MXPA06009197A - A microemulsion preparation of high concentration propofol for anesthetic uses - Google Patents

Abstract

The invention provides a method and a composition for enhancing the dissolution and bioavailable properties of propofol (2, 6 diisopropyl phenol) for use as an intravenously administered anesthetic in mammals. The method produces a self-microemulsifyable emulsion base composition that is utilized in the production of a water-based microemulsiori preparation. In a preferred two (2) component base composition, the base composition consists

Description

A PREPARATION IN MICROEMÜLSION OF PROPOFOL AT HIGH CONCENTRATION FOR ANESTHETIC USES FIELD OF THE INVENTION The present invention relates to the preparation of physiologically isotonic oil-in-water type microemulsions of anesthetic propofol for use as a pharmaceutical for parenteral administration to mammals for the purpose of general anesthesia. BACKGROUND OF THE INVENTION Systems for the dispersion in water of drugs are necessary for the intravenous administration of drugs that are not soluble in water. Some of these systems use dispersions of hydrophobic liquids in water, also known as emulsions. The emulsions can be defined in general as stable dispersions or almost stable in some way uniformly dimensioned drops of liquid in a second liquid vehicle. Microscopic-sized emulsions are frequently divided in the literature into nanoemulsions and microemulsions. Nanoemulsions cover the size range of 50-200 nm and are kinetically stable systems with long-term physical stability (against cremation or sedimentation, flocculation and coalescence). Because nanoemulsion systems are only kinetically but not thermodynamically stable, they must typically be created by energy methods such as as sonication and homogenization at high pressure. Emulsification systems in particular are necessary for the administration of propofol anesthetic (2,6-diisopropyl phenol), a liquid which in its pure state is practically insoluble in water. Propofol is a well-known drug, which is relatively inexpensive to produce as a pure chemical and which is currently widely used in humans and veterinary medicine as a general anesthetic agent. Propofol is capable of producing deep anesthesia, which resolves in a comparatively short time after administration of the drug is discontinued. Currently, the pharmaceutical propofol is prepared by dissolving in soybean oil, then an emulsion of this oil with egg phospholecithin is prepared in order to produce a final concentration of approximately 10% soybean oil in saline, with standardized propofol concentration 1% of the liquid-total preparation. These emulsions, which have the appearance of milk, have droplet sizes of up to 200 nm and can be referred to as "nanoemulsions". Such commercial propofol emulsions, in spite of the addition of preservatives, are similar to the nutritional preparations of intravenous lipids and are excellent preservation means for viruses or even growth media for bacteria. For this reason, all preparations of propofol in the United States are limited to bottles and Single-use ampoules, with instructions for disposing of penetrated containers within the first hours after first use. Distinguished from nanoemulsions are microemulsions, a type of emulsion with a particularly small droplet size, which commonly varies from less than about 5 to 50 nm in diameter. The microemulsions are characteristically optically transparent due to the small light scattering of the very small drops, which gives them a visual appearance similar to the true solutions. Typically, microemulsions are also thermodynamically stable with respect to instability and therefore often form spontaneously, if given enough time. For current purposes, the most desirable microemulsions are assembled spontaneously when certain hydrophobic chemicals and water are mixed by simple agitation of the mixture, without the need for vigorous stirring, such as sonication. In this regard, there is a particular need for the development of propofol microemulsions for intravenous pharmaceutical use that are optically clear, allow the use of light diffraction to detect the presence of potential contamination from foreign elements such as bacteria, which disperse the light. There is also a need for propofol preparations that are not conductive for the development of bacteria and fungi, as are the current preparations of oil and phospholecithin. There is a need for propofol preparations that have a long shelf life and that are easily sterilized. Finally, there is a need for propofol preparations containing well over 1% concentration currently available commercially, for use in larger animals such as horses. Currently such animals requiring general anesthesia must often be transported from the field to an urban anesthesia unit established for gas anesthesia, a procedure that is difficult and costly. A preparation of propofol of high economic concentration that can be taken by the animal in the field would serve the general anesthetic needs of a significant fraction of these animals. Generally the current commercially available emulsion systems for the intravenous supply of propofol use ordinary opaque nanoemulsions of the oil-in-water type. However, recently, a general microemulsion system for pharmaceutical delivery of active compounds in Pat. of E.U. No. 6,602,511 which generally describes a complex formulation for a microemulsion containing: water and a polarity adjusting component, a "surfactant film modifier" (e.g., ethanol), a pharmaceutically acceptable oil (more preferably "a triglyceride containing at least 70% of fatty acids having 8-10 carbon atoms") and a mixture of a hydrophilic and hydrophobic surfactant up to about 15% by weight of the total emulsion. The '511 patent claims that the formulation can be used to emulsify a wide range of active compounds such as a "proton pump inhibitor, a calcium channel blocker, a beta blocker, an anesthetic, a steroid, an antioxidant, an inhibitor of renin, an alkaloid, cytostatics, an anti-coagulant, a lipid regulating agent, an anti-depressant, a neuroleptic, an immunosuppressant, an immunomodulator, an antibiotic [and] an anti-inflammatory agent. " Unfortunately, the patent describes the application of its microemulsion formulation only for two active compounds: felodipine and "indeno indole". The utility of the invention as a microemulsion containing an anesthetic such as propofol is not described. In this regard, it should be noted that the patent states that the invention produces a microemulsion that is "transparent and slightly viscous in a liquid phase", but the patent makes no mention as to the transparency of the microemulsion after the addition of either felodipine or indeno indole However the present inventors denote, that in order to adapt the complex formulation of the patent to intravenous use, it must be necessary to add an amount significant of a liquid vehicle and doing so would cause a significant degradation of the microemulsion's transparency. The patent also discloses the need for a two (2) component surfactant system: a hydrophilic and a hydrophobic surfactant, which is further added to the complexity of the formulation. Here, the? 511 patent follows the common belief that microemulsion systems are made more easily by the use of a "co-surfactant" to decrease the interfacial tension of the drops. However, the inclusion of a hydrophobic surfactant actually retards the formation of the desired microemulsion in water and is completely unnecessary if the hydrophobic surfactant is properly selected. As a result, what is needed is a simple formulation of propofol for the production of high concentrations of propofol in a fully transparent microemulsion that can be used as an intravenously administered anesthetic and, if necessary, can be adequately colored in order to identify the different concentrations of propofol in different preparations. In addition, there is a need for a self-microemulsifiable propofol base composition that uses only a single hydrophilic surfactant, is easy to sterilize, can be stored indefinitely until the anesthetic is needed, after which - - easily reconstituted by the addition of a physiological saline or similar water-based carrier. The present invention satisfies these needs among others. SUMMARY OF THE INVENTION The present invention generally provides a novel method and composition for improving the dissolution properties and bioavailability of propofol (2,6-diisopropyl phenol) for use as an anesthetic administered intravenously in mammals. The method of the present invention produces a self-microemulsifiable emulsion base composition which is used in the production of a water-based microemulsion preparation for use as an anesthetic. In a preferred two (2) component base composition, the base composition consists of: a polyethylene glycol-containing surfactant; and liquid propofol. The microemulsion is prepared by mixing the base composition with a liquid carrier, which results in the formation of a microemulsion containing propofol concentrations of up to about 4% by weight of propofol up to the volume