Classifications

• • 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

Definitions

• the present invention relates to the treatment of impotence in males, enhancement of sexual arousal in females and devices for delivering pharmaceutical compositions to treat impotence in males and sexually stimulate females.
• the invention relates to the use of prostaglandin PGE 2 and/or PGF 2 ⁇ in the treatment of sexual disfunction.
• Impotence in the human male can arise from a variety of psychological and physiological etiologies. For example, long term diabetes, damage to the spinal cord, multiple sclerosis, or nerve damage resulting for example from lower abdomen or prostate surgery, and advancing age can result in impotence. Additionally, there are psychological causes for impotence. For differing reasons, each of the foregoing result in an inability to pressurize the corpora cavernosa, which can result in turn from either an insufficient arterial inflow on the supply side, or an insufficient increase in the venous output resistance to blood flow.
• United States Patent No. 4,596,242 to Fischell discloses a surgically implantable hydraulic system, having a fluid reservoir and pressure generator, a patient manipulable valve, a pressure reservoir and a distensible member responsive to actuation of the valve.
• United States Patent No. 4,596,242 to Fischell discloses a surgically implantable hydraulic system, having a fluid reservoir and pressure generator, a patient manipulable valve, a pressure reservoir and a distensible member responsive to actuation of the valve.
• a variety of other prior art mechanical implants and other devices for this purpose are described in the Background of the Invention section of the United States Patent No. 4,596,242.
• prostaglandin E has been observed to produce erection in some cases, by direct percutaneous injection into the penis or as a meltable pellet placed in the urethra (U.S. Patent Nos. 5,773,020; 5,474,535; 5,242,391).
• PGE 1 in a drug composition known as "trimix”, has also been injected directly into the corpus cavernosa to treat impotence.
• trimix a drug composition known as "trimix”
• Pfizer has made sildenafil citrate available in oral dosages as a treatment for impotence under the trade name, Viagra.
• Viagra is counter indicated for use by men with cardiac disease, death in cardiac patients during or following intercourse has been indicated as a possible side effect, and interaction with nitroglycerine may cause immediate death.
• a new warning has been added to labeling for Viagra warning of a possible occurrence of priapism.
• sildenafil citrate is administered orally, the effect of the drug is systemic and not restricted, as in direct delivery to the penis, to a localized response.
• a method of treating erectile dysfunction in a male patient comprising the step of administering to the patient a unit dose of a formulation comprising an erectile dysfunction treating amount of prostaglandin E 2 compound, or pharmaceutically acceptable salts or derivatives thereof.
• the prostaglandin E 2 compound is preferably formulated together with a pharmaceutically acceptable delivery medium, which may comprise local anesthetic agents and/or a lubricant.
• the anesthetic agent comprises lidocaine.
• the dose of PGE 2 may be in the form of a urethra sized suppository meltable at body temperature, coated on a removable wand, carried on and/or in a porous, non-absorbable wand sized for easy placement into and withdrawal from the urethra, or in physiologically acceptable carrier (saline or water) placed in the urethra via a small diameter tube.
• physiologically acceptable carrier saline or water
• the prostaglandin E 2 compound can also be formulated with a small amount of prostaglandin F 2 ⁇ and/or phentolamine mesylate together with a pharmaceutically acceptable delivery medium and/or a lubricant.
• a unit dose of the formulation in accordance with the present invention will typically be less than about 5 cc in volume, preferably less than about 3 cc and most preferably below about 1 cc.
• the amount of active ingredient in a unit dose will typically be within the range of from about 0.1 mg to about 4.0 mg. More preferably, the amount of prostaglandin E 2 in a unit dose will be within the range of from amount 0.6 mg to about 3.6 mg. This is more than the amount of PGE T required for a beneficial result. However, tests show that the results obtained from use of PGE 1 are much less satisfactory than when PGE 2 is used.
• anesthetic such as lidocaine
• 1.2 mg to about 3.6 mg of PGE 2 may be required.
• adding prostaglandin F 2 ⁇ in amounts of about 0.1 micrograms (0.1 ⁇ g) to about 2.0 ⁇ g to either prostaglandin E 2 or E 1 formulations prevents the burning and aching without noticeably interfering with effectiveness of the prostaglandin.
• a preferred amount is 0.25 ⁇ g of PGF 2 ⁇ per 1 mg of PGE 2 .
• adding phentolamine mesylate to this composition further increases the effectiveness of the composition (increased rigidity and increased but controlled longevity).
