Patent Description:
Microemulsions are used as vehicles for drug delivery. This system can be used by various routes like topical, oral, buccal, sublingual, nasal, vaginal, rectal and intravenous. Advantages of microemulsions are as follows:.

Along with these advantages there are some serious limitations of this drug delivery system. Being fluid in nature, maintaining dose uniformity, handling and transportation are difficult to manage in microemulsions. Although presence of surfactants and co-surfactants impart sufficient stability to this dispersed system, it is affected by environmental conditions like pH, temperature etc..

Hence, to make microemulsions useable for therapeutic purpose, it is necessary to make a drug delivery system from such microemulsions which have dose uniformity, convenience in handling, storage stability and suitability to different routes of administration.

In practical terms, a solid dosage form is preferable to a liquid dosage form in respect of convenience, ease of handling and accurate dosing. Hence, attempts have been made to encapsulate microemulsions in soft gelatine capsules. However, limitation with this kind of delivery is that it can be used only for oral route and not for any other route of administration The dispersed systems in the form of liquids are more prone to instability and excipient incompatibility. Many researchers have attempted to develop powder, re-dispersible emulsion-derived formulations known as dry emulsion from these fluid microemulsions by removing water from water in oil microemulsion, using water soluble or insoluble carriers, by rotary evaporation, lyophilisation or spray drying. However, all of them have some or the other drawback. Common drawback is that the resulting loss of water results in loss of activity of some Active Pharmaceutical Ingredients. This includes, for example, without limitation, macromolecules, particularly enzymes which are sensitive to changes in pH, loss of water, loss of three-dimensional structure. This also includes, without limitation, thermolabile Active Pharmaceutical Ingredients, for example, Ketorolac tromethamine, Doxylamine succinate, tetracycline, misoprostol, methylcobalamine, Cholecalciferol, serratiopeptidase, etc..

<NPL>) lyophilized an amphotericin B containing lecithin-based o/w microemulsion. But the final formulation was an oily cake and was intended to be used after reconstitution in water. The reconstitution involved addition of measured quantity of water and stirring using magnetic stirrer. After this processing microemulsions were obtained. So, the work was done to reduce fluidity of microemulsions and not to convert fluid dosage form to solid dosage form while retaining microemulsion properties.

<CIT>) disclosed a pharmaceutical composition comprising a poorly soluble drug, in powder or microgranular form, comprising an oil/water/oil double microemulsion incorporated into a solid support constituted by a microporous inorganic substance or by an adsorbent colloidal inorganic substance or by a cross-linked swellable in water polymer, wherein said drug is dissolved or dispersed in one or more of the phases of said microemulsion. The composition according to claim <NUM>, formulated with pharmaceutically acceptable excipients or diluents, for use in capsules, pills, sachets and suspensions by incorporation of the o/w/o microemulsion of stage d) into a support in the form of a powder by slowly adding said microemulsion to said support in powder form, maintaining said support under constant mixing/agitation in an equipment selected from high efficiency of mixing granulators, extruders and fluid bed granulators. The solid microporous carrier included cross linked PVP, silica, silicates, zeolytes, alumina, activated carbon, colloidal silica, magnesium trisilicate, argil, magnesium oxide, talc, CMC starch, CMC cellulose, polystyrene, polymethylmethacrylate etc..

Hong et al (<CIT>) disclose a cyclosporin solid-state microemulsion comprising a solidified product consisting essentially of a cyclosporin microemulsion dispersed in an enteric carrier. The enteric polymer containing material was one or more chosen from the group consisting of aqueous methacrylic polymers, hydroxypropyl methylcellulose phthalates, cellulose acetate phthalate and sodium alginate. Here, cyclosporin microemulsion is added to the solution of the enteric carrier and mixed to make it homogeneous. The solution was then evaporated slowly at low temperature under reduced pressure to remove the solvent completely. Cyclosporin solid-state microemulsion film produced was powdered, and formulated into pharmaceutical preparations, that is, capsule, powder, granule and tablet according to conventional methods. The intermediate product is obtained as film, which was powdered, and formulated using conventional methods into the final pharmaceutical dosage form that is other than a film comprising, without limitations, capsule, powder, granule and tablet. Moreover, in this work instead of liquid state microemulsion, a "cyclosporin solid-state microemulsion" i.e. a "solidified product of microemulsion pre-concentrate containing cyclosporin" is used in the sense that they can form microemulsion spontaneously after being dissolved in such external phases as water, etc. Thus, the products of Hong et al do not contain a microemulsion in its liquid form/state.

<CIT>) relates to film products and methods of their preparation that demonstrate a non-self-aggregating uniform heterogeneity. Desirably, the films disintegrate in water and may be formed by a controlled drying process, or other process that maintains the required uniformity of the film. Desirably, the films contain at least one active agent, which may be administered to a user topically, transmucosally, vaginally, ocularly, aurally, nasally, transdermally, or orally.

