TW200404001A - Prostaglandin compositions and methods of treatment for male erectile dysfunction - Google Patents

Abstract

The invention provides methods and compositions for treating erectile dysfunction. The methods include the step of placing within the fossa navicularis of the patient an effective erection-inducing amount of a vasoactive prostaglandin composition of a semi-solid consistency. The composition comprises a vasoactive prostaglandin, a penetration enhancer, a shear-thinning polysaccharide, a lipophilic compound, and an acidic buffer system. The penetration enhancer is an alkyl-2-(N- substituted amino)-alkanoate ester, a (N-substituted amino)-alkanol alkanoate, or a mixture of these enhancers. The lipophilic compound may be an aliphatic C1 to C8 alcohol, aliphatic C2 to C30 ester, an aliphatic C8 to C30 ester, or a mixture of these. The composition includes a buffer system providing a buffered pH value for said composition in the range of about 3 to about 7.4.

Description

200404001 ⑴ 发明, description of the invention (the description of the invention should state: the technical field to which the invention belongs, the prior art, the content, the embodiments and the simple description of the drawings) TECHNICAL FIELD The present invention relates to a composition and method for treating erectile dysfunction, and more In particular, it is related to administering a vasodilator drug to a fossa navicularis of a patient by intra-caval administration. The so-called "impotence" in the prior art means that men cannot achieve and maintain an erection of the penis, so that they cannot have satisfactory sexual intercourse. "Erectile dysfunction" is that "men cannot achieve in all aspects of male sexual function. An erect penis has been suggested for a more precise description, Droller, MJ et al. Impotence. Consensus Development Conference Statement, National Institutes of Health (1993). Erectile dysfunction can begin with a pathological cause (psychogenic erectile dysfunction), an organic cause, or a mixture of the two. Organic causes include physiology, neurological, vascular, and hormonal pathology or a mixture of them. The normal physiology of an erection involves nerve impulses, which can send signals to certain muscles to relax them. These muscles, when contracted, restrict blood flow through the arteries of the penis. When relaxed, muscles significantly increase blood flow. The increased blood flow congests the three groups of erectile tissue in the penis and makes the penis not weak. Congested erectile tissue and muscle structures in the penis can depress adjacent veins, limiting blood flow from the penis. Restriction of blood flow to the penis can increase and support erections. Deficiency of certain hormones, such as acetone, or elevation of other hormones, such as prolactin, can cause erectile dysfunction. Many drugs, such as diuretics, antihypertension, anticonvulsants, etc. Anesthetics, alcohol and psychotherapeutics can cause erections 200404001 ⑺

Murray, F. T. et al. Amer. J. Medical Dysfunction as a Side Effect

Sci. 309: 99-109 (1995). Nerve and blood vessel damage are also possible organic causes of this erectile dysfunction. The disease process involves many women. Diabetes, for example, can damage the nerves and blood vessels, causing obstacles to erectile dysfunction. A significant proportion of all men with diabetes suffer from erectile dysfunction. The methods proposed for the treatment of erectile dysfunction include external devices, sexual treatment, surgical implantation of internal prostheses, direct injection of drugs into the penis, and topical application of drugs. None of these approaches are completely effective. External devices include tourniquets (see Us Pat No, 2,818,855) and vacuum erectile aids applied externally. Although some physicians consider erectile aids 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 found to be effective by Masters and Johnson, but subsequent studies have not shown such impressive results. Freud therapy is not an attractive method for patients. Vickers, M. A. et al. J

Urology 149: 1258-1261 (1993). Surgical implants such as hinged or solid rods and expanded spring-driven or water-based prostheses have been used for some time. The administration of drugs that achieve and strengthen erections is taught in U.S. Pat. No. 4,127,118 (LaTorre). This patent teaches injecting suitable vasodilators, especially adrenergic blockers or smooth muscle relaxants, into the penis to achieve and strengthen erection to treat male impotence. 200404001 Ο) Recently, U.S. Pat. No. 4,801,587 (Voss et al ·) has taught applying ointment to relieve impotence. The ointment consists of the vasodilators papaverine, hydralazine, sodium nitroprusside, phenoxybenzamine, or phentolamine and auxiliary main agents. Composed of a carrier for skin absorption. U.S. Pat. No. 5,256,652 taught by El-Rashidy an aqueous topical composition using a vasodilator, such as papaverine, plus hydroxypropyl cold-cyclodextrin. Prostaglandin E 1 is a derivative of prostate acid, a fatty acid of 20 carbon atoms, expressed by the following formula

And it is commercially available, such as from Chinoin Pharmaceutical and Chemical Works Ltd. (Budapest, Hungary), and its registered name is "Alprostadil USP.". Prostaglandin E i is a vasodilator that can be used to maintain open blood vessels and is therefore particularly useful therein for treating peripheral vascular diseases. Although prostaglandin has been! The potential benefits of percutaneous delivery have long been recognized, but previous efforts to develop topical compositions that can deliver prostaglandins have not been entirely successful. In a commercial version (MUSE®, Vivus, Menlo Park CA), alprostadil is administered as small masses stored in the urethra, using an applicator with a hollow stem length of 3.2 cm and a diameter of 3.5 mm ( Padma-Nathan, H., et al., N. Engl. J. Med., 336: 1-7 (1997), especially see Figure 1). At 200404001 (4)

Padma-Nathan et al. Studied the home treatment portion of '37 .7% of patients receiving MUSE® (8% of medications complained of yin to pain ') and 5.1% experienced minimal urethral trauma compared with patients receiving placebo. 3 · 3% and 1 · Compare. The frequency of these side effects was reported to change in subsequent studies: muse® produced penile pain at m6% of the dose compared to I · 7% of placebo, and minor urethral bleeding was 4.8%

Urol., 159 · 1523-1528 (1998)). In the European population study, 31% of patients with MUSE⑧ reported penile pain or burning sensation, 4.8% had urethral bleeding ’and Er Li ^ / ^ had severe testicular pain " 01 ^ · 1 ^ 11 ^.] !! ! ^. !: ·! ^., ~ 187-192 (1997)). The percentage of patients who responded to MUSE® treatment was defined by having at least one erection considered sufficient to cope with sexual intercourse. The reported scores were J, 43% (Porst, 1997), and 65.9% (Padma-Nathan et al. (1997) and 70.5% (Peterson et al., 1998), although published comments indicate that it has been suggested that the percentage of patients who responded in the latter two studies is more correctly 30-40% (Benson, G., J. Urol ·, 159: 1527-1528 (1998)) 0 In particular, there are currently no commercial sources of topical semi-solid blends that are still useful without support devices such as adhesives, adhesive strips, etc. For example, U.S. Pat. No. 5,380,760 of Wendel et al. Relates to a local prostaglandin blend, which includes a thermosensitive polyisobutylene adhesive strip. Most drugs, when used alone, also include prostaglandin blends, and are unable to penetrate the skin sufficiently to provide adequate levels of drug compared to those obtained from other drug delivery pathways; To overcome this problem, topical drug blends often include a skin penetration enhancer. Skin penetration enhancer can also be called as absorption enhancer 200404001 (5) Receiving enhancer, accelerator, adjuvant, solubilizer, absorption enhancer, etc. Regardless of its name, this agent can be used to improve the absorption of drugs across the skin. The ideal penetration enhancer will not only increase the flux of the drug across the skin, but will not irritate, sensitize or damage the skin. Furthermore, an ideal penetration enhancer should not adversely affect the physical properties of the applicable dosage form (such as an emulsion or gel), or the cosmetic quality of a topical composition. Various compounds have been evaluated for their effectiveness in enhancing skin penetration rates. If so, Percutaneous Penetration Enhancers, Maibach Η. I. and Smith Η. E. (eds.), CRC Press, Inc., Boca Raton, FL (1995), which studies the use and testing of various skin penetration enhancers, and Btiytiktimkin 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) 〇 Prostaglandin £! Fully successful local or transmucosal blends have not yet been identified and commercialized. Unfortunately, prostaglandin E! Can be easily transformed for rearrangement and other reactions. This considerable instability complicates the formulation of the composition for boat delivery. The present invention addresses these issues by providing methods and compositions for semi-solid, anti-separation, and chemically stable compositions that are delivered in a boat. Such vasodilators, preferably prostaglandins E, have relatively rapid and continuous delivery. SUMMARY OF THE INVENTION The present invention proposes a composition and method for treating erectile dysfunction, in which a pharmaceutical composition is applied to the yin of a mammal in a boat-shaped fossa -10-200404001 (6) stem. In another aspect, the present invention provides a composition capable of preparing a pharmaceutical composition for the treatment of erectile dysfunction, and the pharmaceutical composition can be applied to the penis-shaped fossa. The present invention proposes a method for treating erectile dysfunction, which method comprises implanting a prostaglandin E i composition in a scaphoid fossa of a patient in order to erect an effective dose of semi-solid firmness. The composition contains a vasodilator, preferably prostaglandin E 1, a penetration enhancer, a shear-thinning polysaccharide, a lipophilic compound, and an acidic buffer solution system. The permeation enhancer is an alkyl-2- (N-substituted amino) -alkanoate, (N-substituted amino) -alkanol alkanoate, or a mixture of these. The lipophilic compound may be an aliphatic Ci to C8 alcohol, an aliphatic <: 2 to C30 ester, an aliphatic <: 8 to C3Q ester, or a mixture of these. The composition includes a buffered solution system that provides the composition with a buffered pH value in the range of about 3 to about 7.4. The preferred pH is from about 3.0 to about 7.4, more preferably from about 3.0 to about 6.5, and most preferably from about 3.5 to about 6.0. The vasodilator composition of the present invention is placed in the scaphoid fossa, that is, in the scaphoid fossa (fossa navicularis). More advantages. The scaphoid fossa is a naturally inflated space suitable for receiving and retaining semi-solid pharmaceuticals. Semi-solid pharmaceutical products, such as the composition of the present invention, have a high resistance when placed inside, so that they cannot flow through the narrow exits of the space, that is, the urethral orifice and urethra. Flow resistance is proportional to the cross-sectional area and diameter length of the diameter. _ The lining of the scaphoid fossa is a stratified squamous epithelium without keratinization. Compared with the keratinization of the skin on the outer surface of the penis, the former has a stronger permeability. 200404001

