Formulations for transdermal delivery

Abstract

Stable microemulsions that can contain a wide range of water content can be prepared using an organic mixture containing: a) 5 to 60 wt% of a fatty alcohol or fatty ester; b) from 14% to 40% by weight of ethoxylated castor oil; and c) from 20% to 65% by weight of a cosolvent selected from the group consisting of lower alkyl diethylene glycol ethers, lower alkyl triethylene glycol ethers, and propylene glycol diacetate; and d) from 5% to 25% by weight of a chemical permeation enhancer for the skin.

Description

Technical Field

[0001] The present invention relates to formulations for transdermal administration of drugs. Background Art

[0002] It is known that drugs are administered by dissolving in a transdermal formulation which is applied to the skin. The formulation is absorbed through the skin by osmosis and carries the dissolved drug with it.

[0003] Many common formulations for transdermal delivery are microemulsions containing:

[0004] 1. Aqueous solvents suitable for topical application and transdermal delivery;

[0005] 2. Organic solvents suitable for topical application and transdermal delivery;

[0006] 3. Surfactant or surfactant mixture;

[0007] 4. one or more chemical penetration enhancing additives; and

[0008] 5. Drug to be delivered.

[0009] Microemulsions contain micelles in the dispersed phase with an average size of no more than about 300 nm. In some cases, the microemulsion is an "oil-in-water" microemulsion, in which the dispersed phase is organic and the continuous phase is aqueous. In some cases, the microemulsion is a "water-in-oil" microemulsion, in which the dispersed phase is aqueous and the continuous phase is organic. Microemulsions for transdermal delivery are described in the following articles: Lopes, Overcoming the Cutaneous Barrier with Microemulsions, 6(5). Pharmaceutics 52-77(2014).

[0010] Microemulsions for transdermal delivery must meet many competing requirements to be effective. Microemulsions must dissolve the necessary drug at a high enough concentration to make the drug effective. Microemulsions must be absorbed through the skin in high enough amounts to make the drug effective. Microemulsions must remain on the skin without evaporation during the time the drug is expected to be absorbed, which can be several hours for sustained-release formulations. Microemulsions must be stable in storage for a long enough time to be manufactured, transported, stored and used without separating into an oil phase and an aqueous phase. Microemulsions must contain only components that are approved (or can be easily approved) for human contact by regulatory agencies (such as the FDA).

[0011] Many microemulsions have difficulty meeting all of these requirements. Different drugs and different chemical penetration enhancing additives require different ratios of organic solvents and aqueous solvents in the microemulsion to achieve their optimal solubility and skin penetration. However, the need for slow evaporation limits or eliminates the use of lightweight organic components that blend well with water. As a result, many emulsifier packages form stable microemulsions only over a narrow range of organic to water ratios. The optimal organic to water ratio for transdermal delivery of a particular drug may be outside the ratio achievable with the particular organic component.

[0012] What is needed is an organic composition that can maintain a stable microemulsion over a wide range of organic to water ratios so that the organic composition can be formulated to optimal advantage for a variety of drugs. Summary of the invention

[0013] We have discovered that organic compositions comprising fatty alcohols or esters, ethoxylated castor oil and certain co-solvents can maintain stable water-in-oil microemulsions over a relatively wide range of water to organic ratios.

[0014] One aspect of the present invention is an organic composition comprising:

[0015] a) 5 to 60% by weight of fatty alcohol or fatty ester;

[0016] b) 14 to 40% by weight of ethoxylated castor oil; and

[0017] c) 20 to 65 wt% of a co-solvent selected from the group consisting of lower alkyl diethylene glycol ethers, lower alkyl triethylene glycol ethers, and propylene glycol diacetate; and

[0018] d) 5 to 25% by weight of a chemical penetration enhancer for skin,

[0019] The weight percentages are based on the weight of the organic composition.

[0020] The second aspect of the present invention is a microemulsion containing 1 wt % to 40 wt % of water and 60 wt % to 99 wt % of the organic composition as described above.

[0021] A third aspect of the present invention is a method of administering a drug by applying to the skin a microemulsion as described above, the microemulsion containing a dissolved drug in a pharmaceutically effective concentration.

