Topical administration compositions comprising non-steroid anti-inflammatory agents

Abstract

The present disclosure generally relates to topical administration compositions for improving topical compositions, the topical administration compositions comprising at least one active agent, at least one phospholipid, and urea. The active agents of the present disclosure comprise a non-steroid anti-inflammatory drug (NSAID). The topical administration composition of the present disclosure improves the solubility of the NSAID. The present disclosure also relates to a method of making the topical compositions of the present disclosure. The topical composition can be used to treat inflammation, arthritis and / or pain, or conditions of signs and symptoms including inflammation, arthritis and / or pain, by topically administering the topical composition to a subject.

Description

Technical Field

[0001] This disclosure generally relates to an improved topical drug delivery composition that can be used to treat inflammation, arthritis and / or pain, or conditions whose signs and symptoms include inflammation, arthritis and / or pain. Background Technology

[0002] Oral non-steroidal anti-inflammatory drugs (NSAIDs) have analgesic, anti-inflammatory, and antipyretic effects and can be used to relieve pain and inflammation. However, NSAIDs have serious potential side effects, including nausea, vomiting, peptic ulcers, gastrointestinal bleeding (GI hemorrhage), and cardiovascular events.

[0003] When NSAIDs are applied topically, the local drug concentration in muscle and joint tissues is significantly higher than in untreated areas. Furthermore, because these drugs do not pass through the liver before acting, there is no strong metabolism in the liver (the so-called first-pass effect). The required amount of NSAIDs is lower than the oral dose used to achieve similar anti-inflammatory and analgesic effects.

[0004] Diclofenac is a well-known and widely used NSAID, originally developed as a sodium salt for oral or topical application in cream or ointment form. Diclofenac sodium can be readily formulated into powder for oral preparations, but its low water solubility can pose problems in gel or ointment formulations. Furthermore, the effectiveness of topical diclofenac is limited by its poor skin penetration.

[0005] Voltaren gel is a 1% diclofenac sodium emulsion, approved by the Food and Drug Administration (FDA) in 2007. Diclofenac sodium is dissolved in a lipid phase and mixed with a nonionic surfactant to form an emulsion (US 7732489). However, to increase the concentration of diclofenac and reduce the dosage, additional C2 to C4 alkanol and ethylene glycol solvents are required (WO 2016038556103).

[0006] US 4575515 and US 4652557 disclose topical NSAID formulations, one of which comprises 1.5% diclofenac sodium, 45.5% dimethyl sulfoxide (DMSO), 11.79% ethanol, 11.2% propylene glycol, 11.2% glycerin, and water. This formulation uses a large amount of solvent (especially DMSO) to improve solubility and skin penetration.

[0007] EP 1003499 discloses a pharmaceutical preparation for topical application, wherein the pharmaceutical preparation contains diclofenac dissolved in a solvent mixture as an active substance, contains at least one alkyl alcohol having 2 to 4 carbon atoms as a major component, and contains at least one short-chain N-alkylpyrrolidone and at least one pyrrolidone substituted with a long-chain alkyl radical.

[0008] WO 2010 / 060798 discloses a pharmaceutical formulation comprising an aqueous solution containing 1% to 5% (w / v) a pharmaceutically acceptable salt of diclofenac, 3% to 30% (w / v) a polyoxyalkylene ester of at least one hydroxy fatty acid, water as the main component, and, if applicable, a co-solvent.

[0009] US 7138394 discloses that a co-soluble mixture of camphor, menthol, thymol, and similar compounds is a strong solvent for NSAIDs and other substances. The solubility of indomethacin, diclofenac, or ketoprofen in the mixture is increased by between 3 and 20 times.

[0010] WO 2014 / 009793 discloses a volatile silicone-based pharmaceutical or veterinary drug composition containing diclofenac or diclofenac organic base salt as an active ingredient, wherein the diclofenac or diclofenac organic base salt, when dissolved in the volatile silicone-based composition, exerts its anti-inflammatory and analgesic activities in local applications involving deep penetration of the active ingredient into the skin.

[0011] EP 834312 discloses a diclofenac- or salt-based pharmaceutical preparation for the topical treatment of inflammation and pain, the preparation comprising at least one solvent and at least one solubilizer. The solvent is a mixture of water, diethylene glycol monoethyl ether, and, where appropriate, C2 to C6 polyols and their polyesters, esters and ethers, and glycerides and / or ethoxylated derivatives thereof. The solubilizer is at least one phospholipid.

[0012] US 5958379 discloses a sprayable liquid pharmaceutical composition containing at least one active ingredient, diclofenac sodium, and including soybean lecithin as a solubilizer and a gelling agent. Ethanol and ethylene glycol are included as easily evaporable co-solvents.

[0013] US 5738869 describes a phospholipid transdermal drug delivery system containing α-tocopherol, aliphatic alcohols, and diclofenac.

[0014] Improved topical drug delivery systems have been well established, and a recognized approach is the use of penetration enhancers. These enhancers reduce the skin's barrier resistance, thus improving the penetration of the active pharmaceutical ingredient. Diclofenac sodium topical solution 1.5% or 2% w / w (PENNSAID) is indicated for the treatment of signs and symptoms of knee osteoarthritis (hereinafter referred to as knee OA). Other absorption-enhancing components in this product include 45.5% DMSO (United States Pharmacopeia Convention), propylene glycol, and ethanol. DMSO-containing topical diclofenac solution is indicated for the treatment of signs and symptoms of knee OA. The clinical efficacy and safety of this topical diclofenac solution have been demonstrated in multiple clinical trials treating signs and symptoms of knee OA, including improvements in pain, impaired daily activities, and overall health. Furthermore, two randomized controlled trials have demonstrated that this topical diclofenac formulation provides equivalent efficacy compared to therapeutic doses of oral diclofenac, with fewer GI adverse events and less variation in renal and liver laboratory values.

[0015] However, skin-related events were the most common treatment-related adverse events in patients receiving diclofenac sodium in excipient- and placebo-controlled clinical trials. Dry skin was the most common adverse event, occurring in 18.2% to 39.3% of diclofenac sodium recipients, and was significantly more common in this treatment group than in recipients receiving topical placebo or excipient-controlled treatment (p < 0.05). Other common skin-related adverse events reported in clinical trials included rash, paranesthesia, and pruritus. In equivalence studies, significantly more recipients of diclofenac sodium experienced skin-related adverse events (dry skin, rash, pruritus, and vesicular rash) compared to recipients of oral diclofenac. Using large amounts of solvent can increase the solubility and bioavailability of diclofenac, but it can also increase the risk of skin irritation and sensitization.