• the administration step of the method in accordance with the present invention comprises the transurethral administration of the unit dose of formulation.
• the formulation comprises a cream, gel form or saline solution
• the formulation is preferably transurethrally instilled or inserted such as by extrusion through syringe or unit dose administration packet comprising an elongate tubular administration tip.
• An alternative delivery procedure comprises the transurethral placement of a unit dose of the formulation using a coated wand or a suppository containing a quantity of the formulation suitable for delivery to the patient within a preset period of time.
• the suppository can be manually inserted into the distal opening of the urethra.
• a further embodiment provides for urethral insertion of a removable wand, which may be porous, which carries the unit dose in a form which transfers over a controlled period of time through the urethral mucosa.
• Figure 1 is a perspective side view of a first version of the insertable drug delivery device.
• Figure 2 is a cross sectional view taken along line 2-2 of Figure 1.
• Figure 3 is a side view of a second version of the insertable drug delivery device.
• Figure 4 is an end view of the second version of the insertable drug delivery device.
• Figure 5 is a side view of a third version of the insertable drug delivery device.
• Figure 6 is an left end view of the third version of the insertable drug delivery device.
• Figure 7 is an left end view second variation of the third version of the insertable drug delivery device.
• Figure 8 is a cut away side view of the third version of the insertable drug delivery device of Figure 6 inserted in a carrier.
• Figure 9 is a cut away side view of a variation of each of the above versions inserted in a penis.
• Figure 10 is a partial cutaway view of a device for delivery of a liquid dose of impotence treating drug.
• the prostaglandins are a series of cyclic derivatives of certain unsaturated fatty acids. They are found in a variety of tissues, including the prostate gland, the seminal vesicles, the lungs and the brain. These naturally occurring prostaglandin are derived by cyclization of 20-carbon unsaturated fatty acids such as arachidonic acid. See Lehninger, Albert L., Biochemistry. 2d ed. (1975), p. 300 (hereinafter "Lehninger”)-
• PGE 2 prostaglandin E 2
• PGE 2 has the ring configuration characteristic of the E group and contains two side chain double bonds.
• the chemical name for PGE 2 is (5Z, 11 ⁇ , 13E, 15S)-11 , 15-
• Dihydroxy-9-oxo-prosta-5, 13-dien-1-oic acid and the structural formula of one form is represented in Formula I, below.
• the molecular formula is C 20 H 32 O 5 .
• prostaglandin has been well characterized. See. e.g.. Lehninger at p. 687.
• the essential fatty acid linoleic acid is converted into the 20-carbon arachidonic acid, which is then acted upon by prostaglandin synthase, doxygenase enzyme.
• Oxygen atoms are added at carbon atoms 9 and 15, and the product is cyclized by formation of a bond between carbon atoms 8 and 12.
• this synthesized product undergoes conversion into prostaglandin PGE 2 .
• Other types of naturally occurring prostaglandins are derived from different polyunsaturated fatty acids.
• Prostaglandins are known to produce often unpredictable effects over a very wide range of biological activities of a hormonal or regulatory nature.
• Prostaglandin have been reported to both lower and raise blood pressure, to inhibit gastric secretion, dilate bronchi, inhibit lipolysis, antagonize vasopressin-induced anti-diarrhesis, constrict the pupil, increase and decrease the intraocular pressure and produce contraction of the uterus. See, e.g.. Ganong, William F., Review of Medical Physiology. 7th ed. (1975), p. 226 (hereinafter "Ganong").
• the naturally occurring prostaglandin all appear to be capable of affecting the control of vascular and other smooth muscle contractions.
• prostaglandin are known to modify responses to certain synaptic transmitters. They have been reported to mimic the actions of some hormones and to inhibit the actions of certain others. See Ganong at 226.
• PGE 2> and PGF 2 ⁇ Two of the most extensively studied of the prostaglandin are PGE 2> and PGF 2 ⁇ . Both of these molecules are synthesized within the pregnant and non-pregnant uterus. While PGE 2 and PGF 2 ⁇ are similar in mediating some effects, they are different with respect to certain others. Both cause uterine contractions, but they predominate at different sites within the uterus - PGE 2 in the lower uterine segment, PGF 2 ⁇ is more important in generating uterine contractions.
• PGE 2 elevates body temperature, whereas PGF 2 ⁇ has no apparent effect on body temperature.
