HK1090293B - Topical stabilized prostaglandin e compound dosage forms - Google Patents

Description

Locally stabilized prostaglandin E compound dosage forms

Technical Field

The present application relates to room temperature stable, non-aqueous prostaglandin E compound dosage forms suitable for treating sexual dysfunction in male as well as female patients.

Background

Prostaglandins may exhibit expansion or contraction of blood vessels, smooth muscle excitation or inhibition. Prostanoid E, e.g. prostaglandin E₁(PGE₁) It is reported that when it is administered as an aqueous solution in physiological saline by intracavitary injection or topical applicationWhen used, has utility in the treatment of erectile dysfunction, Mahmond et al, j.urology 147: 623-626(1992). However, prostaglandins, e.g. PGE₁And is relatively insoluble in water and thus relatively unstable. As a result, prostaglandins intended for injection are prepared shortly before use, which is relatively inconvenient.

Attempts to use PGE by using alpha-cyclodextrin or beta-cyclodextrin complexes₁This method has been reported to be stable in aqueous systems. Wiese et al, j.pharm.sciences 80: 153-156 (1991); szejtli, J., "Industrial application of Cyclodextrins", Inclusion Compounds III, Academic Press, London, England (1984), pp.355-368. However, even such stable aqueous PGE formulations have limited their practical utility due to their relatively short shelf life.

It has now been found that the stability of prostanoid E can be significantly improved without sacrificing bioavailability by using a specific non-hydrophysically compatible composition that can be stored separately from the topical delivery vehicle and combined with the delivery vehicle just prior to use.

Summary of The Invention

Prostaglandin E compounds are stable as non-aqueous compositions comprising the compound and a bulking agent which may be a non-aqueous liquid or a solid in the form of a tablet, film or powder. Optionally, a skin penetration enhancer may also be included.

Preferred non-aqueous solid dosage forms comprise a prostaglandin E compound substantially homogeneously dispersed in a carrier sheet or film. The prostaglandin compound can be released by introducing a sheet or film portion of a predetermined size directly into a moist body cavity. Alternatively, a predetermined-sized sheet or film portion containing the prostaglandin compound may be dissolved in an aqueous or nonaqueous solvent as a physiologically compatible delivery vehicle for the prostaglandin compound. For topical application, the topical delivery vehicle is viscous and substantially non-flowing, such as a cream, gel, or ointment.

In another embodiment, the pair-compartment dosage form comprises a sealed active agent compartment and a sealed inert agent compartment. The prostaglandin E compound is contained in the active agent compartment along with a filler and optionally a skin penetration enhancer. A physiologically compatible viscous topical delivery vehicle is contained in the inert agent compartment and combined with the contents of the active agent compartment prior to use, preferably mixed just prior to use. The skin permeation enhancer may be included in the inert agent compartment in addition to or instead of the skin permeation enhancer in the active agent compartment.

The dosage forms of the present invention containing the stabilized prostaglandin E compounds may be used to improve sexual dysfunction in human patients, e.g., impotence, premature ejaculation in males, sexual arousal disorder in females, etc.

Description of the preferred embodiments

Prostanoid E is a known compound that can be represented by the following formula:

compounds derived from the above structure and having 9-oxo, 11 α -hydroxy substituents and unsaturation in the side chain are referred to as prostaglandin E compounds, all hereinafter referred to as PGE compounds. This class of compounds includes prostaglandin E, represented by the formula₁(PGE₁)：

A precursor represented by the formulaProstaglandin E₂(or PGE₂)：

Prostaglandin E represented by the formula₃(or PGE₃)：

And their physiologically compatible salts.

PGE compounds have useful therapeutic activities such as vasodilation and are therefore used in therapeutic applications for the treatment of sexual dysfunction in both men and women, for the treatment of lipid metabolism, for the treatment of ulcers, for the treatment of inflammatory skin lesions and the like.

However, PGE compounds are relatively insoluble and tend to decompose, particularly in aqueous solutions or aqueous environments. However, it has now been found that these compounds can be effectively stabilized when providing a sheet-form composition that is easy to handle and measure, thereby providing a convenient dosage form for topical administration either directly or in combination with a viscous delivery vehicle such as a cream, gel, ointment, or the like.