[0016] Therefore, this technology requires a novel topical drug delivery composition to reduce the risk of skin irritation and sensitization. Summary of the Invention

[0017] The purpose of this disclosure is to provide a novel topical formulation in which the solubility of a nonsteroidal anti-inflammatory drug (NSAID) is improved and remains stable throughout the entire shelf life of the composition. Another purpose of this disclosure is to develop a novel topical formulation that facilitates the penetration of NSAIDs through the skin and reduces skin irritation.

[0018] This disclosure relates to a topical formulation for treating inflammation, arthritis, and / or pain, or for treating conditions whose signs and symptoms include inflammation, arthritis, and / or pain. In embodiments, this disclosure provides a topical formulation comprising at least one active agent, at least one phospholipid, and urea, wherein the active agent comprises a nonsteroidal anti-inflammatory drug (NSAID).

[0019] In the embodiments, the active agent is present in an amount between about 0.1% by weight and about 10.0% by weight of the total composition.

[0020] In some embodiments, the nonsteroidal anti-inflammatory drugs (NSAIDs) disclosed herein are selected from the group consisting of: acetylsalicylic acid, sodium salicylate, magnesium colinyl salicylate, disalicylate, diflunisal, salicylsalicylic acid, sulfasalazine, olsalazine, acetaminophen, indomethacin, sulindac, etodolac, tolmetin, diclofenac, ketorolac, ibuprofen, naproxen, flurbiprofen, dopamine, aceclofenac, fenoprofen, oxaprozin, mefenamic acid, and meclofenamic acid. acid), piroxicam, meloxicam, tenoxicam, phenylbutazone, oxyphenbutazone, nabumetone, rofecoxib, celecoxib, any pharmaceutically acceptable salt, its derivatives and mixtures thereof.

[0021] In the embodiments, phospholipids are present in an amount between about 0.1% by weight and about 20.0% by weight of the total composition.

[0022] In the embodiments, the surfactant disclosed herein is phospholipid. In some embodiments, the phospholipids are selected from the group consisting of: phosphatidylcholine (PC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), palmytoylstearoylphosphatidylcholine (PSPC), palmitoyloleylphosphatidylcholine (POPC), dioleylphosphatidylcholine (DOPC), stearoyloleylphosphatidylcholine (SOPC), cardiolipin, plasmalogen, lysophosphatidylcholine (LPC), and phosphatidylethanolamine. Ethanolamine (PE) (phosphatidylcholine), phosphatidyl inositol (PI), phosphatidyl serine (PS), lecithin, lysophosphatidylcholine, soybean lecithin, rapeseed lecithin, corn or sunflower lecithin, egg lecithin, Epicorn 200, Epicorn 100, phospholipone 90G, LIPOID R-100 (rapeseed), LIPOID H-100 (sunflower), LIPOID-S100 (soybean), LIPOID-S75, Phosal 50PG and combinations thereof.

[0023] In the embodiments, urea is present in an amount between about 5.0% by weight and about 50.0% by weight of the total composition.

[0024] In embodiments, the local composition of this disclosure further comprises lower chain alcohols with carbon chain lengths of C2 to C5. In some embodiments, the lower chain alcohols are selected from the group consisting of: ethanol, propanol, isopropanol, butanol, isobutanol, pentanol, isoamyl alcohol, ethylene glycol, propylene glycol, butanediol, isobutylene glycol, pentanediol, isopentanediol, and combinations thereof.

[0025] In embodiments, the topical composition of this disclosure further comprises a pH adjuster. In some embodiments, the pH adjuster is selected from the group consisting of: sodium phosphate, disodium phosphate, sodium bicarbonate, tris(hydroxymethyl)aminomethane, boric acid, sodium hydroxide, hydrochloride, triethylamine, citric acid, alanine, glycine, leucine, lactic acid, phenol, and combinations thereof.

[0026] In some embodiments, the compositions of this disclosure are in the form of creams, ointments, gels, transdermal preparations, foams, sprays, lotions, solutions, emulsions, or suspensions.

[0027] In an embodiment, this disclosure provides a topical composition comprising about 0.1% to about 10.0% by weight of an active agent, about 0.1% to about 20.0% by weight of a phospholipid, and about 5.0% to about 50.0% by weight of urea, wherein the active agent comprises a nonsteroidal anti-inflammatory drug (NSAID).

[0028] In one embodiment, a method for preparing a topical composition of the present disclosure is provided, the method comprising the steps of: (a) dissolving at least one active agent and at least one phospholipid to form an oil phase, (b) adding urea to water to form an aqueous phase, and (c) mixing the oil phase and the aqueous phase to form a homogeneous composition.

[0029] In another embodiment, a method for treating inflammation, arthritis and / or pain, or signs and symptoms including inflammation, arthritis and / or pain, includes: topically applying a topical composition of the present disclosure to a subject requiring treatment, wherein the composition of the present disclosure comprises at least one active agent, at least one phospholipid, and urea.

[0030] Additional embodiments and advantages will become apparent from reading the accompanying drawings and detailed description. Attached Figure Description

[0031] This disclosure will be better understood by reading the following detailed description with reference to the accompanying drawings, in which...

[0032] Figure 1 This is a comparison chart of the skin permeability of formulations 9, 23, and 24.

[0033] Figure 2 This is a comparison chart of skin permeability between formulations of 25-80 ng / BID and 25-160 ng / QD.

[0034] Figure 3 This is a comparison chart of the skin permeability of 4% diclofenac solution (formulation 30) and 2% diclofenac sodium. Detailed Implementation

[0035] Reference will now be made in detail to exemplary embodiments of the invention, examples of which are illustrated in the accompanying drawings. Wherever possible, the same component reference numerals are used in the drawings and description to denote the same or similar parts.

[0036] The following disclosure provides numerous different embodiments or examples for implementing different features of the provided target object. Specific examples are described below to simplify this disclosure. Of course, these are merely examples and are not intended to be limiting.

[0037] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. Otherwise, certain terms used herein have the meanings set forth in the specification.

[0038] Unless the context clearly specifies otherwise, the singular forms “a” and “an” and “the” are used herein to include plural indicators.

