the phrase &# 34 ; safe and therapeutically effective amount &# 39 ;&# 34 ; as used herein , means a sufficient amount of a drug , compound , composition , product or pharmaceutical agent to abate or reverse or treat a malady in a human or other mammal without severely harming the tissues of the mammal to which the drug or pharmaceutical agent is administered . the phrase &# 34 ; pharmaceutically acceptable derivative ,&# 34 ; as used herein , means any pharmaceutically acceptable salt , solvate , ester , or salt of such ester or any other compound which , upon administration to the recipient , is capable of providing ( directly or indirectly ) the intended active ingredient or any active metabolite or residue thereof . the term &# 34 ; substantially free of &# 34 ;, as used herein , means present in quantities that have less than a material effect on , or confer less than a material advantage to , the pharmaceutical composition . a pharmaceutical composition substantially free of ethanol may contain , for example , less than 30 % ethanol , advantageously 0 - 1 % ethanol . a pharmaceutical composition substantially free of edta may contain , for example , less than 0 . 005 % edta . the term &# 34 ; preservative efficacy &# 34 ; or &# 34 ; preservative effectiveness &# 34 ;, as used herein , means that the composition satisfies usp standards as defined in protocol & lt ; 51 & gt ;, p . 1681 , united states pharmacopeia , 1995 ). the preservative is effective in the product examined if ( a ) the concentrations of viable bacteria are reduced to not more than 0 . 1 % of the initial concentrations by the fourteenth day ; ( b ) the concentrations of viable yeasts and molds remain at or below the initial concentrations during the first 14 days ; and ( c ) the concentration of each test microorganism remains at or below these designated levels during the remainder of the 28 - day test period . similar criteria are defined for bp standards ( efficacy of antimicrobial preservation , appendix xvi c , 1995 ), and pheur standards ( efficacy of antimicrobial preservation , chapter viii . 14 , 1992 ). the term &# 34 ; preservative system &# 34 ;, as used herein , means ingredients and conditions ( for example , ph ) which result in preservative efficacy . it will be appreciated by those skilled in the art that reference herein to &# 34 ; treatment &# 34 ; extends to both the prophylaxis and the treatment of an established malady , infection or its symptoms . the term &# 34 ; edta &# 34 ;, as used herein , means ethylenediaminetetraacetic acid , and includes disodium edta ( edetate disodium , ( ethylenedinitrilo ) tetraacetic acid disodium salt , disodium ethylenediaminetetraacetate ), calcium disodium edta , sodium iron ( iii ) edta , and the like . the compositions of the present invention employ a safe and therapeutically effective amount of lamivudine or pharmaceutically acceptable salts , solvates and derivatives thereof , together with a safe and effective amount of pharmaceutically acceptable carriers . according to one aspect of the present invention , there is provided a pharmaceutical composition , substantially free of ethanol and edta , comprising lamivudine and parabens , wherein said composition is formulated at ph & gt ; 5 . 5 . the ph of the formulation of the present invention may be in the range of 5 . 56 - 7 . 4 , advantageously in the range of 5 . 6 - 6 . 5 , and most advantageously in the range of 5 . 8 - 6 . 2 , particularly about 6 . 0 . according to the present invention , any ester of hydroxybenzoate ( parabens ) or combination of such esters may be used , including methyl and propyl paraben and butyl and propyl paraben combinations . in a further aspect of the present invention , there is provided lamivudine formulations containing methyl paraben and propyl paraben . for oral solutions and suspensions , the range of methyl paraben concentration may be 0 . 096 - 0 . 2 % ( 0 . 96 mg / ml to 2 mg / ml ) and the range of propyl paraben concentration may be 0 . 01 % to 0 . 02 % ( 0 . 1 to 0 . 2 mg / ml ). advantageously the range of methyl paraben concentration may be 0 . 15 - 0 . 2 % ( 1 . 5 mg / ml to 2 mg / ml ) and the range of propyl paraben concentration may be 0 . 018 % to 0 . 019 % ( 0 . 18 to 0 . 19 mg / ml ). according to a further aspect of the present invention , any suitable buffer may be used to provide a ph & gt ; 5 . 