HK1034678B - Topical compositions for prostaglandin e1 delivery - Google Patents

Description

Delivery of prostaglandin E1The composition for epidermal administration of

Field of the invention

The present invention relates to pharmaceutical compositions for transdermal administration of prostaglandin drugs to a patient.

Background of the invention

Prostaglandin E₁Is a derivative of prostanoic acid, an aliphatic acid of 20 carbon atoms, represented by the formula:

it is commercially available, for example, under the trade name "Alprostadil USP" from Chinoin pharmaceuticals and chemical processing, Inc. (Budapest, Hungary) and under the trade name "Prostin VR" from Upjohn, Kalamazoo, Michigan.

Prostaglandin E₁Is a vasodilator for maintaining the dilated blood vessel,and thus in particular for the treatment of peripheral vascular diseases. Although prostaglandin E is delivered transdermally₁The potential advantages of the compounds have long been recognized, but significant efforts to develop compositions for the epidermal delivery of prostaglandins have not been completely successful at the present time.

In particular, there is currently no semisolid formulation available on the market for topical administration without a support (e.g. patch, tape, etc.). For example, U.S. Pat. No. 5,380,760(Wendel et al) describes a prostaglandin formulation for topical administration that includes a pressure sensitive adhesive tab of polyisobutylene.

Most drugs, including prostaglandins, have been specifically studied and none of them have been able to penetrate the skin effectively to provide drug concentration levels comparable to other drug delivery routes. To address this problem, pharmaceutical formulations for topical administration typically include an epidermal penetration enhancer. Epidermal penetration enhancers may also be referred to as absorption enhancers, accelerators, adjuvants, solubilizers, adsorption enhancers, and the like. Whatever the name, such agents are used to improve the absorption of drugs through the skin. An ideal permeation enhancer not only increases the flux of the drug through the skin, but should also be non-irritating, sensitizing, or otherwise harmless to the skin. Furthermore, the ideal penetration enhancer should not affect the availability of dosage forms (e.g., creams or gels) or the cosmetic quality of the epicutaneously administered composition.

Many compounds have been evaluated for their effectiveness in increasing the rate of penetration of a drug through the skin, see, for example, "transdermal penetration enhancers" ((R))Percutaneous Penetration EnhancersMaibach h.i. and Smith h.e.eds.; CRC Press, inc., Boca Raton, f.l.1995), which reviews the use and testing of various skin permeation enhancers; see also Guytimkin et al, "chemical means of enhancing transdermal drug permeation in transdermal and epidermal drug delivery systems" ("chemical means of enhancing transdermal drug permeation in transdermal and epidermal drug delivery systems")Chemical Means of Transdermal Drug Permeation Enhancement in transdermal and Topical Drug Delivery Systems Gosh T.K.，PfisterW.R.，Yum S.I.，Eds.；Interpharm Press Inc.，Buffalo Grove，I.L.1997)。

Prostaglandin E₁Have not been identified at present, and unfortunately prostaglandin E₁Are readily converted by rearrangements and other reactions, and this relative instability leads to a more laborious effort in formulating transdermal delivery compositions.

The present invention addresses these problems in order to provide a relatively rapid and sustained delivery of prostaglandin E₁The semi-solid, separation-resistant composition of (a).

Summary of The Invention

Pharmaceutical compositions suitable for topical administration include prostaglandin E₁Penetration enhancers, polysaccharide gums, lipophilic compounds and acidic buffer systems. The penetration enhancer is an alkyl-2- (N, N-disubstituted amino) -alkanoate, an (N, N-disubstituted amino) -alkanol alkanoate, or a mixture thereof. The lipophilic compound may be aliphatic C₁-C₈Alcohols, aliphatic C₈-C₃₀Or mixtures thereof. The composition includes a buffer system capable of providing a buffered pH for the composition in the range of about 3 to 7.4. Stabilizers and emulsifiers may also be included if desired.

The compositions of the present invention may be in the form of semi-solids for topical administration, and when used as a medicament for topical administration, such compositions exhibit relatively high prostaglandin penetration and bioavailability without excessive consumption of prostaglandin concentration, and reduced skin irritation, sensitization and damage.

