WO2021061913A1 - Diclofenac sodium topical solution - Google Patents

Abstract

The present invention provides for a topical formulation that includes diclofenac sodium, as well as methods of manufacturing and using the topical formulation.

Description

DICLOFENAC SODIUM TOPICAL SOLUTION

RELATED APPLICATION

[0001] This application is a PCT International Application and claims priority to and the benefit ofU.S. Provisional Patent Application Serial Number 62/906,776, filed September 27, 2019, the contents of which are incorporated herein it its entirety.

FIELD OF THE INVENTION

[0002] The present invention relates generally to compositions and methods for treating osteoarthritis.

BACKGROUND OF THE INVENTION

[0003] Topical, transdermal products including diclofenac, a non-steroidal antiinflammatory drug (NS AID) of the acetic acid class, or a pharmaceutically acceptable salt thereof, are currently available to patients and consumers in the U.S. and other countries, and are widely used for their analgesic and anti-inflammatory properties, at reduced risk of the systemic adverse effects that can be experienced with oral NS AID formulations.

[0004] Acidic diclofenac has very low water solubility since the only hydrophilic functional group, i.e., the carboxyl group, is involved in the formation of a dimer and therefore not readily available to interact with solvent (Fini et al., “Diclofenac Salts, VIII. Effect of the Counterions on the Permeation through Porcine Membrane from Aqueous Saturated Solutions,” Pharmaceutics 2012, 4, 413-429). Salt forms are often preferred in commercial topical formulations to address solubility problems with the acid; however, the solubility of the sodium salt of diclofenac is still quite low, its kinetic solubility being reported as 40+5 μg/mL for the anhydrous form (Llinas et al., “Diclofenac Solubility: Independent Determination of the Intrinsic Solubility of Three Crystal Forms,” J Med Chem. 2007 Mar 8; 50(5):979-83).

[0005] A low, i.e. 1%, concentration diclofenac sodium topical, transdermal product, formulated as an emulsion-gel (“emulgel”), was approved by the Food and Drug Administration (FDA) in 2007 as being safe and effective for the relief of the pain of osteoarthritis of joints amenable to topical treatment, such as the knees and those of the hands, when topically administered in a four times-daily regimen to lower and/or upper extremities, and is marketed in the U.S. as Voltaren® Gel (diclofenac sodium emulgel, 1%; referred to herein as “DSG 1%” unless otherwise indicated). Studies show that systemic exposure with the recommended use of DSG 1% (4 x 4 g per day applied to 1 knee) is on average 17 times lower than with oral treatment given as 3 x 50 mg per day; and the average peak plasma concentration is 158 times lower than with the oral treatment.

[0006] Additionally, a 1.16 % diclofenac diethylammonium (DEA) (equivalent to 1% sodium) topical emulgel was first approved in Europe in 1985 as Voltaren® (or Voltarol®) 1.16% Emulgel®), and is currently marketed in over 115 countries; see also GB 2,128,087. The DEA formulation has been approved for, e.g., relief of pain, inflammation, and swelling in posttraumatic inflammation of tendons, ligaments, muscles and joints (e.g., due to sprains, strains or bruises), localized forms of soft-tissue rheumatism (e.g., tendonitis, epicondylitis, shoulder- hand syndrome and periarthropathy), and the local management of degenerative joint conditions (e.g., osteoarthritis of the peripheral joints and of the vertebral column). A 2.32% strength diclofenac DEA (equivalent to 2% sodium) emulgel, containing oleyl alcohol as a permeation enhancer, has also been introduced under the Voltaren® (Voltarol®) name (and is hereinafter referred to as “VEG 2%”), affording to patients and consumers outside the U.S. the convenience of a twice-daily (b.i.d.) dosing regimen; see WO 2009/056522. However, the DEA salt form of diclofenac is currently not an approved salt form in the U.S.

[0007] Other topical, transdermal diclofenac sodium products include Solaraze®, a 3% gel for the treatment of actinic keratoses which relies on hyaluronate sodium as a penetration enhancer; as well as Pennsaid® 1.5% and 2% solutions including dimethylsulfoxide (DMSO) as a penetration enhancer.

[0008] It has been a key objective of the inventors to provide to patients and consumers in the U.S. as well as other markets a topical, transdermal diclofenac sodium product having a safe and effective amount of diclofenac sodium (e.g., 2 wt.%) that avoids the need for a relatively large amount of dimethylsulfoxide (DMSO) than is present in Pennsaid® 1.5% and 2% solutions. SUMMARY OF THE INVENTION

[0009] The present invention overcomes disadvantages of the prior art by providing diclofenac sodium gel formulations for the treatment of osteoarthritis that include a lower amount of dimethyl sulfoxide (DMSO), while displaying a suitable and effective: drying time, viscosity, transdermal flux, and pharmacokinetic absorption in vivo, when compared to previously described compositions. In specific embodiments, the diclofenac sodium gel formulations of the present invention provide other advantages including favorable stability at six (6) months, as reflected in the lack of any substantial changes in viscosity, the absence of phase separation and crystallization at low temperatures, and a low level of impurities. Moreover, the present gelled formulations adhere well to the skin, spread easily, dry quickly, and show the requisite in vivo absorption, in comparison to previously described compositions. Thus, the gel formulations of the present invention provide superior means for the delivery of diclofenac sodium through the skin for the treatment of osteoarthritis, as compared to previously described formulations.

[0010] The present invention provides for a topical formulation that includes (i)-(v): (i) diclofenac, or a pharmaceutically acceptable salt thereof, present in at least 1 wt.%; (ii) at least one of (a)-(e): (a) dimethyl sulfoxide (DMSO), (b) transcutol® (2-(2-ethoxyethoxy) ethanol),

(c) ethanol, (d) isopropyl alcohol, (e) cetyl alcohol, (iii) at least one of (a)-(f): (a) propylene glycol, (b) butylene glycol, (c) hexylene glycol, (d) 1,2-hexane did, (e) glycerol, (f) methyl gluceth, (iv) at least one of (a)-(k): (a) emulsifying wax, (b) glyceryl monooleate, (c) phospholipids, (d) polyoxyethylene alkyl ethers, (e) polyoxyethylene, (f) castor oil derivatives, (g) sorbitan fatty acid esters, (h) polyoxyethylene stearates, (i) polyoxyl glycerides, (j) polysorbate, (k) sorbitan esters, (v) at least one of (a)-(f): (a) benzyl alcohol, (b) butylparaben,

(c) ethylparaben, (d) methylparaben, (e) propylparaben, and (f) sorbic acid. In specific embodiments, the topical formulation further includes at least one of (i)— (vii): (i) water, (ii) alpha hydroxy carboxylic acid, (iii) pH adjusting agent, (iv) buffer, (v) antioxidant, (vi) cyclomethicone, and (vii) thickening agent, viscosity-increasing agent, or combination thereof.

[0011] The present invention also provides for a topical formulation that includes: (i) diclofenac sodium; (ii) dimethyl sulfoxide (DMSO); (iii) ethanol; (iv) propylene glycol; (v) glycerol; (vi) Brij® L4 (polyethylene glycol dodecyl ether, polyoxyethylene (4) lauryl ether); (vii) benzyl alcohol; and (viii) PBS Buffer pH 5.5. [0012] The present invention also provides for a topical formulation that includes: (i) diclofenac sodium; (ii) dimethyl sulfoxide (DMSO); (iii) ethanol; (iv) propylene glycol; (v) glycerol; (vi) cyclomethicone 5NF; (vii) benzyl alcohol; and (viii) PBS Buffer pH 9.0.

[0013] The present invention also provides for a topical formulation that includes: (i) diclofenac sodium; (ii) dimethyl sulfoxide (DMSO); (iii) ethanol; (iv) propylene glycol; (v) glycerol; (vi) benzyl alcohol; and (vii) PBS Buffer pH 9.0.

[0014] The present invention also provides for a topical formulation that includes: (i) diclofenac sodium; (ii) dimethyl sulfoxide (DMSO); (iii) ethanol; (iv) propylene glycol; (v) glycerol; (vi) cyclomethicone 5NF; (vii) Brij® L4 (polyethylene glycol dodecyl ether, polyoxyethylene (4) lauryl ether); (viii) hydroxy propyl cellulose (HY119); (ix) benzyl alcohol; and (x) PBS buffer pH 9.0.

