CA2516863C - Poloxamer emulsion preparations - Google Patents

Abstract

An emulsion composition comprising: an aqueous component, a non-ionic block copolymer, and an oil wherein the copolymer comprises at least 10% by weight of the composition.

Description

"Poloxamer Emulsion Preparations"

Field of the Invention This invention relates to microemulsions and compositions useful in a variety of pharmaceutical and personal care products and applications. In particular, it provides microemulsions and compositions useful for topical and/or mucosal application of water insoluble or sparingly soluble active agents to oesophageal, otic, vaginal, rectal or ophthalmic surfaces or for application to the epidermis of an animal (such as skin in human) and/or to treat disorders and imperfections of the skin. It also provides a method for making the microemulsions and compositions comprising water insoluble or sparingly soluble active agents.

Background Art Many of the active agents in pharmaceutical and cosmetic preparations comprise oils or are immiscible or insoluble in water. It can be difficult to deliver an effective amount of these active agents in order to provide the desired therapeutic effect, due to their lack of water solubility. It is therefore often desirable to provide such agents in water-based compositions (eg. for oral administration, topical application, intravenous injection, intramuscular injection, subcutaneous injection etc). One of the methods for preparing such compositions is to form an emulsion.
An emulsion is a heterogeneous system consisting of at least two immiscible liquids (such as a water phase and an oil phase), one of which is dispersed in the other in the form of droplets, with continuous and discontinuous phases. The discontinuous phase is referred to variously as the dispersed or internal phase, whereas the phase in which the dispersion occurs is referred to as the continuous or external phase. When water is the continuous phase, the emulsion is referred to as oil-in-water (OM), and when oil is the continuous phase, the emulsion is referred to as water-in-oil (WIO). OM emulsions are the most frequently used emulsions. However, W/O emulsions are desirable for many applications and would be more, extensively used if problems with instability could be overcome.

Macroemulsions are defined as being formed by high shear mixing and normally having particles of 1 micron to 10 microns in size. Such emulsions are difficult to achieve and possess minimal stability, as the oil and water components separate into distinct phases over time. In addition, the droplet size of the macroemulsion increases with time. Various methods have been developed to stabilize such emulsions, such as the addition of additives such as emulsifiers and finely divided solids.

In contrast, microemulsion systems consisting of oil, water, and appropriate emulsifiers can form spontaneously (i.e. form with minimal agitation) and are therefore thermodynamically stable. This level of thermodynamic stability is highly desirable, but seldom achieved. Microemulsion systems theoretically have an infinite shelf life under normal conditions -without separating, in contrast to the limited life of macroemulsions. In addition, the size of the droplets in such microemulsions remains constant and is typically less than 150 nm (in general between 10-50 nm) and the microemulsion has very low oil/water interfacial tension.

Emulsions such as microemulsions are important for the development of new and effective active agent delivery systems that allow water insoluble or sparingly soluble active agents to be provided in aqueous solutions appropriate for human use. The preparation of such microemulsions represents a major technological hurdle for pharmaceutical delivery systems as one must choose materials that are biocompatible, non-toxic, clinically acceptable and form stable microemulsions.
Furthermore, many of the known emulsion formulations suffer from an inability to ensure a controlled and prolonged release of the active agent at the desired site as they have a very short retention time at the tissue to which they are applied, due to being readily washed away or degraded. This inability is particularly undesirable, since most biologically active agents must remain at the desired site for a prolonged period in order to be effective.

In view of the above, there is a need to provide emulsion formulations for delivery of active agents that are multi-purpose and can be applied to, for example, topical or mucosal tissues. Such emulsions should preferentially have high bioadhesion capability to ensure contact for a prolonged time. Further they should preferentially be able to carry a high amount of active agent to the site of application for a controlled and prolonged release to the desired tissue.

Although stable emulsion preparations have been described, these compositions typically require the use of high temperatures to melt all ingredients of the oil phase to uniformly disperse the particles of one phase through the particles of the other one. Microemulsions are usually formed at temperatures in excess of 75 C, typically about 90 C, and the composition is then cooled slowly over a period of hours or days to room temperature in order to create the emulsion. For large batches this is a costly and time consuming procedure. There is also the risk that the emulsions will be overheated resulting, for example, in the degradation of some of the ingredients.

Another method by which stable emulsions may be prepared is via the use of surfactants or emulsifiers. Typically, surfactants and emulsifiers for the preparation of emulsions are selected from the group consisting of hydrophilic surfactants and mixtures thereof. To function as a surfactant, a compound must necessarily include polar or charged hydrophilic moieties as well as non-polar lipophilic (hydrophobic) moieties; that is, a surfactant compound must be amphiphilic. An empirical parameter commonly used to characterize the relative hydrophilicity and hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value). Surfactants with lower HLB
values are more lipophilic or hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions. Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable. It should be appreciated that the HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical and cosmetic emulsions.

A group of compounds that have been successfully used as surfactants in the production of macro- and microemulsions are the block copolymers of ethylene oxide and propylene oxide, the poloxamers. A number of these compounds have the unusual property that they become liquid when chilled, but harden when warmed, a characteristic known as thermo-reversibility. Such thermo-reversibility is useful in pharmaceutical compounding wherever it is desirable to handle a material in a fluid state, but performance is preferably in a gelled or more viscous state. Such compounds can be drawn into a syringe for accurate dose measurement or easily applied from a bottle or squirted from a dispenser when cold. When the poloxamer warms to body temperature (eg. when applied to skin or mucosal surfaces) it thickens to a suitable consistency to facilitate proper inunction and adhesion.

