Compositions and uses thereof

Abstract

The present invention relates to a composition in the form of a solution or a thixotropic composition in the form of a solution, comprising a pharmaceutically active ingredient, a solubilizer and a thixotropic agent, and to the use thereof.

Description

[0001] This application is a divisional application of 202080017220.9 (Chinese national application number). The international application number of its original original application is PCT / GB2020 / 050316, the application date is February 11, 2020, and the name of the invention is “Novel Composition”. Technical Field

[0002] The present invention relates to a pharmaceutical composition in the form of an aqueous spray suitable for application of a pharmaceutically active substance to the throat / pharynx area. In particular, the present invention relates to a thixotropic composition for the administration of an NSAID. Background Art

[0003] Spray compositions are known for application to various surfaces of the body, such as nasal sprays, breath fresheners and disinfectant sprays for skin application.

[0004] A common problem with spray administration is the low efficiency of the active agent, as the structure of body cavities and sites is often not conducive to the retention of the administered formulation. This is particularly true for water-based spray formulations, which must be sufficiently fluid to be dispensed by a pump device or squeeze spray bottle, but can be expelled from the application area during or immediately after spraying. Since most formulations that enter the oropharyngeal area are swallowed, the majority of the active agent introduced into the oral cavity and / or nose is often not available for its intended use.

[0005] It would be desirable to provide an aqueous composition that could be formulated to have a sufficiently low viscosity to permit spraying with a standard pump mechanism or squeeze spray bottle, but which then rapidly exhibits a significant viscosity rise in order to retain the composition at the site of application.

[0006] Thixotropic compositions exhibit time-dependent shear-thinning properties - under static conditions, the composition is thick or viscous, but thins out and loses viscosity when shaken or stirred. The effect of shaking or stirring is to cause the particles / polymers in the composition to temporarily shear due to the stress applied to them by shaking or stirring.

[0007] However, the materials / agents used to impart thixotropy to the composition are typically polymeric materials. The inclusion of such polymeric materials may affect the ability of the composition to dissolve certain pharmaceutically active compounds. This is because a salt buffer is typically required to dissolve the pharmaceutically active compound. However, the salt buffer interferes with the polymer matrix and destroys the gel structure. As a result, the active substance becomes poorly soluble and flocculation / syneresis occurs.

[0008] In addition, thixotropic spray compositions suitable for application to the nasal cavity are not suitable for application of pharmaceutical active ingredients to the throat / pharynx area due to the spray pattern of such compositions. Nasal sprays form a wide spray angle when applied to ensure that a large surface area of ​​the nasal passage is covered by the spray. In contrast, thixotropic or shear-thinning throat sprays should have a narrow spray angle to ensure that the composition only coats the surface of the throat / pharynx area rather than the entire oral cavity.

[0009] In fact, there are currently no thixotropic compositions suitable for administering pharmaceutical active ingredients to the mucosal tissues of the throat / pharynx region.

[0010] There is a need to provide a thixotropic composition comprising a pharmaceutical active ingredient in solution and having desirable rheological properties. Summary of the invention

[0011] The present invention provides a water-based sprayable composition containing a pharmaceutically active ingredient and a thixotropic material. The composition is a non-Newtonian thixotropic fluid that exhibits a reduced apparent viscosity when subjected to shear forces, but exhibits a high apparent viscosity when standing still; this property allows application by spraying using an off-the-shelf pump spray device or squeeze spray bottle immediately after the application of shear forces (such as the forces generated by vigorously shaking the product container), but causes the sprayed material to remain relatively immobile on the mucous membrane or skin, at least temporarily.

[0012] According to one aspect of the present invention, there is provided a composition comprising a pharmaceutically active ingredient, a solubilizer and a thixotropic agent.

[0013] Preferably, the composition is in the form of a solution.

[0014] Typically, the composition is in the form of a sprayable composition.

[0015] The pharmaceutically active ingredient may be selected from NSAIDs or pharmaceutically acceptable salts thereof. Preferred NSAIDs are selected from the group consisting of flurbiprofen, ketoprofen or diclofenac. More preferred NSAID is flurbiprofen.

[0016] Other pharmaceutically active ingredients that may be used are hexylresorcinol, benzocaine, dextromethorphan, menthol lidocaine, amylmetacresol and 2,4-dichlorobenzyl alcohol or pharmaceutically acceptable salts thereof.

[0017] The composition may include up to about 5% by weight of the composition of the NSAID. Typically, the amount of the NSAID is from 0.5% by weight of the composition to 3% by weight of the composition. More typically, the amount of the NSAID is from 1% by weight of the composition to 2% by weight of the composition.

[0018] The composition may comprise 10-25 mg / ml of the NSAID. Preferably, the composition comprises 15-18 mg / ml of the NSAID. More preferably, the composition comprises 16-17 mg / ml of the NSAID.

[0019] When the active ingredient is selected as hexylresorcinol, the composition may contain 2-5 mg / ml of the active ingredient. When the active ingredient is selected as benzocaine, the composition may contain 10-20 mg / ml. When the active ingredient is selected as dextromethorphan, the composition may contain 15-30 mg / ml. When the active ingredient is selected as menthol, the composition may contain 5-15 mg / ml. When the active ingredient is selected as lidocaine, the composition may contain 2-5 mg / ml. When the active ingredient is selected as amyl metacresol, the composition may contain 0.5-1.5 mg / ml. When the active ingredient is selected as 2,4-dichlorobenzyl alcohol, the composition may contain 1-2.5 mg / ml.

[0020] Preferably, after the shear force is removed, the composition has a very fast viscosity recovery rate. "Very fast viscosity recovery rate" means that within 30 seconds after the shear force is removed, the viscosity of the composition recovers to about 90% of its initial viscosity. More preferably, within 10 seconds after the shear force is removed, the viscosity of the composition recovers to about 90% of its initial viscosity. Most preferably, within 5 seconds after the shear force is removed, the viscosity of the composition recovers to about 90% of its initial viscosity. As used herein, the term "initial viscosity" is the viscosity of the composition before the shear force is applied.

[0021] The thixotropic agent may be present in an amount of 0.1-15 wt % of the composition. Preferably, the thixotropic agent may be present in an amount of 0.5-10 wt % of the composition. More preferably, the thixotropic agent may be present in an amount of 0.5-8 wt % of the composition. More preferably, the thixotropic agent may be present in an amount of 1-5 wt % of the composition.

[0022] The thixotropic agent may be selected from a combination of one or more celluloses and one or more alkali metal carboxyalkyl celluloses, carrageenan and xanthan gum. Preferably, the thixotropic agent is selected from a combination of one or more celluloses and one or more alkali metal carboxyalkyl celluloses.

[0023] A preferred combination of cellulose and alkali metal carboxyalkyl cellulose is microcrystalline cellulose and sodium carboxymethyl cellulose. Typically, this combination comprises 85-95% by weight of microcrystalline cellulose and 5-15% by weight of sodium carboxymethyl cellulose. More typically, this combination comprises 86-92% by weight of microcrystalline cellulose and 8-14% by weight of sodium carboxymethyl cellulose.

[0024] Typically, the compositions of the present invention contain at least about 1.5% by weight and up to about 10% by weight of a cellulose / carboxyalkyl cellulose combination to avoid high viscosities that would prevent spraying with conventional equipment. Preferably, the composition contains about 1.5% by weight to about 5% by weight of the mixture. More preferably, the amount will be about 2.0% by weight to about 3.0% by weight. Most preferably, the composition contains about 2.2% by weight to about 2.8% by weight.

[0025] The solubilizing agent can be present in the composition in an amount of 0.1-15 % by weight. Typically, the solubilizing agent can be present in an amount of 1-10 % by weight. Typically, the solubilizing agent can be present in the composition in an amount of 3-7 % by weight. Typically, the solubilizing agent can be present in an amount of 5-7 % by weight. More typically, the solubilizing agent can be present in an amount of 6 % by weight.

[0026] The solubilizing agent is typically selected from cyclodextrins or combinations thereof. Other solubilizing agents include nonionic surfactants, such as Tween, and propylene glycol.

[0027] The cyclodextrin may be selected from α, β, γ cyclodextrin and derivatives thereof. The cyclodextrin used in the present invention includes natural cyclodextrin and derivatives thereof, including alkylated and hydroxyalkylated derivatives, and branched cyclodextrins, and derivatives with sugar residues are of particular interest. Particularly useful herein are hydroxyethyl, hydroxypropyl (including 2- and 3-hydroxypropyl) and dihydroxypropyl ethers, their corresponding mixed ethers and further mixed ethers with methyl or ethyl, such as methyl-hydroxyethyl, ethyl-hydroxyethyl and ethyl-hydroxypropyl ethers of α, β, γ-cyclodextrin. Specific cyclodextrin derivatives for use herein include α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, methyl-α-cyclodextrin, hydroxyethyl-α-cyclodextrin, hydroxypropyl-α-cyclodextrin, dihydroxypropyl-α-cyclodextrin, methyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, dihydroxypropyl-β-cyclodextrin, methyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, hydroxypropyl-γ-cyclodextrin and dihydroxypropyl-γ-cyclodextrin.

[0028] Preferably, the cyclodextrin comprises more than one cyclodextrin. More preferably, the cyclodextrin comprises 2 cyclodextrins.

[0029] Typically, the molar ratio of cyclodextrin is 1:1 to 1:2 by weight of the composition. Preferably, the molar ratio of cyclodextrin is 1:1.9.

[0030] Alternatively, the molar ratio of cyclodextrin is 1:2.

[0031] The cyclodextrin may include a combination of β-cyclodextrin and hydroxypropyl-β-cyclodextrin.

[0032] The composition may comprise one or more stabilizers. The one or more stabilizers may be selected from ethyl cellulose, hydroxypropyl methyl cellulose and xanthan gum. A preferred stabilizer is xanthan gum.

[0033] The one or more stabilizers may be present in an amount of 0.05-5 wt %. Preferably, the one or more stabilizers are present in an amount of 0.1-1 wt %. More preferably, the one or more stabilizers are present in an amount of 0.15-0.5 wt %.

[0034] The pH of the composition is preferably 6.0-8.0. More preferably, it is 7.0-7.6. Most preferably, the pH is about 7.4.

[0035] The composition may further include one or more buffers. The one or more buffers are selected to ensure that the pH of the composition is about 6.0 to 8.0. Preferably, the one or more buffers are selected to ensure that the pH of the composition is about 7.0 to 7.6. More preferably, one or more buffers are selected to ensure that the pH of the composition is about 7.4.

[0036] The one or more buffers may be present in an amount of 0.1-15 wt%. Preferably, the one or more buffers are present in an amount of 1-5 wt%. More preferably, the one or more buffers are present in an amount of 2-4 wt%.

[0037] Preferably, the one or more buffers are selected from citric acid, disodium hydrogen phosphate, sodium hydrogen phosphate, and combinations thereof.

[0038] Typically, the one or more buffers include citric acid and disodium hydrogen phosphate. More typically, the composition comprises a combination of citric acid and disodium hydrogen phosphate.

[0039] Preferably, the composition comprises 0.1-5 wt% citric acid and 1-10 wt% disodium hydrogen phosphate. More preferably, the composition comprises 0.1-0.5 wt% citric acid and 1-5 wt% disodium hydrogen phosphate.

[0040] The composition may further include other pharmaceutically acceptable excipients selected from sweeteners, anesthetics, flavoring agents, preservatives, pH adjusters and non-ionic buffers.

[0041] The composition may comprise:

[0042] (a) 1-5% NSAID;

[0043] (b) 0.1-15% of a thixotropic agent; and

[0044] (c) 0.1-15% of one or more solubilizing agents.

[0045] The composition may comprise:

[0046] (a) 1-5% NSAID;

[0047] (b) 1-5% thixotropic agent;

[0048] (c) 1-15% of one or more solubilizing agents;

[0049] (d) 0.1-10% of one or more pH adjusting agents; and

[0050] (e) 0.1-15% of one or more buffering agents.

