CA2442479C - Topical compositions for prostaglandin e1 delivery - Google Patents

Abstract

A topical composition of a semi-solid consistency suitable is provided for transdermal application of prostaglandin E1. The composition comprises prostaglandin E1, a penetration enhancer, a polysaccharide gum, a lipophilic compound, and an acidic buffer system. The penetration enhancer :is an alkyl-2-(N,N-disubstituted amino)-alkanoate ester, an (N,N-disubstituted amino)- alkanol alkanoate, or a mixture of these. The lipophilic compound may be an aliphatic C1 to C8 alcohol, an aliphatic C8 to C30 ester, or a mixture of these. The composition includes a buffer system capable of providing a buffered pH value for said composition in the range of about 3 to about 7.4.

Description

-la-TOPICAL COMPOSITIONS FOR PROSTAGLANDIN 8, DhLIVRRY
Technical Field of the Invention ~ This invention relates to pharmaceutical compositions for transdermal or transmucasal administration of prostaglandin drugs~to a patient.
Hackgrous~d of the Invention Prostaglandin $1 is a derivative of prostanoic acid, a 20-carbon atom lipid acid, represented by the formula:
vH
and is commercially available, e.g., from Chinoin Pharmaceutical and Chemical Works Ltd. t8udapest, Hungary) under the designation "Alprostadil USP~ and from The Upjohn y Company (Kalamazoo, Michigan) under the designation ~Prostiri.
VR."
Prostaglandin F.~ is a vasodilator useful to maintain open blood vessels and therefore, to treat peripheral vascular disease among other ailments.

lb Intravenous infusions or injections of prostaglandin E~ have been reported to be an effective treatment of leg ulcers. See Beitner, H., et al., Prostaglandin E, treatment of leg ulcers caused by venous or arterial incompetence, Acta Dermatovener (Stockholm) 1980 60:425-430. In addition, prostaglandin E~
administered intravenously or infra-arterially has previously been shown to be an effective treatment of Raynaud's syndrome, also known as Raynaud's disease, or Raynaud's phenomenon. See Bartolone, S., et al., Efficacy evaluation of prostaglandin El against placebo in patients with progressive systemic sclerosis and significant Raynaud's phenomenon, Minerva Cardioangiol. 1999 May; 47(5):137-43; Seemann, J., et al., Remission of secondary Raynaud phenomenon using infra-arterial prostaglandin El infusion.
A case report, Int Orthop. 1994;18(6) :3 72-4; Langevitz P, et al., Treatment of refractory ischemic skin ulcers in patients with Raynaud's phenomenon with PGE1 infusions. J Rheumatol. 1989 Nov;l6(11):1433-5.
Intravenous drip of Prostaglandin E1 has been reported to be an effective treatment of inflammatory skin lesions (Tohjima, T., & Shiokawa, Y., Effect of prostaglandin El in collagen disease patients with inflammatory skin ulcer, Int J Tissue React. 1983;5(1):1-10). A report of a single patient indicated that intravenous treatment using a liposome formulation of prostaglandin El appeared to be to be an effective treatment of livedo reticudaris (Nonaka, Y., et al., Lipo-prostaglandin E1 therapy for livedo reticularis with ulceration.
Acta Derm Venereol. 1997 May;77(3): 246-7).
A study of twelve patients reported that infra-arterial treatment with prostaglandin El appeared to be an effective treatment of Buerger's disease (thromboangiitis obliterans) (Gruss, J.D., et al., Conservative treatment of inoperable arterial occlusions of the lower extremities with infra-arterial prostaglandin E1. Br J Surg. 1982 Jun; 69 Suppl: S 11-3).

lc Reports of successful treatment of frostbite in animals models has led to the proposal of use of infra-arterial prostaglandin E~ in the clinical treatment of frostbite patients. See Yeager, RA., et al., Treatment of frostbite with.
intra-arterial prostaglandin E1. Am Surg. 1983 Dec; 49(12):665-7.
Several publications have reported that treatment with intravenous prostaglandin Ei improves healing from infections, e.g. recovery of liver function in viral hepatitis (Sinclair, S.B., et al., Biochemical and clinical response of fulminant viral hepatitis to administration of prostaglandin E. A
preliminary report, J Clin Invest. 1989 Oct;84(4):1063-9), protection of liver function in E.coli infection (Mokuno, Y., et al., Prostaglandin E(1) protects against liver injury induced by Escherichia coli infection via a dominant Th2-like response of liver T cells in mice. Hepatology, 1999 Dec;30(6):1464-72), and increasing oxygen extraction capabilities in sepsis (Zhang, H., et al., Prostaglandin E1 increases oxygen extraction capabilities in experimental sepsis. J Surg Res. 1994 Oct; 57(4):470-9.
Reports of animal studies in which wound healing was measured by hydroxyproline content, bursting pressure and histology showed improvement in wound healing by intravenous prostaglandin E~ treatment.
See Cali, R.L., et al., Effect of prostaglandin El and steroid on healing colonic anastomoses. Dis Colon Rectum. 1993 Dec; 36(12):1148-51.
Intravenous prostaglandin El treatment has been reported to improve atherosclerosis. See Creutzig, A., & Caspary, L., Prostanoids in therapy of peripheral arterial occlusive disease. Therapie. 1991 May-Jun; 46(3):241-S;
Sinzinger, H., et al.,. Effect of prostaglandin El on deposition of autologous labelled platelets onto human atherosclerotic lesions in vivo. Postgrad Med J, 1987 Apr;63(738):245-7 and Das, U.N., Atherosclerosis and prostaglandins.
Int J Tissue React. 1982;4(2):127-32.