The desired gelling temperature can be regulated by adjusting the concentration of the block copolymer, with the lower copolymer concentrations giving higher gelling temperatures. Concentrations of the copolymer of at least 18% to 20%
by weight are needed to produce a composition which exhibits such a transition at commercially or physiologically useful temperatures. However, it has been found that incorporating high concentrations of copolymer causes the composition to become extremely viscous or "gelatinised" and solutions containing 18% to 20%
by weight of poloxamer typically have high viscosity even in the "liquid"
phase, so that these solutions can not function under conditions where low viscosity, free-flowing is required prior to transition. For this reason, typical copolymer emulsions usually contain less than 10% copolymer.

Active Agents Active agents are chemical materials or compounds which, when administered to an organism (human or animal, generally human) induce a desired pharmacologic effect. Many of the active agents in pharmaceutical and cosmetic preparations comprise oils or are immiscible or insoluble in water. An example of such an active agent is Tea Tree Oil (TTO).

TTO is isolated by distilling the oil from the stems and leaves of the paperbark tree Melaleuca alternafolia. TTO has medicinal properties including antimicrobial, antiviral, anti-inflammatory and antifungal characteristics. Additionally, TTO
provides a soothing sensation when in contact with a person's skin. However, the properties of TTO can only be exploited by formulating delivery systems suitable to the various conditions required. When TTO products, in the form of aqueous creams, are exposed to air, the TTO component oxidates and some of the chemical components can change their characteristics, affecting the medicament's effectiveness and safety. The presence of many of the emulsifying agents used to solubilize TTO in water also inhibit or inactivate the activity of TTO.
As a gel suspension, TTO tends to separate from the gel base formula, particularly when the suspension contains concentrations of TTO higher than 2%, a process accentuated by changes in temperature (eg. temperatures over 30 C) and/or applying physical shear forces, such as kneading the gel suspension.

To deliver an effective amount of TTO, it is desirable to apply the oil in a form that will both remain in contact with the skin for an extended period of time and deliver the highest concentration of TTO possible. Microemulsion formulations are therefore highly desirable as they are thermodynamically stable.

This invention has as its objective the formation of safe and effective pharmaceutical microemulsion delivery systems that can be manufactured without the need for the high temperature preparation. Other aims and aspects of the present invention will be apparent from the following description of the present invention.

Summary of the Invention According to the present invention there is provided a composition or more specifically a microemulsion for delivery of water-insoluble active agents, comprising: an aqueous component and a non-ionic block copolymer, and at least an oil that is the active agent or has a water-insoluble active agent dissolved therein.

In the present invention, the term "emulsion" includes both macroemulsions and microemulsions.

Compositions of the present invention will desirably possess bioadhesive or mucoadhesive properties. Preferentially, the composition will be in the form of a liquid or a gel. Most preferably, the microemulsion composition will exist as a gel or will be a liquid that is capable of gelatinising upon contact with dermal or mucosal tissue.

According to a second embodiment, the invention provides a microemulsion or a composition for delivery of water-insoluble active agents, comprising an aqueous component and a non-ionic block copolymer, a hydrophilic, non-ionic short chain fatty acid emulsifier, and at least a oil that is the active agent or has a water insoluble active agent dissolved therein.

According to a third embodiment, the invention provides a method for preparing the microemulsion composition, comprising the steps of:
(a) Mixing a copolymer with an aqueous solution at a suitable temperature to substantially dissolve the copolymer in the aqueous solution; and (b) Mixing, at cold temperature, an oil that is the active agent or has a water-insoluble active agent dissolved therein, with the aqueous copolymer solution prepared in step (a) to form a microemulsion.

According to a fourth embodiment, the invention provides a method for preparing the microemulsion composition, comprising the steps of.
(a) Mixing a copolymer with an aqueous solution at a suitable temperature to substantially dissolve the copolymer in the aqueous solution;
(b) Mixing a hydrophilic, non-ionic short chain fatty acid emulsifier with an oil that Is the active agent or has a water-insoluble active agent dissolved therein, at a low temperature to form an oil mixture; and (c) Mixing the solution prepared in step (a) with the solution prepared in step (b) at a low temperature to form a microemulsion.

Also provided herein are microemulsion compositions formed by the above methods.

According to another aspect of the present invention, there Is provided an emulsion composition comprising: an aqueous component, a non-ionic block copolymer, and an oil wherein the copolymer comprises at least 10% by weight of the composition, and wherein the composition is thermoreversibie.

-6a-According to a further aspect of the present invention, there is provided an emulsion composition comprising: an aqueous component, a non-ionic block copolymer, a hydrophilic, non-ionic short chain fatty acid emulsifier, and an oil wherein the copolymer comprises at least 10% by weight of the composition, and wherein the composition is thermoreversible.

According to another aspect of the present invention, there is provided a method for preparing an emulsion composition, comprising the steps of.
(a) Mixing a copolymer with an aqueous solution at a suitable temperature to substantially dissolve the copolymer in the aqueous solution; and (b) Mixing, at cold temperature, an oil that is an active agent or has a water-Insoluble active agent dissolved therein, with the aqueous copolymer solution prepared in step (a) to form an emulsion;
wherein said composition comprises at least 10% by weight of the copolymer.

According to a further aspect of the present invention, there is provided a method for preparing an emulsion composition, comprising the steps of.
(a) Mixing a copolymer with an aqueous solution at a suitable temperature to substantially dissolve the copolymer in the aqueous solution;
(b) Mixing a hydrophilic, non-ionic short chain fatty acid emulsifier with an oil that is an active agent or has a water-insoluble active agent dissolved therein, at a low temperature to form an oil mixture; and (c) Mixing the aqueous solution prepared in step (a) with the oil mixture prepared in step (b) at a low temperature to form an emulsion;
wherein said composition comprises at least 10% by weight of the copolymer.

-6b-According to another aspect of the present invention, there is provided a method for preparing an emulsion composition, comprising the steps of:
(a) Mixing a copolymer with an aqueous solution at a suitable temperature to substantially dissolve the copolymer in the aqueous solution; and (b) Mixing, at a temperature less than about 15 C, an oil that is an active agent or has a water-insoluble active agent dissolved therein, with the aqueous copolymer solution prepared in step (a) to form an emulsion;
wherein said composition comprises at least 10% by weight of the copolymer.

