, a SEP score of 8 to 10 must be achieved after administration of the dose or the patient must have had satisfactory sexual intercourse.
  • Statistical analysis compared before and after response scores using Chi Square statistics. A statistically significant difference (P ⁇ 0.001) between before and after dosing scores was found for each group of patients receiving active medication.
  • the efficacy response rate was determined as the number of intercourse successes out of the total number of intercourse attempts. To be considered a success, a SEP score of 8 to 10 must be achieved after administration of the dose or the patient must have had satisfactory sexual intercourse.
  • Statistical analysis compared before and after response scores using Chi Square statistics. A statistically significant difference (P ⁇ 0.001) between before and after dosing scores was found.
  • the prostaglandin Ei topical composition was extremely effective (75%) in the mild to moderate impotent patient population.
  • the mild to moderate impotence class is the most prevalent class and is estimated to represent 70%> of all erectile dysfunction complaints.
  • the product was less effective (44% ⁇ ) in the severely impotent study population; however, a statistically significant difference was noted between the before and after treatment scores in this group. Even though all of the men in the severe group were totally without any erectile function before the study, 4 of the 7 men (57%) had successful intercourse from at least 3 out of the 10 doses.
  • Table 1 modified to produce four test compositions having PGEi doses of 0 micrograms (meg) (placebo), 100 meg, 200 meg or 300 meg.
  • the inclusion criteria were: the patients were at least 21 years of age with no upper age limit, a history of erectile dysfunction three months or longer in duration, an HEF erectile function domain score less than or equal to 25, and at least 4 attempts of sexual intercourse during the non-treatment period.
  • Phase 3 clinical studies were based on a study design of randomized, placebo controlled, double-blind, and parallel treatment design involving a take-home study in mild to severe erectile dysfunction patient. There were two separate studies performed in the United States at 85 sites. The patient population consisted of 1732 men 24 -87 years of age. Of the starting population, 1410 completed the study, a 18%) drop out rate. The patients were randomly assigned to four parallel treatment groups: placebo, 100 microgram, 200 microgram, and 300 microgram prostaglandin Ei dose. An initial 4 week non-treatment period was followed by 12 weeks of take- home dosing. Up to 25 doses per patient were self-administered over the twelve week treatment period.
  • the patients in the study were mild to severe erectile dysfunction patients, having HEF erectile dysfunction domain scores less than or equal to 25. Questions 1, 2, 3, 4, 5, and 15 of the IIEF were entered into the study.
  • the demographics of the patient population are summarized in Table 15, below. Note that a given patient may have more than one co-morbid condition in his medical history. Table 15
  • composition of the four treatment groups is summarized in Table 16, below. As noted above, a patient may have had more than one co-morbid condition.
  • Diabetes 85 95 86 356 mellitus
  • the measures used a primary efficacy endpoints were: the change in the International Index of Erectile Function (IIEF) Erectile Function Domain score from baseline to final visit compared to placebo; Question 2 of the Sexual Encounter Profile (SEP): "Were you able to insert your penis into your partner's vagina?”; and Question 3 of the SEP: "Did your erection last long enough for you to complete intercourse with ejaculation?" For the response to Q 2 and Q , mean per patient scores were compared to placebo.
  • Secondary efficacy end points included a Global Assessment Question (GAQ): "Did your erections improve while on the study medication?" as well as the scores on other domains on the IIEF. Erectile dysfunction severity was characterized by HEF erectile function domain scores as follows: severe ( ⁇ 11), moderate (11-16), mild to moderate (17-21), mild (22-25) or normal (>26).
  • the percent of patients achieving a normal IIEF score (>26) after treatment was 6% (placebo), 10% (100 meg), 14% (200 meg) and 16% (300 meg).
  • a semi-solid vasoactive prostaglandin composition delivering a dose of about 100 meg to about 400 meg prostaglandin Ei is applied to the fossa navicularis of the penis at least twice a week, every other day, or on a daily basis.
  • the semi-solid vasoactive prostaglandin composition is applied to thefossa navicularis of the penis about 2-30 minutes before sexual intercourse, preferably about 5-15 minutes before sexual intercourse. About 40 to about 60 percent of the treated patients report that they feel that their erections have improved while taking the medication after about three months of treatment.
  • EXAMPLE 15 Treatment of Erectile Dysfunction in Erectile Dysfunction Patients for Whom Oral Phosphodiesterase-5 Inhibitor Therapy Was Ineffective
  • the measures of efficacy of the treatment in the treatment in the subset of erectile dysfunction patients for whom oral phosphodiesterase-5 inhibitor therapy was ineffective are summarized in Tables 30-33, below.
  • the efficacy of the four treatments as measured by the change in the erectile function domain of the IIEF is shown in Table 31 for this subset of patients who completed the study. The two highest dosage levels produced the largest effect.
  • the differences in scores compared to placebo were not significant at the p ⁇ 0.05 level for all dosages.
  • EXAMPLE 16 Treatment of Erectile Dysfunction in Hypertensive Patients
  • the measures of efficacy of the treatment in the subset of patients who had a medical history of hypertension are summarized in Tables 34-37, below.
  • the efficacy of the four treatments as measured by the change in the erectile function domain of the IIEF is shown in Table 35 for this subset of patients who completed the study.
  • the two highest dosage levels produced the largest effect.
  • the differences in scores compared to placebo were significant at the p ⁇ 0.05 level for all dosages, and significant at the p ⁇ 0.001 level for the 200 meg and 300 meg doses.
  • the treatment produced no serious side effects. Most adverse events were localized to the site of application but were mild, short in duration and well tolerated. Overall, the treatment demonstrated efficacy across a broad range of erectile dysfunction severity and co-morbid conditions.
  • EXAMPLE 20 Treatment of Hypertension Patients Also Receiving Alphai Blockers
  • the measures of efficacy of the treatment in the subset of patients who had a medical history of hypertension and who were also being treated with alphai blockers are summarized in Tables 48-51, below. The small sample size limits the calculation of the p values for comparison of differences.