The PGE compound can be incorporated as a substantially uniformly dispersed solid into sheet-form materials, i.e., sheets and films, of physiologically compatible polymeric materials, e.g., cellulose ethers such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, and the like, polysaccharides such as starch, polyvinylpyrrolidone, and the like. Sheet-form materials having a thickness of no more than about 10 mils are commonly referred to as films, while those having a thickness of more than about 10 mils are commonly referred to as sheets. The term "sheet-type" as used herein and in the appended claims refers to both sheets and films. The sheet-type material may be a solid or porous material, such as a sponge or the like. If desired, the sheet-type material having the PGE compound dispersed therein may be converted into a sheet, a tablet, a pill, or the like.

These prepared sheet products may be water soluble for direct introduction into moist body cavities or soluble in non-hydrophysically compatible solvents to prepare creams or ointments suitable for topical application. Of course, the water-soluble portion of the prostaglandin loaded sheet material may also be used to prepare aqueous gels based on polycarbophil, polyoxyethylene, polyoxypropylene block copolymers (e.g., known as poloxamers), and mixtures thereof, as well as non-aqueous gels based on polysorbates, liquid block copolymers of propylene oxide and ethylene oxide, and the like.

The PGE compound-carrying sheet-type material may further contain a physiologically compatible plasticizer, a dissolution enhancer (e.g., hydroxypropyl- β -cyclodextrin), and the like, if necessary.

These PGE-loaded sheet-type materials can be prepared by the following steps: the desired PGE compound is first dissolved in an aliphatic alcohol such as methanol, ethanol, propanol, isopropanol, n-butanol, etc., with or without a skin permeation enhancer, and the solution is then poured continuously into a tumbler, or in batches into a tray or pan, from which the solvent is then evaporated. The resulting sheet or film provides a substantially uniform dispersion of the PGE compound in a non-aqueous medium which can be readily subdivided and distributed into the desired unit doses, each having a predetermined PGE content. The cast sheet or film may also be stored on a solid surface and dissolved just prior to use.

The above unit doses may be used to provide a packaged, paired compartment dosage form in which the active agent compartment contains a unit dose of the PGE compound and the inert agent compartment contains an inert delivery vehicle for topical administration. In packaged, paired-compartment dosage forms embodying the invention, the active agent compartment may also contain the PGE compound and a bulking agent in the form of a non-aqueous liquid, microparticles or granules. Suitable fillers are silicone oils such as polydimethylsiloxanes, e.g., cyclomethicone USP, dimethicone, and the like. Suitable solid fillers for special purposes are cyclodextrins such as hydroxypropyl-beta-cyclodextrin, gamma-cyclodextrin and the like, polysaccharides such as starches, gums and the like, polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose, sugars and the like.

Particularly preferred solid dosage forms of the invention comprise at least one PGE compound, preferably PGE₁And an alkyl (N-substituted amino) ester, both substantially homogeneously dispersed in the carrier sheet or intermixed in a packaged, pair-compartment dosage form compartment. For the purposes of the present invention, PGE₁And PGE₂Particularly preferred are vasoactive agents.

PGE₁And PGE₂Well known to those skilled in the art. Various references can be consulted for its pharmacological activity, side effects and normal dosage range. See, for example, Physician's Desk Reference, 51 th edition (1997), Tlze Merck Index, 12 th edition, Merck&Co., N.J. (1996), and Martindale The Extra Pharnlacopeia, 28 th edition, London, The Pharmaceutical Press (1982). Prostaglandin E and other PGE compounds referenced herein are intended to also include their physiologically compatible derivatives, including physiologically compatible salts and ester derivatives.

PGE compounds such as PGE in solid dosage forms₁The amount is a therapeutically effective amount and can vary as necessary depending on the desired dosage for a particular treatment regimen. The solid dosage forms of the present invention may contain from about 0.05 to about 25 weight percent of the PGE compound, based on the total weight of the composition, preferably from about 0.1 to about 15 weight percent of the PGE compound.