[0051] The composition may comprise:

[0052] (a) 1-5% NSAID;

[0053] (b) 1-5% thixotropic agent;

[0054] (c) 1-15% of one or more solubilizing agents;

[0055] (d) 1-10% of one or more pH adjusting agents; and

[0056] (e) 0.1-15% of one or more buffering agents.

[0057] The composition may comprise:

[0058] (a) 1-5% NSAID;

[0059] (b) 0.5-8% thixotropic agent;

[0060] (c) 1-10% of one or more solubilizing agents;

[0061] (d) 0.1-1% of one or more pH adjusting agents; and

[0062] (e) 1-5% of one or more buffering agents.

[0063] The composition may comprise:

[0064] (a) 1-5% NSAID;

[0065] (b) 0.5-8% thixotropic agent;

[0066] (c) 1-7% of one or more solubilizing agents;

[0067] (d) 0.1-1% of one or more pH adjusting agents; and

[0068] (e) 1-5% of one or more buffering agents.

[0069] The composition may comprise:

[0070] (a) 1-5% NSAID;

[0071] (b) 1-5% thixotropic agent;

[0072] (c) 1-7% of one or more solubilizing agents;

[0073] (d) 0.1-1% of one or more pH adjusting agents; and

[0074] (e) 1-5% of one or more buffering agents.

[0075] The composition may comprise:

[0076] (a) 1-5% NSAID;

[0077] (b) 1-5% thixotropic agent;

[0078] (c) 1-15% of one or more solubilizing agents;

[0079] (d) 0.1-15% of one or more buffering agents; and

[0080] (e) 0.05-5% of one or more stabilizers.

[0081] The composition may comprise:

[0082] (a) 1-5% NSAID;

[0083] (b) 0.5-8% thixotropic agent;

[0084] (c) 1-7% of one or more solubilizing agents;

[0085] (d) 1-5% of one or more buffering agents; and

[0086] (e) 0.05-5% of one or more stabilizers.

[0087] The composition may comprise:

[0088] (a) 1-5% NSAID;

[0089] (b) 1-5% thixotropic agent;

[0090] (c) 1-7% of one or more solubilizing agents;

[0091] (d) 1-5% of one or more buffering agents; and

[0092] (e) 0.05-5% of one or more stabilizers.

[0093] The composition may comprise:

[0094] (a) 1-5% NSAID;

[0095] (b) 1-5% thixotropic agent;

[0096] (c) 1-15% of one or more solubilizing agents;

[0097] (d) 0.1-10% of one or more pH adjusting agents;

[0098] (e) 0.1-15% of one or more buffering agents; and

[0099] (f) 0.05-5% of one or more stabilizers.

[0100] The composition may comprise:

[0101] (a) 1-5% NSAID;

[0102] (b) 1-5% thixotropic agent;

[0103] (c) 1-15% of one or more solubilizing agents;

[0104] (d) 1-10% of one or more pH adjusters; (e) 0.1-15% of one or more buffers; and (f) 0.05-5% of one or more stabilizers.

[0105] The composition may comprise:

[0106] (a) 1-5% NSAID;

[0107] (b) 0.5-8% thixotropic agent;

[0108] (c) 1-10% of one or more solubilizing agents;

[0109] (d) 0.1-1% of one or more pH adjusting agents; (e) 1-5% of one or more buffering agents; and

[0110] (f) 0.1-1% of one or more stabilizers. The composition may comprise:

[0111] (a) 1-5% NSAID;

[0112] (b) 0.5-8% thixotropic agent;

[0113] (c) 1-7% of one or more solubilizing agents;

[0114] (d) 0.1-1% of one or more pH adjusting agents; (e) 1-5% of one or more buffering agents; and

[0115] (f) 0.1-1% of one or more stabilizers. The composition may comprise:

[0116] (a) 1-5% NSAID;

[0117] (b) 1-5% thixotropic agent;

[0118] (c) 1-7% of one or more solubilizing agents;

[0119] (d) 0.1-1% of one or more pH adjusting agents; (e) 1-5% of one or more buffering agents; and

[0120] (f) 0.1-1% of one or more stabilizers.

[0121] The composition may comprise:

[0122] (a) 1-5% NSAID;

[0123] (b) 0.1-15% of a combination of cellulose and alkali metal carboxyalkyl cellulose; and

[0124] (c) 0.1-15% of one or more cyclodextrins.

[0125] The composition may comprise:

[0126] (a) 1-2% flurbiprofen;

[0127] (b) 2-4% of a combination of cellulose and alkali metal carboxyalkyl cellulose; and

[0128] (c) 5-7% of one or more cyclodextrins.

[0129] The composition may comprise:

[0130] (a) 1-5% NSAID;

[0131] (b) 1-5% of a combination of cellulose and alkali metal carboxyalkyl cellulose;

[0132] (c) 1-15% of one or more cyclodextrins;

[0133] (d) 0.1-10% of one or more pH adjusting agents; and

[0134] (e) 0.1-15% of one or more buffering agents.

[0135] The composition may comprise:

[0136] (a) 1-5% NSAID;

[0137] (b) 1-5% of a combination of cellulose and alkali metal carboxyalkyl cellulose;

[0138] (c) 1-15% of one or more cyclodextrins;

[0139] (d) 1-10% of one or more pH adjusting agents; and

[0140] (e) 0.1-15% of one or more buffering agents.

[0141] The composition may comprise:

[0142] (a) 1-5% NSAID;

[0143] (b) 0.5-8% of a combination of cellulose and alkali metal carboxyalkyl cellulose;

[0144] (c) 1-10% of one or more cyclodextrins;

[0145] (d) 0.1-1% of one or more pH adjusting agents; and

[0146] (e) 1-5% of one or more buffering agents.

[0147] The composition may comprise:

[0148] (a) 1-5% NSAID;

[0149] (b) 0.5-8% of a combination of cellulose and alkali metal carboxyalkyl cellulose; (c) 1-7% of one or more cyclodextrins;

[0150] (d) 0.1-1% of one or more pH adjusting agents; and

[0151] (e) 1-5% of one or more buffering agents.

[0152] The composition may comprise:

[0153] (a) 1-2% flurbiprofen;

[0154] (b) 2-4% of a combination of cellulose and alkali metal carboxyalkyl cellulose; (c) 5-7% of one or more cyclodextrins;

[0155] (d) 0.1-0.5% of one or more pH adjusting agents; and

[0156] (e) 2-4% of one or more buffering agents.

[0157] The composition may comprise:

[0158] (a) 1-5% NSAID;

[0159] (b) 1-5% of a combination of cellulose and alkali metal carboxyalkyl cellulose; (c) 1-7% of one or more cyclodextrins;

[0160] (d) 0.1-1% of one or more pH adjusting agents; and

[0161] (e) 1-5% of one or more buffering agents.

[0162] The composition may comprise:

[0163] (a) 1-5% NSAID;

[0164] (b) 1-5% of a combination of cellulose and alkali metal carboxyalkyl cellulose; (c) 1-15% of one or more cyclodextrins;

[0165] (d) 0.1-15% of one or more buffering agents; and

[0166] (e) 0.05-5% of one or more stabilizers.

[0167] The composition may comprise:

[0168] (a) 1-5% NSAID;

[0169] (b) 0.5-8% of a combination of cellulose and alkali metal carboxyalkyl cellulose; (c) 1-7% of one or more cyclodextrins;

[0170] (d) 1-5% of one or more buffering agents; and

[0171] (e) 0.1-1% of one or more stabilizers.

[0172] The composition may comprise:

[0173] (a) 1-5% NSAID;

[0174] (b) 1-5% of a combination of cellulose and alkali metal carboxyalkyl cellulose; (c) 1-7% of one or more cyclodextrins;

[0175] (d) 1-5% of one or more buffering agents; and

[0176] (e) 0.1-1% of one or more stabilizers.

[0177] The composition may comprise:

[0178] (a) 1-5% NSAID;

[0179] (b) 1-5% of a combination of cellulose and alkali metal carboxyalkyl cellulose;

[0180] (c) 1-15% of one or more cyclodextrins;

[0181] (d) 0.1-10% of one or more pH adjusting agents;

[0182] (e) 0.1-15% of one or more buffering agents; and

[0183] (f) 0.05-5% of one or more stabilizers.

[0184] The composition may comprise:

[0185] (a) 1-5% NSAID;

[0186] (b) 1-5% of a combination of cellulose and alkali metal carboxyalkyl cellulose;

[0187] (c) 1-15% of one or more cyclodextrins;

[0188] (d) 1-10% of one or more pH adjusting agents;

[0189] (e) 0.1-15% of one or more buffering agents; and

[0190] (f) 0.05-5% of one or more stabilizers.

[0191] The composition may comprise:

[0192] (a) 1-2% flurbiprofen;

[0193] (b) 2-4% of a combination of cellulose and alkali metal carboxyalkyl cellulose;

[0194] (c) 5-7% of one or more cyclodextrins;

[0195] (d) 0.1-5% of one or more pH adjusting agents;

[0196] (e) 2-4% of one or more buffering agents; and

[0197] (f) 0.1-3% of one or more stabilizers.

[0198] The composition may comprise:

[0199] (a) 1-5% NSAID;

[0200] (b) 0.5-8% of a combination of cellulose and alkali metal carboxyalkyl cellulose;

[0201] (c) 1-7% of one or more cyclodextrins;

[0202] (d) 0.1-1% of one or more pH adjusting agents;

[0203] (e) 1-5% of one or more buffering agents; and

[0204] (f) 0.1-1% of one or more stabilizers.

[0205] The composition may comprise:

[0206] (a) 1-5% NSAID;

[0207] (b) 0.5-8% of a combination of cellulose and alkali metal carboxyalkyl cellulose;

[0208] (c) 1-7% of one or more cyclodextrins;

[0209] (d) 0.1-1% of one or more pH adjusting agents;

[0210] (e) 1-5% of one or more buffering agents; and

[0211] (f) 0.1-1% of one or more stabilizers.

[0212] The composition may comprise:

[0213] (a) 1-5% NSAID;

[0214] (b) 1-5% of a combination of cellulose and alkali metal carboxyalkyl cellulose;

[0215] (c) 1-7% of one or more cyclodextrins;

[0216] (d) 0.1-1% of one or more pH adjusting agents;

[0217] (e) 1-5% of one or more buffering agents; and

[0218] (f) 0.1-1% of one or more stabilizers.

[0219] The composition may comprise:

[0220] (a) 1-5% NSAID;

[0221] (b) 1-5% of a combination of cellulose and alkali metal carboxyalkyl cellulose;

[0222] (c) 1-15% of one or more cyclodextrins;

[0223] (d) 0.1-10% of one or more pH adjusting agents;

[0224] (e) 0.1-15% of one or more buffering agents;

[0225] (f) 0.05-5% of one or more stabilizers; and

[0226] (g) 0.1-1% of a preservative.

[0227] The composition may comprise:

[0228] (a) 1-5% NSAID;

[0229] (b) 0.5-8% of a combination of cellulose and alkali metal carboxyalkyl cellulose;

[0230] (c) 1-7% of one or more cyclodextrins;

[0231] (d) 0.1-1% of one or more pH adjusting agents;

[0232] (e) 1-5% of one or more buffering agents;

[0233] (f) 0.1-1% of one or more stabilizers; and

[0234] (g) 0.1-1% of a preservative.

[0235] The composition may comprise:

[0236] (a) 1-5% NSAID;

[0237] (b) 1-5% of a combination of cellulose and alkali metal carboxyalkyl cellulose;

[0238] (c) 1-7% of one or more cyclodextrins;

[0239] (d) 0.1-1% of one or more pH adjusting agents;

[0240] (e) 1-5% of one or more buffering agents;

[0241] (f) 0.1-1% of one or more stabilizers; and

[0242] (g) 0.1-1% of a preservative.

[0243] The composition may comprise:

[0244] (a) 1-5% NSAID;

[0245] (b) 1-5% of a combination of cellulose and alkali metal carboxyalkyl cellulose;

[0246] (c) 1-15% of one or more cyclodextrins;

[0247] (d) 1-10% of one or more pH adjusting agents;

[0248] (e) 0.1-15% of one or more buffering agents;

[0249] (f) 0.05-5% of one or more stabilizers; and

[0250] (g) 0.1-1% of a preservative.