According to a further aspect of the present invention, there is provided a method for preparing an emulsion composition, comprising the steps of:
(a) Mixing a copolymer with an aqueous solution at a suitable temperature to substantially dissolve the copolymer in the aqueous solution;
(b) Mixing a hydrophilic, non-ionic short chain fatty acid emulsifier with an oil that is an active agent or has a water-insoluble active agent dissolved therein, at a low temperature to form an oil mixture; and (c) Mixing the aqueous solution prepared in step (a) with the oil mixture prepared in step (b) at a temperature less than about 60 C to form an emulsion;
wherein said composition comprises at least 10% by weight of the copolymer.

According to another aspect of the present invention, there is provided an emulsion composition comprising: an aqueous component, a non-ionic block copolymer, and an oil wherein the copolymer comprises at least 15% by weight of the composition.

-6c-According to a further aspect of the present invention, there is provided an emulsion composition comprising: an aqueous component, a non-ionic block copolymer, a hydrophilic, non-ionic short chain fatty acid emulsifier, and an oil wherein the copolymer comprises at least 15% by weight of the composition.

Composition of the invention will have a wide variety of applications. When applied topically to the dermal layer of an animal the compositions may include agents to promote bodily attractiveness or to mask the physical manifestations of a disorder or disease, in lieu or in addition to the treatment of a physical disorder.

The same agent may have either a cosmetic or pharmaceutical effect, depending upon the amounts used and the manner of administration.

In another aspect of the invention, compositions of the invention may be incorporated into other compositions to impart thickening properties to the final composition. Such thickening properties include enhanced overall viscosity, as well as a desirable viscosity response with temperature. The composition may be useful as a thickener in pH ranges where other thickeners are not effective.

In addition, compositions of the invention may be incorporated into other compositions to impart emolliency to the composition. In this respect the composition may also act as a film-forming bioactive agent after it has been applied to the skin or other mucosal membrane. This film-forming bioactive agent may be used as a barrier to prevent water loss from the skin while treating biological challenges.

Other aspects and advantages of the invention will become apparent to those skilled in the art from a review of the ensuing description.

Detailed Description of the Invention General Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described.
It is to be understood that the invention includes all such variation and modifications. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in the specification, individually or collectively and any and all combinations or any two or more of the steps or features.

The present invention is not to be limited in scope by the specific embodiments described herein, which are intended for the purpose of exemplification only.
Functionally equivalent products, compositions and methods are clearly within the scope of the invention as described herein.

No admission is made that any of the references cited herein constitute prior art or are part of the common general knowledge of those working in the field to which this invention relates.

Throughout this specification, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

Other definitions for selected terms used herein may be found within the detailed description of the invention and apply throughout. Unless otherwise defined, all other scientific and technical terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which the invention belongs.

Description of the Preferred Embodiment The present invention provides a microemulsion composition comprising at least 10% by weight of a copolymer that preferentially has thermo-reversible properties. Copolymer levels of this magnitude exceed, to the best of the applicant's knowledge, those found in other oil-copolymer based microemulsion.
When the copolymer used in the microemulsion is thereto-reversible, oil-copolymer combinations may be prepared at a cold temperature. The applicant has found, however, that the combination of an emulsifier with the oil before addition of the copolymer surprisingly allows the microemulsion to be prepared at a low temperature, According to the present invention there is provided a composition or more specifically a microemulsion for delivery of water-insoluble active agents, comprising: an aqueous component and a nonionic block copolymer, and at least an oil that is the active agent or has a water-insoluble active agent dissolved therein.

Microemulsions as described herein will comprise an amount by weight of block copolymer of about 10% to about 50% by weight, more preferably the amount by weight block copolymer will be between about 10.1% and 40% by weight of the emulsion while an amount by weight of the block copolymer between any of the following ranges will be highly desirable: 10.5% to 35%, 11% to 30%, 12% to 25%, 13% to 20% or 14% to 18% by weight of the emulsion. Thus, as an illustration of the invention, the block copolymer may comprise 15% by weight of the emulsion.

In addition to the block copolymer being present in the aforementioned weight ranges in the microemulsion, it will also desirably be a thermo-reversible copolymer.

In a preferred embodiment of the invention, the microemulsion or composition will possess bioadhesive or mucoadhesive properties. Such properties will be consistent with the microemulsion or composition being prepared in either a liquid or more preferably a gel form. When prepared in this manner the microemulsion or composition will be useful for topical and/or mucosal application of water insoluble or sparingly soluble active agents to oesophageal, otic, vaginal, rectal or ophthalmic surfaces, or for application to the epidermis of an animal (such as skin in human) and/or to treat disorders and imperfections of the skin. Desirably, the microemulsion or composition will either exist as a gel or will be prepared in such a manner that it is capable of gelatinising upon contact with dermal or mucosal tissue.

When. preparing a microemulsion in accordance with the first embodiment of the invention, ideally, the oil and the thermo-reversible copolymer will be mixed at a cold temperature. When this is done at a cold temperature at the weight ranges specified herein the composition forms a stable microemulsion capable of application to dermal or mucosal tissue.

In a second embodiment, the invention provides a composition or more specifically a microemulsion for delivery of water-insoluble active agents, comprising: an aqueous component and a non-ionic block copolymer, a hydrophilic non-ionic short chain fatty acid emulsifier and at least an oil that is the active agent or has a water-insoluble active agent dissolved therein.

When preparing a microemulsion in accordance with the second embodiment of the invention, ideally, the oil and the emulsifier will be mixed and then applied to the thermo-reversible copolymer. When this is done at a low temperature at the weight ranges specified herein the composition rapidly forms a stable microemulsion capable of application to dermal or mucosal tissue.

