Topical analgesic cream composition and method of preparation thereof

Abstract

The present invention relates to a pharmaceutical topical analgesic cream composition comprising Mefenamic acid, counterirritants, soothing agent, oil or combination thereof and other pharmaceutically acceptable excipients. The present invention relates to the process for the preparation of pharmaceutical topical analgesic cream composition. Moreover, a topical analgesic cream composition is used in the management of pain in conditions such as osteoarthritis and rheumatoid arthritis.

Description

[0001]

[0002] TOPICAL ANALGESIC CREAM COMPOSITION AND METHOD OF PREPARATION THEREOF

[0003] RELATED DATA

[0004] The present application claims the benefit of priority to the Indian Provisional Patent application no. 202521000790 filed on Jan 3, 2025 and the entire provisional specification.

[0005] FIELD OF INVENTION

[0006] The present invention relates to pharmaceutical topical composition and the method of preparation thereof. It also relates to pharmaceutical topical composition comprises therapeutically effective amount of mefenamic acid and acceptable salt thereof and other pharmaceutically acceptable excipients thereof. It also relates to pharmaceutical topical composition comprises therapeutically effective amount of mefenamic acid and other pharmaceutically acceptable excipients thereof. It also relates to pharmaceutical topical composition comprises mefenamic acid, methyl salicylate, menthol, linseed oil and combination thereof. It also relates to pharmaceutical topical composition comprises mefenamic acid, methyl salicylate, menthol, linseed oil and other pharmaceutically acceptable excipients thereof. Particularly, the present invention relates to the pharmaceutical topical analgesic cream composition used in the management of pain associated with osteoarthritis and rheumatoid arthritis.

[0007] BACKGROUND OF INVENTION

[0008] Rheumatoid arthritis (RA) is nothing but a chronic inflammatory disorder / disease that affects the synovium, harms bones and joints, raises mortality rates, and significantly impairs people's quality of life. The predicted survival for patients of RA is projected to reduce by 3 to 10 years due to greater mortality linked with rheumatoid arthritis and osteoarthritis. RA is considered as a very complex disease because of the interaction of the genetic and also environmental factors that affect its occurrence and manifestation. Mefenamic acid is a well-known non-steroidal anti-inflammatory drug that exerts its therapeutic action by inhibiting cyclooxygenase enzymes COX-1 and COX-2, thereby suppressing prostaglandin synthesis responsible for pain and inflammation. Although effective, mefenamic acid belongs to Biopharmaceutics Classification System (BCS) Class II, exhibiting poor

[0009]

[0010] aqueous solubility and high permeability, which limits its dissolution and bioavailability when administered orally.

[0011] Oral administration of mefenamic acid is further associated with significant drawbacks, including first-pass hepatic metabolism, gastrointestinal irritation, ulceration, and systemic adverse effects, particularly with long-term use in chronic inflammatory conditions. These limitations create a clear need for an alternative delivery system that can provide effective pain relief while minimizing systemic exposure and gastrointestinal complications.

[0012] Topical drug delivery offers a targeted and patient-friendly approach by delivering the active agent directly to the affected site, bypassing first-pass metabolism and reducing systemic side effects. Due to its high permeability, mefenamic acid is particularly suitable for topical administration, allowing efficient penetration into synovial joints and inflamed tissues where therapeutic action is required.

[0013] IN2754 / MUM / 2009 discloses a topical anti-inflammatory formulation comprising a myorelaxant in combination with rubefacient and a counter-irritating agent; IN879 / MUM / 2004 discloses a gel formulations comprising etoricoxib either alone or in combination with methyl salicylate useful for the treatment of painful inflammatory joint diseases like osteoarthritis (OA), rheumatoid arthritis, peri-arthritis, tennis elbow, frozen shoulder, etc.; JPS63287721A discloses an anti-inflammatory analgesic gel agent containing mefenamic acid. It is disclosed a transdermal administration; Indian Drugs, 2023, Vol 60, Issue 1, p33 discloses the Mefenamic acid (MA) topical cream, which would reduce the gastrointestinal associated toxicities related to oral administration; Saudi Pharm J. 2011 Aug 22;20(l):63-67, discloses the topical emulgel of mefenamic acid possess an effective anti-inflammatory and analgesic activity; Nov Appro Drug Des Dev 6(3): NAPDD.MSJD.555690 (2022) discloses the topical emulgel of mefenamic acid possess an effective anti-inflammatory and antinociceptive activity; Drug Deliv, 2016; 23(9): 3573- -3581 discloses the formulation and evaluation of novel controlled release of topical pluronic lecithin organogel of mefenamic acid. There are several prior arts discloses the formulation of mefenamic acid, but none of the prior art discloses the stable topical analgesic cream composition.

[0014] Thus, the inventors of the present invention have successfully addressed the existing drawbacks and formulated a topical analgesic cream formulation. The aim of the present invention is to successfully formulate a topical analgesic cream formulation of Mefenamic acid, methyl salicylates, menthol, linseed oil or combination thereof and pharmaceutically acceptable excipients. To

[0015]

[0016] summarize, the inventors of the present invention have formulated topical analgesic cream composition which provides valuable insights for advancing topical drug delivery systems, enhancing stability, economical and cost-effective preparation process.

[0017] OBJECTIVE OF INVENTION

[0018] An objective of the invention is to formulate topical analgesic cream composition comprising mefenamic acid and atleast one pharmaceutically acceptable excipient.

[0019] Another object of the invention is to formulate topical analgesic cream composition comprising mefenamic acid, counterirritant, cooling agent, oil and combination thereof.