• PGE 2 is a vasodilator and bronchodilator, while PGF 2 ⁇ is a bronchoconstrictor and vasoconstrictor.
• Prostaglandin have been used in gynecology for pregnancy termination. Preparing the cervix with prostaglandin suppository has been found to reduce the incidence of cervical laceration and significant bleeding (Catanzarite at 22).
• Synthetic analogues of prostaglandin PGE 2 such as 16- 16-dimethyl PGE 2 and 9-methylene PGE 2 , have proven useful for the induction of first trimester abortions.
• vaginal suppositories containing 20 milligrams PGE 2 or 3 milligrams 15-methyl PGF 2 ⁇ , or by repeated intramyometrial injections of 15-methyl PGF 2 ⁇ , or by infusing a PGF 2 ⁇ -urea mixture (20 milligrams of PGF 2 ⁇ and 40 milligrams of urea in 100 Ml of 5% dextrose in water) into the amniotic sac.
• prostaglandin have been used for cervical ripening, labor induction and control of post-partum hemorrhage (Catanzarite at 29).
• PGE 2 had been given intravenously, orally and vaginally, but the preferred route is intracervically.
• a PGE 2 gel is now commercially available in Scandinavia, and another PGE 2 , gel is being investigated in the United States.
• the PGE 2 gel can also be used for labor induction (3-5 mg of PGE 2 , prepared by blending a 20 mg suppository with 60 mL of lubricating jelly and using 9-15 mL of the mixture, is placed in the vagina) (Catanzarite at 32).
• Prostaglandin have also been utilized to control post-partum hemorrhage.
• Prostaglandin PGE 2 also known as the "Prostin E 2 " brand of "dinoprostone," is available from Upjohn Company in the form of a vaginal suppository. Indications and usage reported by Upjohn are (i) termination of pregnancy from the 12th through the 20th gestational week, (ii) evacuation of the uterine contents in the management of missed abortion or intrauterine fetal death up to 28 weeks of gestational age, and (iii) in the management of non-metastic gestational trophoblastic disease (benign hydatidiform mole). See The Upjohn Co., Prostin E 2 product description 810 994 009, Oct., 1990. PGE 2 is also available from several sources as a purified, freeze dried or lypholized product which is readily soluble in saline or distilled water.
• Contraindications to the use of prostaglandin PGE 2 include hypersensitivity to dynoprostone, acute pelvic inflammatory disease, or patients with active cardiac pulmonary renal or hepatic disease.
• Upjohn notes that although carcinogenic bioassay studies have not been conducted in animals for PGE 2 (because of the limited indication for use and the short duration of administration), there was no evidence of mutagenicity in either the Micronucleus Test or in the Ames Assay. Upjohn also indicates that a number of adverse reactions may be observed with the use of PGE 2 for abortions. These adverse reactions are related to the contractile effect of PGE 2 on smooth muscle and include vomiting, temperature elevations, diarrhea, nausea, transient diastolic blood pressure decreases, and a number of other effects.
• Upjohn's vaginal suppository contains 20 mg of PGE 2 in a mixture of glycerides of fatty acids.
• Upjohn markets a (15S)-15-methyl analogue of prostaglandin PGF 2 ⁇ under the brand name Hemabate®, also known as "carboprost tromethamine sterile solution.”
• the structural formula of Hemabate® is represented in :
• Hemabate® is indicated for aborting pregnancy between the 13th and 20th weeks of gestation, in certain conditions related to second trimester abortions, and in the treatment of post-partum hemorrhage. See The Upjohn Co., product description 814 350 002, Nov., 1989.
• the prostaglandin solution is injected using a syringe and administered deep in the muscle. Intramuscular injection is also used for treating post-partum uterine bleeding.
• Upjohn also markets prostaglandin PGE ⁇ as the "Prostin VR Pediatric” brand of “alprostadil sterile solution,” which is used to temporarily maintain the patency of the ductus arteriosis until corrective surgery can be performed in neonates having congenital heart defects and who depend upon the patent ductus for their survival.
• PGE ⁇ Prostin VR Pediatric
• alprostadil sterile solution which is used to temporarily maintain the patency of the ductus arteriosis until corrective surgery can be performed in neonates having congenital heart defects and who depend upon the patent ductus for their survival.
• PGE 2 or a pharmaceutically acceptable salt, ester or other derivative thereof is formulated together with a carrier medium which may comprise any of a variety of additional excipients or adjuvants into a form suitable for transurethral delivery.