[0039] Although the numerical ranges and parameters described in this disclosure are approximate, the values ​​presented in specific examples are reported as precisely as possible. However, any numerical value inherently contains a certain degree of error due to the standard deviation present in the corresponding test measurement. Furthermore, the term "about" as used herein generally means within 10.0%, 5.0%, 1.0%, or 0.5% of a given value or range. Therefore, numerical values ​​typically include ±10% of the stated value. For example, a concentration of 1 mg / mL includes 0.9 mg / mL to 1.1 mg / mL. Similarly, a concentration range of 1.0 wt% to 10.0 wt% includes 0.9 wt% to 11.0 wt%. Alternatively, the term "about" means within an acceptable standard error range of an average value as considered by those skilled in the art. Except in operational / working instances, or unless expressly stated otherwise, all numerical ranges, quantities, values, and percentages disclosed herein (e.g., material quantities, durations, temperatures, operating conditions, quantity ratios, and similar parameters) should be understood to be modified by the term “about” in all cases. Therefore, unless indicated to the contrary, the numerical parameters set forth in this disclosure and the appended claims are approximate values ​​that may vary as needed. Finally, each numerical parameter should be interpreted at least according to the number of significant figures reported and by applying common rounding techniques. Ranges herein may be expressed as from one endpoint to another or between two endpoints. Unless otherwise stated, all ranges disclosed herein include the endpoints.

[0040] 1. Definition

[0041] For convenience, certain terms used in the context of this disclosure are collected herein. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0042] As used herein, the term “treatment” is intended to mean achieving a desired pharmacological and / or physiological effect, such as blocking the action of a cyclo-oxygenase enzyme. Such effect may be preventative (in terms of complete or partial prevention of the disease or its symptoms) and / or therapeutic (in terms of partial or complete cure of the disease and / or elimination of side effects that may be caused by the disease). As used herein, “treatment” includes preventative (e.g., preventive), curative, or palliative treatment of diseases in mammals (particularly humans); and includes: (1) preventative (e.g., preventive), curative, or palliative treatment of a disease or condition (e.g., arthritis or osteoarthritis) to prevent the occurrence of the disease or condition in individuals who may be susceptible to the disease but have not yet been diagnosed with it; (2) suppression of the disease (e.g., by preventing the development of the disease); or (3) relief of the disease (e.g., reduction of symptoms associated with the disease).

[0043] The terms “administered, administering, or administration” are used interchangeably in this document to refer to a method of administration, including but not limited to intravenous, intramuscular, intraperitoneal, intraarterial, intracranial, or subcutaneous administration of an agent that provides immune protection to a subject from bacterial infection (e.g., current glycoconjugate vaccines).

[0044] As used herein, the term "effective amount" refers to the amount that, at a given dose and for a necessary period of time, effectively provides a therapeutic effect to a subject receiving treatment. An effective amount of reagent is not necessarily intended to cure the disease or condition, but rather to provide treatment to delay, inhibit, or prevent its onset or to improve its symptoms. The specific effective amount or adequate amount will vary depending on factors such as: the specific condition being treated, the patient's physical condition (e.g., weight, age, or sex), the type of mammal or animal being treated, the duration of treatment, the nature of any concurrent treatments, and the specific formulation used. An effective amount may be expressed, for example, as the total mass of the active agent (e.g., in grams, milligrams, or micrograms) or as the ratio of the mass of the active agent to body weight (e.g., milligrams per kilogram (mg / kg)). An effective amount may be appropriately divided into single, double, or multiple doses to be administered once, twice, or multiple times over a specified period of time.

[0045] The term "pharmaceutically acceptable" refers to molecular entities and compositions that are "generally considered safe," such as those that are physiologically tolerable when administered to humans and generally do not cause allergic reactions or similar adverse reactions (e.g., stomach upset, dizziness, etc.). Preferably, as used herein, "pharmaceutically acceptable" means approved by federal or state regulatory agencies or listed in the United States Pharmacopeia or other recognized pharmacopoeia for use in animals, and more specifically, in humans.

[0046] The terms “subject” and “patient” are used interchangeably herein and are intended to refer to mammals, including humans, that can be treated with the compounds of this disclosure. The term “mammal” means all members of the class Mammalia, including: humans, primates, livestock and farm animals (e.g., rabbits, pigs, sheep, and cattle); and zoo animals, sporting animals, or pet animals; and rodents, such as mice and rats. Furthermore, the terms “subject” and “patient” are intended to refer to both males and females unless one sex is specifically specified. Therefore, the terms “subject” and “patient” include any mammal that can benefit from the treatments of this disclosure. Examples of “subject” or “patient” include, but are not limited to, humans, rats, mice, guinea pigs, monkeys, pigs, goats, cattle, horses, dogs, cats, birds, and poultry. In a preferred embodiment, the subject is a human.

[0047] The terms “comprise,” “comprises,” and “comprising” are used interchangeably in this text to be interpreted as inclusive rather than exclusive. The terms “consist,” “consisting,” “consisting essentially of,” and their variations should be interpreted as exclusive rather than inclusive.

[0048] Unless otherwise stated, the term “environmental conditions” as used herein refers to atmospheric pressure and a temperature of 22°C to 24°C.

[0049] As used herein, the terms "composition" or "formulation" refer to a mixture of excipients or other chemicals prepared according to a specific formulation and preparation procedure. Formulations constitute the final or intermediate form of a pharmaceutical product, cosmetic product, or supplementary product, such as a solution, gel, or foam. Compositions may contain a drug, if applicable. The terms "composition" and "formulation" are used interchangeably in this application.

[0050] 2. Detailed Description of the Embodiments

[0051] This disclosure provides one or more topical compositions comprising at least one active agent, at least one phospholipid, and urea; methods for manufacturing the topical compositions, methods for treatment, and dosage forms. The active agent is used to inhibit cyclooxygenase activity, enabling the pharmaceutical composition to treat conditions (including, for example, inflammation, arthritis, and / or pain) associated with cyclooxygenase activity when applied topically.

[0052] In one embodiment, this disclosure provides a topical composition comprising at least one active agent, at least one phospholipid, and urea, wherein the active agent comprises a nonsteroidal anti-inflammatory drug (NSAID).

[0053] In some embodiments, the nonsteroidal anti-inflammatory drugs (NSAIDs) of this disclosure are selected from the group consisting of: acetylsalicylic acid, sodium salicylate, magnesium colinyl salicylate, disalicylate, diflunisal, salicylsalicylic acid, sulfasalazine, oxetrazine, acetaminophen, indomethacin, sulindac, etodoxacin, tometetin, diclofenac, ketorolac, ibuprofen, naproxen, flurbiprofen, dopprofen, aceclofenac, fenofibrate, oxaprozin, mefenamic acid, meclofenamic acid, piloxica, meloxicam, tenoxica, phenbuzodone, oxyphenbuzodone, nabumetone, rofecoxib, celecoxib, any pharmaceutically acceptable salt, derivatives thereof, and mixtures thereof.

