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"A Non Aqueous Topical Compositon Of Aceclofenac"

Abstract: A novel topical composition having a unique combination of ingredients, and weight percentages thereof, for use as effective carrier vehicles for one or a plurality of active agents such as NASAIDs that is to be applied topically to the skin of a human being or animal. The present ihvention specifically relates to Aceclofenac (alone or in a combination with one or more other active agents) topical composition, preferably, a non-aqueous topical composition useful for treatment of pain, rheumatoid arthritis, osteoarthritis.and other related conditions.

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Patent Information

Application #
Filing Date
29 May 2018
Publication Number
49/2019
Publication Type
INA
Invention Field
CHEMICAL
Status
Email
Parent Application
Patent Number
Legal Status
Grant Date
2023-01-16
Renewal Date

Applicants

PANACEA BIOTEC LIMITED
B-1 EXTN./A-27, MOHAN CO-OPERATIVE INDUSTRIAL ESTATE, MATHURA ROAD, NEW DELHI-110044

Inventors

1. JAIN, RAJESH
B-1 EXTN./A-27, MOHAN CO-OPERATIVE INDUSTRIAL ESTATE, MATHURA ROAD, NEW DELHI-110044
2. SINGH, SUKHJEET
B-1 EXTN./A-27, MOHAN CO-OPERATIVE INDUSTRIAL ESTATE, MATHURA ROAD, NEW DELHI-110044
3. SINGLA, DINESH
B-1 EXTN./A-27, MOHAN CO-OPERATIVE INDUSTRIAL ESTATE, MATHURA ROAD, NEW DELHI-110044

Specification

The present invention relates to novel topical compositions having a unique combination of ingredients, and weight percentages thereof, tor use as effective carrier vehicles for one or a plurality of active agents such as NASAIDs that are to be applied topically to the skin of a human being or animal. The present invention specifically relates to Aceclofenac (alone or in a combination with one or more other active agents) topical composition preferably, a non¬aqueous topical composition. ' - ■' ■ • " BACKGROUND Osteoarthritis is the .most common form of arthritis, affecting millions of people worldwide. It occurs when the protective cartilage on the ends of your bones,wears down over * ' ■' ■ . . . time. The associated pain and disability impair the quality of. life and also pose economic burden to the patient. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely prescribed in Osteoarthritis. In particular, they can deliver a high concentration of drug to the desired site of treatment. Oral NSAIDs are not very patient friendly, as they cause various gastrointestinal adverse effects like .bleeding, ulceration, and perforation. So, inventors had; focused on developing topical formulations that takp* advantage over diverse pharmacologic activities. Currently in the U.S., diclofenac, has been approved for topical administration for the relief of pain of Osteoarthritis of joints amenable to topical treatment, such as the knees and those of the hands. ' . J • • S* ■ ' ' ' WO2008049020 teaches about an invention relating to a hydro-alcoholic topical gel formulation comprising Diclofenac sodium.which has superior transdermal flux properties, ' . ' ^ '. ■ which is used for the topical treatment of pain, such as in Osteoarthritis. . WO2008049020 discloses a hydro-alcoholic topical composition of pharmaceutically acceptable. salt of diclofenac. The non-aqueous topical solution composition 'comprises therapeutically effective amount of pharmaceutical^ acceptable salt of diclofenac, solubilizer, ' -- v • • ■ ^ . ' • ■■■" "■ * ' ' penetration enhancer and solvent, and optionally a humectant, counter irritant, additional penetration enhancer and anti-oxidarits and a process for preparing the same. Advantageously, to enhance the tolerability of diclofenac and to decrease its common side effects, Aceclofehac was developed by its chemical modification. Aceclofenac is an analgesic and non-steroidal anti-inflammatory drug used, in pain, rheumatoid arthritis and osteoarthritis. Aceclofenac is well-tolerated than diclofenac and possesses superior efficacy but is not completely devoid of the NSAID-tagged side effects. To overcome the side effects