TWI324930B - Prostaglandin compositions and methods of treatment for male erectile dysfunction - Google Patents

Description

1324930 (1) 玖, the description of the invention (the description of the invention should be described: the technical field, prior art, content, embodiment and schematic description of the invention) FIELD OF THE INVENTION The present invention relates to compositions and methods for treating erectile dysfunction In particular, it relates to the administration of a vasodilator drug to a patient's scaphoid (fossa navicularis) in a scaphoid manner. The so-called "impotence" of the prior art means that men cannot achieve and maintain an erection of the penis, so that there is no satisfactory sexual intercourse. "Eccentric dysfunction" is "a penis that men cannot reach an erection during all the multifaceted processes of male sexual function." " has been suggested to be more precise, Droller, MJ et al. Impotence. Consensus Development Conference Statement, National Institutes of Health (1993). Erectile dysfunction can begin with a pathological cause (cardiac erectile dysfunction) or an organic cause or a mixture of the two. Mechanical causes include physiology, nerve, vascular and hormonal pathology or a mixture thereof. The normal physiology of erection involves nerve impulses, which transmit signals to certain muscles to relax them. These muscles, when contracted, restrict blood flow through the arteries of the penis. When relaxed, the muscle causes a significant increase in blood flow. The increased blood flow causes three groups of erectile tissue in the penis to become congested, making the penis weak. The erectile tissue and muscle structure of the penis can compress adjacent veins and restrict blood flow out of the penis. Blood outflow penis is controlled to increase and support erection. Loss of certain hormones, such as ketones, or other hormones, such as prolactin, can cause erectile dysfunction. Many drugs, such as diuretics, anti-hypertension, anticonvulsants, etc., anesthetics, alcohol and psychotropic agents can cause erections -6- 1324930

(2) dysfunction 'This is a side effect. Murray, F. T. et al. Amer. J. Medical Sci. 309: 99-109 (1995). Neurological and vascular damage is also an important cause of erectile dysfunction. The disease process involves many aspects. For example, diabetes, which can damage the nerves and blood vessels, causes erectile dysfunction. A large proportion of all diabetic males suffer from erectile dysfunction. The methods proposed for the treatment of erectile dysfunction include external devices, sexual treatments, surgical implantation of internal prostheses, direct injection of drugs into the penis, and topical application of drugs. None of these methods is fully effective. External devices include tourniquets (see U.s. Pat. No. 2, 818, 855) and vacuum erection aids applied externally. Although some physicians consider the addition of erectile auxiliaries as the first choice for treatment, some patients do not want to use this device. O'Keefe, M., et al. Medical Clinics of North America 79: 415-434 (1995). Sexual treatment based on symptoms was first discovered by Masters and Johnson, but later studies did not show such impressive results. Freudian therapy is not another attractive method for patients. Vickers, M. A. et al. J. Urology 149: 1258-1261 (1993) » Surgical implant mechanisms, such as hinged or solid rods and expanded spring-driven or water-based prostheses have been in use for some time. Injecting drugs that can achieve and strengthen erections is taught at U.S. Pat. N6. 4,127,118 (LaTorre). This patent teaches the infusion of a suitable vasodilator, in particular an adrenergic blocker or smooth muscle relaxant, into the penis to achieve and strengthen the erection to treat male impotence. 1324930

(3) Recently, U.S. Pat. No. 4,801,587 (Voss et al.) teaches the application of ointment to relieve impotence. The ointment consists of the vasodilator papaverine, hydralazine, sodium nitroprusside, phenoxybenzamine, or 'phentolamine' and its main The agent consists of a carrier that is absorbed through the skin. U.S. Pat. No. 5,256,652 is taught by El-Rashidy to use a vasodilator, such as papaverine, plus an aqueous topical composition of hydroxypropyl cold-cyclodextrin. Prostaglandin £1 is a derivative of prostatic acid, a fatty acid of 20 carbon atoms, represented by

It is commercially available, for example, from Chinoin Pharmaceutical and Chemical Works Ltd. (Budapest, Hungary) under the registered name "Alprostadil USP." Prostaglandin E! is a vasodilator that can be used to maintain open blood vessels and is therefore particularly useful in the treatment of peripheral vascular disease. While the potential benefits of prostaglandin vaginal delivery have long been recognized, previous efforts to develop topical compositions that deliver prostaglandins have not been entirely successful. In a commercial version (MUSE®, Vivus, Menlo Park CA), alprostadil is administered as a small agglomerate in the urethra, using an applicator with a hollow stem length of 3.2 cm and a diameter of 3.5 mm ( & (111^7 &&11,11., et al., N. Engl. J. Med., 336: Bu 7 (1997), especially see Figure 1). At 1324930 (4)

In the home treatment section of Padma-Nathan et al., 32.7% of patients receiving MUSE® (10.8% of the patients complained of penile pain) and 5.1% experienced minimal urethral trauma, compared with 3 patients who received placebo. 3% and 1. 〇°/〇 comparison. The frequency of these side effects reported changes in the following studies: MUSE® produces penile pain as 17-23.6% of the drug's dose compared with 1_7% of placebo, and mild occlusion has 48% of patients (Peterson, CA· , et al_, J. Urol., 159: 1523-1528 (1998)). In the European population study, 31% of MUSE® patients reported penile pain or burning sensation, 4.8% had urethra '" tile blood' and 2.9% had severe testicular pain (Porst. H. Int. J_ Impot· Res· , 9: 187-192 (1997)). The percentage of patients who responded to MUSE® treatment was defined by having at least one erection as sufficient for sexual intercourse, reported 43% (Porst, 1997), 65.9% (Padma-Nathan et al_, 1997) and 70.5% (Peterson et al., 1998), although published comments have suggested that 'the percentage of patients who responded to the latter two studies is 30-40% correct (Benson, G., J. Urol· , 159: 1527-1528 (1998)). In particular, there is currently no commercial source for local semi-solid blends that are still used in unsupported devices such as adhesives, adhesive strips, etc. ^

Wendel et al., U.S. Pat. No. 5,380,760, is directed to a topical prostaglandin blend comprising a sensible polyisobutyl adhesive strip. Most drugs, when used alone, also include prostaglandin blends and do not adequately penetrate the skin to provide a level of drug concentration comparable to that obtained by other drug delivery routes. To overcome this problem, topical drug blends typically include a skin penetration enhancer. Skin penetration enhancer is also known as suction 1324930

(5) Reinforcing agents, accelerators, adjuvants, solubilizing agents, sorption enhancers, etc. Regardless of its name, this agent can be used to improve the absorption of drugs across the skin. The ideal penetration enhancer not only increases the flux of the drug across the skin, but also does not irritate, sensitize or damage the skin. Further, the desired penetration enhancer should not adversely affect the physical properties of the applicable dosage form (e.g., emulsion or gel), or the cosmetic qualities of the topical composition. Various compounds have been evaluated for their effectiveness in enhancing skin penetration rates. For example, Percutaneous Penetration Enhancers, Maibach Η. I. and Smith Η· E. (eds·), CRC Press, Inc., Boca Raton, FL (1995), in which the use and testing of various skin penetration enhancers, and Biiytiktimkin Et al., Chemical Means of Transdermal Drug Permeation Enhancement in Transdermal and Topical Drug Delivery Systems, Gosh TK, Pfister WR, Yum SI (Eds.), Interpharm Press Inc., Buffalo Grove, IL. (1997). Completely successful local or transmucosal confluences of prostaglandin £1 have not been identified and commercialized. Unfortunately, prostaglandin E i can be easily transformed for rearrangement and other reactions. This considerable instability complicates the composition of the blend for boat delivery. The present invention addresses these problems by providing a semi-solid, anti-separation and chemically stable composition in a boat-like delivery method and composition, such that the vasodilator, preferably prostaglandin E!, has a relatively rapid and sustained delivery. SUMMARY OF THE INVENTION The present invention provides a composition and method for treating erectile dysfunction, wherein a pharmaceutical composition is applied to a mammalian yin in a boat-like application -10 - 1324930

(6) Stems. In another aspect, the present invention provides a composition for preparing a pharmaceutical composition for treating erectile dysfunction, which is a pharmaceutical composition which can be applied to a scaphoid of a penis.

The present invention provides a method of treating erectile dysfunction comprising embedding an erectile effective dose of a semi-solid tense prostaglandin Ei composition in a patient's scaphoid fossa. The composition contains a vasodilator, preferably a prostaglandin E 1, a penetration enhancer, a shear-thinned polysaccharide, a lipophilic compound, and an acidic buffer solution system. The penetration enhancer is an alkyl-2-(N-substituted amino)-alkanoate, (N-substituted amino)-alkanol alkanoate, or a mixture of these. The lipophilic compound can be aliphatic (: 8 alcohol, aliphatic (: 2 to C30 ester, aliphatic C 8 to C 3 oxime ester or mixtures of these. The composition includes a buffer solution system, which can The composition provides a buffered p Η value in the range of from about 3 to about 7.4. Preferably, the ρ Η value is from about 3.0 to about 7.4, more preferably from about 3.0 to about 6.5, most preferably from about 3.5 to about 约. 6.0.