One desirable component of the solid dosage form is a skin permeation enhancer. The skin penetration enhancer may be an alkyl 2- (N-substituted amino) -alkanoate, an (N-substituted amino) -alkanol alkanoate, or a mixture thereof. For ease of reference, the 2- (N-substituted amino) -alkanoic acid alkyl esters and (N-substituted amino) -alkanol alkanoates may be classified under the term alkyl (N-substituted amino) esters.

Alkyl 2- (N-substituted amino) -alkanoates suitable for use in the present invention may be expressed as follows:

wherein n is an integer of from about 4 to about 18; r is selected from hydrogen and C₁-C₇Alkyl, benzyl and phenyl; r₁And R₂Selected from hydrogen and C₁-C₇An alkyl group; r₃And R₄Selected from hydrogen, methyl and ethyl.

Preferred are (N, N-disubstituted amino) -alkanoic acid alkyl esters such as (N, N-disubstituted amino) -acetic acid C₄-C₁₈Alkyl esters and (N, N-disubstituted amino) -propionic acid C₄-C₁₈Alkyl esters and their physiologically compatible salts and derivatives. Typical specific alkyl 2- (N, N-disubstituted amino) -alkanoates include dodecyl 2- (N, N-dimethylamino) -propionate;

and 2- (N, N-dimethylamino) -acetic acid dodecyl ester;

alkyl 2- (N-substituted amino) -alkanoates are known. For example, dodecyl 2- (N, N-dimethylamino) -propionate 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 in U.S. patent 4,980,378 to Wong et al, which is incorporated by reference to the extent not inconsistent. As described therein, alkyl 2- (N, N-disubstituted amino) -alkanoates can be readily prepared by 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 a suitable base such as triethylamine, typically in a suitable solvent such as chloroform. The reaction can be described as follows:

r, R therein₃、R₄And n is as defined above. The reaction temperature may be from about 10C to about 200C or reflux temperature, with room temperature being preferred. Optionally, a solvent is used. If a solvent is used, a variety of organic solvents may be selected. The choice of base is likewise not critical, and preferred bases include tertiary amines such as triethylamine, pyridine, and the like. The reaction time typically extends over a period of about 1 hour to 3 days.

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

r, R therein₁、R₂、R₃And R₄As defined above. An excess of the amine reactant is typically used as the base, and the reaction is conveniently carried out in a suitable solvent, such as an ether. Although the temperature is varied, the second step is preferably carried out at room temperature. The reaction time is generally varied from about 1 hour to several days. Convenient purification techniques may be employed to provide for the use of the resulting ester in physiologically compatible compounds.

Suitable (N-substituted amino) -alkanol alkanoates may be represented by the formula:

wherein n is an integer of from about 5 to about 18; y is an integer from 0 to about 5; r₁、R₂、R₃、R₄、R₅、R₆And R₇Selected from hydrogen, C₁-C₈Alkyl and C₁-C₈An aryl group; r₈Selected from hydrogen, hydroxy, C₁-C₈Alkyl and C₁-C₈And (4) an aryl group.

Preferred are (N-substituted amino) -alkanol alkanoates such as C₅-C₁₈Carboxylic acid esters and their physiologically compatible salts. Typical specific (N, N-disubstituted amino) -alkanol alkanoates include 1- (N, N-dimethylamino) -2-propanol dodecanoate;

1- (N, N-dimethylamino) -2-propanol tetradecanoate;

1- (N, N-dimethylamino) -2-propanol oleate;

(N, N-disubstituted amino) -alkanol alkanoates can be readily prepared by reacting the corresponding aminoalkanols with lauroyl chloride in the presence of triethylamine. Solvents such as chloroform are optional but preferred. For example, 1- (N, N-dimethylamino) -2-propanol is reacted with lauroyl chloride in chloroform and in the presence of triethylamine to form 1- (N, N-dimethylamino) -2-propanol dodecanoate.

Among the skin permeation enhancers suitable for use in the solid dosage forms of the present invention, dodecyl 2- (N, N-dimethylamino) -propionate and crystalline salts thereof are generally preferred. The preparation of such crystalline salts is described in U.S. patent 6,118,020 to buyukittim et al.