[0020] Another object of the invention is to formulate topical analgesic cream composition comprising pharmaceutically effective amount of mefenamic acid, linseed oil and methyl salicylate, menthol and pharmaceutically acceptable excipient thereof.

[0021] Another object of the invention is to overcome the stability challenge of topical analgesic cream composition comprising mefenamic acid.

[0022] Yet another object of the invention is to formulate topical analgesic cream composition by an easy scalable method.

[0023] SUMMARY OF THE INVENTION

[0024] The present invention relates to developing a pharmaceutical topical composition comprising mefenamic acid and pharmaceutically acceptable salt thereof. The present invention relates to developing a pharmaceutical topical composition comprising mefenamic acid and atleast one pharmaceutically acceptable excipient. The invention further relates to the pharmaceutical topical composition comprising mefenamic acid, methyl salicylates, menthol, linseed oil, and pharmaceutically acceptable excipients.

[0025]

[0026] The present invention relates to the process for preparation pharmaceutical topical cream composition comprising mefenamic acid and pharmaceutically acceptable salt thereof. The invention further relates to the process for preparation pharmaceutical topical cream composition comprising mefenamic acid and atleast one pharmaceutically acceptable excipients. Particularly, the present invention relates to the Industry feasible process for preparation pharmaceutical topical cream composition comprising mefenamic acid, methyl salicylates, menthol, linseed oil, and atleast one pharmaceutically acceptable excipients.

[0027] Moreover, the invention is related to the pharmaceutical topical analgesic cream composition of mefenamic acid and atleast one pharmaceutically acceptable excipient used in the management of pain. More particularly, the invention relates to the pharmaceutical topical analgesic cream composition comprising mefenamic acid, methyl salicylates, menthol, linseed oil and combination thereof. The invention relates to the pharmaceutical topical analgesic cream composition comprising mefenamic acid, methyl salicylates, menthol, linseed oil and atleast one pharmaceutically acceptable excipient used in the management of pain associated with osteoarthritis and rheumatoid arthritis.

[0028] DESCRIPTION OF THE DRAWINGS:

[0029] For a more complete understanding of the invention, reference should now be made to the embodiments illustrated in greater detail in the accompanying drawings and described by way of embodiments of the invention.

[0030] Figure 1 : Illustrates Graph of Square root of Time Vs Drug released (pg) / cm2i.e., Cumulative release of (a) Mefenamic acid, (b) Methyl salicylate and (c) Menthol;

[0031] Figure 2: Illustrates anti-inflammatory activity (a) 2 hrs, (b) 4 hrs, (c) 6 hrs, and (d) 8 hrs;

[0032] Figure 3: Illustrates analgesic activity (a) 0 min, (b) 30 min, (c) 60 min, (d) 90 min, and (e) 120 min; and

[0033] Figure 4: Illustrates histopathology of skin (Application Site)

[0034] (Where, NC - Normal Control, HD - High Dose, M - Male, F - Female).

[0035] DETAILED DESCRIPTION OF THE INVENTION

[0036] In describing the embodiment of the invention, specific terminology is chosen for the sake of clarity. However, it is not intended that the invention be limited to the specific terms so selected and

[0037]

[0038] it is to be understood that such specific terms include all technical equivalents that operate in a similar manner to accomplish a similar purpose. As used herein, reference to an element by the indefinite article “a” or “an” does not exclude the possibility that more than one of the elements is present, unless the context clearly requires that there is one and only one of the elements. The disclosure of numerical ranges should be understood as referring to each discrete point within the range, inclusive of endpoints, unless otherwise noted.

[0039] The terms and words used in the following description are not limited to the bibliographical meanings, but, are merely used to enable a clear and consistent understanding of the disclosure. Accordingly, it should be apparent to those skilled in the art that the following description of exemplary embodiments of the present disclosure are provided for illustration purpose only and not for the purpose of limiting the disclosure as defined by the appended claims and their equivalents. Features that are described and / or illustrated with respect to one embodiment may be used in the same way or in a similar way in one or more other embodiments and / or in combination with or instead of the features of the other embodiments.

[0040] The therapeutically effective amount administered to the patient, e.g., a mammal, particularly a human, in the context of the present invention should be sufficient to affect a therapeutic or prophylactic response in the patient over a reasonable time frame. The dose can be readily determined using methods that are well known in the art. One skilled in the art will recognize that the specific dosage level for any particular patient will depend upon a variety of potentially therapeutically relevant factors.

[0041] The term "subject" includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife).

[0042] The term “topical administration” is used in its conventional sense to mean delivery of an active agent to a body surface, such as, the skin, as in, for example, topical drug administration in the prevention or treatment of various skin disorders, the application of cosmetics (including moisturizers,

[0043]

[0044] masks, sunscreens, etc.), and the like. Topical administration, in contrast to transdermal administration, provides a local rather than a systemic effect.

[0045] The term "Treating" or "treatment" of a disease includes (1) preventing the disease from occurring in subject that may be predisposed to the disease but does not yet experience or display symptoms of the disease, (2) inhibiting the disease, i.e., arresting its development, or (3) relieving the disease, i.e., causing regression of the disease.

[0046] The term “Counterirritants” are defined by the US Food and Drug Administration as an externally applied substance that causes irritation or mild inflammation of the skin for the purpose of relieving pain in muscles or joints by reducing inflammation in deeper adjacent structures.