• a carrier medium which may comprise any of a variety of additional excipients or adjuvants into a form suitable for transurethral delivery.
• One approach is to apply the composition to a wand, which may be either porous or non- porous, in sufficient quantities so that the desired dosage is released and absorbed through the mucosa of the urethra when the coated wand is placed in the urethra.
• the wand When an erection of the desired tumescence is obtained the wand is then removed, terminating delivery of the composition, thus significantly reducing the possibility of overdosing.
• the formulation may be provided in the form of a meltable suppository, such a delivery means is unsuitable for removal to terminate delivery of the composition and can result in overdosing as well as the delivery of excess PGE 2 to the vagina of the partner.
• a suitable amount of a freeze dried PGE 2 is dissolved in physiological saline or sterile water and placed within the urethra using a short, small diameter catheter.
• the PGE 2 absorption is rapid with an erection, ensuing within 3-5 minutes, persisting for 1-2 hours depending on dosage.
• alternative replacements for the water carrier include creams or gels which can flow at or above room temperature, for example at body temperature.
• an antidote for reversing the effects of the foregoing PGE 2 treatment comprising administration of an antidotal amount of PGF 2 ⁇ , or pharmaceutically acceptable salts, esters or derivatives thereof.
• PGF 2 ⁇ Preferably, 15-methyl PGF 2 ⁇ is utilized for this purpose.
• This antidote can be delivered in the same manner as discussed above.
• the PGE 2 or PGF 2 ⁇ or combination of PGE 2 and PGF 2 ⁇ with or without other additives as discussed below will comprise a cream, gel, or water based solution although a more solid form such as pellets or a rod- shaped suppository body may also be used.
• the PGF 2 ⁇ may be substituted for delivery purposes. These devices are also applicable to delivery of PGE., compositions or other impotence treatment drugs.
• Administration of the liquid, cream or gel form may be accomplished by transurethral delivery using a syringe without a needle, or with a short blunt cannula attached.
• the liquid, gel or cream forms are preferably provided in unit dose amounts for self administration by the patient.
• compressible unit dose packages are preferably provided with an elongate tubular delivery spout, sized for transurethral insertion.
• the distal end of the urethra is preferably occluded, such as by manual pressure for up to several minutes, to permit sufficient dwell time for absorption.
• a typical male urethra in a flaccid penis is from about 2.5 cm to about 8 cm and the typical diameter of the urethra is from about 1 mm to about 3 mm.
• the wand with PGE 2 and/or PGF 2 ⁇ applied has a diameter approximating the urethra diameter or slightly larger so that the outer surface of the wand is in intimate contact with the mucosal lining of the urethra or swells when inserted.
• the typical length of the insertable portion of the wand is from 20% to 90% of the patients' urethra in the flaccid state, preferred 25%- 40% with some or all of the insertable portion coated with PGE 2 .
• the wand also has an external portion or length for grasping between the users fingers for placement and removal.
• This portion may be of a larger diameter or a flange may be positioned between the insertable portion and the exterior portion to prevent the wand from being inserted too far into the urethra.
• a first embodiment of the drug delivery device, shown in Figure 1 comprises a wand 10 which is sized to be placed within the urethra of the penis.
• the wand has an insertable portion 12 which, in use, resides in the urethra, and a holding portion 14 for grasping by the user during insertion.
• the insertable portion 12 has a partial or complete covering of PGE 2 in a suitable carrier 16.
• Figure 2 shows the wand 10 in cross section.
• the wand is shown as porous, with pores 18, the PGE 2 , with or without a carrier, 16 being both on the surface of the wand 10 and in the pores 18.
• the invention contemplates a nonporous wand 10 with the PGE 2 and carrier coated only on the surface as well as an alternate porous version with the PGE 2 and carrier being on both the surface as well as in the pores.
• the porous version allows delivery of more drug to the patient. However, because some of the drug is within the pores, the delivery rate for that portion may be slower than for the PGE 2 in the surface coating.
• a second embodiment of the drug delivery device shown in Figures 3 and 4, in addition to the features shown in Figures 1 and 2, has a handle 20 for grasping by the user during insertion and removal of the device.
• the shoulder 22 prevents the wand from being inserted too deeply.
• the cap is shown to have a curved profile similar to the rounded shape of the head of the penis. However, any shape is usable as long as the width of the cap is greater than the diameter of the urethra so as to prevent insertion of more than the desired length.