Other and further objectives, objects, features, advantages, embodiments, etc., of the present invention will be apparent to those skilled in the art from the present specification and claims that follow.

DrawingsBrief description of the drawings

In the drawings, FIG. 1 shows 7 prostaglandin E prepared according to the present invention₁Composition of prostaglandin E when penetrating sloughed snake skin₁(iii) osmotic accumulation conditions;

FIG. 2 is a graph comparing 2 prostaglandin E prepared according to the present invention₁Composition and 2 comparative compositions, prostaglandin E when penetrating sloughed snake skin₁The condition of osmotic accumulation.

Detailed description of the invention

The pharmaceutical compositions of the present invention comprise prostaglandin E₁Alkyl (N, N-disubstituted amino) esters, polysaccharide gums, lipophilic compounds and acidic buffer systems.

Prostaglandin E₁It is well known to those skilled in the art that pharmacological activity, side effects and general dosage ranges may be referred to various references, for example, see "commonly used physician references" (a), (b), (c), (d), (Physician′s Desk Reference51st Ed. (1997)) and"Moke index", 12th Ed.，(Merck &Co, n.j.1996); "additional pharmacopoeia of Martinder" ()Martindale The Extra Pharmacopoeia28th Ed., (London, The Pharmaceutical Press 1982). Prostaglandin E₁Other compounds relevant herein include pharmaceutically acceptable derivatives thereof, physiologically compatible salts and ester derivatives thereof.

Prostaglandin E in the pharmaceutical compositions of the present invention₁The amount of (A) is a therapeutically effective amount, which must be determined according to the desired dosage, dosage form (e.g., suppository or epidermal dosage form) and prostaglandin E used₁May vary in particular forms. The compositions generally contain from 0.1% to 1% prostaglandin E by total weight of the composition₁Preferably 0.3% to 0.5%.

An important component of the present invention is a penetration enhancer which is an alkyl-2- (N, N-disubstituted amino) -alkanoate, an (N, N-disubstituted amino) -alkanol alkanoate or mixtures thereof. For convenience, alkyl-2- (N, N-disubstituted amino) -alkanoates and (N, N-disubstituted amino) -alkanol alkanoates are classified together and are referred to as alkyl-2- (N, N-disubstituted amino) esters.

Alkyl-2- (N, N-disubstituted amino) -alkanoic acid esters suitable for the present invention are represented as follows:

wherein n is an integer ranging from about 4 to about 18, and R is selected from the group consisting of H, C₁-C₇A member of the class consisting of alkyl, benzyl and phenyl, R₁And R₂Is H, C₁-C₇Members of the class consisting of alkyl radicals, R₃And R₄Is a member of the class consisting of H, methyl, and ethyl.

Preferred alkyl (N, N-disubstituted amino) -alkanoates are C₄-C₁₈Alkyl (N, N-disubstituted amino) -acetates and C₄-C₁₈Alkyl (N, N-disubstituted amino) propionates; specific examples of alkyl-2- (N, N-disubstituted amino) -alkanoates include dodecyl 2- (N, N-disubstituted amino) propionate (DDAIP):

and dodecyl 2- (N, N-disubstituted amino) acetate (DDAA):

alkyl-2- (N, N-disubstituted amino) -alkanoates are well known, for example dodecyl 2- (N, N-disubstituted amino) propionate (DDAIP), commercially available from Steroids, Ltd. (Chicago, IK). Alternatively, alkyl (N, N-disubstituted amino) -alkanoates may be synthesized from more readily available compounds, such as those described in USP4,980,378(Wong et al), which is incorporated herein by reference for all purposes as if not incompatible with the present invention. As described herein, alkyl (N, N-disubstituted amino) -alkanoates can be readily prepared by a two step synthesis in which a long chain alkyl chloroacetate is prepared by reacting the corresponding long chain alkanol with chloromethylformyl chloride and the like in the presence of a suitable base, such as triethylamine, typically in a solvent, such as chloroform. The reaction is described as follows:

wherein R, R₃，R₄And n is as defined above, the reaction temperature is selected from about 10 ℃ to 200 ℃ or the reflux temperature, preferably room temperature, whether a solvent is used or not is determined as necessary, and if a solvent is used, various organic solvents can be selected, the selection of the base is also not limited, and preferred bases include tertiary amines such as triethylamine, pyridine and the like, and the reaction time is generally about 1 hour to 3 days.