[0047] "Pharmaceutically acceptable excipient" or "excipient" includes, but is not limited to, a combination of drug compound of the present invention to produce a dosage form for topical administration. Any inert material that is combined is included. The term "pharmaceutically acceptable excipient" refers to a pharmacologically active ingredient by a regulatory authority; including but not limited to any emollient / stiffening agent / ointment base, emulsifying agent / solubilizing agent, humectant, thickening / gelling agent, preservative, permeation enhancer, chelating agent, antioxidant, acidify ing / alkalizing / buffering agent, vehicle / solvent, protective agent, buffer, adjuvant, bioavailability promoter carriers, solubilizers (including surfactants), oils, creaming agents, wetting agents, cooling / soothing agent, dispersants, suspending agents and stabilizers shall be included.

[0048] "Pharmaceutical composition" of the present invention refers to a cream composition of mefenamic acid and salt thereof, a vehicle generally accepted in the art for topical administration of the combination of drug compound to a mammal, e.g., a human. Such a medium includes all pharmaceutically acceptable excipients. For the purposes of this disclosure, the phrase "pharmaceutical composition" is interchangeable with the phrase "pharmaceutical formulation".

[0049]

[0050] An analgesic agent, also known as a painkiller or pain reliever, is a medication that reduces pain without altering consciousness or sensory awareness. Analgesics can be classified as opioids or non-opioids, such as nonsteroidal anti-inflammatory drugs.

[0051] While the invention has been described with reference to an exemplary embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from the essential scope thereof. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims. Any combination of the above described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[0052] In one embodiment the invention provides the topical composition, comprising pharmaceutically effective amount of mefenamic acid, and atleast one pharmaceutically acceptable excipient thereof.

[0053] In another embodiment the invention provides the topical composition, comprising mefenamic acid in the range of 1 to 5%w / w, preferably 1 to 3%w / w, more preferably l%w / w based on the total weigh of topical composition and atleast one pharmaceutically acceptable excipient thereof.

[0054] In another embodiment the invention provides the topical composition, comprising pharmaceutically effective amounts of mefenamic acid, oil, counterirritant, soothing agent or combination thereof and pharmaceutically acceptable excipient thereof.

[0055] In another embodiment the invention provides the topical composition, comprising mefenamic acid, oil, counterirritant, soothing agent are present in the ratio of 1 : 3 : 11 : 6, In an embodiment, ratio is 1 : 3 : 11 : 5.25.

[0056]

[0057] In another embodiment, wherein oils are selected from but not limited to linseed oil, cod-liver oil, castor oil, Polyoxyl 40 Hydrogenated castor oil and combination thereof. The oils are present in the range of 3 to 6% w / w.

[0058] In another embodiment, wherein counterirritant is selected from but not limited to methyl salicylate, capsaicin, camphor, menthol and combination thereof. The counterirritants are present in the range of 9 to 12% w / w.

[0059] In another embodiment, wherein cooling or soothing agent is selected from but not limited to peppermint oil, eucalyptus oil, camphor oil, menthol and combination thereof. The cooling / soothing agent is present in range of 4 to 6 % w / w.

[0060] In another embodiment, the invention provides the topical composition, comprising pharmaceutically effective amounts of mefenamic acid, linseed oil, methyl salicylate, menthol and pharmaceutically acceptable excipient thereof.

[0061] In another embodiment, the invention provides the topical composition, comprising 1 to 5% w / w of mefenamic acid, 9 to 12% w / w of methyl salicylate, 3 to 6% w / w of linseed oil, 4 to 6% w / w menthol and pharmaceutically acceptable excipient thereof.

[0062] In another embodiment, wherein other pharmaceutically acceptable excipients are selected from creaming agent, emollients, chelating agents, preservatives, solvents, surfactant, and combination thereof.

[0063] In one embodiment, creaming agents are polymers selected from, but not limited to, Sepineo P600 (Polymer 600) (Acrylamide / Sodium Acryloyldimethyl Taurate Copolymer / Isohexadecane & Polysorbate 80), Sepineo PHD 100 (Polymer Hydro Dispersible 100), Sepineo SE 68 (Self-Emulsifying Polymer 68), Sepineo D.E.R.M (Dermal Emulsion Resilient Matrix) and combination thereof. The creaming agents are present in the range of 3 to 5%w / w.

[0064]

[0065] In another embodiment, wherein chelating agents are selected from, but not limited to, Disodium EDTA (Ethylene Diamine Tetraacetic Acid), Edetate Calcium Disodium (CaNa2EDTA), Edetic Acid (EDTA), Citric Acid (CA), Diethylenetriaminepentaacetic Acid (DTP A), Dimercaprol and combination thereof. The chelating agents are present in the range of 0.03 to 0.06% w / w.

[0066] In another embodiment, wherein preservatives are selected from but not limited to Butylated hydroxytoluene (BHT), methylparaben, propylparaben and combination thereof. The preservatives are present in the range of 0.04 to 0.15% w / w.

[0067] In another embodiment, wherein surfactants are selected from, but not limited to, Tween 80 (Polysorbate 80), Tween 20 (Polysorbate 20), Tween 21 (Polysorbate 21), Tween 40 (Polysorbate 40), Tween 60 (Polysorbate 60), Tween 65 (Polysorbate 65), Tween 85 (Polysorbate 85), Sodium Lauryl Sulfate (SLS), Ammonium Laureth Sulfate (ALS), Cocamidopropyl Betaine (CAPB), Disodium Lauryl Sulfosuccinate (DLSS), Alpha-Olefin Sulfonate (AOS), Cetyl Alcohol (CA), Stearyl Alcohol (SA) and combination thereof. The surfactant present in the range of 6 to 7% w / w.