The copolymer for use In the present invention is preferably a block copolymer of ethylene oxide and propylene oxide (poloxamer) preferably those represented by the formula:

HO(C2H4O)a(C3HSO)b(C2H40)aH
Where 'b' is between 15 and 67 and 'a' is between 2 and 130, and the total proportion of 'a' units amounts to from 20% to 90% by weight of the poloxamer.
The molecular weight of the poloxamer ranges from preferably about 1,000 to 20,000 and it will preferentially have thermo-reversible properties. By way of example only the block copolymer may be poloxamer 407, such as that sold as Pluronico F127 (BASF Corporation) or Synperonic''M PE/F127 (Unigema).

According to the invention the preferred emulsifier is a fatty acid component with a polyethoxylated side chain. For example, suitable emulsifiers might be Laureth-4, Laureth-9, Laureth-23, PPG-26-Buteth-26/PEG-40 Hydrogenated castor oil or PEG-40 Hydrogenated castor oil. When such emulsifiers are used in the invention the amount by weight of the emulsifier will vary generally from about 0.5% to about 50% by weight of the microemulsion.

The physico-chemical characteristics of the present invention make the microemulsion suitable as a delivery vehicle for water insoluble or sparingly soluble active agents. It is particularly welt-suited for transdermal or transmucosal delivery.
In this respect the oil phase may comprise oils commonly used in the food, cosmetic and pharmaceutical industries for example, oils of natural or synthetic origin, long chain alcohols, glyceryl esters of fatty acids or fatty esters of monohydric alcohols. The esters and alcohols can be straight or branch chained, saturated or unsaturated and liquids at room temperature. The oil phase may also contain active agents that are soluble in or miscible with the oil phase.

The oil of the present invention may have inherent pharmaceutical properties and constitute the active agent of the microemulsion and/or may contain dissolved active agents that are soluble or miscible in the oil. The active agents may include, but are not limited to, antimicrobials (such as antibiotics, antifungals and antivirals), anti-inflammatories, antihistaminics, antidepressants, anaesthetics antineoplastics, enzymes, cardiovascular agents, polynucleotides, genetic material, viral vectors, immunoactive agents, imaging agents, immunosuppressive agents, peptides, proteins etc and combinations thereof. Pharmaceutically effective amounts of the selected active agents may be determined using techniques well known in the art.

Preferentially the amount by weight of the oil used in the microemulsion will comprise from about 0.1% to about 80% by weight of the emulsion, more preferably 1% to 30% by weight of the emulsion, with a range of 3% to 15% by weight of the emulsion being highly desirable. In an illustration of the invention the oil will constitute about 6% of the total weight of the emulsion.

In a highly preferred form of the invention the oil is tea tree oil (TTO).
Where the active agent is TTO the microemulsion will have microbicide activity. Such a composition can be used to treat for example; diseases such as sexually transmitted disease (eg. HIV) by vaginal delivery; impetigo and cold sores by topical preparation, elimination of MRSAs by intranasal application and diseases such as otitis media, otitis externa, acne, periodontitis, gingivitis, paronychia, onychomycosis and secondary infections in connection with operations, dermatitis, burns, etc.

According to a third embodiment, the invention provides a method for preparing the microemulsion composition, comprising the steps of:
(a) Mixing a copolymer with an aqueous solution at a suitable temperature to substantially dissolve the copolymer in the aqueous solution; and (b) Mixing, at cold temperature, an oil that is the active agent or has a water-insoluble active agent dissolved therein, with the aqueous copolymer solution prepared instep (a) to form a microemulsion.
According to step (a) in the method the co-polymer is mixed with an aqueous solution at a suitable temperature to substantially dissolve the copolymer in the aqueous solution. Dissolution of the co-polymer with an aqueous solution will occur almost instantaneously at temperatures of around 6 C. Alternatively, the co-polymer may be mixed with the aqueous solution at room temperature if left over night with semi-continuous or continuous stirring.

As used herein "cold temperature" refers to temperatures less than about 15 C, preferably from about 4 C to about 12 C and most preferably less than about 10 C.

According to a fourth embodiment, the invention provides a method for preparing the microemulsion composition, comprising the steps of:
(a) Mixing a copolymer with an aqueous solution at a suitable temperature to substantially dissolve the copolymer in the aqueous solution;
(b) Mixing a hydrophilic, non-ionic short chain fatty acid emulsifier with an oil that is the active agent or has a water-insoluble active agent dissolved therein, at a low temperature to form an oil mixture; and (c) Mixing the solution prepared in step (a) with the solution prepared in step (b) at a low temperature to form a microemulsion.

As used herein "Low temperature" refers to temperatures less than about 60 C, preferably from about 15 C to about 40 C, more preferably from about 20 C to about 30 C and most preferably at about room temperature. The ability to manufacture microemulsions of the present invention at these temperatures is highly significant as it provides a distinguishing feature from most other methods of manufacture of microemulsions which demand the microemulsions be made at about 90 C.

It has been found that a microemulsion composition prepared according to the present invention has the surprising feature that the addition of the oil/emulsifier mixture to the aqueous poloxamer solution at room temperature changes the thermo-reversible nature of the poloxamer by altering the temperature at which.
solidification occurs. This effect is most evident at high ratios of poloxamer to oil.
Microemulsion compositions of the present invention provide clear, colourless gels that are particularly well suited to pharmaceutic and personal care applications. For example, very little residue is formed upon dehydration, which may be important in some applications, such as in optically applied pharmaceutics. An additional advantage of the microemulsion composition of the invention is that they remain clear and translucent before and after the triggering environmental change. These characteristics of the reversibly gelling microemulsion composition make it well suited for use in pharmaceutic compositions.

The practical advantage of this behaviour of the microemulsion composition is that the formulation can be administered as a flowing liquid at ambient temperatures.
Upon contact with body tissues it viscosifies, thus changing its flow properties, and more importantly, its clearance from the site of application is dramatically reduced.