The vasodilator composition of the present invention is placed in a boat-like socket, that is, in a boat-shaped fossa (fossa navicularis), which may be placed on the skin surface of the penis or in the urethra closer to the "sponge body" There are more advantages. The boat-shaped socket is a natural expansion space suitable for receiving and retaining semi-solid medicines. Semi-solid medicines, such as the composition of the present invention, have high resistance when placed therein so that they cannot be used here. The narrow outlet of the space flows, that is, the urethral opening and the urethra. The flow resistance is proportional to the cross-sectional area and the diameter of the diameter. _ The inside of the boat is the unkeratinized squamous epithelium, which is the penis The keratinization of the outer surface skin is compared to the above table, the former has a stronger permeability. -11 - 1324930 (7) Using a short coater, it terminates in the anatomical limit of the scaphoid, compared to the longer coater The high (or close) penetration of the penis into the urethral penis is not invasive. Suitable applicators are described in US Pat. No. 6,224,573, Yeager et al, which is incorporated herein by reference. Preferably, the applicator contains a Storage Wherein a semi-solid prostaglandin E(R) composition that induces an erectile dose is included. The coater is preferably a single use device and contains a single dose of a semisolid prostaglandin Ei composition. In one embodiment An inactive component of the composition of the invention having a position on the coater between the single dose semi-solid prosthetic complex and the tip of the coater. In this embodiment, the use of the coater results in inactivity The composition of the component is deposited in the proximal scaphoid fossa and the distal end of the urethral penis, thus limiting the single-dose semi-solid prostaglandin E i composition so that it cannot reach the scaphoid fossa. The applicator usually has instructions for use, and is located below All or part of it: on the packaging of the painter, on the leaflet of the package, and on the outer surface of the coater itself. The boat-shaped nest contains a large amount of glycogen and bacteria, so it can naturally reduce the p in the space. The value, such a composition with a lower ρ Η value in the acidic range, makes the prostaglandin which has increased solubility ugly! It can be more easily tolerated without excessively stimulating the tissue. The scaphoid is immunologically The cavernous body adjacent to the penis of the urethra is more protective. Place the tip of the applicator in the anatomical limit of the scaphoid, that is, the artificial method of the contaminant is placed directly from the penis surface into the urethra penis. The risk of disease in the barrier is low. -12 - 1324930 (8)

Pharmaceutical compositions suitable for use in a sump cavity contain prostaglandin Ei, a penetration enhancer, a modified polysaccharide gum, a lipophilic compound, and an acidic buffer system. The osmotic enhancer is alkyl-2-(N-substituted amino)-sonic vinegar' (N-substituted amino)-alkanol alkanoate, or a mixture thereof. The lipophilic compound can be an aliphatic CrCs alcohol, an aliphatic Ci-Cw ester, or a mixture of these. The composition includes a buffer solution system which provides a buffered pH between the ranges of from about 3 to about 7.4 for the composition. Stabilizers, preservatives and emulsifiers may also be added if desired. The compositions of the present invention may be in a semi-solid form for use in a boat nest. These compositions exhibit a relatively high prostaglandin penetration and bioavailability to the penis glans when used as a substrate in the scaphoid, and do not require wasted super-prostaglandin concentrations. The composition further exhibits reduced irritation, sensitivity and damage to local tissues. In a further embodiment, the composition can be delivered into the sump using a suitable single dose applicator.

Other and further objects, objects, features, advantages, embodiments and others of the invention are apparent to those skilled in the art. BRIEF DESCRIPTION OF THE DRAWINGS In the drawings, Figure 1 is an anatomical structure of a longitudinal section of a human penis; Figure 2 is an anatomical detailed illustration of a proximal portion of a longitudinal section of a human penis; Figure 3 is a diagram of seven prostaglandins prepared in accordance with the present invention; Accumulation of prostaglandins by the penetration of the E 1 composition through the shaved skin; Figure 4 is a composition of two prostaglandin E i prepared according to the invention via scraping - 13 - 1224930

(9) Accumulated prostaglandin £1 of the bare skin penetration of the hair, plus a comparison of the two comparative compositions. Embodiments Surprisingly, it has been found that a semi-solid prostaglandin Et composition suitable for the treatment of erectile dysfunction can be advantageously placed in a naturally expanding space immediately adjacent to the penis, i.e., fossa navicularis.

The boat nest provides a limitation that is ideally suited for the application of pharmaceutical compositions. The space is lined with an unkeratinized squamous epithelium that is distinguishable from the surface skin covering the glans and the rest of the penis, as well as the columnar epithelial lining of the urethra. It has been found that administration of the compositions of the present invention in the scaphoid has unexpectedly high potency and low incidence of local side effects. The boat nest provides a natural space suitable for the application and retention of pharmaceutical compositions. Semi-solid drugs, such as the compositions of the present invention, have a higher resistance to resistance when placed in the sump, so that they do not flow in this space, i.e., the narrow outlet of the passage and urethra. Therefore, the semi-solid drug whose viscosity is appropriately selected can be naturally retained in the scaphoid cavity to promote absorption of an active agent such as a vasodilator.

The scaphoid nest is part of a natural anti-stagnation system that protects the body against infection. The scaphoid fossa is more immunoprotective than the corpus cavernosum adjacent to the corpus callosum. Therefore, placing the semi-solid drug in the limit of the solution of the sump is not caused by the direct transportation of the contaminant from the surface of the penis into the urethra penis due to the bypass of the natural barrier. As described above, the sump can naturally support the bacterial flora maintained at an acidic pH. Referring to Figure 1, the basic structure of the human penis is illustrated. The scaphoid fossa 110 is a natural enlargement of the male urethral cavity within the 130 gau of the penis glans, extending to the distal end -14 - 1324930 (10) to the urethral diameter 128, and approaching the urethral drooping area 112 (also known as the urethra) "The cavernous area", that is, the part of the urethra that passes through the body of the corpus cavernosum. The urethral globular part 114 is close to the urethral drooping area and passes through the ball sea body muscle 140. Then at the proximal end, An opening 148 is seen in the urethral wall of the spherical urethral gland (Cowper's gland). At a more proximal end, the urethra passes through the prostate 160, where the opening of the ejaculatory tube 156 and the prostatic sac 158 can be seen in the urethral wall.

Referring to Fig. 2, a detailed structural view of the boat nest 11〇 is shown. The urethral opening 128 is externally bounded at the distal end of the scaphoid. The outer side of the glans is covered with keratinized squamous epithelium 186 (Pudney, J., and Anderson, D.J., (1995)

Immunobiology of the human penile urethra, Amer. J. Path., 147: 15 5- 165), which clearly transitions to the squamous squamous epithelium 184 without hepatosaccharide at the proximal end, which is distal The boat-shaped nest is lined with a unique structure.

The scaphoid fossa is widened at the proximal end, and the lining is changed into an unkeratinized stratified squamous epithelium, which contains hepatic glycocalyx 82°. The glycogen in this region can support the bacterial flora, which can reduce the area. The pH' constitutes a natural defense against infection. Holstein, A.F., et al., (1991). Different epithelia in the distal human male urethra, Cell Tiss. Res. 264: 23-32. This unkeratinized squamous epithelium of hepatic vinegar is under hormonal control, and its content increases as the level of estrogen increases (Holstein, et al., 1991). The width of the proximal scaphoid is narrowed and the inner machine is a layered columnar epithelium 180. The semi-solid compositions of the present invention have a moderately selected viscosity' such compositions can naturally remain in the sump. The semi-solid composition exhibits Newtonian or non-Newtonian rheological properties. In some preferred embodiments, the semi-solid -15 - 1324930 of the present invention

(1 The steroid composition exhibits a non-Newtonian rheological property, i.e., wherein the apparent viscosity is determined by the shear rate applied to the composition. The composition preferably has "shear thinning" "shear-thinning" means reducing the apparent viscosity (ratio of shear stress to shear strain rate) at an increasing shear strain rate, regardless of apparent viscosity. The reduction is independent of time (pseudoplastic), time-dependent (shake-denatured) or related to yield stress, which is defined as the stress that must be exceeded before starting to flow (Binham Plastics and General Bingham Plastics ( Bingham plastics and generalized Bingham plastics)). Overview can be found 1^1*1^5, <1.,&\\^11^1115〇11, from >丄.,"]^〇11-newtonian Fluid. , 7 pp. 856-858 in Parker, SP, ed., McGraw-Hill Encyclopedia of Physics, Second Edition, McGraw-Hill, New York, 1993. Suitable viscosity ranges from about 5,000 centipoise (cpip) to Approximately 20,000 cps, preferably from about 7,000 cps to about 13,000 cps ° is also proposed in the method of the invention A relatively non-invasive coater. When a prostaglandin E! composition that effectively induces an erectile dose is placed in a boat pocket, the tip of the applicator does not exceed the delimiter limit of the boat's nest. Preferably, the coater The tip does not exceed the diameter opening by more than 2 cm in the penis, preferably not more than 1 cm, preferably not more than 0.5 cm. Preferably, the applicator includes a storage tank containing a semi-solid which induces an erectile dose. A composition comprising at least one gold tube dilator, preferably a prostaglandin E1 composition. Preferably, the applicator is a single use device and comprises a single dose of semi-solid vasodilator composition. There are instructions for use, in the following places or in some places: packaging containing the painter, in the packaging leaflet, and on the outer surface of the coater itself. -16 - Ϊ324930