[0022] Using only materials approved for medical use, the organic compositions of the present invention can form stable microemulsions having a wide range of water contents, such as 1 wt % to 30 wt %. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figures 1 to 13Each contains a three-phase diagram illustrating a formulation containing, in each diagram, 1 to 10 parts by weight of a mixture of (a) water, (b) isopropyl palmitate (IPP, a fatty ester), and (c) ethoxylated castor oil, a cosolvent, and glyceryl oleate, a nonionic surfactant skin penetration enhancer (SCoS). Figures 1 to 6 Describe embodiments of the present invention, and Figures 7 to 13 Comparative Examples are described. In each figure, "x" indicates a formulation that formed a stable microemulsion under the conditions described in the example, and "o" indicates a formulation that did not form a stable microemulsion.

[0024] A detailed description of each formulation is contained in the working examples. DETAILED DESCRIPTION

[0025] Organic composition

[0026] The organic composition of the present invention contains at least one fatty alcohol or ester, ethoxylated castor oil, at least one specific co-solvent as described above, and a chemical penetration enhancer for the skin. The organic components should be selected to be suitable for transdermal drug delivery systems. In some embodiments, it will be advantageous if all components of the organic system are approved by the FDA for transdermal delivery; in other embodiments, one or more components that can be approved for transdermal delivery in the future can be selected.

[0027] A component in the organic composition is a fatty alcohol or a fatty ester. In some embodiments, the fat component of the fatty alcohol or fatty ester contains at least 4 carbon atoms or at least 8 carbon atoms or at least 10 carbon atoms or at least 12 carbon atoms on average. In some embodiments, the fat component contains at most 32 carbon atoms or at most 24 carbon atoms or at most 18 carbon atoms or at most 16 carbon atoms or at most 12 carbon atoms on average. The example of suitable fatty alcohols includes lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, heptadecanol, pentadecanol and a mixture of these alcohols. In some embodiments, fatty esters are esters of suitable fatty alcohols as described above and lower carboxylic acids (such as acetic acid, propionic acid or butyric acid) with at most 6 carbon atoms. In some embodiments, fatty esters are lower alkyl esters of fatty acids. The example of fatty acid components includes palmitic acid, myristic acid, lauric acid, coconut oil, behenic acid, stearic acid, oleic acid, undecylenic acid, caprylic acid and soybean oil and a mixture of these. In some embodiments, the lower alkyl component attached to the fatty acid contains up to 8 carbon atoms, or 6 carbon atoms, or up to 4 carbon atoms; examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl; exemplary esters for organic solvents include isopropyl palmitate, isopropyl myristate, butyl palmitate, and butyl myristate, glyceryl stearate, ascorbyl palmitate, cetyl palmitate, ethyl myristate, glyceryl palmitate, and sorbitan monopalmitate, and mixtures of these.

[0028] Suitable fatty alcohols and fatty esters are known and commercially available, such as from Aldrich Sigma, Kraft Chemical, and Alfa Chemistry. The fatty alcohol or ester may include a single fatty alcohol or ester. Alternatively, it may include a blend containing two or more fatty alcohols and / or esters.

[0029] One component of the organic composition is ethoxylated castor oil. Ethoxylated castor oil is known and is available, for example, under the trademark TERGITOL TM Castor oil is commercially available from ethylene oxide and Kolliphor. Ethoxylated castor oil is the reaction product of ethylene oxide and castor oil. Castor oil is a triglyceride, an ester derived from glycerol and three fatty acids. In castor oil, the major fatty acid is ricinoleic acid, which has hydroxyl groups pendant from the aliphatic chain. The hydroxyl groups can initiate the polymerization of ethylene oxide in the presence of a catalyst, such as a base, to produce poly(ethylene glycol) chains grafted onto the castor oil at the hydroxyl sites. The polyethylene glycol chains are characterized by repeating ethylene glycol units of formula 1:

[0030] –(-O-C2H4-) x -OH(1)

[0031] wherein x is the number of repeating units. In some embodiments, the average degree of polymerization (the number of repeating units "x") in the poly(ethylene glycol) chains grafted onto the castor oil is at least 20 or at least 25 or at least 27. In some embodiments, the average degree of polymerization in the poly(ethylene glycol) chains grafted onto the castor oil is at most 50 or at most 42 or at most 40 or at most 38. In some embodiments, the ethoxylated castor oil contains saturated polymer chains, and in some embodiments, the ethoxylated castor oil contains some unsaturation.

[0032] One component of the organic composition is at least one co-solvent selected from the group consisting of lower alkyl diethylene glycol ethers, lower alkyl triethylene glycol ethers and propylene glycol diacetate. Examples of suitable co-solvents correspond to one of Formula 2(a) or 2(b):

[0033] R 1 –(-O-C2R 2 4-) n -OH 2(a)

[0034] C2H5-CO-O-C3H6-O-CO-C2H5 2(b)

[0035] Where R 1 is an aliphatic group containing 1 to 4 carbon atoms, each R 2 is independently hydrogen or an alkyl group containing 1 to 4 carbon atoms, and n is the number of repeating units that is greater than 1 and less than 4 on average.