ld Treatment of proliferative skin lesions, specifically psoriatic lesions, with topical prostaglandin compositions (various compositions comprising prostaglandin E~, prostaglandin Ez or prostaglandin F,_a) has been reported to enhance the rate of healing of these skin lesions. See Remy, W., et al., Prostaglandin E2 gel improvement of psoriatic lesions. Int.
J. Dermatol, 1986 May; 25(4):266-8 and Jacobs K.F., Jacobs M.M" Prostaglandin treatment of psoriatic skin.
Clinical observations, Rocky Mt. Med. J. 1974 Sep;71(9):507-10. However, the disclosures of these two reports neither teach nor suggest the topical compositions of the present invention.
While the potential benefits from transdermal delivery of prostaglandin El have long been.
recognized, prior efforts at developing a topical composition for prostaglandin delivery have not~been fully successful.
. In particular, there is presently no commercial source for a topical semi-solid formulation that is useful without a supporting device such as a patch, adhesive strip, and the like. For example, U.S. Patent No.~5,380,76o to Wendel et.al. is directed to a topical prostaglandin formulation that includes a pressure-sensitive, adhesive sheet of _ ~ -polyisobutylene.
Working alone most drugs, prostaglandin formulations included, do not sufficiently permeate the skin to provide drug concentration levels comparable to those obtained from other drug delivery routes. To overcome this problem, topical drug formulations typically include a skin penetration enhancer.
Skin penetration enhancers also may be referred to as absorption enhancers, accelerants, adjuvants, solubilixers, sorption promoters, etc. Whatever the name, such agents serve to improve drug absorption across the skin. Ideal penetration enhancers not only increase drug flux across the skin, but do so without irritating, sensitising, or damaging skin.
Furthexmore, ideal penetration enhancers should not affect available dosage farms (e. g. cream or gel), or cosmetic quality of the topical composition.
A wide variety of compounds have been evaluated as to their effectiveness in enhancing the rate of penetration of drugs through the skin. See, for eacample, Percutaneous Penetration Enhancers, Maibach ~I. I , and Smith H. E. (eds. ) ,