The skin penetration agent is present in an amount sufficient to enhance penetration of the PGE compound into the tissue. The specific amount can be varied as necessary depending on the desired release rate and the specific form of the PEG compound used. Typically, the amount of skin penetrating agent ranges from about 0.01% to about 20%, based on the total weight of the composition administered to the patient.

The desired release rate, including controlled and sustained release of the active compound, can also be adjusted by the choice of topical delivery vehicles, e.g., hydrophobic vehicles such as polydimethylsiloxane and the like. Carboxyl-terminated polydimethylsiloxanes can also enhance skin penetration of the active compounds.

Natural and modified polysaccharide gums may also be present as part of a carrier sheet or topical delivery vehicle. Suitable representative gums are natural and modified galactomannan gums. Galactomannan gums are carbohydrate polymers containing both D-galactose and D-mannose units, or other derivatives of such polymers. There are relatively large amounts of galactomannans, which vary in composition depending on their origin. Galactomannan gums are characterized by a linear structure of β -D-mannopyranosyl units linked (1 → 4). The monovalent α -D-mannopyranosyl unit attached to the main chain (1 → 6) is present as a side chain. Galactomannan gums include guar gum, a powdered endosperm of seeds of one of the two legumes (cyanosis tetragona and psoralcoids) and locust bean gum, which is found in the endosperm of carbotree (ceratonia siliqua) seeds. Suitable modified polysaccharide gums include ethers of natural or substituted polysaccharide gums such as carboxymethyl ethers, ethylene glycol ethers and propylene glycol ethers.

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

Gums, particularly galactomannan gums, are well known raw materials. See, for example, industrial gums: polysaccharides and their derivatives (Polysaccharides & TheirDerivatives), Whistler R.L. and BeMiller J.N (eds.), third edition, Academic Press (1992) and Davidson R.L., Handbook of Water-Soluble Gums and resins (Handbook of Water-Soluble Guuble and Resin), McGraw-Hill, Inc., N.Y. (1980). Most gums are commercially available in a wide variety of forms, usually powders, and are readily used in food and topical compositions. For example, locust bean gum in powder form is available from Tic Gums Inc (Belcam, MD).

When present, the polysaccharide gum is present in an amount of about 0.1% to about 5%, preferably about 0.5% to about 3%, based on the total weight of the composition. In a preferred embodiment, about 2.5% by weight of polysaccharide gum is present.

An optional alternative to polysaccharide gums is polyacrylic acid polymers. One common variation of polyacrylic acid polymers is generically referred to as "carbomer". Carbomers are polyacrylic acid polymers that are photocrosslinked with polyalkenyl polyethers. Commercially available from the B.F. Goodrich Company (Akron, Ohio) under the trademark "CARBOPOL^TM". One particularly preferred carbomer variant is the carbomer variant known as "CARBOPOL 940".

Other polyacrylic acid polymers suitable for use are commercially available under the designationPemulen^TM"(B.F. Goodrich Company) and" POLYCARBOPHIL^TM″(A.H.Robbins，Richmond，VA)。Pemulen^TMThe polymer is C₁₀-C₃₀Copolymers of alkyl acrylates with one or more monomers of acrylic acid, methacrylic acid or their simple esters crosslinked with an allyl ether of sucrose or an allyl ether of pentaerythritol. Polycarbophil^TMThe product is polyacrylic acid crosslinked with butadiene diol.

The concentration of the lipophilic compound necessary will vary depending on other factors such as the desired consistency of the semi-solid and the desired skin penetration enhancing effect. Suitable concentrations of lipophilic compounds are from about 0.5% to about 40% by weight, based on the total weight of the composition. Preferred topical compositions contain from about 7% to about 40% by weight of the lipophilic compound, based on the total weight of the composition.

Where mixtures of aliphatic alcohols and aliphatic esters are used, suitable amounts of alcohol are from about 0.5% to about 75%. In a preferred embodiment, the amount of alcohol is from about 5% to about 15%, while the amount of aliphatic ester is from about 2% to 15% (again based on the total weight of the composition). In another preferred embodiment, the amount of alcohol is from about 0.5% to about 10%, while the amount of aliphatic ester is from 0% to about 10% (again based on the total weight of the composition).