[0251] The composition may comprise:

[0252] (a) 1-5% flurbiprofen;

[0253] (b) 1-5% of a combination of microcrystalline cellulose and sodium carboxymethyl cellulose;

[0254] (c) 1-15% of a combination of β-cyclodextrin and hydroxypropyl-β-cyclodextrin;

[0255] (d) 0.1-5% sodium hydroxide;

[0256] (e) 1-10% disodium hydrogen phosphate;

[0257] (f) 0.1-5% citric acid monohydrate; and

[0258] (g) 0.05-0.5% xanthan gum.

[0259] The composition may comprise:

[0260] (a) 1-5% flurbiprofen;

[0261] (b) 0.5-8% of a combination of microcrystalline cellulose and sodium carboxymethyl cellulose;

[0262] (c) 1-7% of a combination of β-cyclodextrin and hydroxypropyl-β-cyclodextrin;

[0263] (d) 0.1-1% sodium hydroxide;

[0264] (e) 1-5% disodium hydrogen phosphate;

[0265] (f) 0.1-1% citric acid monohydrate; and

[0266] (g) 0.05-0.5% xanthan gum.

[0267] The composition may comprise:

[0268] (a) 1-5% flurbiprofen;

[0269] (b) 1-5% of a combination of microcrystalline cellulose and sodium carboxymethyl cellulose;

[0270] (c) 1-7% of a combination of β-cyclodextrin and hydroxypropyl-β-cyclodextrin;

[0271] (d) 0.1-1% sodium hydroxide;

[0272] (e) 1-5% disodium hydrogen phosphate;

[0273] (f) 0.1-1% citric acid monohydrate; and

[0274] (g) 0.05-0.5% xanthan gum.

[0275] The composition may comprise:

[0276] (a) 1-5% flurbiprofen;

[0277] (b) 1-5% of a combination of microcrystalline cellulose and sodium carboxymethyl cellulose;

[0278] (c) 1-15% of a combination of β-cyclodextrin and hydroxypropyl-β-cyclodextrin;

[0279] (d) 0.1-5% sodium hydroxide;

[0280] (e) 1-10% disodium hydrogen phosphate;

[0281] (f) 0.1-5% citric acid monohydrate;

[0282] (g) 0.05-5% xanthan gum;

[0283] (h) 0.1-5% of methylparaben; and

[0284] (i) 0.1-5% of propylparaben.

[0285] The composition may comprise:

[0286] (a) 1-5% flurbiprofen;

[0287] (b) 1-5% of a combination of microcrystalline cellulose and sodium carboxymethyl cellulose;

[0288] (c) 1-15% of a combination of β-cyclodextrin and hydroxypropyl-β-cyclodextrin;

[0289] (d) 0.1-5% sodium hydroxide;

[0290] (e) 1-10% disodium hydrogen phosphate;

[0291] (f) 0.1-5% citric acid monohydrate;

[0292] (g) 0.05-0.5% xanthan gum;

[0293] (h) 0.1-5% of methylparaben; and

[0294] (i) 0.1-5% of propylparaben.

[0295] The composition may consist essentially of the following ingredients:

[0296] (a) 1-5% NSAID;

[0297] (b) 1-5% of a combination of cellulose and alkali metal carboxyalkyl cellulose;

[0298] (c) 1-15% of one or more cyclodextrins;

[0299] (d) 0.1-10% of one or more pH adjusting agents; and

[0300] (e) 0.1-15% of one or more buffering agents.

[0301] The composition may consist essentially of the following ingredients:

[0302] (a) 1-5% NSAID;

[0303] (b) 1-5% of a combination of cellulose and alkali metal carboxyalkyl cellulose;

[0304] (c) 1-15% of one or more cyclodextrins;

[0305] (d) 1-10% of one or more pH adjusting agents; and

[0306] (e) 0.1-15% of one or more buffering agents.

[0307] The composition may consist essentially of the following ingredients:

[0308] (a) 1-5% NSAID;

[0309] (b) 0.5-8% of a combination of cellulose and alkali metal carboxyalkyl cellulose;

[0310] (c) 1-10% of one or more cyclodextrins;

[0311] (d) 0.1-1% of one or more pH adjusting agents; and

[0312] (e) 1-5% of one or more buffering agents.

[0313] The composition may consist essentially of the following ingredients:

[0314] (a) 1-5% NSAID;

[0315] (b) 0.5-8% of a combination of cellulose and alkali metal carboxyalkyl cellulose;

[0316] (c) 1-7% of one or more cyclodextrins;

[0317] (d) 0.1-1% of one or more pH adjusting agents; and

[0318] (e) 1-5% of one or more buffering agents.

[0319] The composition may consist essentially of the following ingredients:

[0320] (a) 1-5% NSAID;

[0321] (b) 1-5% of a combination of cellulose and alkali metal carboxyalkyl cellulose;

[0322] (c) 1-7% of one or more cyclodextrins;

[0323] (d) 0.1-1% of one or more pH adjusting agents; and

[0324] (e) 1-5% of one or more buffering agents.

[0325] The composition may consist essentially of the following ingredients:

[0326] (a) 1-5% NSAID;

[0327] (b) 1-5% of a combination of cellulose and alkali metal carboxyalkyl cellulose;

[0328] (c) 1-15% of one or more cyclodextrins;

[0329] (d) 0.1-10% of one or more pH adjusting agents;

[0330] (e) 0.1-15% of one or more buffering agents; and

[0331] (f) 0.05-5% of one or more stabilizers.

[0332] The composition may consist essentially of the following ingredients:

[0333] (a) 1-5% NSAID;

[0334] (b) 1-5% of a combination of cellulose and alkali metal carboxyalkyl cellulose;

[0335] (c) 1-15% of one or more cyclodextrins;

[0336] (d) 1-10% of one or more pH adjusting agents;

[0337] (e) 0.1-15% of one or more buffering agents; and

[0338] (f) 0.05-5% of one or more stabilizers.

[0339] The composition may consist essentially of the following ingredients:

[0340] (a) 1-5% NSAID;

[0341] (b) 0.5-8% of a combination of cellulose and alkali metal carboxyalkyl cellulose;

[0342] (c) 1-10% of one or more cyclodextrins;

[0343] (d) 0.1-1% of one or more pH adjusting agents;

[0344] (e) 1-5% of one or more buffering agents; and

[0345] (f) 0.1-1% of one or more stabilizers.

[0346] The composition may consist essentially of the following ingredients:

[0347] (a) 1-5% NSAID;

[0348] (b) 0.5-8% of a combination of cellulose and alkali metal carboxyalkyl cellulose;

[0349] (c) 1-7% of one or more cyclodextrins;

[0350] (d) 0.1-1% of one or more pH adjusting agents;

[0351] (e) 1-5% of one or more buffering agents; and

[0352] (f) 0.1-1% of one or more stabilizers.

[0353] The composition may consist essentially of the following ingredients:

[0354] (a) 1-5% NSAID;

[0355] (b) 1-5% of a combination of cellulose and alkali metal carboxyalkyl cellulose;

[0356] (c) 1-7% of one or more cyclodextrins;

[0357] (d) 0.1-1% of one or more pH adjusting agents;

[0358] (e) 1-5% of one or more buffering agents; and

[0359] (f) 0.1-1% of one or more stabilizers.

[0360] The composition may consist essentially of the following ingredients:

[0361] (a) 1-5% flurbiprofen;

[0362] (b) 1-5% of a combination of cellulose and alkali metal carboxyalkyl cellulose;

[0363] (c) 1-15% of one or more cyclodextrins;

[0364] (d) 0.1-15% of one or more buffering agents; and

[0365] (e) 0.05-5% of one or more stabilizers.

[0366] The composition may consist essentially of the following ingredients:

[0367] (a) 1-5% flurbiprofen;

[0368] (b) 1-5% of a combination of cellulose and alkali metal carboxyalkyl cellulose;

[0369] (c) 1-15% of one or more cyclodextrins;

[0370] (d) 0.1-10% of one or more pH adjusting agents; and

[0371] (e) 0.1-15% of one or more buffering agents.

[0372] The composition may consist essentially of the following ingredients:

[0373] (a) 1-5% flurbiprofen;

[0374] (b) 0.5-8% of a combination of cellulose and alkali metal carboxyalkyl cellulose; (c) 1-7% of one or more cyclodextrins;

[0375] (d) 1-5% of one or more buffering agents; and

[0376] (e) 0.1-1% of one or more stabilizers.

[0377] The composition may consist essentially of the following ingredients:

[0378] (a) 1-5% flurbiprofen;

[0379] (b) 1-5% of a combination of cellulose and alkali metal carboxyalkyl cellulose;

[0380] (c) 1-7% of one or more cyclodextrins;

[0381] (d) 1-5% of one or more buffering agents; and

[0382] (e) 0.1-1% of one or more stabilizers.

[0383] The composition may consist essentially of the following ingredients:

[0384] (a) 1-5% flurbiprofen;

[0385] (b) 1-5% of a combination of cellulose and alkali metal carboxyalkyl cellulose;

[0386] (c) 1-15% of one or more cyclodextrins;

[0387] (d) 0.1-10% of one or more pH adjusting agents;

[0388] (e) 0.1-15% of one or more buffering agents; and

[0389] (f) 0.05-5% of one or more stabilizers.

[0390] The composition may consist essentially of the following ingredients:

[0391] (a) 1-5% flurbiprofen;

[0392] (b) 0.5-8% of a combination of cellulose and alkali metal carboxyalkyl cellulose;

[0393] (c) 1-10% of one or more cyclodextrins;

[0394] (d) 0.1-1% of one or more pH adjusting agents;

[0395] (e) 1-5% of one or more buffering agents; and

[0396] (f) 0.1-1% of one or more stabilizers.

[0397] The composition may consist essentially of the following ingredients:

[0398] (a) 1-5% flurbiprofen;

[0399] (b) 0.5-8% of a combination of cellulose and alkali metal carboxyalkyl cellulose;

[0400] (c) 1-7% of one or more cyclodextrins;

[0401] (d) 0.1-1% of one or more pH adjusting agents;

[0402] (e) 1-5% of one or more buffering agents; and

[0403] (f) 0.1-1% of one or more stabilizers.

[0404] The composition may consist essentially of the following ingredients:

[0405] (a) 1-5% flurbiprofen;

[0406] (b) 1-5% of a combination of cellulose and alkali metal carboxyalkyl cellulose;

[0407] (c) 1-7% of one or more cyclodextrins;

[0408] (d) 0.1-1% of one or more pH adjusting agents;

[0409] (e) 1-5% of one or more buffering agents; and

[0410] (f) 0.1-1% of one or more stabilizers.

[0411] The composition may consist essentially of the following ingredients:

[0412] (a) 1-5% flurbiprofen;

[0413] (b) 1-5% of a combination of cellulose and alkali metal carboxyalkyl cellulose;

[0414] (c) 1-15% of one or more cyclodextrins;

[0415] (d) 1-10% of one or more pH adjusting agents;

[0416] (e) 0.1-15% of one or more buffering agents; and

[0417] (f) 0.05-5% of one or more stabilizers.

[0418] The composition may consist essentially of the following ingredients:

[0419] (a) 1-5% flurbiprofen;

[0420] (b) 1-5% of a combination of microcrystalline cellulose and sodium carboxymethyl cellulose;

[0421] (c) 1-15% of a combination of β-cyclodextrin and hydroxypropyl-β-cyclodextrin;

[0422] (d) 0.1-5% sodium hydroxide;

[0423] (e) 1-10% disodium hydrogen phosphate; and

[0424] (f) 0.1-5% citric acid monohydrate.

[0425] The composition may consist essentially of the following ingredients:

[0426] (a) 1-2% flurbiprofen;

[0427] (b) 2-4% of a combination of cellulose and alkali metal carboxyalkyl cellulose;

[0428] (c) 5-7% of one or more cyclodextrins;

[0429] (d) 0.1-0.5% of one or more pH adjusting agents; and

[0430] (e) 2-4% of one or more buffering agents.