⑺ Use a short applicator that terminates within the anatomical limits of the scaphoid fossa. It is less invasive than penetrating the longer applicator into the urethral penis at a height of (or close to) a few centimeters. Suitable applicators are described in U.S. Pat. No. 6,224,573, Yeager et al, which is incorporated herein by reference. Preferably, the applicator contains a storage tank containing a semi-solid seletonin composition that can erect an erectile dose. The applicator is preferably a single-use device and contains a single dose of a semi-solid prostaglandin E i composition. In a specific embodiment, the inactive component of the composition of the present invention has a position on the applicator between a single-dose semi-solid prostaglandin E i composition and the applicator tip. In this specific example, the use of the applicator will cause the composition of inactive components to be deposited in the proximal scaphoid fossa and the distal part of the urethra penis, thus limiting the single-dose semi-solid prostaglandin E i composition Unable to reach the scaphoid fossa. The applicator usually has instructions for use, located on all or part of the following: on the package with the applicator, on the leaflet of the package, and on the outside surface of the applicator itself. The scaphoid fossa contains a very large amount of glycogen and bacterial clumps, so it can naturally reduce the pΗ value in the space, so the composition with a lower pΗ value in the acidic range makes the prostaglandin with increased solubility easier! Be tolerated without over-stimulating tissue. The scaphoid fossa is more immunologically protective than the cavernous body adjacent to the urethral penis. Placing the tip of the applicator within the anatomical limit of the scaphoid fossa, that is, the manual staining method, from the surface of the penis to the penis of the urethra, the risk of bypassing the natural barrier is low.

-12- 200404001

医药 The pharmaceutical composition suitable for intravesicular administration contains prostaglandin Ei, penetration enhancer, modified polysaccharide gum, lipophilic compound, and acidic buffer system. The penetration enhancer is pit-2-(N-substituted amine)-pit acid vinegar '(N-substituted amine)-alkanol alkanoate, or a mixture of these. The lipophilic compound may be an aliphatic CrCs, an aliphatic Ci-Cw ester, or a mixture of these. The composition includes a buffer solution system that can provide the composition with a buffered pH in the range of about 3 to about 7.4. If desired, stabilizers, preservatives and emulsifiers can also be added. The composition of the present invention can be in a semi-solid form for use in a boat-shaped nest. When used as acting substances in the scaphoid fossa, these compositions exhibit a relatively high prostaglandin permeability and bioavailability to the penis glans, without the need to waste excessive prostaglandin concentrations. The composition further exhibits reduced irritation, sensitivity and damage to local tissues. In a further specific example, the composition can be delivered into a boat fossa using a suitable single-dose applicator. From the scope of this specification and the appended patent applications, the skilled artisan will understand other and further objects, objectives, features, advantages, specific embodiments and other aspects of the present invention. Brief Description of the Drawings In this drawing, Figure 1 is the anatomical structure of the human penis longitudinal section; Figure 2 is a detailed anatomy illustration of the proximal part of the human penis longitudinal section; Figure 3 is the seven prostaglandins prepared according to the present invention Schematic representation of the accumulated prostaglandin E i penetrated by the E i composition through the shaved exposed skin; Figure 4 shows two prostaglandin E i compositions prepared according to the present invention via shaving-13-200404001

(9) Comparison diagram of the accumulated prostaglandin E i penetrated by the bare skin of the hair, plus two comparison compositions. Embodiments Surprisingly, it has been found that a semi-solid prostaglandin Ei composition suitable for treating erectile dysfunction can be beneficially placed in a naturally enlarged space immediately adjacent to the penis tract, namely, a fossa navicularis. The scaphoid fossa provides a restricted location which can be ideally suited for the application of pharmaceutical compositions. This space is lined with non-keratinized layered squamous epithelium, and is distinguishable from the surface skin covering the glans and the rest of the penis, and from the layered columnar epithelium lining of the urethra. It was found that the administration of the composition of the present invention in the scaphoid fossa had unexpectedly high potency and a low incidence of local side effects. The scaphoid nest provides a natural space suitable for the application and retention of pharmaceutical compositions. Semi-solid drugs, such as the composition of the present invention, have a higher resistance when placed in the scaphoid so as not to flow in this space, i.e. the low and narrow exits of the channels and urethra. Therefore, a semi-solid drug with a proper viscosity can be naturally retained in the scaphoid fossa to promote the absorption of active substances such as vasodilators. The scaphoid fossa is part of a natural anti-depressant system that protects the body against infection. The scaphoid fossa is more immune-protective than the corpus cavernosum adjacent to the penile part of the urethra. Therefore, placing the semi-solid medicines within the limits of the scaphoid dissolution agent does not cause disease due to the artificially transported contaminates directly from the surface of the penis into the urethral penis. As mentioned above, scaphoid nests naturally support bacterial flora maintained at an acidic pH. Referring to Figure 1, the basic structure of a human penis is illustrated. The scaphoid fossa 110 is the natural swollen part of the male urethral cavity in the penis glans 1 3 0, which extends to the tip -14- 200404001

(ίο) to the urethral diameter 128, and close to the urethral drooping area 112 (also known as the corpus cavernosum area of the urethra), that is, the portion of the urinary tract passing through the body of the corpora cavernosum 1 3 4 4 Close to the sagging area of the urethra and pass through the corpus cavernosa muscle 140. Then at the more proximal end, the urethral glands (cobb's glands)

Cowper ’s gland) saw an opening 148 in the urethral wall. More proximally, the urethra passes through the prostate 160, where the ejaculation duct 156 and the opening of the prostate capsule 158 can be seen on the wall of the urethra.

Referring to FIG. 2, a detailed structural diagram of the boat-shaped nest 1 110 is shown. The outer opening of the urethral diameter 1 2 8 is located at the distal limit of the scaphoid fossa. The outer skin of the glans is covered with keratinized squamous epithelium 186 (Pudney, J., and Anderson, DJ, (1995) Immunobiology of the human penile urethra, Amer. J. Path., 147: 155-165), which The transition from the proximal end to the non-keratinose-free non-keratinized stratified squamous epithelium left by 184 is a unique structure of the distal scaphoid fossa lining.

