MX2007002487A - Microemulsion&sub-micron emulsion process&compositions - Google Patents

Abstract

There is provided a process for the preparation of an oil in water (O/W) microemulsion or sub-micron emulsion composition for dermal delivery of at least one pharmaceutically active ingredient, the method including the steps of a) Admixing a first part including at least one of the group consisting of animal, mineral or vegetable oils, silanes, siloxanes, esters, fatty acids, fats, halogen compounds or alkoxylated alcohols;and one or more lipophilic surfactants, and a second part including water and at least one hydrophilic surfactant to achieve homogeneity, b) heating the mix of step a) to a phase assembly temperature in the range of 40 - 99°C, preferably 45 - 950C, more preferably 65 - 850C with continuous mixing to obtaina microemulsion or sub-micron emulsion, c) allowing said microemulsion or sub-micron emulsion to cool, and d) adding a third part to said microemulsion or sub-micron emulsion at a temperature between 2°C and said phase assembly temperature, said third part if necessary being premixed and heated until the components are dissolved and including at least one component selected from the group consisting of non-surfactant amphiphilic type compound, surfactant and water with the proviso that when the third part includes water it also includes a non-surfactant amphiphilic type compound and/or surfactant. The phase assembly temperature can be determined visually by the achievement of translucence in the composition or by measures such as conductivity which peaks and then is maintained at a plateau whilst phase assembly occurs. It has been found that whilst if a non-surfactant amphiphilic type compound such as the polyol is added together with the second part as would conventionally be the case, a microemulsion or sub-micron emulsion is not formed, by adding the so called third part, phase assembly occurs at a lower temperature than would be expected and moreover, this phase appears to assist in maintaining the microemulsion or sub-micron emulsion characteristics of the formulation during storage at normal temperatures.

Description

PROCESS AND COMPOSITIONS OF MICROEMULSION AND SUBMICRO EMULSION FIELD OF THE INVENTION The present invention relates to a method for the formulation of microemulsions sub-micro emulsions useful in cosmetic and therapeutic applications in the field of dermatology. In particular, the invention relates to methods of formulating microemulsions and stable sub-micro emulsions containing ingredients that are known to be disturbing to the physical state of the formulation. The invention also relates to cosmetic and therapeutic microemulsion and sub-micron emulsion compositions that arise from these methods. The methods of cosmetic and therapeutic treatment using the microemulsions and sub-micro emulsions are encompassed by the present invention since they are the uses of the compositions arising from the method of formulation in appropriate treatments.

BACKGROUND The size of a particular is critical in its ability to penetrate the skin barrier and therefore in its ability to deliver a pharmaceutically active ingredient for the treatment of local or systemic medical conditions of the patient involved. As the particles become smaller (in particular less than 100 nm), the percentage of exposed surface area of a particle increases in proportion to its total volume when compared to the unrefined material, and therefore increases its potential efficiency. The characteristics of the sub-micron particles in their application for the supply of pharmaceutically active ingredients through the skin barrier can be summarized as follows: Due to the desirable characteristics of the so-called microemulsiones, and sub-micron emulsions, attempts have been made to perfect the means for their manufacture. Essentially, the much higher ratio of emulsifier to dispersed phase is the characteristic that differentiates a microemulsion from a macroemulsion. The intention is to stabilize the phases of oil in water, or vice versa. The nature of the emulsifier (or surfactant) used is clearly of great importance. The oil-in-water micro emulsions are particularly difficult to formulate and, generally speaking, the simple adaptation of the mode, or homogenization means, or the increase in the amount of the present emulsifier will not guarantee the product is a microemulsion. The choice of emulsifier is reported as critical to the success of the formulation (BK: Microemulsion Theory and Practice, Prince, Leon (ed.) Pp33-50, Academic Press, NY, USA, 1977). Water-in-oil systems are made by mixing the oil with the emulsifier, with a little heat if necessary, and then adding water. The amount of water that can be added to a given system of emulsifier and oil may not be high enough for the application being considered. In that case, it becomes necessary to try other emulsifiers. When it is found that the admission of water is allowed, it may be convenient from a processing point of view to add the mixture of emulsifier and oil to the water. Again, heating the system can speed up the mixing process. In the oil, water and emulsifier systems that are capable of forming microemulsions, the order of mixing does not affect the final result. The simplest way to make a microemulsion of oil in water is to mix the oil and the emulsifier and then pour this liquid mixture into the water with moderate agitation. Another technique is to make a crude macroemulsion of the oil and one of the emulsifiers, for example, a soap. When using low volumes of water a gel is formed. This gel is changed to a clear solution by titration with a second surfactant as an alcohol. This system can then be transformed into an opalescent oil-in-water microemulsion of the desired concentration by adding additional water. By far the most common method to make an oil-in-water microemulsion, especially in the trial and error stage, is through the so-called investment process. In actual practice, oils that are susceptible to being microemulsified, that is, "emulsifiable oils", as opposed to those that can be dispersed in micellar solution, are reversed by the slow addition of water from a fluid dispersion of water in oil through a viscoelastic gel stage to a fluid oil in water microemulsion. 100% of the emulsifier can be used in the weight of the oil. After thorough mixing, with heating if necessary, water is added to the mixture in a beaker. This is done in small successive aliquots. If the chemistry is correct, a water dispersion is first formed in clear, transparent oil. This is fluid. As more water is added, approximately in equal volumes of water and oil / emulsifier combination, the system starts to become more viscous. As more water is added, it becomes very viscous, eventually becoming a heavy gel. At this point it is often useful to apply heat to thin the gel and facilitate passage through this stage. With the addition of more water, the gel eventually thins to a fluid-oil oil microemulsion that can be easily identified by its clarity or opalescence. The stages of highly viscous intermediate gel are not microemulsions although sometimes they are referred to, as in the case of oscillation gels used as hair ointments. These systems are actually liquid crystalline phases and they occur due to the particular sequence of mixing used in the formation of the microemulsion. Given the importance of the emulsifier emulsifier for the successful formulation of the microemulsion, systems have been developed to assist in the selection of the emulsifier. One system (Shiroda, K., J. Colloid Interface Sci, 24, 4 (1967)) is based on the temperature at which an emulsifier causes an oil-in-water emulsion to be inverted into a water-in-oil emulsion. It is known as the Phase Investment Temperature System (PIT). It provides information about various oils, phase volume ratios, and the required emulsifier concentration. The system is established in the proposition that the hydrophilic lipophilic balance (the "HLB") of a non-ionic surfactant changes with temperature and that the inversion of the emulsion type occurs when the hydrophilic and lipophilic tendencies of the emulsifier are balanced each. No emulsion is formed at this temperature. The emulsions stabilized with nonionics are in oil-in-water types at elevated temperature. It goes without saying that the use of more than one emulsifier in a composition can positively influence the formulation of a microemulsion. PIT techniques require a significant input of energy in order to achieve a sub-micro emulsion. The process requires high temperature to make the surfactant ethoxylated hydrophobic, so the oil-in-water emulsion is converted into an oil-in-water emulsion, and subsequently, the water-in-oil dispersion is converted to an oil-in-water dispersion. to the subsequent cooling of the formulation. In the end due to the degrading effect that the heat has on certain active ingredients, it would be desirable to reduce the energy requirements of said processes since this would probably reduce the risk of crystallization of the sparingly soluble active ingredients that occurs in the cyclization at normal temperature of the product stored. Microemulsion technology has been the relatively intense research material since the late 1950s when hair gels using technology were developed for the first time. Patent US 6,333,362 (L'OREAL) describes an oil-in-water emulsion of ultrafine foaming wherein the particle size of the oil particles constituting the oil phase varies from 50-1000 nm. The PIT technique is used for the manufacture of the formulation. Example 1 describes a formulation as follows: wherein the sodium lauryl ether sulfate in phase 3 acts as the foaming agent in the supply of product from its pressurized container. To prepare the formulation phases 1 and 2, they were heated separately to 60 ° C and homogenized. Phase 2 was poured slowly, with stirring, over Phase 1 and the mixture was heated to the phase inversion temperature, which was about 85 ° C. The heating was stopped and the unheated Phase 3 was poured and the mixture was allowed to cool while the slow stirring was maintained. Nanoemulsions containing an amphiphilic lipid phase composed of phospholipids, water and oil are known in the art. These emulsions exhibit the disadvantage of being unstable in storage at conventional storage temperatures, that is between 0 and 45 ° C. They lead to yellow compositions and produce rancid odors that develop after several days of storage. An example of said emulsion is described in WO 03/08222 (BEIERDORF AG) In practice there are challenges in the formulation of the microemulsiones. The point at which the composition is inverted from an oil-in-water or water-in-oil formulation, respectively, to a water-in-oil or oil-in-water formulation, known as the "set point" needs to be monitored carefully. If the set point is not reached before the product is poured, the inversion will not occur, and therefore a microemulsion will not be achieved. In particular, high set points can be difficult to achieve and maintain. Additives may be used to reduce the fixation point although these may also have the effect of destabilizing the microemulsion resulting in undesirable alteration of the viscosity of the microemulsion, turbidity, and may also cause loss of the invertible character. In addition, although high levels of emulsifier may be desirable, on the other hand a high emulsifier content could lead to irritation of the user's pile and eyes. Propylene glycol, which is desirably included in dermatological compositions for its ability as a penetration enhancer, is an additive that has been reported as undesirable in microemulsion technology because of its potential to alter or destabilize the formulation. WO 94/08603 (SMITHKLINE BEECHAM CORPORATION) shows how to prevent propylene glycol and other co-surfactants of polyhydroxyl alcohol surfactants due to the processing and stability problems they introduce. Another ingredient that is desirable in dermatological applications is the petrolatum used for its occlusive and emollient properties. However, due to its viscosity it is considered difficult to incorporate in microemulsion formulations. Another challenge in the application of microemulsions to the field of dermatology is the solubilization of the pharmaceutically active ingredients in the formulations. Some pharmaceutically active ingredients are highly soluble in water, or alternatively they are highly soluble in oil. Others are sparingly soluble. A pharmaceutically active ingredient in solution provides better penetration than one in suspension and, both provide better penetration than a drug as a solid. In the case where a pharmaceutically active ingredient is not easily solubilized, the need for an additive such as propylene glycol which can aid in penetration is obvious, although the ease of formation of a microemulsion is inversely reduced. In light of the above, it is an object of this invention to identify methods for formulating microemulsion and sub-micro emulsion formulations that can act as a vehicle for the delivery of a pharmaceutically active ingredient through the skin barrier for cosmetic or therapeutic. It is a secondary object to obtain a means to incorporate one or more microemulsion interruption substances, such as propylene glycol and / or petrolatum within said microemulsion or sub-micro emulsion while maintaining the viscosity, appearance, stability and efficacy of the formulation. Any discussion of the documents, devices, acts or knowledge in this specification is included to explain the context of the invention. It will not be considered as an admission that any information formed part of the prior art basis or of the general knowledge common in the relevant art on or before the priority date of the subject matter in question.