[0068] In another embodiment, wherein emollient is selected from but not limited to Iso -propyl myristate (IPM), petroleum jelly, lanolin, hyaluronic acid, propylene glycol, and glycerin and is present in 2 to 4% w / w.

[0069] In another embodiment, wherein solvents are purified water (p / w), propylene glycol, and benzyl alcohol or combination thereof.

[0070] In another embodiment, the invention provides a topical composition, comprising Mefenamic acid is present in the range of 1 to 5% w / w; Creaming agent is Sepineo P600 (Polymer 600) and is present in the range of 3 to 5 %w / w; Methyl Salicylate is present in the range of 9 to 12% w / w; Cooling / Soothing agent is menthol present in the range of 4 to 6 %w / w; linseed oil present in the range of 3 to 6% w / w; surfactants are present in the range of 4 to 6% w / w; chelating agent is Disodium EDTA and is present in the range of 0.03 to 0.06% w / w; emollient is selected from Iso-propyl

[0071]

[0072] myristate (IPM) and is present in 3% w / w; preservatives are present in the range of 0.04 to 0.15% w / w; propylene Glycol present in the range of 6 to 7% w / w; Benzyl Alcohol is in 1 % w / w; and Purified water present in the range of 15 to 21% w / w.

[0073] In another embodiment, the invention provides a topical composition, comprising:

[0074] i. Mefenamic acid in the range of 1 to 5%w / w;

[0075] ii. Creaming agent is Sepineo P600 (Polymer 600) is present in the range of 3 to 5 %w / w;

[0076] iii. Counterirritant is Methyl Salicylate is present in the range of 9 to 12% w / w; iv. Cooling agent is menthol present in the range of 4 to 6 %w / w;

[0077] v. Oil is linseed oil present in the range of 3 to 6% w / w;

[0078] vi. Surfactants is tween 80 and is present in the range of 4 to 6% w / w;

[0079] vii. Chelating agent is Disodium EDTA and is present in the range of 0.03 to 0.06% w / w; viii. Emollient is selected from Iso-propyl myristate (IPM) is present in the range of 2 to 4% w / w;

[0080] ix. Preservatives are present in the range of 0.02 to 0.15% w / w;

[0081] x. Propylene Glycol present in the range of 6 to 7% w / w;

[0082] xi. Benzyl Alcohol is present in the range of 1 to 1.5% w / w;

[0083] xii. Cod liver oil in present in the range of 10 to 12%w / w;

[0084] xiii. Polyoxyl 40 hydrogenated castor oil is present in the range of 4 to 6%w / w; and xiv. Purified water present in the range of 15 to 21% w / w.

[0085] In another embodiment, the topical pharmaceutical composition may be formulated as, but is not limited to, a cream, gel, ointment, lotion, emulsion, microemulsion, nanoemulsion, paste, foam, spray, solution, suspension, liniment, balm, roll-on formulation, patch, or combinations thereof. In preferred embodiments, the topical pharmaceutical composition formulated as cream.

[0086] In another embodiment, pH of the topical pharmaceutical composition as described herein is in the range of 4.5 to 6.5.

[0087]

[0088] In another embodiment, the mean release rate was found to be 712.97 pg / cm2 / h and the cumulative drug release for Mefenamic acid 83.97%. Particularly, the mean release rate for Mefenamic acid was found to be 4653.95 pg / cm2 / h. and the cumulative drug release was 58.02%. More particularly, the mean release rate for Mefenamic acid was found to be 4718.07 pg / cm2 / h and the cumulative drug release was 90.31%.

[0089] In another embodiment, the present invention provides a process for preparing a topical analgesic cream composition, comprising:

[0090] (a) cream phase is prepared by addition of disodium EDTA into purified water, and dissolving the same under continuous stirring. Sepineo™ P600 is thereafter added to the said mixture under continuous stirring to obtain a thick cream base. Isopropyl myristate is subsequently added to the thick cream base under continuous stirring to form a homogeneous cream phase.

[0091] (b) preservative phase is prepared separately by taking propylene glycol in a suitable container and heating the same to a temperature in the range of about 60 °C to 70 °C. Methylparaben and propylparaben IP are added to the heated propylene glycol under continuous stirring until completely dissolved. Butylated hydroxytoluene (BHT) is thereafter added and dissolved to obtain a clear preservative solution, which is then transferred into the previously prepared cream phase under continuous stirring.

[0092] (c) an active phase by addition of menthol into methyl salicylate and dissolving the same under continuous stirring. Linseed oil is added to the resulting solution under continuous stirring to obtain a uniform active blend,

[0093] The active phase is then transferred into the cream phase containing the preservative phase under continuous stirring. Separately, Tween-80 and polyoxyl hydrogenated castor oil are heated to a temperature range of about 60 °C to 65 °C to obtain a clear solution. Mefenamic acid is added to the cream mixture under continuous stirring until a clear solution is obtained. Cod liver oil is thereafter added under continuous stirring, followed by addition of benzyl alcohol. The final mixture is subjected to homogenization using a homogenizer to obtain a stable, uniform topical analgesic cream composition.

[0094]

[0095] In another embodiment, the present invention discloses a process for preparing a topical analgesic cream composition, wherein the cream phase is prepared without the application of heat. Unlike conventional processes that require heating to melt waxes and oleaginous bases for cream formation, the present process employs a cold-processing technique in which the cream phase is formed at ambient temperature. Specifically, the cream base is prepared by sequentially adding and dissolving selected excipients in purified water under continuous stirring, thereby eliminating the need for thermal energy to liquefy waxy or oily components.