associated with topical diclofenac therapy and to have the benefits associated with topical therapy; Aceclofehac topical gels were prepared. However, Aceclofenac being highly sensitive to moisture it degrades in high humidjty conditions within 48 hrs, mainly, the topical gel preparations was unstable. Patil et al, IJPSR, 2014; Vol. 5(8): 3401-3408. discloses the. comparative study of different formulations of aceclofenac as a topical drug delivery system and describes it's in vitro and in vivocharacterization. As per the findings df'this article cream formulatipns (having small / percentage oif water) were found to be better compositions to gel (higher percentage of water, as compared to cream). Yet any attempt-to formulate Aceclofenac in an aqueous composition, such as gel, cream, emulgel, etc. heretofore been complicated by the fact that Aceclofenac is moisture sensitive due to which its composition undergoes degradation making the composition unsuitable for use. In view of the foregoing, there is a considerable need for improvement in the development of a topical composition of Aceclofenac which is suitable for long term use in the treatment of pain, rheumatoid arthritis, osteoarthritis and other related conditions. The challenge has beien to devislop topical formulations that comprise Aceclofenac,alone or in combination, that take advantage of diverse pharmacologic activities, that are'beyond and unforeseen in treatment of pain, rheumatoid arthritis, osteoarthritis arid other related conditions, while reducing or minimizing the side effects arid while providing a formulation and dosage that leads to and / encourages patient compliance with improved efficacy. The present invention satisfies these and other unmet needs. ■'*'"■ . ^- ' ' '' SUMMARY OF THE INVENTION: It is an object of the present invention to provide novel composition, for topical application to the skin of a human being or animal having unique combination of ingredients, and weight percentages thereof, Which have been determined to have many advantages in comparison with other tqpicalactiye^agerit containing compositions. ■ '■ ^ }- '"■-..-. ; . .■''.-' ; ■ • - It is a specific object of the present invention to provide a topical composition of NS AID like aceclofenac; having a unique combination of ingredients, to provide a safe and highly effective composition. In particular, an object of the present invention is to provide a non-aqueous composition of aceclofenac (alone or in a combination with one or more other active agents), characterized in that the composition is more stable, effective and its application in humans is more safe and convenient. . - ^ - ■ In accordance with the above object, the invention provides a non-aqueous composition of aceclofenac useful for treatment of pain, rheumatoid arthritis, osteoarthritis and other related conditions, wherein the composition is prepared and formulated by using hydrophobic excipients which surprisingly provided better stability and improved efficacy in comparison to aqueous based known compositions. ■ _ K In preferred embodiment of the invention, the non-aqueous composition comprises; aceclofenac, being present alone or in the combination with one or more other active agents in a hydrophobic ointment base which is used in an amount of about 3% to about 70% respectively to the aceclofenac (alone or in combination with other active agents) by weight ratio. The present invention, provides aceclofenac pharmaceutical composition with suitable, anhydrous and hydrophobic characteristics and promotes the absorption of the drug at the topical application site attaining an effective concentration required for analgesic and anti-inflammatory activity,, without making use of the higher dosages which would be otherwise necessary to obtain a comparable activity through systemic administration. BRIEF DESCRIPTIONOF THE DRAWINGS v FIG. 1: Dissolution Profile of 1.5% w/w Aceclofenac ointment (Example 'H') . FIG.2: Shows percentage rise in paw volume in control, reference and test composition of aceclofenac. FIG.3: Shows rise in paw pressure in control, reference and test composition of aceclofenac. >; FIG.4: Shows percentage rise in paw volume in control, reference and test composition of , aceclofenac with'one or more actives; FIG.5: Shows rise.in paw pressure in control, reference and test composition of aceclofenac with one or more actives. DETAILED DESCRIPTION OF TIDE INVENTION: The present invention provides a unique combination of ingredients, and weight . percentages thereof, for use as effective carrier vehicles for one or a plurality of active agents that are to be applied topically jo the skin, of a human being or animal. The present invention specifically relates to Aceclofenac (alone or in combination with one or more other active agents) topical preparation preferably a non-aqueous topical composition, more preferably, the composition is an ointment composition. Before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not limited in its application to the details of construction and the arrangement of the,components, set forth in the following description or exemplified by the examples. The invention is capable of other embodiments or of being practiced or carried out in various ways. Also, it is to be understood that the phraseology and terminology, employed herein is for the purpose of (description and should not be regarded as limiting. i ■ The present invention encompasses a non-aqueous composition of aceclofenac for topical application, further comprising one or more other active agents, methods of releasing, thereby ■ ' " ■ . v. . -■■*■, - . delivering the active ingredients from the composition, methods of preparing the ointment and a method for treating various conditions, diseases and disorders, such as pain, rheumatoid arthritis, osteoarthritis and other related conditions. According to the present invention, the enhanced stability of the composition is achieved by using the hydrophobic ointment base, in the said weight percentages and ratios with jrespect to the active ingredient/s. In addition, without making use of the higher dosages, the non-aqueous Composition of the present invention promotes the absorption of the drug at the topical application site by attaining an effective concentration required for analgesic and anti-inflammatory activity. The present invention comprises aceclofenac at a concentration of between about 0.5% and about 10%, and more preferably between about 0.5% and about 8%, and most preferably about 0.5 % Cetosteryl alcohol 1.00 2.00 6.00 3.00 4.00 . 5.00 1 ■ 6.00 - Example 2: Non-Aqueous Topical Composition of Aceclofenac in Combination with One or More Other Active Agents. Table 2: f Name of Ingredients Range in % I J K L . M N O P Aceclofenac 0.5 1. 1.5 ' 1.5 2. , 5 10 10 Capsaicin 0.002 0.007 0.009 0.01 0.08 0.08 0.1 0.1 Oleum lini 1 1 2 3- 3.50 4 5 5 Menthol 1 ' 1 v ' 3; ■ 5 7. 8 10 10 Methyl salicylate 1 3 15 10 13 16 10 20 Benzyl alcohol 0.01 0.50 2.00 1 2 3.50 5 5 Hard 0.5 . 1.5 . 1.50 2 . 2.50 5.50 4 . 15 V paraffin r White wax 1 0.5 1.5,0 ■ 2 5 10 3 20 Light . -Mineral oil 10 - 4 5 ■ 3 6 7 " 30 1 White petrolatum 64.42 83.. 52.96 58.47 46.35 23.8 13.8: 14.38 Butylated Hydroxy Toluene 0.007 0.02 0.03 0.02 0.07 . 0!08 0:1 0.1 —•. Colloidal Silicon Dioxide 1 1.5 3.50 2 3.50 4 1 5/ Isppropyl myristate 10.00 1.00 10 6 i 5. 8 •2 ■• 10 Cetosteryl alcohol 6 2. . 2 5 . 4 5 6 6 Process of preparation of Non-Aqueous Topical composition of Aceclofenac alone or in combination with other one or more active agents disclosed in Table 1 and Table 2: The Process for manufacturing a non-aqueous composition in finished dosage form for the treatment of pain, rheumatoid arthritis , osteoarthritis and other related conditions, the method comprising: (a) Drug phase: Disperse aceclofenac alone or in combination With other one or more active agents in Isopropyl myristate, (b) Preparation of hydrophobic ointment base: Dispense required quantity of white wax, hard paraffin, white petrolatum, mineral oil & cetosteryl alcohol; add white wax and hard paraffin in container & melt at temperature NMT 70°C; add soft white petrolatum, cetosteryl alcohol & mineral oil in melted wax & melt at temperature of NMT 70°C and stir (c) Final ointment composition: mix (a) and (b) under stirring; Add all other excipients to the above under stirring' and cool under, room temperature and fill in the containers. Table 3: In-house manufactured hydro alcoholic gel based composition Name of Ingredients Range in % Aceclofenac . 