[0036] In some embodiments, R 1 In some embodiments, R 1 is ethyl, and in some embodiments, R 1 It is n-propyl or isopropyl.

[0037] In some embodiments, each R is selected 2 Such that R attached to each repeating alkyl ether unit 2 The total number of carbon atoms in the group averages from 0 to 8 or from 0 to 6 or from 0 to 4 or from 0 to 2 or from 0 to 1. In some embodiments, at least 90% of the repeating alkoxy units are ethoxy units.

[0038] In some embodiments, the number of repeating alkyl ether units (n) is at least 1.5 or at least 1.75 or at least 2. In some embodiments, the number of repeating alkyl ether units is at most 3.5 or at most 3.25 or at most 3.

[0039] Examples of suitable co-solvents include lower alkyl diethylene glycol ethers (such as diethylene glycol monoethyl ether), lower alkyl triethylene glycol ethers (such as triethylene glycol monoethyl ether), and propylene glycol diacetate.

[0040] Diethylene glycol monoethyl ether [C2H5(OCH2CH2)2OH] can be trademarked as CARBITOL TM Propylene glycol diacetate is commercially available under the trademark DOWANOL TM PGDA is commercially available. Other alkoxylated glycol ethers can be produced by the reaction of ethylene oxide with an alcohol in the presence of a catalyst such as a base. In some embodiments, the alcohol is an aliphatic lower alcohol having 1 to 4 carbon atoms, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, or tert-butanol. In some embodiments, the alcohol is saturated. The alcohol corresponds to the formula: R 1 -OH, where R 1 is an aliphatic group containing 1 to 4 carbon atoms.

[0041] One component of the organic composition is a chemical penetration enhancer (CPE) for skin. Chemical penetration enhancers are known and commercially available. They are described in publications such as Vasyuchenko et al. CPE-DB: An Open Database of Chemical Penetration Enhancers, 2021. Pharmaceutics, 13,66. https: / / doi.org / 10.3390 / pharmaceutics13010066; Mathur et al.: Physical and Chemical Penetration Enhancers in Transdermal Drug Delivery System, Asian Journal of Pharmaceutics - July-September 2010, 173-183; Songkro, An Overview of Skin Penetration Enhancers, 31(3) Songklanakarin Songklanakarin J.Sci.Technol .) 》 , 299-321 (May-June 2009); and Som et al., Status of Surfactants as Penetration Enhancers in Transdermal Drug Delivery, 4(1). Pharmacy Journal of Pharmacy and Bioallied Sciences , 2-9 (January-March 2012).

[0042] Some implementations of CPE fall into the following broad categories:

[0043] Solvents, such as ethanol, propylene glycol, diethylene glycol monoethyl ether, oleic acid and dimethyl sulfoxide,

[0044] Terpenes, such as menthol, nerol, camphor, and methyl salicylate, and

[0045] • Surfactants such as polysorbate 80, sodium lauryl sulfate, sucrose monolaurate, glyceryl oleate, benzalkonium chloride, polyoxyl 40 hydrogenated castor oil, didecyldimethylammonium bromide (DDAB) and didecyltrimethylammonium bromide (DTAB).

[0046] In some embodiments, CPE is a surfactant. In some embodiments, CPE is a nonionic surfactant. Examples of suitable nonionic surfactants include alkoxylated fatty alcohols (such as ceteth-20 and laureth-23), alkoxylated fatty acid esters (such as PEG-100 stearate), block copolymers of ethylene oxide and propylene oxide (such as poloxamer 124), sucrose monolaurate, oleyl glyceride, 1-dodecylazacycloheptan-2-one, 2-n-nonyl-1,3-dioxolane and fatty amines. CPE can be commercially available such as with the following trademarks: Pationic, Azone and SEPA.

[0047] The organic composition of the present invention contains 5 to 60 weight percent fatty alcohol or fatty ester. In some embodiments, the organic composition contains no more than 50 weight percent, or no more than 40 weight percent, or no more than 36 weight percent, or no more than 30 weight percent, or no more than 25 weight percent, or no more than 20 weight percent fatty alcohol or fatty ester. In some embodiments, the organic composition contains at least 7 weight percent, or at least 8 weight percent, or at least 9 weight percent fatty alcohol or fatty ester.

