4تركيبة صيدلانية عراقية لمستحضر ايملجل دايكلوفيناك داي اثيل امين(1.16%) وزن/ وزن لعلاج التهاب وآلام المفاصل والعضلات مع دراسة ثباتيتها

Abstract

Abstract This work has been carried out to develop national drug product contains (1.16 %) diclofenac diethylamineas an emulgel, it is used for the local symptomatic relief of pain and inflammation in trauma of the tendons, ligaments , muscles and joints e.g. due to sprains , strains and bruises,localized forms of soft tissue rheumatism. Several emulgel formulations were prepared using different emulgels bases, preservatives and humectants. Selection of best formula relied solely on physicochemical testing of sample exposed to thermal stresses. Stability study was conducted on the product for (6) months at different temperatures and relative humidity to determine the expiration date and the best storage conditions. We obtained non-steroidal anti-inflammatory (NSAID) emulgel of good homogeneity, softness and adhesivity.The expiry date calculated to be not less than (3) years.

Keywords:- diclofenac diethylamine, emulgel .

Introduction Diclofenac is a non-steroidal anti-inflammatory (NSAID) with pronounced analgesic, anti-inflammatory and antipyretic properties. Inhibition of prostaglandin synthesis is the primary mechanism of action of diclofenac [1] . Diclofenac belongs to the class of medications known as nonsteroidal anti-inflammatory drugs (NSAIDs). It works by reducing pain, swelling, and inflammation. Diclofenac topical gel (applied to the skin) is used to relieve pain associated with recent muscle or joint injuries such as sprains, strains, or sports injuries. It is generally used in addition to other non-medication measures (such as getting enough rest) to relieve these discomforts [2] . Effective pharmaceutical ingredients must be formulated in a suitable dosage form to enable the patient to get active and safe drug with good features. Emulgel is a combination of emulsion and gel.Emulgels are having major advantages on novel vesicular systems as well as on conventional systems in various aspects. The emulgel for dermatological use has several favorable properties such as being thixotropic, greaseless, easily spreadable, easily removable, emollient, non-staining, water-soluble, longer shelf life, bio-friendly, transparent & pleasing appearance. Various permeation enhancers can potentiate the effect, so emulgels can be used as better topical drug delivery systems over present systems[2] . Diclofenac diethylamineemulgelis an anti-inflammatory and analgesic preparation designed for topical application. In inflammation and pain of traumatic or rheumatic origin, diclofenac diethylamine emulgel relieves pain, decreases swelling, and shortens the time to return to normal function. Due to an aqueous-alcoholic base the gel exerts a soothing and cooling effect[2] . Diclofenac diethylamineemulgelis a white , pleasantly perfumed, homogeneous, non-greasy emulsion in an aqueous gel. Diclofenac diethylamine isa white to light beige, crystalline powder. Sparingly soluble in water and in acetone, freely soluble in ethanol(96%) and in methanol, practically insoluble in 1M sodium hydroxide. It melts at about(154 ◦C), with decomposition[3] . Diclofenac diethylamine emulgel is a generic drug not manufactured in the Iraqifactories ; therefore , the aim of study is a necessity to have an Iraqi formula for this dosage form with its stability study compatible with specifications of British pharmacopeia. This study is considered one of the important documents for the purposes of registration in the ministry of health. The formula contains diclofenac diethylamine(1.16 %) corresponding to diclofenac sodium (1% w/w) as active ingredient .

Materials and methods The formula contains liquid paraffin ,macrogol cetostearyl ether, carbomer,triethanolamine, perfume, propylene glycol, methyl paraben, propyl paraben,purified water , and preservative as inactive ingredients. Preparation of the emulgel :In suitable Pyrex beaker transfer the following materials ,liquid paraffin,macrogol cetostearyl ether,then heat the mixture at (65 ◦C)in water bath ,cool to (45 ◦C) then we added diclofenac diethylamine, mix well for (15 min) . In another suitable pyrex beaker triturate triethanolamine and carbomer then add purified water. In another suitable pyrex beaker heat propylene glycol at (65 ◦C) in water bath then dissolve methyl paraben and propyl paraben, mix all the mixtures for (15 min) whith continuous stirring .Then add Perfume to the mixture with mixing for (10 min), check the (pH) , it should be between (6 - 7.5) , fill in lacquered aluminum tube.