[0015] The present invention also provides for a topical formulation that includes: (i) diclofenac sodium; (ii) dimethyl sulfoxide (DMSO); (iii) ethanol; (iv) propylene glycol; (v) glycerol; (vi) Brij® L4 (polyethylene glycol dodecyl ether, polyoxyethylene (4) lauryl ether); (vii) hydroxy propyl cellulose (HY119); (viii) benzyl alcohol; and (ix) PBS buffer pH 5.5.

[0016] The present invention also provides for a topical formulation that includes: (i) diclofenac sodium; (ii) dimethyl sulfoxide (DMSO); (iii) Sepineo™ P 600 (acrylamide/sodium acryloyldimethyl taurate copolymer/ isohexadecane & polysorbate 80); (iv) propylene glycol; (v) Transcutol® P (2-(2-ethoxy ethoxy) ethanol); (vi) ethanol; (vii) Klucel™ MF (hydroxypropylcellulose); and (viii) water.

[0017] The present invention also provides for a topical formulation that includes: (i) diclofenac sodium; (ii) dimethyl sulfoxide (DMSO); (iii) Sepineo™ P 600 (acrylamide/sodium acryloyldimethyl taurate copolymer/ isohexadecane & polysorbate 80); (iv) propylene glycol; (v) Transcutol® P (2-(2-ethoxy ethoxy) ethanol); (vi) ethanol; (vii) Klucel™ MF (hydroxypropylcellulose); (viii) trisaminomethane (Tris); and (ix) water.

[0018] The present invention also provides for a topical formulation that includes: (i) diclofenac sodium; (ii) dimethyl sulfoxide; (iii) ethanol; (iv) propylene glycol; (v) glycerin; (vi) benzyl alcohol; (vii) hydroxy propyl cellulose (HF); (viii) cyclomethicone; (ix) dimethyl isosorbide (DMI); and (x) purified water.

[0019] The present invention also provides for a topical formulation that includes: (i) diclofenac sodium; (ii) dimethyl sulfoxide; (iii) ethanol; (iv) propylene glycol; (v) glycerin; (vi) benzyl alcohol; (vii) cetyl alcohol; (viii) hydroxy propyl cellulose (HF); (ix) cyclomethicone; (x) dimethyl isosotbide (DMI); and (xi) Purified Water.

[0020] The present invention also provides for a topical formulation of Example la, lb, or lc (Formulation A-L).

[0021] The present invention further provides for a method of treating pain in a subject suffering from pain. The method includes topically administering to an afflicted area of the subject the topical formulation described herein.

[0022] The present invention further provides for a method of treating osteoarthritis in a subject suffering from articular pain. The method includes topically administering to an afflicted joint area of the subject a therapeutically effective amount of the topical formulation described herein.

[0023] The present invention further provides for a method for treating pain associated with joint diseases characterized by joint pain, degeneration of articular cartilage, impaired movement, and/or stiffness. The method includes topically administering to an afflicted joint area of the subject a therapeutically effective amount of the topical formulation described herein.

[0024] The present invention further provides for a method for treating pain due to osteoarthritis of the knee of a subject in need thereof. The method includes topically administering to the knee area of the subject a therapeutically effective amount of the topical formulation described herein.

DETAILED DESCRIPTION OF THE INVENTION

[0025] The present invention provides for a topical formulation (e.g., topical liquid solution) that includes diclofenac, or a pharmaceutically acceptable salt thereof. The present invention also provides for a method of medical treatment (e.g., treating pain in a subject suffering from pain; treating osteoarthritis in a subject suffering from articular pain; treating pain associated with joint diseases characterized by joint pain, degeneration of articular cartilage, impaired movement, and/or stiffness; and/or treating pain due to osteoarthritis of the knee of a subject in need thereof). The method of medical treatment includes topically administering to an afflicted area of the subject the topical formulation described herein.

Definitions

[0026] As used herein, the following terms have the meanings ascribed to them unless specified otherwise.

[0027] The term “diclofenac sodium” refers to a benzeneacetic acid derivative that is a nonsteroidal anti-inflammatoiy drug (NSAID). The chemical name is 2[(2,6-dichlorophenyl)- ami no]-benzeneacetic acid, monosodium salt. The molecular weight is 318.14. Its molecular formula is C₁₄H₁₀C₁₂NNaO₂, and it has the following chemical structure (as the free acid).

[0028] Diclofenac is sufficiently acidic, such that it can exist in a salt form. Examples of pharmaceutically acceptable salts include those with physiological acceptable anions, such as, sodium and carbonate salts. Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting diclofenac with a suitable base affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.

[0029] The term “dimethyl sulfoxide” or “DMSO” refers to an organosulfur compound with the formula (CH₃)₂SO.

[0030] The term “transcutol®” or “transcutol® P” refers to the compound 2-(2-ethoxyethoxy) ethanol, having the linear formula CH₃CH₂OCH₂CH₂OCH₂CH₂OH. It is commercially available from Gattefosse (Saint-Priest, FR). [0031] The term “Sepineo™ P 600” refers to the composition containing acrylamide/sodium acryloyldimethyl taurate copolymer/ isohexadecane & polysorbate 80. It is commercially available from Seppic Inc. (Cedex, FR).

[0032] The term “Klucel™ MF” refers to the compound hydroxypropylcellulose (HPC) (alternatively known as hydroxy propyl cellulose). It is commercially available from Ashland (Covington, KY).

[0033] The term “cetyl alcohol” (also known as hexadecan-l-ol and palmityl alcohol), refers to a C-16 fatty alcohol with the formula CH₃(CH₂)₁₅OH.

[0034] The term “dimethyl isosorbide” or “DMI” refers to the compound (3R,3aR,6S,6aR)-3,6- Dimethoxyhexahydrofuro[3,2-b]furan l,4:3,6-Dianhydro-2,5-di-0-methyl-D-glucitol. It has a molecular weight of 174.19 g/mol and molecular formula of C₈H₁₄O₄.

[0035] The term “ethanol” refers to the compound with the chemical formula C₂H₆O Its formula can be also written as CH₃-CH₂-OH.

[0036] The term “isopropyl alcohol” or “isopropanol” or “2-propanol” refers to the compound having the IUPAC name propan-2-ol and linear formula CH₃CHOHCH₃.

[0037] The term “propylene glycol” refers to the compound having the IUPAC name propane- 1, 2-diol and the linear formula CH₃CH(0H)CH₂0H.

[0038] The term “butylene glycol” refers to the compound with the chemical name 1,3- butanediol and the linear formula HOCH₂CH₂CHCH₃.

[0039] The term “hexylene glycol” refers to the racemic mixture of the two enantiomers (4R)- (-) and (4S)-(+) of 2-methyl-2,4-pentanediol, which is a compound having the IUPAC name 2- methylpentane-2,4-diol and the linear formula (CH₃)₂C(OH)CH₂CH(OH)CH₃.

[0040] The term “ 1 ,2-hexanediol” refers to the compound having the linear formula CH₃(CH₂)₃CH(OH)CH₂OH and molecular formula C₆H₁₄O₂ [0041] The term “glycerol” or “glycerin” refers to the compound having the name propane- 1, 2, 3-triol and molecular formula C₃H₈O₃.

[0042] The term “methyl gluceth” or “methyl gluceth-10” refers to the compound poly(oxy- 1,2-ethanediyl), alpha-hydro-omega-hydroxy-, ether with methyl D-glucopyranoside (4:1) having the molecular formula C₂₃H₄₆O₁₄.

[0043] The term “emulsifying wax” refers to a substance created when a wax material (either a vegetable wax of some kind or a petroleum-based wax) is treated with a detergent (typically sodium dodecyl sulfate or polysorbates) to cause it to make oil and water bind together into a smooth emulsion. It is a white waxy solid with a low fatty alcohol odor. The ingredients for emulsifying wax are cetearyl alcohol and a polyoxyethylene derivative of a fatty acid ester of sorbitan (a polysorbate).

[0044] The term “glyceryl monooleate” or “glyceryl 1-oleate” or “2,3-dihydroxypropyl oleate” refers to the compound having the IUPAC name 2,3-dihydroxypropyl (Z)-octadec-9- enoate and molecular formula C₂₁H₄₀O₄.