• Figure 6 shows the cap 24 as hemispherical in shape so that it can also serve as a cap to close a carrying container 26, such as shown in Figure 8.
• the cap 24 has threads 28 on its lower surface which can interact with similarly disposed threads 30 on the outer upper end of the container 26.
• the drug containing wand 10 can be inserted in the container 26 and closed and sealed, such as by a sonic or heat weld, to keep the PGE 2 from contamination or dissipation.
• the threads 28 can be replaced by other sealing means such as snap rings or a friction fit, each of which may be further sealed by an externally applied adhesive tape (not shown).
• Figure 7 shows a further variation of the embodiment of Figure 5 wherein the cap 24 is replaced by one or more extensions 32 which radiate outward from the wand 20 at the juncture of the insertable portion 12 and the holding portion 16.
• Figure 7 shows four extensions 32 which can be extended perpendicular to the wand 10 surface to be curved as in Fig. 5.
• FIG. 9 is an enlarged cut away view showing a further embodiment of the PGE 2 delivery device incorporating features shown in Fig. 7 placed within the male urethra.
• the porous wand 10 has the PGE 2 material in a suitable carrier 16 coated on the surface and in the pores of the wand.
• the insertion end of the wand 10 has a rounded tip 42 which has a diameter which approximates the diameter of the urethra.
• a length of the inserted portion 12 is coated with the PGE 2 and carrier composition 16, the composition or the PGE 2 alone also being carried in the pores 18 of the wand 10. As the PGE 2 coating melts or is absorbed, the diameter of the inserted coated portion decreases exposing the rear edge 44 of the rounded tip 42.
• the rear edge 44 acts as a wiper to remove excess PGE 2 and carrier from the urethra, thus substantially stopping the delivery of PGE 2 to the tissue of the penis. In this manner, the chance of overdose or transfer to the sexual partner during intercourse is greatly reduced or eliminated.
• a delivery device 100 for the PGE 2 solution shown in Figure 10 consists of a tube 102 with an integral squeeze bulb 104.
• the dimensions of the device are chosen so that a unit dose 106 of PGE 2 in a suitable solvent is held within the length of the tube and adjacent portion of the squeeze bulb 104 and the squeeze bulb 104 can contain a volume of air 108 such that squeezing of the bulb 104 between two fingers will expel the unit dose.
• squeezing the bulb results in droplet or spray delivery of the tube's contents along at least a portion of the length of the urethra downstream of the inserted end of the tube 102.
• the tube is from about 1.0 to 3.0mm in length, has an outer diameter of about 2.5mm and an inner diameter of about 1mm. This inner and/or outer diameter may be reduced at the insertable end of the tube to ease insertion and to create a spray of delivered product.
• the tube is able to contain about 0.01 to 0.03cc of liquid and the bulb is capable of delivering at least 0.1 cc of air when compressed.
• the tube inner and outer diameter may be smaller and a portion or all of the unit dose may be in the bulb. This allows retention of about 0.01 cc of a liquid in the lumen of the tube.
• the delivery of the liquid composition is not limited to the use of the device of
• the PGE 2 composition applied to the wand depends on whether a porous or nonporous wand is used.
• a liquid solution of the PGE 2> a carrier, and possibly an anesthetic and/or a transport adjuvant such as a meltable, swellable or soluble compound is prepared and the wand is dipped in the solution until sufficient active material is deposited on and in the pores of the wand.
• This may be supplemented by a less fluid composition, with or without PGE 2 applied to the surface of the wand, the surface composition preferably including a lubricant or having lubricating properties.
• PGE 2 While transurethral delivery of PGE 2 is a highly effective means of treating impotence, an undesirable side effect in some individuals is a sensation of urethral burning or pain and cavernous sinus aching in the genital area.
• One approach is to add a lubricant and/or a local anesthetic for desensitization thus masking these side effects.
• the PGE 2 , lubricant and anesthetic are all formulated into a convenient cream. This cream may be prepared, for example, by mixing one Upjohn Prostin E® PGE 2 suppository together with 10 cc of a lidocaine jelly such as Xylocaine® 2% jelly (available from Astra Pharmaceutical Products) and 50 cc.
• Lidocaine HC1 available in a variety of formulations, comprises acetamide, 2- (diethylamino)-N-(2,6-dimethylphenyl) -monohydrochloride.