[0096] In another embodiment, the present invention relates to a topical pharmaceutical composition intended for localized application to a subject for management, alleviation, or mitigation of pain, inflammation, stiffness, swelling, and functional discomfort associated with musculoskeletal, inflammatory, and degenerative conditions, including but not limited to rheumatoid arthritis, osteoarthritis, and related joint disorders.

[0097] In yet another embodiment, the topical pharmaceutical composition may further comprises another therapeutically effective agent selected from anti-inflammatory agents, pain-relieving agents, non-steroidal anti-inflammatory drugs (NSAIDs), local anesthetics, counter-irritants, muscle relaxants, phytoconstituents, herbal extracts, or combinations thereof. The another therapeutically effective agent is present in an amount effective to provide localized therapeutic action at the site of application.

[0098] In another embodiment, the present invention provides a method of use of a topical pharmaceutical composition as described hereinabove, comprising topically applying an effective amount of the composition to a localized area of the body affected by pain, inflammation, stiffness, or swelling associated with but not limited to rheumatoid arthritis or osteoarthritis.

[0099] In another embodiment, the method of use comprises repeated topical application of the composition as described hereinabove to the affected joint or surrounding tissue at predetermined intervals to provide localized therapeutic effect.

[0100]

[0101] In another embodiment, the method of use of the topical pharmaceutical composition as described hereinabove enables adjunctive management of rheumatoid arthritis or osteoarthritis when used alongside systemic therapies, physical therapy, or lifestyle interventions.

[0102] Other embodiments of the present invention disclosure will be apparent to those skilled in the art from consideration of the specification and practice of the disclosed embodiments. The following examples should be considered as exemplary only, with a true scope of the present disclosure being indicated by the claims.

[0103] Experimental

[0104] (I) Examples

[0105] Table 1: Examples of topical analgesic cream composition of Mefenamic acid

[0106]

[0107]

[0108]

[0109] Process of Preparation of Example 1

[0110] The process for preparing a topical analgesic cream composition, comprising:

[0111] (a) cream phase is prepared by addition of disodium EDTA into purified water, and dissolving the same under continuous stirring. Sepineo™ P600 is thereafter added to the said mixture under continuous stirring to obtain a thick cream base. Isopropyl myristate is subsequently added to the thick cream base under continuous stirring to form a homogeneous cream phase.

[0112] (b) preservative phase is prepared separately by taking propylene glycol in a suitable container and heating the same to a temperature in the range of about 60 °C to 70 °C. Methylparaben and propylparaben IP are added to the heated propylene glycol under continuous stirring until completely dissolved. Butylated hydroxytoluene (BHT) is thereafter added and dissolved to obtain a clear preservative solution, which is then transferred into the previously prepared cream phase under continuous stirring.

[0113] (c) an active phase by addition of menthol into methyl salicylate and dissolving the same under continuous stirring. Linseed oil is added to the resulting solution under continuous stirring to obtain a uniform active blend,

[0114]

[0115] The active phase is then transferred into the cream phase containing the preservative phase under continuous stirring. Separately, Tween-80 and polyoxyl hydrogenated castor oil are heated to a temperature range of about 60 °C to 65 °C to obtain a clear solution. Mefenamic acid is added to the cream mixture under continuous stirring until a clear solution is obtained. Cod liver oil is thereafter added under continuous stirring, followed by addition of benzyl alcohol. The final mixture is subjected to homogenization using a homogenizer to obtain a stable, uniform topical analgesic cream composition.

[0116] (II) Evaluation

[0117] (i) Physical Characterization: The composition is semi-solid in nature and white to off-white in colour, free from grittiness and undispersed particles

[0118] (ii) Viscosity:

[0119] A sufficient quantity of the cream was transferred into a 250 ml beaker up to the immersion groove marked on the spindle. The temperature of the sample was adjusted to 25°C using a calibrated temperature control system. Three individual viscosity readings were taken using a Brookfield viscometer equipped with a Helipath T-Bar Spindle (Spindle No.: F-96) at a rotational speed of 2 RPM. The observed viscosity was found to be 333,641 cps.

[0120] (iii) Uniformity Test:

[0121] Approximately 2 g of the cream was taken on the palm and gently pressed and spread using the finger. The sample was carefully observed for the presence of lumps, particles, crystals, or grittiness. The cream was found to be smooth, free from any lumps, particles, crystals, and grittiness, indicating good uniformity and homogeneity.

[0122] (iv) Spreadability Test:

[0123] For the spreadability test, the diameter method was employed. About 0.5-1 g of the cream was weighed and placed centrally on a glass plate or Petri dish. A second glass plate was placed on top of the cream, and a standard weight (50-125 g) was applied for a fixed time of 1 to 5 minutes. After the specified time, the final diameter of the spread film was measured. The observed spread diameter was

[0124]

[0125] 6.7 cm, which is within the acceptable range of 5-7 cm. This indicates that Meftal Cream exhibits better spreadability.