<CIT>) relates to steroid hormone delivery systems and methods of preparing the same. In particular, the steroid hormone delivery systems provided include a primary construct having one or more hydrophobic steroid hormone esters in the form of a liposome, a lipid particle, a micelle, an emulsion or a niosome which is then formulated into a secondary construct for administration.

Retaining compatible solvent at proper pH and other conditions in the microemulsion is needed to retain stability and activity of several pharmaceutical actives, including but not limited to, peptides and enzymes. Hence, a drug delivery system is needed wherein it is a solid dosage form but micro-emulation ingredient in it is not in a dehydrated solid form.

The invention comprises a ready to use film dosage form comprising microemulsion of an Active Pharmaceutical ingredient wherein the microemulsion is embedded in the thin polymeric matrix by immobilization in its original state without removal of water contained in the microemulsion, wherein the moisture content of the film is at least equal to the moisture bound in the emulsion component.

According to an embodiment, the microemulsion may be embedded or immobilized in a thin polymeric matrix that is water soluble.

According to an embodiment, the microemulsion may be embedded in the thin polymeric matrix as a double microemulsion.

According to an embodiment, a micro-emulsion of an Active Pharmaceutical ingredient being capable of being absorbed through mucosal route may be added in a therapeutically effective quantity.

According to an embodiment, microemulsion, wherein the microemulsion may be a water-in-oil (w/o) microemulsion or an oil-in-water microemulsion.

According to an embodiment, the active ingredient that is capable of being absorbed through mucosal route may comprise macromolecules that degrade in gastrointestinal tract or have poor permeability through the biological membranes. The macromolecule that degrades in gastrointestinal tract may be one or more selected from the group consisting of insulin, teriperatide, calcitonin, glucagon, somatostatin, leptin, erythropoietin and antibodies.

The film dosage form may further contain a macromolecule penetration/absorption enhancer.

The active ingredient may be selected from drugs selected, one or more, from the group consisting of Haloperidol, aceclofenac, meloxicam, etoricoxib, fenofibrate, itraconazole, tacrolimus, cyclosporine A, glimipiride, gliclazide, carvedilol, fexofenadine, and zolpidem.

According to an embodiment, the film may be bioadhesive, enabling mucosal administration of drugs.

According to an embodiment, the film dosage form upon dissolution/dispersion of the film produce a micro-emulsion.

In one embodiment, the film dosage form of this invention comprises one or more of features selected from the group consisting of foldable, flexible, non-tacky, fast dissolving or fast dispersing, bioadhesive and enabling mucosal administration of drugs. The said mucosal route comprises one or more selected from the group buccal, sublingual, nasal, rectal and vaginal route.

This invention also comprises a process of making ready to use film dosage form comprising microemulsion of a therapeutically active ingredient immobilized in a thin polymeric matrix comprising steps of forming a film forming dispersion containing film forming polymers, excipients and microemulsion of active pharmaceutical ingredient, casting the same in the form of a film and drying of the cast of the film being carried out by means of drying conditions that suit to retain stability of the active pharmaceutical ingredient.

In one embodiment, the drying conditions are selected that achieves drying of the film retaining the moisture trapped in the microemulsion embedded in the polymeric film. The drying conditions that achieve drying of the film retaining the moisture trapped in the microemulsion embedded in the polymeric film are selected, without limitation, from the group consisting of (a) use of mild heat for thermostable drugs, and (b) carrying out (i) film casting and drying without the need of heat, or (ii) freeze drying for thermolabile drugs. In the process of this invention, the microemulsion is incorporated in liquid state within a range of from a trace quantity to up to <NUM>% of the mass of the film. In the process of this invention, the micro-emulsion in the film forming emulsion may be stabilized by the gels formed upon removal of water during drying.

For the purpose of this specification, microemulsions are defined as a thermodynamically stable, fluid, transparent dispersion of oil and water stabilized by an interfacial film of amphiphillic molecules known as surfactants. Micro-emulsion may be "oil-dispersed in-water" or "water dispersed-in-oil".