• lidocaine jelly can be used having anywhere from about 1% to about 10% and preferably about 2% lidocaine.
• the anesthetic level can largely be dictated by patient preference, as determined through routine experimentation. Although the incidence of adverse effects with Xylocaine ® 2% jelly is very low, caution should be exercised when applying large amounts since the frequency of adverse effects is directly proportional to the total dosage of the local anaesthetic administered. See Astra Pharmaceuticals, product description 021838R11 , June 1986; in Physician's Desk Reference, 45th Edition (1991), at p. 628.
• anesthetic agents can also be used with the formulation of the present invention, as will be appreciated by one skilled in the art.
• novocaine, procaine, tetracaine or benzocaine may be selected.
• Patients allergic to para-aminobenzoic acid derivatives such as procaine, tetracaine and benzocaine have not appeared to show cross sensitivity to lidocaine.
• Lidocaine is also contraindicated in patients with a history of sensitivity to amide type local anesthetics.
• Xylocaine® 2% jelly also contains methylparaben, propylparaben and hydroxypropylmethylcellulose, as well as lidocaine; and, therefor, Xylocaine® is contraindicated for patients with known sensitivities to any of these compounds. See Astra Pharmaceuticals, product description 021838R11, June 1986; in Physician's Desk Reference, 45th Edition (1991), at p. 628.
• the dosage of PGE 2 must be increased over that in a non-lidocaine-containing formulation, and more preferably, the PGE 2 dosage is preferably doubled in a lidocaine- containing formulation in order to obtain the same effect on impotence.
• a further negative of adding an anesthetic is that it masks the pain rather than elevating the cause of the pain and may in fact reduce the pleasurable effects of intercourse by reducing tactile sensitivity. Similar dosage increases are required with PGE., but since PGE., appears to be less soluble in carriers than PGE 2 , adequate dosages of PGE, with anesthetic may not be readily prepared for delivery.
• the total volume of the impotence treating unit dose should be no more than 5 cc, and preferably from about 1 cc to no more than about 2 cc due to the inherent capacity of the urethra. Doses of excessive volume can result in painful administration, and also in retrograde migration of the excess formulation into the prostatic urethra or bladder.
• the total amount of PGE 2 contained in a unit dose will be within the range of from about 0.2 mg to about 5.0 mg. Due to differing etiology of erectile dysfunction, and inherent variations across a population in terms of responsiveness to pharmaceutical agents, some routine experimentation may be desired to determine optimum dosages for a given patient or class of patients.
• doses within the range of from about 0.2 to about 5.0 mg, and preferably from about 0.6 to about 3.6 mg PGE 2 have generally proven sufficient in patients in which a response is likely to occur.
• certain classes of patients are anticipated to be treatable depending upon the etiology of the condition. For example, patients in whom erectile dysfunction is associated with vascular abnormalities such as atherosclerosis which prevents adequate blood inflow are not likely to respond. Patients in whom the dysfunction is a result of such conditions as diabetes, denervation, or psychological status are expected to be more likely to respond.
• the PGF 2 ⁇ will generally be present in an amount within the range of from about 5 to about 50 ⁇ g per 1 cc of formulation, preferably within the range of from about 8 to 20 ⁇ glcc and more preferably about 12 ⁇ g/cc.
• optimum dosage for a given patient can be determined through routine experimentation.
• PGF 2 ⁇ reverses the effect of PGE 2 , i.e. terminates an erection. It has now been found that mixing small amounts of PGF 2 ⁇ with PGE 2 eliminates the burning or aching experienced by some individuals when PGE 2 is used alone. It has further been discovered that, unlike the addition of an anaesthetic to PGE 2 , adding PGF 2 ⁇ in small doses does not reduce the beneficial effects of PGE 2 , alleviates the cause of the pain rather than masking it and does not reduce the desirable sensory effects of intercourse. Further, additional amounts of PGE 2 are generally not required to obtain the same beneficial effects.
• a suitable PGE 2 composition to eliminate the undesirable burning and aching sensation without noticeably reducing the impotence treatment effect of the PGE 2 includes from about 0.1 ⁇ g to about 2.0 ⁇ g of PGF 2 ⁇ Below about 0.1 ⁇ g the burning and aching may persist and above about 2 ⁇ g and erection may occur more slowly and may not be adequate for intercourse.
• a preferred composition includes about 0.25 ⁇ g of PGF 2 ⁇ for each milligram of PGE 2 .