[0045] The term “phospholipids” refers to organic compounds whose structure generally consists of two hydrophobic fatty add “tails” and a hydrophilic “head” consisting of a phosphate group. The two components are usually joined together by a glycerol molecule. The phosphate groups can be modified with simple organic molecules such as choline, ethanolamine or serine. Phospholipids include lecithin, Phospholipon 90G, and Phospholipon 90H.

[0046] The term “polyoxyethylene alkyl ethers” refers to nonionic surfactants made of an alkyl chain with n methylene groups and a hydrophilic part with m oxyethylene units (CnEm). The commercially available products are often a mixture of several CriEm molecules with different m values. Polyoxyethylene alkyl ethers include Brij® S20, Brij® 020, Brij® O10, Brij® CIO, Brij® C20, Brij® LA, Brij® S2, Brij® S20 and other Brij s®. Specific polyoxyethylene alkyl ethers include Brij® L4 and Brij® S20. The Brij® products are commercially available from Sigma-Aldrich (St. Louis, MO) and Croda (East Yorkshire, U.K.).

[0047] The term “polyoxyethylene” or “POE” or “polyethylene glycol” or “PEG” refers to a polyether compound whose structure is commonly expressed as H-(0-CH₂-CH₂)n-0H. [0048] The term “castor oil” refers to a vegetable oil pressed from castor beans. It is a triglyceride in which approximately 90 percent of fatty acid chains are ricinoleates. Oleate and linoleates are the other significant components. Castor oil is well known as a source of ricinoleic acid, a monounsaturated, 18-carbon fatty acid. Among fatty acids, ricinoleic add is unusual in that it has a hydroxyl functional group on the 12th carbon. This functional group causes ricinoleic acid (and castor oil) to be more polar than most fats. The chemical reactivity of the alcohol group also allows chemical derivatization that is not possible with most other seed oils.

[0049] Castor oil derivatives include, e.g., Kolliphor EL (polyethoxylated castor oil), a nonionic surfactant.

[0050] The term “sorbitan esters” refers to those compounds obtained by the esterification of the one or more hydroxyl groups present on sorbitan ( IUPAC name: (3 S)-2-( 1,2- dihydroxy ethyl)tetrahydrofuran-3,4-diol). Sorbitan esters include, e g., sorbitan monostearate (Span® 60), sorbitan tri stearate (Span® 65), sorbitan oleate (Span® 80), and sorbitan monolaurate (Span® 20). The Span® products are commercially available from Sigma- Aldrich (St. Louis, MO) and Croda (East Yorkshire, U.K.).

[0051] The term “sorbitan fatty acid esters” refers to a mixture of partial esters of sorbitol and its anhydrides with fatty adds. [0052] The term “polyoxyethylene stearates” refers to a mixture of the mono and diesters of stearic acid and mixed polyoxyethylene diols having an average polymer length of 7.5 oxy ethylene.

[0053] The term “poly oxy 1 glycerides” refers to a class of emulsifiers derived from the polyglycolysis of vegetable oils with polyoxyethylene glycol. Common brand names include Labrafil M1944CS (linoleoyl polyoxyglyceride), Labrasol (capiylocaproyl polyoxyglyceride), and Gelucire 44/14 (lauroyl polyoxyglyceride).

[0054] The term “polysorbate” refers to a class of emulsifiers that are oily liquids derived from ethoxylated sorbitan (a derivative of sorbitol) esterified with fatty adds, typically stearic, lauric, oleic, or palmitic. Common brand names for polysorbates include Scattics®, Alkest®, Canarcel®, and Tween®. Examples of polysorbates include, e.g., Polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate); Polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate); Polysorbate 60 (polyoxyethylene (20) sorbitan monostearate); and Polysorbate 80 (polyoxyethylene (20) sorbitan monooleate).

[0055] The term “benzyl alcohol” refers to the compound with the IUPAC name phenylmethanol and the linear formula C₆H₅CH₂OH.

[0056] The term “butylparaben” or “butyl p-hydroxybenzoate” refers to the compound having the IUPAC name butyl 4-hydroxybenzoate and the molecular formula C11H14O3.

[0057] The term “ethylparaben” or “ethyl para-hydroxybenzoate” refers to the compound having the IUPAC name ethyl 4-hydroxybenzoate and the molecular formula C9H10O3.

[0058] The term “methylparaben” or “methyl paraben” refers to the compound having the IUPAC name methyl 4-hydroxybenzoate and the linear formula CH3(C6H4(OH)COO).

[0059] The term “propylparaben” refers to refers to the compound having the IUPAC name propyl 4-hydroxybenzoateand the molecular formula C₁₀H₁₂O₃.

[0060] The term “sorbic add” or “2,4-hexadienoic acid” refers to the compound having the IUPAC name (2E,4E)-hexa-2,4-dienoic add and the linear formula CH₃(CH)₄CO₂H. [0061] The term “alpha hydroxy carboxylic acid” or “alpha hydroxy acid” or “AHA” refers to a class of organic compounds that consist of a carboxylic add substituted with a hydroxyl group on the adjacent carbon. They may be naturally occurring or synthetic. AHAs include, e.g., glycolic acid, lactic acid, malic add, citric acid, tartaric acid, and glycolic acid.

[0062] The term “pH adjusting agent” refers to a substance that, when added to an aqueous solution, will change the pH. For example, the pH adjusting agent can be an acid, such that when added to an aqueous solution having a pH of 7, will decrease the pH to below 7. Additionally, the pH adjusting agent can be a base, such that when added to an aqueous solution having a pH of 7, will increase the pH to above 7.

[0063] The term “buffer” refers to either a weak acid or weak base, such that upon added to aqueous solution, forms a buffer solution, which only slightly changes its pH in response to other acids and bases being combined with it, particularly a strong acid or a strong base. A buffer solution (more precisely, pH buffer or hydrogen ion buffer) refers to an aqueous solution consisting of a mixture of a weak acid and its conjugate base, or vice-versa. Its pH changes very little when a small amount of strong acid or base is added to it. Buffer solutions are used as a means of keeping pH at a nearly constant value.

[0064] The term “antioxidant” refers to a substance that inhibits oxidation. The antioxidant can optionally be an antimicrobial agent. Suitable antioxidants include, e.g., benzyl alcohol, butylparaben, ethylparaben, methylparaben, propylparaben, and sorbic acid.

[0065] The term “cyclomethicone” refers to a group of methyl siloxanes, a class of liquid silicones (cyclic polydimethylsiloxane polymers) that possess the characteristics of low viscosity and high volatility.

[0066] The term “thickening agent” or “viscosity-increasing agent” refers to a substance which can increase the thickness or viscosity of a liquid without substantially changing its other properties. Some thickening agents are gelling agents (gellants), forming a gel, dissolving in the liquid phase as a colloid mixture that forms a weakly cohesive internal structure. Others act as mechanical thixotropic additives with discrete particles adhering or interlocking to resist strain. Typical gelling agents include natural gums, starches, pectins, agar-agar and gelatin. Often they are based on polysaccharides or proteins. Examples include: Alginic acid, sodium alginate, potassium alginate, ammonium alginate, calcium alginate - polysaccharides from brown algae; Agar (polysaccharide obtained from red algae); Carrageenan (polysaccharide obtained from red seaweeds); Locust bean gum (natural gum polysaccharide from the seeds of the carob tree); Pectin (polysaccharide obtained from apple or citrus-fruit); and Gelatin (made by partial hydrolysis of animal collagen). The thickening agent or viscosity-increasing agent also includes cellulose thickeners, such as e.g., hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose hydroxypropyl methyl cellulose, methyl cellulose, with preferred products being hydroxypropyl cellulose), carbopols, polyacrylic acid, and polyvinyl alcohol.

[0067] The term “transdermal” is used herein to generally include a process that occurs through the skin. The terms “transdermal” and “percutaneous” are used interchangeably throughout this specification.

[0068] The term “topical formulation” is used herein to generally include a formulation that can be applied to skin or a mucosa. Topical formulations may, for example, be used to confer therapeutic benefit to a patient or cosmetic benefits to a consumer. Topical formulations can be used for both topical and transdermal administration of substances.