Assay method : Diclofenac Diethylamineemulgel contains :- Diclofenac Diethylamine 1.16%w/w Chromatoyraphic System :- Column: C18, (15 cm) Length Flow rate: (1.5 ml / min) Wave length: (254 nm) Retention time : (3.4min) Mobile phase: mixed 100 ml of (0.1% w/v) of orthophosphoric acid and (100ml) of (0.16%) of NaH2PO4, adjust pH to (2.5). Take 25 volume of this mixture and mixed with (75) volume of methanol. Standard preparation : Dissolved an accurately weighed (50mg) of the standard with methanol (100 ml) and then dilute 1ml of the solution to (10 ml) with mobile phase. Test preparation : Shake quantity of gel contain (50mg) of Diclofenac Diethylamine with (50 ml) acetone for (20 min), filter and evaporate the filtrate on water bath until dry, then dissolve the residue in (100ml) mixture of (40 ml) Dist. Water and (60 ml) methanol) , Dilute 1ml of this solution to (10ml) with mobile phase.

Procedure Separately inject equal volumes (20 ml) of the test and standard solution in to the chromatograph, read the chromatograms and measure the response for the major peaks.

Calculation Peak Area of Test % of Diclofenac Diethylamine = ------------------------------X100 Peak Area of standard

Stability study: Stability study was conducted on the product for(6) months at different temperatures (room temperature,40,50,60 ) ◦C to determine the expiration date and the best storage conditions.

Results and discussion Different formulas of emulgel were prepared according to the specification of British Pharmacopoeia 2013. A white homogenous emulgel of acceptable consistency was produced and the physicochemical also our formula showed excellent stability at different temperatures (R.T, 40, 50, and 60) ◦C and the results of stability study and physico – chemical properties of it is presented in table (1) . Calculated of expiry date of selected formula is presented in tables (2) and (3). According to this study, the expiration date has been estimated to be not less than(3) years from the date of manufacturing at room temperature. Table -1-the physico – chemical changes of diclofenac diethylamine emulgel (1.16 %w/w) with time at different temperatures. Storage time (month) Temp. ◦C)) (%) of diclofenac diethylamine pH (6 - 7.5) appearance Zero time R.T 100 6.5 white homogenous gel

1 RT 99.98 6.5 = = = 40 ◦C 99.86 6.5 = = = 50 ◦C 99.60 6.5 = = = 60 ◦C 99.39 6.5 = = =

2 RT 99.96 6.5 = = = 40 ◦C 99.63 6.5 = = = 50 ◦C 99.53 6.5 = = = 60 ◦C 99.24 6.5 = = = 3

RT 99.94 6.5 = = = 40 ◦C 99.58 6.5 = = = 50 ◦C 99.46 6.4 = = = 60 ◦C 98.06 6.4 = = = 4

RT 99.92 6.5 = = = 40 ◦C 99.53 6.5 = = = 50 ◦C 99.39 6.4 = = = 60 ◦C 98.94 6.4 = = = 5

RT 99.92 6.5 = = = 40 ◦C 99.49 6.5 = = = 50 ◦C 99.35 6.4 = = = 60 ◦C 98.85 6.4 = = = 6

RT 99.90 6.5 = = = 40 ◦C 99.48 6.5 = = = 50 ◦C 99.32 6.4 = = = 60 ◦C 98.79 6.4 = = =

Table - 2 -the stability of diclofenac diethylamineemulgel, concentration of diclofenac diethylamine at zero time =100% of the label amount 60◦C 50◦C 40◦C Concentration at R.T Time /day 99.93 99.60 99.86 99.98 30 99.24 99.53 99.63 99.96 60 98.06 99.46 99.58 99.94 90 98.94 99.39 99.53 99.92 120 98.85 99.35 99.49 99.92 150 98.79 99.32 99.48 99.90 180

Regarding the expiry date of the prepared formula we followed the Zero - order rate of reaction that is expected for kinetic of diclofenac diethylamine emulgel particularly in the first stage of reduction of concentration. T90%=0.1C/K Where : C=concentration at zero time K= rate of reaction T= time (day)

Table -3- The 90% at different temperature. T90%Year T90%day Temp. 4 1400 R.T◦c 3.8 1368 40◦c 2.8 1008 50◦c 1.8 648 60◦c

References 1- Sean C Sweetman, 2011, printed by LEGO S.P.A., Martindale 37 the complete Drug Reference, Pharmaceutical Press, USA. 2- Prabhakar Sharma,. Academia.edu.htm,indiaJournal of Drug Discovery and Therapeutics 1 (6) 2013, 57-61 from http://rgpv.academia.edu/PrabhakarSharma. 3-British Pharmacopoeia press, 2013,British Pharmacopoeia, U.K. 4-Kim Huynh,(2009),Accelerating aging, Handbook of stability testing in pharmaceutical development,springer ,USA