of the microemulsion. In a base composition of four (4) components, the base composition consists of; a surfactant, which contains polyethylene glycol; liquid propofol; a solvent miscible in water; and ethanol. The microemulsion is prepared by mixing the base composition with a liquid vehicle, which gives as resulting in the formation of a microemulsion containing propofol concentrations of up to about 10% by weight of propofol for the volume of the microemulsion. The present invention produces a base composition which is a self-microemulsifiable, anhydride, homogeneous and optically clear liquid that can be stored for later use almost indefinitely. As a result, the preparation of the propofol microemulsion upon mixing the base composition with the liquid vehicle can be delayed until the anesthetic is needed in the laboratory, clinic or hospital. In addition, the present invention produces a microemulsion that is thermodynamically stable and also optically transparent. The transparency of the microemulsion allows the anesthetic to be colored with different colors in order to distinguish the different concentrations of propofol, so that accidents involving anesthetics of similar appearance but containing different concentrations of propofol are more easily avoided. The transparency of the microemulsion also makes it easier if the anesthetic has become contaminated. The microemulsion of the present invention is also easily sterilized by simply heating the surfactant before mixing it with the liquid propofol and by using a sterilized liquid vehicle. The features of the invention are also extremely conductive for sterilization with cold filtration filter. DETAILED DESCRIPTION OF THE. INVENTION The present invention generally provides a novel method and compositions for improving the dissolution properties and bioavailability of propofol (2,6-diisopropyl phenol) for use as an anesthetic administered intravenously in mammals. The method of the present invention produces a self-microemulsifiable emulsion base composition which is used in the production of a water-based microemulsion preparation for use as an anesthetic. In a preferred two (2) component base composition, the microemulsion preparation contains propofol concentrations of up to about 4% by weight of propofol for the volume of the microemulsion and in a four (4) component base composition, the preparation of microemulsion contains propofol concentrations of up to about 10% by weight of propofol for the volume of the microemulsion. The preferred two (2) component base composition consists essentially of: a nonionic surfactant, which contains polyethylene glycol (hereinafter referred to as a "PEG-containing surfactant") and a propofol solution containing liquid propofol which has been mixed with 1% vitamin E (free alpha tocopherol) in order to avoid oxidation (hereinafter simply referred to as "propofol" or "liquid propofol") in which the relative concentration of surfactant to propofol included in the base composition is about eight (8) parts or more of surfactant for about one (1) part of propofol. The preferred method of producing the self-microemulsifiable emulsion base composition consists essentially of mixing a predetermined amount of the PEG-containing surfactant, preferably heated to a preparation temperature above its melting point, with a predetermined amount of the liquid propofol. Mixing is carried out simply by mixing or stirring the components for a few minutes or less until the solution becomes clear. The resulting base composition is a self-microemulsifiable, anhydride, homogeneous and optically clear liquid with low viscosity at the preparation temperature. The water-based microemulsion is then prepared by mixing the base composition with a predetermined amount of a liquid vehicle, which contains water and isotonic to the blood, such as 0.9% saline, 5% dextrose or other ionic solutions containing a crystalloid or a colloid that is proposed for peripheral intravenous administration. Again, the mixing is carried out by simply mixing or stirring the components for a few minutes or less until the solution becomes transparent. The preparation of the resulting microemulsion may contain propofol concentrations of up to about 4% by weight of propofol for the volume of the microemulsion (w / v) and still exhibits all the characteristics of a microemulsion. The microemulsion is thermodynamically stable at room temperature and is optically clear, but has a pale yellow color due to the inclusion of propofol. Examples # 1 and # 2 at the end of this section establish specific examples of the preparation of a two (2) component base composition and then using the base prepare a microemulsion containing propofol concentrations of 1% (w / v) and 4% (p / v) respectively. Example # 3 establishes the results of the intravenous administration of the microemulsion containing a 4% propofol concentration prepared as in Example # 2 to a canine without any evidence of pain in the intravenous injection to the conscious animal. Although the preferred method of producing the two (2) component base composition heats the surfactant at a preparation temperature above its melting point, the base can also be prepared at lower preparation temperatures. The lower preparation temperatures only require that the liquid surfactant preparation and the liquid propofol should be mixed or stirred for a longer period of time. In addition to heating the solution, it must also be prepared by sonication or using any mixing method that creates a homogeneous liquid. The ability of the present invention to produce water-based microemulsion preparations containing propofol concentrations of up to 4% by weight of propofol for the volume of the microemulsion, is a significant improvement over the existing oil-in-water preparations that they are only capable of producing propofol concentrations of up to about 1% by weight of propofol for the volume of the preparation. The present invention also constitutes a significant improvement over other attempts to produce an injectable microemulsion containing higher concentrations of propofol. For example, the U.S. Patent. No. 6,602,511 (hereinafter the '511 patent) describes a complex formulation for a microemulsion containing: water (not the main component), a component for adjusting the polarity, a "surfactant film modifier" (eg, ethanol) , a pharmaceutically acceptable oil (more preferably "a triglyceride containing at least 70% of fatty acids having 8-10 carbon atoms") and a mixture of a hydrophilic and hydrophobic surfactant up to about 15% by weight of the total emulsion. The patent 511 claims that the formulation can be used to emulsify a wide range of active compounds such as a "proton pump inhibitor, calcium channel blocker, beta blocker, anesthetic, steroid, antioxidant, renin inhibitor, alkaloid, cytostatics, anticoagulant, lipid regulating agent, anti-depressant, neuroleptic, immunosuppressant, immunomodulator, antibiotic [and] anti-inflammatory agent ". Unfortunately, the patent describes the application of its microemulsion formulation only for two active compounds: felodipine and "indeno indole". The utility of the invention as a microemulsion containing an anesthetic such as propofol is not described. In this regard, it should be noted that the patent states that the invention produces a microemulsion that is "transparent and slightly viscous of a liquid phase", but the patent does not make reference as to the transparency of the microemulsion after the addition of either felodipine or indole indene or after the addition of additional water to this water-in-oil preparation. The present inventors nevertheless point out that in order to adapt the formulation of 511 to intravenous use, it must be necessary to add a significant amount of a liquid vehicle. Since the microemulsions described in the patent? 