[0069] The term “topical administration” is used herein to generally include the delivery of a substance, such as a therapeutically active agent, to the skin or a localized region of the body.

[0070] The term “transdermal administration” is used herein to generally include administration through the skin. Transdermal administration is often applied where systemic delivery of an active is desired, although it may also be useful for delivering an active to tissues underlying the skin with minimal systemic absorption.

[0071] The term “subject” is used herein to generally include humans, particularly human adolescents (e.g., 12-17 years old) and human adults (e.g., at least 18 years old).

[0072] The term “effective amount” is used herein to generally include an amount of topical formulation effective for treating or preventing a disease in a subject as described herein. [0073] The term “treating” with regard to a subject, refers to improving at least one symptom of the subject's disorder. Treating includes curing, improving, or at least partially ameliorating the disorder or the symptoms thereof.

Methods of Use

[0074] Compositions of the invention are particularly suited for use in treating osteoarthritis (OA) chronically. They may also be useful for the treatment of other chronic joint diseases characterized by joint pain, degeneration of articular cartilage, impaired movement, and stiffness. Suitable joints include, e.g., the knee, elbow, hand, wrist and hip. As such, the compositions of the invention can specifically be used for the treatment of the pain of osteoarthritis of the knee(s).

[0075] Suitable amounts per administration will generally depend on the size of the joint, which varies per individual and per joint, however a suitable amount may range from 0.5 ml/cm² to 4.0 ml/cm². Specifically, the amount can range from 2.0 to 3.0 ml/cm².

[0076] Compositions of the present invention may, if desired, be presented in a bottle or jar or other container approved by the FDA, which may contain one or more unit dosage forms containing the active ingredient. The pack or dispenser may also be accompanied by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice indicates approval by the agency of the form of the compositions for human or veterinary administration. Such notice, for example, may be of labeling approved by the U.S. Food and Drug Administration for prescription drugs, or of an approved product insert. Compositions including a preparation of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

Specific Ranges. Values, and Embodiments

[0077] The specific embodiments describing the subject matter, ranges, and values provided below are for illustration purposes only, and do not otherwise limit the scope of the disclosed subject matter, as defined by the claims. [0078] In specific embodiments, the topical formulation further includes at least one of: (i) water, (ii) alpha hydroxy carboxylic acid, (iii) pH adjusting agent, (iv) buffer, (v) antioxidant, (vi) cyclomethicone, and (vii) thickening agent, viscosity-increasing agent, or a combination of thickening agent and viscosity-increasing agent.

[0079] In specific embodiments, the diclofenac, or pharmaceutically acceptable salt thereof, is diclofenac sodium.

[0080] In specific embodiments, the diclofenac, or pharmaceutically acceptable salt thereof, is diclofenac acid.

[0081] In specific embodiments, the diclofenac, or pharmaceutically acceptable salt thereof, is diclofenac sodium present in 2.0 ± 0.2 wt.%, such that each 1 gram of the topical formulation contains 20 ± 2 mg of the diclofenac sodium.

[0082] In specific embodiments, the diclofenac, or pharmaceutically acceptable salt thereof, is diclofenac sodium present in 2.0 ± 0.1 wt.%, such that each 1 gram of the topical formulation contains 20 ± 1 mg of the diclofenac sodium.

[0083] In specific embodiments, the diclofenac, or pharmaceutically acceptable salt thereof, is diclofenac sodium present in 2.0 wt.%, such that each 1 gram of the topical formulation contains 20 mg of the diclofenac sodium.

[0084] In specific embodiments, the topical formulation is a single-phase solution.

[0085] In specific embodiments, the topical formulation is a single-phase gelled solution.

[0086] In specific embodiments, the topical formulation has a viscosity of 500-5000 centipoise.

[0087] In specific embodiments, the topical formulation has a transderm al flux 0.8 to 1.25 times that of a comparative liquid or viscous solution formulation as determined by a direct comparison in a Franz cell procedure at finite dosing, wherein the comparative liquid formulation is Pennsaid® (diclofenac sodium) 2 wt.% topical solution. [0088] In specific embodiments, the topical formulation is chemically stable, such that the diclofenac, or pharmaceutically acceptable salt thereof, degrades by less than 5 wt.% over the course of 6 months under ambient conditions.

[0089] In specific embodiments, the topical formulation is chemically stable, such that the diclofenac, or pharmaceutically acceptable salt thereof, degrades by less than 2.5 wt.% over the course of 6 months under ambient conditions.

[0090] In specific embodiments, the topical formulation is chemically stable, such that the diclofenac, or pharmaceutically acceptable salt thereof, degrades by less than 1 wt.% over the course of 6 months under ambient conditions.

[0091] In specific embodiments, the topical formulation is physically stable, such that after 6 months under ambient conditions, the topical formulation is relatively clear and includes less than 5 wt.% crystalline material.

[0092] In specific embodiments, the topical formulation is physically stable, such that after 6 months under ambient conditions, the topical formulation is relatively clear and includes less than 1 wt.% crystalline material.

[0093] In specific embodiments, wherein upon topical application, the topical formulation has a drying rate that results in a residue of at most 50 wt.% of a starting amount after 12 hours under ambient conditions.

[0094] In specific embodiments, wherein upon topical application, the topical formulation has a drying rate that results in a residue of at most 25 wt.% of a starting amount after 12 hours under ambient conditions.

[0095] In specific embodiments, wherein upon topical application, the topical formulation has a drying rate that results in a residue of at most 10 wt.% of a starting amount after 12 hours under ambient conditions.

[0096] In specific embodiments, wherein upon topical application, the diclofenac, or pharmaceutically acceptable salt thereof, is transdermally delivered and remains locally concentrated. [0097] In specific embodiments, the topical formulation is a topical analgesic.

[0098] In specific embodiments, the topical fonnulation is a transdermal analgesic.

[0099] In specific embodiments, the topical formulation is a non-steroidal anti-inflammatory drug (NSAID) with antipyretic and analgesic actions.

[0100] In specific embodiments, the topical formulation includes dimethyl sulfoxide (DMSO) in 15-20 wt.%.

[0101] In specific embodiments, the topical formulation includes dimethyl sulfoxide (DMSO) in up to 20 wt.%.

[0102] In specific embodiments, the topical formulation includes dimethyl sulfoxide (DMSO) in up to 15 wt.%.

[0103] In specific embodiments, the topical formulation includes dimethyl sulfoxide (DMSO) in up to 10 wt.%.

[0104] In specific embodiments, the topical formulation includes dimethyl sulfoxide (DMSO) in 5-10 wt.%.

[0105] In specific embodiments, the topical formulation includes ethanol in up to 36 wt.%.

[0106] In specific embodiments, the topical formulation includes ethanol in up to 30 wt.%.

[0107] In specific embodiments, the topical formulation includes ethanol in up to 25 wt.%.

[0108] In specific embodiments, the topical formulation includes ethanol in up to 20 wt.%.

[0109] In specific embodiments, the topical formulation includes ethanol in 34-36 wt.%.

[0110] In specific embodiments, the topical formulation includes ethanol in 20-30 wt.%.

[0111] In specific embodiments, the topical formulation includes ethanol in 25-30 wt.%. [0112] In specific embodiments, the topical formulation includes propylene glycol in up to 12 wt.%.

[0113] In specific embodiments, the topical formulation includes propylene glycol in 10-15 wt.%.

[0114] In specific embodiments, the topical formulation includes propylene glycol in 10-12 wt.%.

[0115] In specific embodiments, the topical formulation includes glycerol in up to 3.0 wt.%.

[0116] In specific embodiments, the topical formulation includes glycerol in 2.5-3.0 wt.%.

[0117] In specific embodiments, the topical formulation includes benzyl alcohol in up to 3 wt.%.

[0118] In specific embodiments, the topical formulation includes benzyl alcohol in 2-3 wt.%.

[0119] In specific embodiments, the topical formulation includes the thickening agent, viscosity-increasing agent, or combination thereof, in an aggregate amount of up to 2 wt.%.

[0120] In specific embodiments, the topical formulation includes the thickening agent, viscosity-increasing agent, or combination thereof, in an aggregate amount of 1-2 wt.%.