[0054] In some embodiments, the active agent of this disclosure comprises diclofenac or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutically acceptable salt is diclofenac sodium salt. In some embodiments, the pharmaceutically acceptable salt is mesylate.

[0055] In some embodiments, the active agent of this disclosure is present in an amount between about 0.1 wt% and about 10.0 wt% of the total composition. In some embodiments, the active agent of this disclosure is present in an amount between about 2.0 wt% and about 10.0 wt% of the total composition; for example, in an amount of about 2.0 wt%, about 3.0 wt%, about 4.0 wt%, about 5.0 wt%, about 6.0 wt%, about 7.0 wt%, about 8.0 wt%, about 9.0 wt%, or about 10.0 wt% of the total composition. In some embodiments, the active agent is present in an amount between 0.5% by weight and about 10.0% by weight of the total composition; for example, in an amount of about 0.5% by weight, about 1.0% by weight, about 1.5% by weight, about 2.0% by weight, about 2.5% by weight, about 3.0% by weight, about 3.5% by weight, about 4.0% by weight, about 4.5% by weight, about 5.0% by weight, about 5.5% by weight, about 6.0% by weight, about 6.5% by weight, about 7.0% by weight, about 7.5% by weight, about 8.0% by weight, about 8.5% by weight, about 9.0% by weight, about 9.5% by weight, and about 10.0% by weight of the total composition.

[0056] In some embodiments, the compositions of this disclosure include phospholipids. Phospholipids refer to trimers of glycerol with two fatty acids and one phosphate ion. Phospholipids are also known to increase the moisture content of the skin and the penetration of drugs through the skin. In some embodiments, the phospholipids may be glycerophospholipids selected from monophosphatidylglycerol, diphosphatidylglycerol, and triphosphatidylglycerol. In some embodiments, the phospholipids of this disclosure are selected from the group consisting of: phosphatidylcholine (PC), dipalmitoylphosphatidylcholine (DPPC), distearylphosphatidylcholine (DSPC), palmitoylstearoylphosphatidylcholine (PSPC), palmitoyloleoylphosphatidylcholine (POPC), dioleoylphosphatidylcholine (DOPC), stearoyloleoylphosphatidylcholine (SOPC), cardiolipin, phosphatalopterin, lysophosphatidylcholine (LPC), phosphatidylethanolamine (PE) (cephalin), phosphatidylinositol (PI), phosphatidylserine (PS), lecithin, lysophosphatidylcholine, soybean lecithin, rapeseed lecithin, corn or sunflower lecithin, egg lecithin, Epicorn 200, Epicorn 100, hydrogenated lecithin 90g, lipid R-100 (rapeseed), lipid H-100 (sunflower), lipid-S100 (soybean), lipid-S75, phenobarbital 50PG and combinations thereof.

[0057] In some embodiments, the phospholipids of this disclosure are present in an amount between about 0.1 wt% and about 20.0 wt% of the total composition. In some embodiments, the phospholipids of this disclosure are present in an amount between about 1.0 wt% and about 10.0 wt% of the total composition, for example, in an amount of about 1.0 wt%, about 1.5 wt%, about 2.0 wt%, about 2.5 wt%, about 3.0 wt%, about 3.5 wt%, about 4.0 wt%, about 4.5 wt%, about 5.0 wt%, about 5.5 wt%, about 6.0 wt%, about 6.5 wt%, about 7.0 wt%, about 7.5 wt%, about 8.0 wt%, about 8.5 wt%, about 9.0 wt%, about 9.5 wt%, or about 10.0 wt% of the total composition. In some embodiments, the phospholipids of this disclosure are present in an amount between about 0.1 wt% and about 15.0 wt% of the total composition. In some embodiments, the phospholipids of this disclosure are present in an amount between about 0.1% by weight and about 10.0% by weight of the total composition. In some embodiments, the phospholipids of this disclosure are present in an amount between about 0.1% by weight and about 5.0% by weight of the total composition.

[0058] As is well known, urea possesses skin exfoliating properties, which can be used to control the penetration of the active substance of this disclosure across the dermal barrier. In some embodiments, urea is present in an amount between about 5.0 wt% and about 50.0 wt% of the total composition. In some embodiments, urea is present in an amount between about 5.0 wt% and about 35.0 wt% of the total composition, for example, in an amount of about 5.0 wt%, about 10.0 wt%, about 15.5 wt%, about 20.0 wt%, about 25.0 wt%, about 30.0 wt%, or about 35.5 wt%. In some embodiments, urea is present in an amount between about 10.0 wt% and about 30.0 wt% of the composition; for example, in an amount of about 10.0 wt%, about 15.5 wt%, about 20.0 wt%, about 25.0 wt%, about 30.0 wt%, or about 35.0 wt%. In some embodiments, urea is present in an amount between about 5.0 wt% and about 45.0 wt% of the total composition. In some embodiments, urea is present in an amount between about 5.0 wt% and about 40.0 wt% of the total composition. In some embodiments, urea is present in an amount between about 5.0 wt% and about 35.0 wt% of the total composition. In some embodiments, urea is present in an amount between about 5.0 wt% and about 30.0 wt% of the total composition. In some embodiments, urea is present in an amount between about 5.0 wt% and about 25.0 wt% of the total composition. In some embodiments, urea is present in an amount between about 5.0 wt% and about 20.0 wt% of the total composition.

[0059] To ensure good dispersion of phospholipids in the aqueous phase, in some embodiments, the local composition of this disclosure further comprises lower chain alcohols with carbon chain lengths of C2 to C5. In some embodiments, the lower chain alcohols of this disclosure are selected from the group consisting of ethanol, propanol, isopropanol, butanol, isobutanol, pentanol, isoamyl alcohol, ethylene glycol, propylene glycol, butanediol, isobutylene glycol, pentanediol, isopentanediol, and combinations thereof. In one embodiment, the lower chain alcohol of this disclosure is ethanol.