[0048] The organic composition of the present invention contains 14% to 40% by weight of ethoxylated castor oil. In some embodiments, the organic composition contains no more than 38% by weight, or no more than 35% by weight, or no more than 30% by weight, or no more than 25% by weight of ethoxylated castor oil. In some embodiments, the organic composition contains at least 16% by weight, or at least 18% by weight, or at least 20% by weight of ethoxylated castor oil.

[0049] The organic composition of the present invention contains 20% to 65% by weight of a cosolvent selected from the group consisting of lower alkyl diethylene glycol ethers, lower alkyl triethylene glycol ethers, and propylene glycol diacetate. In some embodiments, the organic composition contains no more than 62% by weight, or no more than 60% by weight, or no more than 55% by weight of a cosolvent. In some embodiments, the organic composition contains at least 22% by weight, or at least 25% by weight, or at least 30% by weight of a cosolvent.

[0050] The organic composition of the present invention contains 5% to 25% by weight of a chemical penetration enhancer (CPE) for skin. In some embodiments, the organic composition contains no more than 20% by weight, or no more than 18% by weight, or no more than 15% by weight, or no more than 12% by weight of CPE. In some embodiments, the organic composition contains at least 7% by weight, or at least 9% by weight, or at least 10% by weight of CPE.

[0051] In some embodiments, the weight ratio of cosolvent to ethoxylated castor oil is at least 2:10 or at least 4:10 or at least 5:10 or at least 55:100. In some embodiments, the weight ratio of cosolvent to ethoxylated castor oil is at most 10:10 or at most 8:10 or at most 7:10 or at most 65:100.

[0052] In some embodiments, the ratio of ethoxylated castor oil to CPE is at least 1:1 or at least 15:10 or at least 18:10. In some embodiments, the ratio of ethoxylated castor oil to CPE is at most 5:1 or at most 3:1 or at most 18:10.

[0053] In some examples, the organic composition contains 0.5 to 0.8 parts by weight of a co-solvent per 1 part by weight of ethoxylated castor oil and CPE, and the components are in the following ratios:

[0054] At least 6 wt% or at least 7 wt% or at least 8 wt% fatty alcohol or ester. Up to 40 wt% or up to 30 wt% or up to 20 wt% or up to 15 wt% or up to 10 wt% fatty alcohol or ester.

[0055] • At least 25 wt. % or at least 32 wt. % or at least 35 wt. % ethoxylated castor oil.

[0056] Up to 45% or up to 40% by weight ethoxylated castor oil.

[0057] • At least 20 wt% or at least 24 wt% or at least 30 wt% co-solvent. Up to 40 wt% or up to 35 wt% co-solvent.

[0058] • At least 10 wt% or at least 13 wt% or at least 15 wt% or at least 18 wt% CPE. Up to 22 wt% or up to 20 wt% CPE.

[0059] In some examples, the organic composition contains 0.8 to 1.2 parts by weight of a co-solvent per 1 part by weight of ethoxylated castor oil and CPE, and the components are in the following ratios:

[0060] At least 6 wt% or at least 7 wt% or at least 8 wt% fatty alcohol or ester. Up to 40 wt% or up to 30 wt% or up to 20 wt% or up to 15 wt% or up to 10 wt% fatty alcohol or ester.

[0061] • At least 20 wt. %, or at least 25 wt. %, or at least 28 wt. % ethoxylated castor oil.

[0062] Up to 35% or up to 32% by weight of ethoxylated castor oil.

[0063] • At least 30 wt% or at least 35 wt% or at least 40 wt% co-solvent. Up to 50 wt% or up to 45 wt% co-solvent.

[0064] • At least 10 wt% or at least 11 wt% or at least 12 wt% CPE. Up to 20 wt% or up to 18 wt% CPE.

[0065] In some examples, the organic composition contains 1.2 to 1.75 parts by weight of the co-solvent per 1 part by weight of the ethoxylated castor oil and the CPE, and the components are in the following ratios:

[0066] • At least 6 wt% or at least 7 wt% or at least 8 wt% fatty alcohol or ester. Up to 30 wt% or up to 27 wt% or up to 25 wt% fatty alcohol or ester.

[0067] • At least 18 wt. %, or at least 20 wt. %, or at least 21 wt. % ethoxylated castor oil.

[0068] Up to 30% or up to 25% by weight of ethoxylated castor oil.

[0069] • At least 40 wt% or at least 42 wt% or at least 45 wt% or at least 48 wt% co-solvent. Up to 60 wt% or up to 58 wt% co-solvent.