[0431] The composition may consist essentially of the following ingredients:

[0432] (a) 1-2% flurbiprofen;

[0433] (b) 2-4% of a combination of cellulose and alkali metal carboxyalkyl cellulose;

[0434] (c) 5-7% of one or more cyclodextrins;

[0435] (d) 0.1-5% of one or more pH adjusting agents;

[0436] The composition may consist essentially of the following ingredients:

[0437] (a) 1-5% flurbiprofen;

[0438] (b) 0.5-8% of a combination of microcrystalline cellulose and sodium carboxymethyl cellulose;

[0439] (c) 1-10% of a combination of β-cyclodextrin and hydroxypropyl-β-cyclodextrin;

[0440] (d) 0.1-1% sodium hydroxide;

[0441] (e) 1-5% disodium hydrogen phosphate; and

[0442] (f) 0.1-1% citric acid monohydrate.

[0443] The composition may consist essentially of the following ingredients:

[0444] (a) 1-5% flurbiprofen;

[0445] (b) 0.5-8% of a combination of microcrystalline cellulose and sodium carboxymethyl cellulose;

[0446] (c) 1-7% of a combination of β-cyclodextrin and hydroxypropyl-β-cyclodextrin;

[0447] (d) 0.1-1% sodium hydroxide;

[0448] (e) 1-5% disodium hydrogen phosphate; and

[0449] (f) 0.1-1% citric acid monohydrate.

[0450] The composition may consist essentially of the following ingredients:

[0451] (a) 1-5% flurbiprofen;

[0452] (b) 1-5% of a combination of microcrystalline cellulose and sodium carboxymethyl cellulose;

[0453] (c) 1-7% of a combination of β-cyclodextrin and hydroxypropyl-β-cyclodextrin;

[0454] (d) 0.1-1% sodium hydroxide;

[0455] (e) 1-5% disodium hydrogen phosphate; and

[0456] (f) 0.1-1% citric acid monohydrate.

[0457] The composition may consist essentially of the following ingredients:

[0458] (a) 1-2% flurbiprofen;

[0459] (b) 2-4% combination of microcrystalline cellulose and sodium carboxymethyl cellulose;

[0460] (c) 5-7% of a combination of β-cyclodextrin and hydroxypropyl-β-cyclodextrin;

[0461] (d) 0.1-5% sodium hydroxide;

[0462] (e) 1-10% disodium hydrogen phosphate; and

[0463] (f) 0.1-5% citric acid monohydrate.

[0464] The composition may consist essentially of the following ingredients:

[0465] (a) 1-5% flurbiprofen;

[0466] (b) 1-5% of a combination of microcrystalline cellulose and sodium carboxymethyl cellulose;

[0467] (c) 1-15% of a combination of β-cyclodextrin and hydroxypropyl-β-cyclodextrin;

[0468] (d) 0.1-5% sodium hydroxide;

[0469] (e) 1-10% disodium hydrogen phosphate;

[0470] (f) 0.1-5% citric acid monohydrate; and

[0471] (g) 0.05-5% xanthan gum.

[0472] The composition may consist essentially of the following ingredients:

[0473] (a) 1-5% flurbiprofen;

[0474] (b) 1-5% of a combination of microcrystalline cellulose and sodium carboxymethyl cellulose;

[0475] (c) 1-15% of a combination of β-cyclodextrin and hydroxypropyl-β-cyclodextrin;

[0476] (d) 0.1-5% sodium hydroxide;

[0477] (e) 1-10% disodium hydrogen phosphate;

[0478] (f) 0.1-5% citric acid monohydrate; and

[0479] (g) 0.05-0.5% xanthan gum.

[0480] The composition may consist essentially of the following ingredients:

[0481] (a) 1-5% flurbiprofen;

[0482] (b) 0.5-8% of a combination of microcrystalline cellulose and sodium carboxymethyl cellulose;

[0483] (c) 1-7% of a combination of β-cyclodextrin and hydroxypropyl-β-cyclodextrin;

[0484] (d) 0.1-1% sodium hydroxide;

[0485] (e) 1-5% disodium hydrogen phosphate;

[0486] (f) 0.1-1% citric acid monohydrate; and

[0487] (g) 0.1-0.5% xanthan gum.

[0488] The composition may consist essentially of the following ingredients:

[0489] (a) 1-5% flurbiprofen;

[0490] (b) 1-5% of a combination of microcrystalline cellulose and sodium carboxymethyl cellulose;

[0491] (c) 1-7% of a combination of β-cyclodextrin and hydroxypropyl-β-cyclodextrin;

[0492] (d) 0.1-1% sodium hydroxide;

[0493] (e) 1-5% disodium hydrogen phosphate;

[0494] (f) 0.1-1% citric acid monohydrate; and

[0495] (g) 0.1-0.5% xanthan gum.

[0496] The composition may consist essentially of the following ingredients:

[0497] (a) 1-2% flurbiprofen;

[0498] (b) 2-4% combination of microcrystalline cellulose and sodium carboxymethyl cellulose;

[0499] (c) 5-7% of a combination of β-cyclodextrin and hydroxypropyl-β-cyclodextrin;

[0500] (d) 0.1-5% sodium hydroxide;

[0501] (e) 1-10% disodium hydrogen phosphate;

[0502] (f) 0.1-5% citric acid monohydrate; and

[0503] (g) 0.1-0.3% xanthan gum.

[0504] The composition may consist essentially of the following ingredients:

[0505] (a) 1-5% flurbiprofen;

[0506] (b) 1-5% of a combination of microcrystalline cellulose and sodium carboxymethyl cellulose;

[0507] (c) 1-15% of a combination of β-cyclodextrin and hydroxypropyl-β-cyclodextrin;

[0508] (d) 0.1-5% sodium hydroxide;

[0509] (e) 1-10% disodium hydrogen phosphate;

[0510] (f) 0.1-5% citric acid monohydrate;

[0511] (g) 0.1-5% of methylparaben; and

[0512] (h) 0.01-5% of propylparaben.

[0513] The composition may consist essentially of the following ingredients:

[0514] (a) 1-5% flurbiprofen;

[0515] (b) 0.5-8% of a combination of microcrystalline cellulose and sodium carboxymethyl cellulose;

[0516] (c) 1-7% of a combination of β-cyclodextrin and hydroxypropyl-β-cyclodextrin;

[0517] (d) 0.1-1% sodium hydroxide;

[0518] (e) 1-5% disodium hydrogen phosphate;

[0519] (f) 0.1-1% citric acid monohydrate;

[0520] (g) 0.1-5% of methylparaben; and

[0521] (h) 0.01-5% of propylparaben.

[0522] The composition may consist essentially of the following ingredients:

[0523] (a) 1-5% flurbiprofen;

[0524] (b) 0.5-8% of a combination of microcrystalline cellulose and sodium carboxymethyl cellulose;

[0525] (c) 1-7% of a combination of β-cyclodextrin and hydroxypropyl-β-cyclodextrin;

[0526] (d) 0.1-1% sodium hydroxide;

[0527] (e) 1-5% disodium hydrogen phosphate;

[0528] (f) 0.1-1% citric acid monohydrate;

[0529] (g) 0.1-0.5% xanthan gum;

[0530] (h) 0.1-5% of methylparaben; and

[0531] (i) 0.01-5% of propylparaben.

[0532] The composition may consist essentially of the following ingredients:

[0533] (a) 1-5% flurbiprofen;

[0534] (b) 1-5% of a combination of microcrystalline cellulose and sodium carboxymethyl cellulose;

[0535] (c) 1-7% of a combination of β-cyclodextrin and hydroxypropyl-β-cyclodextrin;

[0536] (d) 0.1-1% sodium hydroxide;

[0537] (e) 1-5% disodium hydrogen phosphate;

[0538] (f) 0.1-1% citric acid monohydrate;

[0539] (g) 0.1-5% of methylparaben; and

[0540] (h) 0.01-5% of propylparaben.

[0541] The composition may consist essentially of the following ingredients:

[0542] (a) 1-5% flurbiprofen;

[0543] (b) 1-5% of a combination of microcrystalline cellulose and sodium carboxymethyl cellulose;

[0544] (c) 1-7% of a combination of β-cyclodextrin and hydroxypropyl-β-cyclodextrin;

[0545] (d) 0.1-1% sodium hydroxide;

[0546] (e) 1-5% disodium hydrogen phosphate;

[0547] (f) 0.1-1% citric acid monohydrate;

[0548] (g) 0.1-0.5% xanthan gum;

[0549] (h) 0.1-5% of methylparaben; and

[0550] (i) 0.01-5% of propylparaben.

[0551] According to one aspect of the present invention, a sprayable aqueous thixotropic pharmaceutical composition in the form of a solution is provided, wherein the active pharmaceutical ingredient comprises a charged functional group, a thixotropic agent and a solubilizer.

[0552] The pharmaceutically active ingredient may be selected from NSAIDs or pharmaceutically acceptable salts thereof. Preferred NSAIDs are selected from the group consisting of flurbiprofen, ketoprofen or diclofenac. More preferred NSAID is flurbiprofen.

[0553] The composition may include up to about 5% by weight of the composition of the NSAID. Typically, the amount of the NSAID is from 0.5% by weight of the composition to 3% by weight of the composition. More typically, the amount of the NSAID is from 1% by weight of the composition to 2% by weight of the composition.

[0554] The composition may comprise 10-25 mg / ml of the NSAID. Preferably, the composition comprises 15-18 mg / ml of the NSAID. More preferably, the composition comprises 16-17 mg / ml of the NSAID.

[0555] The thixotropic agent may be present in an amount of 0.1-15 wt % of the composition. Preferably, the thixotropic agent may be present in an amount of 0.5-10 wt % of the composition. More preferably, the thixotropic agent may be present in an amount of 0.5-8 wt % of the composition. More preferably, the thixotropic agent may be present in an amount of 1-5 wt % of the composition.

[0556] The thixotropic agent may be selected from a combination of one or more celluloses and one or more alkali metal carboxyalkyl celluloses, carrageenan and xanthan gum. Preferably, the thixotropic agent is selected from a combination of one or more celluloses and one or more alkali metal carboxyalkyl celluloses.

[0557] A preferred combination of cellulose and alkali metal carboxyalkyl cellulose is microcrystalline cellulose and sodium carboxymethyl cellulose. Typically, this combination comprises 85-95% by weight of microcrystalline cellulose and 5-15% by weight of sodium carboxymethyl cellulose. More typically, this combination comprises 86-92% by weight of microcrystalline cellulose and 8-14% by weight of sodium carboxymethyl cellulose.

[0558] Typically, the compositions of the present invention contain at least about 1.5% by weight and up to about 10% by weight of the cellulose / carboxyalkyl cellulose combination to avoid high viscosities that would prevent spraying with conventional equipment. Preferably, the composition will contain about 1.5% by weight to about 5% by weight of the mixture. More preferably, the amount will be about 2.0% by weight to about 3.0% by weight. Most preferably, the composition contains about 2.2% by weight to about 2.8% by weight.

[0559] The solubilizing agent can be present in the composition in an amount of 0.1-15 % by weight. The solubilizing agent can be present in the composition in an amount of 1-10 % by weight. Typically, the solubilizing agent can be present in the composition in an amount of 3-7 % by weight. Typically, the solubilizing agent can be present in an amount of 5-7 % by weight. More typically, the solubilizing agent can be present in an amount of 6 % by weight.

[0560] The solubilizing agent is typically selected from cyclodextrins or combinations thereof. Other solubilizing agents include nonionic surfactants, such as Tween, and propylene glycol.

[0561] The cyclodextrin may be selected from α, β, γ cyclodextrin and derivatives thereof. The cyclodextrin used in the present invention includes natural cyclodextrin and derivatives thereof, including alkylated and hydroxyalkylated derivatives, and branched cyclodextrins, and derivatives with sugar residues are of particular interest. Particularly useful herein are hydroxyethyl, hydroxypropyl (including 2- and 3-hydroxypropyl) and dihydroxypropyl ethers, their corresponding mixed ethers and further mixed ethers with methyl or ethyl, such as methyl-hydroxyethyl, ethyl-hydroxyethyl and ethyl-hydroxypropyl ethers of α, β, γ-cyclodextrin. Specific cyclodextrin derivatives for use herein include α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, methyl-α-cyclodextrin, hydroxyethyl-α-cyclodextrin, hydroxypropyl-α-cyclodextrin, dihydroxypropyl-α-cyclodextrin, methyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, dihydroxypropyl-β-cyclodextrin, methyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, hydroxypropyl-γ-cyclodextrin and dihydroxypropyl-γ-cyclodextrin.