[0060] Lower chain alcohols also act as effective penetration enhancers to improve the bioavailability of diclofenac. However, excessive alcohols can increase the risk of skin irritation. In some embodiments, the lower chain alcohols of this disclosure are present in an amount between about 5.0 wt% and about 30.0 wt% of the total composition; for example, in an amount of about 5.0 wt%, about 10.0 wt%, about 15.0 wt%, about 20.0 wt%, about 25.0 wt%, or about 30.0 wt% of the total composition. In some embodiments, the lower chain alcohols of this disclosure are present in an amount between about 5.0 wt% and about 20.0 wt% of the total composition; for example, in an amount of about 5.0 wt%, about 10.0 wt%, about 15.0 wt%, or about 20.0 wt% of the total composition. In one embodiment, the lower chain alcohols of this disclosure are present in an amount of about 10 wt% of the total composition.

[0061] In some embodiments, the topical composition of this disclosure further comprises a pH adjuster. Diclofenac is unstable in acidic environments and this can accelerate the formation of diclofenac impurities. Ideally, the pH should be controlled within the range of about pH 7 to pH 9, and the addition of a pH adjuster is necessary. In some embodiments, the pH adjuster of this disclosure is selected from the group consisting of: sodium phosphate, disodium phosphate, sodium bicarbonate, tris(hydroxymethyl)aminomethane, boric acid, sodium hydroxide, hydrochloride, triethylamine, citric acid, alanine, glycine, leucine, lactic acid, phenol, and combinations thereof. In one embodiment, the pH adjuster of this disclosure comprises boric acid.

[0062] In some embodiments, the pH adjuster of this disclosure is present in an amount between about 0.5% by weight and about 1.5% by weight of the total composition; for example, in an amount of about 0.5% by weight, about 0.6% by weight, about 0.7% by weight, about 0.8% by weight, about 0.9% by weight, about 1.0% by weight, about 1.1% by weight, about 1.2% by weight, about 1.3% by weight, about 1.4% by weight, or 1.5% by weight. In some embodiments, the pH adjuster of this disclosure is present in an amount between about 0.5% by weight and about 1.0% by weight of the total composition; for example, in an amount of about 0.5% by weight, about 0.6% by weight, about 0.7% by weight, about 0.8% by weight, about 0.9% by weight, or about 1.0% by weight of the total composition. In one embodiment, the pH adjuster of this disclosure is present in an amount of about 1.0% by weight of the total composition.

[0063] In some embodiments, the topical composition of this disclosure further comprises a thickener. In some embodiments, the thickener is selected from the group consisting of: carbopol, xanthan gum, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), methyl cellulose (MC), ethyl cellulose (EC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), chitosan, alginate, hyaluronic acid, and combinations thereof.

[0064] In some embodiments, the topical composition of this disclosure further includes additives such as chelating agents, antioxidants, and preservatives. In some embodiments, the chelating agent is selected from the group consisting of ethylenediaminetetraacetic acid (EDTA), EDTA derivatives, and combinations thereof. In some embodiments, the antioxidant is selected from the group consisting of ascorbic acid, stearates, sodium ascorbate, tocopherols (d-isomers, 1-isomers, and dl-isomers of α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, etc.) and their ester derivatives, nordihydroguaiaretic acid, butylated hydroxytoluene, butylated hydroxyanisole, tributylhydroquinone, and 1-oxo-3-methyl-4-isopropylbenzene, and combinations thereof. In some embodiments, the preservative is selected from the group consisting of: benzoic acid, benzyl alcohol, sodium benzoate, ethylparaben, propylparaben, butylparaben, isothiazolinone, paraben esters (e.g., methylparaben and propylparaben), and combinations thereof. In some embodiments, the preservative is selected from the group consisting of: tocopherol, tocopheryl acetate, ascorbic acid, ascorbyl palmitate, propyl gallate, butylated hydroxytoluene (BHT), butylated hydroxylanisole (BHA), tertiary butylhydroquinone (TBHQ), ethylenediaminetetraacetic acid (EDTA), methylparaben (MP), ethylparaben (EP), propylparaben (PP), butylparaben (BP), benzoic acid, benzyl alcohol, and combinations thereof.

[0065] In some embodiments, the topical compositions of this disclosure are in the form of creams, ointments, gels, transdermal preparations, foams, sprays, lotions, solutions, emulsions, or suspensions.

[0066] In some embodiments, this disclosure provides a topical composition comprising 0.1% to 10.0% by weight of an active agent, 0.1% to 20.0% by weight of a phospholipid, and 5.0% to 50.0% by weight of urea, wherein the active agent comprises a nonsteroidal anti-inflammatory drug (NSAID).

[0067] In some embodiments, this disclosure provides a topical composition comprising 2.0% to 10.0% by weight of an active agent, 1.0% to 10.0% by weight of a phospholipid, and 5.0% to 35.0% by weight of urea, wherein the active agent comprises a nonsteroidal anti-inflammatory drug (NSAID).

[0068] In another embodiment, this disclosure also provides a method for preparing a topical composition of this disclosure, the method comprising (a) dissolving at least one active agent and at least one phospholipid to form an oil phase, (b) adding urea to water to form an aqueous phase, and (c) mixing the oil phase and the aqueous phase to form a homogeneous composition, wherein the active agent comprises a nonsteroidal anti-inflammatory drug (NSAID).

[0069] In yet another embodiment, this disclosure further provides a method for treating inflammation, arthritis and / or pain, or a condition whose signs and symptoms include inflammation, arthritis and / or pain, the method comprising: topically applying a topical composition of the present disclosure to a subject requiring treatment, wherein the composition comprises at least one active agent, at least one phospholipid and urea, and the active agent comprises a nonsteroidal anti-inflammatory drug (NSAID).

[0070] In embodiments, the topical composition of this disclosure can be used to treat inflammation, arthritis, and / or pain, and can be used to treat conditions whose signs and symptoms include inflammation, arthritis, and / or pain. In some embodiments, arthritis and / or pain may include, but is not limited to, arthritis associated with joint pain and stiffness. The most common types of arthritis are osteoarthritis and rheumatoid arthritis. While not wishing to be bound by the following theory, it is believed that application of the topical composition of this disclosure will minimize pain and / or movement impairment, and / or application of the topical composition of this disclosure will inhibit cyclooxygenase activity. In embodiments, the dosing regimen for treating inflammation, and the dosing regimen for treating inflammation, arthritis, and / or pain, comprises application twice daily to the affected area of ​​the skin.

[0071] In another embodiment, this disclosure provides a topical composition for treating inflammation, arthritis and / or pain, or conditions whose signs and symptoms include inflammation, arthritis and / or pain, wherein the topical composition comprises at least one active agent, at least one phospholipid and urea, and the active agent comprises a nonsteroidal anti-inflammatory drug (NSAID).