[0070] • At least 8 wt% or at least 9 wt% or at least 10 wt% CPE. At most 15 wt% or at most 13 wt% CPE.

[0071] In some examples, the organic composition contains 1.75 to 2.5 parts by weight of a co-solvent per 1 part by weight of ethoxylated castor oil and CPE, and the components are in the following ratios:

[0072] At least 6 wt% or at least 7 wt% or at least 8 wt% fatty alcohol or ester. Up to 40 wt% or up to 30 wt% or up to 20 wt% or up to 15 wt% or up to 10 wt% fatty alcohol or ester.

[0073] • At least 15 wt. %, or at least 17 wt. %, or at least 18 wt. % ethoxylated castor oil.

[0074] Up to 25% or up to 22% by weight of ethoxylated castor oil.

[0075] • At least 45 wt% or at least 55 wt% or at least 59 wt% co-solvent. Up to 65 wt% or up to 62 wt% co-solvent.

[0076] At least 5 wt% or at least 6 wt% or at least 8 wt% CPE. Up to 15 wt%

[0077] or up to 12 wt% CPE.

[0078] In some embodiments, the organic composition is capable of forming a stable water-in-oil microemulsion in the range of 5% to 10% by weight of water, or 5% to 15% by weight of water, or 5% to 20% by weight of water, or 5% to 25% by weight of water, or 5% to 30% by weight of water, or 5% to 35% by weight of water. In some embodiments, the organic composition is capable of forming a stable water-in-oil microemulsion in the range of 10% to 20% by weight of water, or 10% to 25% by weight of water, or 10% to 30% by weight of water. "Stable microemulsion" means that the microemulsion can be stored at about 25°C for at least one week without substantially destabilization. "Substantially destabilized" means that the composition shows observable signs of phase separation or emulsification into two or more liquid layers (different emulsion layers, each of which is rich in oil phase or water phase).

[0079] In some examples, the organic composition can form a stable microemulsion with water having a water concentration of 5 wt % to 30 wt %, and the components are in the following ratios:

[0080] • At least 6 wt% or at least 7 wt% or at least 8 wt% fatty alcohol or ester. Up to 25 wt% or up to 20 wt% or up to 20 wt% fatty alcohol or ester.

[0081] At least 20% by weight or at least 22% by weight of ethoxylated castor oil. Up to 30% by weight

[0082] Or up to 25% by weight of ethoxylated castor oil.

[0083] • At least 45 wt% or at least 50 wt% co-solvent. Up to 65 wt% or up to 62 wt% co-solvent.

[0084] • At least 8 wt% or at least 9 wt% CPE. At most 15 wt% or at most 13 wt% CPE.

[0085] In some examples, the organic composition can form a stable microemulsion with water having a water concentration of 5 wt % to 25 wt %, and the components are in the following ratios:

[0086] • At least 6 wt% or at least 7 wt% or at least 8 wt% fatty alcohol or ester. Up to 25 wt% or up to 20 wt% or up to 20 wt% fatty alcohol or ester.

[0087] • At least 25 wt. %, or at least 27 wt. %, or at least 30 wt. % ethoxylated castor oil.

[0088] Up to 40% or up to 38% by weight of ethoxylated castor oil.

[0089] • At least 28 wt% or at least 30 wt% or at least 31 wt% co-solvent. Up to 50 wt% or up to 45 wt% co-solvent.

[0090] • At least 10 wt% or at least 11 wt% CPE. At most 18 wt% or at most 15 wt% CPE.

[0091] In some embodiments, it is advantageous to select the organic component so that the organic composition is liquid and non-volatile at skin temperature. This allows the composition and its water-in-oil microemulsion to be easily applied to the skin and remain in liquid form on the skin for a time suitable for delivering the drug, such as at least 1 hour or at least 2 hours or at least 3 hours or at least 4 hours. In some embodiments, the organic composition melts at a temperature below 30°C or below 25°C or below 20°C or below 10°C or below 0°C. In some embodiments, the organic composition boils at a temperature above 50°C or above 75°C or above 100°C or above 125°C or above 150°C.

[0092] Lotion

[0093] The organic composition as described above is made into a microemulsion by mechanical mixing with water until a microemulsion is formed. In some embodiments, the mixing can be enhanced by ultrasonic treatment. In some embodiments, the blending temperature does not exceed 90°C or 60°C or 40°C.

[0094] In some embodiments, the pH of the water is at least 4, or at least 4.5, or at least 4.75, or at least 5. In some embodiments, the pH of the aqueous solvent is at most 8, or at most 7, or at most 6.5.