The scaphoid fossa widened at the proximal end and the lining changed to a non-keratinized layered squamous epithelium containing glycogen 182. Glycosides in this area can support bacterial flora, which can reduce the pΗ value of the area and constitute 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. The non-keratinized squamous epithelium with glycogen is under the control of hormones, and its content will increase if the level of estrogen increases (Holstein, et al., 1991). The proximal scaphoid fossa narrows in width and is lined with layered columnar epithelium 180. The semi-solid composition of the present invention has a suitably selected viscosity so that the composition can be naturally retained in the scaphoid fossa. The semi-solid composition exhibits Newtonian or non-Newtonian rheological properties. In some preferred embodiments, the semi-solid of the present invention -15-200404001

The bulk composition exhibits non-Newtonian rheological properties, i.e. its apparent viscosity is determined by the shear rate applied to the composition. The composition preferably has a rheological property of '' shear thinning '. Here, "shear-thinning" refers to reducing the apparent viscosity (the ratio of the shear stress to the shear strain rate) with an increasing shear strain rate. It is estimated that regardless of the decrease in apparent viscosity, Time-independent (pseudoplastic), time-dependent (shake deflection) or yield stress, which is defined as the stress that must be exceeded before starting to flow (Bingham plastics and general Bingham plastics and generalized Bingham plastics)). For an overview, see 1 ^ 1 * 145,]., &Amp; ^^ 11 ^ 115〇11, ^^ 丄., "] ^ 〇11 · newtonian Fluid ·" ρρ · 856-858 in Parker, SP, ed ·, McGraw -Hill Encyclopedia of Physics, Second Edition, McGraw-Hill, New York, 1993. A suitable viscosity range is from about 5,000 centipoise (cps) to about 20,000 cps, and the vehicle is delivered from about 7,000 cps to about 13,000 cps. The method of the present invention also proposes a relatively non-invasive coating device. When an effective erectile dose of the prostaglandin E i composition is placed in the scaphoid fossa, the tip of the applicator does not exceed the resolving limit of the scaphoid. Preferably, the tip of the applicator does not exceed the diameter opening in the penis by about 2 cm or more, preferably not more than 1 cm, and most preferably not more than 0.5 cm. More specifically, the applicator includes a storage tank containing a semi-solid composition in an erectile dose, which contains at least one vasodilator, preferably a prostaglandin E 1 composition. In contrast, the applicator is a single-use device and contains a single dose of a semi-solid vasodilator composition. The applicator is usually accompanied by instructions for use, placed in the following places or places: in the package containing the applicator, in the packaging leaflet, and on the outside of the applicator itself. -16-200404001

(12) The pharmaceutical composition of the present invention contains at least one vasodilator, preferably prostaglandin Ei, an alkyl (N-substituted amino) ester, a shear-thinning polysaccharide, a lipophilic compound, and an acidic buffer system. Suitable vasoactive agents include the following, but are not limited to them: nitrates, such as nitroglycerin, isosorbide dinitrate, tetraol nitrate, isoamyl nitrite, sodium nitroprusside, modamidine ( molsidomine) Chlorine compounds (" SIN-1 ") and S-nitroso-N_ethylenyl-d, l-penicillamine ("SNAP"); amino acids such as L-arginine; long And short-acting α-blockers, such as phenoxybenzamine, chloroethionamine, doxazosin, terazosin, phentolamine, pulex Tolazoline, Prazosin, Trimazosin, Alfuzosin, Tamsulosin, and Indoramin Natural herbal composition and its biologically active extracts, such as gosyajinki-gan, Satureja obovata 'bai-hua qian-hu, lipotab, saiboku-to, vinpocetine, (Gingko biloba), bago grass ( bacopa), Gynostemma pentaphyllum, gypenosides, Evodia rutaecarpa, Wu Mozhen Rutaecarpine, dehydroevodiamine, dan-shen, Denmark (salviae miltiorrhizae radix), shosaikoto, Zizyphi fructus, ginseng and its mixture (US Pat, 6,007,824); ergot alkaloids , Such as ergotamine and its homologues, such as acetoamine dihydroergotamine, brazergoline, bromerguride, cianergoline, dracotazone ( delorgotrile), disulergine, ergonovine maleate, ergotamine tartrate -17- 200404001

(13) (ergotamine tartrate), etisulergine, lergotrile, lysergide, mesulergine, metergoline, methy Metergotamine, nicergoline, pergolide, propisergide, proterguride and terguride; antihypertensive Drugs, such as diazoxide, hydralazine, and minoxidil; vasodilators such as nimodepine, leaf dagger

Pinacidil, cyclandelate, dipyridamole and isoxsuprine; chlorpromazine; haloperidol; yohimbine

Trazodone; naturally occurring prostaglandins, such as pGEi, PGAi, PGBi, PGFla, 19-hydroxy-PGAi, 19-hydroxy-PGBi, PGE2, PGA2, PGB2, 19-hydroxy-PGA2, 19-hydroxyl -PGB2, PGE3, PGF3a; semi-synthetic or synthetic natural prostaglandin derivatives, including carboprost tromethamine, dinoprost tromethamine, dinoprostone , Lipipr0St, Gimeprost, Minenoprost, Sulprostone and Tiaprost; and vasoactive intestinal peptides. Prazodox, prostaglandin E! And prostaglandin E2. It is a particularly good vascular active substance that can be used in combination in the method of the present invention. In addition, the simultaneous administration of two or more vasoactive agents may be desirable, and in some cases, they show a synergistic effect. The combination of Pai beta well plus prostaglandin E i has been found to be particularly beneficial in this regard; The latter drug can be used as a peak enhancer, that is, it can increase the rate at which wezocarbine penetrates through the skin or sticky -18-200404001 (14) membrane tissue and enters the bloodstream. Prostaglandin E i is well known to the artisan. See many literatures on its pharmacological activity, side effects and normal dosage range, see: Physician ’s Desk

Reference, 51st Ed. (1997), The Merck Index, 12th Ed., Merck & Co., N. J. (1996), and Martindale The Extra Pharmacopoeia, 28th Ed., London, The Pharmaceutical Press (1982). Formerly, J adenine E! And other compounds referred to in 4 are used to cover pharmaceutically acceptable derivatives, including their physiologically compatible salts and their ester derivatives. The amount of prostaglandin E! In the pharmaceutical composition of the present invention is a therapeutically effective dose, and the particular type of prostaglandin E i used may be changed as necessary according to the desired dose, dosage form (such as suppository or topical). "Prostaglandin," as used herein, refers to prostaglandin free acid and its pharmaceutically acceptable derivatives, including prostaglandin El (PGEi), its pharmaceutically acceptable salts and its lower alkyl esters (wherein The "lower alkyl group" used means that the straight-chain or branched-chain alkyl composition containing 1 to 4 carbon atoms usually has about 0.001% to 1% of the former 1J adenin Eι, and usually contains about 0.05%. 1% prostaglandin Eι, preferably about 0.1% to 0.5%, based on the total weight of the composition. An important component of the present invention is a penetration enhancer. The penetration enhancer is fluorenyl-2- (N -Substituted amino group)-Burnt acid, (N-substituted amine group)-Burnt alcohol acid ester, or a mixture of these. For a convenient reference, alkyl-2- (N-substituted amine group) -Phenyl ester and substituted amino group)-Burnt alcohol ester can be divided into a group under the label of burned 4-base (N-substituted amino group) ester. The alkyl-2- (N-substituted amino group) to which the present invention is applicable may be represented by: 200404001 (15)

R3 〇H c—— r4 〇c- -C——N [R, r2 where η is an integer ranging from about 4 to about 18; R is composed of hydrogen, C, C7 alkyl, fluorenyl, and phenyl Members of the group; 1 and 112 are members of the group consisting of hydrogen and (: "(: 7 alkyl; and R3 and R4 are members of the group consisting of hydrogen, methyl, and ethyl. Preferred is alkyl (N, N-disubstituted amino) -alkanoates such as C4-C18 alkyl (N, N-disubstituted amino) -acetate and C4-C18 alkyl (N, N-disubstituted Amine) -propionate and pharmaceutically acceptable salts and derivatives thereof. Exemplary special alkyl-2- (N, N-disubstituted amino) -alkanoates include 2- (N, N_ Dimethylamino) -dodecyl propionate (DDAIP);

Η OH h3c Pottery 10. C ......... 〇 C-C-NH CH3

And 2- (N, N-dimethylamino) -dodecyl acetate (DDAA);

H3C

H OH I I C-o—C-C N I I Η H

CH3

ch3 -20-200404001

(16) Alkyl-2- (N, N-disubstituted amino) -alkanol esters are known. For example, 2- (N, N-dimethylamino) -dodecyl propionate (DDAIP) is commercially available from Steroids, Ltd. (Chicago, IL). In addition, alkyl · 2- (N, N-disubstituted amino) -alkanoates can be synthesized from readily available compounds, as described by Wong et al in US Pat. No. 4,980,378, which is referenced The extent of inconsistency is incorporated as a reference in this case. As described herein, alkyl-2- (N, N-disubstituted amino) -alkanoate can be easily prepared by a two-step hydrazone synthesis. In the first step, the preparation of long-chain alkyl chloroacetate is equivalent to long-chain alkanol and methyl chloroformate, etc., under suitable storage (such as triethylamine), usually in a suitable solvent such as Reacted with chloroform. The reaction can be shown as follows: h3c

