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|||||||||||||III US005202354A United States Patent (19) (11) Patent Number: 5,202,354 Matsuoka Et Al |||||||||||||III US005202354A United States Patent (19) (11) Patent Number: 5,202,354 Matsuoka et al. 45) Date of Patent: Apr. 13, 1993 (54) COMPOSITION AND METHOD FOR 4,528,295 7/1985 Tabakoff .......... ... 514/562 X REDUCING ACETALDEHYDE TOXCTY 4,593,020 6/1986 Guinot ................................ 514/811 (75) Inventors: Masayoshi Matsuoka, Habikino; Go OTHER PUBLICATIONS Kito, Yao, both of Japan Sprince et al., Agents and Actions, vol. 5/2 (1975), pp. 73) Assignee: Takeda Chemical Industries, Ltd., 164-173. Osaka, Japan Primary Examiner-Arthur C. Prescott (21) Appl. No.: 839,265 Attorney, Agent, or Firn-Wenderoth, Lind & Ponack 22) Filed: Feb. 21, 1992 (57) ABSTRACT A novel composition and method are disclosed for re Related U.S. Application Data ducing acetaldehyde toxicity, especially for preventing (63) Continuation of Ser. No. 13,443, Feb. 10, 1987, aban and relieving hangover symptoms in humans. The com doned. position comprises (a) a compound of the formula: (30) Foreign Application Priority Data Feb. 18, 1986 JP Japan .................................. 61-34494 51) Int: C.5 ..................... A01N 37/00; A01N 43/08 52 U.S. C. ................................. ... 514/562; 514/474; 514/81 wherein R is hydrogen or an acyl group; R' is thiol or 58) Field of Search ................ 514/557, 562, 474,811 sulfonic group; and n is an integer of 1 or 2, (b) ascorbic (56) References Cited acid or a salt thereof and (c) a disulfide type thiamine derivative or a salt thereof. The composition is orally U.S. PATENT DOCUMENTS administered, preferably in the form of tablets. 2,283,817 5/1942 Martin et al. ................... 514/562 X 4,496,548 1/1985 Moldowan et al. .................. 514/27 7 Claims, No Drawings 5,202,354 1. 2 wherein R is hydrogen or an acyl group; R' is thiol or COMPOSITION AND METHOD FOR REDUCING sulfonic (sulfo) group; and n is an integer of 1 or 2, (b) ACETALDEHYDE TOXCTY ascorbic acid or a salt thereof and (c) a disulfide type thiamine derivative or a salt thereof, and to a method This application is a continuation of now abandoned for reducing acetaldehyde toxicity which comprises application Ser. No. 07/013,443 filed Feb. 10, 1987 now administering to human subjects, before and/or after abandoned. drinking, an effective amount of a composition compris The present invention relates to a composition and ing the components as defined above. method for reducing acetaldehyde toxicity, especially Referring to the above general formula (I), the acyl for preventing and relieving katzenjammer. 10 group denoted by R is exemplified by lower alkyl (C- Katzenjammer or hangover which occurs on drink 4)carbonyl groups such as acetyl, propionyl and so on. ing, particularly on excessive drinking, is characterized In the present invention, the L-form compound (I) is by various manifestations such as skin flushes, hot sensa preferably employed but the racemic compound may tion, chest distress, headache, dull headache, nausea, also be used. Examples of (I) include L-cysteine, N vomiting, breath odor, urinous odor, and so on, and at 15 acetyl-L-cysteine, L-homocysteine, L-cysteic acid and times is accompanied by cerebral edema, functional L-homocysteic acid and the corresponding racemates. neuritis and other symptoms. Moreover, the compound (I) may be a mineral acid salt Currently, against such symptoms as heaviness in the such as L-cysteine hydrochloride or an alkali metal salt stomach, nausea, heart-burn, etc., various gastrointesti such as sodium L-cysteinate. Preferred is L-cysteine. nal remedies, crude drugs, etc. are generally ingested in The ascorbic acid mentioned above may be L-ascor hopes of relieving the uncomfortable symptoms. bic acid. The salt of ascorbic acid includes such physio It is generally acknowledged that a hangover is logically acceptable salts as the alkali metal and alkaline mainly caused by unmetabolized residues of acetaldee earth metal salts, for example, the sodium salt, calcium hyde, which is a metabolic intermediate of alcohol, in salt and so on. the drinker's body. Therefore, it has been thought that 25 The disulfide type thiamine derivative may be any of reducing the blood level of acetaldehyde should help the known active vitamin B1 compounds having the prevent and treat hangover symptoms, and further, S-S linkage in the molecule. For example, the follow contribute to the prevention and treatment of liver dam ing compounds may be mentioned. (i) Thiamine disul age associated with acetaldehyde. fide and its derivatives, such as thiamine disulfide For example, Herbert Sprince et al. studied the antag (TDS), bisbentiamine (BTDS), bisbutitiamine (Bu onistic effects of various drugs against the anesthetic TDS), bisibutiamine and so on. (ii) Thiamine alkyl disul and lethal effects of acetaldehyde in animals and re fide derivatives, such as prosultiamine (TPD), fursultia ported that a combination of L-ascorbic acid, L-cys mine (TTFD), octotiamine (TATD) and so on. teine, and thiamine hydrochloride exhibits an excellent In the present invention, said thiamine compound antagonizing effect against acetaldehyde toxicity. 