BRIEF DESCRIPTION OF THE INVENTION A process for the preparation of an oil-in-water (O / W) microemulsion or sub-micro emulsion composition is provided for the dermal delivery of at least one pharmaceutically active ingredient, the method including the steps of a) Mixing a first part which includes at least one of the group comprising animal, mineral or vegetable oils, silanes, siloxanes, esters, fatty acids, fats, halogen compounds or alkoxylated alcohols; and one or more lipophilic surfactants, and a second part including water and at least one hydrophilic surfactant to achieve homogeneity, b) heating the mixture from step a) to a phase assembly temperature in the range of 40 -99 ° C, preferably 45-95 ° C, more preferably 65-85 ° C with continuous mixing to obtain an oil-in-water microemulsion or sub-micro emulsion, c) allow the microemulsion or sub-micro-emulsion to be cool, and d) add a third part to the microemulsion or sub-micro emulsion at a temperature between 2 ° C and the phase assembly temperature, a third if necessary is premixed and heated until the components are dissolved and included by at least one component selected from the group comprising non-surfactant amphiphilic type compound, surfactant and water with the proviso that when the third part includes water it also includes a non-tensile amphiphilic compound. Ioactive and / or surfactant. The phase assembly temperature can be determined visually to obtain the translucency in the composition or through measurements such as the conductivity that reaches a peak and is then maintained on a plateau while the phase assembly is presented. It has been found that if a non-surfactant amphiphilic type compound such as the polyol is added together with the second part as would conventionally be the case, a microemulsion or sub-micro emulsion is not formed. However, by adding the aforementioned third part, the phase assembly occurs at a lower temperature than would be expected and furthermore, this phase seems to help maintain the characteristics of the microemulsion or sub-micro emulsion of the formulation during the Storage at normal temperatures. The water phase of the microemulsion or sub-micro emulsion is desirably added in two aliquots; in aliquots more preferably about 70% and 30% by weight of the total water phase. More preferably still, the second aliquot is added after the microemulsion or sub-micro emulsion has been formed, at a temperature substantially lower than the temperature of the first aliquot, and at a rapid rate in order to reduce the overall temperature of the aliquot. the composition preferably below about 60 ° C whereby the structure of the microemulsion or sub-micro emulsion is fixed. A pharmaceutically active ingredient can be suitably added in one or more of the three parts of the formulation during the preparation. The most appropriate incorporation part will depend on the solubility characteristics of the pharmaceutically active ingredient and the preferred release profile of the resulting formulation. The pharmaceutically active ingredient is preferably one that is insoluble or only sparingly soluble in water. Preferably the pharmaceutically active ingredient is one or more water-insoluble compounds selected from the group comprising corticosteroids, desonide, clobetasol, betamethasone, vitamin D analogues and vitamin A analogs. An occlusive agent having the effect of adding quality Emollient to the formulation is also desirably incorporated into the microemulsions or sub-micro emulsions by means of inclusion in the preparation of the first part of the composition. Preferably the occlusive agent is petrolatum.

The microemulsion or sub-micro emulsion resulting from the process is desirably gassed using a suitable propellant to make it available as a foam or mousse. A preferred form of this process for the preparation of a microemulsion or sub-micro emulsion composition for the dermal delivery of at least one pharmaceutically active ingredient, includes the steps of: a) scheduling a first part that includes at least one of the group comprising animal, mineral or vegetable oils, silanes, siloxanes, esters, fatty acids, fats, halogen compounds or alkoxylated alcohols, and one or more lipophilic surfactants up to a temperature of 40-99 ° C, preferably 45-95 ° C, and more preferably 65-85 ° C and mixing until homogeneity, b) a second part that includes water and at least a hydrophilic surfactant agent up to a temperature of 40-99 ° C, preferably 45-95 ° C, and more preferably 65-85 ° C and mixing to achieve homogeneity, c) adding the second part to the first part to a temperature of 40-99 ° C, preferably 45-95 ° C, and more preferably 65-85 ° C with continuous mixing whereby a microemulsion or sub-micro emulsion is formed at a temperature of phase assembly, d) allow the microemulsion or sub-micro emulsion to cool, and e) add a third part to the microemulsion or sub-micro emulsion at a temperature between room temperature and the phase assembly temperature, the third part that has been pre-mixed, and if necessary heated until the components dissolve and include at least a component selected from the group comprising non-surfactant amphiphilic type compound, surfactant and water with the proviso that when the third part includes water it also includes a non-surfactant amphiphilic type compound and / or surfactant. An oil-in-water or sub-microemulsion microemulsion composition is also provided for dermal delivery of at least one pharmaceutically active ingredient which includes an oil phase dispersed through a water phase, said oil phase including at least one of the group comprising animal, mineral or vegetable oils, silanes, siloxanes, esters, fatty acids, fats, halogen compounds or alkoxylated alcohols; and at least one lipophilic surfactant; and the water phase comprising at least one hydrophilic surfactant, water and optionally a non-surfactant amphiphilic compound, the weight ratio of said at least one hydrophilic surfactant to said at least one lipophilic surfactant which is from about 9.0: 1.0 to 2.0: 3.0. Preferably, the composition includes surfactants having an added HLB number between 8.0 and 15.0, more preferably between 10 and 12 and even more preferably between 9.7 and 11.8. More preferably, the lipophilic surfactant has a HLB number of less than 10, and the hydrophilic surfactant has a HLB number of more than 10. The pharmaceutically active ingredient may suitably be in either or both of said oil phases and / or water. The most suitable incorporation phase will depend on the solubility characteristics of the pharmaceutically active ingredient and the preferred release profile of the formulation. The pharmaceutically active ingredient is preferably one that is insoluble or only sparingly soluble in water. Preferably the pharmaceutically active ingredient is one or more water-insoluble compounds selected from the group consisting of corticosteroids, desonide, clobetasol, betamethasone, vitamin D analogues and vitamin A analogues.

