Topical preparations of cyclooxygenase inhibitors and their uses

Abstract

A topical cyclooxygenase (COX) inhibitor formulation comprising: an inhibitor of COX-1 and / or COX-2; one or more long-chain monounsaturated fatty acids, long-chain monounsaturated fatty alcohols, terpenes, or combinations thereof; and a solvent mixture comprising ethanol, propylene glycol, 2-(2-ethoxyethoxy)ethanol, and optionally dimethyl sulfoxide.

Description

[0001] This application claims the benefit of U.S. Provisional Application No. 62 / 931,466, filed on November 6, 2019, entitled “TOPIC FORMULATIONS OF CYCLOXYGENASE INHIBITORS AND USES THEREOF,” the entire contents of which, including all tables, drawings, and claims, are hereby incorporated herein. Background Art

[0002] The following discussion of the background technology of the present disclosure is only intended to help readers understand the present disclosure, and is not admitted to describe or constitute the prior art of the present disclosure.

[0003] Cyclooxygenase (COX, also referred to as prostaglandin endoperoxide synthase) refers to an enzyme family responsible for forming prostaglandins (including thromboxane and prostaglandins such as prostacyclin) from arachidonic acid. Since prostaglandins are mediators of pain and inflammation, COX is a common drug target. The drug that inhibits prostaglandin G / H synthase (cyclooxygenase or COX) is referred to as COX inhibitor, and the prostaglandin G / H synthase is an enzyme that catalyzes the production of prostaglandins (including prostaglandins, prostacyclin and thromboxane) by arachidonic acid. Common nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen play a role by inhibiting COX-1 and COX-2 enzymes, and NSAIDs such as celecoxib and etoricoxib have specificity to COX-2 isozymes. Although acetaminophen is not considered as NSAID because it has only slight anti-inflammatory activity, it treats pain by blocking COX-2, while also suppressing the reuptake of endogenous cannabinoids.

[0004] The use of COX inhibitors in topical formulations can be beneficial in reducing the likelihood that a patient will experience side effects associated with systemic therapy. Drugs applied directly to the skin can be intended to either achieve a local effect or a systemic effect. Topically applied agents (e.g., topical patches, creams, gels, ointments, solutions, etc.) can be intended to reach local tissues to achieve the desired therapeutic effect, or can act transdermally to produce systemic concentrations comparable to oral medications.

[0005] In the United States, there are several topical NSAID products approved for the treatment of painful conditions. Diclofenac sodium 1% gel (Voltaren gel) is approved for the relief of pain caused by osteoarthritis in joints that are amenable to topical treatment, such as the knees and joints of the hands. This product contains various additional ingredients in a carrier, including isopropyl alcohol, propylene glycol, and water, to help the drug penetrate into the skin. Diclofenac sodium topical solution 1.5% weight / weight (PENNSAID) is indicated for the treatment of signs and symptoms of osteoarthritis of the knee. Additional absorption-enhancing ingredients in this product include DMSO, propylene glycol, water, and alcohol. Diclofenac eporamine 1.3% topical patch (Flector patch) is indicated for the topical treatment of acute pain caused by minor strains, sprains, and contusions. The patch consists of an adhesive material containing 1.3% diclofenac eporamine applied to a nonwoven polyester felt backing and covered with a polypropylene film release liner that is removed prior to application.

[0006] There is evidence that topical formulations can achieve therapeutic drug concentrations in local tissues while maintaining low serum drug levels and potentially avoiding systemic toxicity. Maximum serum concentrations of topical diclofenac preparations have been reported to be 0.4-2.2% of the maximum serum concentrations achieved with oral diclofenac, resulting in significantly reduced systemic exposure. High drug concentrations at the site of action combined with low systemic concentrations may produce efficacy greater than or equal to that of systemic NSAIDs while reducing the risk of adverse reactions. Summary of the invention

[0007] In a first aspect, the present disclosure provides topical cyclooxygenase (COX) inhibitor formulations. These formulations include:

[0008] Inhibitors of COX-1 and / or COX-2;

[0009] from about 1.0 to about 15.0 weight percent of a long chain monounsaturated fatty acid, a long chain monounsaturated fatty alcohol, a terpene, or a combination thereof;

[0010] 0 to about 5.0 wt % poloxamer;

[0011] 0 to about 5.0 weight % of a pharmaceutically acceptable cellulosic excipient;

[0012] a solvent mixture comprising ethanol, propylene glycol, 2-(2-ethoxyethoxy)ethanol, and optionally dimethyl sulfoxide; and

[0013] wherein the formulation comprises about 5.0 wt % or less water.

[0014] In various embodiments, the formulation comprises one or more COX inhibitors selected from cannabinoids (e.g., tetrahydrocannabinol (D9-THC), tetrahydrocannabinolic acid-A (THCA-A), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabigerol (CBG), and cannabigerolic acid (CBGA)), naproxen, acetaminophen, benzydamine, bupropion, diclofenac, etofenamate, flufenamic acid, ibuprofen, indomethacin, ketoprofen, and salicylates (e.g., salicylic acid, salicin, diflunisal, magnesium salicylate, choline salicylate). Preferably, the formulation comprises diclofenac, and most preferably, the formulation comprises about 1.0 to about 2.5% by weight of diclofenac. In certain embodiments, the one or more COX inhibitors in the formulation comprise or consist of about 2% by weight of diclofenac. COX inhibitors may be present in the form of free acids or various salts (e.g., diclofenac sodium, naproxen sodium, triethanolamine salicylate, ibuprofen lysine, etc.) or esters (e.g., diclofenac ethyl, naproxen methyl ester, methyl salicylate, ibuprofen diethylaminoethyl ester, etc.).

[0015] In certain embodiments, the above formulations provide percutaneous absorption of the COX inhibitor, such as at least 7% of the COX inhibitor present in the formulation is diclofenac. Percutaneous absorption (or skin penetration) can be viewed as consisting of a series of steps that occur in sequence: adsorption of penetrant molecules on the surface layer of the stratum corneum, diffusion through the stratum corneum and the living epidermis. In the papillary layer of the dermis, the molecules are absorbed into the microcirculation for subsequent systemic distribution. Methods for measuring percutaneous absorption of topically applied drugs are known in the art. See, for example, Kezic, Hum. Exp. Toxicol. 2008 27(4):289-95. doi:10.1177 / 0960327107085825. Topical COX inhibitor formulations according to the claims of the present invention preferably provide percutaneous absorption of the COX inhibitor of at least 10%.

[0016] In certain embodiments, the topical COX inhibitor formulations of the present disclosure include no more than about 2.5% by weight, preferably about 1% by weight or less, of water. In a most preferred embodiment, the formulation is anhydrous. "Anhydrous" means that the formulation does not include the use of water, whether as water itself or added as a component of a liquid solvent. For example, 95% ethanol, which is an azeotropic mixture containing 5% water, is not used in an anhydrous formulation. However, water may be present in such an anhydrous formulation as a component of a hydrated ionic compound or as a result of hygroscopic absorption.

[0017] As used herein, the term "weight %" refers to (mass of a component / total mass of a formulation) x 100. For example, 2 weight % of diclofenac means 2 g of diclofenac per 100 g of a formulation.