In a second step, a long chain alkyl chloroacetate ester is condensed with an appropriate amine according to the following reaction:

wherein n, R₁，R₂，R₃And R₄As defined above. The excess reagent amine is usually used as a base and the reaction is usually carried out in a suitable solvent, such as diethyl ether. Although the temperature may vary, the second reaction step is preferably carried out at room temperature, and the reaction time generally varies from about 1 hour to 7 days. Esters for pharmaceutical compounds are readily obtained using conventional purification techniques.

Suitable (N, N-disubstituted amino) alkanol alkanoates are represented by the formula:

wherein n is an integer ranging from about 5 to about 18, Y is an integer ranging from 0 to about 5, R₁，R₂，R₃，R₄，R₅，R₆And R₇Is prepared from the reaction product of (A) H,₁-C₈alkyl and C₁-C₈Members of the class consisting of aryl radicals, R₈Is formed from H, hydroxy, C₁-C₈Alkyl and C₁-C₈Aryl groups are members of a class.

A preferred (N, N-disubstituted amino) alkanol alkanoate is C₅-C₁₈Specific examples of carboxylic acid esters, (N, N-disubstituted amino) alkanol alkanoates include 1- (N, N-dimethylamino) -2-propanol laurate (dapdd):

1- (N, N-dimethylamino) -2-propanol myristate (daim):

1- (N, N-dimethylamino) -2-propanol oleate (DAIPO):

(N, N-disubstituted amino) alkanol alkanoates are readily prepared by reacting the corresponding aminoalkanols and lauroyl chloride in the presence of triethylamine, optionally using a solvent such as chloroform, but are preferably used. For example, 1- (N, N-dimethylamino) -2-propanol may be reacted with lauroyl chloride in chloroform in the presence of triethylamine to form 1- (N, N-dimethylamino) -2-propanol laurate (DAIPD).

DDAIP is generally preferred among suitable penetration enhancers for the purposes of the present invention.

The permeation enhancer should be present in an amount sufficient to increase prostaglandin E₁The specific amount must depend on the desired delivery rate and prostaglandin E used₁May vary in particular forms. Generally, the amount is from about 0.5% to about 10% by weight of the total composition, preferably the penetration enhancer comprises about 5% by weight of the composition.

Polysaccharide gums are also important ingredients for the compositions of the present invention, and a suitable representative gum is a galactomannan gum type gum. Galactomannan gums are polymers of carbohydrates containing both D-galactose and D-mannose units, or other derivatives of such polymers. Relatively large amounts of galactomannans are present in the composition and their content in the composition varies depending on its origin. Galactomannan gums are characterized by a linear structure of (1-4) linked β -D-mannopyran units. The single member alpha-D-mannopyran unit linked to the main chains (1-6) is present as a side chain. Galactomannan gums include guar gum, which is the powdered endosperm of any one of the two legume species (cyamposis tetragonalobus and psoralcoids), and locust bean gum, which is found in the endosperm of the seeds of the carob (ceratonia siligua). Locust bean gum is preferred for the present invention.

Other suitable representative gums include agar gum, carrageenan gum, ghatti gum, karaya gum, rhamsan gum, and xanthane gum. The compositions of the present invention may contain mixtures of various gums or mixtures of gums and acidic polymers.

Gums, in particular galactomannan gums, are well known materials, see for example "industrial gums: polysaccharides and derivatives thereof: (Industrial Gums：Polysaccharides & Their Derivetives，Whistler R.L.& BeMiller J.N.(eds.)3rd.，Ed.Academycpress (1992)) and "Water-soluble gums and resin handbook" (Handbook of Water-Soluble Gums & ResinsDavidson r.l., McGraw-Hill, inc., n.y. (1980)). Most gums are commercially available in various forms, usually as powders, and are readily available for use in food and topical compositions, for example powdered locust bean gum is available from Tic GumsInc (Belcam, MD).

