10تركيبة صيدلانية عراقية لمستحضر مرهم علاج البواسير يحتوي على ليدوكايين هايدروكلورايد و بزموث سابكالات مع فلوسينولون اسيتونايد مع دراسة ثباتيتها .

Abstract

Abstract Work has been carried out to develop a new national drug product oleogenous ointment containing lidocaine [ ( HCl ) (2 %) ] , bismuth subgallate (5 %) and floucinolone acetonide (0.1 %) . It is used in the treatment of hemorrhoid, anal fissures and anal pruritus. Several formulations were prepared using different ointment bases, preservatives and humectant. Selection of best formula relied solely on physico-chemical testing of sample release and stability . Stability study was conducted on the product for six months at different temperatures to determine the expiration date and the best storage conditions. From the study we obtained an anti-hemorrhoidal ointment of good homogensity, softness and adhisive.The expiry date calculated to be not less than (3) years.

Keywords :- rectal ointment, hemorrhoid , anal pruritus , anal fissures , lidocaine HCl bismuth subgallate , floucinolone acetonide .

Introduction Anal and perianal pruritus , soreness, and excoriation are best treated by application of blend ointments and suppositories . These conditions occur commonly in patients suffering from hemorrhoids, fistulas and proctitis, cleansing with attention to any minor faecal soiling, adjustment of the diet to avoid hard stool . The use of bulk forming materials such as bran and high residue diet are helpful . Bismuth subgallate is a soothing agents and is a vasoconstrictor that constricts anal blood vessels . Flucinolone acetonide is acorticosteroid . Corticosteroids are often combined with local anesthetics and soothing agents in preparation for hemorrhoids .They are suitable for occasional short term use after exclusion of infections, such as herpes simplex. prolonged use can cause atrophy of the anal skin , hemorrhoids in children are rare [1]. Effective pharmaceutical ingredients must be formulated in a suitable dosage form to enable the patient to get active and safe drug with good features . Lidocaine is a local anesthetic which is used to relieve pain associated with hemorrhoids, it works by blocking the charged sodium channels inside the cell membranes of nerves. In this way, it provides fast relief by blocking pain transmission at the skin before such can even reach the central nervous system[2] . Bismuth compounds have been used for their astringent and anti diarrheal properties in a variety of gastro intestinal disorders, and have been applied topically in skin disorders and anorectal disorders such as hemorrhoids. Certain salts are active against HelicobacterPylori and are used in the treatment of peptic ulcer disease [3]. An ointment containing lidocaine HCl , bismuth subgallate and floucinolone acetonide is a generic drug and it is not manufactured in the Iraqi factories, Therefore, the aim of this study is to prepare an Iraqi formula for this dosage form with its stability study that is to be compatible with specifications of British pharmacopeia. This study is necessary and it's considered to be one of the important documents for the purposes of registration in the Iraqi ministry of health .

Materials and methods Bismuth subgallate , it is a yellow powder, practically insoluble in water and in ethanol (96 per cent) . It dissolves in mineral acids with decomposition and in solutions of alkali hydroxides , producing a reddish brown liquid . Flucinolone acetonide it is a white or almost white, crystalline powder , practically insoluble in water, soluble in acetone and in ethanol. Lidocaine hydrochloride it is a white or almost white , crystalline powder , very soluble in water, freely soluble in ethanol (96 per cent) [4]. Several formulations with different ointment base were prepared and then we selected the best formula. Preparation of the ointment: in a suitable beaker transfer the following materials: white soft paraffin, lanoline anhydrous, hard paraffin and menthol. Heat at (70 ◦C) in water bath and mix well for ( 30 min) , dissolve methyl paraben and propyl paraben in the above mixture and in another pyrex beaker transfer liquid paraffin , add the following active ingredients :lidocaine HCl , fluocinolone acetonide and bismuth subgallate . Mix and homogenize for (15 min) at (45 ◦C) , then mix with the mixture prepared in the first step, then fill in aluminum lacquered tube.

Assay: Assay for flucinolone acetonide : 1 - Standard preparation: - Dissolve (25 mg) of fluocinolon acetonide in )50 mg( of (65 %) Ethanol. - Dilute (0.5 mg) of this solution to (50 mg) with ( 65 %) Ethanol. 2-Test preparation: -weight (1 g) of ointment in( 50 ml) hot hexane. -shake then cool in freeze (10 min) then filter -put the filtrate in separatory funnel. -Extract with (20 ml) of (65 %) Ethanol. -filter the lower layer ( ethanol) through cotton. -Re- extraction of hexane layer with 2 × (10) ml of (65 %) Ethanol. -filter through cotton. -dilute the combined filtrate to (50 ml) with (65 %) ethanol. -Read Test & Standard at (238 nm) in spectrophotometer machine.