[0018] The term "long-chain monounsaturated fatty acid" refers to a fatty acid having at least 14 carbons and one double bond. The term "long-chain monounsaturated fatty alcohol" refers to the equivalent alcohol (that is, an -OH group is attached to the terminal carbon instead of an alkoxy group). For example, the molecular formula of oleic acid is CH3(CH2)7CH=CH(CH2)7COOH, while the molecular formula of the equivalent oleyl alcohol is CH3(CH2)7-CH=CH-(CH2)8OH. Examples of monounsaturated fatty acids belonging to this group include, but are not limited to, the following:

[0019]

[0020]

[0021] In various embodiments, the long chain monounsaturated fatty acids and / or long chain monounsaturated fatty alcohols present in the formulation are fatty acids or alcohols from C16:1 to C22:1. In a preferred embodiment, the long chain monounsaturated fatty acids present in the formulation include or consist of about 1 to about 15% by weight of oleic acid or oleyl alcohol or a mixture thereof, more preferably about 1 to about 10% by weight of oleic acid or oleyl alcohol or a mixture thereof, and most preferably about 1 to about 5% by weight of oleic acid or oleyl alcohol or a mixture thereof. In certain embodiments, the long-chain monounsaturated fatty acids present in the formulation include or consist of about 1% by weight oleic acid or oleyl alcohol or mixtures thereof, about 2% by weight oleic acid or oleyl alcohol or mixtures thereof, about 3% by weight oleic acid or oleyl alcohol or mixtures thereof, about 4% by weight oleic acid or oleyl alcohol or mixtures thereof, about 5% by weight oleic acid or oleyl alcohol or mixtures thereof, about 6% by weight oleic acid or oleyl alcohol or mixtures thereof, about 7% by weight oleic acid or oleyl alcohol or mixtures thereof, about 8% by weight oleic acid or oleyl alcohol or mixtures thereof, about 9% by weight oleic acid or oleyl alcohol or mixtures thereof, or about 10% by weight oleic acid or oleyl alcohol or mixtures thereof.

[0022] Poloxamers are nonionic triblock copolymers consisting of a central hydrophobic chain of polyoxypropylene and two hydrophilic chains of polyoxyethylene located on either side thereof. These copolymers are usually named with the letter P (for poloxamer) followed by three numbers: the first two numbers multiplied by 100 give the approximate molecular weight of the polyoxypropylene core, and the last number multiplied by 10 gives the percentage of polyoxyethylene content. Examples of poloxamers that can be used in the present disclosure include, but are not limited to, poloxamer-101, poloxamer-105, poloxamer-105 benzoate, poloxamer-108, poloxamer-122, poloxamer-123, poloxamer-124, poloxamer-181, poloxamer-182, poloxamer-182 dibenzoate, poloxamer-183, poloxamer-184, poloxamer-185, poloxamer-188, poloxamer-212, poloxamer-213, poloxamer-214, poloxamer-215, poloxamer-216, poloxamer-217, poloxamer-218, poloxamer-219, poloxamer-220, poloxamer-221, poloxamer-223, poloxamer-224, poloxamer-225, poloxamer-226, poloxamer-227, poloxamer-228, poloxamer-229, poloxamer-230, poloxamer-231, poloxamer-232, poloxamer-233, poloxamer-234, poloxamer-235, poloxamer-236, poloxamer-237, poloxamer-238, poloxamer-239, poloxa In a preferred embodiment, the poloxamer present in the formulation comprises or consists of about 0.1 to about 5% by weight of poloxamer-188, or is free of poloxamer.

[0023] Cellulose and its derivatives (e.g., ether and ester derivatives) are excipients commonly used in pharmaceutical synthesis and industrial products with various purposes. Their uses include as suspending agents in oral liquid preparations and as viscosity enhancers in topical preparations. Examples of pharmaceutically acceptable cellulose excipients that can be used in the present disclosure include, but are not limited to, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, and ethyl hydroxyethyl cellulose. In a preferred embodiment, the pharmaceutically acceptable cellulose excipient present in the preparation includes or consists of about 1.0 to about 5% by weight of hydroxypropyl cellulose. In certain embodiments, the cellulose excipient in the preparation includes or consists of: about 1% by weight of hydroxypropyl cellulose, about 2% by weight of hydroxypropyl cellulose, about 3% by weight of hydroxypropyl cellulose, about 4% by weight of hydroxypropyl cellulose, or about 5% by weight of hydroxypropyl cellulose. In certain other embodiments, the preparation does not contain a cellulose excipient.

[0024] An exemplary topical COX inhibitor formulation according to the present disclosure includes the following solvent mixture:

[0025] from about 25.0 to about 50.0 weight % ethanol, from about 2.0 to about 12.5 weight % propylene glycol, from about 0 to about 25.0 weight % DMSO, and from about 20.0 to about 49.9 weight % 2-(2-ethoxyethoxy)ethanol; and wherein the solvent mixture comprises from about 70.0 to about 95.0 weight % of the formulation, and wherein the formulation has about 1 weight % or less water, and is preferably anhydrous.

[0026] In certain embodiments, the formulation includes from about 7.5 to about 12.5 weight percent propylene glycol, more preferably from about 10 to about 12 weight percent propylene glycol.

[0027] In certain embodiments, the formulation includes about 10 to about 30 weight percent 2-(2-ethoxyethoxy)ethanol, more preferably about 20 to about 27.5 weight percent 2-(2-ethoxyethoxy)ethanol.

[0028] In certain embodiments, the formulation comprises from about 25 to about 45% by weight ethanol, more preferably from about 30 to about 40% by weight ethanol.

[0029] In certain embodiments, the formulation comprises about 15 to about 25% by weight of dimethyl sulfoxide, more preferably about 20% by weight of dimethyl sulfoxide. In certain other embodiments, the formulation comprises less than 15% by weight of dimethyl sulfoxide, preferably less than 10% by weight of dimethyl sulfoxide, more preferably less than 5% by weight of dimethyl sulfoxide, and even more preferably 0% by weight of dimethyl sulfoxide.

[0030] Preferred topical COX inhibitor formulations include or consist of:

[0031] about 1.0 to about 2.5 weight percent diclofenac;

[0032] from about 1.0 to about 10.0 weight percent of a long chain monounsaturated fatty acid, a long chain monounsaturated alcohol, or a mixture thereof;

[0033] 0 to about 5.0 wt % poloxamer;

[0034] about 2.0 to about 5.0 weight percent of a pharmaceutically acceptable cellulosic excipient;

[0035] An anhydrous solvent mixture comprising ethanol, propylene glycol, dimethyl sulfoxide and 2-(2-ethoxyethoxy)ethanol,

[0036] wherein the formulation comprises from about 25.0 to about 40.0 weight % ethanol, from about 2.0 to about 12.5 weight % propylene glycol, from about 15.0 to about 25.0 weight % dimethyl sulfoxide, and from about 20.0 to about 49.9 weight % 2-(2-ethoxyethoxy)ethanol; and wherein the solvent mixture comprises from about 70.0 to about 95.0 weight % of the formulation, and wherein the formulation has about 1 weight % or less water and is preferably anhydrous.

[0037] Preferred topical COX inhibitor formulations according to the present disclosure are anhydrous and include or consist of:

[0038] about 2% by weight of diclofenac;

[0039] About 27% ethanol;

[0040] about 8 wt % of oleic acid, oleyl alcohol or a mixture thereof;

[0041] About 0.5% Poloxamer 188;

[0042] About 11% propylene glycol;

[0043] about 3 wt % hydroxypropyl cellulose;

[0044] about 21% by weight DMSO; and

[0045] About 25% by weight 2-(2-ethoxyethoxy)ethanol.

[0046] Another preferred topical COX inhibitor formulation according to the present disclosure is anhydrous and comprises or consists of:

[0047] about 2.0% by weight of diclofenac;

[0048] About 43.5% ethanol;

[0049] about 4.0 weight percent oleic acid, oleyl alcohol, or a mixture thereof;

[0050] 0 wt% Poloxamer 188;

[0051] about 3.0 wt. % propylene glycol;

[0052] about 3.0 wt. % hydroxypropyl cellulose;

[0053] about 20.0 wt. % dimethyl sulfoxide; and

[0054] About 24.5 wt. % 2-(2-ethoxyethoxy)ethanol.