[0072] In yet another embodiment, this disclosure also provides the use of the topical composition of this disclosure in the preparation of an agent for treating inflammation, arthritis and / or pain, or conditions whose signs and symptoms include inflammation, arthritis and / or pain, wherein the topical composition comprises at least one active agent, at least one phospholipid and urea, and the active agent comprises a nonsteroidal anti-inflammatory drug (NSAID).

[0073] In another embodiment, this disclosure also provides a topical composition of the present disclosure for treating inflammation, arthritis and / or pain, or conditions whose signs and symptoms include inflammation, arthritis and / or pain, wherein the topical composition comprises at least one active agent, at least one phospholipid and urea, and the active agent comprises a nonsteroidal anti-inflammatory drug (NSAID).

[0074] In some embodiments, the local components of this disclosure are stable for at least about 20 hours when stored in a closed container at about 30 degrees Celsius and about 90% relative humidity; stable for at least about one week, two weeks, or three weeks when stored at about 40 degrees Celsius and about 60% relative humidity; stable for at least about one month when stored at about 25 degrees Celsius and about 60% relative humidity; stable for at least three months when stored at about 40 degrees Celsius and about 75% relative humidity; stable for at least about three months when stored at about 25 degrees Celsius and about 75% relative humidity; or stable for at least about three months when stored at 15 degrees Celsius at any relative humidity.

[0075] The foregoing summary outlines features of several embodiments to enable those skilled in the art to better understand implementations of this disclosure. Those skilled in the art will understand that they can readily use this disclosure as a basis for designing or modifying other processes and structures to achieve the same purposes and / or advantages as the embodiments described herein. Those skilled in the art will also recognize that such equivalent constructions do not depart from the spirit and scope of this disclosure, and that various changes, substitutions, and modifications can be made thereto without departing from the spirit and scope of this disclosure.

[0076] Example

[0077] Although this disclosure has been discussed with reference to certain embodiments, it should be understood that this disclosure is not limited thereto. While certain embodiments have been discussed in this disclosure, it should be recognized that this disclosure is not limited to those embodiments. Embodiments have been illustrated herein by way of example, and numerous modifications, variations, and other embodiments may be employed, and these modifications, variations, and other embodiments will still fall within the scope of this disclosure.

[0078] Example 1. Urea-phospholipid enhances the solubility of diclofenac sodium.

[0079] Step 1: Preparation of urea and soybean phosphatidylcholine (SPC) solution

[0080] SPC (0%, 1%, 3%, 5%, 8%, 10%, 13%, 15%, 18%, 20%) and urea (0%, 5%, 10%, 20%, 30%, 40%, 50%) were added to an aqueous solution containing 1% boric acid and stirred until completely dissolved. A total of 70 sample solutions with different SPC and urea concentrations were obtained.

[0081] Step 2: Solubility Study of Diclofenac Sodium

[0082] Excess diclofenac sodium was added to each sample solution, and the mixture was stirred overnight at 25°C. The sample solutions were centrifuged at 12,000 rpm for 5 minutes, and a portion of the supernatant was diluted with a suitable diluent and analyzed by high-performance liquid chromatography (HPLC) to determine the solubility of diclofenac sodium in aqueous solutions containing different concentrations of SPC and urea. The results are presented in Table 1.

[0083] The results in Table 1 show that the solubility of diclofenac sodium can be increased by adding urea or SPC, either alone or together. In the absence of SPC, the solubility of diclofenac increased from 19.7 mg / mL to 68.3 mg / mL (3.5-fold) as the urea concentration increased from 0 to 30%. Urea significantly increases the solubility of diclofenac. The solubility of diclofenac is further increased when SPC is present in the solution. This indicates that both SPC and urea contribute to increasing the solubility of diclofenac.

[0084] In the absence of urea, the solubility of diclofenac increased from 19.7 mg / mL to 96.8 mg / mL (4.9-fold) as the concentration of urea (SPC) increased from 0% to 15%. With the addition of urea, the viscosity of the sample decreased; therefore, with an additional 5% urea, the SPC increased to 18%, and the solubility of diclofenac increased to 116.5 mg / mL. When the urea concentration reached 10%, the SPC increased to 20%, and the solubility of diclofenac increased to 136.6 mg / mL. This indicates an interaction between urea and SPC to alter the properties of the solution.

[0085] Table 1

[0086]

[0087] N / A: Not applicable; the sample is too viscous to be separated by centrifugation at 12,000 rpm for undissolved diclofenac.

[0088] Example 2. Changes in the amounts of diclofenac and SPC

[0089] Step 1: Preparation of the oil phase

[0090] The mixture was prepared by adding SPC and diclofenac to ethanol at room temperature until a homogeneous solution or suspension was obtained.

[0091] Step 2: Preparation of the aqueous phase

[0092] Add urea to any desired amount of water and stir until the urea is completely dissolved.

[0093] Step 3: Mix the oil phase and the water phase.

[0094] Diclofenac solution was obtained by combining the oil phase and the aqueous phase and mixing them thoroughly until a homogeneous solution was obtained.

[0095] Table 2 provides formulations containing diclofenac, SPC, and urea.

[0096] As shown in Table 2, the concentration of diclofenac in formulations 1 through 8 varied from 2% by weight to 9% by weight. Stable formulations were also formed. When the ratio of diclofenac sodium to SPC varied from 2:8 to 3:7, a translucent solution was formed. When the ratio of diclofenac sodium to SPC varied from 4:6 to 8:2, a clear solution was formed. As demonstrated in formulation 12, precipitation occurred when the ratio of diclofenac sodium to SPC increased to 9:1, because this exceeded the solubility of diclofenac sodium in the co-solvent carrier.

[0097] Table 2

[0098]

[0099] Example 3. Stability of diclofenac solution

[0100] All formulations in Table 3 were prepared according to the process described in Example 2.

[0101] Table 3 provides formulations containing diclofenac.

[0102] As shown in Table 3, formulation 11, which does not contain urea, showed phase separation after being stored at room temperature for 2 weeks. In contrast, formulations 9 and 10, which have a diclofenac sodium to SPC ratio between 4:6 and 8:2 in Table 3, were stable and remained stable after being stored at room temperature for 2 weeks.

[0103] Table 3

[0104]

[0105] Example 4. Changes in the type and quantity of first-generation and second-generation NSAIDs

[0106] All formulations in Table 4 were prepared according to the process described in Example 2.