This invention comprises a ready to use film dosage form comprising microemulsion of Active Pharmaceutical Ingredients. In one aspect, the film dosage forms of this invention comprise microemulsion of Active Pharmaceutical Ingredients immobilized in thin polymeric matrix. In a further aspect of this invention, the film dosage forms of this invention comprise microemulsion of Active Pharmaceutical Ingredients immobilized by embedding in thin polymeric matrix. In a still further aspect of this invention, the film dosage forms of this invention comprise microemulsion of Active Pharmaceutical Ingredients immobilized by embedding in thin polymeric matrix wherein they contain moisture that is equal to the moisture contained in the microemulsion before adding the same to the film forming emulsion. The fact that micro-emulsions retain their liquid form in the film is evident from the observation that when a film that does not contain microemulsion is dissolved in water, it dissolves completely without leaving behind any particles suspensed in water; whereas when a film that contains microemulsion embedded/immobilized in it is dissolved in water, the microemulsion is detected in the water in colloidal form. Another evidence also comes from the observation that sublingual film of this invention containing insulin was seen to lower blood sugar, which is not possible unless the microemulsion remains in its original form in the film after making the film. Usually, due to water content of the micro-emulsion, the films containing microemulsion in embedded / immobilized form contain additional moisture content that corresponds to the water content of the micro-emulsion immobilized therein. Thus, this invention comprises a pharmaceutical microemulsion in its liquid form immobilized in a thin polymeric matrix of a ready to use film dosage form. In this embodiment, this invention comprises a product which exhibits advantages of both, film and microemulsion. It is an embodiment of this invention that the films of this invention are water soluble, which are also perceived to have same meaning, for the purpose of this invention, as water dissolvable or water dispersible.

In one embodiment the resulting films are foldable, flexible, non-tacky, fast dissolving and upon the dissolution/dispersion produces microemulsion.

In another embodiment of this invention, this film dosage form incorporating microemulsion added in liquid state and further stabilized, can be cut into desired size containing an accurate amount of dose per piece. This makes accurate delivery of dosage convenient.

In a further embodiment, the film dosage form incorporating microemulsion is bioadhesive, enabling buccal, sublingual, nasal, rectal, vaginal routes of administration of drugs.

In another embodiment, the film dosage form incorporating microemulsion comprises a water-in-oil (w/o) microemulsion. In this embodiment, the drugs that may be incorporated in the microemulsion includes, without limitations, insulin, teriperatide, calcitonin, glucagon, somatostatin, leptin, erythropoietin, etc. in another embodiment, vaccines capable of being absorbed through mucosal route are incorporated in the orally dissolving thin film dosage form incorporating Microemulsion. These are the drugs that are not absorbed through gastrointestinal tract since they degrade when ingested. Addition of macromolecule penetration/absorption enhancers, such as, including but not limited to in topical, transdermal, transmucosal dosage forms such as creams, patches, suppositories etc. is common; and addition of the same may also be done in the film dosage forms of this invention.

In another embodiment, the film dosage form incorporating microemulsion in liquid state comprises a oil in water (o/w) microemulsion. In this embodiment, the drugs that may be incorporated in the microemulsion includes, without limitation, poorly water soluble drugs like Haloperidol, meloxicam, etoricoxib, fenofibrate, itraconazole, tacrolimus, cyclosporine A, zolpidem etc..

in a further embodiment, the microemulsion incorporated in the film dosage form of this invention comprises a pharmaceutical Active / drug in therapeutically effective quantity.

In still another embodiment of the film dosage form incorporating microemulsion in liquid state comprises incorporation of the microemulsion from a trace quantity to up to <NUM>% of the mass of the film.

This invention also comprises a process of making a film dosage form incorporating microemulsion in liquid state wherein drying of final film forming dispersion is done by using means that suit to retain stability of the pharmaceutical active/drug. Thus, in one further embodiment, mild heat is used for thermostable drugs, and freeze drying is used for thermolabile drugs. In a further embodiment, for incorporating thermolabile drugs, film casting and drying is done without the need of heat.

This invention also comprises a process of making a film dosage form incorporating microemulsion in liquid state of w/o (water-in-oil) wherein the process comprises a step of preparing a double emulsion, w/o/w (water-in-oil-in-water) of microemulsion in the film forming dispersion. Without getting bound to any theory, it is considered that the double emulsion is considered as providing stability to the product.

This invention also comprises a process of making a film dosage form incorporating microemulsion in liquid state of o/w type (Oil-in-Water type) wherein the process comprises a step of gelating/gelling the microemulsion in the film forming dispersion. Without getting bound to any theory, it is considered that gelating/gelling the microemulsion is considered as providing stability to the product. In one embodiment of this invention, HPMC used as film forming agent acts as gelating/gelling agent.

In one embodiment of this invention the thin film dosage form incorporating microemulsion can be made orally dissolving and can be consumed orally without the need for water.

In another embodiment, the film dosage form incorporating microemulsion in liquid state enables administration of macromolecules that degrade in gastrointestinal tract is done using other routes through mucous membrane. The other routes enabling administration through mucous membrane includes, without limitations, sublingual, buccal, nasal, vaginal, rectal routes etc..

Without getting bound to the theory, it is contemplated that process steps followed for making the films of this invention achieve stabilization of these emulsions by embedding in the polymeric matrix wherein the small droplets of dispersed phase surrounded by surfactant molecules retains their identity and integrity. The said process steps include addition of o/w microemulsion to the highly viscous solution of film forming polymer, adjusting the fluidity to that required for casting a film if required, by adding additional water and drying the film under mild drying conditions such that a good film is formed but the immobilized micro-emulsion does not dry up to make the Active Pharmaceutical Ingredients of the microemulsion inactive.