[0126] (Ill) In-vitro Release Test (IVRT)

[0127] IVRT runs were conducted by using six cells in parallel, using Phosphate buffer pH 7.4 + Ethanol (80:20 v / v) as receptor fluid. The receptor fluid was stirred at 600 rpm, while maintaining the temperature at 32 ± 1°C. Prior to the commencement of the experiment, the receptor chambers were filled with degassed Receptor Fluid. The Diffusion Cell system was allowed to equilibrate at 32 ± 1°C, for approximately 30 min. The cream was accurately weighed (-300 mg) and applied evenly onto the selected Cellulose Nitrate membranes, which were presoaked in the receptor medium for 30 min. Aliquots of 1.0 ml were withdrawn from the receptor chambers of each of the cell every hour and the Diffusion Cells were subsequently replenished with 1.0 ml of receptor medium after each withdrawal. The stirring was stopped during sample withdrawal and immediately resumed once the aliquots were withdrawn and receptor media replenished in all the diffusion cells. Care was taken that the duration between the stopping and resumption of the stirring was less than 1 min. The aliquots were analyzed by using the HPLC and GC methods as described above. The selected receptor fluid was tested for the validation parameters with the active pharmaceutical ingredient to confirm the appropriateness for the IVRT method.

[0128] The cumulative amount of Mefenamic acid, methyl salicylate, and menthol released per unit area was plotted against the square root of time and the release rates were determined. A total of six release rates per cream were obtained. The Average Amount Released (micrograms / sq.cm) is given in table no 2.

[0129] Table 2: Average Amount Released (micrograms / sq.cm)

[0130]

[0131]

[0132]

[0133] The mean release rate for Mefenamic acid was found to be 712.97 pg / cm2 / h. and the cumulative drug release was 83.97%. The mean release rate for Mefenamic acid was found to be 4653.95 pg / cm2 / h. and the cumulative drug release was 58.02%. The mean release rate for Mefenamic acid was found to be 4718.07 pg / cm2 / h. and the cumulative drug release was 90.31%. (Figure la to 1c)

[0134] (IV) Pharmacological Activity

[0135] (a) Anti-Inflammatory activity

[0136] The anti-inflammatory activity of topical formulations was performed using the carrageenan-induced paw edema model in rats.

[0137] Wistar rats (150-200 g) were divided into five groups comprising a G-I (Control group), G-II (Reference Sample 1 as Volini Gel), G-III (Reference sample as Nise Gel), G-IV (Ex 6) and G-V (Ex 1). Inflammation was induced by carrageenan injection (0.1ml, 1% carrageenan solution), and the percentage inhibition of paw edema was measured at 0 min, 30 min, 1, 2, 4, 6, and 8 hours.

[0138] The dose (300mg) for test and marketed formulations were selected based on therapeutic relevance, safety, comparable with each other that should be sufficient to elicit the anti-inflammatory response the experiment.

[0139] Animals were fasted for 12 hours prior to the experiment with free access to water. The baseline paw volume of the right hind paw of each rat was measured using a Vernier caliper, while the left hind paw served as an untreated control. Acute inflammation was induced by subplantar injection of 0.1 mL of 1% carrageenan solution into the right hind paw. Paw volume was recorded at 0 min, 30 min, 1, 2, 4, 6, and 8 hours following carrageenan administration. The extent of paw edema was determined by calculating the difference between the post-injection paw volume and the baseline paw volume. The percentage inhibition of paw edema in the drug -treated groups was calculated relative to the control group using the standard formula. The result are given below in Table 3.

[0140]

[0141] Table 3: Percentage Inhibition with carrageenan induced paw edema in rats

[0142]

[0143]

[0144]

[0145] The percentage inhibition of paw edema was measured at 0 min, 30 min, 1, 2, 4, 6, and 8 hours as depicted in figure 2a to 2d. The topical mefenamic acid cream (l%w / w) of Ex 6 (group IV) shows the anti-inflammatory activity. Whereas, Ex 1 (l%w / w) of composition comprising the mefenamic acid, linseed oil, methyl salicylate and menthol shows enhanced and sustained inhibition of paw edema indicates effective anti-inflammatory action.

[0146] (b) Analgesic activity:

[0147] The analgesic activity was performed using Eddy’s hot plate method in Swiss albino mice. Pain management remains a significant clinical challenge, and topical analgesics offer advantages such as targeted action, improved patient compliance, and reduced systemic side effects. The development of an effective topical formulation therefore warrants systematic pharmacological evaluation.

[0148] Swiss albino mice (20-25 g) were divided into five groups comprising a G-I (Control group), G-II (Reference Sample 1- Volini Gel), G-III (Reference sample 2 - Nise Gel), G-IV (Ex 6) and G-V (Ex 1). The respective creams were applied topically to the plantar surface of the hind paw. The dose for

[0149]

[0150] test (15mg) and marketed formulations (15mg) were selected based on therapeutic relevance, safety, comparable with each other that should be sufficient to elicit the analgesic response the experiment. Analgesic responses were assessed at 0, 30, 60, 90, and 120 minutes following application using Eddy’s hot plate apparatus maintained at 55 °C, with a cut-off time of 20 seconds to prevent tissue damage.

[0151] The latency to nociceptive responses, including paw licking, withdrawal, or jumping, was recorded for each animal using a stopwatch. Data were compiled as mean ± standard deviation and analysed statistically to determine the percentage inhibition of pain relative to the control group (Table 4). The control group showed no significant changes in latency throughout the study period, confirming the absence of analgesic activity. In contrast, all treated groups demonstrated a significant increase in latency, indicating analgesic efficacy. The example 6 showed the analgesic activity. Surprisingly, the example 1 showed the highest and most sustained analgesic effect, maintaining elevated latency times even at 120 minutes, as depicted in Figure 3 (a) to (e).