R3 (CH2) n -c-OH R4

Ο H Cl-C——C-Cl R

R3 OH H3C- (CH2) n-C——0——C——C——Cl

R4 R wherein R, R3, R4 and n are as defined above. The reaction temperature can be selected from about 10 ° C to about 200 ° C, or under reflux, preferably room temperature. The use of solvents is as needed. If a solvent is used, various organic solvents can be selected. In addition, the choice of experience is not strict. Preferred tests 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 and the appropriate amine are as follows: 200404001

(17) Cheng Fu: Η R3 〇 H3C- (CH2) n -c——O——C-C——Cl + HNR, R2-

R4 R r3 oh

I II I

H3C-(CH2) n-C-0-c-C-NRA r4 r where n 'R, Ri' R2, R3 and R4 are as defined above. Excess amine reactants are usually sufficient as a test, and the reaction can conveniently be performed in a suitable solvent, such as diethyl ether. This second step is preferably carried out at room temperature, but the temperature may be changed. The reaction time usually varies from about 1 hour to several days. The resulting esters can be prepared using conventional purification techniques for use in pharmaceutical compounds. Suitable (N-substituted amino) -alkanol alkanoates can be represented by the following formula: Y 0 II h3c- 1 -c ″ 1 II C 0 (] _ -c] _ 1 r4

r2 π y where η is an integer having a value in the range of about 5 to about 18; y is an integer having a value in the range of 0 to about 5; and Ri, R2, R3, R4, R5, trans 6 and R7 are represented by nitrogen 'Ci_Cg alkyl and Ci ~ C8 aryl group members; and Rs -22-200404001 (18) is a member of the group consisting of hydrogen, hydroxyl, Ci-Cs alkyl and CVCs # group. Preferred are (N-substituted amino) -burnt alcohol vinegars, such as C 5-c 1 8 leptates and pharmaceutically acceptable salts thereof. Exemplary special (N, N-disubstituted amino) -alkyl alcohol alkanoates include 1- (N, N-dimethylamino) -2-propanol dodecanoate (DAIPD); 〇 Ο Η xh3 H3C- [CH ^ io-COCCN:

CH3 H ch3 1- (N, N-dimethylamino) -2-propanol myristate (DAIPM)

Ο Η Η II I I / called H3C- [CH2I12-c-Ο-C-C-N

CH3 H ch3 1_ (N, N-dimethylamino) -2-propanol oleate (DAIPO);

HjjC- [CH2I7

o-OMHNC

HI H. C-ICH3 0,

N H3 c

H H3 (N, N-disubstituted amino) -alkanol alkanoate can be prepared by reacting an equivalent amino alkanol with lauryl chloride in the presence of triethylamine. A solvent such as chloroform is desirable but is preferably used. For example, 1- (N, N-dimethylamino) -2-propanol can be reacted with lauryl chloride in chloroform and triethylamine to form 1- (N, N-dimethylamino) 2-propanol dodecanoate (DAIPD). -23-200404001

(19) DDAIP is preferred as the penetration enhancer suitable in the present invention. The penetration enhancer is sufficient to enhance the penetration of prostaglandin E i into the tissue. Specific doses will need to be varied depending on the desired release rate and the type of prostaglandin used. Generally, this amount ranges from about 0.5% to about 10%, based on the total weight of the composition. Preferably, the penetration enhancer is from about 2 to about 5 wt% of the composition. Natural and modified polysaccharide gums are also important components in this composition. Suitable representative gums are natural and modified galactomannan gums. Galactomannan gum is a carbohydrate polymer containing D-galactose and D-mannose units, or a derivative of this polymer. There is a considerable amount of galactomannans, which vary in composition depending on the source. The galactomannan gum is characterized by a linear structure in which the D-mannopyranosyl units are linked by (1-4). The single-member α-D-mannosyl glycosyl unit is linked to the main chain by (1-6) and appears on the side branch. Galactomannan gum includes guar gum, which is the endosperm of crushed seeds of two leguminous plants (Cyamposis tetragonalobus and psoraloids), and locust bean gum, which is found in the seeds of rice ceratonia siliqua Endosperm. Suitable modified polyether gums include ethers of natural or substituted polysaccharide gums such as carboxymethyl ether, hydroxypropyl ether, glycol ether and propylene glycol ether. An exemplary substituted polysaccharide gum is methyl cellulose. A preferred modified polysaccharide gum is a modified guar gum. Suitable shear thinning polysaccharides include, but are not limited to, guar gum, modified guar gum, locust bean gum, xanthan gum carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl fiber Cellulose, hydroxyethyl cellulose, and hydroxypropyl cellulose-24-200404001 (20) vitamins. Preferred shear thinning polysaccharides are natural and modified galactomannan gums, including modified guar gums. Other suitable representative gums include guar gum, carrageenan, ghatti, sycamore gum, rhamnosan, and xanthan gum. The composition of the present invention may contain a mixture of various gums, or a mixture of gums and acidic polymers. Gum and especially galactomannans are well known substances. 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 of the gel packs are commercially available in various forms, 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 content of polysaccharide gum is from about 0.1% to about 5%, based on the total weight of the composition, Among them, about 0.5% to 3% is more preferable. In a preferred embodiment, the polysaccharide gum content is 2.5% wt. Examples for demonstration are shown in the following examples. Polysaccharide gels are optionally substituted by polyacrylic polymers. A common variant of polyacrylic polymer is generally called carbomer. Carbomer is a polyacrylate polymer and a polyalkenyl polyether quietly cross-linked. It can be purchased from BF Goodrich under the trade name "CARBOPOLTM" Company (Akron, Ohio). A special Carbomer variant is f'CARBOPOL 940 ". Other polyacrylic polymers suitable for the present invention are available under the trade names "PemulenTM" (B. F. Goodrich Company) and, POLYCARBOPHILtm "-25-200404001 (21) (AH Robbins, Richmond, VA). € 1! 11116111 ^ The polymer is a copolymer of C19X30 alkyl acrylate and one or more acrylic acid, methacrylic acid monomer, or one of its simple esters, crosslinked with sucrose allyl ether, or allyl ether of quaternary POLYCARBOPHILTM polymer is a polyacrylic acid cross-linked with diethylene glycol. When a polyacrylic acid polymer is present, it is about 0.5% to about 5% in the composition, based on its total weight. Suitable shear thinning polyacrylic polymer Materials include pseudoplastic polyacrylic polymers and copolymers. Another important component of the present invention is lipophilic compounds. In a specific example, lipophilic compounds as used herein refer to lipophilic and hydrophilic agents. CrCUg family alcohol C2-C3G aliphatic esters and their mixtures can be used as lipophilic compounds. Suitable alcohols for illustration are ethanol, n-propanol and isopropanol, and suitable esters are ethyl acetate, butyl acetate, and lauric acid. B , Methyl propionate, isopropyl myristate, isopropyl palm and thus used in the ". May purpose alcohols "includes as many as glycerol, propylene glycol and polyethylene glycol. A mixture of an alcohol and an ester is preferred, and a mixture of ethanol and ethyl laurate is particularly preferred. In a specific embodiment, C 2 -C 3 0 aliphatic esters, and mixtures containing lipophilic compounds thereof include C 8 -C 3 0 fatty acids of glycerol, selected from the group consisting of monoglycerides, diglycerides, Triglycerides and their mixtures. Suitable aliphatic vinegars include glycerol vinegar of saturated fatty acids, unsaturated fatty acids and mixtures thereof. Suitable saturated fatty acids include hexanoic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, mandelic acid, and lignanic acid. Suitable unsaturated fatty acids include oleic acid, linoleic acid, and linolenic acid. Suitable -26- 200404001

(22) Glycerol esters include glyceryl monooleate, glyceryl trioleate, trimyristin and tristearate, preferably trimyristole. The required concentration of the lipophilic compound can be changed as necessary depending on other factors, such as a saturated semi-solid consistency and a saturated skin penetration promoting effect. The concentration of the lipophilic compound may suitably be in the range of 0.5% to 40% by weight, based on the total weight of the composition. Preferred topical compositions contain lipophilic compounds between 7% and 40% by weight, based on the total weight of the composition.