511 are bicontinuous microemulsions or water-in-oil microemulsions in which the main component (approximately 44 to 61%) is oil and a minor component (15%) is surfactant, it is apparent that adding the liquid based on water necessary for intravenous use would cause a significant degradation in the transparency of the emulsion - ie, when it is converted from a water-in-oil preparation to one of oil-in-water, these preparations will no longer be microemulsions. In contrast, the present invention contains sufficient surfactant to produce true oil-in-water microemulsions containing propofol concentrations of up to 4% of the microemulsion, which is completely transparent and capable of further dilution by water without any disruption of the microemulsion system. . There are other advantages of the present invention over the 511 patent unless the present invention is capable of producing an intravenously injectable microemulsion containing a high concentration of propofol by using a very simple system of only one type of surfactant containing PEG and a liquid vehicle such as saline. The '511 patent on the other hand, requires the use of up to six (6) or more chemicals in order to ostensibly produce a water-in-oil microemulsion for pharmaceutical use. Other disadvantages of using some of the components of the 511 patent include greater potential for bacterial growth, due to the fact that some of the preferred components, such as phospholecithins of soy, are sources of both phosphorus and nitrogen. In contrast, the present invention describes mixtures containing only carbon, oxygen and hydrogen in addition to sodium chloride. In addition, the 2-component base preparations of the present invention have compositions that do not contain oil and 4-component base compositions that can be packaged so as not to contain water. The propofol micro emulsion of the present invention has several advantages and characteristics as an injectable anesthetic preparation intravenously that is not possible with the current propofol formulations. For example, the ability of the present invention to produce an anesthetic liquid that is optically clear, allows the anesthetic to be dyed with different colors in order to distinguish the different concentrations of propofol, so that accidents involving solutions of similar appearance, but which contain different concentrations of propofol are more easily avoided. In this regard, the present inventors successfully utilize the compatible intravenous preparations of fluorescein dye (yellow) and methylene blue dye (blue) to color various anesthetic solutions prepared according to the method of the present invention. It will be apparent to those skilled in the art that other compatible medical dyes can be used to produce other colors, such as the potential use of vitamin B12 to produce a primary red color. Another advantage of the present invention is that due to the property of the anesthetic liquid to be optically transparent, it is much easier to detect the presence of any bacterial and fungal contamination by examination, because living cells, as well as many bulky contaminants disperse the light. In this regard, the current anesthetic preparations containing oil and phospholecithin are particularly susceptible to contamination from the growth of bacteria and fungi; however, the anesthetic solution of the present invention is much less likely to be contaminated because it does not require the use of triglyceride or nitrogen or phosphorus oil containing surfactants. Additionally,. The microemulsion preparation of the present invention is easily sterilized. For example, the Solutol® surfactant is sterilized when heated to about 121 ° C, then cooled to about 50 ° C and the liquid propofol can be sterilized by filtration and then added to the molten Solutol®, thus creating a sterile base composition. This composition can in turn be filter sterilized easily if necessary by passing the liquid through a 0.2 micron filter. This base can be packed commercially in sterile mixing bottles. Mixing the sterilized base composition with sterile saline creates a sterile microemulsion liquid preparation. In addition, sterilization of the final microemulsion can also be carried out, if desired, by passing the microemulsion through a 0.2 micron filter. The propofol microemulsions of the present invention pass such filters much more easily than do the current oil-in-water nanoemulsions, such as soy emulsions that pass only bacterial filtration with some difficulty, due to their large droplet size. . Another feature of the present invention is that the self-microemulsifiable emulsion base composition can be stored in a vial, ampule or other similar airtight container almost indefinitely. As a result, the preparation of the propofol microemulsion upon mixing the base composition with a liquid vehicle can be delayed until the anesthetic is needed in the laboratory, clinic or hospital. Although the preferred base composition will solidify after it is cooled to room temperature, the base can be returned to its liquid state easily by heating the base to a temperature of about 45 ° C. Then the liquid microemulsion preparation is easily formed by mixing the liquid base with the liquid carrier. This feature greatly improves the utility and convenience of the microemulsions prepared according to the method of the present invention. Current oil-in-water microemulsions containing the anesthetic propofol can not be prepared in a similar way because they are not thermodynamically stable and require technologically sophisticated emulsification preparation, analogous to the homogenization of the milk. This can not be done in the field or next to the bed. The self-microemulsifiable emulsion base composition of the present invention includes a PEG-containing surfactant that is completely miscible with water, meaning that the PEG-containing surfactant has a high affinity to water and dissolves easily in water, where the surfactant it forms the so-called optically clear "micellar solution" (ie, not a true chemical solution, but rather an apparent solution in which the surfactant actually consists of aggregates that are essentially microemulsion particles lacking chemically distinct nuclei). In a less polar solvent such as ethanol, these kinds of surfactants form true chemical solutions. This is characteristic for forming a spontaneous micellar solution in water which causes the solubilized composition of propofol and this class of surfactant to form a micellar microemulsion in the liquid water-based carrier.

In general, the inventors have discovered that co-surfactants are not required for the formation of microemulsions, while using certain surfactants-containing PEG. PEG-containing surfactant molecules that form acceptable propofol microemulsions in the water-based liquid carrier are characterized by surfactant molecules in which the total length of the polyethylene glycol portion of each surfactant molecule, whether linear or not linear, it is formed 2 to 6 times larger than the length of the hydrophobic hydrocarbon portion of the molecule. A decrease in this ratio below 2 typically does not produce the surfactants that form micellar solutions in water, nor do the surfactants form propofol microemulsions, although such surfactants may form ordinary nanoemulsions. A value above 6 in the ratio of the length of the polyethylene glycol portion to the hydrophobic portion of the surfactant molecule will allow both micellar solutions and microemulsions to form, but will also increase the viscosity and melting point of the surfactant, substantially increasing the time necessary to prepare the base composition. This higher ratio will also reduce the surfactant loading factor, which is defined as the amount of propofol that a given weight of surfactant is able to solubilize in water to In order to form an optically clear microemulsion. The most acceptable PEG-containing surfactants for use as propofol solubilizers share some common characteristics: 1) they are non-ionic and depend on the PEG (polyethoxy) components for their high affinity and for water solubility; 2) the hydrophobic R (s) of the surfactant (s) must be biocompatible and have a melting point near or below the body temperature and 3) the chain or PEG chains attached to one end of the R group (s) must be large enough in total length to limit the size of the micellar aggregates of surfactant in water, which occur due to the increasing interaction of PEG / water. This last characteristic ensures that the smallest type of micellar aggregates (or optically clear microemulsions that resemble in scale micellar aggregates) that are formed in water are thermodynamically stable. Typically, the concentration of the cloud point of the preferred pure surfactants in water is very high or nonexistent. More specifically, the surfactant that contains More preferred PEG for use in the preparation of the base composition of the present invention can be defined as belonging to one of two classes. A first class of surfactant containing PEG has the general structure of [POE (n)] subm-R '-R; where POE is a residue of polyoxyethylene (also known as a polyethylene glycol or PEG residue) of number n of -mer and having xa of these POE functional groups attached to R '; where the value of m is from one to three; wherein R 'is a bond residue, particularly glyceryl, sorbitan, ester, amino or ether (oxygen) functions; and wherein R is a hydrophobic residue consisting of saturated or unsaturated alkyl or alkylphenyl groups. Examples of nonionic surfactants with this first class are polyoxyethylene monoalkyl ethers, polyoxyethylene alkylphenols, polyethylene glycol fatty acid monoesters, polyethylene glycol glycerol fatty acid esters, polyoxyethylene sorbitan fatty acid esters and polyoxyethylene sterols. Mixtures of any of these chemical residues also function as good surfactants for the purposes of the invention. A useful and preferred subclass within the first class of PEG-containing surfactants includes surfactants having a structure defined by a ratio of A, which is the total number of POE-zper units in the surfactant (given by the product of number n of -mer and the number m of chain of total PEG per molecule), a B, which is the number of carbons in the functional group R hydrophobic, which is between approximately 0.7 and 4; preferably with A / B being in the range from about 1 to 2.