[0152] Table 4: Percentage analgesic activity

[0153]

[0154] (V) The acute dermal study:

[0155] The study was performed to evaluate the adverse effects those arises after dermal application of single dose of the Mefenamic Acid, Methyl Salicylate, Menthol and Linseed oil Cream (Ex 1). The study was conducted in female New Zealand White (NZW) rabbits after single-dose dermal application of composition. The composition was applied directly on the skin of NZW rabbits without any dilutions. Initially, a dose range finding was conducted at starting dose of 200.0 mg / kg following by 1000.0 mg / kg and 2000.0 mg / kg to a single female NZW rabbits. Based on the outcome in range finding

[0156]

[0157] study, the main study was conducted with further two animals at the dose of 200.0 mg / kg, 1000.0 mg / kg and 2000.0 mg / kg to confirm the classification outcome.

[0158] All treated animals were observed for a period of 14 days post-application for general health dermal reactions, morbidity, for other signs of clinical toxicity and mortality. Body weights were recorded prior to the sample application on Day 0 and on Day 7 and Day 14. At the end of experiment, animals were euthanized and necropsy was conducted which included careful examination of the external surface of the body, all orifices, and the cranial, thoracic and abdominal cavities and their contents. No mortality or morbidity or any other major clinical signs of toxicity were observed during the study period. Body weight data of animals did not show any characteristic changes in treated animals throughout the experiment.

[0159] No test sample related gross pathological changes were observed. Most tissues were macroscopically unremarkable and the other findings seen were generally consistent with the usual pattern of findings in animals of this strain and age. Since, no abnormal findings were observed in organs / tissues in gross pathology, the histopathology analysis of other organs / tissues were not required.

[0160] No mortality or morbidity or any other clinical signs of toxicity were observed at 2000.0 mg / kg dose during the study period.

[0161] Table 5: Summary of Mortality and Morbidity

[0162]

[0163] (VI) 28 Day Repeated Dose Dermal Toxicity Study:

[0164] The study was performed to evaluate the toxicity profile of the composition after repeated dermal application for a period of 28-days.

[0165]

[0166] The composition (Ex 1) was applied directly on the skin of rabbits without any dilutions. Sixteen rabbits were distributed into four groups, each group comprising of 2 males and 2 females (nulliparous and non- pregnant).

[0167] Table 6: Group of Rabbits for 28 Day Repeated Dose Dermal Toxicity Study

[0168]

[0169] Composition was applied directly on the skin daily as per their body weight for 28 days. Animals were observed daily for general health, clinical toxicity, morbidity and mortality for a period of 28- days. Body weights were recorded prior to the sample application on Day 0 and during application on Day 7, Day 14, Day 21 and Day 28. Feed consumption was recorded weekly. At the end of experiment (28 day), blood samples were collected for hematological and biochemical analysis. Animals were euthanized and necropsy was conducted which included careful examination of the external surface of the body, all orifices, and the cranial, thoracic and abdominal cavities and their contents was conducted. Organs were weighed for group comparison and processed for histopathology evaluation. No significant changes were observed in Hematology, Clinical Biochemistry and Relative Organ, pathological changes, weight when compared with the control group. No any histopathological changes were observed (Figure 4) No abnormal findings were observed in the organs / tissues, clinical pathology parameters (clinical biochemistry and hematology), and histopathological evaluation.

[0170] (VII) Stability Studies:

[0171]

[0172] A stability study was conducted to evaluate the physical, chemical, and microbiological stability of the cream formulation (Ex 1) in accordance with ICH guidelines. The composition was stored in lami tube under long-term conditions of 30°C ± 2°C / 75% RH ± 5% RH for a period of 12 months and accelerated conditions of 40°C ± 2°C / 75% RH ± 5% RH for a period of 6 months and evaluated for appearance, odor, homogeneity, pH, assay of active ingredient(s), and microbiological quality. It was found that the composition is stable for 12 months at 30°C± 2°C / 75% ±5% RH and 6 months 40°C± 2°C 775% ±5% RH. The table 7 below depicts the stability study of the composition.

[0173] Table 7: Stability Study of the Composition

[0174]

[0175]

[0176]

[0177] < < < < < < <

[0178] < < < < < < <

[0179]

Claims

We Claims:

1. A topical pharmaceutical composition comprising of a pharmaceutically effective amount of mefenamic acid and pharmaceutically acceptable excipient thereof.

2. The topical pharmaceutical composition comprising of a mefenamic acid, oil, counterirritant, soothing agent or a combination thereof and pharmaceutically acceptable excipient.

3. The topical composition as claimed in claim 1 and 2, wherein other pharmaceutically acceptable excipients are selected from creaming agents, emollients, chelating agents, preservatives, solvents, surfactant, and combination thereof.

4. The topical composition as claimed in claim 2, wherein oil is selected from linseed oil, codliver oil, castor oil, Polyoxyl 40 Hydrogenated castor oil and combination thereof.

5. The topical composition as claimed in claim 2, wherein counterirritant is selected from methyl salicylate, capsaicin, camphor, menthol and combination thereof.

6. The topical composition as claimed in claim 2, wherein soothing agent is selected from peppermint oil, eucalyptus oil, camphor oil, menthol and combination thereof.

7. The topical composition as claimed in claim 3, wherein creaming agents are selected from Sepineo P600 (Acrylamide / Sodium Acryloyldimethyl Taurate Copolymer Isohexadecane and Polysorbate 80, Sepineo PHD 100 (Polymer Hydro Dispersible 100), Sepineo SE 68 (Self- Emulsifying Polymer 68), Sepineo D.E.R.M (Dermal Emulsion Resilient Matrix) and combination thereof.