An optional but preferred component is an emulsifier. Suitable emulsifiers will exhibit a hydrophilic-lipophilic balance of greater than 10. Sucrose esters, particularly sucrose stearate, are well known emulsifiers from commercial sources that can be used as emulsifiers for the composition. When an emulsifier is used, sucrose stearate is preferably present in an amount up to about 2% by weight of the total weight. The preferred amount of sucrose stearate emulsifier can also be expressed as the weight ratio of emulsifier to polysaccharide gum.

Other suitable emulsifiers are polyoxyethylene sorbitan esters, long-chain alcohols, preferably cetostearyl alcohol, and fatty acid glycerides.

Suitable polyoxyethylene sorbitan esters include monolaurate (Tween 20, Span20), monopalmitate (Tween 40), monostearate (Tween 60), and monooleate (Tween 80) and mixtures thereof. Preferred fatty acid glycerides include glycerol monooleate, triolean, trimyristin and tristearin.

Another optional component is an antifoam, a chemical that reduces the tendency to foam after preparation due to shaking or agitation. Siloxanes are preferred antifoaming agents; however, various alcohols and lipids also exhibit similar properties. In addition to the alcohol, the antifoam agent chosen must be effective at relatively low concentrations and used in minor amounts. Illustrative antifoams are polydimethylsiloxane, cetyl polydimethylsiloxane, polydimethylsiloxane silylate, dimethiconol, a mixture of polydimethylsiloxane and hydrated silica, isopropanol, hexanol, trimethylsiloxysilicates, triphenyltrimethicone, and the like. A particularly preferred antifoam is a mixture of polydimethylsiloxane having an average chain length of 200-300 dimethylsiloxane units and hydrated silica, such antifoam being commercially available under the trade designation SIMETHICONE USP manufactured by Dow Coming Corporation, Michigan.

The composition may, if desired, contain a buffer system. The buffer system is selected so as to maintain or buffer the pH of the composition within a desired range. The term "buffer system" or "buffer" refers to a solute that, when in an aqueous solution, stabilizes the solution to prevent a large change in pH (or hydrogen ion concentration or activity) upon addition of an acid or base. Solutes which determine as such the prevention of pH changes within the above-mentioned range from the initially buffered pH value are well known. While there are a myriad of suitable buffers, potassium phosphate monohydrate has proven effective for the compositions of the present invention as it is preferred.

The final pH of the pharmaceutical composition may vary within physiologically compatible ranges. Necessarily, the final pH does not irritate human skin and preferably facilitates transdermal delivery of the PGE compound. Without violating this limitation, the pH can be selected as desired to improve the stability and adjust the viscosity of the PGE compound. In one embodiment, 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.

For preferred topical delivery vehicles, the remaining component of the composition is water, which must be purified, e.g., deionized water. Such delivery vehicle compositions contain water in the range of from about 50% to about 95% based on the total weight of the composition. The particular amount of water present is not critical, however, should be adjustable to achieve the desired viscosity (typically about 50cps to about 10,000cps) and/or concentration of other components. The topical delivery vehicle preferably has a viscosity of at least about 30 centipoise.