[0107] Ibuprofen, dopprofen, aceclofenac, naproxen, and indomethacin are classified as first-generation NSAIDs, while piloxica and meloxicam are classified as second-generation NSAIDs with selective COX2 inhibitory activity. As shown in Table 4, stable formulations are also formed when the ratio of first-generation NSAIDs to SPC is between 2:5 and 5:3.

[0108] Ibuprofen, dopprofen, and indomethacin comprise 5%, 2.5%, 1%, and 0.5% of the topical commercial product, respectively. These drugs also exhibit high solubility in this system, and formulations with at least twice the activity of commercial products are obtained.

[0109] Table 4

[0110]

[0111] Example 5. In vitro skin penetration test

[0112] Using pigskin as a model membrane, in vitro skin permeation tests were conducted for 48 hours at 32±2°C using a Franz diffusion cell. Pigskin was collected from a sow weighing 30-40 kg and further processed using a dermatome (Zimmer, USA) to control the thickness to 0.45±0.20 mm. The cut pigskin was carefully washed with phosphate-buffered saline, dried with Kimberly-Clark paper towels, and then stored at -80°C. Before use, the pigskin was thawed and then placed in the Franz diffusion cell. The receptor compartment (3 mL) containing a 20% ethanol solution of degassed phosphate-buffered saline at pH 7.4 served as the sink for the active substance. The in vitro test was conducted in an open-cell mode, with an effective diffusion area of ​​0.785 cm². Four microliters (160 nanograms) of formulation 9, 23, or 24 were applied to the donor compartment and then evenly spread onto the skin using a small glass rod. Each sample was administered twice daily (BID). All formulations 9, 23, and 24 in Table 5 were prepared according to the process described in Example 2.

[0113] Table 5

[0114]

[0115] As in Figure 1 The study observed that formulation 9, containing both SPC and urea, exhibited superior skin permeability. After quantitative administration, the diclofenac flux of formulation 9 was higher than that of formulations 23 (without urea) and 24 (without SPC). The combination of SPC and urea in the formulation facilitated the penetration of diclofenac through the skin.

[0116] Example 6. Effects of the Dosing Regimen

[0117] Formulation 25 was subjected to an in vitro skin penetration test according to the method of Example 5, and the effects of the following two dosage regimens on the penetration distribution curve were compared. The first dosage regimen was a once-daily (QD) dose of 4 μL (160 ng diclofenac). The second dosage regimen was a dose volume halved (2 μL, 80 ng diclofenac) administered twice daily (BID), with the total daily dose being the same as the first method. Formulation 25 in Table 6 was prepared according to the process described in Example 2.

[0118] Table 6

[0119]

[0120] As in Figure 2 The study observed that the 160 ng / QD dosing regimen exhibited better penetration than the 80 ng / BID dosing regimen within the first 12 hours due to its higher dose volume. At 24 hours after the second dose, the 80 ng / BID and 160 ng / QD dosing regimens were comparable in flux. However, calculation of the area under the curve (AUC) revealed that the 160 ng / QD dosing regimen had a higher AUC than the 80 ng / BID dosing regimen, and a similar trend was observed with consecutive three-day dose administration.

[0121] Example 7. Skin irritation of the components of this disclosure

[0122] New Zealand white rabbits were used to evaluate all formulations in Table 7. The fur on the rabbits' backs was clipped prior to testing. A 32 μL (1.28 μg diclofenac) sample solution was applied directly to the skin, covering an area of ​​approximately 2.5 cm² × 2.5 cm². The test samples were removed at the end of the 4-hour exposure period. After removal, all areas were allowed to dry, and erythema (0 to 4 points) and edema (0 to 4 points) were scored according to the Draize scoring system at 24 ± 2 hours, 48 ​​± 2 hours, and 72 ± 2 hours. The Primary Irritation Index (PII) was calculated by scoring erythema and edema in all animals at the three scoring time points.

[0123] All formulations in Table 7 were prepared according to the method described in Example 2.

[0124] Table 7

[0125]

[0126]

[0127] Example 8. Comparison of skin penetration with commercially available product—2% diclofenac sodium.

[0128] Formulation 30 was subjected to an in vitro skin penetration study according to the method of Example 5. Four microliters of Formulation 30 (160 nanograms of diclofenac) or a commercially available product (i.e., 2% diclofenac sodium (80 nanograms of diclofenac)) were applied. Formulation 30 was administered once daily (QD), while 2% diclofenac sodium was administered twice daily (BID).

[0129] As in Figure 3 The study observed that the 160 ng / QD dosing regimen of formulation 30 penetrated faster after quantitative administration, reached Cmax at 8 hours after quantitative administration, and decreased to a level comparable to that of 2% diclofenac sodium (80 ng diclofenac) administered according to the product label BID at 24 hours after quantitative administration.

[0130] Compared to 2% diclofenac sodium administered at 80 ng / BID, formulation 30 administered at 160 ng / QD exhibited a shorter Tmax and a higher AUC. This trend suggests that diclofenac solutions using a urea-phospholipid system may have a shorter onset of action and better efficacy than commercially available products.

[0131] Table 8

[0132]

Claims

1. A local component comprising: At least one surfactant; At least one phospholipid and urea; and The active agent mentioned above includes a nonsteroidal anti-inflammatory drug (NSAID).

2. The topical composition according to claim 1, wherein the active agent is present in an amount between about 0.1% by weight and about 10.0% by weight of the total composition.

3. The topical composition according to claim 1 or 2, wherein the nonsteroidal anti-inflammatory drug (NSAID) is selected from the group consisting of: acetylsalicylic acid, sodium salicylate, magnesium colinyl salicylate, disalicylate, diflunisal, salicylsalicylic acid, sulfasalazine, oxetrazine, acetaminophen, indomethacin, sulindac, etodoxacin, tometetin, diclofenac, ketorolac, ibuprofen, naproxen, flurbiprofen, dopprofen, aceclofenac, fenofibrate, oxaprofen, mefenamic acid, meclofenamic acid, piloxica, meloxicam, tenoxica, phenbuzodone, oxyphenbuzodone, nabumetone, rofecoxib, celecoxib, any pharmaceutically acceptable salt, derivatives thereof, and mixtures thereof.

4. The topical composition according to any one of claims 1 to 3, wherein the phospholipid is present in an amount between about 0.1% by weight and about 20.0% by weight of the total amount of the composition.