[0121] In specific embodiments, the polyoxyethylene alkyl ether includes Brij® L4 (polyethylene glycol dodecyl ether, polyoxyethylene (4) lauryl ether).

[0122] In specific embodiments, the topical formulation includes Brij® L4 (polyethylene glycol dodecyl ether, polyoxyethylene (4) lauryl ether), present in up to 2.5 wt.%.

[0123] In specific embodiments, the topical formulation includes Brij® L4 (polyethylene glycol dodecyl ether, polyoxyethylene (4) lauryl ether), present in 1.0-2.5 wt.%.

[0124] In specific embodiments, the topical formulation further includes an alpha hydroxy carboxylic acid. [0125] In specific embodiments, the topical formulation further includes an alpha hydroxy carboxylic acid, wherein the alpha hydroxy carboxylic acid is lactic acid.

[0126] In specific embodiments, the topical formulation further includes an alpha hydroxy carboxylic acid, wherein the lactic acid is present in up to 3 wt.%.

[0127] In specific embodiments, the topical formulation further includes an alpha hydroxy carboxylic acid, wherein the lactic acid is present in 2-3 wt.%.

[0128] In specific embodiments, the topical formulation includes cyclomethicone.

[0129] In specific embodiments, the topical formulation includes cyclomethicone, present in up to 5 wt.%.

[0130] In specific embodiments, the topical formulation includes cyclomethicone, present in up to 3 wt.%.

[0131] In specific embodiments, the topical formulation includes cyclomethicone, present in 1- 5 wt.%.

[0132] In specific embodiments, the topical formulation includes cyclomethicone, present in 2- 3 wt.%.

[0133] In specific embodiments, the topical formulation includes Sepineo™ P 600 (acrylamide/sodium acryloyldimethyl taurate copolymer/ isohexadecane & polysorbate 80).

[0134] In specific embodiments, the topical formulation includes Sepineo™ P 600 (acrylamide/sodium acryloyldimethyl taurate copolymer/ isohexadecane & polysorbate 80), present in up to 3 wt.%.

[0135] In specific embodiments, the topical formulation includes Sepineo™ P 600 (acrylamide/sodium acryloyldimethyl taurate copolymer/ isohexadecane & polysorbate 80), present in 3 wt.%.

[0136] In specific embodiments, the topical formulation includes Transcutol® (2— (2— ethoxy ethoxy) ethanol). [0137] In specific embodiments, the topical formulation includes Transcutol® (2-(2- ethoxyethoxy) ethanol), present in up to 20 wt.%.

[0138] In specific embodiments, the topical formulation includes Transcutol® (2-(2- ethoxy ethoxy) ethanol), present in 20 wt.%.

[0139] In specific embodiments, the topical formulation includes Klucel™ MF (hydroxypropylcellulose).

[0140] In specific embodiments, the topical formulation includes Klucel™ MF (hydroxypropylcell ulose), present in up to 0.65 wt.%.

[0141] In specific embodiments, the topical formulation includes Klucel™ MF (hydroxypropylcellulose), present in 0.5-0.65 wt.%.

[0142] In specific embodiments, the topical formulation includes trisaminomethane (tris).

[0143] In specific embodiments, the topical formulation includes trisaminomethane (tris), present in up to 0.1 wt.%.

[0144] In specific embodiments, the topical formulation includes trisaminomethane (tris), present in 0.1 wt.%.

[0145] In specific embodiments, the topical formulation includes cetyl alcohol.

[0146] In specific embodiments, the topical formulation includes cetyl alcohol, present in up to 7 wt.%.

[0147] In specific embodiments, the topical formulation includes cetyl alcohol, present in 3-7 wt.%.

[0148] In specific embodiments, the topical formulation includes dimethyl isosorbide (DMI).

[0149] In specific embodiments, the topical formulation includes dimethyl isosorbide (DMI), present in up to 15 wt.%. [0150] In specific embodiments, the topical formulation includes dimethyl isosorbide (DM1), present in 15 wt.%.

[0151] In specific embodiments, the topical formulation includes water.

[0152] In specific embodiments, the topical formulation includes water, present in up to 40 wt.%.

[0153] In specific embodiments, the topical formulation includes water, present in up to 25 wt.%.

[0154] In specific embodiments, the topical formulation includes water, present in up to 20 wt.%.

[0155] In specific embodiments, the topical formulation includes water, present in up to 15 wt.%.

[0156] In specific embodiments, the topical formulation includes water, present in 10-40 wt.%.

[0157] In specific embodiments, the topical formulation includes water, present in 30-40 wt.%.

[0158] In specific embodiments, the topical formulation includes water, present in 10-25 wt.%.

[0159] In specific embodiments, the topical formulation includes water, present in 10-15 wt.%.

[0160] In specific embodiments, the topical formulation includes an antioxidant.

[0161] In specific embodiments, the topical formulation includes an antioxidant, present in up to 1 wt.%.

[0162] In specific embodiments, the topical formulation includes an antioxidant, present in 0.01-1 wt.%.

[0163] In specific embodiments, the topical formulation includes hydroxy propyl cellulose (HPC), present in up to 2.0 wt.%. [0164] In specific embodiments, the topical formulation includes hydroxy propyl cellulose (HPC), present in 1.2-2.0 wt.%.

[0165] In specific embodiments, the topical formulation includes a pH adjusting agent and/or buffer.

[0166] In specific embodiments, the topical formulation includes phosphate-buffered saline (PBS) buffer.

[0167] In specific embodiments, the topical formulation includes phosphate-buffered saline (PBS) buffer (pH 5.5).

[0168] In specific embodiments, the topical formulation includes phosphate-buffered saline (PBS) buffer (pH 9.0).

[0169] In specific embodiments, the topical formulation includes phosphate-buffered saline (PBS) buffer (pH 5.5), present in up to 36 wt.%.

[0170] In specific embodiments, the topical formulation includes phosphate-buffered saline (PBS) buffer (pH 5.5), present in 34-36 wt.%.

[0171] In specific embodiments, the topical formulation includes phosphate-buffered saline (PBS) buffer (pH 9.0).

[0172] In specific embodiments, the topical formulation includes phosphate-buffered saline (PBS) buffer (pH 9.0), present in up to 40 wt.%.

[0173] In specific embodiments, the topical formulation includes phosphate-buffered saline (PBS) buffer (pH 9.0), present in 37-40 wt.%.

[0174] In specific embodiments, the topical formulation has a pH of 6.0-10.0.

[0175] In specific embodiments, the topical formulation has a pH of 8 ± 2.

[0176] In specific embodiments, the topical formulation has a pH of 8.12 to 9.59. [0177] In specific embodiments, the topical formulation has a pH of 8.38, 8.12, 9.59, 8.47, 8.83, 8.33, or 8.35.

[0178] In specific embodiments, the topical formulation has a viscosity of 320 to 1455.

[0179] In specific embodiments, the topical formulation has a viscosity of 1396, 1455, 1689, 320, 554, 556, or 680.

[0180] In specific embodiments, the topical formulation includes: diclofenac sodium; dimethyl sulfoxide (DMSO); ethanol; propylene glycol; glycerin; benzyl alcohol; cetyl alcohol; hydroxy propyl cellulose (HF); cyclomethicone; purified water; and dimethyl isosorbide (DMI).

[0181] In specific embodiments, the topical formulation includes: 2 wt.% diclofenac sodium; 15-19 wt.% dimethyl sulfoxide (DMSO); 25.8-28.8 wt.% ethanol; 12 wt.% propylene glycol; 3 wt.% glycerin; 3 wt.% benzyl alcohol; 0-7 wt.% cetyl alcohol; 1.2 wt.% hydroxy propyl cellulose (HF); 5 wt.% cyclomethicone; 11-15 wt.% purified water; and 15 wt.% dimethyl isosorbide (DMI).

[0182] In specific embodiments, the topical formulation includes: diclofenac sodium; dimethyl sulfoxide (DMSO); acirlamide/sodium acryloyldimethyl taurate copolymer; isohexadecane; polysorbate 80; propylene glycol; (2-(2-ethoxyethoxy) ethanol); ethanol; hydroxypropyl cellulose; trisaminomethane (tris); and water.