2 0 CRC Press , Inc . , Boca Raton, F . T... ( 5.995 ) , which surveys the use and testing of various skin penetration enhancers, and Buyuktimkin et al., Chemical Means of Transdermal Drug Permeation Enhancement in Transdermal arid Topical Drug De3~.very Systems , Gosh T.K., Pfister W.R., Yum a.I. (Eds.), Interpharm Press Inc., Buffalo Grove, I.L. (1997).
A fully successful formulation for prostaglandin E,, has not yet been identified. Unfortunately, prostaglandin E~
is readily transformed by rearrangement and other reactions.
This relative instability tends to complicate efforts at formulating composition for transdermal delivery.
The present invention addresses these problems by providing a semi-solid, separation resistant composition for relatively rapid, sustained delivery of prostaglandin E1.
Sumanary of the Tnvention A pharmaceutical composition s~zitable for topical application comprises prostaglandin E1, a penetration enhancer, r ~ -a polysaccharide gum, a lipophilic cotr~pound, and an acidic buffer system. The penetration enhancer is an alkyl-~-(N,I3-disubstituted amino)-alkanoate ester, an (N,I~T-disubstituted amino)-alkanol alkanoate, or a mixture of these. The lipophilic compound may be an aliphatic C1 to Ce alcohol, an aliphatic CB to C3o ester, or a mixture of these. The composition includes a buffer system capable of providing a buffered pH value for said composition in the range of about 3 to about 7.4. If desired, stabilizers and emulsifiers may be included.
Compositions of the present invention can take the form of a semi-solid suitable for topical application. In use as a topical agent, these compositions exhibit relatively high prostaglandin penetration and bioavailability without requiring a wasteful overloading prostaglandin concentration. The compositions further exhibit reduced skin irritation, sensitivity and damage.
The prostaglandin compositions of the present invention are useful for the treatment of diseases such as Raynaud's phenomenon, Itaynaud's disease, Buerger's disease, livedo retcularis, acrocyanosis atherosclerosis, frostbite, vitiligo, alopecia areata, impending gangrene, and other ischemic disorders. Moreover, the ability of the topical prostaglandin compositions of the present invention to increase peripheral circulation renders them useful to enhance the rate of healing of wounds, ulcers, infections and proliferative and inflammatory skin lesions including atopic dermatitis, acne and psoriasis' to treat impotency; or to enhance the rate of absorption of pharmaceutically active agents. In addition, the topical prostaglandin compositions of t:he present invention may be employed to improve skin color and to promote blush.
The compositions of the present invention can thus be used for the manufacture of pharmaceutical compositions and medicaments that are suitable for the prolonged treatment of ' 35 peripheral vascular disease, including the conditions listed above, male erectile dysfunction, female se~cual dysfunction and 4 _ other disorders treated by prostaglandin Ei, while avoiding the low bioavailability and rapid chemical decomposition associated with other delivery methods.
Other and further aims, purposes, features, advantages, embodiments and the like will be apparent to those skilled in the art from the present specification and the appended claims.
Brief Description of the Drawings In the drawings, FIGURE 1 is a graph of the cumulative prostaglandin E1 penetration through shed snake skin of seven prostaglandin El compositions prepared according to the present invention;
FIGURE 2 is a comparison graph of the cumulative prostaglandin 81 penetration through shed snake skin of t~uo prostaglandin E,~ compositions prepared according to the present invention and two comparative compositions.
Detai3.ed Description of the Invention The pharmaceutical composition of the present invention comprises prostaglandin E1, an alkyl (N,N-disubstituted amino ester, a polysaccharide gum, a lipophilic compound, and an acid buffer system.
Prostaglandin E1 is well known to those skilled in the art. Reference may be had to various literature references for its pharmacological activities, side effects, and normal dosage ranges. See for example, Physicaanes Desk Reference, 51st Ed. ~19~7), The Merck Inde~c, 12th Ed., Merck & Co., AT. J.
X1996), and MartindaZe The Extra Pharmacopoeia, 28th Ed., London, The Pharmaceutical Press (1982). Prostaglandin F1 as well as other compounds referenced herein are intended to encompass pharmaceutically acceptable derivatives including physiologically compatible salts and ester derivatives thereof.
The quantity of prostaglandin El in the ~5 pharmaceutical compositions of the present invention is a therapeutically effective amount and necessarily varies according to the desired dose, the doaage form (e. g., suppository or topical), and the particular form of prostaglandin El used. The composition generally contains between 0.l percent to ~. percent prostaglandin E~, preferably 5 from 0.3 percent to 0.5 percent, based on the total weight of the composition.
An important component of the present invention is the penetration enhancer. The penetration enhancer is an alkyl-2-(N,N-disubstituted amino)-alkanoate, an (N,N-disubstituted amino)-alkanol alkanoate, or a mixture of these.
For convenient reference, alkyl-2-(N,N-disubstituted amino)-alkanoates and (N,N-disubstituted amino)-alkanol alkanoates can be grouped together under the label a7.ky1 (N,N-disubstituted amino) esters.
~11ky1-~-(N,N-disubstituted amino)-alkanoates suitable for the present invention ca.n be represented as follows:
H9C-~C~"~2~~ C....~°.._C
R
wherein n is an integer having a value in the range of about to about 18; R is a member of the group consisting of hydrogen, 2 o Cl to C, alkyl , benzyl and phenyl ; R1 and Ra are members of the group consisting of hydrogen and C1 to C? alkyl; and R3 and 124 are members of the group consisting of hydrogen, methyl and ethyl.
Preferred alkyl (N,N-disubstituted amino)-alkanoates are C4 to Cae alkyl (N,N-disubstituted amino) -acetates and C~ to Cl~ alkyl (N,N-disubstituted amino)-propionates. Exemplary ' specific alkyl-2-(N,N-disubstituted amino)-alkanoates include dodecyl 2- (N,N dimethylamino) -~propionat.e (z3DAIP) and dodecyl 2-(N,N-dimethylamino)-acetate (DDAA)g /'tea H'G IC~2l~o H H
Alkyl-2-(N,N-disrabstituted amino)-alkanoates are known. For example, dodeeyl 2-(N,N-dirnethylamino)-propionate (DDAIP) is available from Steroids, Ltd. (Chicago, IL). In addition, alkyl-2-(N,N-disubstituted amino)-alkanoates can be synthesized from more readily available coarpounds as described in U.S. Patent No. 4,98(D,3f8 to Wong et al..
As described therein, alkyl-2-(N,N-disubstituted amino)-alkanoates are readily prepared via a two-step synthesis. In the first step, long chain alkyl chloroacetates are prepared by reaction of the corresponding long chain alkanols with chloromethyl chloroformate or the like in the presence of an appropriate base such as triethylamine, typically in a suitable solvent such as chloroform. The reaction can be depicted as follows:
4 ~~ + X61 .--.-~ ---~c--dc~-~
~c-~ -o---c-wherein R, R3, R4 and n are defined as above. The reaction temperature may be selected from about :LOEC.
to about 200EC. or reflex, with room temperature being preferred. The use of a solvent is optional. If a solvent is used, a wide variety of organic solvents may be selected.
Choice of a base is likewise not critical. preferred bases include tertiary amines such as triethylamine, pyridine and the like. Reaction time generally extends from about one hour to three days.
in the second step, the long chain alkyl chloroacetate is condensed with an appropriate amine according to the scheme:
i~,C--1a~°; -~ o--~-~---~R~~a a wherein n, R, Rl, RZ, R3 and R4 are defined as before. Excess amine reactant is typically used as the base and the reaction is conveniently conducted in a suitable solvent such as ether.
This second step is preferably run at room temperature, although temperature may vary. Reactrion time usually varies from about one hour to several days. Conventional purification techniques can be applied to ready the resulting ester far use in a pharmaceutical compound.
Suitable (N,N-disubstituted amino)-alkanol aikanoates can be represented by the formula:
io wherein n is an integer having a value in the range of about to about 18; y is an integer having a ~ralue in the range of 0 to about 5; and R1, Rz, R3, R9, R5, R6, and R, are members of the group consisting of hydrogen, Cl to C~ alkyl , and Cl to Ce aryl; and Re is a member of the group consisting of hydrogen, hydroxyl , C1 to C8 alkyl , and C, to Ce aryl .
Preferred'(N,N-disubstituted amino}-alkanol alkanoates are CS to C,8 carboxylic acid esters. Exemplary specific (N,N-disubstituted amino)-alkanol alkanoates include ~U 1-(N,N-dimethylamino)-2-propanol dodecanoate (DAIPD};
~ H H
CHs H3C ~GH~j~O t' Q
CI'i3 H ~:H3 1- (N,N-dimethylamino) -2-propanol myristate (DAIPM} ;
_y -1-(N,N-dimethylamino:~-2-propanol oleate (DAIPO);
C H N
~s C [CHI
O ~~H~