[0095] In some embodiments, the microemulsion is an oil-in-water microemulsion.Some embodiments of the oil-in-water microemulsion may contain at least 50% by weight water and at least 20% by weight of an organic composition.

[0096] In some embodiments, the microemulsion is a water-in-oil microemulsion. Some examples of water-in-oil microemulsions contain 1 wt % to 40 wt % water and 60 wt % to 99 wt % organic composition. In some embodiments, the microemulsion contains at least 2 wt % or at least 5 wt % or at least 10 wt % or at least 15 wt % or at least 20 wt % water. In some embodiments, the microemulsion contains up to 36 wt % or up to 32 wt % or up to 30 wt % or up to 25 wt % water.

[0097] In some embodiments of the microemulsion, the dispersed aqueous phase has an average particle size of at most 300 nm. In some embodiments, the average particle size of the dispersed aqueous phase is at most 200 nm, or at most 100 nm, or at most 50 nm, or at most 20 nm. In some embodiments, the average particle size of the dispersed aqueous phase is at most 1 nm, or at most 5 nm, or at most 10 nm. The term "particle size" is used to describe the size of the micelles of the dispersed phase in the microemulsion. This does not mean that the micelles contain solid particles; the micelles can be partially or completely liquid.

[0098] Each component is contained in the microemulsion in a ratio such that a stable microemulsion is formed.

[0099] ·The concentration of water has already been discussed.

[0100] In some embodiments, the concentration of the fatty alcohol or ester in the microemulsion is at least 4 wt % or at least 5 wt % or at least 6 wt %. In some embodiments, the concentration of the fatty alcohol or ester in the microemulsion is at most 35 wt % or at most 25 wt % or at most 20 wt % or at most 15 wt % or at most 10 wt %.

[0101] In some embodiments, the concentration of ethoxylated castor oil in the microemulsion is at least 12 wt % or at least 15 wt % or at least 20 wt % or at least 25 wt % or at least 30 wt %. In some embodiments, the concentration of ethoxylated castor oil in the microemulsion is at most 45 wt % or at most 40 wt % or at most 30 wt % or at most 25 wt % or at most 20 wt %.

[0102] In some embodiments, the concentration of the co-solvent in the microemulsion is at least 20 wt % or at least 25 wt % or at least 30 wt %. In some embodiments, the concentration of the co-solvent in the microemulsion is at most 65 wt % or at most 60 wt % or at most 58 wt %.

[0103] In some embodiments, the concentration of CPE in the microemulsion is at least 5 wt % or at least 7 wt % or at least 9 wt %. In some embodiments, the concentration of CPE in the microemulsion is at most 25 wt % or at most 20 wt % or at most 18 wt %.

[0104] Some examples of microemulsions include:

[0105] 25 to 30% by weight of water;

[0106] • At least 5 wt% or at least 6 wt% fatty alcohol or ester. Up to 25 wt% or up to 20 wt% fatty alcohol or ester.

[0107] • At least 15 wt. %, or at least 17 wt. %, or at least 18 wt. % ethoxylated castor oil.

[0108] Up to 25% or up to 22% by weight of ethoxylated castor oil.

[0109] • At least 30 wt% or at least 35 wt% or at least 37 wt% co-solvent. Up to 50 wt% or up to 48 wt% co-solvent.

[0110] • At least 6 wt% or at least 7 wt% CPE. At most 12 wt% or at most 10 wt% CPE.

[0111] Some examples of microemulsions include:

[0112] 20 to 25% by weight of water;

[0113] • At least 5 wt% or at least 6 wt% fatty alcohol or ester. Up to 20 wt% or up to 18 wt% fatty alcohol or ester.

[0114] At least 12% or at least 14% by weight of ethoxylated castor oil. Up to 35% by weight

[0115] Or up to 32% by weight of ethoxylated castor oil.

[0116] • At least 25 wt% or at least 27 wt% co-solvent. Up to 50 wt% or up to 48 wt% co-solvent.

[0117] • At least 6 wt% or at least 7 wt% CPE. At most 18 wt% or at most 15 wt% CPE.

[0118] In some embodiments, the microemulsion can be easily applied to the skin and remain in liquid form on the skin for a time suitable for delivering the drug, such as at least 1 hour, or at least 2 hours, or at least 3 hours, or at least 4 hours. In some embodiments, the microemulsion melts at a temperature below 30°C, or below 25°C, or below 20°C, or below 10°C, or below 0°C. In some embodiments, the microemulsion boils at a temperature above 50°C, or above 75°C, or above 100°C, or above 125°C, or above 150°C.