[0055] Another preferred topical COX inhibitor formulation according to the present disclosure is anhydrous and comprises or consists of:

[0056] about 2.0% by weight of diclofenac;

[0057] About 37.5% ethanol;

[0058] about 2.0 wt. % oleic acid, oleyl alcohol, or a mixture thereof;

[0059] 0 wt% Poloxamer 188;

[0060] about 11.0 weight percent propylene glycol;

[0061] about 3.0 wt. % hydroxypropyl cellulose;

[0062] about 20.0 wt. % dimethyl sulfoxide; and

[0063] About 24.5 wt. % 2-(2-ethoxyethoxy)ethanol.

[0064] As used throughout this specification, the term "about" refers to + / - 10% of a given value.

[0065] A list of exemplary formulations of the present disclosure can be found in the following table. In each case, the values ​​recited in the table may include + / - 10% of each value within the range thereof:

[0066]

[0067] Element weight% weight% weight% weight% Oleic acid 8.0 8.0 8.0 4.0 DMSO 21.0 21.0 21.0 20.0 Trascutol 26.0 26.0 26.0 24.5 Diclofenac Sodium 2.0 2.0 2.0 2.0 Propylene glycol 11.0 11.0 11.0 3.0 Poloxamer P188 3.0 0.5 0 0 100% ethanol 26.0 28.5 29.0 43.5 Hydroxypropyl Cellulose 3.0 3.0 3.0 3.0 water 0 0 0 0 total 100 100 100 100

[0068]

[0069] Element weight% weight% weight% weight% Oleic acid 8.0 8.0 8.0 8.0 DMSO 16.0 21.0 16.0 21.0 Trascutol 26.0 21.0 21.0 16.0 Diclofenac Sodium 2.0 2.0 2.0 2.0 Propylene glycol 11.0 11.0 11.0 11.0 Poloxamer P188 0 0 0 0 Ethanol 34.0 34.0 39.0 39.0 Hydroxypropyl cellulose 3.0 3.0 3.0 3.0 water 0 0 0 0 total 100 100 100 100

[0070] Element weight% Oleic acid 0 glycerin 0 DMSO 20.0 Trascutol 24.5 Diclofenac Sodium 2.0 Propylene glycol 11.0 Poloxamer P188 0 Dehydrated ethanol 35.5 Hydroxypropyl Cellulose 3.0 water 0 Oleyl alcohol 4.0 total 100

[0071] In a related aspect, the present disclosure provides a method for locally treating a pain attack in a part of the human body, the method comprising topically applying a topical COX inhibitor formulation described in the present disclosure to the part. In various embodiments, the pain attack is an acute pain attack or a chronic pain attack. Examples of pain attacks that can be treated include, but are not limited to, pain caused by osteoarthritis, rheumatoid arthritis, mild to moderate inflammation and tissue damage, lower back pain, inflammatory joint diseases (e.g., ankylosing spondylitis, psoriatic arthritis, reactive arthritis), tennis elbow, headaches, postoperative pain, muscle stiffness and pain caused by Parkinson's disease, and traumatic injuries. In a preferred embodiment, the method is used to locally treat pain from osteoarthritis of the knee, comprising topically applying a topical COX inhibitor formulation according to the present disclosure to the knee.

[0072] In certain embodiments, the dose of the topical COX inhibitor formulation according to the present disclosure applied provides a COX inhibitor dose of about 80 mg, about 40 mg, about 30 mg, about 20 mg, or about 10 mg. For example, in certain embodiments, applying 4 mL of a 2% by weight diclofenac formulation will provide a topical dose of 80 mg diclofenac; 2 mL will provide 40 mg diclofenac, 1 mL will provide 20 mg diclofenac, and so on.

[0073] In some embodiments, the preparation of the present invention is in the form of a gel, lotion, cream, spray, aerosol, ointment, emulsion, suspension, liposome system, paint, patch, bandage, buccal tablet, wafer, sublingual tablet, suppository, vaginal dosage form or occlusive dressing. In a specific embodiment, the preparation is a gel. In some embodiments, the preparation of the present invention is directly applied to the skin in the form of, for example, a gel, ointment or cream, or is indirectly applied to the skin by a patch, bandage or other occlusive dressing. Depending on the patient's condition, the preparation of the present invention can be applied once a day, or multiple times a day. In some embodiments, the preparation is suitable for daily administration once, twice, three times or four times, and the administration time is as needed, and is suitably a few days to a few weeks to a few months, or longer as needed. The composition can be applied to any skin surface, including hands, arms, trunk, back, legs, feet, etc.

[0074] It should be understood that the present disclosure is not limited in its application to the construction details and component arrangements set forth in the following description or shown in the accompanying drawings. In addition to those embodiments described, the present disclosure is capable of other embodiments and can be practiced and executed in various ways. In addition, it should be understood that the words and terms used herein and the abstract are for descriptive purposes and should not be considered restrictive.

[0075] Therefore, those skilled in the art will recognize that the concepts upon which the present disclosure is based can be readily used as a basis for designing other structures, methods and systems for achieving the several purposes of the present disclosure. Therefore, it is important that the claims be considered to include such equivalent constructions as long as they do not depart from the spirit and scope of the present disclosure. BRIEF DESCRIPTION OF THE DRAWINGS

[0076] Figure 1 : Table 1 Skin permeation flux data of 2% diclofenac formulation.

[0077] Figure 2 : Table 1 Skin permeation delivery dose data of 2% diclofenac formulation.

[0078] Figure 3 : Transdermal dose data delivered by 2% diclofenac formulation D34 and Pennsaid.

[0079] Figure 4 : Skin retention dose data for 2% diclofenac formulation D34 and Pennsaid.

[0080] Figure 5 : Delivered transdermal dose data for 2% diclofenac formulation D34 and Pennsaid, expressed as percent diclofenac delivered.

[0081] Figure 6 : Skin permeation flux data of 2% diclofenac formulation D34 and Pennsaid.

[0082] Figure 7 : Transdermal dose data delivered by 2% diclofenac formulations D51-D55 and Pennsaid.

[0083] Figure 8 : Skin permeation flux data for 2% diclofenac formulations D51-D55 and Pennsaid.

[0084] Fig. 9 : Transdermal dose data delivered by 2% diclofenac formulations D37-D39 and Pennsaid.

[0085] Fig.10 : Delivered transdermal dose data for 2% diclofenac formulations D37-D39 and Pennsaid, expressed as percent diclofenac delivered.

[0086] Fig.11 : Skin permeation flux data for 2% diclofenac formulations D37-D39 and Pennsaid.

[0087] Fig.12 : Transdermal dose data delivered by 2% diclofenac formulations D51-D55 and Pennsaid.

[0088] Fig.13 : Transdermal dose data delivered by 2% diclofenac formulation D56 and Pennsaid.

[0089] Fig.14 : Transdermal dose data delivered by 2% diclofenac formulations D57-D59 and Pennsaid. DETAILED DESCRIPTION

[0090] The greatest obstacles to transdermal topical delivery of COX inhibitors are the barrier properties of the skin's outermost layer, the stratum corneum (SC), skin binding, skin metabolism, skin toxicity, and prolonged lag time.