5 . advantageously , sodium citrate or phosphate may be used . the compositions of the present invention may optionally employ diluents , solubilizers , flavoring agents , viscosity - increasing agents ( e . g . polyethylene glycol ), sweeteners , buffers , or any other excipients commonly used in the art . methods for the preparation of lamivudine are described in wo92 / 20669 and wo95 / 29174 both incorporated by reference herein . included in the invention are the pharmaceutically acceptable salts , esters , or salts of such esters of lamivudine , or any other compound which , upon administration of a safe and therapeutically effective amount of the compound to a human subject , is capable of providing ( directly or indirectly ) the antivirally active metabolite or residue thereof . the compositions of the present invention may be formulated using methods and techniques suitable for the compositions &# 39 ; physical and chemical characteristics and that are commonly employed by persons skilled in the art of preparing oral dosage forms ( remington , the science and practice of pharmacy , 19th ed ., 1995 ). the formulations according to the invention may be presented in various forms adapted for direct oral administration including liquid forms , for example , syrups , suspensions , or solutions . the formulations , according to the invention , may include other pharmaceutically acceptable carriers as excipients conventionally used in such formulations . thus , for example , syrups may include sugar syrup , sorbitol or hydrogenated glucose syrup . suspensions may include suspending agents such as methylcellulose , microcrystalline cellulose , croscarmellose sodium or dispersible cellulose . solutions may include sweeteners such as liquid glucose , laevulose , xylitol , maltitol , or lycasin . the formulations may optionally be flavored with artificial or natural flavors . the formulations include those suitable for oral administration . the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy . such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients . in general the formulations can be prepared by uniformly and intimately bringing into association the active ingredient with carriers . formulations of the present invention suitable for oral administration may be presented as a solution or a suspension in an aqueous liquid or a non - aqueous liquid ; or as an oil - in - water liquid emulsion or a water - in - oil liquid emulsion . the formulations of the present invention may be made using methods and techniques that are commonly employed in preparing preparations within the pharmaceutical industry . in the formulations according to the invention , the amount required of lamivudine will depend upon a number of factors including the severity of the condition to be treated and the age and condition of the recipient and will ultimately be at the discretion of the attendant physician . in general , however , a suitable , effective dose may be in the range of 0 . 1 - 20 mg / kg body weight of recipient per day , advantageously 0 . 1 - 5 mg / kg / day . the desired dose may preferably presented as one , two , three , four or more sub - doses , for example , containing 0 . 1 - 100 mg / ml , advantageously 5 - 20 mg / ml . the formulations according to the invention may be used for the treatment or prophylaxis of human retroviral infections including hiv infections , and the consequent clinical conditions resulting from such infections , for example , aids , arc , progressive generalized lymphadenopathy ( pgl ) and hiv - seropositive and aids - antibody - positive conditions . the formulations according to the invention may be used for the treatment or prophylaxis of human hepatitis b ( hbv ) infections and the consequent clinical conditions resulting from such infections . the formulations according to the invention may be employed in medical therapy in combination with other therapeutic agents suitable in the treatment of hiv infections , such as nucleoside reverse transcriptase inhibitors for example zidovudine , zalcitabine , didanosine , stavudine , 5 - chloro - 2 &# 39 ;, 3 &# 39 ;- dideoxy - 3 &# 39 ;- fluorouridine and ( 2r , 5s )- 5 - fluoro - 1 -[ 2 -( hydroxymethyl ) 1 , 3 - oxathiolan - 5 - yl ] cytosine , 1592u89 ; non - nucleoside reverse transcriptase inhibitors for example nevirapine , tibo , and α - apa ; hiv protease inhibitors for example saquinavir , indinavir , ritonavir , 141w94 ; other anti - hiv agents for example soluble cd4 ; immune modulators fcr example interleukin ii , erythropoetin , tucaresol ; and interferons for example α - interferon . the formulations according to the present invention may be employed in medical therapy in combination with other therapeutic agents suitable in the treatment of hbv infections , such as α - interferon . the components of such combination therapy may be administered simultaneously , in either separate or combined formulations or at different times , e . g . sequentially such that a combined effect is achieved . the following non - limiting examples are included to illustrate the present invention but are not intended to limit the reasonable scope thereof . ______________________________________ingredient quantity / 1000 l batch______________________________________lamivudine * 10 . 