Examples of nonionic surfactants within this subclass are PEG-15 monolaurate, PEG-20 monolaurate, PEG-32 monolaurate, PEG-48 monolaurate, PEG-13 monooleate, PEG monooleate. -15, PEG-20 monooleate, PEG-32 monooleate, PEG-72 monooleate, PEG-15 monostearate, PEG-660 hydroxystearate ("Solutol®" from BASF Corporation), monostearate of PEG-23, monostearate of PEG-40, monostearate of PEG-72, glyceryl laurate of PEG-20, glyceryl laurate of PEG-30, glyceryl stearate of PEG-20, glyceryl oleate of PEG-20, glyceryl monooleate of PEG-30, glyceryl monolaurate from PEG-30, glyceryl monolaurate from PEG-40, sorbitan monooleate from PEG-20 (polysorbate 80, Tween 80), sorbitan monolaurate from PEG-20 (Tween 20), sorbitan monopalmitate from PEG-20 (Tween 40) and sorbitan stearate of PEG-20 (Tween 60), sorbitan monooleate of PEG-40, sorbitan monolaurate of PEG-80, lauryl ether of POE-23, oleyl ether of PEO -20, nonyl phenol series of PEG 30-60 (Triton N series), octyl phenol series of PEG 30-55 (Triton X series, particularly X-305 (POE 30) and X-405 (POE 40) . Mixtures of any of these surfactants also work well. A second class of PEG-containing surfactants is derived from triglyceride oils and has the general structure of [R '- (POE) subn] sub3-glyceride, where POE is a polyoxyethylene residue (also known as a residue). of polyethylene glycol or PEG) of number n of -mer, inserted between fatty acid acyl residues R 'and a glycerol residue (glyceride) which has been bound directly before the polyethoxylation to the acyl residues as a common triglyceride . Examples of nonionic surfactants with this second class are polyoxyethylated vegetable oils, such as polyethoxylated corn oil or polyethoxylated castor oil. Mixtures of these polyethoxylated vegetable oils also function as good surfactants for the purposes of the invention. A preferred subclass within the second class of PEG-containing surfactants includes surfactants having a structure further defined by a ratio of A, which is the total number of POE-zaer units in the surfactant (given by the product of number n of -mez- and the number 3 chain of PEG per total molecule), to B, which is the number of carbons in the 3 residues R'of fatty acid that is between approximately 0.5 and 3; preferably with A / B being in the range from about 0.6 to 1.5. Examples of nonionic surfactants within this subclass are palm seed oil of PEG-40, hydrogenated castor oil of PEG-50, castor oil of PEG-40, castor oil of PEG-35 (eg, Cremaphor® -35), PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil and PEG-60 corn oil. The Mixtures of these surfactants also work well for the purposes of the invention. '" A third class of surfactants containing PEG, analogous to the two above, can theoretically be made by polyethoxylation of diester compounds consisting of biocompatible dialcohol fatty acid esters, such as propylene glycol. The inventors expect that these compounds will have substantially the same properties as those described in the first two classes of PEG-containing surfactants, while the ratio of fatty acid carbons from residue R to mer number of PEG is maintained between 0.5 to 4. Finally , it should be noted that mixtures of the two chemically defined classes of surfactants containing PEG also work well in the present invention. All preferred PEG-containing surfactants are compatible and work well when used as mixtures, but it is a feature of the invention that particular mixtures are not necessary or preferred and preferred surfactants have been selected to function as simple agents in the production of microemulsions. This is in contrast to previous inventions that specify certain mixtures of surfactant directed to achieve particular proportions of "HLB" (hydrophobic lipophilic balance) for a mixture of 2 or more types of surfactants.

Adding a surfactant containing PEG, such as PEG-660 hydroxystearate (Solutol® from BASF Corporation) in water causes the formation of a "micellar solution" of self-aggregated surfactant groupings of about 12 nm in diameter. The solution forms an optically clear dispersion analog to a microemulsion, but technically not a microemulsion because the homogeneous liquid contains only a component other than water. With the addition of a hydrophobic host solute, such as propofol, such micellar solutions are generally described as "microemulsions". However, it is questionable whether the molecular structure of such aggregates is always that of the classical two-component lipid-in-water emulsion containing a fine drop of hydrophobic substance "coated" with surfactant. The Doppler light scattering studies made by the inventors show that the microemulsions formed from all the classes of surfactants described in the present invention have diameters as small as 2 nm (120 Angstroms), meaning that the particle radius is just less than the length of a single molecule of uncoiled surfactant (approximately 7 nm). Such small, simple structures have no room for a hydrophobic liquid drop core of classical emulsion, but must contain their included solvents and hydrophobic host molecules (such as propofol) in a nucleus relatively rolled,. tightly interwoven by the hydrophobic heads of the surfactant assembly, which interlock and probably reach from opposite sides of the micelle. Depending on the specific PEG-containing surfactant selected for use in the preparation of the liquid microemulsion preparation, propofol concentrations of up to about 4% by weight of propofol to the volume of the microemulsion preparation are achievable. However, in this respect due to the relatively low viscosity of Solutol®, this is the most preferred PEG-containing surfactant since the use of Solutol® produces a microemulsion having the highest concentration of propofol of about 4%. Again, the microemulsion preparation is transparent. In the four (4) component base composition of the present invention, water-based microemulsion preparations contain propofol concentrations of up to about 10% by weight of propofol so that the volume of the microemulsion is achievable by including a miscible solvent in water and ethanol in the base composition. In this embodiment, the base composition consists essentially of: a surfactant containing PEG; liquid propofol; a solvent miscible in water; and ethanol, in which the relative concentration of surfactant to propofol included in the composition base is not less than about three (3) parts and preferably about three (3) to five (5) parts of surfactant to about one (1) part of propofol, the relative concentration of water miscible solvent to propofol is about three (3) to five (5) parts of solvent to approximately ten (10) parts of propofol and the relative concentration of ethanol to propofol is from about five (5) to six (6) parts of ethanol to about ten (10) parts of propofol. In this embodiment the preferred method for producing the self-microemulsifiable emulsion base composition consists essentially of mixing in any order a predetermined amount of PEG-containing surfactant, preferably heated to a preparation temperature above its melting point, with the amounts predetermined liquid propofol, solvent miscible in water and ethanol as co-solvent. The mixing is carried out by simply stirring or stirring the components for a few minutes or less until the solution becomes clear. The resulting base composition is a self-emulsifiable, anhydride, homogeneous and optically clear liquid with low viscosity at the preparation temperature. The water-based microemulsion is then prepared at room temperature by mixing the base composition with a predetermined amount of the liquid vehicle that it contains water and isotonic to the blood, such as 0.9% saline, 5% dextrose or other isotonic solutions containing a crystalloid or a colloid which is proposed for intravenous administration. Again, the mixing is carried out by simply mixing or stirring the components for a few minutes or less until the solution becomes clear. The resulting microemulsion preparation can contain propofol concentrations of up to about 10% by weight of propofol to the volume of the preparation and still exhibits the characteristics of a microemulsion. The microemulsion is thermodynamically stable at room temperature and is optically clear, but has a pale yellow color due to the inclusion of propofol. Examples # 4, # 6 and # 7 at the end of this section set forth specific examples of this embodiment in the preparation of a self-microemulsifiable emulsion base composition and then using the base to prepare a microemulsion containing propofol concentrations of about 1. % (w / v) and up to approximately 10% (w / v). Example # 5 establishes the results for the administration of a microemulsion containing a 10% propofol concentration prepared as in Example # 4 for a canine. Example # 8 establishes the results of the administration of a microemulsion containing a concentration of propofol of 1% prepared as in Example # 7 for a canine. This formulation of the present invention also exhibits substantial advantages over other attempts to solubilize propofol for use as an anesthetic. Clearly, the ability of this embodiment to produce propofol concentrations in a microemulsion of up to 10% by weight of the microemulsion is a further substantial improvement over the oil-in-water type preparations. And comparing this embodiment of the present invention with the formulation described in the '511 patent reveals that the present invention is once again observed to be a significant improvement over the formulation described in the' 511 patent. In addition to the fact that this embodiment of the present invention produces a microemulsion that is transparent in all water concentrations and therefore superior to the water-in-oil formulation of the? 511, this modality also contains fewer components than the components described in the patent? 