The (N,N-disubstituted amino)--alkanol alkanoates are readily prepared by reacting the corresponding aminoalkinol with lauroyl chloride in the presence crf triethylamine. A
solvent such as chloroform is optional but preferred. For example, 1-(N,N-dimethylamino)-2-propanol can be reacted with lauroyl chloride in chloroform and in the presence of triethylamine to force 1- (N,N-dirnethylanuno) -2-propanol dodecanoate (DAIPD).
Among the suitable penetration enhancers for the present invention DD~P is generally preferred.
The penetration enhar~.cer is present in an amount sufficient to enhance the penetration of the prostaglandin E1.
The specific amount varies necessarily according to the desired release rate and the specific form of ~>rostaglandin E~ used.
Generally, this amount ranges from about 0.5 percent to about . 10 percent, based on the total weight of the composition.
Preferably. the penetration enhancer is about 5 weight percent . of the composition.
Polysaccharide gums are also an important ingredient to the present composition. Suitable representative gums are those in the galactomannan gum category. A galactomannan gum is a carbohydrate polymer containing D-galactose and D-mannose units, or other derivatives of such a polymer. There is a relatively large number of galactomannans, which vary in composition depending on their origin. The galactomannan gum is characterized by a linear structure of (3-D-mannopyranosyl units linked (1--~4) . Single cnembered a-D-ma.nopyran~syl units, linked (1-~6) with the main chain, are present as side branches. Galactomannan gums include guar gum, which is the pulverized endosperm of the seed of either of two leguminous plants (Cyamposis tetragona3obus and psora3oids) and locust bean gum, which is found in the endosperm of the seeds of the carobtree (cerator~ia siliqua}. Zocust bean gum is preferred for the present invention.
Other suitable representative gums include agar guni, carrageenan gum, ghatti gum, karaya gum, rhamsan gum and xanthan gum. The composition of the present invention may contain a mixture of various gums, or mixture of gums and acidic polymers.
Gums, and galactomannan gums in particular, are well-known materials. See for instance, Industrial Gums:
Polysaccharides & Their .T~erxvat.~ves, ~Ihistler R. h. and BeMiller J.N. (eds.), 3rd Ed. Academic Press (1992} and Davidson R. h. , Handbook of Water-Solub~.e Gums & ,Resins, McGraw-Hill, Inc., ~T.Y. (1980). Most gums are commercially available in various forms, commonly a powder, and ready for use in foods and topical compositions. For example, locust bean gum in powdered form is available from Tic Gums Inc.
(Belcam, MD) .
The polysaccharide gums are represerit in the range from about 0.5 percent to about 5 percent, ~>ased on the total weight of the composition, with the preferred range being from 0.5 percent to 2 percent. Illustrative compositions are given in the examples, below.
An optional alternative to the polysaccharide gum is a polyacrylic acid polymer. A common variety of polyacrylic acid polymer is known generically as ~~ca.rbomer." Carbomer is ~1 polyacrylic acid polymers lightly cross-linked with polyalkenyl polyether. It is commercially available from the B. F. Goodrich Company (Akron, Ohio) under the designation "CARBOPOL~'~"''." A particularly preferred variety of carbomer is that designated as "CARBOPOL 940."
Other polyacrylic acid polymers suitable for use in practicing this invention are those commercially available under the designations "PemulenTa'" (P. F. Goodrich Company) and "P~LYCARBOPHILT'''" (A.~i. Bobbins, Richmond, '~lA) . The PemuleraT""
polymers are copolymers of Clo to C3o alkyl acrylates and one or more monomers of acrylic acid, methacrylic acid~or one of their simple esters crosslinked with an allyl ether of sucrose or an allyl ether of pentaerythritol. The POTJYCARBOPIiIL~" enhancer is a polyacrylic acid cross-linked with divinyl glycol.
Where polyacrylic acid polymers are present, they represent about 0.5 percent to about 5 percent of the composition, based on its total weight.
Another important component of the present invention is a lipophilic compound. The term lipophilic compound as used herein refers to an agent that is both lipophilic and hydrophilic. The Cl to CB aliphatic alcohols, the C2 to C3o aliphatic esters, and their mixtures can serve as lipophilic compound. Illustrative suitable alcohols are ethanol, n-propanol and isopropanol, while suitable esters are ethyl acetate, butyl acetate, ethyl laurate, methyl propionate and isopropyl myristate. As used herein, the term ''aliphatic alcohol°' includes polyols such as glycexol, propylene glycol and polyethylene glycols. A mixture of alcohol and ester is preferred, and iw particular, a mixture of ethanol and ethyl laurate myristate is most preferred.
The concentration of lipophilic compound required necessarily varies according to other factors such as the desired semi-solid consistency and the desired skin penetration promoting effects. The preferred topical composition contains lipophilic compound in the range of 7 percent to 40 percent by weight based on the total weight of the composition. Where a mixture of aliphatic alcohol and aliphatic ester are employed, the preferred amount of alcohol is in the range of 5 percent to 15 percent, while that of aliphatic ester is in the range from percent to 15 percent (again based on the total weight of the composition) . .
An optional, but preferred, component of the present invention is an emulsifier. Although not a critical factor, a suitable emulsifier generally will exhibit a hydrophilic-lipophilic balance number greater than ~Ø Sucrose esters, and 1~ specifically sucrose stearate, can serve as emulsifiers for the topical composition of the present invention. Sucrose stearate is a well known emulsifier available from various commercial sources. When an em~,zlsifier is used, ~,ucrose stearate present up to about 2 percent, based on the total weight of the composition, is preferred. The preferred amount of sucrose stearate emulsifier can also be expressed as a weight ratio of emulsifier to polysaccharide gum. A ratio of 1 to 6 emulsifier to gum is preferred, and a ratio of 1 to 4 is most preferred to generate the desired semi-solid consistency and separation resistance.
The present invention includes an acid buffer system.
Acid buffer systems serve to maintain or buffer the pH of compositions within a desired range. The term "buffer system"
or "buffer" as used herein has reference to a solute agent or agents which, when in a water solution, stabilize such solution against a major change in pH (or hydrogen ion concentration or activity) when acids or bases are added thereto. Solute agent or agents which are thus responsible for a resistance to change in pH from a starting buffered pH value in the range indicated above are well known. While their are countless suitable buffers, potassium phosphate monohydrate has proven effective for compositions of the present invention. , The final pH value of the pharmaceutical composition of the present invention may vary within the physiologically compatible range. Necessarily, the final pH value is not irritating to human skin. Without violating this constraint,