An occlusive agent is also desirably incorporated into the microemulsions or sub-micro emulsions in the oil phase of the composition. Preferably the occlusive agent is petrolatum. The microemulsion or sub-micro emulsion is preferably formulated as a foam or "mousse" through the inclusion of a suitable propellant. An oil-in-water or sub-micro-emulsion microemulsion composition is further provided, said composition prepared through the process including the steps of a) mixing a first part including at least one of the group comprising animal, mineral or animal oils. vegetables, silanes, siloxanes, esters, fatty acids, fats, halogen compounds or alkoxylated alcohols; and one or more lipophilic surfactants, and a second part including water and at least one hydrophilic surfactant to achieve homogeneity, b) stage the mixture from step a) to a phase assembly temperature in the range of 40 -99 ° C, preferably 45-95 ° C, more preferably 65-85 ° C with continuous mixing to obtain an oil-in-water microemulsion or sub-micro emulsion, c) allow the microemulsion or sub-micro emulsion to cool, and d) add a third part to the microemulsion or sub-micro emulsion at a temperature between 20 ° C and the phase assembly temperature, the third part if necessary that is premixed and heated until the components are dissolved and includes less one component selected from the group comprising non-surfactant amphiphilic type compound, surfactant and water with the proviso that when the third part includes water it also includes a non-tensile amphiphilic type compound. tivo and / or surfactant. The water phase of the microemulsion or sub-micro emulsion is desirably added in two aliquots; in aliquots of greater preference of about 70% and 30% by weight of the total water phase. More preferably still, the second aliquot is added after the microemulsion or sub-micro emulsion has been formed, at a temperature substantially below the temperature of the first aliquot, and at a rapid rate in order to reduce the overall temperature of the composition preferably below about 60 ° C whereby the structure of the microemulsion or sub-micro emulsion is fixed. A pharmaceutically active ingredient can be incorporated in an appropriate manner in one or more of the three parts of the formulation during the preparation. The most suitable incorporation part will depend on the solubility characteristics of the pharmaceutically active ingredient and the preferred release profile of the resulting formulation. The pharmaceutically active ingredient is preferably one that is insoluble or only sparingly soluble in water. Preferably the pharmaceutically active ingredient is one or more water insoluble compounds selected from the group comprising corticosteroids, desonide, clobetasol, betamethasone, vitamin D analogs and vitamin A analogs. An occlusive agent is also desirably incorporated into the microemulsions or sub-micro emulsions through inclusion in the preparation of the oil phase of the composition. Preferably the occlusive agent is petrolatum. The microemulsion or sub-micro emulsion resulting from the process is desirably gassed using a suitable propellant to be available as a foam or mousse. Preferably, an oil-in-water microemulsion composition or sub-micro emulsion is provided, the composition being prepared through the process including the steps of a) heating a first part including at least one of the group comprising oils animal, mineral or vegetable, silanes, siloxanes, esters, fatty acids, fats, halogen compounds or alkoxylated alcohols, and one or more lipophilic surfactants up to a temperature of 40-99 ° C, preferably 45-95 ° C, and more preferably 65-85 ° C and mixing until homogeneity, b) heating a second part including water and at least one hydrophilic surfactant up to a temperature of 40-99 ° C , preferably 45-95 ° C, and more preferably 65-85 ° C and mix until homogeneous, c) add the second part to the first part at a temperature of 40-99 ° C, preferably 45-95 ° C, and more preferably 65-85 ° C with continuous mixing so that a microemulsion or sub-micro emulsion is formed at a phase assembly temperature, d) cool the microemulsion or sub-micro emulsion, and e) add a third part to the microemulsion or sub-micro emulsion at a temperature between room temperature and the temperature of phase assembly, the third part that has been premixed, and if necessary heated until dissolved and includes at least one selected component from the group comprising amphiphilic type compound no surfactant, surfactant and water with the proviso that when the third part includes water it also includes a non-surfactant amphiphilic type compound and / or surfactant. The invention further provides a method for the medical or cosmetic treatment of a dermal condition which includes applying to the skin of a patient in need of such treatment an effective amount of oil-in-water or sub-micro-emulsion microemulsion composition which includes minus a pharmaceutically active ingredient, which includes an oil phase dispersed through a water phase, the oil phase including at least one of the group comprising animal, mineral or vegetable oils, silanes, siloxanes, asters, fatty acids , fats, halogen compounds or alkoxylated alcohols; and at least one lipophilic surfactant, and the water phase includes at least one hydrophilic surfactant, water and optionally a non-surfactant amphiphilic type compound, the weight ratio of said at least one hydrophilic surfactant to said at least one lipophilic surfactant which is from about 9.0: 1.0 to 2.0: 3.0. A pharmaceutically active ingredient can be suitably incorporated in one or more of the phases of the composition. The most appropriate incorporation phase will depend on the solubility characteristics of the pharmaceutically active ingredient and the preferred release profile of the resulting formulation. The pharmaceutically active ingredient is preferably one that is insoluble or only sparingly soluble in water. Preferably the pharmaceutically active ingredient is one or more water-insoluble compounds selected from the group comprising corticosteroids, desonide, clobetasol, betamethasone, vitamin D analogs and vitamin A analogs. An occlusive agent is also desirably incorporated into the microemulsions or sub-micro emulsions by inclusion in the oil phase of the composition. Preferably the occlusive agent is petrolatum. The microemulsion or sub-micro emulsion is preferably formulated as a foam or "mousse" by the inclusion of a suitable propellant. There is further provided a use of an oil-in-water or sub-micro-emulsion microemulsion composition which includes an oil phase dispersed through a water phase, said oil phase including at least one of the group comprising animal oils , minerals or vegetables, silanes, siloxanes, esters, fatty acids, fats, halogen compounds or alkoxylated alcohols; and at least one lipophilic surfactant, and the water phase includes at least one hydrophilic surfactant, water and optionally a non-surfactant amphiphilic type compound, the weight ratio of said at least one hydrophilic surfactant to said at least one lipophilic surfactant which is from about 9.0: 1.0 to 2.0: 3.0 for the preparation of a cosmetic or medical preparation for the treatment of a dermal condition. Preferably, the composition includes surfactants having an added HLB number between 8.0 and 15.0, more preferably between 10 and 12, and still more preferably between 9.7 and 11.8. More preferably, the lipophilic surfactant has a HLB number of less than 10, and the hydrophilic surfactant has a HLB number of greater than 0. A pharmaceutically active ingredient can be suitably incorporated in one or more of the phases of the composition during the preparation. The most appropriate incorporation phase will depend on the solubility characteristics of the pharmaceutically active ingredient and the preferred release profile of the resulting formulation. Preferably the pharmaceutically active ingredient is one insoluble or sparingly soluble in water. Preferably the pharmaceutically active ingredient is one or more water insoluble compounds selected from the group comprising corticosteroids, desonide, clobetasol, betamethasone, vitamin D analogs and vitamin A analogs. An occlusive agent is also desirably incorporated into the microemulsions or sub-micro emulsions by inclusion in the preparation of the oil phase of the composition. Preferably the occlusive agent is petrolatum. The microemulsion or sub-micro emulsion is preferably formulated as a foam or "mousse" by the inclusion of a suitable propellant.

The invention further provides, in a process for the preparation of an oil-in-water or sub-micro-emulsion microemulsion composition, the use of a third part in the preparation of said composition, said third part including at least one selected component from the group comprising non-surfactant amphiphilic type compound, surfactant and water with the proviso that when the third part includes water it also includes a non-surfactant amphiphilic type compound and / or surfactant compound, said third part is incorporated within the composition Subsequent to the establishment of a microemulsion or sub-micro emulsion formed by an oil phase that includes at least one of the group comprising animal, mineral or vegetable oils, silanes, silicones, esters, fatty acids, fats, halogen compounds or alcohols alkoxylated; and at least one lipophilic surfactant which is emulsified through a water phase including water and at least one hydrophilic surfactant through a temperature-induced phase assembly process.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 is a schematic flow diagram showing a preferred embodiment of the invention in which a microemulsion of cyclohexol propionate free of 0.05% ethanol is prepared. The method is described in detail in Example 6. Figure 2 is a graphic representation of a preferred method of the formulations according to the invention utilizing corticosteroid cyclobetasol propionate. Figure 3 is a timeline of a preferred preparation method of the formulations according to the invention using the corticosteroid desonide.

Figure 4 is a graphical representation of the method illustrated in the timeline of Figure 3. Figure 5 shows the effect on the particle size distribution of the variation of the ratio of the surfactants in betamethasone valerate compositions of according to the invention. Figure 6 shows the conductivity response from the heating of various compositions according to the invention up to the assembly temperature, and then the cooling thereof. Figure 7 is a schematic flow diagram of the process used to produce the material formulation of the clinical treatments described in Example 14.