[0091] Different approaches have been developed to enhance transdermal absorption, including the use of drug derivatives that promote drug diffusion through the SC, supersaturated systems, physical methods, and chemical permeation enhancers (absorption enhancers). In this regard, many chemicals have been used for their ability to promote skin permeation, including fatty acids, fatty acid esters, fatty alcohols or fatty alcohol ethers, fatty ethers, lower alcohols, glycerides, polyols, diols, amides (e.g., N,N-diethyl-m-toluamide), amines, terpenes, polar solvents, pyrrolidones and their derivatives, sulfoxides, azone or laurocapram, surfactants, lecithin, polyols, diols, quaternary ammonium compounds, silicones, alkanoic acid esters, certain biological agents, enzymes, complexing agents, macrocyclic compounds, solvents, etc.

[0092] As used herein, "permeation enhancement" refers to increasing the permeability of the skin to an active pharmaceutical ingredient (API), thereby increasing the rate at which the API penetrates the skin. Similarly, a "permeation enhancer" (PE) refers to an agent or mixture of agents that achieves such permeation enhancement. PE mixtures suitable for use in the present disclosure promote API penetration through the skin by one or more of the following mechanisms: (1) by increasing the diffusivity of the drug in the skin; (2) by causing SC lipid fluidization, which leads to a decrease in barrier function (reversible effect); (3) by increasing and optimizing the thermodynamic activity of the drug in the carrier; (4) by affecting the partition coefficient of the drug; and (5) by increasing its release from the formulation into the upper layers of the skin.

[0093] In certain embodiments, PE mixtures suitable for use in the present disclosure have one or more of the following characteristics: non-toxic, non-irritating, non-allergenic and / or non-sensitizing to the skin; pharmacologically inert, at least at concentrations required to exert sufficient penetration; immediate, predictable and / or reversible effect; easy incorporation into pharmaceutical preparations; and cosmetically acceptable.

[0094] Fatty Acid Penetration Enhancers

[0095] The PE mixture of the present disclosure preferably includes one or more fatty acids, such as long-chain fatty acids. For example, the fatty acid can be oleic acid (cis-9-octadecenoic acid) or its functional derivatives. In certain embodiments, PE is a fatty acid ester, a fatty alcohol or a fatty alcohol ether, a fatty ether, a lower alcohol, a glyceride, a polyol, a diol, an amide (e.g., N, N-diethyl-m-toluamide), an amine, a terpene, a polar solvent or a mixture thereof. In certain embodiments, the fatty acid is an alkanoic acid, a capric acid, a diacid, an ethyl octadecanoic acid, a caproic acid, a lactic acid, a lauric acid, a linoleic acid, a linolenic acid, a neodecanoic acid, an oleic acid (cis-9-octadecenoic acid), a palmitic acid, a nonanoic acid, a propionic acid or an 11-octadecenoic acid. In certain embodiments, PE is at least one of a C8-C22 fatty acid, such as isopropyl myristate.

[0096] Although not wishing to be bound by any particular theory, it is believed that the fatty acid PE of the present disclosure selectively interferes with the intercellular lipid bilayer in the SC, thereby enhancing the penetration of the API to the SC. In certain embodiments, based on the general trend that unsaturated fatty acids are more effective than saturated fatty acids in enhancing percutaneous absorption (e.g., more than 5 times, 10 times, 15 times, 20 times or more), the difference in penetration enhancement effect can be adjusted by adjusting the number of double bonds and the cis / trans configuration of the fatty acid isomers, especially for lipophilic drugs / APIs.

[0097] In certain embodiments, PE is oleic acid, linoleic acid, α-linolenic acid, arachidonic acid, palmitic acid, lauric acid, caprylic acid, isostearic acid, isopropyl myristate or myristic acid, optionally also including propylene glycol, ethanol, 2-ethyl-1,3-hexanediol and one or more of dextran. In certain embodiments, PE is palmitic acid, and a topical preparation is prepared to enhance the penetration of API to SC (particularly alkyl-rich regions). In certain embodiments, PE is myristic acid, and a topical preparation is prepared to enhance the penetration of API to the epidermis. In certain embodiments, PE is octyl salicylate, and a topical preparation is prepared to enhance the penetration of water-soluble or oil-soluble API into the epidermis and dermis.

[0098] Additional fatty acid based PEs can be found in MX 9705070, GR 1004995, US 2005-020552A1, WO 05 / 060540, CA 2,420,895, MX 9800545, WO 04 / 054552, NZ 537359, WO 98 / 18417, WO 96 / 30020, DE 4301783, US 4.

[0099] Terpene Penetration Enhancers

[0100] Terpenes can be used as penetration enhancers in pharmaceutical and cosmetic preparations due to their high enhancement effect and low skin irritation. Terpenes are mainly extracted from medicinal plants and are volatile compounds whose molecular components consist only of carbon, hydrogen and oxygen atoms. The basic chemical structure of terpenes consists of many repeating isoprene (C5H8) units used to classify terpenes. Some terpenes (e.g., 1,8-cineole, menthol and menthone) are included in the list of generally recognized as safe (GRAS) agents issued by the U.S. Food and Drug Administration. Examples of terpenes suitable for the present disclosure can be selected from menthol, D-limonene, geraniol, nerolidol and mixtures thereof.

[0101] Sulfoxide penetration enhancers

[0102] In certain embodiments, PE mixtures suitable for the present disclosure include dimethyl sulfoxide (DMSO) for enhancing the penetration of hydrophilic and lipophilic APIs. Other DMSO-based PEs that can replace DMSO include similar chemically related compounds such as dimethylacetamide (DMAC), dimethylformamide (DMF), cyclic sulfoxides, decyl methyl sulfoxide, dimethyl sulfoxide, and 2-hydroxyundecyl methyl sulfoxide.

[0103] Ethylene glycol penetration enhancer

[0104] In certain embodiments, PE mixtures suitable for use in the present disclosure include one or more glycol-based compounds, such as monoalkyl ethers of diethylene glycol, preferably diethylene glycol monoethyl ether or diethylene glycol monomethyl ether or other dipropylene glycol, propylene glycol, 1,2-butylene glycol, and the like. Currently, the U.S. Food and Drug Administration (FDA) inactive ingredient database lists diethylene glycol monoethyl ether (Transcutol) for topical (up to 49.9%) and transdermal (up to 5%) routes of administration. An important property of Transcutol is its ability to dissolve a wide range of hydrophilic and lipophilic active substances. Its solubility exceeds that of PG and EtOH, making it a very useful pharmaceutical excipient. Due to its negative log P of approximately 0.5, Transcutol is considered to be a polar protic solubilizer that exhibits affinity and good miscibility also with hydrophobic groups. The ability of solvents with negative log P values ​​to easily penetrate the stratum corneum contrasts with lipophilic active substances (log P values ​​of 2-3) that penetrate the stratum corneum more easily than active substances with negative log P values. Transcutol is compatible with most pharmaceutical excipients; soluble in common solvents such as glycerol, ethanol, propylene glycol, and water; miscible in polar lipids such as medium chain triglycerides and polyethylene glycol-based surfactants (polyoxyglycerol triesters); but insoluble in nonpolar mineral oil or dimethicone. Due to its high solubility and miscibility with water, Transcutol may hydrate depending on relative humidity conditions.

[0105] Emulsifier

[0106] The production of formulations for topical application to the skin or mucosal surfaces generally requires mixing the oil phase with an emulsifier. An emulsifier is a pharmaceutically acceptable surfactant, which can be a small molecule, oligomer, or polymer. It can be nonionic, cationic, or anionic. It can be natural or synthetic.

