Lewis, PLEASANT-TASTING RANITIDINE FORMULATION 17321.002WO0 PLEASANT-TASTING RANITIDINE FORMULATION PRIORITY OF INVENTON 5 This application claims priority to United States Provisional Patent Application Number 60/948,606 that was filed on July 9, 2007, which application is incorporated herein by reference. BACKGROUND OF THE INVENTION 10 Gastroesophageal reflux is a major cause of morbidity in children [Sandhu and Sawzcenko, Indian J Pediatr 66 (Suppl 1), S5]. In fact, gastroesophageal reflux disease (GERD) occurs with higher prevalence among infants than among older children or adults [Cezard, Digestion 69 (Suppl 1), 3], occurring frequently during the first several months of life [Vandenplas et al., 15 Early Hum Dev 81, 1011]. GERD that occurs at night, disturbing sleep patterns, requires special attention [Orr, Eur J Gastroenterol Hepatol 17, 113]. Among the agents indicated for the treatment of GERD are the histamine H2 receptor antagonists, including cimetidine, famotidine, nizatidine and ranitidine [Tougas and Armstrong, Can J Gastroenterol 11 (Suppl B), 51B]. 21) Each of these agents has a bitter taste, and infants are known to reject bitter tasting liquids [Kajiura et al., Dev Psychobiol 25, 375]. However, in order to maximize adherence to the therapeutic regimen, an oral liquid dosage form tends to be preferred for infants and older children, even in the case of a very bitter active agent [Schaefer and Michaelis, J Antimicrob Chemother 34 (Suppl A), 25 33]. H2-antagonists are subject to degradation. Degradation products include I-[2-(5-Dimethylaminomethyl)-2-furanyl)methyl sulfinyl]ethyl-amino]-1 aminomethyl-2-nitroethene, referred to as "Related Compound C;" and (N-[2-[5 [(dimethylaminomethyl]-furanylthio]ethyl]-N'-methyl-2-nitroethene- 1,1 -diamine 30 N-oxide), referred to as "Related Compound X." A useful oral liquid formulation of an H2-antagonist is one that is stable and in which degradation is limited. Several prior art oral liquid formulations of H2-antagonists contain ethanol. For a variety of reasons, including ethical concerns and the direct 1 Lewis, PLEASANT-TASTING RANITIDINE FORMULATION 17321.002WO1 pharmacological effect and possible toxicity of ethanol in very small children, it is desirable to possess an oral liquid formulation of an H2-antagonist that is essentially free of ethanol. It would therefore be desirable to possess an oral liquid formulation of an 5 H2-antagonist that is pleasant-tasting and stable and which is free of ethanol. The present invention provides such a formulation. SUMMARY OF THE INVENTION The invention possesses several aspects, including, inter alia, the 10 following: Aspect 1. An ethanol-free aqueous ranitidine hydrochloride solution formulation suitable for oral administration to a human subject, the formulation comprising ranitidine and a pharmaceutically acceptable citrate salt and optionally other pharmaceutically acceptable excipients, and wherein the ratio of 15 ranitidine present in the sample to the label claim of ranitidine is no less than about 90% in a sample of the formulation which has been stored within a suitable container-closure system for about I month at 40 degrees Celsius and 75% relative humidity. Aspect 2. A formulation according to Aspect 1, wherein the ratio of 20 ranitidine present in the sample to the label claim of ranitidine is no less than about 90% in a sample of the formulation which has been stored within a suitable container-closure system for about 2 months at 40 degrees Celsius and 75% relative humidity. Aspect 3. A formulation according to Aspect 2, wherein the ratio of 25 ranitidine present in the sample to the label claim of ranitidine is no less than about 90% in a sample of the formulation which has been stored within a suitable container-closure system for about 3 months at 40 degrees Celsius and 75% relative humidity. Aspect 4. A formulation according to Aspect 1, 2 or 3, comprising from 30 about 0.1% to about 3% (wt./vol.) citrate salt. Aspect 5. A formulation according to Aspect 4, comprising from about 0.5% to about 2% citrate salt. Aspect 6. A formulation according to Aspect 5, comprising about 1% citrate salt. 2 Lewis, PLEASANT-TASTING RANITIDINE FORMULATION 17321.002WOI Aspect 7. A formulation according to Aspect 6, comprising about 1% sodium citrate dihydrate. Aspect 8. A formulation according to any of Aspects 4-7, wherein the pH of the formulation is between about 7.1 and about 7.3. 