Those skilled in the art will appreciate that microemulsion composition of the present invention may be utilized for a wide variety of pharmaceutic and personal care applications. To prepare a pharmaceutic composition, an effective amount of pharmaceutically active agent(s) which imparts the desirable pharmaceutic effect is incorporated into the reversibly gelling composition of the present invention.
When prepared according to the method of the invention the microemulsion composition can further include one or more pharmaceutically acceptable additives, excipients carriers and diluents. Such additives, excipients carriers and diluents include, without limitation, water, saline, ethanol, dextrose, glycerol, lactose, dextrose, sucrose sorbitol, mannitol, starches, gum acacia, calcium phosphates, alginate, tragacanth, gelatine, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose,, water syrup, methyl cellulose, methyl and propylhydroxybenzoates, talc, magnesium stearate and mineral oil or combinations thereof. The formulations can additionally include lubricating agents, pH buffering agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents, antifoaming agents, polymers, antioxidants, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof. The particular selection of constituent that can be included in the compositions described herein will generally depend on the type of preparation.

In addition, an acid or a base may be incorporated into the microemulsion composition to facilitate processing, to enhance stability, or for other reasons.
Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminium hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminium silicate, synthetic aluminium silicate, synthetic hydrocalcite, magnesium aluminium hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris (hydroxymethyl) aminomethane (TRIS) and the like. Also suitable are bases that are salts of a pharmaceutically acceptable acid, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like. Salts of polyprotic acids, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used. When the base is a salt, the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, and the like. Preferred cations include sodium, potassium, lithium, magnesium, calcium and ammonium.

Suitable acids are pharmaceutically acceptable organic or inorganic acids.
Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like.

Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid and the like.

When the hydrophilic active agent is subject to enzymatic degradation, the present compositions can also include an enzyme inhibiting agent. Enzyme inhibiting agents are shown for example, in Bernskop-Schnurch (1998),"The use of inhibitory agents to overcome enzymatic barrier to perorally administered therapeutic peptides and proteins," Controlled Release 52: 1-16.

Generally, inhibitory agents can be divided into the following classes:
inhibitors that are not based on amino acids (such as P-aminobenzamidine, FK-448, camostat mesylate and sodium glycocholate); amino acids and modified amino acids (such as aminoboronic acid derivatives and n-acetylcysteine); peptides and modified peptides (such as bacitracin, phosphinic acid dipeptide derivatives, pepstatin, antipain, leupeptin, chymostatin, elastatin, bestatin, hosphoramindon, puromycin, cytochalasin potatocarboxy peptidase inhibitor, and amastatin);
polypeptide protease inhibitors (such as aprotinin, Bowman-Birk inhibitor, soybean trypsin inhibitor, chicken egg white trypsin inhibitor, chicken ovoinhibitor, and human pancreatic trypsin inhibitor); complexing agents (such as EDTA, EGTA, 1,10-phenanthroline and hydroxychinoline); and mucoadhesive polymers and polymer-inhibitor conjugates (such as polyacrylate derivatives, chitosan, celluiosics, chitosan-EDTA, chitosan-EDTA-antipain, polyacrylic acid-bacitracin, carboxymethyl cellulose-pepstatin and polyacrylic acid-Bowman-Birk inhibitor).
The choice and levels of the enzyme inhibitor are based on toxicity, specificity of the proteases and the potency of inhibition.

A discussion of particular applications and formulations follows.

Esophageal, oral cavity and buccal applications: One indication for the use of this microemulsion composition would be to provide a suitable vehicle for delivering a pharmaceutic effect within the oesophageal lining. In this respect the mucoadhesive properties of the microemulsion composition of the invention make that composition desirable for controlling and facilitating a pharmaceutic effect to the oesophageal lining. The shear sensitivity of the microemulsion composition could also be taken advantage of in applications in which a liquid treatments is sprayed under high shear conditions onto the oral cavity, where the solution adheres and viscosifies to provide a reservoir for antibacterial agents, such as chlorohexadine, or a breath freshener.

Ophthalmic applications: Most ophthalmic drugs are applied to the eye, typically to the precorneal area. The most common dosage form is a liquid drop. Drug bioavailability is generally low because liquid formulations are quickly cleared from the eye by tearing and blinking, resulting in the need for frequent dosing and uneven drug delivery.

The microemulsion composition described herein provides a new vehicle for achieving greater bioavailability of topically administered insoluble or partially soluble ophthalmic active agents. Formulations containing such active agents can be applied as drops that viscosify or gel upon contact with eye. Since gelling can be accomplished with low concentrations of the polymer, blurring can be minimized upon drop instillation.

When used in this manner the microemulsion composition would preferentially be used for delivering bioactive materials, such as anaesthetics, mydriatics and cycloplegics, antimicrobial agents (antibacterial, antifungal, antiviral), anti-inflammatory agents, agents for the treatment of glaucoma, ocular decongestants, diagnostic agents, and wound healing agents.

Nasal applications: Microemulsion compositions of the invention may also be used for delivery of drugs to the nasal cavity. Nasal drug delivery has been considered as an alternative to parenteral routes of administration of drugs that demonstrate low oral bioavailability. In order to increase the bioavailability of nasally administered drugs, efforts have been made to increase the residence time of formulations in the nasal cavity. Nasal delivery of drugs can offer advantages over other methods of delivery, including rapid systemic absorption, lower dosing, more rapid onset of desired therapeutic effects, and improved pharmacokinetics. In addition, it provides an alternative route for administering peptide drugs, which generally have low bioavailability via the oral route and are normally administered parenterally.