8. The topical composition as claimed in claim 3, wherein emollient is selected from Iso-propyl myristate (IPM), petroleum jelly, lanolin, hyaluronic acid, glycerin and combination thereof.

9. The topical composition as claimed in claim 3, wherein chelating agents are selected from Disodium EDTA (Ethylene Diamine Tetraacetic Acid), Edetate Calcium Disodium (CaNaiEDTA), Edetic Acid (EDTA), Citric Acid (CA), Diethylenetriaminepentaacetic Acid (DTP A), Dimercaprol and combination thereof.

10. The topical composition as claimed in claim 3, wherein preservatives are selected from Butylated hydroxytoluene (BHT), methylparaben, propylparaben and combination thereof.

11. The topical composition as claimed in claim 3, wherein surfactants are selected from Tween 80 (Polysorbate 80), Tween 20 (Polysorbate 20), Tween 21 (Polysorbate 21), Tween 40 (Polysorbate 40), Tween 60 (Polysorbate 60), Tween 65 (Polysorbate 65), Tween 85 (Polysorbate 85), Sodium Lauryl Sulfate (SLS), Ammonium Laureth Sulfate (ALS), Cocamidopropyl Betaine (CAPB), Disodium Lauryl Sulfosuccinate (DLSS), Alpha-Olefin Sulfonate (AOS), Cetyl Alcohol (CA), Stearyl Alcohol (SA), Polyoxyl 40 Hydrogenated castor oil and combination thereof.

12. The topical composition as claimed in claim 3, wherein solvents are purified water, propylene glycol, benzyl alcohol and mixture thereof.

13. The topical composition as claimed in claim 1, comprising Mefenamic acid in the range of 1 to 5% w / w of total weight of the topical composition.

14. The topical composition as claimed in claim 2, comprisingi. Mefenamic acid in the range of 1 to 5%w / w;ii. Creaming agent is Sepineo P600 (Polymer 600) is present in the range of 3 to 5 %w / w;iii. Counterirritant is Methyl Salicylate is present in the range of 9 to 12% w / w; iv. Cooling agent is menthol present in the range of 4 to 6 %w / w;v. Oil is linseed oil present in the range of 3 to 6% w / w;vi. Surfactants is tween 80 and is present in the range of 4 to 6% w / w;vii. Chelating agent is Disodium EDTA and is present in the range of 0.03 to 0.06% w / w; viii. Emollient is selected from Iso-propyl myristate (IPM) is present in the range of 2 to 4% w / w;ix. Preservatives are present in the range of 0.02 to 0.15% w / w;x. Propylene Glycol present in the range of 6 to 7% w / w;xi. Benzyl Alcohol is present in the range of 1 to 1.5% w / w; andxii. Cod liver oil in present in the range of 10 to 12%w / w;xiii. Polyoxyl 40 hydrogenated castor oil is present in the range of 4 to 6%w / w; and xiv. Purified water present in the range of 15 to 21% w / w.

15. The topical composition as claimed in claim 1 and 2 is in the form of a cream, gel, ointment, lotion, emulsion, microemulsion, nanoemulsion, paste, foam, spray, solution, suspension, liniment, balm, roll-on formulation, patch, or combinations thereof.

16. A process of preparing a topical composition as claimed in claim 1 and 2 comprising steps of:(a) cream phase is prepared by addition of chelating agents into purified water, and dissolving the same under continuous stirring. Creaming agents is thereafter added to the said mixture under continuous stirring to obtain a thick cream base, emollient is subsequently added to the thick cream base under continuous stirring to form a homogeneous cream phase.(b) preservative phase is prepared separately by taking propylene glycol in a suitable container and heating the same to a temperature in the range of about 60 °C to 70 °C. Methylparaben and propylparaben IP are added to the heated propylene glycol under continuous stirring until completely dissolved. Butylated hydroxytoluene (BHT) is thereafter added and dissolved to obtain a clear preservative solution, which is then transferred into the previously prepared cream phase under continuous stirring.(c) an active phase by addition of menthol into methyl salicylate and dissolving the same under continuous stirring. Linseed oil is added to the resulting solution under continuous stirring to obtain a uniform active blend. The active phase is then transferred into the cream phase containing the preservative phase under continuous stirring. Separately, surfactant and polyoxyl hydrogenated castor oil are heated to a temperature range of about 60 °C to 65 °C toobtain a clear solution. Mefenamic acid is added to the cream mixture under continuous stirring until a clear solution is obtained. Cod liver oil is thereafter added under continuous stirring, followed by addition of benzyl alcohol. The final mixture is subjected to homogenization using a homogenizer to obtain a stable, uniform topical analgesic composition.

17. Use of the topical pharmaceutical composition as claimed in claim 1 and 2 for the management, alleviation, or mitigation of pain, inflammation, stiffness, swelling, and functional discomfort associated with musculoskeletal, inflammatory, and degenerative conditions by topically applying an effective amount of the composition to a localized area of the body affected by such conditions.

18. Use of the topical pharmaceutical composition as claimed in claim 1 and 2 for the management, alleviation, or mitigation of pain, inflammation, stiffness, swelling, and functional discomfort associated with musculoskeletal, inflammatory, and degenerative conditions by topically applying an effective amount of the composition to a localized area of the body affected by rheumatoid arthritis, osteoarthritis, and related joint disorders.

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