DETAILED DESCRIPTION OF THE INVENTION In compositions traditionally prepared for dermal delivery of pharmaceutically active ingredients it is conventional to add the pharmaceutically active ingredient and any amphiphilic, non-surfactant type compound, which includes, for example, a solvent for the active ingredient or a polyol which acts as a solvent, emollient or Penetration enhancer to the phase in which they are soluble, before the oil phase and the water phase are mixed together. This results in a product that is an emulsion or dispersion of one phase in the other. Without limitation to theory, it was found that by the addition of a third part, a microemulsion or sub-micro emulsion can be formed which has the advantages described in the preamble of this specification. This is a particularly useful phenomenon where it is desirable to use pharmaceutically active ingredients that tend toward insolubility except in solvents including a polyol and / or alcohol. By effectively reducing the temperature at which the phase assembly is achieved, the active ingredients that are degraded by exposure to temperature are retained more than the prior art formulations. It is therefore considered that the storage life of the formulations according to the invention can be extended compared to the prior art compositions. Without wishing to be bound by theory, it is considered that when non-surfactant amphiphilic components such as propylene glycol, a typical polyol used in detergent formulations due to its ability as a penetration enhancer, and a solvent is present in the water phase, interferes with the formation of assembly or packing of the surfactants present in the composition around the oil particles and prevents the formation of microemulsion size particles. The same is true for phenoxy ethanol, conservative. Through the process of the invention, it is possible to reproducibly produce sub-micron size particles at low temperature in the range of 100-600 nm with most particles that are in the range of 100-200 nm. The exclusion of propylene glycol from the initial water / oil phase mixing seems to allow the surfactants present the ability to pack into a microemulsion structure at a lower temperature than would otherwise be achieved and with the assistance of the manipulation of the temperature, for fixing in place. Through this specification, the term "amphiphilic, non-surfactant type compound" will be considered to include compounds that are miscible with water and other organic excipients, and which may act as a solvent for a pharmaceutically active ingredient not soluble in water, although You may also have other options in the formulations. Examples of compounds that fall within the scope of this term are alcohols that include propylene glycol, dichlorobenzyl alcohol, phenoxyethanol, transcutol P, panthenol; polyols such as glycerin; alkoxylated alcohols including polyethylene glycol of different molecular weight; heterocyclic compounds including methyl pyrrolidine; and aprotic solvents including dimethyl sulfoxide. Preferred amphiphilic compounds, non-surfactants, are phenoxyethanol and propylene glycol. Phenoxyethanol can be present in amounts of up to 2% w / w and propylene glycol is present desirably in amounts of up to 50% w / w, more preferably in amounts of up to 30% w / w, and even more so preferable in amounts up to 25% w / w. Through this specification the term "water-soluble" when used in connection with a pharmaceutically active ingredient will be considered to represent compounds that have significant aqueous solubility and that commonly exhibit low solubility in non-aqueous solvents. The term "water-insoluble" when used in relation to pharmaceutically active ingredients will be considered to represent compounds that do not have appreciable aqueous solubility and that commonly favor hydrophobic solvents. The term "phase assembly temperature" when used throughout this specification shall be taken to represent the temperature at which the maximum translucency of the dispersion is observed when preparing oil-in-water microemulsions or sub-micro emulsions in accordance with the processes described. This temperature point is consistent with the temperature at which tiny particles are assembled. Preferably, in the methods, processes and compositions according to the invention, the oil phase includes an occlusive agent which has the effect of adding an emollient quality to the formulations. A preferred occlusive agent is petrolatum. Although it is present at an ambient temperature as a solid, using the preparation process of the invention, it has been found that the petrolatum can be successfully incorporated into a formulation that is low in viscosity and suitable for pressurized supply. Other occlusive agents that can be incorporated into the compositions and according to the processes of the invention are microcrystalline wax, beeswax, paraffin wax and lanolin wax. Notably, the petrolatum, a preferred occlusive agent is comprised of about 50% w / w of mineral oil and about 50% w / w of microcrystalline wax and paraffin. Desirably, the wax component will not add more than 25% w / w of the total oil phase. Preferably in the methods, processes and compositions of the invention the water phase of the formulation is added in two aliquots; in aliquots more preferably about 70% and 30% by weight of the total water phase. More preferably still, the second aliquot is added after the microemulsion or sub-micro emulsion has been formed, at a temperature substantially below that of the first aliquot, and at a rapid rate to reduce the overall temperature of the composition of preferably below about 60 ° C whereby the structure of the microemulsion or sub-micro emulsion is fixed. The two aliquots can be a homogeneous mixture of all the components in the phase or can be different components of the phase for example water together with non-surfactant amphiphilic type compound and / or surfactant alone. A pharmaceutically active ingredient can be introduced into one or more of the three parts of the preparation with the result that in the microemulsion or sub-micro emulsion according to the invention, the active ingredient can be present in the continuous water phase or the discontinuous oil phase or both. Through appropriate handling, the formulations of the invention can be designed as slow release or delayed release compositions by, for example, placing the active ingredient in the phase in which it is substantially or completely insoluble. When the pharmaceutically active ingredient is introduced in the first part, solvents, co-solvents and coupling agents may also optionally be present. Preferred solvents may include acetyl tributyl citrate, tributyl citrate and other suitable solvents. Coupling agents help to bind or improve the miscibility of oils that are immiscible with the oil phase and help to obtain clarity. Suitable coupling agents according to the invention are organic, non-ionic, virtually insoluble in water, miscible with oily / fatty / lipophilic materials and exhibit solubility for pasty and / or solid fatty / lipophilic materials. Isopropyl myristate is a suitable coupling agent. Others include, but are not limited to, polyglyceryl esters, isocetyl alcohol, octyl methoxycinnamate, octyl dimethyl PABA, tocopheryl acetate, and lanolin alcohols. Preferably the pharmaceutically active ingredient is introduced in the second part, and more preferably is introduced in the third part where it appears that its presence together with the non-surfactant amphiphilic type compound serves to improve the transdermal performance of the composition. An amphiphilic, non-surfactant-type compound also appears to assist in the distribution of the pharmaceutically active agent through the desired phase. In particular, when the pharmaceutically active agent is desirably present in both the oil phase and the water phase, no water-miscible organic solvent is required in the oil phase and neither is an organic solvent miscible with the oil phase required. water in the water phase. As the amount of water miscible organic solvent increases, it is observed that the rate of diffusion of the active agent through the skin barrier is increased. A slower flow is observed when the active is dissolved within the oil phase 2 It contains organic solvent. Particularly in the case where the pharmaceutically active agent is only sparingly soluble in water or insoluble in water, the addition of an increased amount of organic solvent to the water phase could assist in the separation of the pharmaceutically active agent within the water phase. Therefore, when the active agent is present in the continuous water phase, the active agent is available for rapid treatment of the patient's condition. The active agent in the oil phase may be available through other skin diffusion trajectories for longer term treatment regimens. The water phase may also include pH regulators such as, but not limited to, citric acid and potassium citrate, disodium EDTA and tetrasodium EDTA, disodium EDTA and disodium phosphate, and preservatives such as, but not limited to phenoxyethanol and dichlorobenzyl alcohol . When the pharmaceutically active ingredient is included in the water phase, this phase can also include a functional water soluble organic component which includes humectants, solvents for the active ingredient and penetration enhancers. Substances that may be included in the formulations of the invention in the water phase and fall within one or more of these categories include but are not limited to propylene carbonate, transcutol, ethoxydiglycol, polyhydric alcohols such as glycerol, sorbitol and propylene glycol. The pharmaceutically active ingredient can be any chemical substance or combination of chemicals that are registered for the purposes of cosmetic or medical treatment and that are dermally available. The pharmaceutically active ingredients may be present in the composition in different forms, depending on which form produces the optimum delivery characteristics. Therefore, in the case of drugs, it may be in its base or free acid form, or in the form of salts, esters, or any other pharmacologically acceptable derivatives, or as components of molecular complexes, analogs, metabolites or prodrugs. Preferably the active ingredient is a corticosteroid selected from the group comprising betamethasone valerate, clobetasol desonide and propionate or vitamin D or vitamin A analogs. The pharmaceutically active ingredient can alternatively be a drug that is normally delivered via oral, parenteral, percutaneous, perungual or rectal. Other examples of pharmaceutically active ingredients that can be administered by means of the compositions of this invention include, but are not limited to: Cardioactive medicaments, for example, organic nitrates such as nitroglycerin, isosorbide dinitrate, and isosorbide mononitrate; quinidine sulfate; procainamide; thiazides such as bendroflumethiazide, chlorothiazide, and hydrochlorothiazide; nifedipine; nicardipine; adrenergic blocking agents, such as timolol and propranolol; verapamil; diltiazem; captopril; clonidine and prazosin. Androgenic steroids, such as testosterone, methyltestosterone and fluoxymesterone. Estrogens, such as conjugated estrogens, esterified estrogens, estropipate, 17beta estradiol, 17beta-estradiol valerate, equilin, mestranol, estrone, estriol, 17beta-ethinyl estradiol, and diethylstilboestrol. Progestational agents, such as progesterone, 19-norprogesterone, norethindrone, norethindrone acetate, melengestrol, chlormadinone, ethisterone, medroxyprogesterone acetate, hydroxyprogesterone caproate, ethinodiol diacetate, norethynodrel, 17alpha hydroxyprogesterone, dydrogesterone, dimetisterone, ethinyltinrenol, norgestrel, demegestone, promegestone, and megestrol acetate. Drugs that have an effect on the central nervous system, for example sedatives, hypnotics, anti-anxiety agents, analgesics and anesthetics, such as doral, buprenorphine, naloxone, haloperidol, fluphenazine, pentobarbital, phenobarbital, secobarbital, codeine, lidocaine, tetracaine, dyclonine, dibucaine, metocaine, cocaine, procaine, mepivacaine, bupivacaine, etidocaine, prilocaine, benzocaine, fentanyl, and nicotine. Nutritional agents, such as vitamins, essential amino additives and essential fats. Anti-inflammatory agents, such as hydrocortisone, cortisone, dexamethasone, fluocinolone, triamcinolone, medrisone, prednisolone, flurandrenolide, prednisone, halcinonide, methylprednisolone, flurandrenolide, prednisone, halcinonide, methylprednisolone, fludrocortisone, corticosterone, parametasone, betamethasone, ibuprofen, naproxen, fenoprofen , fenbufen, flurbiprofen, indoprofen, ketoprofen, suprofen, indomethacin, piroxicam, aspirin, salicylic acid, diflunisal, methyl salicylate, phenylbutazone, sulindac, mefenamic acid, sodium meclofenamate, tolmetin, and the like. Antihistamines, such as diphenhydramine, dimenhydrinate, perphenazine, triprolidine, pyrilamine, chlorcyclizine, promethazine, carbinoxamine, tripelenamine, brompheniramine, hydroxyzine, cyclizine, meclizine, chlorprenaline, ternaadine, and chlorpheniramine. Respiratory agents, such as theophylline and beta2-adrenergic agonists such as albuterol, terbutaline, metaproterenol, ritodrine, carbuterol, fenoterol, quinterenol, rimiterol, solmefamol, soterenol, and tetroquinol. Sympathomimetics, such as dopamine, norepinephrine, phenylpropanolamine, phenylephrine, pseudoephedrine, amphetamine, propylhexedrine and epinephrine. Myotics, such as pilocarpine, and the like. Cholinergic agonists, such as choline, acetylcholine, methacholine, carbachol, bethanechol, pilocarpine, muscarine, and arecoline. Antimuscarinic or muscarinic cholinergic blocking agents such as atropine, scopolamine, homatropine, metescopolamine, homatropine meililbromide, metanyl, cyclopentolate, tropicamide, .propantelin, anisotropin, dicyclomine, and eucatropine. idriatics, such as atropine, cyclopentolate, homatropine, scopolamine, tropicamide, eucatropine and hydroxyamphetamine. Psychic energizers such as 3- (2-aminopropyl) indole, 3- (2-aminobutyl) indole, and the like. Anti-infectives, such as antivirals, for example acyclovir, allylamines and in particular antibiotics of terbinafine hydrochloride and naftifine hydrochloride, including penicillin, tetracycline, chloramphenicol, sulfacetamide, sulfamethazine, sulfadiazine, sulfamerazine, sulfametizole and sulfisoxazole; antivirals, which include idoxuridine; antibacterials, such as erythromycin and clarithromycin; and other anti-infectives including nitrofurazone and the like. Vitamins such as vitamins A, D and E. Humoral agents, such as prostaglandins, natural and synthetic, for example PGE1, PGF2alpha, and PGF2alpha, and misoprostol PGE1 analogue. Antispasmodics, such as atropine, metantelin, papaverine, cinnaminine, and methscopolamine. Antidepressant drugs, such as isocarboxazid, phenelzine, tranylcypromine, mipramine, amitriptyline, trimipramine, doxepin, desipramine, nortriptyline, protriptyline, amoxapine, maprotiline, and trazodone. Anti-diabetics, such as insulin, and anti-cancer drugs such as tamoxifen and methotrexate.