- 3.3 -the pH may be selected to improve prostaglandin E1 stability and to adjust consistency when required. With these factors accounted for, the preferred pH value is about 3.0 to 7.4. The most preferred pH range is from about ~.5 to about 6.~.
The remaining component of the composition is water, which is necessarily purified. The composition contains water in the range of about 50 to about 90 percent, based on the total weight of the composition. The spec~_fic amount of water present is not critical, however, being adjustable to obtain the desired consistency and/or concentration of the other components.
A further embodiment of the present invention is a topical composition which comprises prostaglandin E1, an alkyl (N,N-disubstituted amino) ester., a polysaccharide gum or a polyacrylic acid polymer, a lipophilic compound and an acidic buffer, which are contained as 0.5 to 5 weight percent locust bean gum, 0.5 to 25 weight percent dodecyl (N,N-dimethyl amino)-proportionate, 0.5 to 80 weight percent ethanol, and 0.5 to 80 weight percent isopropyl myristate, based on the total weight of the composition.
A further embodiment of the present invention is a topical composition which comprises prostaglandin E~_, an alkyl (N,N-disubstituted amino) ester, a polysaccharide gum or a polyacrylic acid polymer, a lipophilic compound and an acidic buffer, which are contained as 0.5 to 5 weight percent locust bean gum, 0.5 to 5 weight percent dodecyl (N,N-dimethyl amino)-proportionate, 0.5 to 25 weight percent ethanol, and 0.5 to 25 weight percent ethyl laurate, based on the total weight of the composition for the manufacture of a topical pharmaceutical dosage form.