511 that in this modality does not contain a hydrophobic surfactant. This embodiment of the present invention also exhibits all the advantages and features of the preferred embodiment and exhibits at least two additional advantages. An obvious advantage is that even higher concentrations of propofol are achievable, making the anesthetic useful in large mammals (for example, a 500 kg horse requires approximately 1.5 grams of propofol for the induction of general anesthesia, which is 75 ml of 5% microemulsion, but 375 ml of 1% emulsion). Another advantage relates to the ability to be able to retard the mixing of the base composition with the liquid vehicle. In the preferred embodiment, it was noted that the base composition can be added to the liquid vehicle at any time after the base was prepared, but that the base needs to be re-heated before doing so. In this mode there is no need to reheat the base, because it does not solidify at room temperature, instead it remains a thermodynamically stable and transparent liquid. As a result, the base prepared in accordance with this formulation can be stored indefinitely and sometimes shipped to a laboratory, clinic or hospital where it can be added directly to a liquid vehicle in order to form the injectable microemulsion intravenously. A specific example of the ability to use a base composition that has been prepared in accordance with this embodiment is set forth in Example # 9. Water-miscible biocompatible solvents for use in the present invention should be biocompatible and non-toxic to mammals and generally be selected from one of three (3) ester groups: monoesters, diesters and triesters. Esters are formed to from a group of liquids composed of aliphatic acid (saturated and unsaturated, straight chain and branched) or alcohol 'residues. The monoesters are composed of residues from mono-alcohols and mono-acids. The diesters are composed of residues of mono-acids and di-alcohols or from di-acids and mono-alcohols. The triesters are composed of mono-acids and tri-alcohols or tri-acids and mono-alcohols. For monoesters, the preferred saturated or unsaturated aliphatic acid residues are selected from the group containing acetic acid, propionic or other saturated or unsaturated biocompatible aliphatic acids. Fatty acids with an even number of Csub8 carbons of length or greater are preferred because of the unpleasant taste and odor of the short chain fatty acids and the ester preparations containing them. The saturated or unsaturated aliphatic alcohol residue for the ester is preferably selected from the group containing ethyl, n-propyl alcohol or other saturated or unsaturated biocompatible aliphatic alcohols. Many such alcohols are straight chain mono-alcohols of eight or more carbons, such as n-octanol. Alkyl alcohols with an even number of carbons are preferred. Preferred examples of monoester solvents are ethyl oleate, propylene glycol dicaprylate, isopropyl myristate, ethyl laurate, butyl oleate, oleyl acetate, oleyl propionate, octyl octanoate, octyl decanonate and oleyl oleate.

Preferred diesters are also selected due to the biocompatibility of alcohols and carboxylic acids derived from ester residues, as well as the selection of residues to formulate an ester that is liquid at a temperature close to the body. Each residue will preferably correspond to a carboxylic acid or alcohol that is biocompatible. A diester may be composed of two carboxylic acid residues condensed with a dihydroxy or one di-carboxylic acid residue with two mono-alcohols. For diesters derived from di-alcohols and mono-acids, the preferred di-alcohol is selected from the group of small biocompatible di-hydroxy alcohols, such as propylene glycol, 1,2-butanediol and 1,3-butanediol. The preferred aliphatic mono-acids are selected from the group containing acetic or propionic acid or the aliphatic acids which are fatty acids with an even number of Csub8 carbons of length or greater. Preferred examples of such liquid diesters based on di-alcohols and mono-acids are propylene glycol dilaurate, propylene glycol dioleate, propylene glycol dicaprylate and 1,2-butane glycol dioleate. For the diesters derived from di-acids and mono-alcohols, the di-acids can generally be selected from the group of di-carboxylic acids, in which the aliphatic acid residues are di-carboxylic acids saturated or unsaturated biocompatible aliphatics such as succinic acid, fumaric acid, malic acid, malonic acid, glutaric acid, 2-oxoglutaric acid or higher chain dicarboxylic acids such as sebasic acid. For diesters derived from monoalcohols, the mono-alcohols for use with short dicarboxylic acids (such as succinic acid, fumaric acid, malic acid, malonic acid, glutaric acid, 2-oxoglutaric acid) are selected from the group of monohydroxy biocompatible alcohols of 10 carbons or more, with particular attention to capril alcohol and oleyl alcohol as forming esters with suitably low melting points but also adequately low irritating qualities of tissue and acceptable odor. This usually requires esters with a total carbon number of 16 or more. Preferred examples of such liquid diesters based on di-acids and mono-alcohols are dioleyl fumarate, dioleyl malonate and di-propyl sebac. Mixed esters such as capryl oleoyl succinate are also suitable. Compatible triesters can be composed of biocompatible tri-alcohol residues, such as glycerol and mono-acids. Alternatively, the triesters can also be made from esters of biocompatible tricarboxylic acids, such as citric and isocitric acid and monoalcohols. Preferred tri-alcohol triesters include natural liquid triglycerides and others - synthetic triglycerides. These triglycerides include but are not restricted to, glycerol trioleate, medium chain triglyceride oil and mixed glyceride esters in which acyl groups derived from caprylic and oleic acid are preferred. The corresponding liquid triesters derived from tricarboxylic acid esters and monoalcohols include but are not restricted to, tricapril citrate, trioleyl citrate, tricapryl isocitrate, trioleyl isocitrate and esters of mixed alcohol of citric and isocitric acid. Finally, the water-miscible biocompatible solvents for use in the present invention can also be selected from the group of benzoic acid esters of ethanol, n-propanol, isopropanol and benzyl alcohol. Oleaic acid can also be used directly as a solvent. Depending on the miscible solvent in specific water selected for use in preparing the anesthetic solution, propofol concentrations of up to 10% by weight of propofol for the volume of the microemulsion preparation are achievable. However, in this regard, due to the relatively low viscosities of the surfactant containing PEG Solutol® and the ethyl oleate solvent, these substances are most preferred in that their use produces an anesthetic microemulsion containing the highest concentration of propofol of 10% by weight of propofol for the volume of the microemulsion liquid. Again, such an anesthetic is a transparent propofol microemulsion, which has a very faint opalescence. When it is further diluted to 6% by weight propofol / total liquid volume, this microemulsion will exhibit excellent optical clarity. It will be apparent to those skilled in the art that in addition to the solvents described above, any of the solvents can be mixed with any of the other solvents without departing from the scope of the present invention. EXAMPLES Example # 1: Microepulsion of 1% Propofol (weight / volume = w / v) in saline using PEG 23 monostearate alone. One gram of PEG-23 monostearate was heated in a 20 ml glass bottle sufficiently to melt the surfactant, after which 100 mg of propofol was mixed. Before solidifying this mixture, 9 ml of hot physiological saline (0.9% w / v sodium chloride in water, hereinafter referred to as "saline") was mixed to give a final microemulsion containing 1% propofol by weight . This emulsion is optically transparent (with some minor opalescence) and colored very pale yellow from propofol. This solution is comparable to product of 1% commercial propofol, but does not contain soy or egg products to support microbial growth. Example # 2: 4% Propofol micro-emulsion (w / v) in saline using Solutol HS-15 alone. To make 4% propofol, 3.2 grams of Solutol HS-15 were melted as previously described and 400 mg of propofol was added and mixed to form the base emulsion. Then hot salt was slowly mixed in the base emulsion. After adding 4 ml of saline, a characteristic gel is formed, the characteristic of the resulting bicontinuous fluid from approximately equal values of water and emulsifying agent. After a total of 6.4 ml of saline was added, a total of 10 ml of optically clear microemulsion of free flow of drug in water was obtained, which is 32% by weight of Solutol HS-15. Such emulsions and solutions contain approximately 30% Solutol-HS are of sufficiently low viscosity for intravenous injection without pain, according to the pharmacological literature of Solutol HS-15. The resulting microemulsion contains a propofol concentration of 4% w / v (4 times the standard commercial concentration present) and was found to be suitable for direct intravenous injection, as are all the microemulsions based on Solutol HS-15 described below. Example # 3: Anesthesia of a dog with the microemulsion prepared in Example # 2. An animal of 30.5 kg has been pre-treated with 25 mg of acepromazine and 0.2 mg of atropine. He was conscious with his eyes open, but sedated when he injected with 3 ml (120 mg of propofol = approximately 4 mg / kg) of 4% propofol solution from example # 2 directly into a leg vein. Within 30 seconds the dog relaxed completely and assessed quickly on level 3, plane 2 of anesthesia, without reflex of flicker, inability to hold the jaw closed and did not arch for endotracheal intubation. The apnea lasted 15 seconds, then spontaneous breathing began. The animal tolerated the endotracheal tube for 35 minutes before opening the eyes and began the bowing behavior, requiring the removal of the tube. The animal recovered completely within one hour. When the same animal was treated identically the following day, but without pre-treatment of acepromazine or atropine, it showed awareness and bowing 12 minutes after the post-anesthetic administration. When a fully conscious animal was given intravenously without pretreatment, it was observed during the injection that this microemulsion does not cause any effect prior to the unconsciousness, except for a brief patting of the tongue (it is considered indicative of the animal anesthetic test). The animal showed no evidence of nausea / vomiting or IV injection pain.