1.5% KlucelHF 1-2% Carbomer940 1-2% Ethanol95% 24-30% , Purified water 60-75% triaceteih 0.01-0.05% -N, N,N-dimethylacetamide 1.5-2.5% Phosphoric acid 2-3% Perfume MSC-03 2-5% Perfume-0106-G * I Example 3: Stability study comparison of Non-Aqueous Composition of Aceclofenac and In-house manufactured hydro alcoholic gel based composition. Comparative Assay and Related Substances of Aceclofenac when exposed. to accelerated stability studies of Non-Aqueous Composition of Aceclofenac mentioned in Example C and In-house manufactured hydro alcoholic gel based composition given in Table 3. Table 4: Product Hydro Alcoholic gel based composition Example 'C' of Table 1 Stability Condition Stability Condition - Limits Initial 40°C/75%RH 1 Month Initial 40°C/75%RH 1 Month ' Assay • 90%-110% 100.66% 88.72% 99.38% 100.69% Related Substances . Diclofenac NMT5% 0.16 3.74 1.18 2.96 Any secondary peak other than diclofenac NMT1%-. 0111 7.1 i 0.06 0.07. Sum of all the secondary peaks excluding Diclofenac peak NMT 2% 0.33 13.66 .0.22 0.22 As is evident from above table A; the non-aqueous ointment based composition of Example C, when exposed to accelerate stress conditions, showed an in-significant drop in assay as compared to hydro alcoholic gel based formulation, which showed significant drop in assay of aceclofenac to 88.72 % w/w when analyzed at 1 month 40°C/75% RH condition. Example 4: Stability Studies of ointment composition of 'example H' The compoisition of example H was subjected to stability studies at several stability conditions like 40°C/75%RH, 25°C/60%RH and 30°C/65%RH. At the end of the certain period, the aceclofenac content of the composition, diclofenac and other impurity contents were determined. Table 5: Period _ (Months) Condition (°e/%RH) Assay Related Substances Each gm contains not less than 90% and not more than 110.0% of the labelled amount of Aceclofenac IP Diclofenac NMT 5% Single highest impurity NMT 1% Total Impurities NMT 2% • Initial 100.6 3.99 0.07 0.2 1M 40/75 . 97.64, 3.93 0.07 0.18 3M , 25/60 100.60 4.07 0.06 0.15 . 30/65 99.28 4.25 0.06 0.17 40/75 95.98 4.21 0.06 .0.16, 6M 25/60 99.23 4.71 0.04 0.15 30/65 99.37 4.81 0.04 0.16 40/75 99.76 4.83 0.04 0.15 9M 25/60 99.75 4.34 0.14 0.26 12M 25/60. , 99.11 4.64. 0.16 0.18 30/65 , 99.96 4.72 0.14 0.16 It can be observed from the Table 5, that aceclofenac content of the composition of 'example H' v is not less than 90% and not more than 110.0% of the labelled amount. Diclofenac and other impurity contents were also well within the set limits. This indicates(that formulated non¬aqueous compositions of aceclofenac are stable. The term, "stable" is used herein to mean that upon storage of the pharmaceutical compositions, riot more than 10%, preferably not more than 8% and most preferably not mbre than 5% of diclofenac impurity is present in the formulation. The percentage of impurity is calculated on the basis of the ratio of the integrated peak of the impurity to the integrated peak of impurity standard, when analyzed by HPLC. Example 5: The amount of the drug release from a given dosage form is an essential to drug product development. An in vitro release profile studies were carried out to demonstrate the release pattern of the developed test composition (Example 'H' of present invention). This study was conducted by Franz diffusion cell system. Cellophane membrane (0.45 jam) is used as a dissolution membrane which separates the donor compartment containing the test product from the receptor compartment filled with collection medium. Quantity of sample application on membrane was selected based on the amount required to cover membrane area and spread uniformly. About 5 mg of sample was optimized for application. 