The polysaccharide gum is present in the range of about 0.5% to 5%, preferably in the range of about 0.5% to 2% by weight of the total composition, the composition being specified in the examples below.

An optional alternative to polysaccharide gums is polyacrylic acid polymers, a common variety of which are commonly referred to as carbomers. Carbomers are polyacrylic acid polymers lightly crosslinked with polyalkenyl polyethers and available under the trade designation "CARBOPOL" from b.f. goodrich Company (Akron, Ohio)^IMThe trade name "CARBOPOL 940" is "commercially available, particularly preferred carbomer.

Other polyacrylic acid polymers suitable for use in the present invention are commercially available "Pemulen^TM"(B.F. Goodrich Company) and" POLYCARBOPHIL^TM”(A.H.Robbins，Richmond，VA)。“Pemulen^TM"Polymer is C₁₀-C₃₀Copolymers of an alkyl acrylate of (a) 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; POLYCARBOPHIL^TM"reinforcing agent is polyacrylic acid crosslinked with divinyl glycol.

When present, the polyacrylic acid polymer is present in an amount of about 0.5 to 5% by weight of the total composition.

Other important components of the present invention are lipophilic compounds, which as used herein is the term lipophilic compound referring to agents that are both lipophilic and hydrophilic. C₁-C₈Fatty alcohol of (C)₂-C₃₀The fatty acid esters of (a) and mixtures thereof may be used as lipophilic compounds. Representative combinationsSuitable fatty alcohols are ethanol, n-propanol and isopropanol, and suitable esters are ethyl acetate, butyl acetate, ethyl laurate, methyl propionate and isopropyl myristate. As used herein, "fatty alcohols" include polyols such as glycerol, propylene glycol and polyethylene glycols. Mixtures of alcohols and esters are preferred, in particular mixtures of ethanol and ethyl laurate, with ethyl myristate being most preferred.

The concentration of lipophilic compound required must vary depending on other factors, such as the desired semi-solid stability and skin penetration promoting effect, preferred transdermal compositions contain from about 7% to 40% lipophilic compound by total weight of the composition, with a preferred amount of fatty alcohol being in the range of about 5% to 15% when a mixture of fatty alcohol and fatty acid ester is used, and a preferred amount of fatty acid ester being in the range of about 2% to 15% (still based on the total weight of the composition).

The invention is optionally used, but the preferred ingredient is an emulsifier, although not critical, suitable emulsifiers will generally have a hydrophilic-lipophilic balance number of greater than 10. Sucrose esters, particularly sucrose stearate, may be used as an emulsifier in the topical compositions of the present invention. Sucrose stearate is a well known emulsifier from a variety of commercial sources, and when an emulsifier is used, it is preferred that sucrose stearate be up to about 2% by weight of the total composition. The preferred amount of sucrose stearate emulsifier can also be expressed as a weight ratio of emulsifier to polysaccharide gum, with a ratio of 1: 4 being preferred for producing the desired homogeneity and separation resistance of the semi-solid composition.

The present invention includes an acidic buffer system for maintaining or buffering a desired pH range. The term "buffer system" or "buffering agent" as used herein refers to a solute or an agent that, when dissolved in an aqueous solution, stabilizes the solution such that the pH (or hydrogen ion concentration, or activity) does not change significantly when an acid or base is added. Such solutes or agents are known for preventing the pH from initially buffering the pH to a value that varies within the above specified range. While there are many suitable buffers, potassium phosphate monohydrate has proven effective for the compositions of the present invention.

The final pH of the pharmaceutical composition of the present invention may vary within a physiologically acceptable range, and the final pH must not irritate human skin. Prostaglandin E can be modified by selecting the pH without violating the above constraints₁Stability and, if necessary, uniformity. With these considerations in mind, the preferred pH is from about 3.0 to about 7.4, with the most preferred pH range being from about 3.5 to about 6.0.

The remainder of the composition is water, which must be pure water. The composition contains water in the range of about 50% to 90% by total weight of the composition, the specific amount of water is not limited but can be adjusted to obtain the desired homogeneity and/or to bring the concentration of other ingredients to the desired level.