• a typical composition to produce an erection effective for intercourse comprises 1.Omg PGE 2 - 0.25 ⁇ gm PGF 2 ⁇ and 0.25mg phentolamine mesylate in about 0.2cc of a suitable carrier, such as sterile water. Smaller or larger doses, volumes or variations on the ratios of components may be used to adjust to particular patient response and disease etiology.
• a fluid, cream, gel system or solid suppository can be used and the carrier can be absorbed directly, or allowed to be expelled following sufficient dwell time which may be controlled by occluding the distal end of the urethra.
• more solid delivery vehicles may be used such as an ovoid or rod-shaped suppository.
• Suppositories can be formulated from any of a variety of materials which exhibit sufficient physical integrity to permit transurethral insertion and which will then permit delivery of the medication. Once installed, the structural component of the suppository may break down under the influence of body heat.
• An advantage of applying the meltable composition to the surface of the wand is that the wand can be removed once the desired erection is achieved, thus terminating drug delivery, a procedure not afforded by suppository products.
• the PGE 2 composition placed in the pores of the wand can be protected until delivery by applying a sealing material on the surface of the wand, the sealing material melting or dissolving when placed within the urethra.
• materials can be used which will dissolve in an aqueous environment at a pH within the range of that typical of the urethra.
• One suitable composition is a mixture of glycerides of fatty acids such as that used with the Prostin E 2 ® product.
• Other suitable compositions include various cellulose based materials such as hydroxypropylmethylcellulose or collagen compositions which can be prepared as a fluid water-based material, a viscous solution, a gel or a water swellable dry coating.
• One skilled in the art can identify numerous physiologically acceptable water soluble materials or hydrogels which can be used for the purposes set forth above.
• Relatively rigid rod-shaped delivery vehicles may be fashioned from materials having a micro porous structure for the time release of entrapped pharmaceutical.
• transurethral insertion of a wand is that it can be inserted for a predetermined period of time and then removed following delivery of an efficacious amount of drug.
• the removable time release delivery structure has the added advantage of providing a range of flexibility in the total delivered dose. Thus, the patient, by leaving the implant in place for relatively shorter or longer periods of time, can optimize the dose within a preset maximum range.
• compositions disclosed herein can be readily dispersed along the length of the urethra allowing delivery through a large area of tissue surface, thus reducing or eliminating the undesirable effects of delivering high dose concentrations to a very localized area, including slower dispersion, localized discomfort and less pronounced effectiveness.
• a batch of PGE 2 cream was prepared by mixing 40 mg of PGE 2 suppository (obtained as the "Prostin E 2 " suppository from the Upjohn Company) with 10 cc of 2% Xylocaine jelly and 50 cc of K-Y surgical lubrication jelly (hydroxyethyl-cellulose, obtained from Johnson & Johnson). Mixing was accomplished by stirring until the mixture appeared homogenous upon visual inspection. The result was a PGE 2 cream having approximately 1.3 mg of PGE 2 per 2 cc of cream. A portion of the cream was reserved for placement directly into the urethra while a second portion was applied to the surface of a wand. Approximately 2 cc of cream was applied to a 4 cm of the insertable length of a porous wand to produce a coated product 5 mm in diameter. This can be readily inserted and removed from the urethra.
• the homogenecity of a bath of PGE 2 is ensured by inclusion of a methylene blue marker.
• PGE 2 suppository (“Prostin E 2 " from the Upjohn Company) is sliced into thin slices and allowed to soften at room temperature for 15 minutes. A small drop of 1% methylene blue solution (American quinine, Shirley, New York) is placed onto each slice to serve as a marker for homogenicity. The softened slices are thereafter geometrically mixed with the contents of a 56.7 gram tube of K-Y jelly to yield a homogenous mixture, as evidenced by blue color uniformity. The theoretical content of the final product is approximately 0.68 milligrams of PGE 2 per 2 cc of gel.
• a portion of the cream was reserved for placement directly into the urethra while a second portion was applied to the surface of a wand.
• the gel was applied to 4 cm of the insertable length of a porous wand to produce an insertable product having a 3.0 to 5.0 mm diameter for insertion in the male urethra.
• EXAMPLE III Preparation of Lipid Based Intraurethral PGE Cream
• a batch of PGE 2 cream in cocoa butter is prepared by placing one 20 mg.
• PGE 2 suppository Prostin E 2 by the Upjohn Company
• Shredded cocoa butter is added to the melted suppository with stirring to bring the total mass to approximately 20 grams.