00 kg sucrose 200 . 0 kg methyl hydroxybenzoate 1 . 50 kg propyl hydroxybenzoate 180 g artificial strawberry flavor 800 g artificial banana flavor 600 g sodium citrate dihydrate 11 g citric acid anhydrous 1 g propylene glycol ** 19 . 4 l naoh / hcl , adjust as necessary ph 6 . 0 purified water to 1000 l______________________________________ * quantity may be corrected for purity . ** volume of propylene glycol is calculated by weight using the true density of 1 . 033 g / ml to an appropriately sized auxiliary vessel , 19 . 4l of propylene glycol was added . while mixing , 1 . 50 kg of methyl hydroxybenzoate and 180 g of propyl hydroxybenzoate were added to the propylene glycol and mixed to dissolve . purified water was dispensed into a stainless steel vessel with an attached mixer . while mixing , the parabens and glycol solution , 200 . 0 kg sucrose , 1 g citric acid anhydrous , 11 g sodium citrate dihyrate , 800 g artificial strawberry flavor , 600 g artificial banana flavor and 10 kg of lamivudine were added and mixed . a sufficient quantity of purified water to make 201 . 65 kg was added and mixed . the solution was sampled and the ph was measured and adjusted to ph 6 . 0 . the solution was filtered through a clarifying filter into an appropriately sized receiving vessel . antimicrobial preservative effectiveness testing was performed using the method described in the united states pharmacopeia 23 & lt ; 51 & gt ;( 1995 ), united states pharmacopeial convention , rockville , md ., 1994 , p . 1681 . table 1 . antimicrobial preservative efficacy testing results for lamivudine 10 mg / ml ethanol - free oral solution ( example 1 ) yeast and mold ( a . niger , c . albicans ,): 1 log reduction by day 14 , no increase to day 28 . bacteria : 3 log reduction by day 14 , no increase to day 28 . ______________________________________ log reduction at each test inoculum incubation time ( days ) organism per ml 7 14 21 28______________________________________staphylococcus 9 . 6 × 10 . sup . 5 5 . 50 5 . 98 5 . 98 5 . 98 aureus escherichia 8 . 0 × 10 . sup . 5 5 . 90 5 . 90 5 . 90 5 . 90 coli pseudomonas 1 . 7 × 10 . sup . 5 5 . 23 5 . 23 5 . 23 5 . 23 aeruginosa candida 9 . 6 × 10 . sup . 5 3 . 69 5 . 98 5 . 98 5 . 98 albicans aspergillus 1 . 4 × 10 . sup . 5 4 . 55 5 . 15 5 . 15 5 . 15 niger______________________________________ antimicrobial preservative effectiveness testing was performed using the method described in the united states pharmacopeia 23 & lt ; 51 & gt ;( 1995 ), united states pharmacopeial convention , rockville , md ., 1994 , p . 1681 . table 2 . 14 day log reduction values for lamivudine formulations ( 10 mg / ml ). yeast and mold ( a . niger , c . albicans , z rouxii ): 1 log reduction by day 14 , no increase to day 28 . bacteria : 3 log reduction by day 14 , no increase to day 28 . __________________________________________________________________________ph m - para p - para c . albicans a . niger z . rouxii s . aureus e . coli p . cepacia p . aeru . __________________________________________________________________________5 . 7 0 . 960 0 . 12 2 . 120 3 . 850 3 . 66 5 . 03 5 . 34 5 . 01 5 . 28 6 . 3 0 . 960 0 . 12 1 . 980 5 . 230 5 . 04 5 . 15 5 . 04 5 . 19 4 . 98 5 . 5 1 . 350 0 . 16 5 . 630 ** 5 . 230 5 . 04 5 . 15 5 . 34 5 . 49 4 . 98 6 . 5 1 . 350 0 . 16 5 . 630 5 . 230 5 . 04 5 . 33 5 . 16 5 . 49 4 . 80 5 . 5 1 . 440 0 . 16 5 . 630 5 . 230 5 . 04 5 . 15 5 . 34 5 . 49 5 . 28 6 . 5 1 . 440 0 . 16 5 . 630 5 . 230 5 . 04 5 . 63 5 . 64 5 . 49 4 . 98 6 . 0 1 . 800 0 . 20 5 . 630 5 . 230 5 . 04 5 . 15 5 . 64 5 . 19 5 . 28 6 . 0 * 1 . 800 0 . 20 5 . 630 5 . 230 5 . 04 5 . 63 5 . 64 5 . 19 5 . 28 5 . 5 1 . 200 0 . 15 1 . 36 5 . 5 0 . 960 0 . 12 0 . 77__________________________________________________________________________ * placebo ** bold numbers represent 100 % reduction
the present invention relates to pharmaceutical formulations containing - 4 - amino - 1 --- pyrimidin - 2 - one - 2 &# 39 ;, 3 &# 39 ;- dideoxy , 3 &# 39 ;- thiacytidine , lamivudine , that are substantially free of ethanol and ethylenediamine - tetraacitic acid , and their use in medical therapy .