[0562] Preferably, the cyclodextrin comprises more than one cyclodextrin. More preferably, the cyclodextrin comprises 2 cyclodextrins.

[0563] Typically, the molar ratio of cyclodextrin is 1:1 to 1:2 by weight of the composition. Preferably, the molar ratio of cyclodextrin is 1:1.9.

[0564] Alternatively, the molar ratio of cyclodextrin is 1:2.

[0565] The cyclodextrin may include a combination of β-cyclodextrin and hydroxypropyl-β-cyclodextrin.

[0566] The composition may comprise one or more stabilizers. The one or more stabilizers may be selected from ethyl cellulose, hydroxypropyl methyl cellulose and xanthan gum. A preferred stabilizer is xanthan gum.

[0567] The one or more stabilizers may be present in an amount of 0.05-5 wt %. Preferably, the one or more stabilizers are present in an amount of 0.1-1 wt %. More preferably, the one or more stabilizers are present in an amount of 0.15-0.5 wt %.

[0568] The pH of the composition is preferably 6.0-8.0. More preferably, it is 7.0-7.6. Most preferably, the pH is about 7.4.

[0569] The composition may further include one or more buffers. The one or more buffers are selected to ensure that the pH of the composition is about 6.0 to 8.0. Preferably, the one or more buffers are selected to ensure that the pH of the composition is about 7.0 to 7.6. More preferably, one or more buffers are selected to ensure that the pH of the composition is about 7.4.

[0570] Preferably, the one or more buffers are selected from citric acid, disodium hydrogen phosphate, sodium hydrogen phosphate, and combinations thereof.

[0571] Typically, the one or more buffers include citric acid and disodium hydrogen phosphate. More typically, the composition comprises a combination of citric acid and disodium hydrogen phosphate.

[0572] Preferably, the composition comprises 0.1-5 wt% citric acid and 1-10 wt% disodium hydrogen phosphate. More preferably, the composition comprises 0.1-0.5 wt% citric acid and 1-5 wt% disodium hydrogen phosphate.

[0573] The composition may further include other pharmaceutically acceptable excipients selected from sweeteners, anesthetics, flavoring agents, preservatives, pH adjusters and non-ionic buffers.

[0574] According to one aspect of the present invention, there is provided a thixotropic composition comprising an active pharmaceutical ingredient, wherein the composition has a low shear viscosity of 30-80 Pascal seconds (Pa.s) and a high shear viscosity of 0.01-5 Pascal seconds (Pa.s).

[0575] Preferably, the low shear viscosity of the composition is 40 to 70 Pascal seconds (Pa.s). More preferably, the low shear viscosity of the composition is 45 to 65 Pascal seconds (Pa.s). Most preferably, the low shear viscosity of the composition is 50 to 60 Pascal seconds (Pa.s).

[0576] Preferably, the high shear viscosity of the composition is from 0.05 Pascal seconds (Pa.s) to 2.5 Pascal seconds (Pa.s). More preferably, the high shear viscosity of the composition is from 0.075 Pascal seconds (Pa.s) to 1.5 Pascal seconds (Pa.s). Most preferably, the high shear viscosity of the composition is from 0.1 Pascal seconds (Pa.s) to 1 Pascal seconds (Pa.s).

[0577] Preferably, the high shear viscosity of the composition is 0.1 Pascal seconds (Pa.s) to 1 Pascal seconds (Pa.s), and the low shear viscosity is 50 Pascal seconds (Pa.s) to 60 Pascal seconds (Pa.s).

[0578] The pharmaceutically active ingredient may be selected from NSAIDs or pharmaceutically acceptable salts thereof. Preferred NSAIDs are selected from the group consisting of flurbiprofen, ketoprofen or diclofenac. More preferred NSAID is flurbiprofen.

[0579] Other pharmaceutically active ingredients that may be used are hexylresorcinol, benzocaine, dextromethorphan, menthol lidocaine, amylmetacresol and 2,4-dichlorobenzyl alcohol or pharmaceutically acceptable salts thereof.

[0580] The composition may include up to about 5% by weight of the composition of the NSAID. Typically, the amount of the NSAID is from 0.5% by weight of the composition to 3% by weight of the composition. More typically, the amount of the NSAID is from 1% by weight of the composition to 2% by weight of the composition.

[0581] The composition may comprise 10-25 mg / ml of the NSAID. Preferably, the composition comprises 15-18 mg / ml of the NSAID. More preferably, the composition comprises 16-17 mg / ml of the NSAID.

[0582] When the active ingredient is selected as hexylresorcinol, the composition may contain 2-5 mg / ml of the active ingredient. When the active ingredient is selected as benzocaine, the composition may contain 10-20 mg / ml. When the active ingredient is selected as dextromethorphan, the composition may contain 15-30 mg / ml. When the active ingredient is selected as menthol, the composition may contain 5-15 mg / ml. When the active ingredient is selected as lidocaine, the composition may contain 2-5 mg / ml. When the active ingredient is selected as amyl metacresol, the composition may contain 0.5-1.5 mg / ml. When the active ingredient is selected as 2,4-dichlorobenzyl alcohol, the composition may contain 1-2.5 mg / ml.

[0583] Preferably, after the shear force is removed, the composition has a very fast viscosity recovery rate. "Very fast viscosity recovery rate" means that within 30 seconds after the shear force is removed, the viscosity of the composition recovers to about 90% of its initial viscosity. More preferably, within 10 seconds after the shear force is removed, the viscosity of the composition recovers to about 90% of its initial viscosity. Most preferably, within 5 seconds after the shear force is removed, the viscosity of the composition recovers to about 90% of its initial viscosity. As used herein, the term "initial viscosity" is the viscosity of the composition before the shear force is applied.

[0584] The thixotropic agent may be present in an amount of 0.1-15 wt % of the composition. Preferably, the thixotropic agent may be present in an amount of 0.5-10 wt % of the composition. More preferably, the thixotropic agent may be present in an amount of 0.5-8 wt % of the composition. More preferably, the thixotropic agent may be present in an amount of 1-5 wt % of the composition.

[0585] The thixotropic agent may be selected from a combination of one or more celluloses and one or more alkali metal carboxyalkyl celluloses, carrageenan and xanthan gum. Preferably, the thixotropic agent is selected from a combination of one or more celluloses and one or more alkali metal carboxyalkyl celluloses.

[0586] A preferred combination of cellulose and alkali metal carboxyalkyl cellulose is microcrystalline cellulose and sodium carboxymethyl cellulose. Typically, this combination comprises 85-95% by weight of microcrystalline cellulose and 5-15% by weight of sodium carboxymethyl cellulose. More typically, this combination comprises 86-92% by weight of microcrystalline cellulose and 8-14% by weight of sodium carboxymethyl cellulose.

[0587] Typically, the compositions of the present invention contain at least about 1.5% by weight and up to about 10% by weight of the cellulose / carboxyalkyl cellulose combination to avoid high viscosities that would prevent spraying with conventional equipment. Preferably, the composition will contain about 1.5% by weight to about 5% by weight of the mixture. More preferably, the amount will be about 2.0% by weight to about 3.0% by weight. Most preferably, the composition contains about 2.2% by weight to about 2.8% by weight.

[0588] The solubilizing agent can be present in the composition in an amount of 0.1-15 % by weight. The solubilizing agent can be present in the composition in an amount of 1-10 % by weight. Typically, the solubilizing agent can be present in the composition in an amount of 3-7 % by weight. Typically, the solubilizing agent can be present in an amount of 5-7 % by weight. More typically, the solubilizing agent can be present in an amount of 6 % by weight.

[0589] The solubilizing agent is typically selected from cyclodextrins or combinations thereof. Other solubilizing agents include nonionic surfactants, such as Tween, and propylene glycol.

[0590] The cyclodextrin may be selected from α, β, γ cyclodextrin and derivatives thereof. The cyclodextrin used in the present invention includes natural cyclodextrin and derivatives thereof, including alkylated and hydroxyalkylated derivatives, and branched cyclodextrins, and derivatives with sugar residues are of particular interest. Particularly useful herein are hydroxyethyl, hydroxypropyl (including 2- and 3-hydroxypropyl) and dihydroxypropyl ethers, their corresponding mixed ethers and further mixed ethers with methyl or ethyl, such as methyl-hydroxyethyl, ethyl-hydroxyethyl and ethyl-hydroxypropyl ethers of α, β, γ-cyclodextrin. Specific cyclodextrin derivatives for use herein include α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, methyl-α-cyclodextrin, hydroxyethyl-α-cyclodextrin, hydroxypropyl-α-cyclodextrin, dihydroxypropyl-α-cyclodextrin, methyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, dihydroxypropyl-β-cyclodextrin, methyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, hydroxypropyl-γ-cyclodextrin and dihydroxypropyl-γ-cyclodextrin.

[0591] Preferably, the cyclodextrin comprises more than one cyclodextrin. More preferably, the cyclodextrin comprises 2 cyclodextrins.

[0592] Typically, the molar ratio of cyclodextrin is 1:1 to 1:2 by weight of the composition. Preferably, the molar ratio of cyclodextrin is 1:1.9.

[0593] Alternatively, the molar ratio of cyclodextrin is 1:2.

[0594] The cyclodextrin may include a combination of β-cyclodextrin and hydroxypropyl-β-cyclodextrin.

[0595] The composition may comprise one or more stabilizers. The one or more stabilizers may be selected from ethyl cellulose, hydroxypropyl methyl cellulose and xanthan gum. A preferred stabilizer is xanthan gum.

[0596] The one or more stabilizers may be present in an amount of 0.05-5 wt %. Preferably, the one or more stabilizers are present in an amount of 0.1-1 wt %. More preferably, the one or more stabilizers are present in an amount of 0.15-0.5 wt %.

[0597] The pH of the composition is preferably 6.0-8.0. More preferably, it is 7.0-7.6. Most preferably, the pH is about 7.4.

[0598] The composition may further include one or more buffers. The one or more buffers are selected to ensure that the pH of the composition is about 6.0 to 8.0. Preferably, the one or more buffers are selected to ensure that the pH of the composition is about 7.0 to 7.6. More preferably, one or more buffers are selected to ensure that the pH of the composition is about 7.4.

[0599] The one or more buffers may be present in an amount of 0.1-15 wt%. Preferably, the one or more buffers are present in an amount of 1-5 wt%. More preferably, the one or more buffers are present in an amount of 2-4 wt%.

[0600] Preferably, the one or more buffers are selected from citric acid, disodium hydrogen phosphate, sodium hydrogen phosphate, and combinations thereof.

[0601] Typically, the one or more buffers include citric acid and disodium hydrogen phosphate. More typically, the composition comprises a combination of citric acid and disodium hydrogen phosphate.

[0602] Preferably, the composition comprises 0.1-5 wt% citric acid and 1-10 wt% disodium hydrogen phosphate. More preferably, the composition comprises 0.1-0.5 wt% citric acid and 1-5 wt% disodium hydrogen phosphate.

[0603] The composition may further include other pharmaceutically acceptable excipients selected from sweeteners, anesthetics, flavoring agents, preservatives, pH adjusters and non-ionic buffers.

