Patented July 26, 1949 2,477,491 UNITED STATES PATENT office VITAMIN coMPosTIONs Henry C. Miller, Indianapolis, Ind., assignor to Eli Lilly, and Company, Indianapolis, Ind., a corporation of Indiana No Drawing. Application August 18, 1947, Serial No. 769,323 3 Claims. (C.16-81) 2 This invention relates to vitamin preparations tamin contained in the multiple vitamin prepara and more particularly to the prevention of loss of tion is incorporated in the preparation as one of vitamin B1 potency in multiple vitamin prepara several of its acid addition salts. Acid addition tions. salts of the antipelagra "vitamin. I have found to There are available today many multiple vita be highly effective in preventing the undesirable min preparations, comprising mixtures of two or destructive action are the hydrochloric, hydro more of the various solid or crystalline vita bromic and nitric acid addition salts, mins. These preparations are commonly mar Thus, in accordance with the above disclosure, keted as solid vitamin products, usually in the my invention comprises the provision of solid form of tablets or in gelatin capsules. O multiple vitamin preparations, containing vita A vitamin which, because of its importance to min B1 and the antipelagra vitamin, in which the human nutrition, is frequently used in such vitamin B1 retains its potency over a long period preparations is that known as the antineuritic of time. Moreover, my invention provides a vitamin, i.e. vitamin B1. This vitamin is also method of protecting vitamin B1 contained in known as thiamine or thiamine hydrochloride, s solid, multiple vitamin preparations from the ad the latter indicating the form in which it is com verse or destructive action of the antipelagra mercially available. It is known, however, that vitamin also contained therein. in many multiple vitamin preparations the vita The following specific examples are illustrative min B1 potency of the product decreases mark of vitamin compositions, containing vitamin B1 edly with the passage of time. This loss in and the antipelagra vitamin, and employing my potency has been shown by chemical and animal invention. tests to result from the actual chemical destruc tion of the vitamin rather than to any masking Eacample 1 or similar effect exerted by other vitamins con A multiple vitamin preparation comprising tained in the preparation. Because of this de members of the so-called B-complex vitamins struction it has been common for manufacturers and suitable for filling capsules, may be made up to compound many vitamin preparations with as in the following proportions, each capsule to con much as 50 percent excess of vitamin B1 in order tain the amounts of ingredients given below: to offset the loss which occurs between the period Thiamine hydrochloride ------mg-- 10 of manufacture and ultimate sale to the con SO Riboflavin ------mg - 10 Sumer. This use of an excess of vitamin B is Pyridoxine hydrochloride. ------mg-- 5 disadvantageous not only in that it is wasteful of the relatively expensive thiamine hydrochloride Calcium pantothenate ------mg-25 and therefore increases the cost of the product, Nicotinamide h"drochloride ------mg-- ) but also because it eliminates all possibility of Eacample 2 marketing a product of constant and uniform A multiple vitamin preparation comprising vitamin B1 potency suitable for accurate dosage. vitamin C and vitamins of the B-complex, and Furthermore there always exists the possibility suitable for filling capsules is made up in the foll that the vitamin B1 content of the marketed lowing proportions, each capsule to contain the product may fall to such a low value as to afford O amounts of ingredients given below. no beneficial therapeutic effect. The present invention has for its objects the Thiamine hydrochloride ------mg-- i. avoidance of the loss of vitamin B1 potency in Riboflavin ------ng-- 2 multiple vitamin preparations, and the provision AScorbic acid ------mg-- 50 of multiple vitamin preparations wherein the 45 Pyridoxine hydrochloride ------mg-- 0.5 vitamin B1 potency remains relatively constant Calcium pantothenate ------mg-- 3.3 Over long periods of time. Other objects will be Nicotinamide hydrochloride ------mg-10 apparent from the following disclosure. . Eacample 3 In pursuance of the above and other objects, I have discovered that the marked destruction of 50 A multiple vitamin preparation comprising sever the vitamin B1 observed in many multiple vitamin eral vitamins of the B-complex, and