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

If necessary, the components of the present invention preferably have an emulsifier. Although not a critical factor, suitable emulsifiers usually exhibit a hydrophilic-lipophilic balance index above 10. Sucrose esters and special sucrose stearate can be used as modifying agents for the topical composition of the present invention. Sucrose stearate is a well-known emulsifier and is available from various commercial sources. When an emulsifier is used, the sucrose stearate content can be as high as 2%, which is preferred based on the total weight of the composition. The preferred content of sucrose stearate emulsifier can also be expressed as the weight ratio of emulsifier to polysaccharide gum. A ratio of 1 to 6 of emulsifier to gum is preferred, and a ratio of 1 to 4 is optimal to produce the desired semi-solid consistency and resistance to separation. Other emulsifiers are also suitable, and include polyoxyethylene sorbitan esters, long-chain alcohols, preferably cetylstearate, and fatty acid glycerides. -27- 200404001

(23) Suitable polyoxyethylene sorbitan esters include monolaurates (Tween 20, Span 20), monopalmitate (Tween 40), monohard moon acid vinegar (Tween 60), and monooleic acid Esters (Tween 80) and mixtures thereof. Preferred fatty acid glycerides include glyceryl monooleate, glyceryl trioleate, trimyristin and tristearin. The invention further includes an acidic buffer solution system. An acidic buffer solution system can maintain or buffer the pH of the composition within a desired range. The term "buffering system" or "buffering substance" as used herein means a solute agent or agent that stabilizes this solution in an aqueous solution to antagonize acid or the main change in pH when the acid is added (or hydrogen ion concentration or active). Negative resistance pH changes, solutes or interacting substances starting from the initial buffer pH in the indicated range are well known. Although there are many other suitable buffer solutions, such as an acetate buffer solution, potassium phosphate-hydrate has proven to be effective for the composition of the present invention. Suitable buffer concentrations range from about 0.005M to about 1.0M. A preferred buffer solution concentration ranges from about 0.05M to about 0.2M. In many preferred specific examples, the buffer solution concentration is 0.1 M. The final pH value of the pharmaceutical composition of the present invention can be varied within a physiologically compatible range. Necessarily, the final pΗ value is not irritating to human skin. To avoid this limitation, ρ ρ is selected to improve the stability of prostaglandin E i and adjust the consistency if necessary. In one embodiment, the preferred pp value is from about 3.0 to about 7.4, preferably from about 3.0 to about 6.5, and most preferably from about 3.5 to about 6.0. The other component in the composition is water, which must be purified. The water content of the composition ranges from about 50 to about 90%, based on the total weight of the composition. However, the water content is not critical and can be adjusted to obtain desired consistency and / or other groups -28- 200404001

(24) concentration. Alternatively, known percutaneous penetration enhancers can be added if desired. Illustrative examples are dimethyl sulfoxide (DMSO), dimethyl acetamide (DMA), 2-pyrrolidone, N, N-diethyl-meta-toluidine (DEET), 1-deca Dialkylazacycloheptan-2-one (AzoneTM, registered trade name of Nelson Research), N, N-dimethylformamidine, N-methyl-2-pyrrolidone, mirror calcium acetate, Hendulone, di-sigmalocene derivatives, laurocapram derivatives, and macrocyclic enhancers such as macrocyclic ketones. Prostaglandin E i stabilizers, colorants, shakers, and preservatives can also be added but should not unduly limit the skin penetration of prostaglandin E i or adversely affect the desired semi-solid consistency. Dosage forms of the semi-solid pharmaceutical composition of the present invention include emulsions, gels, ointments, colloidal suspensions, and the like, as well as compositions suitable for use with similar devices such as transdermal patches. The components listed above can be mixed in any order and manner to produce a stable composition in which the prostaglandin E i is evenly dispersed in the semi-solid blend. One possible way to prepare this composition is to uniformly disperse the polysaccharide gum (or polyacrylic acid) in a pre-mixed water / buffer solution, and then homogenize (ie, mix) the resulting mixture Part A). When present, the emulsifier is added to the water / buffer solution and redispersed into the polysaccharide gum. The pΗ value of Part A can be adjusted to the desired level using any suitable method, such as adding concentrated phosphoric acid or sodium hydroxide Separately, the prostaglandin E i is dissolved in the fatty compound under agitation, which may itself be an alcohol, an ester or a mixture of an alcohol and an ester. Then, osmosis can be added -29-200404001

(25)

Strong agent. In addition, when the lipophilic compound includes an alcohol and an ester, the prostaglandin E i is soluble in the alcohol, and a penetration enhancer is added, followed by an ester. In either case, the resulting mixture is a mixture containing prostaglandin Eι ("Part B"). The final step consists of adding part B (eg dropwise) to part A quite slowly, with fixed mixing.

The resulting topical composition, when compared, exhibits the above-mentioned beneficial properties, including improved prostaglandin Ei penetration and bioavailability without drug overload, reduced skin damage and related inflammation, and available dosage forms Increase flexibility. These compositions are useful in the long-term treatment of peripheral vascular disease, male impotence and other disorders that can be treated with prostaglandin E i. At the same time, the problems of low bioavailability and rapid chemical decomposition associated with other delivery methods can be avoided. When the prostaglandin E! Is applied to the skin of the patient in the topical composition of the present invention, a predetermined dose of prostaglandin E i can be continuously administered to the patient, and a single or multiple doses are not administered by injection. Appearing non-desire effect. With a sustained dose rate, the level of prostaglandin E i in the target tissue of the patient can be better maintained within the most suitable therapeutic range. In a specific example, the present invention provides a composition containing about 0.01% to about 5% modified polysaccharide gum; about 0.001% to about 1% prostaglandin, selected from PGEi, a pharmaceutically acceptable salt thereof, A group consisting of a lower carbamate and a mixture thereof; about 0.5% to about 10% DDAIP or a salt thereof; and about 0.5% to about 10% of a lower alcohol selected from the group consisting of ethanol, propanol, isopropanol, and mixtures thereof ; 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- 200404001

(26) Weight of the substance, and acid buffer solution. The preferred composition also contains about 2% higher sucrose stearate. The composition optionally also contains up to about 5% emulsifier, preferably up to 2% emulsifier. Suitable emulsifiers include glyceryl monooleate, glycerol trioleate and trimyristin and tristearin. The preferred emulsifier, three beans, provokes sperm. The implementation of the present invention is illustrated by the following examples. These examples are intended to illustrate the invention and not to limit its scope. Changes in the therapeutic composition that do not adversely affect the efficacy of prostaglandin E! Are obvious to the skilled artisan and are within the scope of the present invention. For example, additional components such as coloring agents, antimicrobial preservatives, emulsifiers, perfumes, prostaglandin EI stabilizers, etc. may be incorporated into the composition, as long as the resulting composition retains the characteristics as desired above. When present, the preservative is typically added in an amount of from about 0.05% to about 0.30%. Suitable preservatives include methyl paraben (methyl paba), propyl paraben (propyl PABA) and butylhydroxytoluene (ΒΗΤ). Suitable fragrances and aromas are known in the art; suitable aromas may be as high as about 5% of myrtenol, preferably about 2% of myrtenol, based on the total weight of the composition. The composition of the present invention may also contain a small amount, about 0.01 to about 4% of a local anesthetic by weight (if necessary 1. The local anesthetic typically includes: lidocaine 'dyclonine, dibuca Dibucaine, its pharmaceutically acceptable salts, and mixtures thereof. In a preferred embodiment, the local anesthetic is about 0.5% dacronin, by weight of the composition. Unless otherwise indicated, each combination The material is prepared by traditional blending of the individual indicator components.

Example 1: Topical Prostaglandin E i Composition A 200404001

(27) Composition A was prepared as follows. Part a of the composition was formed by dissolving 0.4 parts by weight of prostaglandin Ei (Alprostadil USP) in 5 parts by weight of ethanol. Next, 5 parts by weight of 2- (N, N-dimethylamino) -dodecyl propionate are mixed with the alcohol-prostaglandin E i solution, and 5 parts by weight of ethyl laurate are added. . Part B was prepared starting from a water / buffer solution at pH 5.5. A water / buffer solution was prepared by adding a sufficient amount of potassium phosphate-hydrate to pure water to form a 0.1 M solution. The pH of the water / buffer solution was adjusted to 5.5 with a strong alkaline solution (1N sodium hydroxide) and a strong acid (1N phosphoric acid). The buffer solution makes up about 80 parts of the total composition. All parts shown here are by weight. 0.5 parts by weight of ethyl laurate was added to the buffer solution. Next, locust bean gum (in powder form) was dispersed in a buffer solution and homogenized with a homogenizer. Table 1 below is a list of components. The resulting composition is a dispersible semi-solid formulation suitable for application to the skin without the need for support devices such as patches and sticky strips. The composition is homogeneous in appearance and resists separation. In the same manner, additional exemplary compositions B-VII were prepared using the components listed in Table 1. As shown above, in other specific examples, such as the composition η, the composition may include a modified polysaccharide gum, a suitable modified hemican mannan gum such as guar gum, and polyacrylic acid may also be used for polymerization. Substitute polysaccharide gum. Composition A was evaluated for skin penetration based on the shaved bare skin as a model barrier. The shaved exposed skin was obtained from Animal Care Unit of the University 〇f Kailas. The head and tail sections are removed, the skin is divided into test sections at will, and then hydrated by soaking. -32- 200404001

(28) Samples were re-evaluated using Franz-type diffusion units (surface area: 1.8 cm2). In particular, the skin sheet covers the top of the receiver unit of the direct diffusion unit assembly, where a small magnetic rod is inserted and filled with an isotonic buffer solution. Place a sealing layer over the skin slice, and then the donor unit. These two units are sandwiched together. A known amount of the blend is applied to the bottom of a small capped vial (weighing 0.5 g) and it does fit the donor unit to ensure uniform distribution. The vial is placed on the skin of the donor unit. In order to reduce the evaporation of the components, the supplier unit and the vial and waterproof tape are wrapped well. The unit was transferred to a stirred water bath (321). Samples are drawn from the unit every hour; for a total of 4 hours, the concentration of prostaglandin E! Is analyzed, where the change in concentration represents the amount of penetration. Tests were performed on multiple skin samples and the data generated were averaged. For the evaluation of drug penetration using the shaved exposed skin, the discussion can be found in Higuchi's U.S. Pat. No. 4,771,004, which is incorporated herein by reference. Prostaglandin E penetrates rapidly for 4 hours at a fairly sustained rate. The results of the permeation studies are shown in Table 2 and Figure 3 below.