3- calculation:

Assay Where : T =Test St = standard Assay for lidocaine HCL: - Weight (11 g) of oint. = (220 mg) of lidocaine HCL in (250 ml) conical flask. - Add (50 ml) of ethanol (96 %) then heat on water bath until melted. -Then add (5 ml) of (0.01 N) HCl. - Titrate with ( 0.1 N) NaOH using methyl red as Indicator. - Color change from pink to yellow. Calculation : Each (1 ml) of (0.1 N) NaOH =(27.08 mg) lidocaine HCL

Assay

Assay for Bismuth subgallate: -Weigth (2 g) of oint. = (50 mg) bismuth subgallate in(250 ml) conical flask. add (20 ml) of mix (HNO3: H2O) (1:1).- Heat to boiling for(2 min) .- add(10 ml) D.W. and boil for (1 min).- add(200 ml) D.W.- -Add about (50 mg) of xylenol orange as indicator. titrate with (0.1 N) sod EDTA.- Change colour from (pink to yellow) Calculation :- Each (1 ml) of (0.1 N) Sod.EDTA=(20.9 mg) of bismuth subgallat Assay

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 ointment were prepared according to the specification of British pharmacopeia 2013. A very homogenous ointment was obtained : that is characterized by the well-dispersed active constituents. The result of stability study showed that the prepared ointment has a good stability in the assays at different temperatures (R.T, 40, 50, and 60) ◦C. Stability studies of the selected formula at different temperatures are presented in tables (1) and (2) . 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 physical – chemical changes of lidocaine HCl , bismuth subgallate and fluocinolone acetonide Ointment. Storage time (month) Temp. % of Fluocinolone acetonide % of Bismuth subgallate %of Lidocaine HCL appearance Zero time R.T 99.98 99.98 98.89 Yellow homogenous oint.

1 R.T 99.98 99.98 98.88 = 40 C° 99.68 99.68 98.53 = 50 C° 99.60 99.24 98.28 = 60 C° 99.39 99.23 97.68 =

2 R.T 99.96 99.76 98.76 = 40 C° 99.63 99.53 98.38 = 50 C° 99.53 98.90 97.88 = 60 C° 99.24 98.43 96.88 = 3

R.T 99.94 99.64 98.64 = 40 C° 99.58 99.38 98.23 = 50 C° 99.46 98.52 97.48 = 60 C° 98.96 97.63 96.08 = 4

R.T 99.92 99.52 98.52 = 40 C° 99.53 99.23 98.08 = 50 C° 99.39 98.14 97.08 = 60 C° 98.94 96.83 95.28 = 5

R.T 99.90 99.40 98.40 = 40 C° 99.45 99.08 97.93 = 50 C° 99.32 97.76 96.68 = 60 C° 98.79 96.73 94.48 = 6

R.T 99.80 99.35 98.20 = 40 C° 98.48 98.98 97.45 = 50 C° 98.30 97.50 96.30 = 60 C° 98.60 96.60 94.20 =

Regarding the expiry date of the prepared formula we followed the Zero - order rate of reaction that is expected for kinetic of lidocaine HCL , bismuth subgallate and fluocinolone acetonide 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 Table - 2 - The (T90%) of lidocaine HCl , bismuth subgallate and fluocinolone acetonide at different temperature. Temp. T90% year fluocinolone acetonide T90% year bismuth subgallate T90% year lidocaine HCL R.T 4 8 7.89 40 C° 3.8 4 3.66 50 C° 2.8 1.8 3 60 C° 1.8 1 2.19

References 1-British national formulary (70) ,2015, Royal Pharmaceutical Society, London, Rectal and anal disorders 78,united kingdom. 2 - Onlinefrom, http://www.progressivehealth.com/hemorrhoid-ointment .htm. 3- Sean C Sweetman, 2010, printed by LEGO S.P.A., Martindale 36 the complete Drug Reference, Pharmaceutical Press, USA, page (1710 ). 4- British Pharmacopoeia press, 2013, British Pharmacopoeia, U.K. 5- Kim Huynh,(2009),Accelerating aging, Handbook of stability testing in pharmaceutical development,springer ,USA .