[0183] In specific embodiments, the topical formulation includes: diclofenac sodium; dimethyl sulfoxide (DMSO); Sepineo™ P 600 (acrylamide/sodium acryloyldimethyl taurate copolymer/ isohexadecane & polysorbate 80); propylene glycol; Transcutol® P (2-(2-ethoxyethoxy) ethanol); ethanol; Klucel™ MF (hydroxypropylcellulose); trisaminomethane (tris); and water.

[0184] In specific embodiments, the topical formulation includes: 2 wt.% diclofenac sodium;

19 wt.% dimethyl sulfoxide (DMSO); 3 wt.% Sepineo™ P 600 (acrylamide/sodium acryloyl- dimethyl taurate copolymer/isohexadecane & polysorbate 80); 15 wt.% propylene glycol; 20 wt.% Transcutol® P (2-(2-ethoxy ethoxy) ethanol); 20-30 wt.% ethanol; 0.5-0.65 wt.% Klucel™ MF (hydroxypropylcellulose); 0-0.1 wt.% trisaminomethane (tris); and 10.5-20.5 wt.% water. [0185] in specific embodiments, the topical formulation includes any one of Formulations A -

E.

[0186] in specific embodiments, the topical formulation includes any one of Formulations F -

H.

[0187] In specific embodiments, the topical formulation includes any one of Formulations I -

L.

[0188] In specific embodiments, the topical formulation is administered at least once daily.

[0189] In specific embodiments, the topical formulation is administered twice daily. [0190] In specific embodiments, the topical formulation is administered 1-3 times daily.

[0191] In specific embodiments, one knee is afflicted with pain and the topical formulation is administered to that one knee afflicted with pain, such that one knee is treated.

[0192] In specific embodiments, both knees afflicted with pain and the topical formulation is administered to the both knees afflicted with pain, such that both knees are treated.

[0193] In specific embodiments, the topical formulation is administered to one or both knees afflicted with pain, such that 40 mg of diclofenac sodium is applied to each painful knee, 2 times a day.

[0194] In specific embodiments, the topical formulation, relative to a comparative liquid formulation, administration of the topical formulation of claim 1 results in a lower incidence, severity, and/or duration of adverse reactions including at least one of dryness, exfoliation, erythema, pruritus, pain, induration, rash, and scabbing; and wherein the comparative liquid formulation is Pennsaid® (diclofenac sodium) 2 wt.% topical solution.

[0195] In specific embodiments, the topical formulation is (i) dispensed directly onto a knee, or first into the hand and then onto the knee, and (ii) spread evenly around the front, back and sides of the knee.

[0196] In specific embodiments, the topical formulation is (i) dispensed directly onto a knee, or first into the hand, and then onto the knee, (ii) spread evenly around the front, back and sides of the knee, and (iii) both hands are washed completely.

[0197] In specific embodiments, the topical formulation is (i) dispensed directly onto a knee, or first into the hand and then onto the knee, (ii) spread evenly around the front, back and sides of the knee, and (iii) waiting until the area is completely dry before (a) covering the area with clothing, (b) topically applying to the area sunscreen, insect repellent, cosmetics, or topical medication, or (c) skin-to-skin contact between other people and the treated knee.

[0198] In specific embodiments, the topical formulation is applied to clean, dry skin. Enumerated Embodiments

[0199] Specific enumerated embodiments <1> to <50> provided below are for illustration purposes only, and do not otherwise limit the scope of the disclosed subject matter, as defined by the claims. These enumerated embodiments encompass all combinations, sub-combinations, and multiply referenced (e.g., multiply dependent) combinations described therein.

[0200] <1> A topical formulation including (i)-(v):

(i) diclofenac, or a pharmaceutically acceptable salt thereof, present in at least 1 wt.%;

(ii) at least one of (a)-(e):

(a) dimethyl sulfoxide (DMSO),

(b) transcutol® (2-(2-ethoxyethoxy) ethanol),

(c) ethanol,

(d) isopropyl alcohol,

(e) cetyl alcohol,

(iii) at least one of (a)-(f):

(a) propylene glycol,

(b) butylene glycol,

(c) hexylene glycol,

(d) 1,2-hexane diol,

(e) glycerol,

(f) methyl gluceth,

(iv) at least one of (a)— (k):

(a) emulsifying wax,

(b) glyceryl monooleate,

(c) phospholipids,

(d) polyoxyethylene alkyl ethers, (e) polyoxyethylene,

(f) castor oil derivatives,

(g) sorbitan fatty acid esters,

(h) polyoxyethylene stearates,

(i) polyoxylglycerides,

(j) polysorbate,

(k) sorbitan esters,

(v) at least one of (a)-(f):

(a) benzyl alcohol,

(b) butylparaben,

(c) ethylparaben,

(d) m ethylparaben,

(e) propylparaben,

(f) sorbic acid.

[0201] <2 > The topical formulation of embodiment <1>, further including at least one of (i)-

(nii):

(i) water,

(ii) alpha hydroxy carboxylic acid,

(iii) pH adjusting agent,

(iv) buffer,

(v) antioxidant,

(vi) cyclomethicone, and

(vii) thickening agent, viscosity-increasing agent, or combination thereof.

[0202] <3> The topical formulation of any one of the above embodiments, wherein the diclofenac, or pharmaceutically acceptable salt thereof, is diclofenac sodium. [0203] <4 > The topical formulation of any one of the above embodiments, wherein the diclofenac, or pharmaceutically acceptable salt thereof, is diclofenac acid.

[0204] <5 > The topical formulation of any one of the above embodiments, wherein the diclofenac, or pharmaceutically acceptable salt thereof, is diclofenac sodium present in 2.0 wt.%, such that each 1 gram of the topical formulation contains 20 mg of the diclofenac sodium.

[0205] <6 > The topical formulation of any one of the above embodiments, which is a single phase solution.

[0206] <7> The topical formulation of any one of the above embodiments, having a viscosity of 500-5000 centipoise.

[0207] <8 > The topical formulation of any one of the above embodiments, having a transdermal flux 0.8 to 1.25 times that of a comparative liquid or viscous solution formulation as determined by a direct comparison in a Franz cell procedure at finite dosing, wherein the comparative liquid formulation is Pennsaid® (diclofenac sodium) 2 wt.% topical solution.

[0208] <9 > The topical formulation of any one of the above embodiments, which is chemically stable, such that the diclofenac, or pharmaceutically acceptable salt thereof, degrades by less than 2.5 wt.% over the course of 6 months under ambient conditions.

[0209] <10>The topical formulation of any one of the above embodiments, which is physically stable, such that after 6 months under ambient conditions, the topical formulation is relatively clear and includes less than 1 wt.% crystalline material.

[0210] <11 >The topical formulation of any one of the above embodiments, wherein upon topical application, the topical formulation has a drying rate that results in a residue of at most 50 wt.% of a starting amount after 12 hours under ambient conditions.

[0211] <12>The topical formulation of any one of the above embodiments, wherein upon topical application, the diclofenac, or pharmaceutically acceptable salt thereof, is transdermally delivered and remains locally concentrated. [0212] <13 >The topical formulation of any one of the above embodiments, including the dimethyl sulfoxide (DMSO) in up to 10 wt.%.

[0213] <14.>The topical formulation of any one of the above embodiments, including the dimethyl sulfoxide (DMSO) in 5-10 wt.%.

[0214] <15.>The topical formulation of any one of the above embodiments, including the ethanol in up to 36 wt.%.

[0215] <16>The topical formulation of any one of the above embodiments, including the ethanol in 34—36 wt.%.

[0216] <17>The topical formulation of any one of the above embodiments, including the propylene glycol in up to 12 wt.%.

[0217] <18>The topical formulation of any one of the above embodiments, including the propylene glycol in 10-12 wt.%.

[0218] <19>The topical formulation of any one of the above embodiments, including the glycerol in up to 3.0 wt.%.

[0219] <20.>The topical formulation of any one of the above embodiments, including the glycerol in 2.5-3.0 wt.%.

[0220] <21 >The topical formulation of any one of the above embodiments, including the benzyl alcohol in up to 3 wt.%.

[0221] <22>The topical formulation of any one of the above embodiments, including the benzyl alcohol in 2-3 wt.%.