Example 2: Topical Prostaglandin E i Composition B Composition B was prepared using the components listed in Table 1 below. Composition B contained more prostaglandin E i than composition A. Regardless of this increased drug load, Composition B exhibited a similar semi-solid consistency and uniform appearance. The penetration of prostaglandin E i was detected according to the technique described in Example 1. Composition B provides relatively fast and continuous delivery of prostaglandin E i. The results are shown in Table 2 and Fig. 3.

Example 3: Topical Prostaglandin E i Composition C Composition C was prepared using the components listed in Table 1 below. Forefront of Composition B 200404001

(29)

Adrenaline 1 is more than composition A or B. The increased drug load has little or no effect on consistency or appearance, which is essentially consistent with compositions A and B. Prostaglandin E i penetration was detected again using the technique described in Example 1. According to this test, Composition C also provided fairly fast and continuous delivery of prostaglandin E t. The results are shown in Table 2 and Figure 3 below.

Example 4: Topical Prostaglandin E 1 Composition D

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

Example 5: Topical Prostaglandin E i Composition E

Composition E was prepared using the components listed in Table 1 below. In order to evaluate the repeatability of the composition of the present invention, composition D was applied to composition E. The repeatability of the examples is demonstrated by the beneficial semi-solid consistency and separation resistance of Composition E. The penetration of prostaglandin E i was still detected using the technique described in Example 1. Similarly, prostaglandin E! Is still delivered in composition E fairly quickly and continuously. The results are shown in Table 2 and Figure 3 below.

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

Example 7: Topical Prostaglandin E i Composition G Composition G was prepared using the ingredients listed in Table 1. Composition G repeated the prescription for Composition F, but omitted the ester component (ethyl laurate) and increased ethanol levels. -34-200404001 (30) The resulting composition B is a retardable semi-solid, which has a homogeneous appearance and resistance to separation. The permeation analysis is shown in Table 2 and Fig. 3. Although still beneficial, these results reflect the comparative benefits of the compositions of the present invention from lipophilic compounds, including both the ester component and the alcohol component. Table 1: Composition of topical prostaglandin E i composition (wt%) ABCDEFG Η Part A: Prehydrated Locust Bean Gum 3 3 3 3 3 3 3-Prehydrated and Modified Guar Gum 3 Water / Buffer Substance ( (pH 5.5) 82 81 81 81 81 81 81 81 81 Sucrose stearate 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5-Part B: Prostaglandin £ 1 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: Comparison of penetration profile Table 2 shows the cumulative amount of prostaglandin E in the composition according to the examples of the present invention. 4 hours. These data demonstrate the ability of the present invention to transdermally deliver prostaglandin E1 drugs. Figure 3 shows the graph produced by the data shown in Table 1. Obviously, and as shown in the figure, the composition of the present invention can deliver effective skin penetration effects at a relatively fast and sustained rate. As the prostaglandin E i load in the source composition increases, the cumulative osmotic effect also increases. Table 2: Cumulative prostaglandin E i osmotic effect (μg / cm²) Hour A Β CDEFG 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 -35-200404001 (31) In order to further evaluate the effectiveness of the composition of the present invention, a comparative example kit / a comparative example (Comparative Example 1) was prepared using the same composition of compositions D and E . Table 3: Comparative example, except that DDAIP permeation enhancer is omitted. As for the second comparative example (Comparative Example 2), DDAIp was omitted again, but the ethanol level increased considerably. Specific components are listed in Table 3 below. Group Injury (by weight) Comparison Composition 1 Comparison Composition 2 ------- Part A: " ^ " " ^^ Hydrobin bean gum 3 3 Water / Buffer substance (pH 5.5) 86 81 Sucrose stearate 0.5 0.3 Part B: Prostaglandin £ 1 0.4 0.4 Ethanol 5 10 Ethyl laurate 5 5 The penetration of prostaglandin E 1 was evaluated according to the technique described in Example 1. The results are shown in the table below 4 ° Table 4: Cumulative prostaglandin E i permeation effect (μg / cm 2) of the comparative example Hour Comparative composition 1 Comparative composition 2 1 2.64 1.55 2 4.46 3.69 3 6.59 6.63 4 9.67 11.05 Table 4 of The data are compared with the graph of an example composition with the same prostaglandin E load, ie, compositions D and £ in FIG. 4. Permeation data demonstrate that the composition according to the invention < composition is greatly beneficial due to the presence of a DDAIP penetration enhancer. Example 9: Vision 7 Soil Early Double-blind and Open-label Clinical Trial I. 0.4% wt prostaglandin E i (pre-36-200404001)

(32) The safety and efficacy of a prostaglandin Ei or alprostadil) topical composition (Example D and composition D of Table 1 above). The study consisted of a double-blind, blank control and crossover section and an open-label section. A double-blind blank control portion of the study was entered and completed by 64 people (Table 5 below). 79 people entered and completed the open-label portion of the study (Table 5 below). The following is a discussion of the results of clinical studies. Inclusion Criteria 1. Male, 21-70 years (inclusive). 2. A medical history of erectile dysfunction, which is defined as the failure to reach and maintain an erection of sufficient hardness for sexual intercourse during the past 6 months due to psychogenic, neurogenic, and vascular causes. This includes patients who still have erections that can have sexual intercourse but do not last long enough. It is usually the typical complaint of a man with mild to moderate impotence at the onset of age. Erectile dysfunction is based on a medical history and physical examination. Exclusion criteria 1. History of urethral stricture or obstruction. 2. Any combination found from medical history, physical examination or screening, which means that there is an initial impairment of heart, liver and / or kidney function (such as congestive heart failure, unstable angina, recent acute myocardial infarction, uncontrolled Good diabetes is caused by hormone erectile dysfunction), which can affect the results of the research from the perspective of researchers. 3. People with a history of penile surgery, including penile implants, prostatectomy or prostate cancer, and penile trauma include paraplegia or tetraplegia. 4. Any condition that may cause abnormal erections, such as sickle cell anemia -37-200404001

(33) Blood, multiple myeloma or leukemia. 5. Hypertension, (diastolic blood pressure > 90 or systolic blood pressure > 150 when sitting down) needs to be treated with methods other than angiotensin converting enzyme inhibitor (A C E inhibitor). 6. Physical examination reveals the existence of sexually transmitted diseases. 7. Intracavernous injection or external erection device used within 4 weeks before study entry. 8. Peyronie's Disease or any palpable fibrous scar or spot on the penis, evidence of curvature due to swelling and strong irritation, or abnormalities in the skin of the penis or glans. 9. Any concomitant drugs known to interfere with sexually transmitted diseases, such as antidepressants, certain antihypertensive drugs, sedative hormones, and certain allergic drugs. 10. Underwent any examination and treatment within 30 days of entering the study. 11. Unable or unwilling to give consent for notification. The patient population in this study consisted of men aged 49-70 years. Table 5. Part of the patients included in the study area No. 1 No. 2 No. 3 Total double-blind 30 34 0 64 Open mark 32 8 39 79 Using the six-point classification level, there are patients before and after administration Clinical efficacy was assessed in the history and patient evaluation questionnaire (Table 6). In the double-blind part of the study, each patient was given (1) the blank group and ⑴ active dose in a crossover manner, and there was a wash-out period of 5 to 7 days. In the open-label section, the patient-only gave (1) activity dose. Clinical supplies are packaged in single-dose containers, each containing 250 mg (net weight) of the emulsion and 1.0 mg of prostaglandin E i. (34) 200404001 Μ The political response rate is determined by the number of men who have sufficient erection to have sex with their father. In order to be full of masters and bureaus: be regarded as successful, it must be after the administration has reached the level of 8 out of 10 people, the patient must be sexual intercourse. The paired t-test, fine jbub, and palpitation analysis were used to compare the reaction order before and after administration. It was found that there were statistically significant differences before and during administration of the two drugs that received active drugs. At the same time, the significance of the total can be seen in the active and blank groups, in Yu Xi, and between the mother institutes. Table 6. Grade 6 for assessing the severity of male erectile dysfunction (impotence) and its classification progression classification definition 0 2 4 6 8 10 Non-functional severe impotence 'Very few functional severe impotence Severe impotence with some functions relieved Moderate impotence Non-impotence but some loss of function Non-impotence with full function Table 7. Diseases included due to impotence classification severely alleviated to moderate double-blind 39 25 Open marker 63 16 Total patients 102 41 0 0 0 64 79 143 are found that the topical prostaglandin El composition is safe and effective in men with impotence of moderate to severe impotence. The efficacy rate in men with severe impotence was 64.7% (66/102 patients). It was 100% in men with moderate to moderate impotence (41/41 patients). The overall clinical performance of the study was 74.8% (107/143 patients), as shown in Table 8 below. -39- 200404001