5 Aspect 9. A formulation according to any of Aspects 4-8, further comprising grape flavor. Aspect 10. A formulation according to any of the preceding Aspects, wherein Method A is used for the determination of the ratio of ranitidine present in the sample to the label claim of ranitidine. 10 Aspect 11. An ethanol-free aqueous ranitidine hydrochloride solution formulation suitable for oral administration to a human subject, the formulation comprising ranitidine and a pharmaceutically acceptable citrate salt and optionally other pharmaceutically acceptable excipients, and wherein the ratio of 1-[2-(5-Dimethylaminomethyl)-2-furanyl)methyl sulfinyl]ethyl-amino]- 1 15 aminomethyl-2-nitroethene to the sum of 1-[2-(5-Dimethylaminomethyl)-2 furanyl)methyl sulfinyl]ethyl-amino]-1-aminomethyl-2-nitroethene plus ranitidine in the sample is not more than about 1% in a sample of the formulation which has been stored within a suitable container-closure system for about I month at 40 degrees Celsius and 75 % relative humidity. 20 Aspect 12. A formulation according to Aspect 11, wherein the ratio of 1 [2-(5-Dimethylaminomethyl)-2-furanyl)methy sulfinyl]ethyl-amino]-1 aminomethyl-2-nitroethene to the sum of 1-[2-(5-Dimethylaminomethyl)-2 furanyl)methyl sul finyl]ethyl-amino]-1 -aminomethyl-2-nitroethene plus ranitidine in the sample is not more than about 1% in a sample of the formulation 25 which has been stored within a suitable container-closure system for about 2 months at 40 degrees Celsius and 75 % relative humidity. Aspect 13. A formulation according to Aspect 12, wherein the ratio of 1 [2-(5-Dimethylaminomethyl)-2-furanyl)methyl sulfinyl]ethyl-amino]- I aminomethyl-2-nitroethene to the sum of 1-[2-(5-Dimethylaminomethyl)-2 30 furanyl)methyl sulfinyl]ethyl-amino]-I -aminomethyl-2-nitroethene plus ranitidine in the sample is not more than about 1% in a sample of the formulation which has been stored within a suitable container-closure system for about 3 months at 40 degrees Celsius and 75 % relative humidity. 3 Lewis, PLEASANT-TASTING RANITIDINE FORMULATION 17321.002WO1 Aspect 14. A formulation according to Aspect 11, 12 or 13, comprising from about 0.1% to about 3% (wt./vol.) citrate salt. Aspect 15. A formulation according to Aspect 14, comprising from about 0.5% to about 2% citrate salt. 5 Aspect 16. A formulation according to Aspect 15, comprising about 1 % citrate salt. Aspect 17. A formulation according to Aspect 16, comprising about 1% sodium citrate dihydrate. Aspect 18. A formulation according to any of Aspects 14-17, wherein 10 the pH of the formulation is between about 7.1 and about 7.3. Aspect 19. A formulation according to any of Aspects 14-18, further comprising grape flavor. Aspect 20. A formulation according to any of the preceding Aspects, wherein Method A is used for the determination of the ratio of 1-[2-(5 15 Dimethylaminomethyl)-2-furanyl)methyl sulfinyl]ethyl-amino]- 1 -aminomethyl 2-nitroethene to the sum of 1-[2-(5-Dimethylaminomethyl)-2-furanyl)methyl sulfinyl]ethyl-amino]-1 -aminomethyl-2-nitroethene plus ranitidine. DETAILED DESCRIPTION AND EXAMPLES 20 As used in connection with the invention, the terms "free of ethanol" and "ethanol-free" and "lacking ethanol" are equivalent to one another. Each denotes the absence of material concentrations of ethanol but does not exclude adventitious ethanol, such as that which might be present as an impurity in an excipient. For example, a formulation having a final concentration of ethanol 25 greater than about 1% would not be "ethanol-free." A variety of formulations lacking ethanol were developed and tested. Formulations were evaluated with respect to taste. It was found that inclusion of a certain amount of saccharin sodium, sodium chloride, and sorbitol was associated with a favorable taste. Further inclusion