(12) The pharmaceutical composition of the present invention contains at least one vasodilator, preferably prostaglandin i, an alkyl (N-substituted amino) ester, a shear-thinned polysaccharide, a lipophilic compound and an acidic buffer system β

Suitable vasoactive agents include, but are not limited to, nitrates such as nitroglycerin, isosorbide dinitrate, tetraol nitrate, isovaleronitrile nitrite, sodium nitroperate, and dolomite ( Molsidomine) chlorohydrate compound rSIN-l") and S-nitroso-N-acetyl-d-l-l-mycomycin ("SNAP"); amino acid such as L-arginine; long and short Alpha-blockers such as phenolphthalein, acetophenone, doxazosin, terazosin, phentolamine, princerol (tolazoline),. Prazosin, trimazosin, alfuzosin, tamsulosin and indoramin; natural herbal compositions for vasodilation and Bioactive extracts such as gosyajinki-gan, Satureja obovata, bai-hua qian-hu, lipotab, saiboku-to, vinpocetine, (Gingko biloba), bacopa, Gynostemma Pentaphyllum), Gynostemma total soap: y: (gypenosides), Evodia rutaecarpa, rutaecarpine, dehydroevodiamine, dan-shen, Denmark (salviae miltiorrhizae radix), shosaikoto, scorpion ( Zizyphi fructus), ginseng and mixtures thereof (US Pat. 6,007,824); ergot alkaloids, such as ergotamine and its homologues, such as acetamidine dihydroergotamine, brazergoline, broccoli兰 (bromerguride), cianergoline, delorgotrile, disulergine, ergonovine maleate, ergotamine tartaramine-17 - 1324930

(13)

(ergotamine tartrate), etisulergine, lergotrile, lysergide, mesulergine, metergoline, ergotamine Metergotamine), nicergoline, pergolide, propisergide, proterguride and terguride; antihypertensive drugs, such as Diazoxide, hydralazine and minoxidil; vasodilators such as nimodepine, <» pinacidil, cyclomandelate ), dipyridamole and isoxsuprine; chlorpromazine; haloperidol; yohimbine; trazodone; naturally occurring prostate , such as PGE丨, PGA!, PGB丨, PGFla, 19-hydroxy-PGA, 19-hydroxy-PGB [, PGE2, PGA2, PGB2, 19-hydroxy-PGA2, 19-hydroxy-PGB2, PGE3, PGF3tt; Semi-synthetic or synthetic natural prostaglandin derivatives, including carbopol tromethamine (carbo) Prost tromethamine), dinoprost tromethamine, dinoprostone, lipoprost, gemeprost, metenoprost, sulprostone And tiaprost; and vasoactive intestinal peptides. Triazolam, prostaglandin [and prostaglandin E2. It is a particularly good vasoactive agent that can be used in combination with the method of the present invention. In addition, the simultaneous administration of more than two vasoactive agents may be desirable, and in some cases, a synergistic effect, a combination of screaming wells and prostaglandin E, is found to be particularly beneficial in this regard; The latter drug can be used as an infiltration enhancer for the brigade u well, that is, it can increase the penetration of the 9 bottom well into the skin or stick to the -18-1324930

(14) The rate at which the membrane tissue enters the bloodstream. Prostaglandin artisans are well known. See the literature on its pharmacological activities, side effects and normal dose ranges, see: 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) » Prostaglandin E1 And other compounds referenced herein are intended to encompass pharmaceutically acceptable derivatives, including physiologically compatible salts thereof, and ester derivatives thereof.

The amount of prostaglandin E1 in the pharmaceutical composition of the present invention is a therapeutically effective dose, and may be in a dosage form (e.g., suppository or topical) depending on the desired dosage, and the particular form of prostaglandin E! used is necessarily changed. The term "prostaglandin" as used herein refers to prostaglandin free acid and pharmaceutically acceptable derivatives thereof, including prostaglandin E (PGE!)'s pharmaceutically acceptable salt thereof and its lower alkyl group. The "lower thiol" used herein refers to a direct bond or a branched chain having 1 to 4 carbon atoms. The composition usually has about 〇. 〇〇1% to 1% prostaglandin E, usually It is about 0.05% to 1% prostaglandin El, preferably about 0.1% to 0.5%, based on the total weight of the composition.

An important component of the invention is an osmotic booster. The osmotic enhancer is alkyl-2-(N-substituted amino)-antacid vinegar, (N-substituted amino) 垸 烧 烧 烧, or a mixture of these 11 is a suitable reference, a base - 2-(N-Substituted Amino)-Siucinated vinegar and (N-substituted amino)-co-alcohol vinegar can be grouped under a certain (n-substituted amino) ester label. The tiger base-2-(N-substituted amine group) to which the present invention is applicable may be represented by the following: -19- 1324930

Wherein η is an integer having a value in the range of from about 4 to about 18; R is a group of hydrogen, (^-(:7 alkyl, fluorenyl and stupid), R1 and R 2 are from the mouse and C 1 - a member of the group consisting of C 7 entertainment groups; and R 3 and R 4 are members of a group consisting of hydrogen, methyl and ethyl groups. Preferred are alkyl (N,N-disubstituted amino)-alkanoates. , such as (: 4-(: 18 alkyl (N, N-disubstituted amino)-acetate and C4-Cl8 alkyl (Ν, Ν-disubstituted amino)-propionate and its pharmaceutically Acceptable salts and derivatives thereof. Exemplary special alkyl-2-(indole, fluorene-disubstituted amino)-alkanoates include 2-(anthracene, fluorenyl-dimethylamino)-propionic acid dodecane Base ester (DDAIP); Η Ο Η , CH3 H3C——(CH2]i〇-C——0——C——C——N;

H CH, ch3 and 2-(N,N-dimethylamino)-dodecyl acetate (DDAA); Η Η • CH3 H3C-[CH2]10-C——0-C-C-N;

H

H ch3 -20 - 1324930

(16)

Alkyl-2-(N,N-disubstituted amino)-alkanol esters are known. For example, 2-(N,N-dimethylamino)-propionic acid dodecyl ester (DDAIP) is commercially available from Steroids, Ltd. (Chicago, IL). Further, the alkyl-2-(N,N-disubstituted amino)-alkanoate can be synthesized from a relatively readily available compound, as described in U.S. Pat. No. 4,980,378, toW. It is not the degree of inconsistency that is referenced in this case. As described therein, the alkyl-2-(N,N-disubstituted amino)-alkanoic acid vinegar can be easily prepared by a two-step synthesis. In the first step, the preparation of the long-chain alkyl acid acetate will be equivalent to long-chain alkanols and methyl formate, etc., in a suitable storage (such as triethylamine), usually in a suitable solvent. Chloroform, reacted. The reaction can be shown as follows: h3c R3 (CH2)n -c-OH + R4

0 H Cl-C-C-Cl I R

R3 oh

H3C-(CH,)n-C——0——C——C——Cl r4 r wherein R, R3, R4 and n are as defined above. The reaction temperature may be optionally from about 10 ° C to about 200 ° C, or at reflux, preferably at room temperature. The use of the solvent is as desired. If a solvent is used, various organic solvents can be selected. In addition, the choice of base is not strict. Preferred bases include tertiary amines such as triethylamine, pyridine and the like. The reaction time is usually extended from 1 hour to 3 days. In the second step, the long chain alkyl chloroacetate is fused with the appropriate amine according to the following flow -21 - 1324930 (17) = 0 Η h3c- (CH2)n -c- 0-C-C-C! HNRtR2 r4

R H3c—(CH2)n

3 a 4 R --0-R o

OMMHC

H-c-R

2 R wherein n, R, Ri, R 2 , R 3 and R 4 are as defined above. The excess amine reactant is usually charged and the reaction can be conveniently carried out in a suitable solvent such as diethyl ether. This second step is preferably carried out at room temperature, but the temperature may also vary. The beta reaction time typically varies from about 1 hour to several days. The resulting ester can be prepared using conventional purification techniques for application to pharmaceutical compounds. Suitable (Ν-substituted amino)-alkanol alkanoates can be represented by the following formula: ο h3c- -C- r4 -c-ο-c- Ββ c-