[0119] In some embodiments, the drug is dissolved in the microemulsion at a pharmaceutically effective concentration. The drug can be dissolved in the microemulsion after it is formed. Alternatively, the drug can be dissolved in the components of the microemulsion before the microemulsion is formed. Suitable drugs and their effective doses are open and known, and suitable drugs are commercially available. Examples of drugs commonly used by skin penetration include lidocaine, scopolamine, nitroglycerin, clonidine, estrogen, testosterone, fentanyl, nicotine, hydrocortisone, ibuprofen, diazepam, tenoxicam, piroxicam, triprolidine, amlodipine, methyl nicotinate, benzocaine, atenolol, tolnaftate, benzoyl peroxide, mupirocin and salicylic acid. In some embodiments, based on the weight of the microemulsion, the concentration of the drug in the microemulsion is at least 0.1% by weight or at least 0.5% by weight or at least 1% by weight. In some embodiments, the concentration of the drug in the microemulsion is at most 10 weight % or at most 8 weight % or at most 6 weight % based on the weight of the microemulsion.

[0120] The microemulsion may optionally contain other additives useful in topical applications. Examples include thickeners and flow modifiers, colorants, fragrances, and fillers. In some embodiments, the total concentration of additives excluding fillers is at most 10 wt % or at most 5 wt % or at most 2 wt % of the total composition. The above listed weight percentages of the microemulsion components and the organic composition components do not include these other additives and specifically do not include fillers.

[0121] In some embodiments, the microemulsion compositions of the present invention can be stored at 25°C for up to one month, or at least 2 months, or at least 3 months, or at least 4 months, or at least 6 months, or at least 1 year without substantial destabilization.

[0122] The microemulsions of the invention containing drugs can be used to administer drugs by application to the skin or by infusion into a patch adhered to the skin. They can be used as sprayable lotions. Gelling agents or viscosity modifiers can be added to the microemulsions to form creams and ointments that can be applied directly to the skin. Uses and applications are described in patents (such as PCT Publication WO 02 / 09763) and in publications such as

[0123] Lopes, Overcoming the skin barrier with microemulsions, 6 Pharmaceutics 52-77(2014);

[0124] Kreilgaard, Effects of microemulsions on drug delivery to the skin, 54 Advanced Drug Delivery Review (AdvancedDrugDeliveryReviews)》 , Suppl. 1, S77-S98 (2002); and

[0125] Langley et al., ed. The Role of Microstructure in Topical Drug Development Microstructure in Topical Drug Product Development) , Springer International Publishing, 2019.

[0126] Example

[0127] Measurement procedure

[0128] Micelle size was measured by dynamic light scattering as described in the publication “Surfactant Micelle Characterization using Dynamic Light Scattering” (2015) published by Malvern Instruments Ltd, currently available at https: / / instrumat.ch / wp-content / uploads / 2016 / 08 / Surfactant-Micelle-Characterization-AN101104-LRLL.pdf.

[0129] Example 1: Emulsion study

[0130] A series of solvent mixtures were prepared containing the indicated amounts of component A (ethoxylated castor oil), component B (nonionic surfactant CPE) and one of components C1-C9 (co-solvent):

[0131]

[0132]

[0133] Each solvent mixture was blended with isopropyl palmitate (fatty ester) at weight ratios of 1:9, 2:8, 3:7, 4:6, 5:5, 6:4, 7:3, 8:2, and 9:1 to form an organic composition.

[0134] Each organic composition was blended with water to form a water-in-oil microemulsion, starting at 2.8 wt % water and increasing from 2.8 wt % to 50 wt %. Each microemulsion was blended by shaking for 30 minutes using a plate shaker, followed by 90 minutes of sonication, followed by further shaking for 30 minutes. Each microemulsion was allowed to stand for about 1 hour, and then visually inspected to determine whether it was clear and homogeneous (indicating a stable microemulsion) or turbid or formed layers (indicating that the microemulsion was unstable).

[0135] The results are shown in Figures 1 to 13 , where "x" indicates a formulation that forms a stable microemulsion under the conditions described in the Examples, and "o" indicates a formulation that does not form a stable microemulsion.

[0136] Example 2: Drug Flux

[0137] A set of formulations were prepared as described in Example 1, containing 52% to 54% isopropyl palmitate; 35% to 37% of a blend of ethoxylated castor oil (ECO), olein (1:2 weight ratio with ECO) and a cosolvent as shown in Table 3 below (10:6 weight ratio with ECO and olein); 6% to 10% water; and 2.5% to 2.6% lidocaine. A control containing 2.5% by weight lidocaine dissolved in isopropyl palmitate was also prepared.