Anorectic drugs, such as dextroamphetamine, methamphetamine, phenylpropanolamine, fenfluramine, diethylpropion, mazindol, and phentermine. Anti-allergens, such as antazoline, metapirilene, chlorpheniramine, pyrilamine and pheniramine. Tranquilizers, such as reserpine, chlorpromazine, and antianxiety benzodiazepines such as alprazolam, chlordiazepoxide, clorazeptate, halazepam, oxazepam, prazepam, clonazepam, flurazepam, triazolam, lorazepam and diazepam. Antipsychotics, such as thiopropazate, chlorpromazine, triflupromazine, mesoridazine, piperacetazine, thioridazine, acetophenazine, fluphenazine, perphenazine, trifluoperazine, chlorpratixene, thiothixene, haloperidol, bromperidol, loxapine, and molindone. Decongestants, such as phenylephrine, ephedrine, naphazoline, antipyretics, such as aspirin, salicylamide, and the like. Antimigraine agents, such as dihydroergotamine and pizotiline. Drugs to treat nausea and vomiting, such as chlorpromazine, perphenazine, prochlorperazine, promethazine, scopolamine, hiacin hydrobromide, triethylperazine, triflupromazine, and trimeprazine. Anti-malarial, such as 4-aminoquinolines, alpha-aminoquinolines, chloroquine, and pyrimethamine. Anti-ulcer agents such as misoprostol, omeprazole, and enprostil. Peptides and proteins, such as drugs for Parkinson's disease, spasticity, and acute muscle spasms, such as levodopa, carbidopa, amantadine, apomorphine, bromocriptine, selegiline (deprenyl), trihexyphenidyl hydrochloride, benzotropin mesylate, procyclidine hydrochloride, baclofen, diazepam, dantrolene, insulin, erythropoietin and growth hormone. Anti-estrogen or hormone agents, such as tamoxifen or human chorionic gonadotropin. Nucleotides and nucleic acids (for example DNA). The third part may be present in the compositions according to the invention in an amount from 0.1% w / w to 50% w / w. The first part of the methods, processes and compositions according to the invention preferably conform to 1-30% w / w of the total resulting composition. The individual components of this phase each preferably have a solubility parameter of about 5.7 - 8.1 cal / cc and together, more preferably, when combined, they have a calculated solubility parameter of 7.0 - 7.4 cal / cc and Even more preferably, they will be in a liquid state at the phase assembly temperature of the composition. The oils that may be used in the methods, processes and compositions according to the invention may include but are not limited to one or more of mineral oils, petrolatum, caprylic / capric triglyceride, peanut oil, cyclomethicone, cod liver oil , isopropyl myristate and alkoxylated oils including ethoxylated, propoxylated or ethoxylated-propoxylated oils. Cosmetic grade oils such as dioctyl cyclohexane, cetearyl sonoate, C12-C15 alkyl benzoate, oleyl oleate, octyl hydroxy stearate and octyl dodecanol may also be suitable. In preferred processes, methods and compositions according to the invention, the oil phase includes petrolatum, mineral oil, esters and cyclomethicone. Even more preferably, the oil phase includes petrolatum, mineral oil, an ester which is isopropyl myristate, acetyl tributyl citrate, or tributyl citrate and cyclomethicone in an approximate ratio of 1: 1: 1: 1. More preferably, the oil phase includes about 25% petrolatum, 25% mineral oil, 25% isopropyl myristate and 25% cyclomethicone. One of the problems confronted with conventional emulsion formulations is the extent to which they have to be redispersed if, at rest, a separation occurs. The ability to redisperse is important for the commercial acceptance of a product. In the methods, processes and compositions according to the invention, this problem has been solved by optimizing the oil phase to reduce the proportion of petrolatum, introducing co-solvents and coupling agents and reducing the presence of any solid surfactants that exhibit solubility in the oil phase while ensuring that the surfactant remains functional. Other components of the oil phase may include but are not limited to lauryl lactate, isosteareth-2-octanoate, alkoxylated derivatives of lauric, oleic or stearic acid, each of which may act as emulsifiers, humectants, or coupling agents; octyl salicylate and oleyl oleate that can act as skin penetrants; polyglyceryl-3-laurate, diisopropyl sebacate, which can act as an emollient, solubilizer or coupling agent or Hydramol PGPL (PEG, PPG-8/3 laurate). The total amount of oil in the oil phase can be about 1-30% w / w. The nature of the surfactants (also known as emulsifiers) which can be used in the compositions resulting from the preferred processes of the invention will vary, and as described in the preamble of this specification can be subjected to experimentation before to be perfected. Variations may arise as a result of the components of the selected oil phase, the pharmaceutically active ingredient and possibly even the temperature parameters under which the process was conducted. Generally, commercial microemulsion gels are based on phosphate esters and non-ionic emulsifiers, although it is possible to formulate systems based on non-ionic emulsifiers only. Ethoxylated fatty alcohols are the most popular nonionic emulsifiers used. These include ethoxylates of: lanolin alcohols (laneths) oleyl alcohol (oleths), lauryl alcohol (laureths), cetyl alcohols (ceteths), stearic alcohol (steareths), keto-stearyl alcohols (ceteareths) and isocetyl alcohol (isoceteths). Phosphate esters include those based on ethoxylated lauryl alcohol (laureth phosphates) and ethoxylated oleyl alcohol (oleth phosphates). In general, the greater the ethoxylation of a surfactant, the greater is its HLB, the higher the temperature at which a microemulsion or sub-micro emulsion is formed, and the greater the particle size of the resulting formulation. The ethoxylation has a large defect in the ability of the composition to assemble as a microemulsion or sub-micro emulsion as compared to the carbon chain length of the surfactant. When describing emulsifiers for microemulsion gels, it is useful to remember that a high molecular weight emulsifier and a low molecular weight oil may be the optimal combination. In the processes, methods and compositions according to a preferred embodiment of the invention, the lipophilic surfactants can be selected from the group comprising fatty alcohols such as cetyl alcohol, isocetyl alcohol or stearyl alcohol; glyceryl esters and derivatives thereof such as glyceryl monostearate and glyceryl monoleate; esters such as methyl glucose sesquistearate; sorbitan derivatives such as sorbitan laurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate and sorbitan sesquioleate. The lipophilic surfactants can be selected from the group comprising fatty acids such as palmitic acid and stearic acid. The hydrophilic nonionic surfactants can be selected from the group comprising alkoxylated carboxylic acids such as PEG 40 stearate; alkoxylated alcohols such as ceteareth -12, -20 and -30, oleth 10 and laureth -4 and -23 and steareth-4; sorbitan derivatives such as polysorbate 40, polysorbate 60 and polysorbate 80; glyceryl esters and derivatives thereof such as hydrogenated castor oil PEG-40 and castor oil PEG-35. The minimum concentration of the surfactant minimum surfactant in the methods, processes and compositions according to one form of the invention appears to be about 1.8% w / w using 1% w / w oil phase. The maximum concentration of surfactant in the compositions according to one form of the invention appears to be about 20.1% w / w using 10% w / w of the oil phase. It also appears that the surfactant: oil ratio can also contribute to the ability of the compositions prepared according to the processes of the invention to form sub-micro emulsions and microemulsions. A preferred ratio of surfactant: oil is from about 1: 3 to 3: 1. In the compositions of the invention, the surfactant system includes at least two surfactants, one lipophilic and one hydrophilic. Preferably, the surfactant system includes surfactants having an aggregate HLB number between 8.0 and 15.0, more preferably between 10 and 12 and still more preferably between 9.7 and 11.8. More preferably, the lipophilic surfactants have a HLB number of less than 10, and the hydrophobic surfactants have a HLB number of more than 10. Preferred candidates as surfactants in the compositions according to the invention are laurate of sorbitan and cetyl alcohol used in the first phase of oil, and Ceteareth-20 or oleth 10 in the second phase of water. In a system of two surfactants (one lipophilic and one hydrophilic), the preferred concentration range of hydrophilic surfactant: lipophilic surfactant is from about 9: 1 to 1.0: 1.0. In a system of three surfactants using a hydrophilic surfactant and two lipophilic surfactants, a preferred ratio of the surfactants is from 8: 1: 1 to 4: 5: 1. That is to say, the total hydrophobic-propyl ratio is preferably from 4: 1 to 2: 3. In a system of four surfactants using two hydrophilic surfactants and two lipophilic surfactants, a preferred ratio of the surfactants is 2.5: 2.5: 4.0: 1.0 to 3.0: 3.0: 3.0: 1.0. That is, the total hydrophilic: lipophilic ratio is preferably from 3.0: 2.0 to 1: 1. Other additives that may be present in the compositions prepared according to the invention not mentioned yet include but are not limited to preservatives such as dichlorobenzyl alcohol; antioxidants such as BHT, humectants such as lactic acid, urea and Ajidew? -50 / Sodium PCA; and polymers, thickeners or gums such as Eudragit NE40D. Commonly, these additives are organic and exhibit some miscibility with water and other organic ingredients and can generally be incorporated together with the active agent. The compositions according to the invention can be in any physical form to suit their purpose. In a fourth part of the preparation process of the microemulsions or sub-micro emulsions of the invention it is possible to introduce a propellant into the microemulsion so that the composition can be supplied as a foam or aerosol mousse. In this case the propellant can be selected from hydrocarbons such as P70; ethers such as dimethyl ether and halogen compounds such as Hydrofluorocarbon 134A. The propellant can be present in amounts of approximately 5-20% w / w.