[0107] Many emulsifiers can be used in the present disclosure. In certain embodiments, emulsifier can include: sodium lauryl sulfate, or nonionic emulsifier (such as glyceryl stearate and / or PEG 100 stearate). Other representative emulsifiers include but are not limited to gelatin, casein, lecithin (phospholipid), gum arabic, cholesterol, tragacanth, polyoxyethylene alkyl ether (for example polyethylene glycol ether such as polycetomel 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters (for example commercially available Tweens), polyoxyethylene stearate, colloidal silicon dioxide, sodium lauryl sulfate, carboxymethylcellulose calcium, sodium carboxymethylcellulose, methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose and magnesium aluminum silicate. Most of these surface modifiers are known pharmaceutical excipients, and are described in detail in the Handbook of Pharmaceutical Excipients, the Pharmaceutical Press, 1986 jointly published by the American Pharmaceutical Association and the British Pharmaceutical Society.

[0108] Other examples of surfactants include tyloxapol, poloxamer and polyoxime. Poloxamers are water-soluble triblock copolymers consisting of hydrophilic polyethylene oxide (PEO) and hydrophobic polypropylene oxide (PPO) blocks linked together. The amphiphilic nature of these block copolymers can be changed by controlling the length of the PEO and / or PPO block components (Ahmed et al., 2001). Several members of this poloxamer chemical family (such as poloxamer 188 and 407) are known to be biocompatible and nontoxic to mammalian cells and tissues, which makes them useful in biomedical applications. These surfactants are known to be incorporated into or onto mammalian cell membranes, thereby reducing protein adsorption and cell adhesion.

[0109] Other emulsifiers include lecithin, dialkyl esters of sodium sulfosuccinate, such as Aerosol OT (which is the dioctyl ester of sodium sulfosuccinate, available from American Cyanamid), Duponol P (which is sodium lauryl sulfate, available from DuPont), Triton X-200 (which is an alkyl aryl polyether sulfonate, available from Rohm and Haas), 20 and 80 (which are polyoxyethylene sorbitan fatty acid esters, available from Croda, Inc.), Crodesta F1 10 (which are a mixture of sucrose stearate and sucrose distearate, available from Croda, Inc.), Crodesta SL-40 (which are available from Croda, Inc.), and SA90HCO (which are Ci8H 37-CH2(CON(CH3)CH2(CHOH)4CH2OH)2), decanoyl-N-methylglucamide; n-decyl-p-D-glucopyranoside; n-decyl-p-D-maltopyranoside; n-dodecyl-p-d-glucopyranoside; n-dodecyl-p-d-maltoside; heptanoyl-N-methylglucamide; n-heptyl-p-d-glucopyranoside; n-heptyl-p-d-thioglucopyranoside; n-hexyl-p-d-glucopyranoside; nonanoyl-N-methylglucamide; n-acyl-p-d-glucopyranoside; octanoyl-N-methylglucamide; n-octyl-p-d-glucopyranoside; octyl-p-d-thioglucopyranoside; and the like.

[0110] Many polymeric emulsifiers such as poloxamers and cellulose excipients also act as gelling agents. Gels are semisolid, three-dimensional polymer matrices that include a small amount of solid dispersed in a relatively large amount of liquid but have more solid-like properties. Gels exhibit mechanical properties characteristic of solids, with both the dispersed components and the dispersion medium extending continuously throughout the system. Gels are typically transparent or translucent semisolid preparations that are favored by patients because of their unobtrusiveness. Topical gel preparations provide a suitable delivery system for drugs because they are less greasy and provide better application performance and stability compared to creams and ointments.

[0111] Other Ingredients

[0112] In certain embodiments, the composition may also include one or more additives or combinations thereof, including, but not limited to, humectants; texture enhancers; humidity regulators; pH adjusters; osmotic pressure regulators; UV-A and UV-B screeners; and antioxidants. For example, the antioxidant may be alpha-tocopherol, butylated hydroxyanisole or butylated hydroxytoluene, superoxide dismutase, panthenol, or certain metal chelators. One skilled in the art will be able to select optional compounds to be added to these compositions such that the advantageous properties inherently associated with the present disclosure are not or are not substantially adversely affected by the intended addition.

[0113] In addition, the composition may also include one or more additional active agents, such as antihistamines; corticosteroids, local anesthetics, local analgesics and antibiotics. In various embodiments, the antihistamine may be diphenhydramine hydrochloride or chlorpheniramine maleate; the corticosteroid may be hydrocortisone, hydrocortisone-21-monoester (such as hydrocortisone-21-acetate, hydrocortisone-21-butyrate, hydrocortisone-21-propionate, hydrocortisone-21-valerate, etc.) and hydrocortisone-17,21-diester (such as hydrocortisone-17,21-diacetate, hydrocortisone The local anesthetic may be benzocaine, lidocaine, prilocaine, and dibucaine; the local analgesic may be 1-menthol, d,1-camphor, or capsaicin.

[0114] Preferred embodiments of the present disclosure:

[0115] 1. A topical cyclooxygenase (COX) inhibitor preparation, the topical cyclooxygenase (COX) inhibitor preparation comprising

[0116] One or more COX inhibitors that inhibit human COX-1, human COX-2, or both human COX-1 and human COX-2;

[0117] from about 1.0 to about 15.0 weight percent of a long chain monounsaturated fatty acid, a long chain monounsaturated fatty alcohol, a terpene, or a combination thereof;

[0118] 0 to about 5.0 wt % poloxamer;

[0119] 1.0 to about 5.0 weight percent of a pharmaceutically acceptable cellulosic excipient;

[0120] a solvent mixture comprising ethanol, propylene glycol, 2-(2-ethoxyethoxy)ethanol, and optionally dimethyl sulfoxide; and

[0121] wherein the formulation comprises about 5.0 wt % or less water.

[0122] 2. The topical COX inhibitor formulation of embodiment 1, wherein the formulation comprises a COX inhibitor selected from the group consisting of naproxen, acetaminophen, benzydamine, bufenac, diclofenac, etofenamate, flufenamic acid, ibuprofen, indomethacin, ketoprofen, salicylic acid, salicin, diflunisal, magnesium salicylate, and choline salicylate.

[0123] 3. The topical COX inhibitor formulation according to embodiment 2, wherein the one or more COX inhibitors present in the formulation consists of diclofenac.

[0124] 4. The topical COX inhibitor formulation of embodiment 3, wherein the formulation comprises about 1.0 to about 2.5% by weight of diclofenac.

[0125] 5. The topical COX inhibitor formulation of embodiment 4, wherein the formulation provides a percutaneous absorption of at least about 7% of diclofenac.

[0126] 6. The topical COX inhibitor formulation of embodiment 5, wherein the formulation provides a percutaneous absorption of at least about 10% of diclofenac.

[0127] 7. The topical COX inhibitor formulation of any one of embodiments 1-6, wherein the formulation comprises about 1.0 wt. % or less water.

[0128] 8. The topical COX inhibitor formulation of embodiment 7, wherein the formulation is anhydrous.

[0129] 9. A topical COX inhibitor formulation according to any one of embodiments 1-8, wherein the formulation comprises about 25.0 to about 50.0 weight % ethanol, about 2.0 to about 12.5 weight % propylene glycol, about 0 to about 25.0 weight % dimethyl sulfoxide, and about 20.0 to about 49.9 weight % 2-(2-ethoxyethoxy)ethanol; and wherein the solvent mixture accounts for about 70.0 to about 95.0 weight % of the formulation.

[0130] 10. The topical COX inhibitor formulation of any one of embodiments 1-9, wherein the formulation comprises from about 1.0 to about 10.0 weight % of a long chain monounsaturated fatty acid, a long chain monounsaturated alcohol, or a mixture thereof.

[0131] 11. The topical COX inhibitor formulation according to any one of embodiments 1 to 10, wherein the long chain monounsaturated fatty acid, long chain monounsaturated alcohol or mixture thereof present in the formulation comprises or consists of oleic acid, oleyl alcohol or mixture thereof.