- 13a -Additionally, known transdermal penetration enhancers can also be added, if desired. Illustrative are dimethyl sulfoxide (DMSO), dimethyl acetamide (DMA), 2-pyrrolidone, N,N-diethyl-m-toluamide (DEFT), 1-dodecylazacycloheptane-2-one (Azone"~', a registered trademark of Nelson Research), N,N-dimethylformamide, N-methyl-2-pyrrolidone, calcium thioglycolate, oxazolidinone, dioxolane derivatives, laurocapram derivatives, and macrocyc3.ic enhancers such as macrocyclic ketones.
Prostaglandin E1 stabilizers, coloring agents, rheological agents, and preservatives can be added to the extent that they do not overly limit prostaglandin E1 skin penetration or prevent the desired semi-solid consistency.
Contemplated dosage forms of the semi-solid pharmaceutical composition of the present invention are creams, gels, and the like, also including but not limited to compositions suitable for use with transdermal patches and like devices.
The ingredients listed above may be combined in any order and manner that produces a stable composition comprising a prostaglandin E, evenly dispersed throughout a semi-solid formulation. One available approach to preparing such compositions involves evenly dispersing the polysaccharide gum (or polyacrylic acid) in a premixed water/buffer solution and then thoroughly homogenizing (i.e. mixing) the resulting mixture, which, will be labelled '°Part A, g° When present, the emulsifier is added to the water/buffer solution before dispersing the polysaccharide gum. Any suitable method of adjusting the pH value of Part A to the desired level may be used, for example, by adding concentrated phosphoric acid or a sodium hydroxide.
Separately, the prostaglandin. El is dissolved with agitation in the lipophilic compound, 'which itself may be a mixture of alcohols, esters, or alcohol with ester. INext, the penetration enhaneer is added. Alternatively, when the lipophilic compound includes both an alcohol and an ester, the prostaglandin E1 can be dissolved in tree alcohol before adding the penetration enhancer followed by the ester. Tn either case, the resulting mixture will be labelled °~Part B." The final step involves slow addition (e.g. dropwise~ of Part B
into Part A under constant mixing.
The resulting topical composition., when compared to existing commercially available compositions, exhibits the advantageous properties described abovEe, including improved prostaglandin El permeation and bioavailabi:Lity without drug overloading, reduced damage and related inflammation to skin ar mucous membranes, and increased flexibility in design of dosage forms. These compositions can be used for the manufacture of pharmaceutical compositions that are suitable for the prolonged treatment of peripheral vascular disease, male impotency, male erectile dysfunction, female sexual dysfunction. and other disorders treated by prostaglandin Ea, while avoiding the low bioavailability and rapid chemical decomposition associated with other delivery methods. These compositions can be used for the manufacture of pharmaceutical compc'sitions that are suitable for the enhancement of the sexual response of normal (i.e., orgasmic' human females. Application of prostaglandin E1 .
in a topical composition of the present invention to the skin or mucous membrane of a patient allows a predetermined amount of prostaglandin E1 to be administered continuously to the patient and avoids undesirable effects present with a single or multiple administrations of larger dosages by injection. By maintaining a sustained dosage rate, the prostaglandin El level in the patient's target tissue can be better maintained within the optimal therapeutic range.
v The practice of the present invention is demonstrated in the following examples. These examples are meant to illustrate the invention rather than to limit its scope.' Variations in the treating compositions which. do not adversely affect the effectiveness of prostaglandin El will be evident to one skilled in the art, and are within t:he scope of this invention. For example, additional ingr_edients~such as coloring agents, anti-microbial preservatives, emulsifiers, perfumes, prostaglandin E1 stabilizers, and the like may be included in the compositions as long as the resulting composition retains desirable properties, as described above.
Unless otherwise indicated, each composition is prepared by conventionally admix~.ng the respective ~i.ndicated components together.
FXA~IPLE l: Top~.cal prostaglandisa E~ Composa~t~.on .pr Composition A was prepared as follows. Part A was formed by dissolving 0.4 parts prostaglandin El (Alprostadil USP) in 5 parts ethyl alcohol. Next, 5 parts dodecyl 2-(N,N-dimethylamino)-propionate were mixed into the alcohol-prostaglandin E~ solution, followed by 5 parts ethyl laurate.
Part B was prepared starting from a pH 5.5 water/buffer solution. The water/buffer solution was prepared by adding sufficient potassium phosphate monohydried to purified water to create a O.Z M solution. The pH of the water/buffer solution was adjusted to 5..5 with a strong base solution tl N sodium hydroxide) and a strong acid (1 N
phosphoric acid). The buffer solution represented about 80 parts of the total composition.
To the buffer solution, was added 0.5 parts ethyl laurate. Next, the locust bean gum (in powder form) was dispersed in the buffer solution and homogenized using a homogenizer. TABLE 1, below, contains a list of ingredients.

1.
The resulting composition was a spreadable, semi-solid suitable for application to the skin without the need for supporting devices such. as patches and adhesive strips, The composition was both homogenous in appearance and resistant to separation.
Composition A was evaluated for skin penetration using -shed snake skin as a model barrier. Shed snake skin was obtained from the Animal Care Unit of the University of Kansas.
With head and tail sections removed, the skin was randomly :l0 divided into test sections and then hydrated by soaking.
The samples were then evaluated using Franz-type Diffusion Cells. (surface area 1.8 cmx) . Specifically, skin pieces were mounted on top of a receptor-cell of a vertical diffusion cell assembly in which a small magnetic bar was inserted and filled with an isotonic buffer. A seal was placed on top of the skin section followed by a donor cell. The two cells were clamped together. Known amounts of the formulations were applied on the bottom of a small capped vial (weight .5 grams) which fits exactly to the donor cell to ensure uniform distribution. The vials were placed on the skin in the donor cell. To reduce the evaporation of irhe ingredients, the donor cell and vial were gently taped togei=her with a water-resistant adhesive band. The cells were transferred to a stirred water bath (32°C.). Samples were withdrawn from the cells each hour 2S for four hours arid analyzed for the concentration of prostaglandin E1, with changes in concentration indicating the amount penetrating. Tests with multiple skin samples yielded data that were averaged.
For a discussion of the use of shed snake skin in the evaluation of drug penetration, see U.S. Fatent No. 4,771,004 to Higuchi.
The prostaglandin E,, penetrated quickly at a relatively sustained rate for four hours. The results of the penetration study are presented in TABLE 2, below, and in FIGURE 1.

EXAMPLE 2: Topical Prostaglandin EI Composition B
Composition B was prepared using the ingredients listed in TABLE 1, below. Composition 1B contained more prostaglandin E1 than Composition A. Despite this increased drug loading, Composition B exhibited a similar semiasolid consistency and homogenous appearance. The penetration of prostaglandin E1 was measured according to the technique described in Example 1. Composition B provided a relatively fast, sustained delivery of prostaglandin El. The results are presented in TABLE 2, below, and in FIGURE 1.
EXAMPLE 3: Topical Prostaglandiza. El Coaip~osit~.on C
Composition C was prepared using the ingredients listed in TABLE 1, below. Composition B contained more prostaglandin El than either Composition A or B. The increased drug loading had little or no effect on the consistency or appearance, which substantially matched that of Compositions A
and B. The penetration of prostaglandin E1 was again measured according to the technique described in Example 1. According to this test, Composition C also provided a relatively fast, sustained delivery of prostaglandin E1. The results are presented in TABLE 2, below, and in FIGURE 1.
EXAPSPLE 4: Topical Prostaglandin El Composition 19 Composition D was prepared using the ingredients listed in TABLE 1, below. The level of prostaglandin Ea was again increased without substantially affecting the favorable consistency and separation resistance. The penetration of prostaglandin E1 was again measured according to the technique described in Example 1. The results are presented in TABLE B, below, and in FIGURE 1..
EXAMPLE 5: Topical Prostaglandin Ei Composition E
Composition E was prepared using the ingredients listed in TABLE 1, below. To assess the repeatability of compositions according to the present invention, the recipe of Composition D was again applied for Composition E.