Other known transdermal penetration enhancers may also be used to facilitate the delivery of the class E prostaglandin compound. Examples are sulfoxides such as dimethyl sulfoxide (DMSO), and the like; cyclic amides such as 1-dodecylazacycloheptan-2-one(s) ((R))A registered trademark of nelson research, inc.); amides such as N, N-Dimethylacetamide (DMA) N, N-diethyltoluamide, N-dimethylformamide, N-dimethyloctanamide, N-dimethyldecanamide, and the like; pyrrolidone derivatives such as N-methyl-2-pyrrolidone, 2-pyrrolidone-5-carboxylic acid, N- (2-hydroxyethyl) -2-pyrrolidone or their fatty acid esters, 1-lauryl-4-methoxycarbonyl-2-pyrrolidone, N-tallowalkyl pyrrolidone and the like; polyhydric alcohols such as propylene glycol, ethylene glycol, polyethylene glycol, dipropylene glycol, glycerin, hexanetriol, and the like; straight and branched chain fatty acids such as oleic acid, linoleic acid, lauric acid, valeric acid, heptanoic acid, hexanoic acid, myristic acid, isovaleric acid, octylvaleric acid, trimethylhexanoic acid, isostearic acid, etc.; alcohols such as ethanol, propanol, butanol, octanol, oleyl alcohol, stearyl alcohol, linoleyl alcohol and the like; anionic surfactants such as sodium laurate, sodium lauryl sulfate and the like; cationic surfactants such as benzalkonium chlorideAmmonium, dodecyltrimethylammonium chloride, hexadecyltrimethylammonium bromide, and the like; nonionic surfactants such as propoxylated polyoxyethylene ethers, e.g., Poloxamer 231, Poloxamer 182, Poloxamer 184, and the like, ethoxylated fatty acids, e.g., Tween 20, Myrj 45, and the like, sorbitan derivatives, e.g., Tween 40, Tween 60, Tween 80, Span 60, and the like, ethoxylated alcohols, e.g., polyoxyethylene (4) lauryl ether (Brij 30), polyoxyethylene (2) oleyl ether (Brij 93), and the like, lecithin and lecithin derivatives, and the like; terpenes such as D-limonene, alpha-pinene, beta-carane, alpha-terpineol, carvone, menthone, oxidized limonene, oxidized alpha-pinene, eucalyptus oil, and the like.

Also suitable as skin penetration enhancers are organic acids and esters such as salicylic acid, methyl salicylate, citric acid, succinic acid, and the like.

PGE compound stabilizers such as organic acids and alcohols, cyclodextrins, colorants, rheological agents and preservatives may be added to the extent that permeation of the PGE compound is not limited.

The components listed above may be mixed in any order and manner that results in a stable composition that is capable of maximally accommodating a PEG compound, such as PEG and the like, preferably substantially homogeneously dispersed in the composition. A convenient method of preparing such a composition comprises uniformly dispersing the polysaccharide gum (or polyacrylic acid) in a pre-mixed water/buffer solution and then thoroughly homogenizing (i.e. mixing) the resulting mixture. When present, the emulsifier is added to the water/buffer prior to dispersing the polysaccharide gum. Any suitable method of adjusting the pH to the desired level may be used, for example, by adding concentrated phosphoric acid or sodium hydroxide.

The PGE compound, with or without the penetration enhancer, is then combined and mixed prior to use.

The resulting composition is ready for topical, intrameatal, or vaginal administration.

These compositions can be used for the long-term treatment of peripheral vascular disease, male impotence, and other conditions treated or treatable with PEG, while avoiding the low bioavailability and rapid chemical breakdown associated with other delivery methods.

In one embodiment, a formulation ready for administration contains from about 0.01% to about 5% of a modified polysaccharide gum; about 0.001% to about 1% of a PGE compound, preferably PGE₁Or physiologically compatible salts thereof, lower alkyl esters thereof, and mixtures thereof; from about 0.5% to 10% of dodecyl 2- (N, N-dimethylamino) -propionate or a salt thereof; from about 0.5% to about 10% of a lower alcohol selected from the group consisting of: ethanol, propanol, isopropanol, and mixtures thereof; from about 0.5% to about 10% of an ester selected from the group consisting of: ethyl laurate, isopropyl myristate, isopropyl laurate, and mixtures thereof; based on the weight of the formulation, and an acidic buffer. Preferably, the formulation also contains up to about 2% by weight sucrose stearate.