35 may be used either in its free form or as a physiologi Agents and Actions, Vol. 5/2, pp. 164-173 (1975)). cally acceptable salt such as hydrochloride, nitrate and Today, in view of the high frequency of drinking in other mineral acid salts. It should be understood that daily life and the increasing consumption of alcohol, a since the thiamine compound may interact with said need has been keenly felt for the development of an compound (I), the formulation is made so as to avoid etiotropically effective medication for the prevention direct contact of the two compounds. and treatment of hangover symptoms apparently associ In a further aspect of the present invention, a chola ated with the toxic action of acetaldehyde. gogue is added to the above 3-component formulation The present inventors found surprisingly that the to provide a product having a still improved acetalde addition of fursultiamine (TTFD), which is in common hyde-detoxicating effect. use as the so-called activated vitamin B1, to a basal 45 The cholagogue is exemplified by ursodesoxycholic mixture of L-cysteine and L-ascorbic acid results in a acid, dehydrocholic acid, osalmid(hydroxyphenyl sali remarkably greater acetaldehyde-antagonizing effect as cylamide), phenylpropanol, anethole trithione, cy compared with the conventional ternary mixture of clobutyrol calcium, cyclobutyrol, hymecromone, L-cysteine, L-ascorbic acid and thiamine hydrochlo trepibutone, chenodeoxycholic acid, etc. but is not lim ride. It was also found that the formulation containing 50 ited to those mentioned. Thus, any component having activated vitamin B1 increases mitocondrial acetalde hepatic circulation increasing activity or liver function hyde dehydrogenase activity in rats. Further, the pres improving activity can be employed. In the practice of ent inventors found that the addition of ursodesoxy the present invention, the use of cholic acid derivatives cholic acid, a cholagogue, to the above formula of L having steroid nuclei, particularly ursodesoxycholic cysteine, L-ascorbic acid and fursultiamine results in a 55 acid, is preferred. further potentiated antagonism against the anesthetic The position having acetaldehyde-detoxicating effect and lethal effects of acetaldehyde. of the present invention is not limited to a composition The present invention is the result of further investi consisting of the above-mentioned three components or gations based on the above findings. four components. If necessary, various vitamins and the The present invention is therefore directed to a com 60 like, such as calcium pantothenate, nicotinamide, ribo position for reducing acetaldehyde toxicity comprising, flavine, tocopherol acetate, etc., may be added to the as combined active components, an effective amount of composition. (a) a compound of the formula: The composition according to the present invention can be orally administered to human subjects. As to 65 dosage forms, tablets, granules, capsules and other op R-NH-H-cooh (I) tional forms can be provided. For the manufacture of such preparations, the established pharmaceutical pro cedures such as sugar coating, granulation, etc. can be 5,202,354 3 4. employed. Thus, solid preparations may be produced using excipients such as lactose, starch, crystalline cellu -continued lose, potassium hydrogen phosphate, etc., lubricants Dosage such as magnesium stearate, talc, etc., and binders such Formula Components (mg/kg) as starch, polyvinylpyrrolidone, methylcellulose, hy L-Cysteine 169 B Thiamine hydrochloride 100 droxypropylcellulose, and so on. In the case of a prepa L-Ascorbic acid 352 ration containing the compound (I) and a pharmaceuti L-Cysteine 169 cally active substance which would interact therewith, C L-Ascorbic acid 352 such as a disulfide type thiamine derivative, a sugar L-Cysteine 69 O D Fursultiamine hydrochloride 50 coated tablet containing one of the components in the L-Ascorbic acid 352 plain tablet core and the other in the sugar coat may be L-Cysteine 169 provided. Alternative methods include the method E Fursultiamine hydrochloride 20 which comprises granulating these components into L-Ascorbic acid 352 L-Cysteine 69 independent granules and blending them, the method F Fursultiamine hydrochloride 50 which comprises coating some of the granules and tab 15 Ursodesoxycholic acid 30 leting them with the remaining granules, and the nucle L-Ascorbic acid 352 ation tableting method in which the two components L-Cysteine 69 G Fursultiamine hydrochloride 20 are formed into the core and the outer layer, respec Ursodesoxycholic acid 30 tively. L-Ascorbic acid 352 The dosage of each component may be selected gen L-Cysteine 169 erally from the following ranges. Note: (a) Compound (I) Formulas B and C are a formulation for comparision. About 150 to 300 mg/day (about 150 to 300 parts by weight (1) The results with Formula A, B and C are shown (b) Ascorbic acid or a salt thereof (as free ascorbic 25 in Table 1. acid) About 250 to 2000 mg/day(about 250 to 2000 p by TABLE 1.
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