1% w/v Cremophore A25 in Phosphate buffer 6.8. Methanol (1:1) is used as dissolution media (7 mL).in receptor compartment. The in vitro release profile of test product was performed throughout a period of 8 hour. Samples were withdrawn at predetermined different time intervals and analyzed Nusing ' '■ ' ' * ■ . '' . ■ HPLC for drug release content. At the end of the 8 hours, around 55.78%. was released in the collection medium (Figure 1). This indicates that developed test composition is capable to sustain a drug release over a period of time due to entrapment of the drug in hydrophobic •' ' . ^ . * - . . * matrix. ' ■ • The Cumulative amount release Q (|ig/cm\) and Flux (|ig/ml/Vt) of Aceclofenac ointment base were calculated using amount of drug release at different time points during Franz diffusion ■ ■."•' *■ • . . study. Surface area of diffusion (A) was 1.766 cm2 Cumulative drug release (|ig/cm ) of analyte is determined by following equation: Q= [C„V+-Z£?CiS]/A '.;■■■'' •:■■■— Eqi Where, Q=Cumulatiye amount of Aceclofenac released per surface area of membrane (fig/err?) C„N= Concentration of Aceclofenac (fig/mL) determined at nth sampling interval V= Volume of individual Franz diffusion cell, 7 mL ' >: Tif^t CiS = Sum of concentration of Aceclofenac (fig/mL) determined at sampling intervals 1 through n-1 S= Sampling volume, 1 mL x A= Surface area of diffusion, L76_cm2 Flux = 0W* Eq2 Where, Q=Cumulative amount of Aceclofenac released per surface area of membrane (fig/cm2) V/ = Square root of time ; The calculated cumulative amount release per square area of membrane arid flux over 8 h was found to be 61.97fig/cm and 21.91fig/cm /hour respectively. Example 6: Further, Efficacy studies on animals comparing analgesic and anti-inflammatory effect of Test composition (Example CG'. of present invention) which is. a non-aqueous topical composition of Aceclofenac and Reference (Table 3 of present invention) which is in-house composition of hydro-alcoholic gel composition of Aceclofenac, v^ere performed in rats and their details are provided below: Objective: To evaluate the Analgesic and Anti-inflaimmatory effect of Topical ' dosage form in rats. Materials Animal: Wister Rats of either sex Groups: ' 1, Carrageenan control (n=6) ' 2. Topical composition (Reference; Table 3) 3. Topical composition (Test Composition: Example C) Dose: 200 mg (apprbx.y Route of Administration: Topical Duration of Study: one'day Experimental Procedure: Treatment Schedule: Each topical composition was applied to the left hind paw 45 minutes prior to the carrageenan injection. Paw withdrawal latency and paw volume were measured at 1, 2 and 4h after the carrageenan challenge. ^ Carrageenan induced inflammation: Acute inflammation was induced in the left hirid paw by injecting 0:1 ml.of. freshly prepared solution of 1% carrageenan. After!, 2 and 4h of carrageenan challenge, the response to inflammatory pain was determined by measuring the paw yolume. Inflammation is expressed as percentage increase in the paw volume. Carrageenan induced hyperalgesia: Acute inflammation was induced in the left hind paw by injecting 0.1 ml of freshly prepared solution of 1% carrageenan. After 1, 2 and 4h of carrageenan challenge, the response to inflammatory pain was determined by measuring the mechanical nociceptive. pressure by paw pressure test using ANALGESIOMETER. The nociceptive threshold was taken as the end point at whichthe rat vocalized or struggled vigorously.. ) / Table 6: Data showing the percentage rise in paw volume at different time point Group Nos. of rats Percentage.rise in paw volume (milliliter of water displaced after inflammation & shown as percentage rise in paw volume) lhr 2hr 4hr Carrageenan Control 1 65.58 66.54 76.59 2 ■ ■• 55.56 58.20 . 75.54 . : .. 3 54.17 54.12 76.03 4 ' 66.83 65.23 89.97 • 5 89.45 86.96 126.65 6 68:32 91.56 123.78 , Mean 66.65 70.44 94.76 Std Dev 12.67 15.35 24.22 . , SEM 5.17.' 6.27 9.89 Aceclofenac gel 1 56.45 51.87 55.90 2 51.12 48.56 : 60.25 3 . ■ ' ' 56.45 . 