In addition, if desired, known penetration enhancers for dermal penetration may also be used, practical examples being dimethyl sulfoxide (DMSO), Dimethylacetamide (DMA), 2-pyrrolidone, N, N-Diethyltoluamide (DEET), 1-dodecylazacycloheptan-2-one (Azone, trademark registered by Nelson Research), N, N-dimethylformamide, N-methyl-2-pyrrolidone, calcium thioglycolate, oxazolidinone, dioxolane derivatives, lauryl nitrogen  ketone derivatives and macrocyclic enhancers, such as macrocyclic ketones.

Prostaglandin E may be added₁Stabilizers, colorants, rheological agents and preservatives, in amounts which do not unduly limit prostaglandin E₁Or prevent the desired homogeneity of the semi-solid.

Contemplated dosage forms of the semi-solid pharmaceutical compositions of the present invention are creams or gels, and the like, and also include, but are not limited to, suitable compositions for transdermal patches and the like.

The above components may be combined in any order and manner as long as prostaglandin E-containing compounds are obtained₁A stable composition uniformly dispersed in the semisolid formulation. A suitable method of preparing such a composition comprises uniformly dispersing the polysaccharide gum (or polyacrylic acid)In a pre-mixed water/buffer solution, the resulting mixture is then homogenized (i.e., mixed) thoroughly, which is labeled "a parts". If desired, the emulsifier is added to the water/buffer solution before the polysaccharide gum is dispersed. The pH of part a may be adjusted to the desired level using any suitable method, such as by the addition of concentrated phosphoric acid or sodium hydroxide.

In addition, prostaglandin E₁Dissolved in a lipophilic compound, which may itself be an alcohol, an ester or a mixture of an alcohol and an ester, with stirring, and then added with a penetration enhancer. When the lipophilic compound comprises both an alcohol and an ester, the penetration enhancer is added first, followed by the ester, and then the prostaglandin E₁Dissolved in alcohol. The resulting mixture was labeled "part B" in both cases. The last step consists in slowly adding (for example dropwise) part B to part A with constant stirring.

When compared, the resulting epidermal administration composition exhibits the above-described excellent properties, including an improvement in prostaglandin E₁Permeability and bioavailability, no need for excess drug, reduced skin damage and associated inflammation, and flexibility in designing dosage forms. The composition can be used for treating peripheral vascular disease, impotence and other diseases using prostaglandin E₁The disease being treated extends the duration of treatment while avoiding low bioavailability and rapid chemical breakdown associated with other delivery methods. Prostaglandin E in the composition for epidermal administration of the present invention₁Applied to the skin of a patient such that a predetermined amount of prostaglandin E is present₁Can be administered to a patient continuously, avoiding the undesirable effects of administering large doses by injection one or more times. Prostaglandin E in target tissue of patient by maintaining sustained dose rate₁Can be well maintained in the optimal therapeutic range.

The following examples illustrate the practice of the invention, which are intended to be illustrative and not limiting of the scope of the invention, and to those skilled in the art without compromising prostaglandin E₁In the case of effectiveness of (a), it is clear that various changes are made to the composition, which changes are intended to be within the scope of the present invention. For example, additional ingredients, such as colorants, antimicrobial preservatives, emulsifiers, fragrances, prostaglandin E₁The stabilizer and the like may be contained in the composition as long as the resulting composition retains the desired properties as described above. Each composition was prepared by conventional methods, separately mixing the indicated ingredients together, unless otherwise indicated.

Example 1: epidermal administration of prostaglandin E₁Composition A of

Composition A is prepared by dissolving 0.4 part prostaglandin E1(Alprostadil USP) in 5 parts ethanol to form A parts, and mixing 5 parts dodecyl 2- (N, N-dimethylamino) propionate with the alcohol-prostaglandin E₁To the solution of (4), 5 parts of ethyl laurate was subsequently added.