The microemulsion or sub-micro emulsion can also be formulated as a gel, cream, lotion or patch depending on its purpose. For example, thickeners such as sodium carboxymethyl cellulose or gelling agents such as water soluble polymers, carbomer and xanthan can be added when a gel formulation is required. The following examples are provided in order to illustrate the scope of the invention although they will not be considered to limit, as will be appreciated by the skilled person, the means by which the following formulations can be altered while still resulting in formulations that they fall within the broadest scope of the invention.

EXAMPLES Examples 1 and 1A show a composition having surfactant ratios according to the prior art, and wherein the propylene glycol, generally considered to be a disturbance of the sub-micro emulsions is added together with other components in an aqueous phase of the stage. individual of the process. These examples are provided for comparison purposes and not to illustrate the invention. Examples 2-5A show six different compositions using the pharmaceutically active ingredients clobetasol propionate, desonide or betamethasone-17-valerate in formulations according to the preferred embodiments of the invention wherein the ratios of surfactants are of the desired ratio range . Examples 4 and 5 according to the invention are compositions that include propellant. Examples 2-5A can be further processed into useful formulations such as a lotion, spray, gel, paste, foam or any other suitable dosage form.

EXAMPLE 1 Examples 1 and 1A show a ratio of Ceteareth-20 surfactants: sorbitan laurate: cetyl alcohol 6.5: 1.5: 2.0 wherein the propylene glycol is introduced in a single step to the aqueous phase of the composition. This product is separated at rest, has little redispersion capacity in the container and requires continuous mixing in the process that is expensive in large-scale manufacturing.

Example 2 Example 5A Examples 5 and 5A show a ratio of Ceteareth-20 surfactants: sorbitan laurate: cetyl alcohol 5.0: 4.0: 1.0. Examples 2-5A show good physical stability, use less expensive manufacturing techniques and show good redispersibility.

Example 6 Figure 1 shows the preparation of a 0.05% ethanol-free clobetasol propionate foam of the same type as Example 2 according to a preferred process according to the invention. This process has been successfully scaled as follows. Petrolatum, light mineral oil, isopropyl myristate, sorbitan monolaurate and cetearyl alcohol are added in specified amounts to the primary compound formation tank as the oil phase. This phase is mixed in the tank and heated to 75-80 ° C. The cimeticone is added and the mixture is continued at 75-80 ° C until the oil phase is of uniform consistency. To elaborate the water phase, purified water, citric acid and potassium citrate are added in a kettle. This water phase is mixed and heated to 80-85 ° C. Ceteareth-20 is then added and mixing is continued at 80-85 ° C until complete dissolution of all components occurs. The third part containing the active agent ("the active phase") is prepared by the addition of specified amounts of propylene glycol and phenoxyethanol in a kettle. The mixing of this part is started, the active agent is added, clobetasol and the phase is heated to 55-60 ° C. Mixing is continued until the complete dissolution of all components occurs. The cooling of the temperature of this part is allowed, or it is cooled in a water bath up to 30 ° C. Approximately 70% of the mixture of the water phase is then added to the mixture of the oil phase in the primary compound formation tank. The two phases are mixed together and heated to 85-90 ° C. Approximately the remaining 30% of the water phase is cooled to 20-25 ° C in a chilled water bath. Then the mixing of the oil / water phase in the primary compound formation tank is continued and the mixture is cooled to 72-78 ° C, the rest of the mixture of the water phase (approximately 30%) is added to the oil / water phase in the primary compound formation tank. Simultaneously, cooling starts to reach a temperature of 35-40 ° C. The content of the active phase kettle is added to the oil / water mixture in the primary compound formation tank. Mixing is continued and the temperature is reduced to 20-25 ° C. The resulting composition is supplied in containers at room temperature.

Example 7 This example details the preparation of a Desonide formulation according to a preferred process of the invention. The method results in a composition of 17% Propylene glycol and Desonide. This process has not been scaled. The element numbers in the following composition list correspond to the element numbers in the process description that follows.

Elements 1 to 6 are added to the reaction vessel, stirred and heated to 60-80 ° C to form the oil phase. The temperature is maintained or re-established before adding the water phase (see below). To prepare the water phase, water at room temperature, citric acid anhydrous and potassium citrate, monohydride are added to a vessel of suitable size and are stirred together. Ceteareth-20 is added, and the mixture is heated to a maximum of 50 ° C until the ceteareth-20 completely dissolves. The water phase is separated into two parts. Approximately 30% of the mixture of the water phase is cooled to 20-30 ° C. The remaining 70% 70% of the mixture of the water phase is added to the mixing vessel of the oil phase at its existing temperature. The mixing vessel containing the oil phase and most of the water phase is heated to 80-85 ° C with complete mixing to ensure uniformity. The temperature will be maintained at this level for approximately 10 minutes to assist in obtaining uniformity. The mixture will be a water-in-oil emulsion and will be a very white color. The conductivity will be less than 100 s / cm.

The oil-in-water mixture will be allowed to cool to approximately 73 ° C. When approaching assembly temperature the cooling rate will be no more than 1o per minute. At the assembly temperature the conductivity? changes from a large negative value to an almost constant value. When the mixing vessel reaches approximately 73 ° C as described, the remaining 30% of the water phase which is at 20-30 ° C is added and the mixing vessel is immediately cooled. Rapid addition of the remaining amount of the water phase is desirable, and the temperature of the mixture will be about 60 ° C at the completion of the addition of the remaining water phase mixture. Phase 3 containing propylene glycol is prepared by adding elements 11 to 13 to a suitable container and heating until the Desonide dissolves. After the dissolution of the Desonide, the mixture must be cooled to less than 30 ° C. The oil-in-water emulsion mixture will be cooled to about 35-40 ° C by agitation and phase 3 is then added at a rate such that the entire mixture is not added until at least 5-10 minutes have elapsed. An unsatisfactory rate of addition will be evidenced by the presence of a two-layer product having an oil film in the upper part at rest. The mixing vessel containing all the components is cooled by stirring to about 25-30 ° C. The resulting emulsion will be maintained at approximately 20-25 ° C before filling and will remain homogeneous for at least 48 hours without agitation. Temperatures can vary up to about 5 ° C depending on the sorbitan laurate (oil phase) used. Conductivity tests are recommended to determine the set point or assembly temperature of the microemulsion.

Example 8 This example demonstrates the effect on the compositions by varying the parameters of the surfactant ratio, the variation of the temperature of the presetting point and the cooling rate of the post-adjustment point. Table 1 summarizes the effects of the variation of the parameters of the preparation of batches of 1.5 kg mainly of the compositions according to the preferred aspects of the invention. As shown in the chart, the ratio of Ceteareth-20: sorbitan laurate is adjusted, the temperature of phase 1 and phase 2 is mixed before the combination, and subsequent to the combination, it is adjusted and the cooling rate of the combination of the two phases is adjusted and observations of appearance, stability are made and the particle size. Lot numbers 367-14, 367-16, 367-22, E207 / 1/1 and 328-68 were considered successful. Figure 2 is a graphical representation of the method of this example that graphs the rate of addition of the different components of the compositions.

Example 9 Figure 3 shows the timeline of a preferred preparation process of a 15 kg large scale Desonide composition according to one aspect of the invention. The timeline shows a slow addition of the water, the phase until the inversion of the phases occurs, determined by the conductance measurements, so that the rapid addition of the rest of the water phase is carried out. The resulting composition is a blue-white emulsion that leaves no residue on glass. Only a small amount of foaming is present mainly during the rapid addition of the remainder of the water phase. The temperature of the mixture was maintained between 70-75 ° C during the mixing although the cooling started immediately after the addition of the water phase had been completed. Most of the particles checked under a microscope were much less than 1 μp? diameter. The composition remained stable for 3 days. Figure 4 is a graphical representation of the process of this example that changes the rate of addition of the various components of the composition.