61.65 65.12 4 54.12 . 50.12 - 61.12 5 49.16 43.24 . 62.22 . 6 44.45 51,87. 62.35 Mean 51.96 51.22 61:16 Std Dev 4.69 V 6.03 3.06 SEM 1.91 2.46 1.25 Aceclofenac ointment 1 ■ • . 36.65 35.23 41.78 .:' 2 ... ' 35.65 36.12 40.94 3 . ■ ' 36.98 34.56 ■41.12 4 . 40.58 34.56 35.56 5 39.79 38.64 41,12 6 . 40.94 32,12 32.15 Mean 38.43 35.20 38.78 Std Dev 2.27 2.14 3.97 • SEM 0.93 0.88 1.62 1 s As seen from the data, carrageenan control group shows increase in paw volume at 1, 2 and 4 hours indicating inflammation. In-house aqueous gel composition shows less increase in paw volume at 1, 2 and 4 hours as compared to.carrageenan control group. But the Non-aqueous composition of aceclofenac of present invention shows comparatively much lesser increase in paw volume at 1, 2'and 4 hours which are statistically significant as compared to carrageenan control group as well as the reference group, indicating better efficacy in terms of anti-inflammatory effect (Figure 2). " ■ ... - r Table 7: Data showing the rise in paw pressure (*30gms) at different time point Group Nos. of rats •i.. Rise in Paw Pressure (gms) (Value at . Scale) lhr 2hr 4hr •> Carrageenan Control i 4.5 5:5. ■"■■. 5.5 2 4 4.5 3 3 4-5 3.5 3.5 4 . 5.5 5 . ' 4.5 -5 4.5 2.5 4.5 6 • 3.5 ' 3 .4 • = Mean value at Scale (K) 4.42 4.00 -4.17 Mean Pressure (K*30) 132.6 120 125.1 Std Dev 0.66 1.18 0.88 • SEM 0.27 0.48 0.36 • *-Aceclofenac gel 1 ■5- ■■ 7 6.5 2 6.5 8 :1 3 .7 - 7.5 7.5 4 .7.5 7.5 . 10.5 ■"5 5.5" . 5.5 8 6 7 8 9 Mean value at Scale (K) 6.42 7.25 8.08 Mean Pressure (K*30) 192.6 217.5 242.4 Std Dev 0.97 0.94 1.46 SEM ' 0.40 0.38 0.60 Aceclofenac ointment 1 11 8.5 12.5 '. 2 10 7.5 13 . 3 8 8 8:5 4 9.5 14 10.5 5 8 13 9.5 6 12 13 11 Mean value at Scale (K) 9.75 10.67 10.83 Mean Pressure (K*30) 1 292.5 320.1 324.9 Std Dev 1.60 2.96 1.72 SEM 0.66 1.21 0.70 #As 30 gm wieight is already attached to analgesiometer; each reading on scale need to be multiplied by 30 to give the actual pressure applied on paw. Graphical representation of this data is shown in Figure 3. Analgesic effect ' • " In carrageenan control group the propensity to bear the weight in paw is less when tested at 1, 2 and 4 hours. In in-house aqueous gel composition it shows little'increase in propensity to bear the weight at 1, 2 and 4 hours as compared to carrageenan control group. But again the Non- . - ^ * aqueous composition of aceclofenac of present invention shows statistically significant increase /■ ■ ■ ■ in propensity to bear the weight at 1, 2 and 4 hours as compared to carrageenan control group as well as the reference group at all-time points, indicating better efficacy in terms of analgesic effect. ' , Thus, in case of the non-aqueous composition of aceclofenac of the present invention, the analgesic and anti-inflammatory effect started earlier and was maintained up to 4 hrs, indicating long term and better efficacy. ^ » , _ . Example 7: An Animal Study was performed comparing a Non-Aqueous composition of Example 'J' according to the Present Invention with Gel Based Marketed Composition in India (Hifenac Gel®) Objective: To evaluate the analgesic and anti-inflammatory effect of Topical dosage form in rats. Materials ,y Animal: Wister Rats of either sex Groups: 1- Carrageenan control (n=6) 2. Hifenac gel group (n=6) (Reference; Hifenac gel)' 3- Aceclofenac and one or more active agents ointment composition (n=6) (Test; Example 'J') Dose: 200 mg (approx.) Route of Administration: Topical Duration of Study: one day ^ Experimental Procedure: Treatment Schedule: Each topical composition was applied to the left hind paw 45 minutes prior. ; to the carrageenan injection. Paw withdrawal latency and paw volume were measured at 1, 2 and 4h after the carrageenan (challenge. ' ; ■■■■ .'