Re

N r2 y wherein n is an integer having a value in the range of from about 5 to about 18; y is an integer having a value in the range of from about 5 to about 5; and Ri, R 2 , R 3 , R 4 , R 5 , 6 and R 7 are nitrogen ^ Ci_C8 is a member of the group consisting of aryl groups and Ci_C8 aryl groups; and R_8 -22- 1324930 (18) is a member of the group consisting of hydrogen, hydroxy, c "c8 alkyl and c"c8#. Is an (N-substituted amino)-alkanol alkanoate such as a C5-C18 carboxylate and a pharmaceutically acceptable salt thereof. Exemplary specific (N,N-disubstituted amino)-alcohol The acid ester includes 1-(N,N-dimethylamino)-2-propanol dodecanoate (DAIPD); H3C-ICH2]10-OII c-o-

H H xh3 -c- •C——N;

CH3 H ch3 1-(N,N-dimethylamino)-2-propanol myristate (DAIPM); Ο Η Η xh3

H3C——[CH2112-C-Ο-C-C-N; CH3 H ch3 1-(N,N-dimethylamino)-2-propanol oleate (DAIPO); ΟII h3c——[CH217- c one o

Hi

HI c - H

N

The (N,N-disubstituted amino)-alkanol alkanoate can be prepared by reacting a comparable aminoalkanol with a lauryl based gas in the presence of triethylamine. Solvents such as gas are required as needed but are preferably used. For example, 1-(N,N-dimethylamino)-2-propanol can be reacted with a lauryl group gas in the presence of trimethylamine to form 1-(N,N-dimethylamino group). )-2-propanol dodecanoate (DAIPD). -23 - 1324930

(20) Wess. Preferred shear-thinning polysaccharides are natural and modified galactomannan gums, including modified guar gums. Other suitable representative gums include guar gum, carrageenan, ghatti, karaya gum, rhamnose and xanthan gum. The compositions of the present invention may contain a mixture of various gums, or a mixture of gums and acidic polymers. Gum and especially galactomannan are well known materials. See, Industrial Gums: Polysaccharides & Their Derivatives, Whistler RL and BeMiller JN (eds.) 3rd Ed. Academic Press (1992) and Davidson RL, Handbook of Water-Soluble Gums & Resins, McGraw-Hill, Inc_, NY (1980). Most types of glue sets are commercially available, usually in powder form, and are ready for use in food and topical compositions. For example, locust bean gum in powder form can be purchased from Tic Gums Inc. (Belcam, MD). When present, the polysaccharide gum is present in an amount of from about 0.1% to about 5%, based on the total weight of the composition, with from about 0.5% to about 3% being preferred. In a preferred embodiment, the polysaccharide gum content is 2.5% wt. Examples for demonstration are shown in the examples below. An alternative to the polysaccharide gel is a polyacrylic acid polymer. A common variant of polyacrylic acid polymers is generally referred to as carbomer "carbomer". Carbomer is a cross-linking of a polyacrylate polymer with a polyalkenyl polyether. It can be traded as "CARBOPOLTM" BF Goodrich Company (Akron, Ohio). The Tektronix carbomer variant is "CARBOPOL 940". Other polyacrylic acid polymers suitable for use in the present invention are sold under the trade name "PemulenTM" (BF Goodrich Company) and "POLYCARBOPHILtm" -25 - 1324930

(21) (A.H. Robbins, Richmond, VA) is available for purchase.卩61111116111'1^The polymer is a copolymer of C19-C3 decyl acrylate and one or more acrylic acid, methacrylic acid monomer, or one of its simple esters is crosslinked with sucrose allyl ether, or quaternary alcohol Propyl ether. The POLYCARBOPHILTM polymer is crosslinked with polyacrylic acid to diethylene glycol. When a polyacrylic acid polymer is present, it is from about 0.5% to about 5% by weight of the composition, based on its total weight. Suitable shear-thinning polyacrylic acid polymers include pseudoplastic polyacrylic acid polymers and copolymers. Another important component of the invention is a lipophilic compound. In a specific example, the lipophilic compound is used herein to mean a lipophilic and hydrophilic agent. Ci-Cdg alcohols, C2-C3G aliphatic esters and mixtures thereof can be used as lipophilic compounds. Suitable alcohols for illustration are ethanol, n-propanol and isopropanol, and suitable esters are ethyl acetate, butyl acetate, ethyl laurate, methyl propionate, isopropyl myristate and palm Isopropyl acid. The "moon-type alcohol" as used herein includes, for example, glycerin, propylene glycol and polyethylene glycol. A mixture of an alcohol and an ester is preferred, and particularly a mixture of ethanol and ethyl laurate is preferred. In a particular embodiment, the C 2 -C 3 〇 aliphatic ester, and mixtures thereof comprising the lipophilic compound comprise a C8-C30 fatty acid ester of glycerol selected from the group consisting of monoglycerides, diglycerides, triglycerides and The mixture consists of a mixture. Suitable aliphatic esters include glycerides 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, camellic acid, and lauric acid. Suitable unsaturated fatty acids include oleic acid, linoleic acid, and linoleic acid. Suitable -26- 1324930

(22) The glycerin esters include glycerol monooleate, glyceryl trioleate, trimyristyl and tristearic acid, preferably trimyceps sinensis. The concentration of the lipophilic compound required may be varied depending on other factors, such as saturated semi-solid consistency and saturated skin penetration promoting action. The concentration of the lipophilic compound may suitably be in the range of from 0.5% to 40% by weight, based on the total weight of the composition. Preferably, the topical compositions comprise a lipophilic compound between 7% and 40% by weight based on the total weight of the composition.

When a mixture of an aliphatic alcohol and an aliphatic ester is used, an appropriate amount of the alcohol is in the range of about 0.5% to 10%. In a preferred embodiment, the alcohol content is in the range of from about 5% to about 15%, and the aliphatic ester is in the range of from about 2% to about 15% (again based on the total weight of the composition). In another preferred embodiment, the level of alcohol is in the range of from about 0.5% to about 10%, and the aliphatic ester is in the range of from 0% to 10% (also based on the total weight of the composition).

The components of the present invention preferably have an emulsifier, as desired. Although not a critical factor, suitable emulsifiers typically exhibit a hydrophilic-lipophilic balance index above 10%. Sucrose esters and particular sucrose stearates can be used as modifiers in the topical compositions of the present invention. Sucrose stearate is a well known emulsifier available from a variety of commercial sources. When an emulsifier is used, the sucrose stearate content can be as high as 2%, preferably based on the total weight of the composition. The preferred content of the sucrose stearate emulsifier can also be expressed as the weight ratio of the emulsifier to the polysaccharide gum. The ratio of the emulsifier to the rubber of 1 to 6 is preferred, and the ratio of 1 to 4 is optimal to produce the desired semi-solid consistency and separation resistance. Other emulsifiers are also suitable, and include polyoxyethylene sorbitan esters, long chain alcohols, preferably cetearyl stearate, and fatty acid glycerides. -27 - 1324930

(23) Suitable poly Span 20), and monooleic acid including mono-olein. In the present invention, the composition of the rushing system "*, whose p Η value is mainly changed, is effectively buffered by the well-known acid salt of the system. The buffer solution is exemplified in the present invention. Do not violate this if necessary, about 3.0 to about the composition of the water at about the content of non-oxyethylene sorbitan ester including monolaurate (Tween 20, monopalmitic acid vinegar (Tween 40), monostearic acid vinegar (Tween 60 ), Tween 80 and mixtures thereof. Preferred fatty acids glycerol acetate, triolein, trimyristyl and tristearyl further include an acidic buffer solution system. Depreciation is maintained or buffered within the desired range. And "slow L" buffer material" as used herein means a solute or as a solution in aqueous solution that stabilizes the solution against acid or acid addition (or hydrogen) Ion concentration or activity). The solute or effect of the initial buffer p Η value in the range indicated by the negative pH resistance. Although there are many other suitable buffer solutions, such as vinegar solution, potassium phosphate-hydrate Suitable buffering concentrations for the compositions of the present invention range from about 0.005 Torr to about 1.0 Torr. Preferred liquid concentrations range from about 0.05 Torr to about 0.2 Torr. In many preferred embodiments, the buffer solution concentration is 0.1 Torr. The final pH of the compound can be physiologically compatible. Necessary, the final p Η value is not irritating to human skin. To limit, ρ Η should be chosen to improve prostaglandin, stability, and adjust consistency. In the examples, a preferred pH is 7.4, preferably from about 3.0 to about 6.5, most preferably from about 3.5 to about 6.0. The other component is water, which must be purified. The composition contains from 50 to about 90%. Within the total weight of the composition. However, the water is strictly adjustable and can be adjusted to the desired consistency and / or other groups -28 - 1324930

(24) The concentration of the parts. In addition, a known penetration osmosis enhancer may be added if desired. For example, diterpenoid (DMSO), dimethyl acetamide (DMA), 2-pyrrolidone, hydrazine, hydrazine-diethyl-meta-toluidine (DEET), 1-ten Dialkylazetidin-2-one (AzoneTM, trade name of Nelson Research), N,N-dimethylformamide, N-methyl-2-pyrrolidone, calcium thioglycolate, hydrazine It is a ketone, a dioxon derivative, a nitrogen (laurocapram) derivative, and a macrocyclic enhancer such as macroketone. Prostaglandin E i stabilizers, colorants, shakers, and preservatives may also be added but should not unduly limit the skin penetration of prostaglandin E i or adversely affect the desired rich solids consistency. The semi-solid pharmaceutical composition of the present invention comprises emulsions, gels, ointments, colloidal suspensions and the like, and also includes compositions suitable for use in a similar manner to a transdermal patch or the like. The above components may be combined in any order and manner to produce a prostaglandin! a stable composition uniformly dispersed in a semi-solid blend. One useful route to prepare this composition involves uniformly dispersing the polysaccharide gum (or polyacrylic acid) in a premixed water/buffer solution and then homogenizing (ie, mixing) the resulting mixture ("A portion When present, the emulsifier is added to the water/buffer solution and then dispersed into the polysaccharide gum. The pH of Part A can be adjusted to the desired level using any suitable method, such as the addition of concentrated phosphoric acid or hydrogen. Sodium oxide 0 Separately, prostaglandin E ^ is dissolved in a fatty compound under agitation, which may itself be an alcohol, an ester or a mixture of an alcohol and an ester. Then, an infiltration plus -29- 1324930 may be added.