Variations of therapeutic compositions that do not adversely affect the efficacy of the PGE compounds will be apparent to those skilled in the art and are therefore within the scope of this invention. For example, as noted above, additional components such as colorants, antimicrobial preservatives, emulsifiers, lubricants, flavorants, PGE compound stabilizers, and the like, may be included so long as the resulting formulation retains the desired properties. When present, preservatives are typically added in amounts of about 0.05 to about 0.30%. Suitable preservatives include methyl paraben (methyl PABA), propyl paraben (propyl PABA) and Butylated Hydroxytoluene (BHT). Suitable flavorants and aromas are known in the art; suitable perfumes are up to about 5% and perfumes are known in the art; suitable flavoring agents are up to about 5% myrtenol, preferably about 2% myrtenol, based on the total weight of the composition. If desired, the compositions of the present invention may also contain a minor amount of about 0.01 to about 4% by weight of a local anesthetic. Typical local anesthetics include lidocaine, benzocaine, dacromethazine, dibucaine, their physiologically compatible salts, and mixtures thereof. In a preferred embodiment, the local anesthetic is about 0.5% dacromeo ramie, based on the total weight of the composition.

Exemplary two-compartment dosage forms are shown below:

amount, parts by weight

Active agent compartment Preference is given to More preferably

PGE₁ 0.025-10 0.05-0.5

2- (N, N-dimethylamino) 0.025-100.05-2.5

Dodecyl propionate HCl

Lactose 1-502.5-10

Inert agent compartment

Hydroxypropyl methylcellulose 0.05-2.51-6

Polysiloxane antifoaming agent 0.001-50.1-2

Hydroxypropyl-beta-cyclodextrin 0.5-251-10

Water (deionized or U.S.P.) 5-7520-60

5-7520-60 parts of ethanol

Preservatives such as methyl paraben, propyl paraben, benzalkonium chloride, benzathine chloride and the like may also be included if desired.

Another two-compartment dosage form is also represented as follows:

amount, parts by weight

Active agent compartment

PGE₁ 0.2

2- (N, N-dimethylamino) -propionic acid dodecyl ester HCl 2.5

Non-aqueous ethanol, USP 5

Inert agent compartment

Guar gum 2.5

Lauric acid ethyl ester 3

Water, USP, in 0.1M KH₂PO_yNF 100

Buffering to pH5.5, appropriate amount

Sodium hydroxide, appropriate amount, pH5.5

For casting containing PGE₁An exemplary two-part composition of the film is shown below.

Amount, parts by weight

Preference is given to More preferably

Part A

PGE₁ 0.025-10 0.05-0.5

2- (N, N-dimethylamino) -0.025-100.05-2.5

Dodecyl propionate HCl

Hydroxypropyl-beta-cyclodextrin 0.05-251-10

Part B

Hydroxypropyl methylcellulose 0.05-251-6

Polyethylene glycol 8000 powder 0.05-250.5-5

Polysiloxane antifoaming agent 0.001-50.1-2

Hydroxypropyl-beta-cyclodextrin 0.5-251-10

Water (deionized or U.S.P.) 5-9020-60

5-7520-60 parts of ethanol

Parts a and B were mixed under stirring, the resulting mixture was cast as a thin layer on the surface, and the ethanol was evaporated to produce a thin layer, i.e., a sheet or film, depending on the thickness of the cast thin layer.

The invention is further illustrated by the following examples.

Examples1: two-compartment packaged dosage form

By mixing hydroxypropyl methylcellulose (2 g)；E4M; dow chemical Co., 8000 powder (0.5 g), deionized water (97.5 g) and minor amounts of antifoam(s) ((R))Dow Coming corp., Midland, MI) were mixed together to prepare a viscous topical delivery vehicle.

An aliquot of deionized water (about 25 grams) was first heated to about 80 ℃, and hydroxypropyl methylcellulose (2 grams) was added while stirring until dissolved. A small amount of antifoam was added to the hot solution.

Polyethylene glycol powder (0.5 g; PEG 8000) was added to cold deionized water (50 g) with stirring until dissolved, resulting in a cold polyethylene glycol solution.

The resulting cold and hot solutions were combined with stirring, more deionized water was added to the combined solution (approx 100 g), and the resulting solution was placed in an ice bath and cooled to 30 ℃ with continued stirring. The pH of the resulting solution was measured to be 6.25.

The solution is suitable as a component of an inert agent compartment in a two-compartment dosage form. Ethanol may be added to make a solution suitable for casting sheet-like unit doses such as films or sheets.

By mixing dry prostaglandin E₁(0.018 g) was mixed with dodecyl 2- (N, N-dimethylamino) -propionate (0.12 g) to prepare the active agent compartment ingredients.