Example 10 This example demonstrates the effect of varying the ratio of the emulsifiers in a composition prepared according to an embodiment of the invention wherein the pharmaceutically active ingredient is betamethasone valerate and the emulsifiers are Ceteareth-20, sorbitan laurate and cetyl alcohol . It also shows the effect of the variation of the mode of addition of the water phase; either all at once, or in two separate stages, the first stage that is added at a lower speed than the second stage. Figure 5 shows the results of this example in graphic form. The acronym "BMV" is Betametasone valerate. The compositions E208 / 2/1-E208 / 2/8 are prepared as follows according to different preferred embodiments of the invention: E208 / 2/1 - 4.0: 5.0: 1.0 ratio of Ceteareth-20: laurate of: cetyl alcohol, all water phase added at one time - heated up to 81 ° C E208 / 2/2 - 4.5: 4.5: 1.0 ratio of Ceteareth-20: sorbitan laurate: cetyl alcohol, the whole water phase added at once - heated 82 ° C E208 / 2/3 - 5.5: 3.5: 1.0 ratio of Ceteareth-20: sorbitan laurate: cetyl alcohol, the whole phase of water added at one time - heated 94 ° C E208 / 2/4 - 5.0: 4.0: 1.0 ratio of Ceteareth-20: sorbitan laurate: cetyl alcohol, all water phase added at one time - heated 84 ° C E208 / 2/5 - 4.5: 4.5: 1.0 ratio of Ceteareth-20: sorbitan laurate: cetyl alcohol, the whole phase of water added at one time - heated to 92 ° C E208 / 2/6 - 4.5: 4.5: 1.0 ratio of Ceteareth-20: sorbitol laurate: cetyl alcohol, all the f add water added at one time - heated 78 ° C E208 / 2/7 - 5.0: 4.0: 1.0 ratio of Ceteareth-20: sorbitan laurate: cetyl alcohol, water phase added in two portions (70/30 hot: cold) stir agitated glycol to the addition - heated to 74 ° C E208 / 2/8 - 5.0: 4.0: 1.0 ratio of Ceteareth-20: sorbitol laurate: cetyl alcohol phase of water added in two portions (70/30 hot: cold) propylene glycol without agitation to the addition - heated up to 74 ° C. This example shows a microemulsion covering the objects of the invention can be made in various ratios of surfactants. In order to determine the point at which a microemulsion is formed, conductance tests are recommended. The conductivity will descend drastically immediately to the occurrence of the phase assembly at the microemulsion set point. Using the compositions E208 / 2/7, E208 / 2/8, E208 / 2/6 and E208 / 2/4 (left to right through the key), Figure 6 shows a plot of the conductivity of the compositions against the temperature of the oil water phase mixture and shows the conductivity response from the heating up to the assembly temperature and the subsequent cooling and the addition of the active phase. The highest section, or range of assembly temperature, of the conductivity graph demonstrates the tendency that the set point of the compositions according to the invention can be reduced by decreasing the relative proportion of the hydrophilic surfactant in the surfactant system. The assembly temperature is also reduced when the water phase is separated into two aliquots. It is proposed that the separation of the water phase has the same effect as the reduction of the relative proportion of the hydrophilic surfactant and the subsequent reduction of the assembly temperature of the microemulsion.

Example 11 This example demonstrates the effect on the appearance and particle size of the variation of the parameters of the processes described so far in the present. Table 2 shows that the phase in which the surfactant is added, and the presence or absence of amphiphilic, non-surfactant substances in the composition prior to the emulsification of the compositions, has an effect on the particle size of the composition. In the context of the example, it will be appreciated that the compositions covering the objects of the invention are those in which the water phase is added to the oil phase, Ceteareth-20 is present in the water phase, and the remaining surfactants they are present in the oil phase, and wherein the addition of the non-surfactant amphiphilic components of the composition is effected after the emulsification of the composition at the phase assembly temperature. In this case, the composition appears to have acceptable stability, and a particle size of less than 0.2 μm.

Example 12 In order to demonstrate the chemical and physical stability of the compositions prepared according to a process of the invention as compared to those of the prior art, the following tests were carried out. In the compositions prepared according to the process of the invention (12B) the polyol and / or alcohol are added in a third phase after the emulsification and cooling of the oil-in-water emulsion formed in the first stage of the process. In the compositions prepared according to the prior art processes (12A) the polyol and / or alcohol are added to the oil-in-water emulsion before the emulsification and cooling of the composition.

Table 3 shows the 6-month stability data associated with a composition according to example 12A; a type composition of the prior art.

Example 12A Manufacturing Method 1. Part 1 preparation: Add items 2 to 8 inside the mixing container. Heat to 600 ° C and shake to combine. Maintain the temperature before adding Clobetasol propionate. Stir until dissolved, then increase the temperature to 80-85 ° C in preparation for the addition of part 2. 2. Part 2 preparation: Add elements 9 to 13 to a mixing vessel and heat up to 80-85 ° C * with agitation until a clear solution forms. 3. Emulsification: Shake part 1 well (without introducing air) then add part 2. Initially add part 2 at a lower speed. During the addition of part 2, a period of higher viscosity will be present than that which may require an increased agitation speed, for a short time, to ensure complete mixing. 4. Homogenization: Cool the emulsion with agitation to 40 ° C (cool at a reasonably fast speed). Homogenize the emulsion if the average particle size is > 2.5 μ ?? or the maximum particle size is > 15 μ ?? Cool the emulsion to 25 ° C with agitation.

Example 12B Manufacturing Method 1. Part 1 preparation: Add items 1 to 6 inside the mixing container. Heat to 60-80 ° C and shake to combine. Maintain temperature before adding Part 2A. 2. Part 2 preparation: Add Element 7 (Water) at room temperature, Element 9 (Citric acid, anhydrous) and Element 10 (Potassium citrate, monohydride) to an appropriate sized container. Shake well and add all Element 8 (Cetomacrogol 1000 BP). Heat to a maximum of 50 ° C until the Cetomacrogol has completely dissolved (above 50 ° C the cetomacrogol melts and will agglutinate and form a large mass). 3. Part 2 separation: Carry out a weighing to verify part 2 and then separate it into Part 2A - containing 70% of Part 2 Part 2B - containing 30% of Part 2 Cool part 2B up to 20-30 ° C ( ideally 20-25 ° C). 4. Part 2A addition: Add part 2A to the mixing vessel. Part 2A can be added immediately after dissolving Cetomacrogol when it is hot, or if it was previously prepared and cooled to room temperature. 5. Heat the mixing vessel to at least 80-85 ° C (part 1 + part 2A), with proper mixing and hold for 10 minutes. When the conductivity is measured, it will be <; 100 pS / cm, otherwise, increase the temperature. Allow the mixing vessel to cool slowly to 73.0 ° C. When approaching the target temperature (73.0 ° C) the cooling rate will be no more than 10 ° C per minute. This will correspond to the maximum clarity of the emulsion. It is also the point at which the AC Conductivity changes from a large negative value to approximately zero constant. 6. Addition of Part 2B: When the mixing vessel reaches 73.0 ° C, pump part 2B (which is at 25 ° C) and immediately start cooling the mixing vessel. The addition of part 2B will be completed in 90 s. The temperature of the mre will be about 60 ° C at the completion of the addition of part 2B. 7. Addition of Part 3: Cool with stirring the mixing vessel to 35-40 ° C. Part 3 will be prepared in advance through the addition of Elements 11 through 13 into a suitable container and heating until Clobetasol dissolves. Cool part 3 to < 30 ° C after the Clobetasol has dissolved and added to the mixing vessel at a speed to last at least 5-10 min. 8. Cool with stirring the mixing vessel to 25-30 ° C (25 ° C preferable). Execute a weight check. The base emulsion will be maintained at 20-25 ° C before filling. The base emulsion will remain homogeneous for at least 48 hr without agitation. Table 4 shows the 3-month stability data associated with a composition according to example 12B; a composition prepared according to a form of the invention.

Comparing Tables 3 and 4 it can be seen that the active ingredient, clobetasol propionate and the preservative, phenoxyethanol, which are routinely analyzed, are not affected by the physical form of the emulsion (ie, prior art against a composition of according to the invention).

Example 13 The physical stability of the formulation prepared according to the methods of the invention has been confirmed using a Turbiscan Transmission Graph which shows that after 4 days, the dispersed phase is homogeneously distributed throughout the sample which means that it does not Phase separation has occurred.

Example 14 Using the formulation set forth below and employing the procedure illustrated in FIG. 7, a critical phase II test was conducted as described.

The randomized phase II clinical trial involved 106 patients showing mild to moderate atopic dermatitis who had a 4-week treatment and had follow-up for the subsequent three weeks. Patients whose ages of patients were from 3 months to 17 years were administered the above composition formulated as a foam in a ratio of 2: 1 (composition of desonide: desonide without vehicle). The primary end points of the study were determined to be the following: Static Global Researcher Determination; clear (0) or almost clear (1), and erythema; 0 or 1, and Hardening / Papulation; 0 or 1, and ISGA; minimal improvement of 2 degrees. There were multiple secondary terminal points. The results of Part 2 showed that they were the primary endpoint that was validated, a response rate of 53% in patients treated with the desonide formulation and a response rate of 12% in patients treated with the vehicle lacking the agent active desonide (placebo). The response speed to the placebo was as expected. The response speed to the desonide formulation was almost twice the expected rate (53% versus 27%). The formulations according to the invention show surprising and unexpected advantages over the expected response.