(25) Strongener. Further, when the lipophilic compound includes an alcohol and an ester, the prostaglandin E 1 is soluble in the alcohol, and then a penetration enhancer is added, followed by an ester. In either case, the resulting mixture is a mixture of prostaglandin E! (" Part B"). The final step consists of adding Part B quite slowly (eg, by drop) to Part A, under fixed mixing.

The resulting topical composition, when compared to exhibit the beneficial properties described above, including improved prostaglandin Ei penetration and bioavailability without drug overload, has reduced skin damage and associated inflammation, and is available in a dosage form Increase the elasticity. These compositions are useful for the treatment of peripheral vascular disease, male impotence and other disorders that can be treated with prostaglandin Et. At the same time, it can avoid the problems of low bioavailability and rapid chemical decomposition associated with other delivery methods. When prostaglandin E i is applied to the patient's skin on the topical composition of the present invention, a predetermined dose of prostaglandin E! can be administered continuously to the patient, and no single or multiple doses of the larger dose are administered by injection. The non-desirant role that arises. At a sustained dose rate, the level of prostaglandin Ei in the patient's target tissue is preferably maintained within the most appropriate therapeutic range. In one embodiment, the invention provides a composition comprising from about 0.01% to about 5% modified polysaccharide gum; from about 0.001% to about 1% prostaglandin, selected from PGE, a pharmaceutically acceptable salt thereof a group of lower alkyl esters and mixtures thereof; from about 0.5% to about 10% DDAIP or a salt thereof; from about 0.5% to about 10% lower alcohols selected from the group consisting of ethanol, propanol, isopropanol and mixtures thereof a group; from about 0.5% to about 10% of an ester selected from the group consisting of ethyl laurate, isopropyl myristate, isopropyl laurate, and mixtures thereof; according to the combination -30 - (26) 1324930

The weight of the material is 2% of the sugar cane. : Three meat beans, the invention, the damage to the ground in the present microbes into the group. When 0.30%. The parabens of p-hydroxybenzene are measured. The local cause of this is that it is acceptable to take the drunken drug unless it is used as an example. The compound also contains a South African meter and an acid buffer solution. Preferred sugar stearates. The composition is also required to contain up to about 5% emulsified sentence ^ 'up to up to 2% milk. Suitable emulsifiers include glycerol monooleate gt _ bis oleic acid glycerin and quercetin and tristearate. The preferred emulsification #丨_ + 阳二豆豆精精明" can be illustrated by the following examples. These & A and A examples are for illustrative purposes only and are not intended to limit the scope thereof. The treatment composition has a T<change, which does not have the effect of prostaglandin', which is obvious to the artist in the poor, and within the scope of the disclosure. For example, 'extra red, such as coloring agents, anti-preservatives, emulsifiers, perfumes, prostaglandin 1 stabilizers, etc.', as long as the resulting composition retains the specificity as described above, 'preservatives usually The amount of the preservative added is from about 5% to about suitable to include methyl formate (methyl PAB A) formic acid (propyl PABA) and butyl perylene toluene (βητ). Suitable a and aroma are known in the art; suitable aromas can be up to about 5% enol, preferably about 2% camphorol, and the compositions according to the composition may also contain a small amount of 'about 0 〇 1 to about 4% by weight of anesthetic (if necessary 1. Local anesthetics typically include! dyclonine, dibucaine, pharmaceutically acceptable salts and mixtures thereof. In a preferred embodiment, the local anesthetic is about 0.5% dyclonine, based on the weight of the composition. Also shown, each composition is prepared from conventional blended individual indicator components.

1 : Topical prostaglandin E, Composition A • 31 - 1324930 (27) Composition A was prepared as follows. Part A of the composition is formed by dissolving 04 parts by weight of prostaglandin Ei (Alprostadil USP) in 5 parts by weight of ethanol, and 5 parts by weight of 2-(N,N-dimethylamine). Base)_-undecyl propionate is mixed with alcohol-prostaglandin solution, and 5 parts by weight of ethyl laurate is added. Part B was prepared starting from a water/buffer solution of ρΗ5_5. The water/buffer solution was prepared by adding a sufficient amount of potassium phosphate-hydrate to the pure water to form a 0. 1 Torr bath. The ρ Η value of the water/buffer solution was adjusted to 5.5 with a strong alkali solution (1 Ν sodium hydroxide) and a strong acid (1 Ν phosphoric acid). The buffer solution comprised about 80 parts of the total composition. All parts are shown in the weighted parts. Ethyl laurate, 0.5 parts by weight, was added to the buffer solution. Next, locust bean gum (in powder form) was dispersed in a buffer solution' and homogenized by a homogenizer. Table 1 below is the component list. The resulting composition is a dispersible semi-solid formulation suitable for application to the skin without the need for support means such as patches and viscous strips. The composition is homogeneous in appearance and resistant to resistance. In the same manner, an additional exemplary composition Β-Η was prepared using the components listed in Table 1. As indicated above, in other embodiments, such as composition η, the composition may comprise a modified polysaccharide gum, a suitable modified half-glycan mannan gum such as guar gum, or, in addition, polyacrylic acid polymerization. Substituting polyglycan gum. • The evaluation of skin penetration by the composition Α釺 is based on the shaved bare skin as a model barrier. The bare skin of the cut hair was obtained from the Animal Care Unit of the Univefsity of Kansas. Remove the head and tail segments, and arbitrarily divide the skin into test sections and hydrate them by soaking. -32- 1324930

(28)

The sample was evaluated using a Franz-type diffusion unit (surface area of 1.8 square centimeters). In particular, the skin sheet is placed over the top of the receiver unit of the direct diffusion unit combination, in which a small magnetic rod is inserted and filled with an isotonic buffer solution. Place a layer of seal over the skin section and then the donor unit. These two units are clamped together. A known amount of blend was applied to the bottom of a small covered vial (weight 0.5 g) which did match the donor unit to ensure a uniform distribution. The vial is placed on the skin of the donor unit. In order to reduce the evaporation of components, the supplier unit and the vial and waterproof tape are covered. The unit was transferred to a stirred water bath (32 ° C). The sample was withdrawn from the unit every hour; for a total of 4 hours, the concentration of prostaglandin E i was analyzed, wherein the change in concentration indicates the amount of permeation. Test with multiple skin samples and the resulting data is averaged. For an assessment of the use of viscous bare skin for drug penetration, a discussion of U.S. Pat. No. 4,771,004 to Higuchi is incorporated herein by reference.

Prostaglandin E! can penetrate rapidly for a period of 4 hours at a fairly sustained rate. The results of the bleed study are shown in Table 2 below and Figure 3.

Example 2: Topical Prostaglandin E i Composition B

Composition B was prepared using the components listed in Table 1 below. Composition B contained more than the previous composition of adenosine E i . It is estimated that Composition B exhibits a similar semi-solid consistency and a uniform appearance regardless of the increased drug load. The penetration of prostaglandin E i was detected by the technique described in Example 1. Composition B provides a fast and sustained delivery of prostaglandin E i . The results are shown in Table 2 and Figure 3.

Example 3: Topical prostaglandin E, Composition C Composition C was prepared using the components listed in Table 1 below. Composition B contains the forefront -33 - 1324930

(29) Adenine Ε! More than composition A or B. The increased drug load has little or no effect on consistency or appearance, which substantially conforms to compositions A and B. The penetration of prostaglandin E! was again detected by the technique described in Example 1. According to this test, Composition C also provided a fairly rapid and sustained delivery of prostaglandin Ei. The results are shown in Table 2 below and Figure 3.