[0604] The thixotropic composition can be in the form of a solution, the solution comprising 1-5% by weight of flurbiprofen or a pharmaceutically acceptable salt thereof, 5-7% by weight of a solubilizer selected from cyclodextrin or a combination thereof, 1.5-5% by weight of a thixotropic agent selected from a combination of one or more celluloses and one or more alkali metal carboxyalkyl celluloses, 0.1-1% by weight of one or more stabilizers selected from ethyl cellulose, hydroxypropyl methylcellulose and xanthan gum, and 1-5% by weight of one or more buffers selected from citric acid, disodium hydrogen phosphate, sodium hydrogen phosphate and a combination thereof, wherein the low shear viscosity of the composition is 30-80 Pascal seconds (Pa.s), and the high shear viscosity is 0.01-5 Pascal seconds (Pa.s). Preferably, the amount of flurbiprofen is 1-2% by weight of the composition. Preferably, the amount of the thixotropic agent is 2-3% by weight of the composition. Preferably, the amount of the stabilizer is 0.1-0.5% by weight of the composition. Preferably, the amount of the buffer is 2-4% by weight of the composition. Preferably, the high shear viscosity of the composition is 0.1 Pascal seconds (Pa.s) to 1 Pascal seconds (Pa.s), and the low shear viscosity is 50 Pascal seconds (Pa.s) to 60 Pascal seconds (Pa.s).

[0605] The thixotropic composition can be in the form of a solution, which is essentially composed of the following ingredients: 1-5% by weight of flurbiprofen or a pharmaceutically acceptable salt thereof, 5-7% by weight of a solubilizer selected from cyclodextrin or a combination thereof, 1.5-5% by weight of a thixotropic agent selected from a combination of one or more celluloses and one or more alkali metal carboxyalkyl celluloses, 0.1-1% by weight of one or more stabilizers selected from ethyl cellulose, hydroxypropyl methylcellulose and xanthan gum, and 1-5% by weight of one or more buffers selected from citric acid, disodium hydrogen phosphate, sodium hydrogen phosphate and a combination thereof, wherein the low shear viscosity of the composition is 30-80 Pascal seconds (Pa.s) and the high shear viscosity is 0.01-5 Pascal seconds (Pa.s). Preferably, the amount of flurbiprofen is 1-2% by weight of the composition. Preferably, the amount of the thixotropic agent is 2-3% by weight of the composition. Preferably, the amount of the stabilizer is 0.1-0.5% by weight of the composition. Preferably, the amount of the buffer is 2-4% by weight of the composition. Preferably, the high shear viscosity of the composition is 0.1 Pascal seconds (Pa.s) to 1 Pascal seconds (Pa.s), and the low shear viscosity is 50 Pascal seconds (Pa.s) to 60 Pascal seconds (Pa.s).

[0606] According to one aspect of the present invention, there is provided a thixotropic composition comprising an NSAID or a pharmaceutically acceptable salt thereof, wherein the composition has a yield point of 1-30 Pa.

[0607] Preferably, the yield point is 2-8Pa.

[0608] Alternatively, the yield point may be 10-16 Pa.

[0609] The pharmaceutically active ingredient may be selected from NSAIDs or pharmaceutically acceptable salts thereof. Preferred NSAIDs are selected from the group consisting of flurbiprofen, ketoprofen or diclofenac. More preferred NSAID is flurbiprofen.

[0610] Other pharmaceutically active ingredients that may be used are hexylresorcinol, benzocaine, dextromethorphan, menthol lidocaine, amylmetacresol and 2,4-dichlorobenzyl alcohol or pharmaceutically acceptable salts thereof.

[0611] The composition may include up to about 5% by weight of the composition of the NSAID. Typically, the amount of the NSAID is from 0.5% by weight of the composition to 3% by weight of the composition. More typically, the amount of the NSAID is from 1% by weight of the composition to 2% by weight of the composition.

[0612] The composition may comprise 10-25 mg / ml of the NSAID. Preferably, the composition comprises 15-18 mg / ml of the NSAID. More preferably, the composition comprises 16-17 mg / ml of the NSAID.

[0613] When the active ingredient is selected as hexylresorcinol, the composition may contain 2-5 mg / ml of the active ingredient. When the active ingredient is selected as benzocaine, the composition may contain 10-20 mg / ml. When the active ingredient is selected as dextromethorphan, the composition may contain 15-30 mg / ml. When the active ingredient is selected as menthol, the composition may contain 5-15 mg / ml. When the active ingredient is selected as lidocaine, the composition may contain 2-5 mg / ml. When the active ingredient is selected as amyl metacresol, the composition may contain 0.5-1.5 mg / ml. When the active ingredient is selected as 2,4-dichlorobenzyl alcohol, the composition may contain 1-2.5 mg / ml.

[0614] Preferably, after the shear force is removed, the composition has a very fast viscosity recovery rate. "Very fast viscosity recovery rate" means that within 30 seconds after the shear force is removed, the viscosity of the composition recovers to about 90% of its initial viscosity. More preferably, within 10 seconds after the shear force is removed, the viscosity of the composition recovers to about 90% of its initial viscosity. Most preferably, within 5 seconds after the shear force is removed, the viscosity of the composition recovers to about 90% of its initial viscosity. As used herein, the term "initial viscosity" is the viscosity of the composition before the shear force is applied.

[0615] The thixotropic agent may be present in an amount of 0.1-15 wt % of the composition. Preferably, the thixotropic agent may be present in an amount of 0.5-10 wt % of the composition. More preferably, the thixotropic agent may be present in an amount of 0.5-8 wt % of the composition. More preferably, the thixotropic agent may be present in an amount of 1-5 wt % of the composition.

[0616] The thixotropic agent may be selected from a combination of one or more celluloses and one or more alkali metal carboxyalkyl celluloses, carrageenan and xanthan gum. Preferably, the thixotropic agent is selected from a combination of one or more celluloses and one or more alkali metal carboxyalkyl celluloses.

[0617] A preferred combination of cellulose and alkali metal carboxyalkyl cellulose is microcrystalline cellulose and sodium carboxymethyl cellulose. Typically, this combination comprises 85-95% by weight of microcrystalline cellulose and 5-15% by weight of sodium carboxymethyl cellulose. More typically, this combination comprises 86-92% by weight of microcrystalline cellulose and 8-14% by weight of sodium carboxymethyl cellulose.

[0618] Typically, the compositions of the present invention contain at least about 1.5% by weight and up to about 10% by weight of the cellulose / carboxyalkyl cellulose combination to avoid high viscosities that would prevent spraying with conventional equipment. Preferably, the composition will contain about 1.5% by weight to about 5% by weight of the mixture. More preferably, the amount will be about 2.0% by weight to about 3.0% by weight. Most preferably, the composition contains about 2.2% by weight to about 2.8% by weight.

[0619] Typically, when the composition contains 1.5 to 2.4 wt % of the combination of cellulose and alkali metal carboxyalkyl cellulose, the yield point is 2-8.

[0620] Typically, when the composition comprises 2.4 to 3.0 wt% of a combination of cellulose and alkali metal carboxyalkyl cellulose, the yield point is 10-20. More typically, when the composition comprises 2.4 to 3.0 wt% of a combination of cellulose and alkali metal carboxyalkyl cellulose, the yield point is 10-16.

[0621] The solubilizing agent can be present in the composition in an amount of 0.1-15 % by weight. The solubilizing agent can be present in the composition in an amount of 1-10 % by weight. Typically, the solubilizing agent can be present in the composition in an amount of 3-7 % by weight. Typically, the solubilizing agent can be present in an amount of 5-7 % by weight. More typically, the solubilizing agent can be present in an amount of 6 % by weight.

[0622] The solubilizing agent is typically selected from cyclodextrins or combinations thereof. Other solubilizing agents include nonionic surfactants, such as Tween, and propylene glycol.

[0623] The cyclodextrin may be selected from α, β, γ cyclodextrin and derivatives thereof. The cyclodextrin used in the present invention includes natural cyclodextrin and derivatives thereof, including alkylated and hydroxyalkylated derivatives, and branched cyclodextrins, and derivatives with sugar residues are of particular interest. Particularly useful herein are hydroxyethyl, hydroxypropyl (including 2- and 3-hydroxypropyl) and dihydroxypropyl ethers, their corresponding mixed ethers and further mixed ethers with methyl or ethyl, such as methyl-hydroxyethyl, ethyl-hydroxyethyl and ethyl-hydroxypropyl ethers of α, β, γ-cyclodextrin. Specific cyclodextrin derivatives for use herein include α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, methyl-α-cyclodextrin, hydroxyethyl-α-cyclodextrin, hydroxypropyl-α-cyclodextrin, dihydroxypropyl-α-cyclodextrin, methyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, dihydroxypropyl-β-cyclodextrin, methyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, hydroxypropyl-γ-cyclodextrin and dihydroxypropyl-γ-cyclodextrin.

[0624] Preferably, the cyclodextrin comprises more than one cyclodextrin. More preferably, the cyclodextrin comprises 2 cyclodextrins.

[0625] Typically, the molar ratio of cyclodextrin is 1:1 to 1:2 by weight of the composition. Preferably, the molar ratio of cyclodextrin is 1:1.9.

[0626] Alternatively, the molar ratio of cyclodextrin is 1:2.

[0627] The cyclodextrin may include a combination of β-cyclodextrin and hydroxypropyl-β-cyclodextrin.

[0628] The pH of the composition is preferably 6.0-8.0. More preferably, it is 7.0-7.6. Most preferably, the pH is about 7.4.

[0629] The composition may comprise one or more stabilizers. The one or more stabilizers may be selected from ethyl cellulose, hydroxypropyl methyl cellulose and xanthan gum. A preferred stabilizer is xanthan gum.

[0630] The one or more stabilizers may be present in an amount of 0.05-5 wt %. Preferably, the one or more stabilizers are present in an amount of 0.1-1 wt %. More preferably, the one or more stabilizers are present in an amount of 0.15-0.5 wt %.

[0631] The pH of the composition is preferably 6.0-8.0. More preferably, it is 7.0-7.6. Most preferably, the pH is about 7.4.

[0632] The composition may further include one or more buffers. The one or more buffers are selected to ensure that the pH of the composition is about 6.0 to 8.0. Preferably, the one or more buffers are selected to ensure that the pH of the composition is about 7.0 to 7.6. More preferably, one or more buffers are selected to ensure that the pH of the composition is about 7.4.

[0633] The one or more buffers may be present in an amount of 0.1-15 wt%. Preferably, the one or more buffers are present in an amount of 1-5 wt%. More preferably, the one or more buffers are present in an amount of 2-4 wt%.

[0634] Preferably, the one or more buffers are selected from citric acid, disodium hydrogen phosphate, sodium hydrogen phosphate, and combinations thereof.

[0635] Typically, the one or more buffers include citric acid and disodium hydrogen phosphate. More typically, the composition comprises a combination of citric acid and disodium hydrogen phosphate.

[0636] Preferably, the composition comprises 0.1-5 wt% citric acid and 1-10 wt% disodium hydrogen phosphate. More preferably, the composition comprises 0.1-0.5 wt% citric acid and 1-5 wt% disodium hydrogen phosphate.

[0637] The composition may further include other pharmaceutically acceptable excipients selected from sweeteners, anesthetics, flavoring agents, preservatives, pH adjusters and non-ionic buffers.

[0638] The thixotropic composition may be in the form of a solution comprising 1-5% by weight of flurbiprofen or a pharmaceutically acceptable salt thereof, 5-7% by weight of a solubilizer selected from cyclodextrin or a combination thereof, 1.5-5% by weight of a thixotropic agent selected from a combination of one or more celluloses and one or more alkali metal carboxyalkyl celluloses, 0.1-1% by weight of one or more stabilizers selected from ethyl cellulose, hydroxypropyl methylcellulose and xanthan gum, and 1-5% by weight of one or more buffers selected from citric acid, disodium hydrogen phosphate, sodium hydrogen phosphate and a combination thereof, wherein the yield point of the composition is 1-30 Pa. Preferably, the amount of flurbiprofen is 1-2% by weight of the composition.

[0639] In a preferred embodiment, the amount of the thixotropic agent is 2.5-3% by weight of the composition, the amount of the stabilizer is 0.1-0.5% by weight of the composition, the amount of the buffer is 2-4% by weight of the composition, and the yield point of the composition is 10-16 Pa.

[0640] In an alternative embodiment, the amount of flurbiprofen is 1-2% by weight of the composition, the amount of the thixotropic agent is 2-2.4% by weight of the composition, the amount of the stabilizer is 0.1-1% by weight of the composition, the amount of the buffer is 2-4% by weight of the composition, and the yield point of the composition is 2-8 Pa.