Example 15 A sub-micro emulsion formulation of betamethasone valerate at 0.12% was prepared to demonstrate the ability to dissolve a pharmaceutically active agent in the oil phase. The following formulation was prepared.

The formulation was prepared according to the following protocol: • Combine elements 1 and 2. Shake until dissolved completely. • Add elements 3, 4, 5 and 6. Heat up to 60 ° C and shake until dissolved. • In a separate kettle, combine items 7, 8, 9 and 10. Shake until dissolved.

• With agitation, add 70% of the water phase to the clear, warm oil phase. Continue agitation and heating while recording the temperature and conductivity. • Continue heating and stirring until the assembly temperature is passed (approximately 74 ° C). Remove the emulsion from the heat and place in a cooling stirrer. • Continue stirring and add the remaining water phase to the temperature when the conductivity is at a maximum (approximately 70-72 ° C). • Cool with agitation up to 30 ° C. Balance with water to explain evaporation loss. • Test the pH and adjust to pH 4 (if required) The physical characteristics of the formulation are summarized as follows In conclusion it will be appreciated that the process of the invention allows the formation of a stable microemulsion or sub-micro emulsion oil-in-water which allows the inclusion of a hydrocarbon propellant so that a foam can be dispersed when the resulting product is use. In addition, the resulting foam appears stable and effective. It will be appreciated that the scope of the invention described herein is not limited to the specific embodiments described herein in the examples but extends to the general principles of the invention as set forth in the brief description and in the detailed description of the invention. previous invention.

Claims (21)

1. A process for the preparation of a microemulsion composition or sub-micro emulsion oil in water (O / W) for dermal delivery of at least one pharmaceutically active ingredient, the method characterized in that it includes the steps of a) mixing a first part that includes at least one of the group comprising animal, mineral or vegetable oils, silanes, siloxanes, esters, fatty acids, fats, halogen compounds, and alkoxylated alcohols; and one or more lipophilic surfactants, and a second part including water and at least one hydrophilic surfactant to achieve homogeneity, b) heating the mixture from step a) to a phase assembly temperature in the range of 40-99 ° C, preferably 45-95 ° C, more preferably 65-85 ° C with continuous mixing to obtain a microemulsion or sub-micro emulsion oil in water, c) allow the microemulsion or sub-micro emulsion to cool, and d) add a third part to the microemulsion or sub-micro emulsion at a temperature between 2 ° C and the phase assembly temperature, the third part which if necessary is premixed and heated until the components are dissolved and includes less one component selected from the group comprising non-surfactant amphiphilic type compound, surfactant and water with the proviso that when the third part includes water it also includes a non-surfactant amphiphilic type compound. or and / or surfactant.

2. The process according to claim 1, further characterized in that the second part is added in two aliquots, said aliquots being preferably about 70% and 30% by weight of the second part, respectively.

3. The process according to claim 2, further characterized in that the second aliquot is added after the microemulsion or sub-micro emulsion has been formed, at a temperature substantially below the temperature of the first aliquot, and at a rapid speed in a manner that reduces the overall temperature of the composition preferably below about 60 ° C whereby the microemulsion structure or sub-micro emulsion is fixed.

4. The process according to claim 1, further characterized in that an occlusive agent is present in said first part.

5. The process according to claim 4, further characterized in that the occlusive agent is petrolatum.

The process according to any of claims 1-5, further characterized in that a pharmaceutically active agent is included in at least one of the first part, the second part, and the third part.

7. The process according to claim 6, further characterized in that the pharmaceutically active ingredient is insoluble or only sparingly soluble in water.

8. The process according to claim 6, further characterized in that the pharmaceutically active ingredient is one or more water-insoluble compounds selected from corticosteroids, desonide, clobetasol, betamethasone, vitamin D analogues, and vitamin A analogs.

9. The process according to claim 1, further characterized in that it includes the steps of a) heating a first part that includes at least one group comprising animal, mineral or vegetable oils, silanes, siloxanes, esters, fatty acids, fats, compounds of halogen, and alkoxylated alcohols; and one or more lipophilic surfactants up to a temperature of 40-99 ° C, preferably 45-95 ° C, and more preferably 65-85 ° C and mixing until homogeneous, b) heating a second part including water and at least one hydrophilic surfactant up to a temperature of 40-99 ° C, preferably 45-95 ° C, and more preferably 65-85 ° C and mixing to achieve homogeneity, c) adding the second part to the first part at a temperature of 40-99 ° C, preferably 45-95 ° C, and more preferably 65-85 ° C with continuous mixing whereby a microemulsion or sub-micro emulsion is formed at a phase assembly temperature, d) allowing the microemulsion or sub-micro-emulsion to cool down. micro emulsion, and e) add a third part to the microemulsion or sub-micro emulsion at a temperature between room temperature and the phase assembly temperature, said third part that has been premixed, and if necessary heated until the components and includes at least one component selected from the non-surfactant amphiphilic type compound, surfactant, and water with the proviso that when the third part includes water it also includes a non-surfactant amphiphilic type compound and / or surfactant.

10. An oil-in-water microemulsion or sub-micro emulsion composition for dermal delivery of at least one pharmaceutically active ingredient characterized in that it comprises an oil phase dispersed through a water phase, the oil phase including at least one one of the group comprising animal, mineral or vegetable oils, silanes, siloxanes, esters, fatty acids, fats, halogen compounds, and alkoxylated alcohols; and at least one lipophilic surfactant; and the water phase which includes at least one hydrophobic surfactant, water and optionally non-surfactant amphiphilic compound, the weight ratio of said at least one hydrophilic surfactant to said at least one lipophilic surfactant which is from about 9.0: 1.0 to 2.0: 3.0.

The composition according to claim 10, further characterized in that the surfactants have an added HLB number between 8.0 and 15.0, more preferably between 10 and 12, and still more preferably between 9.7 and 11.8.

The composition according to claim 10, further characterized in that the lipophilic surfactant has a HLB number less than 10, and the hydrophilic surfactant has a HLB number greater than 10.

The composition according to claim 10, characterized further because an occlusive agent is included in the oil phase.

14. The composition according to claim 3, further characterized in that the occlusive agent is petrolatum.

15. The composition according to any of claims 10-14, further characterized in that it includes a pharmaceutically active agent that is insoluble or only sparingly soluble in water.

16. The composition according to claim 15, further characterized in that the pharmaceutically active agent is one or more water-insoluble compounds selected from corticosteroids, desonide, ciobetasoi, betamethasone, vitamin D analogues, and vitamin A analogues.

The composition according to claim 15, further characterized in that the pharmaceutically active agent is in the water phase.

18. The composition according to claim 5, further characterized in that the pharmaceutically active agent is in the oil phase.

19. The composition according to claim 15, further characterized in that the pharmaceutically active agent is in the oil phase and in the water phase.

20. Use of an effective amount of a microemon composition or sub-micro emon oil in water in the preparation of a medicament in the form of a topical composition for medical or cosmetological treatment of a dermal condition in a patient in need thereof, in wherein the microemon composition or oil-in-water sub-micro emon comprises an oil phase dispersed through a water phase, the oil phase including at least one of the group comprising animal, mineral or vegetable oils, silanes, siloxanes, esters, fatty acids, fats, halogen compounds, and alkoxylated alcohols; and at least one lipophilic surfactant, and the water phase including at least one surfactant hidrof yl-, water and optionally an amphiphilic compound type no surfactant, the weight ratio of said at least one hydrophilic surfactant to said at least one lipophilic surfactant which is from about 9.0: 1.0 to 2.0: 3.0. The use according to claim 20, further characterized in that the oil-in-water microemon or sub-micro emon composition includes at least one pharmaceutically active ingredient. SUMMARY A process for the preparation of an oil-in-water (O / W) microemon or sub-micro emon composition for dermal delivery of at least one pharmaceutically active ingredient is provided, the method including the steps of a) mixing a first part which includes at least one of the group comprising animal, mineral or vegetable oils, silanes, siloxanes, esters, fatty acids, fats, halogen compounds or alkoxylated alcohols; and one or more agents tensioacíivos lipophilic, and a second part including water and at least one hydrophilic surfactant to achieve homogeneity, b) heating the mixture of step a) to a temperature assembly phase in the range of 40 -99 ° C, preferably 45-95 ° C, more preferably 65-85 ° C with continuous mixing to form the microemon or sub-micron emon, c) cooling the microemon or sub-micron emon, d) adding a third part to the microemon or sub-micro emon at a temperature between 2 ° C and the temperature of phase assembly, the third part that if necessary is premixed and heated until the components are dissolved and includes at least one selected component from the group comprising non-surfactant amphiphilic type compound, surfactant and water with the proviso that when the third part includes water it also includes a non-surfactant amphiphilic type compound and / or surfactant. or active. The phase assembly temperature can be determined visually by obtaining the translucency in the composition or through measurements such as the conductivity that reaches a peak and is then maintained on a plateau while the phase assembly occurs. It has been found that if a compound amphiphilic type no surfactant such as the polyol is added together with the second part as would conventionally be the case, a microemon or sub-micron emon is formed by adding the third ring part, The phase assembly occurs at a lower temperature than would be expected and, in addition, this phase appears to help maintain the characteristics of the microemon or sub-micro emon of the formulation during storage at normal temperatures.