Example 4: Topical prostaglandin E(R) Composition D Composition D was prepared using the components listed in Table 1 below. The level of prostaglandin E! is again increased without substantially affecting the beneficial consistency and resistance to separation. The penetration of prostaglandin E! was again detected by the technique described in Example 1. The results are shown in Table 2 below and Figure 3.

Example 5: Topical Prostaglandin E! Composition E Composition E was prepared using the components listed in Table 1 below. To evaluate the repeatability of the compositions of the present invention, Formulation D was applied to Composition E. The repeatability of the examples can be confirmed by the beneficial semi-solid consistency and separation resistance of the composition E. The osmotic effect of prostaglandin E i was still detected by the technique described in Example 1. Similarly, prostaglandin E! still has a fairly fast and sustained delivery in Composition E. The results are shown in Table 2 below and Figure 3.

Example 6: Topical prostaglandin E i composition F is in composition F to increase the level of prostaglandin E i . Specific components are listed in Table 1. The beneficial consistency and separation resistance are not reduced. The results of the permeation analysis are shown in Table 2 below and Figure 3.

Example 7: Topical prostaglandin E 1 composition G Composition G was prepared using the components listed in Table 1. Composition G repeated the formulation of Composition F, but the ester component (ethyl laurate) was omitted and the ethanol level was increased. -34- 1324930

(30) The resulting composition B is a retardable semi-solid having a homogeneous appearance and resistance to separation. The permeation analysis is shown in Table 2 and Figure 3. While still beneficial, these results reflect the comparative benefit of the compositions of the present invention from lipophilic compounds, including both the ester component and the alcohol component. Table 1: Topical prostaglandin E i composition component (wt%) ABCDEFG Η Part A: Pre-hydrated locust bean gum 3 3 3 3 3 3 3 - Pre-hydrated and modified guar gum - 3 water/buffer substance (pH 5.5) 82 81 81 81 81 81 81 81 Sucrose stearate 0.5 0.5 0.5 0.5 0.5 0.5 0.5 - Part B: Prostaglandin E| 0.1 0.2 0.3 0.4 0.4 0.5 0.4 0.3 DDAIP 5 5 5 5 5 5 5 2.5 Ethanol 5 5 5 5 5 5 10 5 ethyl laurate 5 5 5 5 5 5 3 Example 8: Infiltration rim comparison Table 2 shows the prostaglandin in the composition according to the examples of the present invention! Cumulative amount, 4 hours in total. These data demonstrate the ability of the present invention to deliver prostaglandin E! drugs. Figure 3 shows the graph produced by the data shown in Table 1. Obviously, and as shown in the figure, the compositions of the present invention deliver effective skin penetration at a relatively fast and sustained rate. In the source composition, the increase in the 'm adenine E! load is also increased. Table 2: Cumulative prostaglandin E i osmosis (μg/cm 2 ) hours ABCDEFG 1 1.96 3.37 5.47 7.20 7.09 10.38 3.03 2 5.49 9.72 18.06 21.26 16.6 25.03 8.17 3 11.25 18.18 30.34 35.53 28.24 42.18 12.93 4 13.98 23.48 38.49 47.98 41.1 52.13 18.71 - 35 - Steps to evaluate the efficacy of the compositions of the invention, a comparative example composition was prepared. The first comparative example (Comparative Example 1) was prepared in the same formulation as Compositions D and E, μ except that the DDAIP seepage enhancer was omitted. As for the second comparative example (Comparative Example 2), DDAIP was omitted again, but The components in which the ethanol level is increased by a considerable amount of β # S u are listed in Table 3 below. Table 3: Comparative Examples Α Part: Part b. Prostate in the following Table 4 ___ Component (by weight) Comparison Composition 1 Comparison of combined sugar hydrated locust bean gum 3 3 Water eight buffer material (pH 5·5) 86 81 Sucrose stearate 0.5 0.3 Prostaglandin £1 0.4 0.4 Ethanol 5 10 Ethyl laurate 5 5 The osmotic effect was evaluated according to the technique described in Example 1. The results are shown in Table 4: Comparative Examples of Accumulated Prostaglandins [Permeability (μg/cm 2 ) Solution Comparative Composition 1 Comparison Composition 2 - 1 1.64 1.55 2 4.46 3.69 3 6.59 6.63 4 9.67 11.05 4 The data is compared to the example compositions having the same prostaglandin Hi loading, namely compositions D and E in Figure 4. The bleed data demonstrates that the grading based on the presence of the DDAIP penetration enhancer is of great benefit. Example 9: Separate use Double-blind and open-label: ϋ 1 Clinical trials Three at -36- 1324930

(32) Safety and potency of a topical composition of a genonin E or an alprostadil (composition D of Example 4 and Table 1 above). This study consisted of a double-blind, blank control and a partial and open-labeled part. The double-blind blank control portion of the study was entered into the study by 64 people (Table 5 below). 79 people entered and completed the open-label portion of the study (Table 5 below). The following synthesis is a discussion of the results of clinical research. Inclusion criteria 1. Male, 21-70 years old (included). 2. A history of medical history of erectile dysfunction, defined as an erection of sufficient hardness for sexual intercourse due to psychogenic, neurogenic, and vascular sources in the past 6 months. This includes patients who are still erected for sexual intercourse but not long lasting. It is usually the typical complaint of a moderate to moderate impotence man. Erectile dysfunction is based on medical history and physical examination. Exclude the quasi-test 1. Have a history of urethral stricture or obstruction. 2. Any combination found by medical history, physical examination or screening, which means that there is a heart, liver and/or kidney function damage (such as congestive heart failure, unstable angina, recent acute myocardial infarction, control is not present) Good diabetes, derived from hormonal erectile dysfunction, can influence research results from the perspective of the investigator. 3. Those with a history of penile surgery, including penile implants, prostatectomy or prostate cancer, penile trauma including paraplegia or quadruple. 4. Any condition that may cause an abnormal erection, such as sputum type cell poor -37 - 1324930

(33) Blood, multiple myeloma or leukemia. 5. Hypertension, (diastolic blood pressure when sitting down > 90 or systolic blood pressure > 150) should be treated with an angiotensin converting enzyme inhibitor (A C E inhibitor). 6. Physical examination reveals the existence of a sexually transmitted disease. 7. Intracavernosal injection or an external erectile device was used within 4 weeks prior to the study.

8. Peyronie's Disease or any palpable fibrous sputum or plaque on the penis, evidence of flexion due to swelling and tough stimuli, or abnormalities in the penis or glans mucosa. 9. Any concomitant drug known to interfere with sexually transmitted diseases, such as antidepressants, certain antihypertensives, sedatives, and certain allergic drugs. 10_ Received any examination and treatment within 30 days of entering the study. 11. Unable or unwilling to give notice of consent. The patient population in this study consisted of men between the ages of 49 and 70. Table 5. Patient Partially Incorporated by the Research Office No. 1 No. 2 No. 3 Total Double Blind 30 34 0 64 Open Mark 32 8 39 79 Using a six-point classification, patients are present before and after dosing Clinical efficacy can be assessed in the medical history and patient assessment questionnaires (Table 6). In the double-blind part of the study, each patient was given a cross-over (1) blank group and 1 (1) active dose, and a washout period of 5 to 7 days, in the open one, the patient only gave ( 1)

Active dose. The clinical supply is packaged in a single-dose container, each containing 2,500 mg (net weight) of the emulsion and 1 · gram of prostaglandin E. -38- (34) Jurassic > The decision on the political response rate is determined by the number of men in the total number of men. In order to be considered successful, it must be 8 or more of the 1 person after the administration, or the patient must have sexual intercourse. Using a paired t• test, a total analysis comparing the response levels before and after dosing found that patients in each group receiving the active drug, regardless of the double-blind h or open-label portion of the study, before and during dosing There is a statistically significant difference " at the same time, between the active and blank groups, the total significance is visible in each study. Table 6_Evaluation of male erectile dysfunction (impotence) severity of the six levels of its classification series classification definition _ 0 severe impotence without function 2 severe impotence with very little function 4 severe impotence with some functions 6 mitigation to Moderate impotence 8 non-impurity but some loss of function 10 Fully functional non-impairing table 7. Patients not included in impotence due to impotence classification 0 64 0 79 0 143 _ Thai weight moderate to moderate double blind 39 25 Open Mark 63 16 Total Number of Patients 102 41 The 'local prostaglandin El composition was found to be safe and effective in menopausal men with moderate to severe impotence. The proportion of men in severe impotence was 64.7% (66/102 patients) and in men with moderate to moderate impotence was 100〇/〇 (41/41 patients). The overall clinical efficacy of the study was 74 8〇/〇 (1〇7/143 patients), as shown in Table 8 below. -39, 1324930