(35) Table 8. Overall clinical efficacy ratio _double-blind portion_open-label portion Mixed overall ratio 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 PO.OOl prostaglandin £ 1 topical composition in It is extremely effective (100%) in alleviating to moderate impotence. The mild to moderate impotence rating is the most common rating and it 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 response to efficacy in the blank group was 3 (4.7%) among 64 patients. This is a far cry from the expected rate of about 10% reported in other clinical studies. This lower percentage may be due to the fact that the majority (63%) of patients included in the double-blind portion were 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 valid (8 or 10 at the classification level). Table 9. Clinical efficacy ratio of impotence classification in the study No. 1 No. 2 No. 3 Double-blind with severe mixed efficacy 85.7% (24/28) 63.6% (7/11) No patient 79.5% Impotence Open-marked 72.2% (13/18) 33.3% (2/6) Entered 51.3% (20/39) (31/39) 55.6% Alleviated to double-blind 100% (2/2) 100% (23/23) Patient-free (35/63) 100% Moderate impotence 100% (14/14) 100% (2/2) Enter patient-free (25/25) 100% Low (Table 9). (16/16) This is mainly due to the fact that the number of patients with severe impotence was significantly larger than the double-blind portion in the open-label portion of the study (Table 8). For male -40-(36) 200404001 sex included in the open-label part of the study, 79.7% (63/79) were evaluated as severe impotence, and only 60.9% of those who were double-blind were rated as severe impotence (39/64). Name and evil ^) The percentage of the efficacy of Du Jue's Chongyang group is expected to be lower, because these people are ashamed I 疋 I am rare or not

In essence, it can be expected that raising the impotence level significantly from 0, 2 or 4 to 8 or 10 will be very difficult. Although the majority of patients with severe impotence progressed, there were still 36 people (36/102 or 35.3%) with adequate treatment. Sergeant 7: ", Fan Zhi's progress can be considered effective. In this study The adverse effect seen in the study was to ease the transient burning or itching at the application site. No systemic toxic side effects were observed. At the same time, none of the couples involved in the study had side effects. None of the patients withdrew from the study or could not be followed. Example 10: A multi-use open-label clinical trial evaluated 0.4% prostaglandin E! Topical composition (Example 4 and Composition D in Table 1 above) in three study sites with an additional study of 56 people. Safety and efficacy. 5 6 male patients with organic erectile dysfunction entered the study and completed it. Patients based on their International Index of Erectile Dysfunction (IIEF) and pre-dose sexual encounter profile ( Sexual Encounter Profile (SEP) response group. 49 people were classified as having mild to moderate erectile dysfunction, and 7 people had severe erectile dysfunction. Each patient was required to use 3 to 10 doses. The drug, which lasted for 4 weeks, was used in a multi-use study at home. The overall efficacy ratio of the moderate to moderate group was 75%. The results of this study were consistent with the overall efficacy ratio of the mixture reported in Example 9 above. None of the patients withdrew from this Multi-use study with no serious side effects. Inclusion Criterion -41-200404001

(37) 1. Male, 21-70 years old (inclusive). 2. Have a history of erectile dysfunction, which is defined as that in the past 6 months, due to psychogenic, neurogenic, vascular, and other reasons, erections of sufficient hardness for sexual intercourse cannot be achieved and maintained. This includes patients who still have an erection but have not lasted long enough for intercourse. It is usually the typical complaint of men who begin with a mild to moderate impotence at the onset of age. Erectile dysfunction is based on a medical history and physical examination. Exclusion criteria 1. History of urethral stricture or obstruction. 2. Any combination found through medical history, physical examination, or screening, which indicates the presence of pre-existing heart, liver, and / or renal impairment (such as congestive heart failure, unstable angina, or recent acute myocardial infarction. Well-controlled diabetes originates from hormonal erectile dysfunction) This can affect the results of the study in the opinion of the viewer. 3. History of penile surgery, including penile implants, prostatectomy or prostate cancer, and penile trauma including paraplegia or tetraplegia. 4. Any condition that can cause abnormal erections, such as sickle cell anemia, multiple myeloma, or white jk disease. 5. Hypertension, (diastolic blood pressure > 90 or systolic blood pressure > 150 when sitting down) needs to be treated with methods other than angiotensin converting enzyme inhibitor (ACE inhibitor). 6. The existence of sexually transmitted diseases is determined by a physical examination. 7. Within 4 weeks before entering this study, use intracavernosal injection or an external erectile device. 8. North Looney's disease or any palpable fibrous scar on the penis or -42-200404001 (38) There is evidence of curvature in swelling and hard irritation, or abnormalities in the skin of the penis or glans. 9. Any concomitant drugs known to interfere with sexually transmitted diseases, such as antidepressants, certain antihypertensive drugs, sedative hormones, and certain allergic drugs. 10. Have received any review treatment within 30 days of entering this study. 11. Unable or unwilling to submit consent form. For example, the patient population in the study consisted of men aged 49-70 years. Table ίο. Patients enrolled in the research office _ Patients enrolled in the research office __

No. 1 No. 2 No. 3 Total 22 13 21 56 Before and after administration, the six-point classification scale (Table 12) using the international index of erectile dysfunction (Table n) and the profile of sexual encounters (SEP). The patient's medical history was evaluated in the patient sweat assessment questionnaire. Each patient was given an active dose and required to take the drug at home and have sex as often as possible within 4 weeks. The drug is packaged on a specially designed single-dose applicator. Table 11 · Erectile function is based on the International Index Ⅰ-Classification __ < 12 Severe impotence of inorganic energy 12-18 Low degree of moderate energy impotence 18-24 There are some functions to relieve impotence 24+ None Dysfunction determines the effective response ratio based on the number of successful sexual intercourse attempts. In order to be considered successful, the patient must have a satisfactory sexual intercourse after s E P, etc., and, and the patient must have reached 8 to 10 after administration. Using Chi-Square Statistics (Chi 200404001

(39)

Square) Statistical analysis compares the response levels before and after. A statistically significant difference between the pre- and post-dose grades was seen in each group of patients receiving the active drug (ρ < 0.001). Table 12 Summary of sexual encounters (S EP): Assess male erectile dysfunction (impotence) Six points of severity classification classification definition 0 Non-functional severe impotence 2 Very few functional moderate impotence 4 Moderate impotence with some functions Degree impotence 6 Moderate impotence 8 Non-impotence with some loss of function 10 Full-function non-impotence The efficacy response ratio is determined by the number of successful intercourses in the total number of intercourse attempts. To be considered successful, a grade of 8 to 10 must be achieved after administration, or the patient must have satisfactory sexual intercourse. Chi Square statistics were used to analyze and compare the response levels before and after administration. Statistically significant differences can be seen between the grades before and after administration (P < 0.001). Table 13. Patients included by impotence classification___Severe_Relaxed to moderate_Total patients 7 49 56 Table 14.Efficacy of each group of patients' efficacy__Effectiveness of attempted to ease to moderately severe 36/49 (74 %) 178/239 (75%) 4/7 (57%) 16/36 (44%) -44- 200404001