[0641] The thixotropic composition may be in the form of a solution, which is essentially composed of the following ingredients: 1-5% by weight of flurbiprofen or a pharmaceutically acceptable salt thereof, 5-7% by weight of a solubilizer selected from cyclodextrin or a combination thereof, 1.5-5% by weight of a thixotropic agent selected from a combination of one or more celluloses and one or more alkali metal carboxyalkyl celluloses, 0.1-1% by weight of one or more stabilizers selected from ethyl cellulose, hydroxypropyl methylcellulose and xanthan gum, and 1-5% by weight of one or more buffers selected from citric acid, disodium hydrogen phosphate, sodium hydrogen phosphate and a combination thereof, wherein the yield point of the composition is 1-30 Pa. In a preferred embodiment, the amount of the thixotropic agent is 2.5-3% by weight of the composition, the amount of the stabilizer is 0.1-1% by weight of the composition, the amount of the buffer is 2-4% by weight of the composition, and the yield point of the composition is 10-16 Pa. In an alternative embodiment, the amount of flurbiprofen is 1-2% by weight of the composition, the amount of the thixotropic agent is 2-2.4% by weight of the composition, the amount of the stabilizer is 0.1-0.5% by weight of the composition, the amount of the buffer is 2-4% by weight of the composition, and the yield point of the composition is 2-8 Pa.

[0642] According to one aspect of the present invention, there is provided a use of the composition comprising a pharmaceutically active ingredient as described in the above aspects for treating sore throat including throat inflammation and pharyngeal irritation.

[0643] The pharmaceutically active ingredient may be selected from NSAIDs or pharmaceutically acceptable salts thereof. Preferred NSAIDs are selected from the group consisting of flurbiprofen, ketoprofen or diclofenac. More preferred NSAID is flurbiprofen.

[0644] Other pharmaceutically active ingredients that may be used are hexylresorcinol, benzocaine, dextromethorphan, menthol lidocaine, amylmetacresol and 2,4-dichlorobenzyl alcohol or pharmaceutically acceptable salts thereof.

[0645] The composition may include up to about 5% by weight of the composition of the NSAID. Typically, the amount of the NSAID is from 0.5% by weight of the composition to 3% by weight of the composition. More typically, the amount of the NSAID is from 1% by weight of the composition to 2% by weight of the composition.

[0646] The NSAID is topically administered at a dose of 1-20 mg. Preferably, the dose is 5-15 mg of the NSAID. More preferably, the dose is 8-10 mg of the NSAID.

[0647] The composition comprises 10-25 mg / ml of NSAID. Preferably, the composition comprises 15-18 mg / ml of NSAID. More preferably, the composition comprises 16-17 mg / ml of NSAID.

[0648] When the active ingredient is selected as hexylresorcinol, the composition may contain 2-5 mg / ml of the active ingredient. When the active ingredient is selected as benzocaine, the composition may contain 10-20 mg / ml. When the active ingredient is selected as dextromethorphan, the composition may contain 15-30 mg / ml. When the active ingredient is selected as menthol, the composition may contain 5-15 mg / ml. When the active ingredient is selected as lidocaine, the composition may contain 2-5 mg / ml. When the active ingredient is selected as amyl metacresol, the composition may contain 0.5-1.5 mg / ml. When the active ingredient is selected as 2,4-dichlorobenzyl alcohol, the composition may contain 1-2.5 mg / ml.

[0649] According to one aspect of the present invention, there is provided a method for producing the composition according to the first aspect, comprising the following steps:

[0650] (a) providing a first liquid composition comprising a pharmaceutically active agent;

[0651] (b) providing a second liquid composition comprising a thixotropic agent; and

[0652] (c) mixing the first composition with the second composition.

[0653] Typically, the first composition is added to the second composition.

[0654] The pharmaceutically active ingredient may be selected from NSAIDs or pharmaceutically acceptable salts thereof. Preferred NSAIDs are selected from the group consisting of flurbiprofen, ketoprofen or diclofenac. More preferred NSAID is flurbiprofen.

[0655] Other pharmaceutically active ingredients that may be used are hexylresorcinol, benzocaine, dextromethorphan, menthol lidocaine, amylmetacresol and 2,4-dichlorobenzyl alcohol or pharmaceutically acceptable salts thereof.

[0656] The first liquid composition may contain up to about 10% by weight of the composition of the NSAID. Typically, the amount of the NSAID is from 1% by weight of the first liquid composition to 6% by weight of the composition. More typically, the amount of the NSAID is from 2% by weight to 4% by weight of the first liquid composition.

[0657] The first composition is formed by combining the pharmaceutically active agent and the solubilizing agent.

[0658] The solubilizing agent is typically selected from cyclodextrins or combinations thereof.

[0659] The solubilizing agent is typically selected from cyclodextrins or combinations thereof. Other solubilizing agents include nonionic surfactants, such as Tween, and propylene glycol.

[0660] The cyclodextrin may be selected from α, β, γ cyclodextrin and derivatives thereof. The cyclodextrin used in the present invention includes natural cyclodextrin and derivatives thereof, including alkylated and hydroxyalkylated derivatives, and branched cyclodextrins, and derivatives with sugar residues are of particular interest. Particularly useful herein are hydroxyethyl, hydroxypropyl (including 2- and 3-hydroxypropyl) and dihydroxypropyl ethers, their corresponding mixed ethers and further mixed ethers with methyl or ethyl, such as methyl-hydroxyethyl, ethyl-hydroxyethyl and ethyl-hydroxypropyl ethers of α, β, γ-cyclodextrin. Specific cyclodextrin derivatives for use herein include α-cyclodextrin, hydroxyethyl-α-cyclodextrin, hydroxypropyl-α-cyclodextrin, dihydroxypropyl-α-cyclodextrin, methyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, dihydroxypropyl-β-cyclodextrin, methyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, hydroxypropyl-γ-cyclodextrin and dihydroxypropyl-γ-cyclodextrin.

[0661] Preferably, the cyclodextrin comprises more than one cyclodextrin. More preferably, the cyclodextrin comprises β-cyclodextrin and hydroxypropyl-β-cyclodextrin.

[0662] The second composition may include a combination of cellulose and an alkali metal carboxyalkyl cellulose.

[0663] For the avoidance of doubt, the term "NSAID" as used herein refers to nonsteroidal anti-inflammatory drugs in free acid form.

[0664] The compositions of the present invention are all water-based compositions.

[0665] As used herein, the term "pharmaceutically acceptable salt" refers to: alkali metal salts (i.e., those elements of Group I of the Periodic Table of Elements), especially sodium or potassium; alkaline earth metal salts (i.e., those elements of Group II of the Periodic Table of Elements), especially calcium or magnesium; other metal salts, such as aluminum salts; amino acid salts, such as lysine salts or arginine salts; or amine salts, such as melamine salts.

[0666] As used herein, the term "thixotropic" is used to describe one or more agents, such as certain gels or viscous liquids, that thin when subjected to a vibratory force such as simple shaking, and then thicken again when left standing. Thixotropic behavior is observed when long-chain molecules tend to orient themselves in the direction of flow; as the applied force increases, the resistance to flow decreases. However, when the high shear stress is removed, the solution quickly returns to its original viscous state.

[0667] A sprayable composition according to the invention is a composition which can be applied to the mucosal surfaces of the throat / pharynx area in the form of a fine droplet spray.

[0668] The terms "solubilizing agent", "solubilizing agent" and "solubilizing agent" have the same meaning.

[0669] As used herein, terms such as "preferably", "more preferably", "most preferably", "typically", "more typically" and "most typically" indicate preferred features of the compositions of the present invention.

[0670] As used herein, "about" means within a range of + / - 10% of a given value or number.

[0671] Viscosity measurements were performed at room temperature (25°C) using a Discovery Series Hybrid Rheometer equipped with a 40 mm cross-hatch plate measuring system with a gap set to 300 μm during analysis. A solvent trap cap was used to minimize drying of the sample at the exposed edge. After a 30 s equilibration time at room temperature (25°C), the samples were exposed to -1 Up to 15000s -1 A shear rate ramp scan was performed, logarithmically scaled, with 8 points per decade of shear rate, 30 s of shear was applied at each rate, and the viscosity was calculated over the last 5 s of each step.

[0672] The yield point is the stress point at which the product begins to flow and its viscosity decreases. The yield point is measured using a Discovery Series Hybrid Rheometer equipped with a 40 mm cross-hatch plate measuring system, with the gap set to 300 μm during analysis. A solvent trap cap is used to minimize drying of the sample on the exposed edge. After a 60 second equilibration time at room temperature (25°C), a shear stress sweep from 0.1 Pa to 100 Pa is applied to the sample, logarithmically spaced, with 8 points per decade of shear stress.

[0673] Steady-state sensing is employed to ensure that individual viscosity readings have reached an acceptable degree of elastic or thixotropic equilibrium before being recorded. At each step of the test, viscosity is monitored every 10 seconds. Viscosity is recorded only if 3 consecutive measurements are within 5% of each other. A 60 second timeout is set: if equilibrium viscosity is not reached after this time, the viscosity at that moment is recorded regardless of the degree of equilibrium.

[0674] Rheological experiments were performed using a Kinexus rheometer using parallel plates to determine the recovery of the initial viscosity of the composition. The measurements were performed at room temperature (25°C). A three-step shear test was performed. In the three-step shear test, the sample was subjected to a shear test at 0.1 s. -1 The low shear rate was exposed for 60 s, followed by 100 s -1 The high shear rate, finally at 0.1s -1 The samples were exposed to low shear rate for 10 min. BRIEF DESCRIPTION OF THE DRAWINGS

[0675] The present invention will now be described in more detail with reference to the following examples and accompanying drawings, in which:

[0676] Figure 1 The retention curves for the exemplary compositions of the present invention, the lozenges and the control composition when the profile is 45° are illustrated.

[0677] Figure 2 The retention curves for the exemplary compositions of the present invention, the lozenges and the control compositions when the model is 30° are illustrated.

[0678] Figure 3 The corresponding areas under the curves calculated from the retention curves for each composition are shown.

[0679] Figure 4 The effect of shear rate on viscosity of exemplary embodiments of the compositions of the present invention and deionized water are illustrated.

[0680] Figure 5 The relative mucoadhesive properties of the compositions of the present invention when measured at low shear rates are illustrated. DETAILED DESCRIPTION

[0681]

[0682] Preparation method

[0683] The composition as described in Example 1 or Example 2 can be prepared in the following manner. Prepare an aqueous sodium hydroxide solution. In addition, an aqueous mixture of flurbiprofen, disodium hydrogen phosphate, hydroxypropyl-β-cyclodextrin, β-cyclodextrin, citric acid, methylparaben and propylparaben is also prepared. The aqueous sodium hydroxide solution is added to the aqueous mixture containing flurbiprofen under cooling to form a premix solution. In a separate container, a combination of microcrystalline cellulose and sodium carboxymethyl cellulose is added to water. The mixture is homogenized before the premix solution is added, while maintaining the stirring of the homogenized mixture. The resulting product can now be distributed into suitable storage containers.

[0684] In Examples 3 and 4, xanthan gum was added to the aqueous combination of microcrystalline cellulose and sodium carboxymethyl cellulose.

[0685] The retention curves of embodiments of the compositions of the present invention are examined using a device for measuring adhesion on mucosal tissue. The model includes a slope to which a cellulose membrane is applied. The cellulose membrane is hydrated in an aqueous mixture containing mucin to simulate the surface of the throat. A sample of the thixotropic composition of the present invention is applied to the membrane. The membrane is then washed continuously with artificial saliva for 30 minutes. Samples are collected periodically. Each eluted sample is tested to determine how much of the composition is retained on the slope.

[0686] Figure 1 The retention of the composition on the model inclined surface when the angle is 45° is illustrated. This angle was chosen to simulate the application of the composition to the individual while awake. The results are shown in Table 1.

[0687] Table 1 - Awakening Model

[0688]

[0689] Figure 2 The retention of the composition on the model slope is illustrated when the angle is 30°. This angle was chosen to simulate the application of the composition to the individual while sleeping. The results are shown in Table 2.