Mild drying conditions include, without limitation, drying at room temperature below <NUM>, including at a temperature ranging from <NUM>° - <NUM>, freeze drying etc..

A polymeric gelling agent acts as gelling agent for stabilizing dispersed phase of microemulsion. In illustrative examples, HPMC (Hydroxypropyl Methyl Cellulose) have been used as a gelling agent. However, alternative polymeric gelling agents may also be used in place of HPMC, including, without limitation, acacia, alginic acid, bentonite, Carbopols® (now known as carbomers), carboxymethylcellulose. ethylcellulose, gelatin, hydroxyethylcellulose, hydroxypropyl cellulose, magnesium aluminum silicate (Veegum®), methylcellulose, poloxamers (Pluronics®), polyvinyl alcohol, sodium alginate, tragacanth, and xanthan gum. The resulting solution is dried at low temperature ranging from <NUM>° to <NUM>° to <NUM> or by freeze drying depending on the temperature sensitivity of the Active Pharmaceutical ingredient added to the film. In the case of thermolabile Active Pharmaceutical Ingredients, the films are dried using freeze drying process. Surfactants may also be used to keep the microemulsion dispersed in the film forming emulsion. Tween <NUM> is used in the illustration in this specifictaion; but any other surfactant may be used, including, without limitation, benzalkonium chloride, benzethonium chloride, sodium or potassium oleate, triethanolamine stearate, sodium lauryl sulfate, sodium dioctyl sulfosuccinate, sodium docusate, sorbitan esters (Spans®), polyoxyethylene derivatives of sorbitan esters (Tweens®), glyceryl esters, labrasol, etc..

in one embodiment, the film dosage form incorporating microemulsion in liquid state is packed as Unit Dose in simple packaging means. The simple packaging means include, without limitations, a pouch packing or a strip packing. It may be appreciated here that incorporation of microemulsions in liquid form in a ready to use film, the competitive advantages of microemulsions over other dosage forms are retained. Shortcomings of vaccine delivery by oral route, for example polio vaccine, which is in liquid state, get overcome when they are administered through other mucosal routes. Problems of the oral vaccines which are involved in storage, transportation, cool-chain and administration to a child without spillage during administration on account of the resistance of the child to drink it, regurgitation etc. can be overcome by incorporating the same in the film dosage form of this invention.

In a further embodiment of an orally dissolving thin film dosage form incorporating microemulsion in liquid state, bioavailability of protein and peptide drugs through oral route can potentially be increased by using suitable penetration enhancers in the microemulsion.

It is obvious that the packaging of the orally dissolving thin film dosage form incorporating microemulsion in liquid state does not need sophisticated packaging system as is required in the case of metered sprays etc..

The invention is illustrated by following non-limiting example. Any obvious variation or equivalent of it is considered and intended to be included in the scope of this disclosure. The below example shall make all other variations suggested above obvious to a person skilled in the art and can be achieved by routine experimentation.

Solution A was prepared by mixing Labrasol, Span <NUM> and Propylene glycol and to this Oleic acid was added.

Insulin loaded water-in-oil (w/o) microemulsion of Insulin was prepared by mixing Insulin, Span <NUM> and propylene glycol in <NUM>, <NUM> and <NUM> grams respectively. This is then added to <NUM> of oleic acid. To this mixture <NUM> of water is added slowly.

Particle size of Insulin Loaded w/o emulsion had particles of size in the range of <NUM> to <NUM>.

An orally dissolving thin film dosage form incorporating microemulsion in liquid state containing w/o microemulsion of insulin was made by using following steps:.

Efficacy of Insulin administered as microemulsion though sub-lingual film.

The Insulin loaded sub-lingual films of Example <NUM> were administered to four diabetic human volunteers by sublingual route at fasting stage and this stage was maintained during the study period. Each film contained dose of insulin equivalent to <NUM> IU. and blood glucose levels were measured at <NUM>, <NUM> and <NUM> hours. Reduction in blood glucose levels was observed in the range of <NUM>±<NUM>/dl.

Example <NUM>: Preparation of film dosage form containing no microemulsion and size of particles after dissolution in water. Example <NUM> is not a part of invention; the example illustrates the effect of the invention as the example illustrates what happens when film dosage form is prepared without microemulsion.

Claim 1:
A ready to use film dosage form
characterised by comprising microemulsion of an Active Pharmaceutical ingredient
wherein the microemulsion is embedded in the thin polymeric matrix by immobilization in its original state without removal of water contained in the microemulsion,
wherein the moisture content of the film is at least equal to the moisture bound in the emulsion component.