-Repeatability was substantially confirmed by Composition E's favorable, semi-solid consistency and separation resistance.
The penetration of prostaglandin E1 Was again measured according to the technique described in Example 1. The prostaglandin El delivery from Composition E was again relatively fast and sustained. The results are_presented in TABLE 2, belOW, and .iri FIGURE 1.
EXAMPhE 6: Topical Pxostag~.andin 81 Composition F
The level of prostaglandin E1 was again increased for Composition F. The specific ingredients are listed in TABLE 1.
The favorable consistency and separation resistance was undiminished. The results of a penetration analysis are presented in TABLE 2, below, and in FIGURE 1.
EXAMPIeE 7: Topical. Prostaglandin El Comg?osition G
35 Composition G was prepared using the ingredients listed in TABLE 1. For Composition G, the recipe Of Composition F was repeated except that the ester component (ester laurate) was omitted and the level of ethanol was increased a corresponding amount. The resulting composition was also a spreadable, semi-solid having a homogenous appearance and resistance to separation. The results of a penetration analysis are presented in TABLE 2, below, and in FIGURE 1. while still favorable, these results reflect the relative benefit to compositions of the present invention from a lipophilic compound that includes both an ester component and an alcohol component.
TABt..E 1: Topical prostaglandin E, Compositions Ingredient (j A B C D E F G

Part A: prehydrated Locust 3 3 3 3 3 3 3 bean gum wateribuffer (pH 5.5j 81 81 81 8i 81 81 81 sucrose stearate 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Part B: prostaglandin E9 0.1 0.2 0.3 0.4 0.4 0.5 0.4 t)DAIP 5 5 5 5 5 5 5 ethanol 5 5 5 5 5 5 10 ethyl iaurate 5 5 5 5 5 5 -EXAMPLE 8s Comparison of Penetration Profi~.es TABLE 2 shows the cumulative amount of prostaglandin E1 penetrating each hour for 4 hours for each example composition according to the present invention. These data demonstrate the ability of the present invention to delivery prostaglandin E1 drugs transdermally.
FIGURE 1 is graph generated from the data presented in TABLE 1. Significantly, and well represented in graphical form, compositions according to the present invention deliver effective skin penetration relatively fast and at a sustained rate. As expected, cumulative penetration increases with increased prostaglandin E1 loading of the source composition.
1.5 TABLE 2: Cuasutative P~ostaglandia E, Penetration Q~glcm:) HOUf ~ B C ~ E - F Ca 1 1.96 3.37 5.47 7.20 7.09 10.38 3.03 2 5.49 9.72 18.06 21.2616.6 2x.03 8.1 ~

3 11.2518.1830.34 35.5328..2442.18 12.93

4 13.9823.4838.49 47.9841.1 52.13 18.71 To further asses the effectiveness of compositions according the present invention, comparative example compositions were prepared. A first comparative example (Comparative Example 1.) was prepared with the same recipe as Compositions-D and E except that the DDAIP penetration enhancer was omitted. For A second comparative example (Comparative Example 2), the DDAIP was again omitted, but the level of ethanol was increased a corresponding amount. The specific ingredients used are listed in TABLE 3, below.

TABLE 3: Comparative 1_xampies Comparative Comparative ingredient (wt~~) ConupositioraComposition 2 -Part A: prehydrated locust 3 3 bean gin water/bulfier (pH 5.5) 86 81 sucrose stearate 0.5 0.5 Part B: prostaglandin ~, 0.4 ' ~.4 ethanol .5 10 ethyllaurate ~5 6 The penetration of prostaglandin E1 from. was evaluated according to the technique described in Example~l. The results are presented in TABLE 4, below.
TABLE 4: ComparaYrve Examples Cumulative Prostaglandin E, Penetration (tcglcm~) Comparative Comparative Hoarr Composition 1 Composition ~
1 2.64 1.55 2 4.46 3,69 3 6.59 6.83 4 9.61 11.65 Io The data of TABLE 4 are compared graphically to the example compositions haring the same prostaglandin Ea loading, Compositions D and E. The penetration data demonstrate that compositions according to the present invention benefit greatly I5 from the presence of the DDAIP penetration enhancer.
The foregoing specification is-intended as illustrative and is Trot to be taken as limiting. Still other variations within the spirit and the scope of the invention are possible and will readily present themselves to those skilled 20 in the art.

Claims (21)

THE EMBODIMENTS OF THE INVENTION FOR WHICH AN EXCLUSIVE PROPERTY
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. Use of prostaglandin E1;
a skin penetration enhancer which is a member of the group consisting of an alkyl-2-(N,N-disubstituted amino)-alkanoate, an (N,N-disubstituted amino)-alkanol alkanoate, and a mixture thereof;
a polysaccharide gum or a polyacrylic acid polymer;
a lipophilic compound which is a member of the group consisting of an aliphatic C1 to C8 alcohol, an aliphatic C8 to C30 ester, and a mixture thereof; purified water and an acidic buffer system providing a buffered pH value for said composition in the range of 3 to 7.4, for the preparation of a topical composition for (i) enhancing the rate of healing of wounds, ulcers, infections and proliferative and inflammatory skin lesions, or (ii) treating a condition which is a member of the group consisting of Raynaud's phenomenon, Raynaud's disease, Buerger's disease, livedo reticularis, atherosclerosis and frostbite.