[0132] 12. The topical COX inhibitor formulation of any one of embodiments 1-11, wherein the formulation comprises a poloxamer selected from the group consisting of poloxamer-101, poloxamer-105, poloxamer-105 benzoate, poloxamer-108, poloxamer-122, poloxamer-123, poloxamer-124, poloxamer-181, poloxamer-182, poloxamer-182 dibenzoate, poloxamer-183, poloxamer-184, poloxamer-185, poloxamer-186, poloxamer-187, poloxamer-188, poloxamer-189, poloxamer-190, poloxamer-191, poloxamer-192, poloxamer-193, poloxamer-194, poloxamer-195, poloxamer-196, poloxamer-197, poloxamer-198 8. The group consisting of poloxamer-212, poloxamer-215, poloxamer-217, poloxamer-231, poloxamer-234, poloxamer-235, poloxamer-237, poloxamer-238, poloxamer-282, poloxamer-284, poloxamer-288, poloxamer-331, poloxamer-333, poloxamer-334, poloxamer-335, poloxamer-338, poloxamer-401, poloxamer-402, poloxamer-403 and poloxamer-407.

[0133] 13. The topical COX inhibitor formulation of embodiment 12, wherein the formulation comprises 0 to about 5.0 wt % of poloxamer-188.

[0134] 14. The topical COX inhibitor formulation of any one of embodiments 1-11, wherein the formulation comprises a pharmaceutically acceptable cellulose excipient selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose and ethyl hydroxyethyl cellulose.

[0135] 15. The topical COX inhibitor formulation of embodiment 14, wherein the formulation comprises about 1.0 to about 5.0 weight % hydroxypropyl cellulose.

[0136] 16. The topical COX inhibitor formulation of embodiment 1, wherein the formulation comprises: about 1.0 to about 2.5 weight % diclofenac;

[0137] about 1.0 to about 10.0 weight percent oleic acid, oleyl alcohol, or mixtures thereof;

[0138] 0 to about 5.0 wt % poloxamer;

[0139] about 2.0 to about 5.0 weight percent hydroxypropyl cellulose;

[0140] An anhydrous solvent mixture comprising ethanol, propylene glycol, dimethyl sulfoxide and 2-(2-ethoxyethoxy)ethanol,

[0141] wherein the formulation comprises from about 25.0 to about 50.0 weight percent ethanol, from about 2.0 to about 12.5 weight percent propylene glycol, from about 15.0 to about 25.0 weight percent dimethyl sulfoxide, and from about 20.0 to about 49.9 weight percent 2-(2-ethoxyethoxy)ethanol; and wherein the solvent mixture comprises from about 70.0 to about 95.0 weight percent of the formulation.

[0142] 17. The topical COX inhibitor formulation of embodiment 1, wherein the formulation is anhydrous and comprises or consists of:

[0143] about 2.0% by weight of diclofenac;

[0144] about 27.0% by weight ethanol;

[0145] about 8.0 wt % oleic acid, oleyl alcohol, or a mixture thereof;

[0146] about 0.5 wt % Poloxamer 188;

[0147] about 11.0 weight percent propylene glycol;

[0148] about 3.0 wt. % hydroxypropyl cellulose;

[0149] about 21.0 wt. % dimethyl sulfoxide; and

[0150] About 25.0 wt. % 2-(2-ethoxyethoxy)ethanol.

[0151] 18. The topical COX inhibitor formulation of embodiment 1, wherein the formulation is anhydrous and comprises or consists of:

[0152] about 2.0% by weight of diclofenac;

[0153] About 43.5% ethanol;

[0154] about 4.0 weight percent oleic acid, oleyl alcohol, or a mixture thereof;

[0155] 0 wt% Poloxamer 188;

[0156] about 3.0 wt. % propylene glycol;

[0157] about 3.0 wt. % hydroxypropyl cellulose;

[0158] about 20.0 wt. % dimethyl sulfoxide; and

[0159] About 24.5 wt. % 2-(2-ethoxyethoxy)ethanol.

[0160] 19. The topical COX inhibitor formulation of embodiment 1, wherein the formulation is anhydrous and comprises or consists of:

[0161] about 2.0% by weight of diclofenac;

[0162] About 37.5% ethanol;

[0163] about 2.0 wt. % oleic acid, oleyl alcohol, or a mixture thereof;

[0164] 0 wt% Poloxamer 188;

[0165] about 11.0 weight percent propylene glycol;

[0166] about 3.0 wt. % hydroxypropyl cellulose;

[0167] about 20.0 wt. % dimethyl sulfoxide; and

[0168] About 24.5 wt. % 2-(2-ethoxyethoxy)ethanol.

[0169] 20. The topical COX inhibitor formulation of embodiment 1, wherein the formulation is anhydrous and comprises or consists of:

[0170] about 2.0% by weight of diclofenac;

[0171] About 31.5% ethanol;

[0172] about 8.0 wt % oleic acid, oleyl alcohol, or a mixture thereof;

[0173] 0 wt% Poloxamer 188;

[0174] about 11.0 weight percent propylene glycol;

[0175] about 3.0 wt. % hydroxypropyl cellulose;

[0176] about 20.0 wt. % dimethyl sulfoxide; and

[0177] About 24.5 wt. % 2-(2-ethoxyethoxy)ethanol.

[0178] 21. A method for topically treating an episode of pain at a site in the human body, the method comprising topically applying to the site a topical COX inhibitor formulation according to any one of embodiments 1-20.

[0179] 22. The method of embodiment 21, wherein the pain episode is an acute pain episode.

[0180] 23. The method of embodiment 21, wherein the pain episode is a chronic pain episode.

[0181] 24. A method of topically treating osteoarthritis pain of the knee, said method comprising topically applying to said knee a topical COX inhibitor formulation according to any one of embodiments 1-20.

[0182] 25. The method of any one of embodiments 21-24, wherein the COX inhibitor is diclofenac and the topical dose of diclofenac is about 80 mg or less.

[0183] 26. The method of embodiment 25, wherein the topical dose of diclofenac is about 80 mg, about 40 mg, about 30 mg, about 20 mg, or about 10 mg.

[0184] 27. The method of any one of embodiments 21-26, wherein the topical COX inhibitor formulation comprises about 2% by weight of diclofenac.

[0185] Example

[0186] The following examples are used to illustrate the present disclosure. These examples are in no way intended to limit the scope of the present disclosure.

[0187] Example 1: Topical Diclofenac Formulation

[0188] Material:

[0189] DMSO, CAS No.: 67-68-5

[0190] Oleic acid, CAS No. 112-80-1

[0191] Trascutol (diethylene glycol monoethyl ether; 2-(2-ethoxyethoxy)ethanol), CAS No. 111-90-0

[0192] Ethanol, 200 proof, anhydrous, CAS No. 64-17-5

[0193] Poloxamer 188, CAS No. 9003-11-6

[0194] 1,2-Propanediol, CAS No.: 57-55-6

[0195] Klucel TM GF Pharm (Hydroxypropylcellulose (HPC), CAS No.: 9004-64-2)

[0196] Diclofenac sodium (2-[(2,6-dichlorophenyl)amino]phenylacetic acid sodium salt), CAS number: 15307-79-6

[0197] Method for preparing 2% diclofenac formulation:

[0198] Oleic acid was heated to 60°C and then Poloxamer 188 was mixed and dissolved in the oleic acid.

[0199] At 20°C, add propylene glycol to DMSO while mixing. Slowly add hydroxypropyl cellulose to the mixture. Mix for 1 hour.

[0200] Heat transcutol to 60° and dissolve diclofenac sodium in the transcutol.