Microemulsion composition would potentially be useful for delivering agents such as decongestants, antihistamines, anti-osteoporosis agents, hormones, antineoplastic agents, Parkinsonism drugs, etc. The composition may also be used for the application of vaccines, such as those against the influenza virus.
Vaginal/rectal applications: Microemulsion compositions of the invention are also indicated for the delivery of bioactive agents (such as TTO) to the vaginal or the rectal cavity. These delivery routes have been considered as an alternative to parenteral routes of administration of bioactive agents that demonstrate low oral bioavailability. In order to increase the bioavailability of vaginally or rectally administered bioactive agents, efforts have been made to increase the residence time of formulations in these cavities. These routes offer advantages over other methods of delivery, including rapid systemic absorption, lower dosing, more rapid onset of desired therapeutic effects, and improved pharmacokinetics.

Veterinary applications: Microemulsion compositions of the invention may also be useful in the treatment of not only human conditions but in providing treatments for animal care. For veterinary products, the microemulsion compositions is indicated for the preparation of topical dermal products, such as antibacterials, antifungals, antipruritics, and antiseborrheia, antiodor, and antiseptic/wound healing preparations. Otic products would include ear cleaners with or without actives, such as, antifungals. Ophthalmic products would include eye moisturizers or antimicrobial preparations.

Personal Care Applications: Microemulsion compositions of the invention may also be particularly well suited for cosmetic applications. For example, very little residue is formed upon dehydration, which may be important in some applications, such as in topically applied cosmetics. An additional advantage of the composition of the invention is that it remains clear and translucent above and below the critical temperature or pH. These characteristics of the microemulsion compositions make it well suited for use in cosmetic compositions.

To prepare a cosmetic composition, an effective amount of cosmetically active agent(s) that imparts the desirable cosmetic effect is incorporated into the microemulsion composition of the present invention. Preferably the selected agent lends itself to a homogeneous dispersion through out the microemulsion composition. It is contemplated as within the scope of the invention that the reversibly gelling composition compositions of the present invention may be prepared under sterile conditions.

Exemplary cosmetic and personal care applications, in which the microemulsion composition may be used include, but are not limited to, baby products, bath preparations, eye makeup preparations, fragrance preparations, noncolouring hair preparations, colour cosmetics, hair colouring preparations, makeup preparations, manicuring preparations, oral hygiene products, shaving preparations, skin care preparations, and suntan preparations such as suntan creams, gels and lotions, indoor tanning preparations.

The cosmetic composition may be in any form. Suitable forms include but are not limited to lotions, creams, sticks, roll-ons formulations, mousses, aerosol sprays, pad-applied formulations, and film-forming formulations.

Preparation of the above-named cosmetic compositions and others may be accomplished with reference to any of the cosmetic formulation guidebooks and industry journals which are available in the cosmetic industry. These references supply standard formulations which may be modified by the addition or substitution of the microemulsion composition of the present invention into the formulation.
Suitable guidebooks include Cosmetics and Toiletries Magazine, Vol. 111 (March, 1996); Formular Ideas for Personal Care; Croda, Inc, Parsippany, N. J. (1993);
and Cosmeticon: Cosmetic Formular, BASF.

Preparation of pharmaceutic compositions may be accomplished with reference to any of the pharmaceutic formulation guidebooks and industry journals which are available in the pharmaceutic industry. These references supply standard formulations which may be modified by the addition or substitution of the microemulsion compositions of the present invention. Suitable guidebooks include Pharmaceutics and Toiletries Magazine, Vol. 111 (March, 1996);
Formular Ideas for Personal Care; Croda, Inc, Parsippany, N. J. (1993); and Pharmaceuticon: Pharmaceutic Formular, BASF.

Exemplary drugs or therapeutics delivery systems which may be administered using the aqueous responsive compositions of the invention include, but are in no way limited to, mucosal therapies, such as esophageal, otic, rectal, buccal, oral, vaginal; and urological applications; topical therapies, such as wound care, skin care and teat dips; and intravenous/subcutaneous therapies, such as intramuscular, intrabone (e.g., joints), spinal and subcutaneous therapies, tissue supplementation, adhesion prevention and parenteral drug delivery.
The term "animal" used herein Is taken to mean mammals, such as primates, including humans, sheep, horses, cattle, pigs, dogs, cats, rats, mice; It also includes, birds, reptiles, and fish.

As will be understood by those skilled in the art, two or more pharmaceutical agents may be combined for specific effects. The necessary amounts of active ingredient can be determined by simple experimentation.

The Invention is now described with reference to the following examples which are presented for the purpose of illustration only and are not limiting of the invention.

Best Mode(s) for Carrying Out the Invention Example 1 -- Manufacture of Vaginal gel B
Part A
Add 15.6 g Lutrol F127 to 84.4 g deionised water, which is held at a temperature of 60C. Combine with slow mixing to reduce air entrapment and place under vacuum for a few minutes to remove any trapped air after Lutrol F127 is dissolved.

PartB
Add 0.20 g fumaric acid to 5.0 g alcohol by stirring until dissolved. Cool the solution to 10 C.

Part C
Combine 3.0 g Tea Tree oil, 5.0 g propylene glycol and 2.0 g undecylenic acid and mix to dissolve all ingredients. Cool the solution to 100C.

Gel preparation Place 84.8 g of the Lutrol F127 solution of Part A in a vessel and hold at 100C.
Slowly add 5.2 g of the fumaric acid solution of Part B and mix well, maintaining the solution at 100C. Slowly add 10.0 g of the Tea Tree oil solution of Part C
with gentle stirring and whilst maintaining the solution at 100C. If necessary, remove any aeration by placing the gel under vacuum. Allow the gel to warm to room temperature.
Example 2 -- Manufacture of Poloxamer gel 8C
Part A
Heat 76.3 g deionised water to 60-65 C, slowly add 16.7 g poloxamer 407 and stir gently for approximately 2 hours or until all the poloxamer is dissolved and the solution thickens. Allow the solution to cool to room temperature and leave overnight. Adjust the pH of the solution to 4.2-5.0 with potassium hydroxide.