Example # 4: Preparation of 10% (w / v) propofol microemulsion in saline using Solutol HS-15, ethanol and ethyl oleate as the hydrophobic co-solvent. To make 10% propofol microemulsion, 3.0 grams of Solutol HS-15 were melted as previously described and 1.0 g of propofol, 0.3 g of ethyl oleate and 0.6 grams of ethanol were added and mixed to form the base emulsion. Then the hot salt was mixed slowly in the base emulsion. After the addition of 5.1 ml of saline, a total of 10 ml of optically clear (but slightly opalescent) microemulsion of free drug flow in water was obtained, which is 30% by weight of Solutol HS-15. The emulsion described is 10% by weight of propofol (10 times the commercial concentration) and after filtration of 0.2 microns it was found suitable for slow intravenous direct injection. MCT and benzyl acetate oil at the same weight as ethyl oleate can replace ethyl oleate in this 10% preparation, although for these co-solvents an equal weight ratio of ethanol to propofol should typically be used for the highest concentrations of propofol such as 10% p / v. Thus, 3.0 grams of Solutol, 1.0 grams of propofol, 1.0 grams of ethanol, 0.3 grams of MCT and 4.7 grams of saline, in the above mixture, would be used to obtain a 10% propofol microemulsion using MCT.

Example # 5: Anesthesia of a dog with 10% w / v microemulsion prepared as in Example # 4 using ethyl oleate. An animal of 23.3 kg was not pre-treated. It was injected with 1.5 ml (150 mg of propofol = about 6 mg / kg) of 10% propofol solution of example # 4 directly into a leg vein. Within 30 seconds the dog relaxed and was quickly assessed at level 3, level 2 of anesthesia, without reflex of flicker, inability to hold the jaw closed and without arching in the endotracheal intubation. Apnea was not noticed. The animal tolerated the endotracheal tube for 11 minutes before opening its eyes and initiated bowing behavior, necessitating removal of the tube. The animal raised its head at 15 minutes after giving anesthesia. Example # 6: Preparation of 5% Propofol microemulsion w / v in saline using Solutol HS-15, ethanol and ethyl oleate as a hydrophobic co-solvent. To make 5% propofol, 2.5 grams of Solutol HS-15 were melted as previously described and 0.5 g of propofol, 0.25 g of ethyl oleate and 0.5 grams of ethanol were added and mixed to form the base emulsion. Then hot saline (50 ° C) was slowly mixed in the base emulsion. After the addition of 6.25 ml of saline, a total of 10 ml of optically clear flow microemulsion was obtained % drug free in water, which is 25% by weight of Solutol HS-15. After sterile filtration this is suitable for injection. This 5% microemulsion was found to maintain excellent optical clarity and stability for more than one year at room temperature. Example # 7: Preparation of 3% (w / v) of propofol microemulsion in saline using Solutol HS-15, ethanol and ethyl oleate as a hydrophobic co-solvent. To make 3% propofol microemulsion which is suitable for further dilution, with complete clarity and without opalescence, at lower concentrations such as 2% or 1% the following method was used: 2.4 grams of Solutol HS-15 were melted as previously described and 0.3 g of propofol, 0.15 g of ethyl oleate and 0.3 grams of ethanol were added and mixed to form the base emulsion. Then hot saline (50 ° C) was slowly mixed into the emulsion base. After the addition of 6.85 ml of saline, a total of 10 ml of 3% free-flowing, optically clear microemulsion in saline was obtained, which is 24% by weight of Solutol HS-15. After sterile filtration this is suitable for injection. Additional dilutions at 2% or 1% of drug (w / v) as used below can be done by the simple addition of physiological saline to this microemulsion. Example # 8: Anesthesia of a dog with 1% (w / v) of - propofol microemulsion, prepared as in Example # 7 using MCT instead of ethyl oleate, then diluted with saline. To make lower concentrations of propofol, a part of the microemulsion of Example # 4 or the equivalent made with MCT instead of ethyl oleate, can be appropriately diluted with 3 parts of saline for a final propofol concentration of 1%. Microemulsions greater than 4% propofol typically exhibit brief turbidity in the addition of salt, which is reduced and again becomes transparently opalescent in the mixing. Properly constructed microemulsions of less than 3% propofol as in Example # 7, which have a higher proportion of Solutol to propofol, typically remain completely transparent optically after dilution and mixing. Such microemulsions are stable to the eye with or without refrigeration, for at least 8 weeks. Such a 1% propofol microemulsion was made as in Example # 4 but replacing ethyl oleate with MCT and finally diluted to 1% propofol content with saline. A 15.4 kg dog pretreated with 15 mg of acepromazine and 0.2 mg of atropine exhibited a lapse of 15 minutes between anesthesia and return of the reflex to arch, after 70 mg (7 ml = approximately 3 mg / ml) was given. this 1% preparation of - propofol by IV. This is indistinguishable at the dose of propofol anesthetic needed and typically responds to them, when commercially available 1% propofol preparations are used in dogs. Example # 9: Preparation of liquid anhydrous microemulsion base containing 13.3% (w / v) propofol, using Solutol HS-15, ethanol and ethyl oleate as a hydrophobic co-solvent. To make 13.3% propofol liquid microemulsion base suitable to reconstitute 5% propofol microemulsion at room temperature with saline, 80.0 grams of Solutol HS-15 were melted as previously described and 16.0 g of propofol, 8.0 g of ethyl oleate and 16.0 grams of ethanol and mixed to form the microemulsion base. The base can then be filtered and stored at room temperature in a brown glass jar under air or vacuum. For reconstitution, an adequate amount of microemulsion base is removed from the bottle with a syringe and needle and reconstituted with sterile physiological saline at room temperature for injection. A ratio of 8 parts of saline to 3 parts of liquid base was used, gently stirring the mixture for 1 to 2 minutes in the syringe or a second bottle at room temperature. The 5% w / v microemulsion preparation resulting from propofol is suitable for intravenous injection after approximately 5 minutes of spontaneous bubbling.

- - Although the present invention has been described in its preferred embodiment and in certain other embodiments, it will be recognized by those skilled in the art that other embodiments and features may be provided without departing from the scope of the invention, which is defined by the appended claims.