[0201] While mixing, add transcutol / diclofenac sodium to DMSO / propylene glycol. Mix with oleic acid / poloxamer 188, then add ethanol and mix until homogeneous.

[0202] Alternative method without Poloxamer 188:

[0203] Propylene glycol was added to DMSO at 20°C while mixing.

[0204] Diclofenac sodium was dissolved in transcutol at 20°C.

[0205] While mixing, add transcutol / diclofenac sodium to DMSO / propylene glycol. Slowly add hydroxypropyl cellulose to the mixture. Then add ethanol and mix until smooth. Add oleic acid and mix until smooth.

[0206] Exemplary Formulations of the Disclosure (wt%)

[0207] Diclofenac sodium 1.8-2.2 wt%

[0208] DMSO 18.0-22.0 wt%

[0209] Transcutol 15.0-25.0%

[0210] Propylene glycol 10.0-12.0 wt%

[0211] Ethanol 25.0-40.0 wt%

[0212] Hydroxypropyl cellulose 2.7-3.3 wt%

[0213] Poloxamer P188 0.0-3.0 wt%

[0214] Oleic acid 7.0-9.0 wt%

[0215] Example 2. Penetration test

[0216] The Franz diffusion cell experiment is used to analyze the flux rate of diclofenac in the composition taught by the present disclosure through human skin. See, for example, Bartosova and Bajgar, Transdermal Drug Delivery In Vitro Using Diffusion Cells, Curr. Med. Chem. 2012, 19: 4671-4677.

[0217] In the examples described herein, a Franz diffusion cell ("FDC") with a 3.3 mL receptor pore volume was used with either porcine skin or human cadaver skin. For human cadaver skin, split-thickness human cadaver skin (0.015"-0.018") was obtained from AlloSource (Centennial, CO) or Skin Bank New York Fireworks (New York, NY). The skin tissue was prepared from a tissue bank to a thickness of approximately 250 μm and shipped frozen on dry ice. All information obtained from the cadaver skin supplier regarding tissue source, donor information, body site, tissue condition, and storage period prior to receipt was maintained in the study file. Upon receipt of the donor skin, the skin pieces were stored at -20°C prior to use. Prior to use, the skin pieces were removed from the refrigerator and completely thawed at ambient temperature.

[0218] Donor hole treatment about 0.55cm 2 The receptor wells were filled with PBS containing 0.01% sodium azide ("receptor fluid"), which was shown to provide sink conditions throughout the experiment. The receptor wells of the FDC were maintained at 37°C in a stirring dry block (temperature of the skin surface was 32°C ± 0.5°C), while the receptor fluid in the receptor wells was continuously stirred using a magnetic stirring bar. The donor and receptor chambers were clamped around the skin piece using clamping forceps under uniform pressure.

[0219] After assembling the FDC, the skin was allowed to hydrate in contact with the receptor fluid for 20 minutes. Any FDC showing signs of leakage during this period was discarded.

[0220] Prior to application of the test formulation, the integrity and quality of each skin piece was tested by measuring the transdermal flux or transdermal resistance ("TEER") of tritiated water (skin integrity is not usually tested on porcine skin pieces). TEER measurements were performed as follows. An aliquot of 150 μL of PBS was introduced into each FDC donor well. After 10 minutes, a blunt electrode probe was placed into the donor well and rested gently on the skin surface under its own weight. A second electrode was then inserted into the receptor fluid through the sampling port on the receptor chamber of the FDC. An alternating current (AC) signal with a root mean square (RMS) of 100 mV at 100 Hz was applied to the skin using a waveform generator, and the impedance was then measured using a digital multimeter, with the results recorded in kΩ. Any FDC showing abnormally low impedance (nominal value <2 kΩ) was discarded, and the FDC was sorted according to the size of the measured impedance reading. The test article was then assigned to the batch of FDCs so that a replicate of each test article was applied to skin pieces with an average transdermal resistance value that was almost equal.

[0221] After the membrane integrity test was completed and the cells were properly sorted, samples of the test articles were applied to the stratum corneum of the skin. The study employed a one-time dosing regimen. Six replicates of each of the test formulations were examined in a typical batch of approximately 36 FDCs in total.

[0222] The dose was applied using a Nichiryo positive displacement pipette. The dose was dispensed from the pipette into the skin and spread over the surface using the blunt end of a glass rod. For most experiments, a typical inhaled dose was 10 mL of formulation per cell. The formulation itself was typically made at 1 wt%. Assuming a 10 mL dose applied to the skin, no loss of glass rod in spreading the formulation, a 1% weight percent of active substance in the formulation, a specific gravity of the formulation of 1.0, and a surface area of ​​0.55 cm per cell. 2 , then the diclofenac dose per FDC is about 181.8 mg / cm 2 .

[0223] At a preset time, typically 24 hours, samples were drawn from each receptor well. Using a graduated Hamilton-type syringe, 300 μl aliquots were drawn from the sampling port of each FDC at 24 hours. Each aliquot drawn was introduced into a well of a 96-well microtiter plate. Samples were stored in a refrigerator at 4-8°C prior to HPLC analysis. Samples were analyzed within 5 days of collection.

[0224] At 24 hours, the skin was tape-stripped three times with Scotch tape, each tape stripping consisting of applying a piece of Scotch tape to the skin with light pressure and peeling off the tape, thereby systematically removing the uppermost layer of the stratum corneum. The tape was discarded.

[0225] After tape stripping is complete, separate the remaining skin into epidermal and dermal portions using a pair of spatulas. If necessary, place the skin on a hot plate set to 60°C for one minute to help facilitate separation of the skin. The epidermal and dermal portions are then placed separately into glass bottles, to which 3 ml of DMSO is added. The skin pieces are then incubated at 40°C for 24 hours with gentle agitation. After the 24-hour incubation period, samples are collected.

[0226] The samples drawn from the receptor wells and skin extracts were then analyzed by a validated HPLC method using Chemstation software. The AUC for diclofenac was recorded and converted to mg / ml values ​​using a calibration curve derived from the AUC values ​​of the calibration standards and the known concentration values. These mg / ml values ​​were imported into the Study Results Excel workbook. These concentrations were then multiplied by the receptor volume (3.3 mL) or the skin extract volume (3 ml) and then divided by the skin surface area exposed to the receptor fluid (0.55 cm 2 ), the unit is mg / cm 2 In each case, the concentration of the active substance is analyzed and reported.

[0227] Formulations tested (Table 1)

[0228]

[0229] Figure 1 The skin permeation flux data for the 2% diclofenac formulation in Table 1 are depicted, while Figure 2 The skin permeation delivery dose data for the 2% diclofenac formulation in Table 1 are depicted.

[0230] Embodiment 3:

[0231] Extrapolating from formulation D32, other formulations containing decreasing amounts of DMSO and increasing amounts of transcutol were tested by the same method.

[0232] Formulations tested (Table 2):

[0233]

[0234] Figure 3 , Figure 4 and Figure 5 A head-to-head comparison of Pennsaid and formulation D34 as delivered transdermal dose, dose retained in the skin, and calculated as percent diclofenac delivered is depicted. It can be seen that formulation D34 delivered significantly more diclofenac transdermally than Pennsaid, while Pennsaid retained a greater amount in the epidermis and dermis. At 48 hours, the percent transdermal delivery of diclofenac in formulation D34 was greater than 15%.

[0235] Figure 6 The diclofenac flux of the two formulations is shown over time. The maximum flux of diclofenac was observed within 12 hours after application.

[0236] Embodiment 4:

[0237] Other formulations varying the amounts of oleic acid, propylene glycol, and ethanol were tested by the same method.