B parts were prepared starting from a ph5.5 water/buffer solution: the pH of the water/buffer solution was adjusted to 5.5 with a strong alkaline solution (1N sodium hydroxide) and a strong acidic solution (1N phosphoric acid) by adding sufficient potassium phosphate monohydrate to the pure water to give a 0.1M solution. The buffer solution is about 80 parts of the total composition.

To the buffer solution was added 0.5 part of ethyl laurate, and locust bean gum (powder) was dispersed into the buffer solution and homogenized by a homogenizer, the ingredients of which are listed in table 1 below.

The resulting composition is a spreadable semi-solid suitable for application to the skin, does not require a support such as a patch or adhesive tape, and is uniform in both appearance and resistance to separation.

Evaluation of prostaglandin E Using sloughed snake skin as model Barrier layer₁Skin permeation performance of (1) skin permeation performance of sloughed snakeskins obtained from the animal protection unit of the Kansas university, head and tail portions were removed, the skins were randomly cut into test pieces, and then soaked with water.

Frane type diffusion cell for sample (surface 1.8 cm)²) And (6) evaluating. In particular, the present invention relates to a method for producing,the snake skin was placed on top of the receiving cell in a vertical diffusion cell into which a magnetic rod was inserted and isotonic buffer was added. A washer is placed above the snake skin sheet, and then a sample feeding pool is placed, and the two pools are clamped together. A known amount of the formulation was placed on the bottom of a capped vial (5 g in weight) that was just fit into the dosing well to ensure uniform distribution. The vial was placed on the snake skin in the sample well. To reduce evaporation of the ingredients, the cuvette and vial were gently taped together with waterproof tape. The whole unit was placed in a stirred water bath (32 ℃). Samples were withdrawn from the cell hourly for a total of 4 hours and analyzed for prostaglandin E₁The change in concentration indicates the amount of permeation. The test will be performed with a plurality of snake skin samples and the results will be averaged.

For a discussion of the evaluation of the use of ecdysis-type snake skin in drug penetration, see USP4,771,004(Higuchi), the non-incompatible contents of which are incorporated herein by reference.

Prostaglandin E in 4 hours₁The permeation rapidly proceeded at a relatively constant rate and the results of the permeation studies are set forth in table 2 below and fig. 1.

Example 2: epidermal administration of prostaglandin E₁Composition B

Composition B was prepared using the ingredients listed in table 1. Composition B contains more prostaglandin E than composition A₁Composition B exhibited similar semi-solid homogeneity and uniform appearance despite increased drug dosage. Prostaglandin E was determined as described in example 1₁Permeability. Composition B provides prostaglandin E₁The results are shown in table 2 and fig. 1.

Example 3: epidermal administration of prostaglandin E₁Composition C

Composition C was prepared using the ingredients listed in table 1 below. Composition C contains more prostaglandin E than composition A or B₁Increased drug dosage had little (or no) effect on uniformity and appearance, and was practically comparable to composition a or B. Still in accordance with the implementationProstaglandin E assay as described in example 1₁Permeability. According to this test, composition C also provided prostaglandin E₁The results are shown in table 2 below and fig. 1.

Example 4: epidermal administration of prostaglandin E₁Composition D

Composition D was prepared using the ingredients listed in table 1 below. Increasing prostaglandin E₁The content of (a) has practically no influence on good uniformity and separation resistance. Prostaglandin E was measured again as described in example 1₁Permeability. The results are shown in table 2 below and fig. 1.

Example 5: epidermal administration of prostaglandin E₁Composition E

Composition E was prepared using the ingredients listed in table 1 below. Composition E was again formulated with composition D in order to evaluate the reproducibility of the compositions of the invention. The good semi-solid homogeneity and separation resistance of composition E actually confirmed its reproducibility. Prostaglandin E was measured again as described in example 1₁Permeability. Prostaglandin E of composition E₁The transport was still rather rapid and constant and the results are given in table 2 below and in figure 1.

Example 6: epidermal administration of prostaglandin E₁Composition F

Prostaglandin E in composition F₁The levels of specific components are increased, the specific components are shown in table 1, good uniformity and separation stability are not decreased, and the results of permeation analysis are shown in table 2 below and fig. 1.