5. The topical composition according to any one of claims 1 to 4, wherein the phospholipid is selected from the group consisting of: phosphatidylcholine (PC), dipalmitoylphosphatidylcholine (DPPC), distearylphosphatidylcholine (DSPC), palmitoylstearoylphosphatidylcholine (PSPC), palmitoyloleoylphosphatidylcholine (POPC), dioleoylphosphatidylcholine (DOPC), stearoyloleoylphosphatidylcholine (SOPC), cardiolipin, phosphatalopterin, lysophosphatidylcholine (LPC), phosphatidylethanolamine (PE) (cephalin), phosphatidylinositol (PI), phosphatidylserine (PS), lecithin, lysophosphatidylcholine, soybean lecithin, rapeseed lecithin, corn or sunflower lecithin, egg lecithin, Epicoron 200, Epicoron 100, hydrogenated lecithin 90g, lipid R-100 (rapeseed), lipid H-100 (sunflower), lipid-S100 (soybean), lipid-S75, phenobarbital 50PG and combinations thereof.

6. The topical composition according to any one of claims 1 to 5, wherein the urea is present in an amount between about 5.0% by weight and about 50.0% by weight of the total amount of the composition.

7. The topical composition according to any one of claims 1 to 6 further comprises a lower chain alcohol having a carbon chain length of C2 to C5.

8. The topical composition according to claim 7, wherein the lower chain alcohol is selected from the group consisting of: ethanol, propanol, isopropanol, butanol, isobutanol, pentanol, isoamyl alcohol, ethylene glycol, propylene glycol, butanediol, isobutylene glycol, pentanediol, isopentanediol, and combinations thereof.

9. The topical composition according to any one of claims 1 to 8 further comprises a pH adjuster.

10. The topical composition according to claim 9, wherein the pH adjuster is selected from the group consisting of: sodium phosphate, disodium phosphate, sodium bicarbonate, tris(hydroxymethyl)aminomethane, boric acid, sodium hydroxide, hydrochloride, triethylamine, citric acid, alanine, glycine, leucine, lactic acid, phenol, and combinations thereof.

11. The topical composition according to any one of claims 1 to 10, wherein the topical composition is in the form of a cream, ointment, gel, transdermal preparation, foam, spray, lotion, solution, emulsion or suspension.

12. The topical composition according to any one of claims 1 to 11, wherein the topical composition comprises about 0.1% to about 10.0% by weight of the active agent, about 0.1% to about 20.0% by weight of the phospholipid, and about 5.0% to about 50.0% by weight of the urea, wherein the active agent comprises the nonsteroidal anti-inflammatory drug (NSAID).

13. A method for treating inflammation, arthritis, and / or pain, or a condition whose signs and symptoms include inflammation, arthritis, and / or pain, comprising: The topical composition as described in claim 1 is applied topically to a subject requiring treatment.

14. The method of claim 13, wherein the active agent is present in the topical composition in an amount between about 0.1% by weight and about 10.0% by weight of the total amount of the composition.

15. The method according to claim 13 or 14, wherein in the topical composition, the nonsteroidal anti-inflammatory drug (NSAID) is selected from the group consisting of: acetylsalicylic acid, sodium salicylate, magnesium colinyl salicylate, disalicylate, diflunisal, salicylsalicylic acid, sulfasalazine, oxetrazine, acetaminophen, indomethacin, sulindac, etodoxacin, tometetin, diclofenac, ketorolac, ibuprofen, naproxen, flurbiprofen, dopofol, fenofol, oxaprozin, mefenamic acid, meclofenamic acid, pelosicard, meloxicam, tenoxicam, phenazole, oxyphenazole, nabumetone, rofecoxib, celecoxib, any pharmaceutically acceptable salt, derivatives thereof, and mixtures thereof.

16. The method of claim 13, wherein the phospholipid is present in the topical composition in an amount between about 0.1% by weight and about 20.0% by weight of the total amount of the composition.

17. The method according to any one of claims 13 to 16, wherein in the topical composition, the phospholipid is selected from the group consisting of: phosphatidylcholine (PC), dipalmitoylphosphatidylcholine (DPPC), distearylphosphatidylcholine (DSPC), palmitoylstearoylphosphatidylcholine (PSPC), palmitoyloleoylphosphatidylcholine (POPC), dioleoylphosphatidylcholine (DOPC), stearoyloleoylphosphatidylcholine (SOPC), cardiolipin, phosphatalopterin, lysophosphatidylcholine (LPC), phosphatidylethanolamine (PE) (cephalin), phosphatidylinositol (PI), phosphatidylserine (PS), lecithin, lysophosphatidylcholine, soybean lecithin, rapeseed lecithin, corn or sunflower lecithin, egg lecithin, Epicoron 200, Epicoron 100, hydrogenated lecithin 90g, lipid R-100 (rapeseed), lipid H-100 (sunflower), lipid-S100 (soybean), lipid-S75, phenobarbital 50PG and combinations thereof.

18. The method according to any one of claims 13 to 17, wherein the urea is present in the topical composition in an amount between about 5.0% by weight and about 50.0% by weight of the total amount of the composition.

19. The method of claim 13, wherein the local component further comprises a lower chain alcohol having a carbon chain length of C2 to C5.

20. The method of claim 19, wherein the lower chain alcohol is selected from the group consisting of ethanol, propanol, isopropanol, butanol, isobutanol, pentanol, isoamyl alcohol, ethylene glycol, propylene glycol, butanediol, isobutylene glycol, pentanediol, isopentanediol, and combinations thereof.

21. The method according to any one of claims 13 to 20, wherein the topical composition further comprises a pH adjuster.

22. The method of claim 21, wherein the pH adjuster is selected from the group consisting of: sodium phosphate, disodium phosphate, sodium bicarbonate, tris(hydroxymethyl)aminomethane, boric acid, sodium hydroxide, hydrochloride, triethylamine, citric acid, alanine, glycine, leucine, lactic acid, phenol, and combinations thereof.

23. The method according to any one of claims 13 to 22, wherein the topical composition is in the form of a cream, ointment, gel, transdermal preparation, foam, spray, lotion, solution, emulsion or suspension.

24. A method for preparing a topical composition, the method comprising: (a) dissolving at least one active agent and at least one phospholipid to form an oil phase, (b) adding urea to water to form an aqueous phase, and (c) mixing the oil phase with the aqueous phase to form a homogeneous composition, wherein the active agent comprises a nonsteroidal anti-inflammatory drug (NSAID).

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