[0238] Formulations tested (Table 3):

[0239]

[0240] Figure 7 The skin permeation delivery dose data of the 2% diclofenac formulation in Table 1 are depicted, while Figure 8 Depicted are the skin permeation flux data for the 2% diclofenac formulations in Table 1. As shown, these formulations can deliver an equivalent amount of diclofenac as formulation D1C, with significantly less DMSO and at much lower doses of formulation administered.

[0241] Embodiment 5:

[0242] Other formulations with varying amounts of transcutol and ethanol were tested by the same method.

[0243] Formulations tested (Table 4):

[0244]

[0245] Fig. 9 , 10 and 11 depict a head-to-head comparison of Pennsaid and formulation D34 as transdermal dose delivered, dose retained in the skin, and calculated as percentage of diclofenac delivered.

[0246] Embodiment 6:

[0247] Other formulations varying the amounts of oleic acid, propylene glycol, and ethanol were tested by the same method.

[0248] Formulations tested (Table 5):

[0249]

[0250] In this set of formulations, the oleic acid concentration was dropped from a high concentration of 8.0% to 2.0%. The test data began to change the dose, from 6μL of Pennsaid to 3μL of the formulation. This is the data showing that the formulation has better penetration at 1 / 2 this dose. In the second data set of formulation D56, a second dose of 6μL of Pennsaid and 3μL of formulation D56 was used to simulate a second application. The control for all data sets was the actual Pennsaid product. See Fig.12 and Fig.13 .

[0251] exist Fig.12 In the figure, column 1: Pennsaid 2% diclofenac, DC1 control, dose 6μL; column 2: 2% diclofenac D51, dose -3μL; column 3: 2% diclofenac D52, dose -3μL; column 4: 2% diclofenac D53, dose -3μL; column 4, 2% diclofenac D53; column 5: 2% diclofenac D54; column 6: 2% diclofenac D55.

[0252] exist Fig.13 Arm #1: DIC Pennsaid, dose 6 μL; Arm #2: D56, dose 6 μL; Arm #3: D56, dose 3 μL; Arm #4: D1C Pennsaid with another 6 μL dose at 24 hours; Arm #4: D56 with another 3 μL dose at 24 hours.

[0253] The cadaver skin permeation data showed that 2% diclofenac in the Pennsaid (6 μL dose) and formulation D56 (3 μL dose) products permeated into the epidermis and dermis and permeated through the cadaver skin samples. The following calculations show the retention of these formulations per cm after 48 hours. 2 The amount of diclofenac sodium on the skin surface. As shown in the figure, compared with formulation D56, the Pennsaid product has a skin surface / cm 2 There was almost seven times more diclofenac sodium residue on the surface, which for a topical prescription medication may be of concern to consumers who administer it repeatedly on a daily basis.

[0254]

[0255] Embodiment 7:

[0256] Other formulations varying the amounts of oleic acid, propylene glycol, and ethanol were tested by the same method.

[0257]

[0258] In these formulations, no oleic acid was added to the formulation. In formulation D58, 4.0% glycerol was added. In formulation D59, oleyl alcohol was added in an amount of 4.0%.

[0259] In the absence of oleic acid in the formulation, the permeation of diclofenac was significantly reduced to a level less than that of Pennsaid. Oleic acid and oleyl alcohol enhanced the permeation of diclofenac.

[0260] exist Fig.14 Middle, Arm#1: DIC Pennsaid; Arm#2: D57; Arm#3: D58; Arm#4: D59.

[0261] Example 8: Publications

[0262] The following publications are incorporated herein by reference in their entirety.

[0263] McPherson and Cimino,Topical NSAID Formulations,Pain Medicine,Volume14,Issue suppl_1,December 2013,Pages S35–S39,doi.org / 10.1111 / pme.12288

[0264] WO2009081217

[0265] WO2016033308

[0266] WO2017173269

[0267] US 9101591

[0268] One skilled in the art will readily appreciate that the present disclosure is well adapted to carry out these objects and obtain the objects and advantages mentioned, as well as those inherent therein.The examples provided herein are representative of preferred embodiments, are exemplary, and are not intended to limit the scope of the present disclosure.

[0269] It is obvious to those skilled in the art that various substitutions and modifications can be made to the contents disclosed herein without departing from the scope and spirit of the disclosure.

[0270] All patents and publications mentioned in the specification are indicative of the levels of ordinary skill in the art to which the disclosure pertains. All patents and publications are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.

[0271] The present disclosure illustratively described herein can be appropriately practiced without any one or more elements, one or more limitations that are not specifically disclosed herein. Thus, for example, in each instance herein, any one of the terms "comprising", "consisting essentially of" and "consisting of" can be replaced by any one of the other two terms. The terms and expressions that have been adopted are used as descriptive terms rather than restrictive terms, and when using these terms and expressions, it is not intended to exclude any equivalents of the features shown and described or parts thereof, but it should be appreciated that various modifications are possible within the scope of the disclosure claimed. Therefore, it should be understood that although the present disclosure has been specifically disclosed by preferred embodiments and optional features, those skilled in the art may modify and vary the concepts disclosed herein, and such modifications and variations are considered to be within the scope of the present disclosure as defined by the appended claims.

[0272] Other embodiments are set forth in the following claims.

Claims

1. A topical diclofenac preparation, wherein: The formulation is anhydrous and consists of: 1.8 to 2.2% by weight of diclofenac sodium; 25 to 40% by weight of anhydrous ethanol; 7.0 to 9.0 wt % oleic acid, oleyl alcohol or mixtures thereof; 10.0 to 12.0 wt. % propylene glycol; 2.7 to 3.3 wt % hydroxypropyl cellulose; 18 to 22 wt % dimethyl sulfoxide; and 15.0 to 25.0 wt. % 2-(2-ethoxyethoxy)ethanol.

2. A topical diclofenac preparation, wherein: The formulation is anhydrous and consists of: about 2.0% by weight of diclofenac sodium; about 31.5% by weight of anhydrous ethanol; about 8.0 weight percent oleic acid, oleyl alcohol, or mixtures thereof; about 11.0 weight percent propylene glycol; about 3.0 wt. % hydroxypropyl cellulose; about 20.0 wt. % dimethyl sulfoxide; and about 24.5% by weight of 2-(2-ethoxyethoxy)ethanol, Wherein "about" means + / - 10% of the above value.

3. The topical diclofenac preparation according to claim 1 or 2, wherein The amount of diclofenac sodium was 2% by weight.

4. The topical diclofenac formulation according to claim 3, wherein The preparation consists of the following: 2% by weight of diclofenac sodium; 31.5% anhydrous ethanol; 8% by weight of oleic acid or oleyl alcohol; 11% by weight of propylene glycol; 3% by weight hydroxypropyl cellulose; 20 wt% dimethyl sulfoxide; and 24.5 wt. % 2-(2-ethoxyethoxy)ethanol.

5. The topical diclofenac formulation of claim 2, wherein: The preparation consists of the following: 2% by weight of diclofenac sodium; 29% by weight of anhydrous ethanol; 8% by weight of oleic acid or oleyl alcohol; 11% by weight of propylene glycol; 3% by weight hydroxypropyl cellulose; 21 wt% dimethyl sulfoxide; and 26 wt% 2-(2-ethoxyethoxy)ethanol.

6. Use of a topical diclofenac formulation according to any one of claims 1 to 5 in the manufacture of a medicament for the local treatment of painful episodes at a site on the human body, said treatment comprising topically applying said topical diclofenac formulation to said site.

7. The use according to claim 6, wherein The pain episode is an acute pain episode or a chronic pain episode.

8. The use according to claim 6, wherein The pain episode was pain from osteoarthritis of the knee.

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