[0222] <23 >The topical formulation of embodiment <2>, including the cyclomethicone in up to 3 wt.%.

[0223] <24>The topical formulation of embodiment <2>, including the cyclomethicone in 2-3 wt.%. [0224] <25>The topical formulation of embodiment <2>, including the water in up to 40 wt.%.

[0225] <26.>The topical formulation of embodiment <2>, including the water in 30-40 wt.%.

[0226] <27.>The topical formulation of embodiment <2>, including the antioxidant in up to 1 wt.%.

[0227] <28.>The topical formulation of embodiment <2>, including the antioxidant in 0.01-1 wt.%.

[0228] <29>The topical formulation of embodiment <2>, having a pH of 6.0-10.0.

[0229] <30.>The topical formulation of embodiment <2>, including the thickening agent, viscosity-increasing agent, or a combination thereof, in an aggregate amount of up to 2 wt.%.

[0230] <31 >The topical formulation of embodiment <2>, including the thickening agent, viscosity-increasing agent, or a combination thereof, in an aggregate amount of 1-3 wt.%.

[0231] <32>The topical formulation of embodiment <2>, wherein the thickening agent, viscosity-increasing agent, or a combination thereof, includes at least one of hydroxy propyl cellulose (HPC) and Sepineo™ P 600 (acrylamide/sodium acryloyldimethyl taurate copolymer/ isohexadecane & polysorbate 80).

[0232] <33.>The topical formulation of any one of the above embodiments, wherein the polyoxyethylene alkyl ether includes Brij® L4 (polyethylene glycol dodecyl ether, polyoxyethylene (4) lauryl ether).

[0233] <34>The topical formulation of embodiment <33>, wherein the Brij® L4 is present in up to 2.5 wt.%.

[0234] <35>The topical formulation of embodiment <33>, wherein the Brij® L4 is present in 1.0-2.5 wt.%.

[0235] <36.>The topical formulation of embodiment <2>, wherein the alpha hydroxy carboxylic acid is lactic acid. [0236] <37>The topical formulation of embodiment <36>, wherein the lactic acid is present in up to 3 wt.%.

[0237] <38.>The topical formulation of embodiment <36>, wherein the lactic acid is present in 2-3 wt.%.

[0238] <39.>A method for treating pain in a subject suffering from pain, said method including the topical administration to an afflicted area of said subject the topical formulation of any one of embodiments <1> to <38>.

[0239] <40>A method of treating osteoarthritis in a subject suffering from articular pain, said method including the topical administration to an afflicted joint area of said subject a therapeutically effective amount of the topical formulation of any one of embodiments <1> to <38>.

[0240] <41 >A method for treating pain associated with joint diseases characterized by joint pain, degeneration of articular cartilage, impaired movement, and/or stiffness, said method including the topical administration to an afflicted joint area of said subject a therapeutically effective amount of the topical formulation of any one of embodiments <1> to <38>.

[0241] <42>A method for treating pain due to osteoarthritis of the knee of a subject in need thereof, said method including the topical administration to the knee area of said subject a therapeutically effective amount of the topical formulation of any one of embodiments <1> to <38>.

[0242] <43>The method of any one of embodiments <39> to <42>, wherein the administration is twice daily.

[0243] <44>The method of any one of embodiments <39> to <42>, wherein 40 mg of diclofenac sodium is applied to each painful knee, 2 times a day.

[0244] <45>The method of any one of embodiments <39> to <42>, wherein relative to a comparative liquid formulation, administration of the topical formulation results in a lower incidence, severity, and/or duration of adverse reactions including at least one of dryness, exfoliation, erythema, pruritus, pain, induration, rash, and scabbing; and wherein the comparative liquid formulation is Pennsaid® (diclofenac sodium) 2 wt.% topical solution.

[0245] <46 >The method of any one of embodiments <39> to <42>, wherein the topical formulation is (i) dispensed directly onto a knee, or first into the hand and then onto the knee, and (ii) spread evenly around the front, back and sides of the knee.

[0246] <47>The method of embodiment <46>, further including washing hands completely after administering the topical formulation.

[0247] <48>The method of embodiment <46>, further including waiting until the area is completely dry before (i) covering the area with clothing, (ii) topically applying to the area sunscreen, insect repellent, cosmetics, or topical medication, or (iii) skin-to-skin contact between other people and the treated knee.

[0248] <49.>The method of embodiment <46>, wherein the topical formulation is applied to clean, dry skin.

[0249] <50>The method of embodiment <46>, wherein both knees are treated.

[0250] The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention.

Examples

[0251] These examples serve to provide guidance to a skilled artisan to prepare and use the compositions and methods of the invention. While particular embodiments of the present invention are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the inventions.

[0252] Example la: Formulations A - E.

[0253] Example lb: Formulations F-H.

[0254] Example lc: Formulations I - L.

I (%w/w) J (%w/w) K (%w/w) L (%w/w)

[0255] Example 2: Manufacturing Process

[0256] The compositions of (lb) were manufactured by process as depicted below.

[0257] (1) Quantity of Purified water of the composition was divided into two parts: a) For Klucel™ MF (HPC) phase and as rinse water (For Sepineo™ P 600).

[0258] (2) Processing in Main mixing vessel: Batch quantity of propylene glycol was weighed in an SS vessel. Klucel™ MF (HPC) was dispersed into the propylene glycol phase under stirring at 600 ± 200 rpm. Stirring continued for -30-40 min until uniform phase was obtained. Further weighed quantity of water for Klucel™ MF phase was added under stirring at 500 ± 200 rpm. Stirring was continued for ~1.5 h until homogenous gel phase was obtained.

[0259] (3) Preparation of Diclofenac sodium phase: To weighed quantity of dimethyl sulfoxide (DMSO) in an SS vessel, batch quantity of transcutol® P was added under stirring at 500 ± 200 rpm. Stirring was done for ~10 min until uniform. Further weighed quantity of diclofenac sodium was added under stirring at 500 ± 200 rpm. Stirring was continued until complete solubilization of diclofenac sodium.

[0260] (4) Processing in Main mixing vessel: To Klucel™ MF phase of Step II, weighed quantity of Sepineo™ P 600 was added under stirring at 500 ± 200 rpm. The Sepineo™ P 600 beaker was rinsed thoroughly with part of purified water kept aside as rinse. The rinsates were also added to the main vessel. Stirring was continued for ~20-30 min until thick homogenous phase was obtained. Further to the main vessel, the diclofenac sodium phase (Step III) was added at 500 ± 300 rpm. Stirring was continued for ~2 h until homogenous viscous phase was observed. Further, weighed quantity of ethanol was added to the main vessel under stirring at 500 ± 200 rpm. The main vessel was maintained in a water bath (15±2°C). Stirring was continued for ~45 min until uniform homogenous phase was obtained. Weight of the batch was then recorded to determine percentage yield.

[0261] The Formulation C in addition to above steps has step of

[0262] (5) Preparation of Tris phase: To weighed quantity of Tris in a beaker, required quantity of purified water was added. Contents were manually stirred until clear phase was observed. This phase along with solutions from steps (I) to (I ) are mixed to yield final solution.

[0263] Example 3a: The composition of example (la) were evaluated for Flux through skin

[0264] Example 3b: The compositions of examples (1b) & (1c) were observed for assay of diclofenac sodium, DMSO and ethanol; appearance, pH and viscosity are reported in the table below

[0265] Example 3c: pK Parameters

[0266] The formulation of invention shall be further evaluated for pharmacokinetic (PK) parameters. The study design may be as “Randomized, Open Label, Balanced, Two-Treatment, Two-Sequence Single Dose, Crossover design”.

[0267] The treatments shall be Diclofenac sodium solution 2 % of present invention compared to Diclofenac sodium 2% solution (Pennsaid® 2%).

[0268] The subjects that participate in the study shall be healthy males and non-pregnant females from general population. During the study the study drug shall be applied to all subjects and Plasma samples shall be collected at predefined time-points after the study drug application. These samples shall be further analyzed using a fully validated bioanalytical assay to measure the concentration of diclofenac in plasma. The Bio-equivalence shall be determined by pharmacokinetic endpoints such as C max (peak plasma concentration) and AUC (area under the plasma concentration time curve) that are reflective of rate and extent of absorption, respectively.