of a certain amount of grape 30 flavor was associated with a particularly favorable taste, although any combination of flavorings and sweeteners may be used. Formulations were also evaluated with respect to stability. Inclusion of a certain amount of citrate in the formulation was associated with favorable stability (apparently slowing the formation of Related Compound C) and also favorable taste. A formulation 4 Lewis, PLEASANT-TASTING RANITIDINE FORMULATION 17321.002WO1 according to the invention may comprise any pharmaceutically acceptable salt of citrate, preferably sodium citrate, and particularly preferably sodium citrate dihydrate. A formulation according to the invention may comprise from about 0.1% to about 3% (wt./vol.), and preferably from about 0.5% to about 2%, and 5 particularly preferably about I% sodium citrate dihydrate. Suitable formulations may also include other stabilizers (e.g., parabens), thickening agents, buffers, etc. In one preferred embodiment, the thickening agent includes hypromellose, and such formulation is substantially free of, e.g., cellulose gum (sodium carboxymethylcellulose). In another preferred embodiment, the thickening agent 10 includes cellulose gum (sodium carboxymethylcellulose), and is substantially free of hypromellose. Examples of the variety of formulations developed and tested were as described in the following Table 1: 5 -~ ~O b 00 kO Ct11 __ _ _ to0 0. - c- o * - - - ~ - 0 ~ - - ___ - _ __ - _CD L.. \C 50 6 00- V 0 00 m I 0 (= C.' 00 6C V 00 00 . o -0 c 0 0 -C 0 ( (N0 . 0 i E 0 - 0 >I0 C ~~ ~ 00 - 0 -0 - 0 0 00 CA -n C/ /) 7; n u .
00 lo I 00 ON 00 kf V; ~ CD 6to u O 00 Lewis, PLEASANT-TASTING RANITIDINE FORMULATION 17321.002WO1 A validated stability-indicating method may be used for the assay of ranitidine HC1, Related Compound C, and Related Compound X. A particular such method was used and is referred to in this application as "Method A." The following describes typical settings and conditions for Method A, as performed on a 5 suitable HPLC system. Standards for ranitidine and Related Compound C are available from USP. Dilutions of standards and samples are as needed for optimal detection. A UV detector is set for detection at 322 nm. The chromatographic column used is a Zorbax SB CN, 150 mm X 4.6 mm, Cat #863953.905, or equivalent. The column temperature is ambient temperature. The injection volume 10 is typically 10 microliters. Mobile Phase A is made by mixing 950 mL 0.1 M ammonium acetate, 50 mL acetonitrile, 10 mL acetic acid, and 2 mL triethylamine. Mobile Phase B is made by mixing 700 mL 0.1 M ammonium acetate, 300 mL acetonitrile, 10 mL acetic acid, and 2 mL triethylamine. A typical flow program is as in the following Table 2: 15 Table 2 Time %A %B Flow Rate [ml/min] 0 100 0 0.5 5.5 minutes 100 0 0.5 5.6 minutes 100 0 1.7 18.0 minutes 100 0 1.7 18.1 minutes 0 100 1.0 34.0 minutes 0 100 1.0 34.1 minutes 100 - 1.7 40.0 minutes 100 - 1.7 NOTE: The flow rates and time programs may be adjusted slightly to obtain the desired retention time for a particular peak and/or to ensure that no peak of interest elutes on the chromatographic baseline shoulders which occur as the 20 mobile phase flow program change either from A to B or from B to A. 8 Lewis, PLEASANT-TASTING RANITIDINE FORMULATION 17321.002WO0 Further details of Method A are as are commonly practiced in the pharmaceutical arts. A distinct peak is observed for ranitidine. Another, distinct peak is typically observed for Related Compound C, and yet another for Related Compound X. All other peaks observed, if any, upon analysis of a sample are 5 considered as being for "Other Related Substances." The area response of each peak is calculated and recorded. The % individual substance (Pi) is calculated according to the following equation: Pi = (Rsi x 100) / (Ru x CC), where si= area response of the individual substance in the sample; Ru = sum of the area responses of ranitidine, Related Compound C, Related Compound X and any unknown in the 10 sample; CC, = response factor of the individual substance in comparison to ranitidine. For any unknown, CCi is taken to be 1. The percent total impurities is the sum of the individual Pi for substances other than ranitidine. Retention times (RT), relative retention times (RRT) and response factors (CC) at 322 nm are typically as follows, but may vary somewhat, according to what is reasonably to be 15 expected in the pharmaceutical arts: Related Compound C: RT = 6.1; RRT = 0.6; CC = 0.97; Related Compound X: RT = 13.1; RRT = 1.3; CC = 0.77; Ranitidine: RT = 10.1; RRT = 1; CC = 1. A formulation according to the invention may be made as follows. A first volume of water is placed in a first container and heated to 75-80 degrees Celsius. 