Part B
Combine 3.0 g of PPG-26-Buteth-26/PEG-40 Hydrogenated castor oil, 3.0 g Tea Tree oil and 1.0 g d-alpha tocopheryl acetate with gentle mixing.

Gel Preparation Add 7.0 g of the Tea Tree oil solution of Part B to 93.0 g of the room temperature poloxamer solution of Part A. Mix with gentle stirring until the solution thickens.
Example 3 -- Manufacture of Poloxamer gel 8E
Part A
Heat 73.4 g deionised water to 60-65 C, slowly add 16.0 g poloxamer 407 and stir gently for approximately 2 hours or until all the poloxamer is dissolved and the solution thickens. Allow the solution to cool to room temperature and leave overnight. Adjust the pH of the solution to 4.2-5.0 with potassium hydroxide.
Part B
Combine 2.0 g Laureth-4, 1.0 g of Laureth-23, 6.0 g Tea Tree oil and 1.0 g d-alpha tocopheryl acetate, 0.1 g of 1.0 M (1 U/g) retinyl palmitate and 0.5 g panthenol. Heat solution to 40-45 C with gentle mixing to dissolve all components.

Gel Preparation Add 10.6 g of the Tea Tree oil solution of Part B to 89.4 g of the room temperature poloxamer solution of Part A. Mix with gentle stirring until the solution thickens.
Example 4 -- Testing of gel formulations against microorganisms The products were tested using macrodilution and microdilution methods, using a 96-well microtitre tray. The highest concentration of gel tested was 50%
product.
The test organisms were Staphylococcus aureus NCTC 6571, Escherichia coli NCTC 10418, Pseudomonas aeruginosa NCTC 10662 and the yeast Candida albicans ATCC 10231.

Inocula were prepared in double strength Mueller Hinton broth, resulting in a final concentration of single strength broth and organisms at a final concentration of approximately 5 x 105 cfu/mL. Tests were incubated at 37 C for 24 hours. After this time, trays were subcultured by removing 5 L from tray wells and spot inoculating onto Mueller Hinton agar. All subcultures were incubated for 24 hours and the colonies counted.

The minimum inhibitory concentration (MIC) was defined as the lowest concentration of product resulting in the maintenance or reduction of the inoculum. The minimum cidal concentration (MCC) was defined as the lowest concentration of product resulting in the death of 99.9% of the inoculum.

MIC/MCC
Product TTO%
C. albicans S. aureus E. coil P. aeruginosa Vaginal gel B 3.0 <0.78/<0.78 <2.1/<2.1 4.2/4.2 33.0/33.0 Poloxamer gel 8C 3.0 -- >1.5/>1.5 -- >1.5/>1.5 Poloxamer gel 8E 6.0 0.38/0.38 0.75/0.75 <0.19/<0.19 >3.0/>3.0

Claims (61)

1. A method for preparing an emulsion composition, comprising the steps of:
(a) mixing a copolymer with an aqueous solution at a suitable temperature to substantially dissolve the copolymer in the aqueous solution; and (b) mixing, at a temperature less than about 15°C, an oil that is an active agent or has a water-insoluble active agent dissolved therein, with the aqueous copolymer solution prepared in step (a) to form an emulsion;
wherein said composition comprises at least 10% by weight of the copolymer.

2. The method of claim 1 wherein the oil is mixed with the aqueous copolymer solution prepared in step (a) at a temperature between about 4°C to 12°C.

3. The method of claim 1 wherein the oil is mixed with the aqueous copolymer solution prepared in step (a) at a temperature less than about 10°C.

4. A method for preparing an emulsion composition, comprising the steps of:
(a) mixing a copolymer with an aqueous solution at a suitable temperature to substantially dissolve the copolymer in the aqueous solution;
(b) mixing a hydrophilic, non-ionic short chain fatty acid emulsifier with an oil that is an active agent or has a water-insoluble active agent dissolved therein, at a low temperature to form an oil mixture; and (c) mixing the aqueous solution prepared in step (a) with the oil mixture prepared in step (b) at a temperature less than about 60°C to form an emulsion;

wherein said composition comprises at least 10% by weight of the copolymer.

5. The method of claim 4 wherein the aqueous solution prepared in step (a) is mixed with the oil mixture prepared in step (b) at a temperature between about 15°C to 40°C.

6. The method of claim 4 wherein the aqueous solution prepared in step (a) is mixed with the oil mixture prepared in step (b) at a temperature between about 20°C to 30°C .

7. The method of claim 4 wherein the aqueous solution prepared in step (a) is mixed with the oil mixture prepared in step (b) at room temperature.

8. The method of claim 1 or 4 wherein the copolymer is dissolved at a temperature of about 6°C.

9. The method of claim 1 or 4 wherein the copolymer is dissolved at room temperature with semi-continuous or continuous stirring.

10. An emulsion composition formed by the method of claim 1.

11. An emulsion composition formed by the method of claim 1 comprising:
an aqueous component, a non-ionic block copolymer, and an oil wherein the copolymer comprises at least 10% by weight of the composition.

12. An emulsion composition formed by the method of claim 4.

13. An emulsion composition formed by the method of claim 4 comprising:
an aqueous component, a non-ionic block copolymer, a hydrophilic, non-ionic short chain fatty acid emulsifier, and an oil wherein the copolymer comprises at least 10% by weight of the composition.

14. The composition of any one of claims 10 to 13 wherein the emulsion is a microemulsion.

15. The composition of any one of claims 10 to 13 wherein the copolymer comprises about 10% to 50% by weight of the composition.

16. The composition of any one of claims 10 to 13 wherein the copolymer comprises about 10.1 % to 40% by weight of the composition.

17. The composition of any one of claims 10 to 13 wherein the composition comprises an amount by weight of the block copolymer between any of the following ranges: 10.5% to 35%, 11 % to 30%, 12% to 25%, 13% to 20% or 14% to 18% by weight of the composition.