[0690] Table 2 - Sleep Model

[0691]

[0692] from Figure 1 and Figure 2 As can be seen from the results, these compositions were retained on the model slopes for significantly longer periods of time compared to the tablets. Figure 3 As can be seen from the "Area Under the Curve" graph shown, the flurbiprofen in the composition is able to provide a longer local effect on the throat surface.

[0693] The results obtained using this model indicate that the composition remains on the mucosal tissue despite the effects of gravity due to its high viscosity, which is due to its gel-like nature at rest due to its high molecular weight, and also due to hydrogen bonding and ionic attractions between the composition and the mucosal surface.

[0694] In addition, mucoadhesion studies were performed on the compositions of the present invention. Mucin solutions were used to replicate / simulate the mucosal surface of the throat / pharynx region. Samples were prepared as follows:

[0695] A mucin solution was prepared using deionized water and porcine gastric mucin (II). The solution was prepared at a concentration of 10%, the pH was adjusted to 6.2 using 0.5 M NaOH solution, and then diluted with deionized water to a final concentration of 6% before use. 3 g of the prepared mucin solution was mixed with an equal weight of the sample to be tested to obtain a final mucin concentration of 3% (w / w). For control samples, the mucin solution and the sample to be studied were diluted to 50% (w / w) of their initial concentration using deionized water. All samples were prepared in duplicate and equilibrated overnight at 5°C before any analysis.

[0696] Mucoadhesion studies Testing was performed on a research rheometer (DHR2, TA Instruments) equipped with a 60 mm aluminum plate measuring system with a gap set to 200 μm during analysis. A solvent trap cap was used to minimize drying of the sample at the exposed edge.

[0697] Mucoadhesion studies were performed to identify rheological changes indicative of synergistic interactions between the compositions of the invention and the mucin solution. These changes were identified and quantified by measuring viscosity at low and high shear rates.

[0698] The example compositions were analyzed alone and when mixed with the prepared mucin solution. Zero shear viscosity (η o ) is the ideal target for the example composition; it is believed that this zero shear viscosity provides a suitable indicator of the product's in situ behavior. This is input into the following two equations to give the "rheological synergy parameter" Δη o and Δη o / η o .

[0699] Δη o =η o(混合) -(η o(样品) +η o(粘蛋白) )

[0700] Δη o / η o +1, where η o =η o(样品) +η o(粘蛋白)

[0701] Δη o is the difference between the actual viscosity of the composition mixed with mucin and the theoretical value; the theoretical value is defined as the η of the sample and mucin when analyzed separately. o The sum of the values. o / η o +1 describes the relative rheological synergy, which represents the η relative to the individual samples and mucin. o relative increase.

[0702] Values ​​greater than 1 indicate some interaction with mucin; for example, a value of 2 would mean that the measured viscosity of a sample mixed with mucin was twice as high as expected.

[0703] The results for the tested compositions are shown in Table 3.

[0704] Table 3

[0705]

[0706] Figure 5 Results obtained at low shear rates are illustrated.

[0707] The composition contains a variety of functional groups that can form hydrogen bonds. The presence of these groups promotes strong interactions with the surface of the throat mucosa, allowing the composition to remain on the throat mucosal tissue for a longer period of time. In addition, since the gel matrix is ​​not easily washed away by saliva due to its structure, the attraction between the composition and the mucosal surface has more time to form. This increases the contact time of the active ingredient with the throat, enhancing the local effect and efficacy.

[0708] from Figure 4 It can be seen that when shear or stress is applied to the composition of the present invention, the viscosity decreases. A higher rate of shear / stress results in a composition having a lower viscosity. After the shear / stress is removed, the viscosity of the composition returns to its initial viscosity, confirming that the composition exhibits shear-thinning or thixotropic behavior.

[0709] The present invention has the advantage of providing a composition which has sufficient viscosity to remain on the throat surface for a sufficient period of time so that the active ingredient contained therein exhibits a local effect, but which, upon application of shear forces, can be converted into a sprayable composition which can be applied to the inflamed / infected area of ​​the throat surface with a high degree of accuracy.

[0710] Further modifications of the present invention may be made without departing from the scope of the invention described herein.

Claims

1. A composition in the form of a solution, comprising: (a) 1-5% NSAID; (b) 0.1-15% of a combination of cellulose and alkali metal carboxyalkyl cellulose; and (c) 0.1-15% of one or more cyclodextrins.

2. The composition according to claim 1, wherein The composition comprises: (a) 1-5% NSAID; (b) 1-5% of a combination of cellulose and alkali metal carboxyalkyl cellulose; (c) 1-15% of one or more cyclodextrins; (d) 0.1-10% of one or more pH adjusting agents; and (e) 0.1-15% of one or more buffering agents.

3. The composition according to claim 1 or 2, wherein The composition comprises: (a) 1-5% NSAID; (b) 1-5% of a combination of cellulose and alkali metal carboxyalkyl cellulose; (c) 1-15% of one or more cyclodextrins; (d) 0.1-10% of one or more pH adjusting agents; (e) 0.1-15% of one or more buffering agents; and (f) 0.05-5% of one or more stabilizers.

4. The composition according to claim 1, wherein The composition comprises: (a) 1-2% flurbiprofen; (b) 2-4% of a combination of cellulose and alkali metal carboxyalkyl cellulose; and (c) 5-7% of one or more cyclodextrins.

5. The composition according to claim 4, wherein The composition comprises: (a) 1-2% flurbiprofen; (b) 2-4% of a combination of cellulose and alkali metal carboxyalkyl cellulose; (c) 5-7% of one or more cyclodextrins; (d) 0.1-0.5% of one or more pH adjusting agents; and (e) 2-4% of one or more buffering agents.

6. The composition according to claim 4 or 5, wherein The composition comprises: (a) 1-2% flurbiprofen; (b) 2-4% of a combination of cellulose and alkali metal carboxyalkyl cellulose; (c) 5-7% of one or more cyclodextrins; (d) 0.1-5% of one or more pH adjusting agents; (e) 2-4% of one or more buffering agents; and (f) 0.1-3% of one or more stabilizers.

7. The composition of claim 3, wherein The composition consists essentially of the following ingredients: (a) 1-5% flurbiprofen; (b) 1-5% of a combination of cellulose and alkali metal carboxyalkyl cellulose; (c) 1-15% of one or more cyclodextrins; (d) 0.1-10% of one or more pH adjusting agents; and (e) 0.1-15% of one or more buffering agents.

8. The composition of claim 3, wherein The composition consists essentially of the following ingredients: (a) 1-5% flurbiprofen; (b) 1-5% of a combination of microcrystalline cellulose and sodium carboxymethyl cellulose; (c) 1-15% of a combination of β-cyclodextrin and hydroxypropyl-β-cyclodextrin; (d) 0.1-5% sodium hydroxide; (e) 1-10% disodium hydrogen phosphate; and (f) 0.1-5% citric acid monohydrate.

9. The composition of claim 5, wherein The composition consists essentially of the following ingredients: (a) 1-2% flurbiprofen; (b) 2-4% of a combination of cellulose and alkali metal carboxyalkyl cellulose; (c) 5-7% of one or more cyclodextrins; (d) 0.1-0.5% of one or more pH adjusting agents; and (e) 2-4% of one or more buffering agents.

10. The composition according to claim 6, wherein The composition consists essentially of the following ingredients: (a) 1-2% flurbiprofen; (b) 2-4% of a combination of cellulose and alkali metal carboxyalkyl cellulose; (c) 5-7% of one or more cyclodextrins; (d) 0.1-5% of one or more pH adjusting agents; (e) 2-4% of one or more buffering agents; and (f) 0.1-0.3% of one or more stabilizers.

11. The composition according to claim 5, wherein The composition consists essentially of the following ingredients: (a) 1-2% flurbiprofen; (b) 2-4% combination of microcrystalline cellulose and sodium carboxymethyl cellulose; (c) 5-7% of a combination of β-cyclodextrin and hydroxypropyl-β-cyclodextrin; (d) 0.1-5% sodium hydroxide; (e) 1-10% disodium hydrogen phosphate; and (f) 0.1-5% citric acid monohydrate.

12. The composition of claim 5, wherein The composition consists essentially of the following ingredients: (a) 1-2% flurbiprofen; (b) 2-4% combination of microcrystalline cellulose and sodium carboxymethyl cellulose; (c) 5-7% of a combination of β-cyclodextrin and hydroxypropyl-β-cyclodextrin; (d) 0.1-5% sodium hydroxide; (e) 1-10% disodium hydrogen phosphate; (f) 0.1-5% citric acid monohydrate; and (g) 0.1-0.3% xanthan gum.

13. A thixotropic composition in the form of a solution, comprising 1-5 wt% of flurbiprofen or a pharmaceutically acceptable salt thereof, 5-7 wt% of a solubilizing agent selected from cyclodextrin or a combination thereof, 1.5-5 wt% of a thixotropic agent selected from a combination of one or more celluloses and one or more alkali metal carboxyalkyl celluloses, 0.1-1 wt% of one or more stabilizers selected from ethyl cellulose, hydroxypropyl methyl cellulose and xanthan gum, 1-5 wt% of one or more buffers selected from citric acid, disodium hydrogen phosphate, sodium hydrogen phosphate and a combination thereof, and 0.1-1 wt% of one or more pH adjusters, wherein: The composition has a low shear viscosity of 30-80 Pascal seconds (Pa.s) and a high shear viscosity of 0.01-5 Pascal seconds (Pa.s).

14. The composition of claim 13, wherein The amount of flurbiprofen is 1-2% by weight of the composition, the amount of the thixotropic agent is 2-3% by weight of the composition, the amount of the stabilizer is 0.1-1% by weight of the composition, the amount of the buffer is 2-4% by weight of the composition, the amount of the pH adjuster is 0.2-0.5% by weight of the composition, and the high shear viscosity of the composition is 0.1 Pascal seconds (Pa.s) to 1 Pascal seconds (Pa.s), and the low shear viscosity is 50 Pascal seconds (Pa.s) to 60 Pascal seconds (Pa.s).

15. The composition according to claim 13 or 14, wherein The composition is in the form of a solution, which is essentially composed of the following ingredients: 1-5% by weight of flurbiprofen or a pharmaceutically acceptable salt thereof, 5-7% by weight of a solubilizer selected from cyclodextrin or a combination thereof, 1.5-7% by weight of a thixotropic agent selected from a combination of one or more celluloses and one or more alkali metal carboxyalkyl celluloses, 0.1-1% by weight of one or more stabilizers selected from ethyl cellulose, hydroxypropyl methylcellulose and xanthan gum, 1-5% by weight of one or more buffers selected from citric acid, disodium hydrogen phosphate, sodium hydrogen phosphate and a combination thereof, and 0.1-1% by weight of one or more pH adjusters, wherein the low shear viscosity of the composition is 30-80 Pascal seconds (Pa.s) and the high shear viscosity is 0.01-5 Pascal seconds (Pa.s).

16. The composition of any one of claims 13 to 15, wherein The thixotropic composition is in the form of a solution, which is essentially composed of the following ingredients: 1-2 weight % of flurbiprofen or a pharmaceutically acceptable salt thereof, 5-7 weight % of a solubilizer selected from cyclodextrin or a combination thereof, 2-4 weight % of a thixotropic agent selected from a combination of one or more celluloses and one or more alkali metal carboxyalkyl celluloses, 0.1-0.5 weight % of one or more stabilizers selected from ethyl cellulose, hydroxypropyl methylcellulose and xanthan gum, 2-4 weight % of one or more buffers selected from citric acid, disodium hydrogen phosphate, sodium hydrogen phosphate and a combination thereof, and 0.1-1 weight % of one or more pH adjusters, wherein the low shear viscosity of the composition is 50-60 Pascal seconds (Pa.s) and the high shear viscosity is 0.1-1 Pascal seconds (Pa.s).

17. Use of the composition of any one of claims 1 to 16 in the preparation of a medicament for treating sore throat including pharyngitis and pharyngeal irritation.

Images