2. Use of an effective amount of a topical composition comprising prostaglandin E1;
a skin penetration enhancer which is a member of the group consisting of an alkyl-2-(N,N-disubstituted amino)-alkanoate, an (N,N-disubstituted amino)-alkanol alkanoate, and a mixture thereof;
a polysaccharide gum or a polyacrylic acid polymer;
a lipophilic compound which is a member of the group consisting of an aliphatic C1 to C8 alcohol, an aliphatic C8 to C30 ester, and a mixture thereof; purified water and an acidic buffer system providing a buffered pH value for said composition in the range of 3 to 7.4, for (i) enhancing the rate of healing of wounds, ulcers, infections and proliferative and inflammatory skin lesions, or (ii) treating a condition which is a member of the group consisting of Raynaud's phenomenon, Raynaud's disease, Buerger's disease, livedo reticularis, atherosclerosis and frostbite in a subject in need of such therapy.

3. The use in accordance with claim 1 or 2 wherein said penetration enhancer is an alkyl-2-(N,N-disubstituted amino)-alkanoate represented by the formula:

wherein n is an integer having a value in the range of 4 to 18; R is a member of the group consisting of hydrogen, C1 to C7 alkyl, benzyl and phenyl; R1 and R2 are members of the group consisting of hydrogen and C1 to C7 alkyl; and R3 and R4 are members of the group consisting of hydrogen, methyl and ethyl.

4. The use in accordance with claim 1 or 2 wherein said penetration enhancer is a C4 to C18 alkyl (N,N-disubstituted amino)-acetate.

5. The use in accordance with claim 1 or 2 wherein said penetration enhancer is dodecyl (N,N-dimethylamino)-acetate or dodecyl 2-(N,N-dimethylamino)-propionate.

6. The use in accordance with claim 1 or 2 wherein said penetration enhancer is an (N,N-disubstituted amino)-alkanol alkanoate represented by the formula:

wherein n is an integer having a value in the range of 5 to 18; y is an integer having a value in the range of 0 to about 5; and R1, R2, R3, R4, R5, R6, and R7 are members of the group consisting of hydrogen, C1 to C8 alkyl, and aryl of up to 8 C-atoms; and R8 is a member of the group consisting of hydrogen, hydroxyl, C1 to C8 alkyl, and aryl of up to 8 C-atoms.

7. The use in accordance with claim 1 or 2 wherein said penetration enhancer is a C5 to C18 (N,N-disubstituted amino)-alkanol alkanoate.

8. The use in accordance with claim 1 or 2 wherein said penetration enhancer is a member of the group consisting of 1-(N,N-dimethylamino)-2-propanol dodecanoate, 1-(N,N-dimethylamino)-2-propanol myristate and 1-(N,N-dimethylamino)-2-propanol oleate.

9. The use in accordance with claim 1 or 2 wherein said polysaccharide gum is a galactomannan gum.

10. The use in accordance with claim 9 wherein said galactomannan gum is a locust bean gum or a guar gum.

11. The use in accordance with claim 1 or 2 wherein said lipophilic compound is selected from the group consisting of ethanol, n-propanol, isopropanol, glycerol, propylene glycol, polyethylene glycol, ethyl acetate, butyl acetate, methyl propionate, isopropyl myristate, ethyl laurate and a mixture thereof.

12. The use in accordance with claim 1 or 2 wherein said lipophilic compound is a mixture of ethanol and isopropyl myristate or a mixture of ethanol and ethyl laurate.

13. The use in accordance with claim 1 or 2 wherein said penetration enhancer is a dodecyl 2-(N,N-dimethylamino)-propionate, said polysaccharide gum is a locust bean gum, and said lipophilic compound is a mixture of ethanol and ethyl laurate.

14. The use in accordance with claim 1 or 2 wherein said topical composition contains 0.5 to 5 weight percent locust bean gum, 0.5 to 10 weight percent dodecyl 2-(N,N-dimethylamino)-propionate, 5 to 15 weight percent ethanol, and 2 to 15 weight percent isopropyl myristate, based on the total weight of the composition.

15. The use in accordance with claim 1 or 2, wherein said topical composition contains 0.5 to 5 weight percent locust bean gum, 0.5 to 5 weight percent dodecyl 2-(N,N-dimethylamino)-propionate, 5 to 15 weight percent ethanol, and 2 to 15 weight percent ethyl laurate, based on the total weight of the composition.

16. The use in accordance with any one of claims 1 to 15 wherein the topical composition further contains an emulsifier.

17. The use in accordance with claim 16 wherein said emulsifier is a sucrose ester.

18. The use in accordance with claim 17 wherein said sucrose ester is sucrose stearate.

19. The use in accordance with claim 1 or 2 wherein said polyacrylic acid polymer is a carbomer.

20. The use in accordance with any one of claims 1 to 19 wherein said topical composition is for transdermal or transmucosal administration.

21. The use in accordance with any one of claims 1 to 20 wherein said skin lesion is atopic dermatitis, acne or psoriasis.