(35) Table 8. Overall clinical efficacy ratio _ double-blind part _ open-label part mixed overall proportion blank group 4.7% (3/64) - 4.7% (3/64) active drug 87.5% (56/64 64.6% (51/79) 74.8% (107/143) PO.OOl P0.001 Prostaglandin 1 topical composition is extremely effective (100%) in the moderate to moderate impotence patient population. The mode of moderate to moderate impotence is the most common grade and is estimated to account for 70% of all erectile dysfunction complainers. This product was also very effective in the severe impotence study population (64.7%). In the double-blind portion of the study, the median efficacy of the blank group was seen in 64 patients with a median of 3 (4.7%). This is a far cry from the approximately 10% expected ratio reported in other clinical studies. This lower proportion may be due to the fact that the majority of patients (63%) who are included in the double-blind segment are classified as severe impotence. In the blank group, although 17 of the 64 patients (26.6%) showed improvement, only 3 (3) had sufficient improvement to be evaluated as effective (8 or 10 in the classification level). Table 9. Clinical efficacy ratio of impotence classification in part No. 1 No. 2 No. 3 Mixed effect severe impotence double blindness 85.7% (24/28) 63.6% (7/11) No patient entered 79.5 % (31/39) Open - Mark 72.2% (13/18) 33.3% (2/6) 51.3% (20/39) 55.6% (35/63) Moderate to moderate double blind 100% (2/2) 100% (23/23) No patient enters 100% (25/25) Impotence open marker 100% (14/14) 100% (2/2) No patient enters 100% (16/16) Open marker effectiveness ratio The double-blind efficacy ratio was low (Table 9). This was mainly due to the fact that in the open-label portion of the study, the number of severe impotence patients was quite large and more than double-blind (Table 8). For males included in the open-label part of the study -40 - 1324930 (36), 79.7 Λ (63/79) was assessed as severe impotence, while those who entered the double-blind portion were rated as severe impotence, accounting for only 60.9%. (39/64) 效力 The proportion of efficacy in severe impotence groups is expected to be lower because these people are defined as having little or no function. Substantially, it is expected that it is difficult to raise the impotence level from 〇, 2 or 4 to 8 or 1 疋 疋. Although most of the severe impotence patients showed significant improvement, there were still 36 people (j6/102 or 35.3%) who did not have sufficient progress to be considered effective.

The adverse effect seen in this study is to ease the transitional burning or itching sensation at the site of application. No systemic toxic side effects were observed. At the same time, none of the couples involved in the study reported side effects. None—The patient withdraws from the study or cannot be tracked. Example 10: Multi-use open-label clinical trial

The safety and efficacy of 〇 4% prostaglandin E! topical compositions (Example 4 and Composition D of Table 1, above) were evaluated in an additional study of a total of 56 in three research locations. Fifty-six male patients with organic erectile dysfunction entered the study and completed it. Patients were grouped according to their International Index of Erectile Dysfunction (IIEF) and Sexual Encounter Profile (SEP) response. 49 people had moderate to moderate erectile dysfunction And 7 people were severe erectile dysfunction. Each patient was asked to use 3 to 10 doses of medication for 4 weeks' under multi-use study at home. The overall effectiveness ratio of the moderate to moderate group was 75% ° Λ $ The results were consistent with the overall efficacy ratio of the mixture reported in Example 9. None of the patients withdrew from this multi-use study and no serious side effects were observed. Inclusion criteria -41 - 1324930 (37) 1. Male, 21-70 years old (including 2. There is a history of erectile dysfunction, defined as an erection that cannot be achieved and maintains adequate stiffness for sexual intercourse due to psychogenic, neurogenic, vascular sources, etc. over the past 6 months. There are still patients who can have an erect sexual intercourse but are not long-lasting. The typical age of the general palliative to moderate impotence men. erectile dysfunction with medical history and physical examination The basis of diagnosis. Exclusions 1. History of urethral stricture or obstruction 2. Any combination of findings from medical history, physical examination or screening, indicating the presence of pre-existing heart, liver and/or renal impairment (eg congestive heart) Failure, unstable angina, or recent acute myocardial infarction, uncontrolled diabetes, hormone-induced erectile dysfunction) can affect the results of the study in the view of the examiner. 3. History of penile surgery, including penile implants Inclusion, prostatectomy or prostate cancer, penile trauma includes paraplegia or four treatments. 4. Any condition that can cause abnormal erection, such as sputum cell anemia, multiple myeloma, or leukemia. The next diastolic blood pressure > 90 or systolic blood pressure > 150) should be treated by an angiotensin-converting enzyme inhibitor (ACE inhibitor). 6. Physical examination determines the presence of sexually transmitted diseases. Intracavernous injection or external erectile device was used within 4 weeks prior to the study. 8. North Looney's disease or any palpable fibrous sputum on the penis or -42 - 1324 930

(38) Spot adhesion, evidence of curvature in swelling and hard irritation, or abnormalities in the penis skin or glans membrane. 9. Any concomitant drug known to interfere with sexually transmitted diseases, such as antidepressants, antihypertensives, sedatives, and certain allergic drugs. 10. Received any review within 30 days of entering the study. 11. Unable or unwilling to submit a consent form. For example, the patient population in the study consisted of men aged 49-70. Table 10. Patients included in the research office _ patients included in the research office _

No. 1 No. 2 No. 3 Total 22 13 21 56 The sex assessment shall be based on the international index of erectile dysfunction (Table 1 1) and the encounter profile (SEP) six-point classification series before and after administration (Table 12), clinical efficacy was assessed by a patient history B patient assessment questionnaire. Each patient was given 10 active doses and was asked to take the drug at home and had sexual intercourse as many times as possible within 4 weeks. Drug packaging Specially designed single dose applicator. Table 11. Erectile function is defined by international index classification <12 Inorganic energy severe impotence 12-18 Less organic energy Moderate impotence 18-24 Some functions of palliative impotence 24 + Inorganic dysfunction than level in attempted sexual intercourse The number of successful sexual intercourses in the total number determines the efficacy response. In order to be considered successful, it is necessary to achieve a S E P of 8 to 10 after administration, or the patient must have satisfactory sexual intercourse. Using Chi-square Statistics (Chi -43 - 1324930 (39)

Square) Statistical analysis compares the response levels before and after. Statistically significant differences between the pre- and post-dose levels were observed in each group of patients receiving the active drug (Ρ<〇·〇〇1). Table 12 Sexual Encounter Profile (SEP): Assessment of male erectile dysfunction (impotence) Severity of six-point classification classification definition 0 Non-functional severe impotence 2 Minimal function of moderate impotence 4 Moderate yang with some functions Wilt 6 Moderate impotence 8 Non-impurity with some loss of function 10 Full-function non-impurity is determined by the number of successful sexual intercourse in the total number of sexual intercourse. In order to be considered successful, it must be 8 to 1 s E P level after administration, or the patient must have a satisfactory sexual meaning. The Chi-square statistics were used to analyze the response levels before and after the drug administration. The statistically significant difference can be seen between the levels before and after the administration. <:Ρ<0·001). Table 13. Inclusion of patients with severe mitigation by impotence classification to patients in the middle reaches of the population 7 49 56 Table 14. Efficacy of each group of patients ·» 效力 Patient's efficacy attempt. Effectiveness to moderate 36/49 (74%) 178/ 239 (75%) severe 4/7 (57%) 16/36 (44%) -44 - 1324930

(40) As previously discussed, prostaglandin E! topical compositions are extremely effective (75%) in the moderate to moderate impotence patient population. The mode of moderate to moderate impotence is the most common grade and is estimated to account for 70% of all complaints of erectile dysfunction. » The product is ineffective in the severe impotence group (44%); however, in this group of patients before treatment Statistically significant differences can still be seen later. Even though all men in this severe impotence type did not have any erectile function (before administration), at least 3 of the 10 doses allowed 4 (57%) of the 7 men to have successful sexual intercourse. The adverse side effects seen in this study were mild temporary burning or itching at the application site. There are no systemic toxic side effects. At the same time, none of the spouses involved in this study reported adverse side effects. None of the patients withdrew from the study or lost track. The results of this clinical study show that the use of the prostaglandin E i 0.4% topical composition of the present invention to treat palliative, moderate to severe impotence is safe and effective. The foregoing description is intended to be illustrative only and not intended to be limiting. Further variations in the spirit and scope of the present invention are still possible and are apparent to the artist. Figure representation symbol 110 boat nest 1 12 urethra sea body area 114 urethral spheroidal part 128 urinary tract diameter 130 stalk turtle head -45 - (41) (41)

Spongy body sponge corpus cavernosum opening ejaculation tube prostate gland prostate layered columnar epithelium keratinized squamous epithelium keratinized squamous epithelium keratinized squamous epithelium -46 -

Claims (1)

