3تركيبة صيدلانية عراقية لمستحضر اسايكلوفير معلق فموي 200ملغم/ 5مل لعلاج عدوى الهربس البسيط مع دراسة ثباتيتها

Abstract

Abstract This work has been carried out to develop national drug product contains (4 % w/v) acyclovir as oral suspension , Which is indicated for the acute treatment of herpes zoster (shingles) , is indicated for the treatment of initial episodes and the management of recurrent episodes of genital herpes is indicated for the treatment of chickenpox (varicella) and other viral infections . Several formulations were prepared using different suspensions bases, preservatives and suspending agents. Selection of the best formula relied solely on physico-chemical testing . Stability study was conducted on the product for (6) months at different temperatures to determine the expiration date and the best storage conditions. From the study good homogeneity obtained of an antiviral oral suspension . The expiry date calculated to be not less than (2.5) years.

Keywords :- Acyclovir , oral suspension , herpes simplex .

Introduction Herpes simplex infections , including herpes keratitis , herpes labialis, and genital herpes , respond to acyclovir by the intravenous , oral , or topical route, given as soon as possible after symptoms appear[1] . Acyclovir is a synthetic nucleoside analogue active against herpes viruses [1] . The drug is an antiviral agent. It works by attacking the herpes simplex virus, of which there are two types: 1- Type (1) herpes simplex virus is the usual cause of cold sores around the mouth. It also causes up to half of the cases of genital herpes. 2- Type (2) herpes simplex virus usually only causes genital herpes. It can sometimes cause cold sores [2] . Acyclovir suspension is indicated for the treatment of Herpes simplex virus infections of the skin and mucous membranes, including initial and recurrent genital herpes (excluding neonatal (HSV) and severe (HSV) infections in immunocompromised children) [3]. Acyclovir suspension is indicated for the suppression (prevention of recurrences) of recurrent herpes simplex infections in immunocompetent patients[3] . Acyclovir suspension is indicated for the prophylaxis of Herpes simplex infections in immunocompromised patients [3] . Acyclovir suspension is indicated for the treatment of Varicella (chickenpox) and Herpes zoster (shingles) infections. Studies have shown that early treatment of shingles with Acyclovir has a beneficial effect on pain and can reduce the incidence of post-herpetic neuralgia (zoster-associated pain) [3]. Acyclovir is a White or almost white, crystalline powder, slightly soluble in water, freely soluble in dimethyl sulfoxide , very slightly soluble in ethanol (96 per cent). It dissolves in dilute solutions of mineral acids and alkali hydroxides [4] . Acyclovir suspension is a generic drug not manufactured in the Iraqi factories;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 united states pharmacopeia. This study is considered one of the important documents for the purposes of registration in the ministry of health. The formula contains acyclovir (4% w/w) as an active ingredient.

Materials and methods Several formulations with different suspension base were prepared and selected the best formula. The selected formula contains sorbitol (70 %), carboxey methyl cellulos sodium , glycerin, methylparaben , sodium saccharin , propylparaben , tween 80 , xanthan gum , pinapple flavor and distilled water as inactive ingredients. In suitable pyrex beaker transfer the following materials, deionized water, methyl paraben ,propyl paraben ,sodium saccharin ,sorbitol (70 %) ,then boil the mixture until dissolve the materials then cool to room temperature (R.T). In another pyrex beaker triturate carboxey methyl cellulos sodium and xanthan gum with glycerin , then add to previous mixture with continuous mixing . In another pyrex beaker mix and homogenous the following materials , tween 80 ,glycerin , distilled water, acyclovir, then add to previous mixture, mix and homogenize for (20 min),add pineapple flavor , mix for (10 min) , check the (pH) , it should be between (4.5-7) , fill in (100 ml) amber glass.

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 A white homogenous suspension was obtained and the physico – chemical properties of it is presented in table (1) .The results of stability studies is presented in tables (2) and (3). In this study, different formulas of suspension were prepared according to the specification of united state pharmacopoeia 2013. Awhite homogenous suspension of acceptable consistency was produced and the physicochemical also our formula showed excellent stability at different temperatures (R.T, 40, 50, and 60) ◦C . According to this study, the expiration date has been estimated to be not less than ( 2.5) years from the date of manufacturing at room temperature. Table -1-The physico chemical changes of acyclovir suspension cream 200 mg / 5 ml) with time at different temperatures.) Storage time (month) Temp. (◦C) (%) of pH (4. 5 - 7) Appearance Zero time R.T 102.69 5.9 White homogenous susp.

1 RT 102.66 5.9 = = = 40 ◦C 102.46 5.82 = = = 50 ◦C 102.08 5.80 = = = 60 ◦C 101.78 5.8 = = =

2 RT 102.63 5.83 = = = 40 ◦C 102.43 5.82 = = = 50 ◦C 102.05 5.81 = = = 60 ◦C 101.37 5.75 = = = 3

RT 102.6 5.81 = = = 40 ◦C 102.4 5.80 = = = 50 ◦C 102.02 5.79 = = = 60 ◦C 101.72 5.74 = = = 4

RT 102.57 5.8 = = = 40 ◦C 102.37 5.79 = = = 50 ◦C 101.99 5.77 = = = 60 ◦C 101.69 5.72 = = = 5

RT 102.54 5.79 = = = 40 ◦C 102.34 5.77 = = = 50 ◦C 101.96 5.76 = = = 60 ◦C 101.66 5.70 = = = 6

RT 102.51 5.77 = = = 40 ◦C 102.31 5.73 = = = 50 ◦C 101.93 5.72 = = = 60 ◦C 101.63 5.70 = = =

Table - 2 -The stability study of acyclovir cream , concentration of acyclovir at zero of the label amount time = 102.69% t 60◦C 50◦C 40◦C Concentration at R.T Time /day 101.78 102.08 102.46 102.66 30 101.37 102.05 102.4 102.63 60 101.72 102.02 102.4 102.6 90 101.69 101.99 102.37 102.57 120 101.66 101.96 102.34 102.54 150 101.63 101.93 102.31 102.51 180 Regarding the expiry date of the prepared formula we followed the Zero – order rate of reaction that is expected for kinetic of acyclovir 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 T90% remaining of active acyclovir suspension at different temperatures . T90% Year T90% day Temp. 3.5 1277.5 R.T◦C 3 1095 40◦C 2 730 50◦C 1.5 547.5 60◦C References 1- Sean C Sweetman, 2011, printed by LEGO S.P.A., Martindale 37 the complete Drug Reference, Pharmaceutical Press, USA page (953) . 2- Online from, http://patient.info/medicine/aciclovir. 3- Online from, http://www.medicines.ie/medicine/6900/SPC/Zovirax Oral Suspension +200mg /(last updated on medicines.ie: 21/07/2015) . 4- British Pharmacopoeia press, 2013, British Pharmacopoeia, U.K. 5- United state Pharmacopoeia press, 2010, U.S.P 30, U.S.A.