-..' . ■ ■■ ■ y '/". '. ■ Carrageenan induced inflammation: Acute inflammation induced in the left hind paw by injecting 0.1 ml of freshly prepared solution of 1% carrageehan. After 1, 2 and 4h of carrageenan challenge, the response to inflammatory pain was determined by measuring the paw volume. Inflammation is expressed as percentage increase in the paw volume. Carrageehan induced hyperalgesia: Acute inflammation induced in the left hind paw by injecting 0.1 ml of freshly prepared" solution of 1% carrageenan. After 1, 2 and 4h of carrageenan challenge, the response to inflammatory pain was determined by measuring the mechanical -nociceptive. pressure by paw pressure test using ANALGESIOMETER. The nociceptive threshold was taken as the end point at which the rat vocalized or struggled vigorously. Table 8: Data showing the percentage rise in paw volume at different time point Group Nos. of rat Percentage rise in paw volume lhr \2hr 4hr Carrageenan Control 1 65.45 44.97 76.03 2 47.84 58.20 101.34 3 54.17 48.42. 87.89 4 66.83 59.92, 101.34 5 87.56 86.96 126.65 6 78.33 91.56 . 123.78 Mean 66.70 65.00 102,84 Std Dev 14.73 19.68 19.76 SEM " 6.01 8.03 8.07 HifenacGel (Combo- M/S Intas Pharmaceutical) 1 43,24 i 45.56 60.50 2 44.97 46.69 32.31 3 49.57 40.12 56.47 4 52.44 45.54 79.48 5 43.82 43:24 62.22 6 45.54 41.12 81.78 • Mean 46.60 43.71 62.13 Std Dev 3.63 2.66 17.95 I SEM' : 1.48 1.09 7.33 Test Combo formulation 1 22.13 22.13 41.12 2 32.12 26.54 35.56 3 35.65 27.89 33.12 .4 24.1,5., : 24.15 . 34.15 5 ' 25.12 25.54 . . 41.11 6 25.98. 25.14 33.56. Mean 27,53 '.. 25.23 36.44 StdDev 5.21 1.98 . ■■: 3.72 . '•'SEM v * 2,-13" 0.81 1.52 Anti-inflammatory effect: Carrageenan control group shows increase in paw volume at 1, 2 and 4 hours indicating inflammation. Hifenac gel composition shows less increase in paw^volume at 1, 2 and 4 hours as compared to carrageenan control group (Table 8). But the Non-aqueous composition of aceclofenac of present invention shows comparatively much lesser increase in paw volume at 1, -..•"' ■'- ." * ■/ .■■■•■■ 2 and 4 hours which is statistically significant as compared to carrageenan control group as well as the reference group, indicating better efficacy in terms of anti-inflammatory effect (Figure 4). Table 9: Data showing the rise in paw pressure (gms) at different time point Group Nos. of rat Rise in paw Pressure (*30gms) lhr , 2hr 4hr Carrageenan Control 1 .4.5 8 5.5. 2 5.5 4.5 . 3 : 3 4.5 3.5 3.5 • 4 6 5 4.5 5 4 2.5 4.5 6 3.5 2.5 4 . Mean value at / Scale (K) 4.67 4.33 4.17 Mean Pressure (K*30) 140.1 129.9 125.1 Std Dev 0.93 2.07 0.88 •-' SEM ■- 0.38 0.84 0.36 Hifenac Gel (Combo-M/S Intas Pharmaceutical) / ■ ... 1 9.5 10.5 7.5 2 10.5 9.5 8 . v 3 7.5 - 10.5 8.5 4 9:5 5,5 8.5 5 : ■ 7 6 8 ^ / 4 6 12.5 , 8.5 10.5 Mean value at Scale (K) 9.42/ 8.42 8.50 Mean Pressure (K*30) - 282.6 252.6 255 StdDev 2.01 2.20 105 SEM ■ ' 0.82 0.90 0.43 Test Combo formulation v 1 10.5 '■: 1.0.5 10.5 >• ■• 2 10.5 12.5 9.5. ' 3 . .11.5 11 11 4 12:5 11.5. 10.5 5 13 11 12 6 17 12.5 9.5 Mean value at Scale (K) 12.50 11.50 10.50 Mean Pressure :" (K*30) 375 345 315 StdDev 2.43 0.84 0.95 SEM 0.99 0.34 0.39 Analgesic effect In carrageenan control group Ihe propensity to bear the weight in paw is less (Table 9) when tested at 4, 2 and 4 hours. Hifehac gel composition shows little increase in propensity to bear the weight at 1, 2 and 4 hours as compared to carrageenan control group. While the Non-aqueous composition of aceclofenac of present invention shows statistically significant increase in propensity to bear the weight at 1, 2 and 4 hours as compared to carrageenan control group as well as the reference groups at all-time points, indicating better efficacy in terms of analgesic effect (Figure 5). , / \* ■■ i .... , Thus, in case of the non-aqueous composition of aceclofenac of the present invention, the analgesic and antirinflammatory effect started earlier and was maintained up to 4 hrs, indicating long term and better efficacy . ' While the invention has been described with respect to a limited number of embodiments, those skilled in the art, having benefit of this disclosure, will appreciate that other embodiments can be devised which, do riot depart from the scope of the invention as disclosed herein. Accordingly, the scope of the inventiqmshould be limited only by the attached claims. References: 1.. WO2008049020 . 