Claims (73)

1. - CLAIMS 1. A microemulsifiable base composition consisting of: a) propofol; and b) a nonionic surfactant.
2. 2. The base composition of claim 1 wherein the nonionic surfactant is included in the base composition in a concentration of about eight (8) parts or more of the nonionic surfactant to one (1) part of propofol.
3. 3. The base composition of claim 1 wherein the propofol contains free alpha tocopherol.
4. 4. The base composition of claim 1 wherein the nonionic surfactant contains polyethylene glycol.
5. 5. The base composition of claim 1 wherein the nonionic surfactant is PEG-660 hydroxystearate.
6. 6. The base composition of claim 1 wherein the base composition is anhydrous.
7. 7. The base composition of claim 1 wherein the base composition is homogeneous.
8. 8. The base composition of claim 1 wherein the base composition is optically clear.
9. 9. A microemulsion consisting of: a) the base composition of claim 1, 2, 3, 4, 5, 6, 7 or 8; Y - - b) a liquid vehicle 10.
10. The microemulsion of claim 9 in which the liquid vehicle contains water.
11. The microemulsion of claim 9 in which the liquid carrier is isotonic to the blood.
12. The microemulsion of claim 9 in which the liquid carrier is 0.9% saline in water.
13. The microemulsion of claim 9 in which the liquid carrier is 5% dextrose in water.
14. The microemulsion of claim 9 in which the liquid carrier is an isotonic solution containing a crystalloid.
15. 15. The microemulsion of claim 9 wherein the liquid carrier is an isotonic solution containing a colloid.
16. 16. The microemulsion of claim 9 wherein the microemulsion is thermodynamically stable.
17. 17. The microemulsion of claim 9 wherein the microemulsion is optically transparent.
18. 18. The microemulsion of claim 9 wherein the concentration of the propofol is included in the microemulsion in an amount of up to about 1% by weight of the propofol for the volume of the microemulsion.
19. 19. The microemulsion of claim 9 wherein the concentration of the propofol is included in the - microemulsion in an amount of up to about 4% by weight of propofol for the volume of the microemulsion.
20. 20. The microemulsion of claim 9 which is injectable intravenously in a mammal.
21. 21. A self-microemulsifiable base composition consisting of: a) propofol; b) a non-ionic surfactant; c) a solvent miscible in water; and d) ethanol.
22. 22. The base composition of claim 21 wherein the relative concentration of the nonionic surfactant to propofol included in the base composition is from about three (3) to five (5) parts of surfactant to about one (1) part of propofol. , the relative concentration of the water miscible solvent to propofol is about three (3) to five (5) parts of solvent to about ten (10) parts of propofol, and the relative concentration of ethanol to propofol is approximately five (5) to six (6) parts of ethanol to about ten (10) parts of propofol.
23. 23. The base composition of claim 21 wherein the relative concentration of the nonionic surfactant to propofol included in the base composition is not less than about three (3) parts of surfactant a - - about one (1) part of propofol, the relative concentration of the water-miscible solvent to propofol is about three (3) to five (5) parts of solvent to about ten (10) parts of propofol, and the relative concentration of ethanol to Propofol is approximately five (5) to six (6) parts of ethanol to approximately ten (10) parts of propofol.
24. 24. The base composition of claim 21 wherein the propofol contains free alpha tocopherol.
25. 25. The base composition of claim 21 wherein the nonionic surfactant contains polyethylene glycol.
26. 26. The base composition of claim 21 wherein the nonionic surfactant is PEG-660 hydroxystearate.
27. 27. The base composition of claim 21 in which the water-miscible solvent is ethyl oleate.
28. 28. The base composition of claim 21 wherein the base composition is anhydrous.
29. 29. The base composition of claim 21 wherein the base composition is homogeneous.
30. 30. The base composition of claim 21 wherein the base composition is optically clear.
31. 31. A microemulsion consisting of: a) the base composition of claim 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30; Y 4 - . 4 - b) a liquid vehicle.
32. 32. The microemulsion of claim 31 in which the liquid vehicle contains water.
33. 33. The microemulsion of claim 31 in which the liquid carrier is isotonic to the blood.
34. 34. The microemulsion of claim 31 wherein the liquid vehicle is 0.9% saline in water.
35. 35. The microemulsion of claim 31 in which the liquid carrier is 5% dextrose in water.
36. 36. The microemulsion of claim 31 in which the liquid carrier is an isotonic solution containing a crystalloid.
37. 37. The microemulsion of claim 31 wherein the liquid carrier is an isotonic solution containing a colloid.
38. 38. The microemulsion of claim 31 wherein the microemulsion is thermodynamically stable.
39. 39. The microemulsion of claim 31 wherein the microemulsion is optically transparent.
40. 40. The microemulsion of claim 31 wherein the concentration of propofol is included in the microemulsion in an amount of up to about 5% by weight of the propofol for the volume of the microemulsion.
41. 41. The microemulsion of claim 31 wherein the concentration of the propofol is included in the microemulsion in an amount of up to about 10% by weight of the propofol for the volume of the microemulsion.
42. 42. The microemulsion of claim 31 which is injectable intravenously in a mammal.
43. 43. A method for preparing the self-microemulsifiable base composition of claim 1 comprising the steps of: a) heating a predetermined amount of the non-ionic surfactant to the preparation temperature above its melting point; and b) combining the nonionic surfactant and a predetermined amount of the propofol.
44. 44. A method for preparing the self-microemulsifiable base composition of claim 21 comprising the steps of: a) heating a predetermined amount of the nonionic surfactant to the preparation temperature above its melting point; and b) combining the nonionic surfactant and a predetermined amount of the miscible solvent in water, ethanol and propofol.
45. 45. The base composition as in claim 1 wherein the nonionic surfactant has the general structure [POE (n)] subm-R '-R; where POE is a polyoxyethylene residue (also known as polyethylene residue) - - glycol or PEG) of number n of -mer, and having m of these POE functional groups attached to R '; where the value of m is from one to three; wherein R 'is a bond residue, particularly glyceryl, sorbitan, ester, amino or ether (oxygen) functions; and wherein R is a hydrophobic residue consisting of saturated or unsaturated alkyl or alkylphenyl groups.
46. 46. The base composition as in claim 45 wherein the nonionic surfactant is selected from the group consisting of polyoxyethylene monoalkyl ethers, polyoxyethylene alkylphenols, polyethylene glycol fatty acid monoesters, polyethylene glycerol fatty acid esters glycol, fatty acid esters of polyoxyethylene sorbitan and polyoxyethylene sterols.
47. 47. The base composition as in claim 45 wherein the structure of the non-ionic surfactant is further defined by a ratio of A, the total number of meme-units of POE in the surfactant (given by the product of the number n of - xaex and the m number of the total PEG chain per molecule); to B, the number of carbons in the hydrophobic functional group R, is between approximately 0.7 and 4, preferably with A / B in the range of approximately 1 to 2.