20 Any substances that are relatively insoluble in water at room temperature, such as parabens, may then be mixed in with the first volume of water until dissolved to form a first solution. A second volume of water is placed in a second container at room temperature. Any substances that are relatively soluble in water at room temperature are mixed in with the second volume of water until dissolved to form a 25 second solution. The first solution is cooled to room temperature. Once the first solution has been cooled to room temperature, the first and second solutions are intermixed to form an intermixed solution. The pH of the intermixed solution is measured and adjusted if necessary to the desired pH, such as to between about 7.1 and about 7.3, to form a pH-adjusted intermixed solution. To the pH-adjusted 30 intermixed solution is added purified water USP (q.s.) so that the desired final volume of solution is obtained, to form a formulation according to the invention. 9 Lewis, PLEASANT-TASTING RANITIDINE FORMULATION 17321.002WO1 A formulation according to the invention may be administered to a human patient in need of relief, for example, of one or more of the symptoms of GERD. For example, a volume of a formulation according to the invention may be administered perorally B.I.D., for example, by spoon or by medicine dropper, so 5 that, for example, a dosage of from about 5 mg/kg/day to about 10 mg/kg/day is achieved. When a formulation according to Table I is made, it is made so as to contain 1.68% (wt./vol.) ranitidine hydrochloride. For this reason, 1.68% (wt./vol.) ranitidine hydrochloride may be referred to as the "label claim." 10 By way of still further example, a formulation containing sodium citrate according to Table 1 was evaluated with respect to stability. Such evaluations of stability are typically conducted by placing a volume of the formulation in a suitable container-closure system in a controlled environment of a certain temperature and relative humidity for a fixed period of time. Results of such stability studies 15 included those shown in the following Table 3, where each of the "Criteria" refers to specifications which every formulation was expected to meet, and each "Experiment" refers to a particular instance of a formulation's having met one or more of the Criteria: Table 3 Time Temp. RH % label Related claim Compound ranitidine C Criterion A I mo. 40 C. 75% NLT 90% NMT 1% Expt. B 2 mo. 40 C. 75% 97.8% 0.64% Expt. C 2 mo. 40 C. 75% 97.1% 0.55% Criterion D 2 mo. 40 C. 75% NLT 90% NMT 1% Expt. E 3 mo. 40 C. 75% 95.6% 0.87% Expt. F 3 mo. 40 C. 75% 96.0% 0.72% Criterion G 3 mo. 40 C. 75% NLT 90% NMT 1% Expt. H 3 mo. 25 C. 60% 98.8% 0.26% Expt. I 3 mo. 25 C. 60% 99.0% 0.21% Criterion J 3 mo. 25 C. 60% NLT 90% NMT 1% 10 ("NLT" denotes "not less than;" "NMT" denotes "not more than") All publications, patents and patent applications are incorporated herein by reference. What is disclosed hitherto in the specification is by way of example only and not of limitation. Equivalents will be readily apparent to those skilled in the art. Therefore the invention is to be limited only according to the legal and equitable scope properly accorded the following claims, including any and all equivalents. Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. The reference to any prior art in this specification is not, and should not be taken as, an acknowledgement or any form of suggestion that the prior art forms part of the common general knowledge in Australia. 11