suitable for preparations is, in large part, caused by the co filling capsules is made up in the following pro presence of the antipelagra vitamin, i.e. nico portions, each capsule to contain the amounts of tinamide or nicotinic acid. I have further dis ingredients given below. covered that this destructive action may be sub 55 Thiamine hydrochloride ------mg-- 5 stantially inhibited and the loss in vitamin B1 Riboflavin ------imme -- - - - me - w - - - - reas -mg-- 10 potency largely prevented if the antipelagra, vi Nicotinic acid hydrochloride ------mg- 50 377,491 3 4. Eacample 4 Was present as the hydrochloride, hydrobromide A multiple vitamin preparation consisting of or nitrate salt showed substantially the original thiamine hydrochloride and nicotinamide hydro Vitamin B potency at the completion of the test, chloride, and suitable for filling capsules is made whereas all other compositions containing nico up in the following proportions, each capsule to tinanide in some form, showed a loss in vitamin contain the amounts of ingredients given below: B1 potency of about 20 percent or more. Iain unable to explain the reason for this sur Thiamin hydrochloride ------mg-- 10 prising protective or stabilizing effect. I am ac Nicotinamide hydrochloride ------mg-- 150 quainted with prior art Frost et al., J. Am. Chem. The illustrative compositions shown in the pre O Soc. 66, 425 (1944) which teaches that solutions ceding examples may also contain filler material of thianine hydrochloride are stable at about in quantity sufficient to make up the bulk neces pH 4, but this art fails to explain my invention, sary to insure completely filled capsules. The not only because any stable compositions are compositions may if desired be marketed as pow Solids, but also because the data of the table ders or as tablets. In the latter case it is, of s show that not all salts of the antipelagra vita course, as known to the tableting art, desirable rain are effective even though the presence of to add filler and binder material. Such Salts would confer upon the composition, Compositions of the type illustrated by the if in solution, a low pH favorable to vitamin B above examples have been found to retain sub stability. stantially all of their thiamine hydrochloride cairn: potency even when subjected to adverse condi 1. A solid autiple vitamin preparation com tions of heat. The effectiveness of my invention prising vitamin B1 and a member of the group in producing stable vitamin products is illustrated consisting of nicotinamide hydrochloride, nico by the table which discloses comparative data as tinamide hydrobromide, nicotinamide nitrate, to the stability of thiamine hydrochloride in mu nicotinic acid hydrochloride, nicotinic acid hydro tiple vitamin products exposed to a temperature broaide and Iaicotinic acid nitrate. of about 120 F. for a period of about 2 days, 2. A solid multiple vitamin preparation com these conditions representing conditions compar prising witainia B and nicotinamide hydrochlo able to an aging period of about one year at or ride. dinary ambient temperatures. The substances 3. A solid multiple vitamin preparation com employed in the test, in addition to vitamin B1 prising witainian B. alad nicotinic acid hydrochlo and nicotinamide, also coratained other vitamins ride. of the B-complex, namely riboflavin, panto HENRY C. MLLER, thenic acid, and pyridoxine. EFERENCES CEO Nicotinanide compound Percenthydrochloride of thianine ent The following references are of record in the present Imaining after 2 EE pH1 file of this patent: days at 120°F. presen UNITED STATES PATENTS Control (no nicotiaanaide present)------3.5 4.5 Ninter Narae Oste Nicotina aide------4.3 4.5 2,33,688 Fox------Dec. 30, 1947 Nicotinamide hydrochloride-- 4.2 3.9 Nicotiaanide hydrobromide-- 4.3 3. OTHER REFERENCES Nicotinamide nitrate.------4.8 3. Nicotinamide phosphate------3.9 3. Gutimata: Micdern Drug Encyclopedia, 3rd ed. Nicotina Inide I?aaleate------5.0 3.9 (1946), page 84. (Copy in Division 43). Nicotinamide salicylate.------4.0 3.9 Heilbron: Dictionary of Organic Compounds, Determined by testing an aqueous mixture of one part vol. 3 (1943), page 6. (Copy in Division 59.) of e composition under test with about 10 parts of Gautier Compt. Read, vol. 214, pages 368 to e. 31, Feb. 23, 1942. (Copy in Scientific Library.) From the data in the table it will be observed 50 U.S. Dispensatory, 24th ed. (1947), pages 39. that the compositions in which the nicotinanide (Copy in Div. 43.)