[0138] The drug flux of each formulation was measured using a jacketed Franz cell with a receiver volume of 12 mL, which was maintained at 37°C and had a diffusion area of ​​1.767 cm2. A synthetic polysulfone membrane of 0.45 μm thickness was used as a model skin. The receiver was filled with phosphate buffered saline solution, and 300 μl of microemulsion sample was added to the other side of the artificial skin. The concentration of lidocaine in the receiver solution was periodically determined by withdrawing 250 μl of PBS buffer. The receiver was replenished with the same volume of fresh buffer. The increase in the weight of lidocaine in the receiver volume over time produced a drug diffusion curve for each microemulsion formulation. All samples were run in triplicate, and the data were fitted between 1 hour and 3 hours.

[0139]

[0140] The results show that the formulations of the present invention are effective for drug delivery.

Claims

1. An organic composition, comprising: a) 5 to 60% by weight of fatty alcohol or fatty ester; b) 14 to 40% by weight of ethoxylated castor oil; c) 20 to 65 wt% of a co-solvent selected from the group consisting of lower alkyl diethylene glycol ethers, lower alkyl triethylene glycol ethers, and propylene glycol diacetate; and d) 5 to 25% by weight of a chemical penetration enhancer for skin, The weight percentages are based on the weight of the organic composition, excluding other additives and fillers.

2. The composition of claim 1, wherein the composition comprises no more than 40% by weight of fatty alcohol or fatty ester.

3. The composition according to claim 2, wherein the co-solvent is a lower alkyl diethylene glycol ether or a lower alkyl triethylene glycol ether.

4. The composition according to claim 2, wherein the co-solvent is diethylene glycol monoethyl ether or triethylene glycol monoethyl ether.

5. The composition of claim 2, wherein the fatty alcohol or ester is a fatty ester.

6. The composition according to claim 1, wherein the concentration of the components is: a) 7 to 15% by weight of fatty alcohols or esters; b) 32 to 45% by weight of ethoxylated castor oil; c) 24 to 40 wt % of a co-solvent; and d) 15 to 22% by weight of CPE, The weight percentages are based on the weight of the organic composition, excluding other additives and fillers.

7. The composition according to claim 1, wherein the concentrations of the components are: a) 7 to 30% by weight of fatty alcohols or esters; b) 20 to 35% by weight of ethoxylated castor oil; c) 30 wt % to 50 wt % of a co-solvent; and d) 10 to 20 wt. % CPE, The weight percentages are based on the weight of the organic composition, excluding other additives and fillers.

8. The composition of claim 1, wherein the concentrations of the components are: a) 7 to 15% by weight of fatty alcohols or esters; b) 18 to 30% by weight of ethoxylated castor oil; c) 40 to 60 wt % of a co-solvent; and d) 8 to 15 wt. % CPE, The weight percentages are based on the weight of the organic composition, excluding other additives and fillers.

9. The composition of claim 1, wherein the concentrations of the components are: a) 6 to 20% by weight of fatty alcohols or esters; b) 15 to 25% by weight of ethoxylated castor oil; c) 45 wt % to 65 wt % of a co-solvent; and d) 5 to 15 wt. % CPE, The weight percentages are based on the weight of the organic composition, excluding other additives and fillers.

10. The composition of claim 1, which is capable of forming a stable water-in-oil emulsion having a water content of 5 to 30 wt%. 11 . A water-in-oil microemulsion comprising 1 to 40 wt % of water and 60 to 99 wt % of the organic composition according to claim 1 .

12. The microemulsion according to claim 11, comprising: a) 25% to 30% by weight of water; b) 5 to 25% by weight of fatty alcohols or esters; c) 15 to 25% by weight of ethoxylated castor oil; d) 30 wt % to 50 wt % of a co-solvent; and e) 6 to 12 wt. % CPE, The weight percentages do not include other additives and fillers.

13. The microemulsion according to claim 11, comprising: a) 20 to 25% by weight of water; b) 5 to 20% by weight of fatty alcohols or esters; c) 12 to 35% by weight of ethoxylated castor oil; d) 25 to 50 wt % of a co-solvent; and e) 6 to 18 wt. % CPE, The weight percentages do not include other additives and fillers.

14. The microemulsion according to claim 11, further comprising a drug at a pharmaceutically effective concentration.

15. A method of administering a drug by applying the microemulsion according to claim 14 to the skin.

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