The active ingredient prepared as described above was then mixed with 3 grams of the inert composition described above and ethanol (3 grams) was added.

In this way, a clear, viscous gel suitable for topical or intrameatal administration is obtained. The pH of the resulting gel was measured to be 4.5.

Example 2:comprising PGE₁And a skin permeation enhancer

A portion of the clear gel prepared as described in example 1 was spread on a glass plate using a 6-mil film spreader and then dried for several hours until a film was produced. Upon addition of a small amount of water (100 mg), a 1-inch square film reconstituted a clear gel in about 15 seconds.

Example 3: comprising PGE₁Film of (2)

Handle PGE₁The powder (0.024 g) was mixed with an aqueous solution having the following components:

hydroxypropyl methylcellulose 0.06 g

PEG 8000 powder 0.015 g

2.925 g of deionized water

Nonaqueous ethanol 3 g

Then prepared according to the same method as described in example 1 above. Mixing PGE₁The resulting composition with the aqueous solution is shaken vigorously for 15-30 seconds until PGE₁Until dissolved in the solution.

The resulting solution was poured into a glass dish and then dried under ambient conditions for about 3.5 hours. Obtaining a substantially uniform dispersion of PGE-containing in the glass plate₁A film of (2).

Example 4: comprising PGE₁And 2- (N, N-dimethylamino) -dodecyl propionate films

PGE was prepared by the method of example 3₁(0.024 g) and dodecyl 2- (N, N-dimethylamino) -propionate (0.03 g) were dissolved in an aqueous solution containing the following components:

hydroxypropyl methylcellulose 0.06 g

PEG 8000 powder 0.015 g

Deionized water 2.9 g

Nonaqueous ethanol 3 g

The resulting solution was poured into a glass pan, spread with a 6-mil film spreader, and then dried for about 3.5 hours. Obtaining a substantially uniform dispersion of PGE-containing in the glass plate₁And 2- (N, N-dimethylamino) -dodecyl propionate. The film is readily miscible with water.

Claims (2)

1. A packaged multicomponent dosage form comprising a sealed active agent compartment and a sealed inert agent compartment, said sealed active agent compartment comprising from about 0.025 to about 10 parts by weight prostaglandin E₁About 0.025 to about 10 parts by weight of dodecyl 2- (N, N-dimethylamino) -propionate hydrochloride, and about 0.05 to about 25 parts by weight of hydroxypropyl-beta-cyclodextrin, said sealed inert compartment comprising about 0.05 to about 25 parts by weight of hydroxypropyl methylcellulose, about 0.05 to about 25 parts by weight of polyethylene glycol 8000, about 0.001 to about 5 parts by weight of an antifoaming agent, about 0.5 to about 25 parts by weightAmounts of hydroxypropyl-beta-cyclodextrin, about 5 to about 90 parts by weight water, and about 5 to about 75 parts by weight ethanol, wherein upon mixing, casting onto a surface and drying of the contents of the active agent compartment and the inert agent compartment, the dosage form is formed to contain prostaglandin E₁The film of (1).

2. A packaged multicomponent dosage form comprising a sealed active agent compartment and a sealed inert agent compartment, said sealed active agent compartment comprising from about 0.05 to about 0.5 parts by weight prostaglandin E₁About 0.05 to about 2.5 parts by weight of dodecyl 2- (N, N-dimethylamino) -propionate hydrochloride, and about 1 to about 10 parts by weight of hydroxypropyl-beta-cyclodextrin, and the sealed inert compartment comprises about 1 to about 6 parts by weight of hydroxypropyl methylcellulose, about 0.5 to about 5 parts by weight polyethylene glycol 8000, about 0.1 to about 2 parts by weight antifoam, about 1 to about 10 parts by weight hydroxypropyl-beta-cyclodextrin, about 20 to about 60 parts by weight water, and about 20 to about 60 parts by weight ethanol, wherein upon mixing, pouring onto a surface, and drying the contents of the active and inert compartments, the dosage form is formed to contain prostaglandin E₁The film of (1).