• the temperature of the mixture is kept at or below about 33° C. Higher temperatures are to be avoided, as they have been reported to cause the crystalline form of the cocoa butter to change, resulting in aberrations in bioavailability.
• Transformations in the crystalline form of the cocoa butter are visually observed as a change from opalescent to transparent.
• the mixture is stirred thoroughly and a first portion poured into suppository molds.
• the material is thereafter allowed to cool at room temperature for about 15 minutes, and thereafter is placed in the refrigerator to facilitate further solidification.
• the suppositories may thereafter be removed from the mold, individually packaged and placed in refrigerated storage under anhydrous conditions.
• a second portion of the mixture was applied to 4 cm of the insertable length of a porous wand which was about 2 mm in diameter using a tubular mold.
• the material is thereafter allowed to cool at room temperature for about 15 minutes, and thereafter is placed in the refrigerator to facilitate further solidification in to 5 mm diameter coated wands.
• the coated wands are thereafter removed from the mold, individually packaged and placed in refrigerated storage under anhydrous conditions.
• PGE 2 cream was prepared and administered in accordance with the procedures of Examples I and IV, except that a 20 mg PGE 2 suppository was used instead of a 40 mg suppository.
• This cream contained approximately 0.7 mg of PGE 2 per 2 cc of cream.
• Two cc of cream was used to treat each of ten impotent men between the ages of 50 and 70. After 15 to 30 minutes, treatment response was rated as no penile tumescence, partial tumescence, or full tumescence. As a result, four of the ten men treated had no response, two had partial tumescence, and four had full tumescence.
• 60% of the men treated showed at least partial penile tumescence in response to the intraurethral PGE 2 cream.
• Those treated with the cream treated wand would be expected to have a similar response.
• a wand carrying approximately 5 mg of PGE 2 in a hydrogel polymer carrier was placed into the urethral meatus of a 65 year old impotent male patient.
• Detumescence commenced at approximately 1 hour after removal.
• An antidotal formulation is prepared by mixing approximately 250 micrograms of prostaglandin F 2 ⁇ obtained as Hemabate, marketed by Upjohn, in approximately 20 cc of K-Y jelly. Mixing is accomplished manually until visual observation reveals a homogenous composition. A dose of approximately 1 cc of the foregoing formulation was instilled into the urethra of an erect penis, to reverse the results of the PGE 2 treatment in accordance with the present invention. Following delivery of the PGF 2 ⁇ there is immediate relief of pain and within 5 minutes detumescence resulted.
• Freeze dried PGE 2 was obtained from Chinoin Pharmaceutical and Chemical Works Co. Ltd., Budapest, Hungary. Three different solutions were prepared with PGE 2 concentration being 0.5, 1.0 or 1.5 mg/ 0.1 cc of physiological saline. Samples were also prepared with the addition of PGF 2 ⁇ to the PGE 2 solution in the amount of 0.25 ⁇ g/1.Omg PGE 2 The several different solutions were instilled into the urethra of a normally impotent male at a distance of at least about 1 cc from the external opening of the urethra. An erection suitable for sexual intercourse occurred within about 3 to 5 minutes after placement of the solution and the erection lasted about 1 hour.
• PGE 2 when applied to the mucous membrane of the introitus, labia minora, and/or clitoris of female external genitalia can also cause a physiological response reported to enhance sexual relations by causing engorgement of the treated tissue with blood in a manner similar to the creation of an erection in a male.
• PGE 2 prepared in a cream in the same manner as described above, when applied to the external female genitalia, increases blood flow to the tissue treated which, in turn, causes a temporary swelling of the external genitalia to which applied and an enhanced sensitivity to external stimuli.
• a typical response is engorgement of the genitalia, redness, swelling and increased sensitivity typical of a normal response in an aroused female, the response occurring within about 10-15 minutes following application.
• a similar response results from use of PGE 2 dissolved in a liquid carrier, such as water, when applied onto the genitalia or dispensed from a spray dispenser onto the external genitalia.
• PGE 2 /PGF 2 ⁇ can also be used with a similar result. It is also believed that the addition of phentolamine mesylate will also have a beneficial effect.

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• 1998
  • 1998-12-15 EP EP98963194A patent/EP1059926A2/de not_active Withdrawn
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  • 1998-12-15 CN CN 98812205 patent/CN1282249A/zh active Pending
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