2. Patil et al., IJPSR, 2014; Vol. 5(8): 3401-3408 3. Development and Validation of In vitro Release Testing Methods for Semisolid Formulations; Technical Brief, 2009, Volume 10, Particle Sciences. 4. Modi PB and Shah NJ. Optimization of an in vitro release test for topical formulations containing eberconazole nitrate and mometasone furoate. Der Pharma Chemica. 2015; 7(8): 1-9. We claim: 1.A stable, non-aqueous composition for topical delivery of a drug comprising: (i). ■ ' " • _ . ■ ■ ^ ■ '■ ■■'.''. aceclofenac drug alone or in a combination with one or more other active agents or a pharmaceutical^ acceptable salt thereof; (ii) hydrophobic ointment base and (iii) ... . . •■ .•*'•- . ■. ■ • f\- isopropyl myristate as a permeation enhancer. 2. The composition according to the claims 1 wherein the other active agents are selected from groups comprising analgesic, anti-inflammatory and combination of the same. 3. The composition according to the claims 2 wherein the other drugs are capsaicin, oleum lini, menthol, methyl salicylate, diclofenac, nimesulide, ibuprofen and ketoprofen. 4. The composition according to the claims 1 wherein hydrophobic ointment base is selected from group consisting of petrolatum, hard paraffin, liquid paraffin, petroleuiri / jelly, yellow bees wax, white wax, white petrolatum, shea butter, spermaceti and mixtures thereof, wherein the concentration of hydrophobic base is not less than about 70 % to about 90% of total composition. _ 5. The composition according to the claims 1 wherein isopropyl myristate is used as a pehrieation enhancer in a concentration of about 3.0 to about 10.0% by weight; 6. The composition according to the claim 1 further comprises thickeners, emollients and preservatives. .■■'...• 7. The composition according to the ciaim 6 wherein the thickener is colloidal silicon dioxide. " • 8. The composition according to the claim 7 wherein the thickener is present at a concentration of about 1.0 to about 5.0 % by weight * ■ . 9. The composition according to the claims 6 wherein the emollient is cetosteryl alcohol. 10. The composition^ according to the claims 9 wherein.the emollient is present at a. , concentration of about 3.0 to about 10.0 % by weight.

Documents

Application Documents

# Name Date
1 201811019996-Other Patent Document-290518.pdf 2018-06-04
2 201811019996-Form 3-290518.pdf 2018-06-04
3 201811019996-Form 2(Title Page)-290518.pdf 2018-06-04
4 201811019996-Form 1-290518.pdf 2018-06-04
5 201811019996-Other Patent Document-280519.pdf 2019-05-30
6 201811019996-Form 5-280519.pdf 2019-05-30
7 201811019996-Form 3-280519.pdf 2019-05-30
8 201811019996-Form 2(Title Page)-280519.pdf 2019-05-30
9 201811019996-OTHERS-250920.pdf 2021-10-18
10 201811019996-OTHERS-250920-.pdf 2021-10-18
11 201811019996-OTHERS-200121.pdf 2021-10-18
12 201811019996-OTHERS-130320.pdf 2021-10-18
13 201811019996-Other Patent Document-130320.pdf 2021-10-18
14 201811019996-Other Patent Document-130320-.pdf 2021-10-18
15 201811019996-Form 6-130320.pdf 2021-10-18
16 201811019996-Form 5-250920.pdf 2021-10-18
17 201811019996-Form 3-250920.pdf 2021-10-18
18 201811019996-Form 2(Title Page)-200121.pdf 2021-10-18
19 201811019996-Form 18-130320.pdf 2021-10-18
20 201811019996-FER.pdf 2021-10-18
21 201811019996-Examination Report Reply Recieved-200121.pdf 2021-10-18
22 201811019996-Drawing-200121.pdf 2021-10-18
23 201811019996-Description(Complete)-200121.pdf 2021-10-18
24 201811019996-Correspondence-250920.pdf 2021-10-18
25 201811019996-Claims-200121.pdf 2021-10-18
26 201811019996-Abstract-200121.pdf 2021-10-18
27 201811019996-US(14)-HearingNotice-(HearingDate-08-09-2022).pdf 2022-08-02
28 201811019996-US(14)-ExtendedHearingNotice-(HearingDate-16-09-2022).pdf 2022-08-19
29 201811019996-Others-290922.pdf 2022-10-25
30 201811019996-Correspondence-290922.pdf 2022-10-25
31 201811019996-Claims-290922.pdf 2022-10-25
32 201811019996-PatentCertificate16-01-2023.pdf 2023-01-16
33 201811019996-IntimationOfGrant16-01-2023.pdf 2023-01-16

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