1324930 Patent application 1. A semi-solid composition for application to a fossa navicularis, comprising: a vasoactive prostaglandin selected from the group consisting of PGE i, a pharmaceutically acceptable salt thereof, a group of lower alkyl alkoxides and mixtures thereof; a skin penetration enhancer which is one of the following groups: an alkyl-2-(N-substituted amino alkanoate of the formula: ^3 : Η H3C~~(CH2)n—*〇—〇—C—(j: l R where n is an integer in the range of 4 to 18; R is hydrogen, alkyl, benzyl and phenyl a member of the group; 1^ and 112 are members of a group consisting of hydrogen and C^-C? alkyl; and R3 and R4 are members of a group consisting of hydrogen, methyl and ethyl. N-substituted amino)-alkanol alkanoate ο R5 H3C ·〇r4 -Q—〇—~C Re C- % Yn where n is an integer in the range of from about 5 to about 18; y is an integer in the range from 〇 to about 5; and R, R2, R3, R4, R5, 116 and R7 81517-960523.doc 1324930 a member of a group consisting of hydrogen, a Ci-C8 alkyl group and a c3-c8 aryl group; and R8 is a member of a group consisting of hydrogen, a hydroxyl group, a C^-Cs alkyl group and a c3-c8 aryl group, which is medically Acceptable salts and mixtures thereof; shear-thinned polysaccharides selected from the group consisting of galactomannan gum, modified galactomannan gum, guar gum, modified guar gum, and locust bean gum a group of yellow gum, carboxymethyl cellulose, sulfhydryl cellulose, hydroxypropyl fluorenyl cellulose, hydroxymethyl cellulose, and hydroxypropyl cellulose; a lipophilic compound, which is composed of aliphatic C a member of the group consisting of: -Cs alcohol, an aliphatic C8-C3G ester, and mixtures thereof; water; and an acidic buffer solution system providing a buffered pH of the composition in the range of 3 to 6.5, wherein the semi-solid composition The viscosity is from about 5,000 centipoise (5 Pa s) to about 20,000 centipoise (2 (^8) ° 2. The semi-solid composition according to claim 1 of the patent scope' The shear-thinned polysaccharide has a viscosity of from about 7,000 centipoise (7 Pa s) to about 13,000 centipoise (13 Pa s). 3. The semi-solid composition according to claim 1, wherein the shear-thinning polysaccharide A natural or modified galactomannan gum. 4. The semi-solid composition according to claim 3, wherein the modified galactomannan gum is a modified guar gum. Apply for a semi-solid composition of Patent No. 1, wherein the lipophilic 81517-960523.doc 1324930 The compound is at least one aliphatic C8-C3 decyl ester. 6. The semi-solid composition of claim 1, wherein the composition comprises at least one glycerin derived from the group consisting of monoglycerides, diglycerides, triglycerides, and mixtures thereof. 7. The semi-solid composition according to claim 1, wherein the composition comprises at least one glycerin S selected from the group consisting of glycerol monooleate, triolein, trimyristyl, tristearyl a group of fine and its mixture. 8. The semi-solid composition according to claim 1, wherein the composition further comprises an emulsifier selected from the group consisting of sucrose esters, polyoxyethylene sorbitan esters, long chain alcohols, and glycerides. group. 9. The semi-solid composition according to item 8 of the patent application, wherein the emulsifier is at least one glyceride selected from the group consisting of glycerol monooleate, glycerol trioleate, trimethyl myristate, tristearate a group of its mixtures. 10. The semi-solid composition of claim 1, wherein the composition further comprises a fragrance. 11. The semi-solid composition of claim 1, wherein the composition further comprises up to about 5% of the camphorolol, based on the total weight of the composition. 12. The semi-solid composition of claim 1, wherein the composition further comprises a preservative. 13. The semi-solid composition of claim 1, wherein the composition further comprises a local anesthetic. 81517-960523.doc 1324930 14. Use of a semi-solid prostaglandin composition for the preparation of a pharmaceutical composition for treating an erectile dysfunction patient in need of such therapy, and the pharmaceutical composition for administration to a scaphoid fossa of a patient, wherein the semi-solid prostate The composition comprises a vasoactive prostaglandin selected from the group consisting of PGE!, a pharmaceutically acceptable salt thereof, a group of lower alkyl esters and mixtures thereof, and a skin penetration enhancer which is in the group consisting of One member: alkyl-2-(N-substituted amino)-alkanoate 下 下 Where η is an integer having a value in the range of 4 to 18; R is a group of hydrogen, Ci-C^ pit base 'mercapto group and phenyl group, and Rl and Κ·2 are wind and Ci-C? a member of a group consisting of alkyl groups; and R3 and R4 are members of a group consisting of hydrogen, methyl and ethyl, (N-substituted amino)-alkanol alkanoates of the formula Wherein η is an integer having a value in the range of from about 5 to about 18; y is an integer in the range of from 0 to about 5; and R!, R2' R3, R4, R5, Ruler 6, and R? 81517-960523.doc -4- 1324930 is a member of a group consisting of hydrogen, a Ci-C8 alkyl group and a c3-c8$ group; and R8 is a member of a group consisting of hydrogen, a hydroxyl group, a Ci-Cs alkyl group and a c3-c8 aryl group, a pharmaceutically acceptable salt thereof and a mixture thereof; a shear-thinned polysaccharide selected from the group consisting of galactomannan gum, modified galactomannan gum, guar gum, modified guar gum, a group of locust bean gum, xanthan gum, carboxymethyl cellulose, methyl cellulose, hydroxypropyl fluorenyl cellulose, hydroxymethyl cellulose, and hydroxypropyl cellulose; a lipophilic compound a member of the group consisting of aliphatic c!-c8 alcohols, aliphatic c8-c30 esters, and mixtures thereof; water; and an acidic buffer system providing a buffered pH in the range of compositions 3 to 6.5, wherein the semi-solid combination The viscosity of the substance is from about 5,000 centipoise (5 Pa s) to about 20,000 centipoise (20 to 33). 15. According to the use of item 14 of the patent application, the shear thinning Natural sugar or a modified galactomannan gum. 16. The use according to claim 15 wherein the modified galactomannan gum is a modified guar gum. 17. The use according to item 16 of the patent application, wherein the modified guar gum is guar gum. 18. The use according to claim 14 wherein the lipophilic compound is at least one aliphatic C8-C3 oxime ester. 81517-960523.doc 1324930 19. The use according to claim 14 wherein the composition comprises at least one glyceride selected from the group consisting of monoglycerides, diglycerides, triglycerides and mixtures thereof. 20. The use according to claim 14 wherein the composition comprises at least one glyceride selected from the group consisting of glycerol monooleate, glycerol trioleate, trimyristyl, tristearate and A group of mixed compositions. 21. The use according to claim 14 wherein the composition further comprises an emulsifier selected from the group consisting of sucrose esters, polyoxyethylene sorbane vinegar, long chain alcohols, and glycerin. 22. The use according to claim 21, wherein the emulsifier is at least one glyceride selected from the group consisting of glycerol monooleate, glyceryl trioleate, trimethyl myristate, tristearate and a group of mixtures. 23. The use according to claim 14 wherein the composition further comprises a fragrance. 24. The use according to claim 14 wherein the composition further comprises up to about 5% of camphorolol, based on the total weight of the composition. 25. The use according to claim 14 wherein the composition further comprises a preservative. 26. The use according to claim 14, wherein the composition further comprises a local anesthetic. 27. A prostaglandin E composition for administration to a scaphoid, comprising: a shear-thinned modified galactomannan gum; a prostaglandin selected from PGE, which is pharmaceutically acceptable Accept the salt, its 81517-960523.doc 1324930 a group consisting of a lower alkyl ester and a mixture thereof; 0.5% to 10% of 2-(N,N-dimethylamino)-propionic acid dodecyl ester (DD AIP) or a pharmaceutically acceptable salt thereof, Depending on the total weight of the composition; 0.5% to 10%, based on the total weight of the composition, lower alcohol, selected from the group consisting of ethanol, propanol, isopropanol and mixtures thereof; 0.5% to 10% An ester selected from the group consisting of ethyl laurate, isopropyl myristate, isopropyl laurate, and mixtures thereof, based on the total weight of the composition; water; and an acidic buffer system providing composition 3 a buffered p Η value in the range of 6.5, wherein the semi-solid composition has a viscosity of from about 5,000 centipoise (5 Pa s) to about 20,000 centipoise (20 to 35) ° 28. According to the scope of claim 2 The composition of the present invention further comprises an emulsifier selected from the group consisting of sucrose esters, polyoxyethylene sorbitan esters, long-chain alcohols, and glycerol. 29. The composition according to claim 28, wherein the emulsifier is sucrose stearate. 30. The composition of claim 28, wherein the emulsifier comprises at least one glyceride selected from the group consisting of glycerol monooleate, glycerol trioleate, trimyristyl, tristearyl and a group of mixtures thereof. 31. The composition of claim 27, wherein the composition further comprises a fragrance. The composition of claim 27, wherein the composition further contains up to about 5% of the camphorolol, based on the total weight of the composition. 33. The composition of claim 27, wherein the composition further comprises a preservative. 34. The composition of claim 27, wherein the composition further comprises a local anesthetic. 35. The composition of claim 27, wherein the modified galactomannan gum is a modified guar gum. 36. The composition of claim 27, wherein the modified guar gum is guar gum. 81517-960523.doc