18. The composition of any one of claims 10 to 13 wherein the copolymer comprises 15% by weight of the composition.

19. An emulsion composition formed by the method of claim 1 comprising:
an aqueous component, a non-ionic block copolymer, and an oil wherein the copolymer comprises at least 15% by weight of the composition.

20. An emulsion composition formed by the method of claim 4 comprising:
an aqueous component, a non-ionic block copolymer, a hydrophilic, non-ionic short chain fatty acid emulsifier, and an oil wherein the copolymer comprises at least 15% by weight of the composition.

21. The composition of any one of claims 10 to 13 wherein the copolymer comprises a thermo-reversible copolymer.

22. The composition of any one of claims 18 to 20 wherein the copolymer comprises a block copolymer of ethylene oxide and propylene oxide.

23. The composition of claim 22 wherein the copolymer is represented by the formula:

HO(C2H4O)a(C3H6O)b(C2H4O)a H
where 'b' is between 15 and 67 and 'a' is between 2 and 130, and the total proportion of 'a' units amounts to from 20% to 90% by weight of the copolymer.

24. The composition of claim 23 wherein the molecular weight of the copolymer ranges from about 1,000 to 20,000.

25. The composition of claim 22 wherein the copolymer is poloxamer 407.

26. The composition of any one of claims 13 to 15 and 22 wherein the emulsifier is a fatty acid component with a polyethoxylated side chain.

27. The composition of claim 12 or 13 wherein the emulsifier is chosen from the list comprising: Laureth-4, Laureth-9, Laureth-23, PPG-26-Buteth-26/PEG-40 Hydrogenated castor oil, and PEG-40 Hydrogenated castor oil.

28. The composition of claim 12 or 13 wherein the emulsifier comprises about 0.5% to 50% by weight of the emulsion.

29. The composition of any one of claims 10 to 13 wherein the oil is an active agent or has a water-insoluble active agent dissolved therein.

30. The composition of any one of claims 10 to 13 wherein the oil is chosen from the list comprising: long chain alcohols, glyceryl esters of fatty acids and fatty esters of monohydric alcohols.

31. The composition of claim 30 wherein the esters and alcohols are liquids at room temperature.

32. The composition of any one of claims 10 to 13 wherein the oil contains at least one active agent that is soluble in or miscible with the oil phase.

33. The composition of any one of claims 10 to 13 wherein the oil constitutes an active agent of the emulsion.

34. The composition of claim 33 wherein the oil contains at least one active agent that is soluble in or miscible with the oil phase.

35. The composition of any one of claims 32 to 34 wherein the active agent is selected from the group comprising: antimicrobials, anti-inflammatories, antihistaminics, antidepressants, anaesthetics, antineoplastics, enzymes, cardiovascular agents, polynucleotides, genetic material, viral vectors, immunoactive agents, imaging agents, immunosuppressive agents, peptides, proteins and combinations thereof.

36. The composition of claim 35 wherein the antimicrobials are antibiotics, antifungals, or antivirals.

37. The composition of any one of claims 32 to 34 wherein the active agent is present in a pharmaceutically effective amount.

38. The composition of any one of claims 10 to 13 wherein the oil comprises about 1% to 30% by weight of the emulsion.

39. The composition of any one of claims 10 to 13 wherein the oil comprises about 3% to 15% by weight of the emulsion.

40. The composition of any one of claims 10 to 13 wherein the oil comprises 6% by weight of the emulsion.

41. The composition of any one of claims 10 to 13 wherein the oil is tea tree oil (TTO).

42. The composition of claim 41 that has microbicide activity.

43. The composition of any one of claims 10 to 13 wherein the emulsion possesses bioadhesive or mucoadhesive properties.

44. The composition of any one of claims 10 to 13 wherein the emulsion is in the form of a liquid or a gel.

45. The composition of claim 44 wherein the emulsion composition is a gel.

46. The composition of any one of claims 10 to 13 wherein the emulsion composition is a liquid that forms a gel upon contact with dermal or mucosal tissue.

47. Use of the composition of any one of claims 10 to 13 for topical application to the epidermal surfaces of an animal.

48. Use of the composition of any one of claims 10 to 13 for mucosal application to the oesophageal, otic, vaginal, rectal or ophthalmic surfaces of an animal.

49. Use according to claim 47 wherein the composition further comprises agents to promote bodily attractiveness or to mask the physical manifestations of a disorder or disease.

50. Use according to claim 49 wherein the composition also treats a physical disorder.

51. Use of the composition of any one of claims 10 to 13 to impart thickening properties to other compositions.

52. Use according to claim 51 wherein the composition imparts enhanced overall viscosity.

53. Use according to claim 51 wherein the composition imparts a viscosity response with temperature.

54. Use of the composition of any one of claims 10 to 13 to impart emolliency properties to other compositions.

55. Use of the composition of any one of claims 10 to 13 as a film-forming bioactive agent on the skin or other mucosal membrane.

56. A use according to claim 55 wherein the film-forming bioactive agent further acts as a barrier to prevent water loss from the skin.

57. Use of the composition of claim 42 to treat a disease selected from the group comprising: sexually transmitted diseases, HIV, impetigo, cold sores, otitis media, otitis externa, acne, periodontitis, gingivitis, paronychia, onychomycosis and secondary infections, said secondary infections comprising infections in connection with operations, dermatitis or burns.

58. The composition of any one of claims 10 to 13 further comprising one or more pharmaceutically acceptable additives, excipients, carriers or diluents.

59. The composition of any one of claims 10 to 13 wherein the composition further comprises one or more pharmaceutically acceptable acids or bases.

60. The composition of any one of claims 10 to 13 wherein the composition further comprises one or more pharmaceutically acceptable salts of an acid or a base.

61. The composition of any one of claims 10 to 13 wherein the composition further comprises one or more pharmaceutically acceptable enzyme inhibiting agents.