48. 48. The base composition as in claim 47 in which the non-ionic surfactant is selected from the group consisting of PEG-15 monolaurate, P.EG-20 monolaurate, PEG-32 monolaurate, PEG-48 monolaurate, PEG-13 monooleate, P-monooleate. .EG-15, PEG-20 monooleate, P.EG-32 monooleate, PEG-12 monooleate, PEG-15 monostearate, PEG-660 hydroxystearate (Solutol® from BASF Corporation), PEG-23 monostearate , PEG-40 monostearate, PEG-12 monostearate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-2 glyceryl oleate, PEG-30 glyceryl monooleate, glyceryl monolaurate of PEG-30, glyceryl monolaurate of PEG-40, sorbitan monooleate of PEG-20 (polysorbate 80, Tween 80), sorbitan PEG 20 monolaurate (Tween 20), sorbitan PEG-20 monopalmitate, (Tween 40) and sorbitan PEG 20 stearate (Tween 60), sorbitan PEG-40 monooleate, sorbitan PEG-80 monolaurate, POE-23 lauryl ether, oleyl ether of POE-20, nonyl phenol series of PEG 30-60 (Triton N series) and octyl phenol series of PEG 30-55 (Triton X series, particularly X-305 (POE 30) and X-405 (POE 40
49. 49. The base composition as in claim 46 or 47 in which the nonionic surfactant has the general structure [R- (POE) subn] sub3-glyceride, wherein POE is a polyoxyethylene residue (also known as a residue of polyethylene glycol or PEG) of the number n of -mer, insert between fatty acid acyl residues R and a glycerol residue (glyceride), which has been attached before the polyethoxylation, directly to the acyl residues as a common triglyceride.
50. 50. The base composition as in the claim 49 in which the non-ionic surfactant is a polyoxyethylated vegetable oil.
51. 51. The base composition as in claim 49 wherein the structure of the non-ionic surfactant is further defined by the ratio of A, the total number of POE-units of POE in the surfactant (given by the product of the number n of - mex and number 3 of the total PEG chain per molecule); to B, the carbon number in the residues R of the fatty acid 3 is between about 0.5 and 3, preferably with A / B being in the range of about 0.6 to 1.5.
52. 52. The base composition as in claim 51 wherein the nonionic surfactant is selected from the group consisting of PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil. , PEG-35 castor oil (e.g., Cremaphor®-35), PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil and corn oil. PEG-60.
53. 53. The base composition as in the claim 21 in which the non-ionic surfactant has the general structure [POE (n)] subm-R '-R; wherein POE is a polyoxyethylene residue (also known as a polyethylene glycol or PEG residue) of n number of -221er, and having m of these POE functional groups attached to R '; where the value of ai is from one to three; wherein R 'is a bond residue, particularly glyceryl, sorbitan, ester, amino or ether (oxygen) functions; and wherein R is a hydrophobic residue consisting of saturated or unsaturated alkyl or alkylphenyl groups.
54. 54. The base composition as in claim 53 in which the nonionic surfactant is selected from the group consisting of polyoxyethylene monoalkyl ethers, polyoxyethylene alkylphenols, polyethylene glycol fatty acid monoesters, polyethylene glycerol fatty acid esters glycol, fatty acid esters of polyoxyethylene sorbitan and polyoxyethylene sterols.
55. 55. The base composition as in claim 53 wherein the structure of the non-ionic surfactant is further defined by a ratio of A, the total number of meme-units of POE in the surfactant (given by the product of the number n of - nier and the m number of the total PEG chain per molecule); to B, the number of carbons in the hydrophobic functional group R, is between approximately

    0. 7 and 4, preferably with A / B in the range of about 1 to 2.
56. 56. The base composition as in claim 55 in which the nonionic surfactant is selected from the group consisting of PEG-15 monolaurate, monolaurate PEG-20, PEG-32 monolaurate, PEG-48 monolaurate, PEG-13 monooleate, PEG-15 monooleate, PEG-20 monooleate, PEG-32 monooleate, PEG-12 monooleate, PEG-12 monostearate 15, PEG-660 hydroxy-stearate 15 (Solutol® from BASF Corporation), PEG-23 monostearate, PEG-40 monostearate, PEG-12 monostearate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, glyceryl stearate of PEG-20, glyceryl oleate of PEG-20, glyceryl monooleate of PEG-30, glyceryl monolaurate of PEG-30, glyceryl monolaurate of PEG-40, sorbitan monooleate of PEG-20 (polysorbate 80, Tween 80), sorbitan PEG 20 monolaurate (Tween 20), sorbitan PEG-20 monopalmitate, (Tween 40) and sorbitan PEG 20 stearate (Tween 60), sorbitan PEG-40 monooleate, sorbitan PEG-80 monolaurate, POE-23 lauryl ether, oleyl ether of POE-20, nonyl phenol series of PEG 30-60 (Triton N series) and octyl phenol series of PEG 30-55 (Triton X series, particularly X-305 (POE 30) and X-405 (POE 40
57. 57. The base composition as in claim 54 or 55 in which the nonionic surfactant has the general structure [R- (POE) subn] sub3-glyceride; where POE is a polyoxyethylene residue (also known as a polyethylene glycol or PEG residue) of the number n of -mex, inserted between fatty acid acyl residues R and a glycerol residue (glyceride), which has been bound before polyethoxylation, directly to the acyl residues as a common triglyceride.
58. 58. The base composition as in claim 57 wherein the nonionic surfactant is a polyoxyethylated vegetable oil.
59. 59. The base composition as in claim 57 in which the structure of the non-ionic surfactant is further defined by the ratio of A, the total number of POE-units of POE in the surfactant (given by the product of the number n of - 2pe.ry and number 3 of the total PEG chain per molecule); to B, the carbon number in the residues R of the fatty acid 3 is between about 0.5 and 3, preferably with A / B being in the range of about 0.6 to 1.5.
60. 60. The base composition as in the claim 59 in which the nonionic surfactant is selected from the group consisting of palm seed oil of PEG-40, hydrogenated castor oil of PEG-50, castor oil of PEG-40, castor oil of PEG-35 ( eg, Cremaphor®-35), PEG-60 castor oil, hydrogenated castor oil from PEG-40, PEG-60 hydrogenated castor oil and PEG-60 corn oil.
61. 61. The base composition as in claim 21 in which the water-miscible solvent is a monoester derived from an aliphatic acid and a monoalcohol.
62. 62. The base composition as in claim 61 wherein the monoester is ethyl oleate, isopropyl myristate, ethyl laurate, butyl oleate, oleyl acetate, oleyl propionate, octyl octanoate, octyl decanonate or oleyl oleate.
63. 63. The base composition as in the claim 21 in which the water-miscible solvent is a diester derived from a di-alcohol and a mono-acid.
64. 64. The base composition as in claim 63 wherein the diester is propylene glycol dilaurate, propylene glycol dioleate, propylene glycol dicaprylate or 1,2-butane glycol dioleate.
65. 65. The base composition as in claim 21 in which the water-miscible solvent is a diester derived from a di-acid and a mono-alcohol.
66. 66. The base composition as in the claim 65 in which the diester is dioleyl succinate, diethyl fumarate, diethyl malate or diethyl adipate.
67. 67. The base composition as in claim 21 in which the water-miscible solvent is a triester derived from an aliphatic acid and a trialcohol.
68. 68. The base composition as in the claim 67 in which the triester is a triglyceride.
69. 69. The base composition as in the claim 68 in which the triglyceride is glycerol tri-oleate or a medium chain triglyceride oil.
70. 70. The base composition as in claim 21 wherein the water miscible solvent is a triester derived from an aliphatic tri-carboxylic acid and a mono-alcohol.
71. 71. The base composition as in the claim 70 in which the triester is a triethyl citrate, tributyl citrate or triethyl isocitrate.
72. 72. The base composition as in claim 21 wherein the water-miscible solvent is selected from the group consisting of esters of ethanol, n-propanol, isopropanol of benzoic acid and benzyl alcohol.
73. 73. The base composition as in claim 21 in which the water-miscible solvent is oleic acid.