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Abstract

L'invention concerne des procédés relatifs au traitement des troubles de l'érection chez un patient en état co-morbide, qui consistent à appliquer dans la fossette naviculaire de l'urètre une quantité de composition semi-solide vasoactive à base de prostaglandine induisant l'érection.
PCT/US2003/027885 2002-09-06 2003-09-05 Procedes de traitement des troubles de l'erection chez l'homme WO2004022064A1 (fr)

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EA200500452A EA200500452A1 (ru) 2002-09-06 2003-09-05 Способы лечения эректильной дисфункции у мужчин
EP03755790A EP1534297A1 (fr) 2002-09-06 2003-09-05 Procedes de traitement des troubles de l'erection chez l'homme
JP2004534659A JP2006512291A (ja) 2002-09-06 2003-09-05 男性勃起障害の治療方法
CA002493723A CA2493723A1 (fr) 2002-09-06 2003-09-05 Procedes de traitement des troubles de l'erection chez l'homme
AU2003273291A AU2003273291A1 (en) 2002-09-06 2003-09-05 Methods of treatment of male erectile dysfuntion
IL16627305A IL166273A0 (en) 2002-09-06 2005-01-13 Methods of treatment of male erectile dysfunction
NO20050658A NO20050658L (no) 2002-09-06 2005-02-08 Fremgangsmater for behandling av erektil dysfunksjon i menn

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Publication number Priority date Publication date Assignee Title
WO2004084908A1 (fr) * 2003-03-21 2004-10-07 Nexmed (Holdings), Inc. Compositions de prostaglandine pour le traitement de dyserection
WO2004084861A2 (fr) * 2003-03-21 2004-10-07 Nexmed (Holdings), Inc. Promotion de l'angiogenese par des compositions de prostaglandine et techniques a cet effet
JP2008526854A (ja) * 2005-01-06 2008-07-24 ネクスメツド・ホールデイングス・インコーポレイテツド 局所安定化プロスタグランジンｅ化合物剤形
EP3266458A1 (fr) 2016-07-05 2018-01-10 Fagron B.V. Procédé et composition et kit pour traiter un dysfonctionnement érectile

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WO2001051053A1 (fr) * 2000-01-10 2001-07-19 Nexmed Holdings, Inc. Compositions de prostaglandine et procede de traitement de dyserection male
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004084908A1 (fr) * 2003-03-21 2004-10-07 Nexmed (Holdings), Inc. Compositions de prostaglandine pour le traitement de dyserection
WO2004084861A2 (fr) * 2003-03-21 2004-10-07 Nexmed (Holdings), Inc. Promotion de l'angiogenese par des compositions de prostaglandine et techniques a cet effet
WO2004084861A3 (fr) * 2003-03-21 2005-01-27 Nexmed Holdings Inc Promotion de l'angiogenese par des compositions de prostaglandine et techniques a cet effet
JP2008526854A (ja) * 2005-01-06 2008-07-24 ネクスメツド・ホールデイングス・インコーポレイテツド 局所安定化プロスタグランジンｅ化合物剤形
EP3266458A1 (fr) 2016-07-05 2018-01-10 Fagron B.V. Procédé et composition et kit pour traiter un dysfonctionnement érectile

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