(40) As previously discussed, prostaglandin E i topical compositions are extremely effective (75%) in a population of patients with moderate to moderate impotence. Moderate to moderate impotence is the most common grade and is estimated to account for 70% of all complaints of erectile dysfunction. The product was less effective in the severe impotence group (44%); however, statistically significant differences were still seen in this group of patients before and after treatment. Even though all men in this severe type of impotence had no erectile function (before administration), at least 3 out of 10 doses allowed 4 (57%) of 7 men to have successful sexual intercourse. The adverse side effects seen in this study were mild temporary burning or itching at the site of application. 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 follow-up. The results of this clinical study show that moderate to severe impotence is safe and effective using the prostaglandin Eι 0.4% topical composition of the present invention to treat remission. The foregoing description is intended to be illustrative only and not intended to be limiting. Other changes within the spirit and scope of the present invention are still possible and obvious to the skilled artist. Schematic representation of symbols 110 Boat shaped fossa 1 12 Urethral sponge body area 1 14 Urethral spherical part 128 Urethral diameter 130 Penis glans -45-(41) (41)

Cavernous body Cavernous body Cavernous cavernous muscle Opening Ejaculatory duct Prostatic sac Prostate Layered columnar epithelium Non-keratinized layered squamous epithelium Non-keratinized layered squamous epithelium Keratinized layered squamous epithelium -46-

Claims (1)

200404001 Fanyuan, a patent application 1. A semi-solid composition containing: vasoactive prostaglandins; skin penetration enhancers, which are composed of alkyl-2- (N, N_ substituted aminoalkanoates (N-substituted amino) -alkanol alkanoate, a member of the group consisting of pharmaceutically acceptable salts and mixtures thereof; shear-thinning polysaccharides; A member of the group consisting of aliphatic CrCs, aliphatic C8-C30 esters, and mixtures thereof; and an acidic buffer solution system. 2. The semi-solid composition according to item 1 of the patent application scope, wherein the vasoactive prostaglandin is selected from the group consisting of PGEi , PGAi, PGBi, PGFla, 19-hydroxy-PGAi, 19-hydroxy-PGBi, PGE2, PGA2, PGB2, 19-hydroxy-PGA2, 19-hydroxy-PGB2, PGE3, PGF3 and mixtures thereof. 3. According to The semi-solid composition of the scope of the patent application item 1, wherein the shear-thinning polysaccharide has a viscosity of about 5,000 centipoise to about 20,000 centipoise. 4. The semi-solid composition of the scope of the patent application item 1, wherein the shear -Thinned polysaccharide has a viscosity of about 7,000 centipoise to about 13,000 centipoise 5. The semi-solid composition according to item 1 of the scope of the patent application, wherein the shear-thinning polysaccharide is a modified galactomannan gum. 6. The semi-solid composition according to item 5 of the scope of patent application, Wherein the modified galactomannan polyil gum is a modified guar gum. 7. The semi-solid composition according to item 1 of the patent application scope, wherein the lipophilic compound is at least one aliphatic C8-C3 〇ester. 200404001 8. The semi-solid composition according to item 1 of the scope of patent application, wherein the lipophilic compound is at least one glycerol ester, which is selected from the group consisting of monoglycerol ester, diglycerides, triglycerides, and mixtures thereof. 9. The semi-solid composition according to item 1 of the patent application scope, wherein the lipophilic compound is at least one glyceride selected from the group consisting of glyceryl monooleate, glyceryl trioleate, myristin, and stearin And its mixtures. 10. The semi-solid composition according to item 1 of the patent application range, wherein the acidic buffer system can provide a buffered pH of the composition in the range of about 3 to about 6.5. 11. The semi-solid composition according to item 1 of the patent application scope, wherein the composition further contains an emulsifier selected from the group consisting of sucrose esters, polyoxyethylene sorbitan polysaccharide esters, long-chain alcohols, and glycerides. 12. The semi-solid composition according to item 1 of the scope of the patent application, wherein the emulsifier is at least one glycerin g, which is selected from the group consisting of glycerol monooleate, glyceryl trioleate, trimyristin, and tristearin. A group of sperms and their mixtures. 13. The semi-solid composition according to item 1 of the patent application, wherein the composition further contains a perfume. 14. The semi-solid composition according to item 1 of the scope of the patent application, wherein the composition further contains up to about 5% of the myrtenol, based on the total weight of the composition. 15. The semi-solid composition according to item 1 of the patent application scope, wherein the composition further contains a preservative. 200404001 16. The semi-solid composition according to item 1 of the patent application scope, wherein the composition further contains a local anesthetic. 17. —The use of a semi-solid prostaglandin composition, which contains vasoactive prostaglandins; a skin penetration enhancer, which is composed of alkyl-2- (N, N-substituted amino) -alkanoates, (N-substituted amino) -alkanol alkanoate, one of the group consisting of pharmaceutically acceptable salts and mixtures thereof; shear-thinning polyacetic acid; lipophilic compound, which is composed of aliphatic (^-(^ Alcohol, aliphatic C8-C30 ester, and a member of the group consisting of mixtures thereof; and an acidic buffer system, which can be used to prepare a pharmaceutical composition to treat patients with erectile dysfunction requiring this therapy.) Application to the fossa navicularis of the patient. 18. Use according to item 17 of the patent application, wherein the shear-thinning polysaccharide is a modified galactomannan gum. 19. According to the patent application The use according to item 18, wherein the modified galactomannan gum is a modified guar gum. 20. The use according to item 17 of the patent application scope, wherein the lipophilic compound is at least one aliphatic c8-c3 〇 Vinegar 21. According to the 17th scope of the patent application Use, wherein the lipophilic compound is at least one glyceride, selected from the group consisting of monoglyceride, diglyceride, triglyceride and mixtures thereof. 22. The use according to item 17 of the scope of patent application, wherein the lipophilic compound is At least one glyceride, which is selected from the group consisting of glyceryl monooleate, triple oil 200404001 A group of glycerides, trimyristin, tristearin and mixtures thereof. 23. The use according to item 17 of the patent application range, wherein the acidic buffer system can provide the composition with a buffered pH in the range of about 3 to about 6.5. 24. The use according to item 17 of the scope of patent application, wherein the composition further comprises an emulsifier selected from the group consisting of sucrose ester, polyoxyethylene sorbitan ester, long-chain alcohol, and glyceride. 25. Use according to item 17 of the scope of the patent application, wherein the emulsifier is at least one glyceride, which is selected from the group consisting of glyceryl monooleate, glyceryl trioleate, trimyristin, tristearin and mixtures Group of people. 26. The use according to item 17 of the application, wherein the composition further comprises a perfume. 27. The use according to item 17 of the scope of patent application, wherein the composition further contains up to 5% of citronellol, based on the total weight of the composition. 28. The use according to item 17 of the patent application scope, wherein the composition further contains a preservative. 29. The use according to item 17 of the scope of patent application, wherein the composition further contains a local anesthetic. 30. A prostaglandin E! Composition containing a prostaglandin Eι suitable for administration in a scaphoid fossa, which contains: a shear-modified galactomannan gum; a prostaglandin free PGEi, which is pharmaceutically Groups of acceptable salts, low-carbon esters and mixtures thereof; about 0.5% to about 10% of DDAIP or a pharmaceutically acceptable salt thereof, based on the total weight of the composition; 200404001 About 0.5% to about 10%, based on the total weight of the composition, the lower alcohol is selected from the group consisting of ethanol, propanol, isopropanol, and mixtures thereof; about 0.5% to about 10% of the ester is selected from ethyl laurate A group consisting of esters, isoractone myristate, isopropyl laurate and mixtures thereof, based on the total weight of the composition; and an acidic buffer system. 31. The composition according to claim 30 of the application, further comprising an emulsifier selected from the group consisting of sucrose esters, polyoxyethylene sorbitan esters, long-chain alcohols, and glycerides. 32. The composition according to item 30 of the application, wherein the emulsifier is sucrose stearate. 33. The composition according to item 30 of the application, wherein the emulsifier contains at least one glyceride selected from the group consisting of glyceryl monooleate, glyceryl trioleate, trimyristin, tristearate Groups of mixtures. 34. The composition according to item 30 of the application, wherein the composition further contains a fragrance. 35. The composition according to item 30 of the scope of patent application, wherein the composition further contains up to about 5% of peperol, based on the total weight of the composition. 36. The composition according to item 30 of the scope of patent application, wherein the composition further contains a preservative. 37. The composition according to item 30 of the scope of patent application, wherein the composition further contains a local anesthetic. 38. A semi-solid composition containing: vasoactive prostaglandins; 200404001 skin penetration enhancer, which is composed of alkyl-2- (N, N-substituted amino) -alkanoates, (N -Substituted amino) -alkanol alkanoate, a member of the group consisting of pharmaceutically acceptable salts and mixtures thereof; shear-thinning polypropylene polymer; lipophilic compound, which is composed of aliphatic C ^ -Cs alcohol, aliphatic C8-C30 ester, and a member of the group thereof; and an acidic buffer solution system.