Example 7: epidermal administration of prostaglandin E₁Composition G

Composition G was prepared using the ingredients listed in table 1 below. For composition G, the formulation of composition F was repeated except that the ester component (laurate) was omitted and the amount of ethanol added was correspondingly increased, and the resulting composition was also a spreadable semi-solid with uniform appearance and separation resistance, and the results of the permeation analysis are shown in table 2 below and in fig. 1. The results, which reflect the corresponding advantages of the compositions according to the invention due to the use of lipophilic compounds comprising an ester component and an alcohol component, are still very good.

Table 1: epidermal administration of prostaglandin E₁Composition comprising a metal oxide and a metal oxide

Ingredient (Wt%) A B C D E F G

A part of pre-hydrated locust bean gum 3333333

Water/buffer (pH5.5) 81818181818181

Sucrose stearate 0.50.50.50.50.50.50.5

B part prostaglandin E₁ 0.1 0.2 0.3 0.4 0.4 0.5 0.4

DDAIP 5 5 5 5 5 5 5

Ethanol 55555510

Lauric acid ethyl ester 555555-

Example 8: comparison of permeation profiles

Table 2 shows prostaglandin E per hour over a period of 4 hours for the compositions of the various embodiments of the present invention₁Cumulative amount of penetration. These data demonstrate the transdermal delivery of prostaglandin E by the compositions of the present invention₁The ability of the drug.

Fig. 1 is a graph obtained from the data shown in table 1. Clearly and suitably graphically displaying that the composition of the invention is capable of relatively rapid and constant speedEffectively penetrating the skin. As expected, the cumulative permeation was dependent on prostaglandin E in the composition₁The amount increases with increasing use.

Table 2: cumulative amount of penetration of prostaglandin E1 (. mu.g/cm)²)

Time AB C D E F G

(hours)

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

To further evaluate the effectiveness of the compositions of the present invention, comparative example compositions were prepared. The first comparative example (comparative example 1) was prepared in the same formulation as compositions D and E, except that the use of DDAIP permeation enhancer was omitted. Comparative example 2 (comparative example 2) also omitted DDAIP, but the amount of ethanol used was increased by a corresponding amount, and the specific ingredients used are listed in table 3 below.

Table 3: comparative examples

Component (Wt%) comparative example composition 1 comparative example composition 2

A part of pre-hydrated locust bean gum 33

Water/buffer (pH5.5) 8681

Sucrose stearate 0.50.5

B part prostaglandin E₁ 0.4 0.4

Ethanol 510

Lauric acid ethyl ester 55

Prostaglandin E was evaluated as described in example 1₁The results are shown in Table 4 below.

Table 4: comparative examples

Prostaglandin E₁Cumulative permeation amount (μ g/cm)²)

Composition of time comparative example 1 composition of comparative example 2

(hours)

1 2.64 1.55

2 4.46 3.69

3 6.59 6.63

4 9.67 11.05

The data in Table 4 are graphically depicted for prostaglandin E at the same levels₁Examples compositions D and E were compared and the penetration data demonstrate that the advantages of the compositions of the present invention are primarily a result of the presence of DDAIP penetration enhancer.

The foregoing description is intended only to illustrate the invention and is not intended to limit the invention, and other variations within the spirit and scope of the invention are possible and will be apparent to those skilled in the art.

Claims (4)

1. A semi-solid epidermal delivery composition comprising, based on the total weight of the composition:

0.1-1 wt.% prostaglandin E₁；

0.5-10% by weight of a skin penetration enhancer which is dodecyl 2- (N, N-dimethylamino) propionate;

0.5-5% by weight of locust bean gum;

7-40% by weight of a lipophilic compound selected from the group consisting of ethanol, ethyl laurate, and mixtures thereof;

an acidic buffer system capable of providing a pH of from 3 to 7.4 to the composition.

2. The topical composition in accordance with claim 1 wherein said lipophilic compound is ethyl laurate.

3. The topical composition in accordance with claim 1 wherein said lipophilic compound is a mixture of 5-15% by weight ethanol and 2-15% by weight ethyl laurate.

4. The topical composition in accordance with claim 1 further comprising sucrose stearate as an emulsifier.