Claims

1. A topical formulation comprising (i)-(v):

(i) diclofenac, or a pharmaceutically acceptable salt thereof, present in at least 1 wt.%;

(ii) at least one of (a)-(e):

(a) dimethyl sulfoxide (DMSO),

(b) transcutol® (2-(2-ethoxyethoxy) ethanol),

(c) ethanol,

(d) i sopropy I al cohol ,

(e) cetyl alcohol,

(iii) at least one of (a)— (f):

(a) propylene glycol,

(b) butylene glycol,

(c) hexylene glycol,

(d) 1,2-hexane diol,

(e) glycerol,

(f) methyl gluceth,

(iv) at least one of (a)-(k):

(a) emulsifying wax,

(b) glyceryl monooleate,

(c) phospholipids,

(d) polyoxyethylene alkyl ethers, (e) polyoxyethylene,

(f) castor oil derivatives,

(g) sorbitan fatty acid esters,

(h) polyoxyethylene stearates,

(i) polyoxylglycerides,

(j) polysorbate,

(k) sorbitan esters,

(v) at least one of (a)-(f):

(a) benzyl alcohol,

(b) butylparaben,

(c) ethylparaben,

(d) methylparaben,

(e) propylparaben,

(f) sorbic acid.

2. The topical formulation of claim 1, further comprising at least one of (i)— (vii):

(i) water,

(ii) alpha hydroxy carboxylic acid,

(iii) pH adjusting agent,

(iv) buffer,

(v) antioxidant,

(vi) cyclomethicone, and (vii) thickening agent, viscosity-increasing agent, or combination thereof.

3. The topical formulation of claim 1, wherein the diclofenac, or pharmaceutically acceptable salt thereof, is diclofenac sodium.

4. The topical formulation of claim 1, wherein the diclofenac, or pharmaceutically acceptable salt thereof, is diclofenac acid.

5. The topical formulation of claim 1, wherein the diclofenac, or pharmaceutically acceptable salt thereof, is diclofenac sodium present in 2.0 wt.%, such that each 1 gram of the topical formulation contains 20 mg of the diclofenac sodium.

6. The topical formulation of claim 1, which is a single phase solution.

7. The topical formulation of claim 1, having a viscosity of 500-5000 centi poise.

8. The topical formulation of claim 1, having a transdermal flux 0.8 to 1.25 times that of a comparative liquid or viscous solution formulation as determined by a direct comparison in a Franz cell procedure at finite dosing, wherein the comparative liquid formulation is Pennsaid® (diclofenac sodium) 2 wt.% topical solution.

9. The topical formulation of claim 1, which is chemically stable, such that the diclofenac, or pharmaceutically acceptable salt thereof, degrades by less than 2.5 wt.% over the course of 6 months under ambient conditions.

10. The topical formulation of claim 1, which is physically stable, such that after 6 months under ambient conditions, the topical formulation is relatively clear and comprises less than 1 wt.% crystalline material.

11. The topical formulation of claim 1, wherein upon topical application, the topical formulation has a drying rate that results in a residue of at most 50 wt.% of a starting amount after 12 hours under ambient conditions.

12. The topical formulation of claim 1, wherein upon topical application, the diclofenac, or pharmaceutically acceptable salt thereof, is transdermally delivered and remains locally concentrated.

13. The topical formulation of claim 1, comprising the dimethyl sulfoxide (DMSO) in up to 10 wt.%.

14. The topical formulation of claim 1, comprising the dimethyl sulfoxide (DMSO) in 5-10 wt.%.

15. The topical formulation of claim 1, comprising the ethanol in up to 36 wt.%.

16. The topical formulation of claim 1, comprising the ethanol in 34—36 wt.%.

17. The topical formulation of claim 1 , comprising the propylene glycol in up to 12 wt.%.

18. The topical formulation of claim 1 , comprising the propylene glycol in 10-12 wt.%.

19. The topical formulation of claim 1, comprising the glycerol in up to 3.0 wt.%.

20. The topical formulation of claim 1, comprising the glycerol in 2.5-3.0 wt.%.

21. The topical formulation of claim 1, comprising the benzyl alcohol in up to 3 wt.%.

22. The topical formulation of claim 1, comprising the benzyl alcohol in 2-3 wt.%.

23. The topical formulation of claim 2, comprising the cyclomethicone in up to 3 wt.%.

24. The topical formulation of claim 2, comprising the cyclomethicone in 2-3 wt.%.

25. The topical formulation of claim 2, comprising the water in up to 40 wt.%.

26. The topical formulation of claim 2, comprising the water in 30-40 wt.%.

27. The topical formulation of claim 2, comprising the antioxidant in up to 1 wt.%.

28. The topical formulation of claim 2, comprising the antioxidant in 0.01-1 wt.%.

29. The topical formulation of claim 2, having a pH of 6.0-10.0.

30. The topical formulation of claim 2, comprising the thickening agent, viscosity-increasing agent, or a combination thereof, in an aggregate amount of up to 2 wt.%.

31. The topical formulation of claim 2, comprising the thickening agent, viscosity-increasing agent, or a combination thereof, in an aggregate amount of 1-3 wt.%.

32. The topical formulation of claim 2, wherein the thickening agent, viscosity-increasing agent, or a combination thereof, comprises at least one of hydroxy propyl cellulose (HPC) and Sepineo™ P 600 (acrylamide/sodium acryloyldimethyl taurate copolymer/ isohexadecane & polysorbate 80).

33. The topical formulation of claim 1, wherein the polyoxyethylene alkyl ether comprises Brij® L4 (polyethylene glycol dodecyl ether, polyoxyethylene (4) lauryl ether).

34. The topical formulation of claim 33, wherein the Brij® L4 is present in up to 2.5 wt.%.

35. The topical formulation of claim 33, wherein the Brij® L4 is present in 1.0-2.5 wt.%.

36. The topical formulation of claim 2, wherein the alpha hydroxy carboxylic acid is lactic acid.

37. The topical formulation of claim 36, wherein the lactic add is present in up to 3 wt.%.

38. The topical formulation of claim 36, wherein the lactic add is present in 2-3 wt.%.

39. A method for treating pain in a subject suffering from pain, said method comprising the topical administration to an afflicted area of said subject the topical formulation of any one of claims 1-38.

40. A method of treating osteoarthritis in a subject suffering from articular pain, said method comprising the topical administration to an afflicted joint area of said subject a therapeutically effective amount of the topical formulation of any one of claims 1-38.

41. A method for treating pain associated with j oint di seases characterized by j oint pain, degeneration of articular cartilage, impaired movement, and/or stiffness, said method comprising the topical administration to an afflicted joint area of said subject a therapeutically effective amount of the topical formulation of any one of claims 1-38.

42. A method for treating pain due to osteoarthritis of the knee of a subject in need thereof, said method comprising the topical administration to the knee area of said subject a therapeutically effective amount of the topical formulation of any one of claims 1-38.

43. The method of any one of claims 39-42, wherein the administration is twice daily.

44. The method of any one of claims 39-42, wherein 40 mg of diclofenac sodium is applied to each painful knee, 2 times a day.

45. The method of any one of claims 39-42, wherein relative to a comparative liquid formulation, administration of the topical formulation of claim 1 results in a lower incidence, severity, and/or duration of adverse reactions including at least one of dryness, exfoliation, erythema, pruritus, pain, induration, rash, and scabbing; and wherein the comparative liquid formulation is Pennsaid® (diclofenac sodium) 2 wt.% topical solution.

46. The method of any one of claims 39-42, wherein the topical formulation of claim 1 is (i) dispensed directly onto a knee, or first into the hand and then onto the knee, and (ii) spread evenly around the front, back and sides of the knee.

47. The method of claim 46, further comprising washing hands completely after administering the topical formulation.

48. The method of claim 46, further comprising waiting until the area is completely dry before (i) covering the area with clothing, (ii) topically applying to the area sunscreen, insect repellent, cosmetics, or topical medication, or (iii) skin-to-skin contact between other people and the treated knee.

49. The method of claim 46, wherein the topical formulation is applied to clean, dry skin.

50. The method of claim 46, wherein both knees are treated.