Multivitamin preparations

A major pharmaceutical use of poly(oxyethylene) sorbitan fatty acid esters is in the solubilization of the oil-soluble vitamins A and D. In this way, multivitamin preparations can be made which combine both water- and oil-soluble vitamins in a palatable form. 

The biotin market is divided between agricultural and human use, with —90% of biotin used in the animal health care market and —10% for the human nutritional market. The major producers of biotin are Hoffmann-La Roche, Lon2a, E. Merck-Darmstadt, Rhc ne-Poulenc, Sumitomo Pharmaceutical, E. Sung, and Tanabe Seiyaku (100). Worldwide production of biotin in 1994 was approximately 60 metric tons. The Hst price for pure biotin in 1995 was — 7.00/g whereas, the Hst price for technical feed-grade biotin was — 5.50/g. Biotin is used in various pharmaceutical, food, and special dietary products, including multivitamin preparations in Hquid, tablet, capsule, or powder forms. One of the commercially available products of i7-biotin is Britrit-1, which is a 1% biotin trituration used in food premixes. 

Both nicotinic acid and nicotinamide have been used in the enrichment of bread, flour, and other grain-derived products. Animal feed is routinely supplemented with nicotinic acid and nicotinamide. Nicotinamide is also used in multivitamin preparations. Nicotinic acid is rarely used in this appHcation. The amide and carboxyHc acid have been used as a hrightener in electroplating baths and as stabili2er for pigmentation in cured meats. 

Preferably, high pressure Hquid chromatography (hplc) is used to separate the active pre- and cis-isomers of vitamin D from other isomers and allows their analysis by comparison with the chromatograph of a sample of pure reference i j -vitainin D, which is equiUbrated to a mixture of pre- and cis-isomers (82,84,85). This method is more sensitive and provides information on isomer distribution as well as the active pre- and cis-isomer content of a vitamin D sample. It is appHcable to most forms of vitamin D, including the more dilute formulations, ie, multivitamin preparations containing at least 1 lU/g (AOAC Methods 979.24 980.26 981.17 982.29 985.27) (82). The practical problem of isolation of the vitamin material from interfering and extraneous components is the limiting factor in the assay of low level formulations. 

Avoid die use of multivitamin preparations unless such use has been approved by the primary healtii care provider. 

In view of the reported growing importance ascribed to folic acid deficiency in the prevention of various disease conditions, such as neural tube defects, megaloblastic anemia, colon cancer, and colorectal cancer, a dissolution requirement is specified for folic acid when it is present in multivitamin-mineral combination products. Currently, the dissolution standard required in the official articles of dietary supplements (including vitamin-mineral combination products) places folic acid outside the index vitamin hierarchy. Therefore, a mandatory dissolution test for folic acid is required that is independent of and in addition to the mandatory index vitamin test for multivitamin preparations containing folic acid. 

Administration of FA can mask a vitamin B12 deficiency. Vitamin B12 is required for the conversion of methyltet-rahydro-FA to tetrahydro-FA, which is important for DNA synthesis (B). Inhibition of this reaction due to B12 deficiency can be compensated by increased FA intake. The anemia is readily corrected however, nerve degeneration progresses unchecked and its cause is made more difficult to diagnose by the absence of hematological changes. Indiscriminate use of FA-containing multivitamin preparations can, therefore, be harmful... 

Except during pregnancy and lactation, do not give folic acid in therapeutic doses greater than 0.4 mg/day until pernicious anemia has been ruled out. Do not include daily doses exceeding the Recommended Dietary Allowance in multivitamin preparations if therapeutic amounts are necessary, give folic acid separately. Elderly It may be prudent to consider the status of folate in people older than 65 years of age. 

Proquin XR Proquin XR and other oral formulations of ciprofloxacin are not interchangeable. Proquin XR should be administered orally once daily for 3 days with a main meal of the day, preferably the evening meal. Proquin XR should be administered at least 4 hours before or 2 hours after antacids containing magnesium or aluminum, sucralfate, Videx (didanosine) chewable/buffered tablets or pediatric powder, metal cations such as iron, and multivitamin preparations containing zinc. Pragy/n XR tablets should be taken whole and never split, crushed, or chewed. 

Administer oral doses of moxifloxacin at least 4 hours before or 8 hours after antacids containing magnesium or aluminum, sucralfate, metal cations such as iron, multivitamin preparations with zinc, or didanosine (chewable/buffered tablets or pediatric powder for oral solution). 

Vitamin D comes in many formulations, including multivitamin preparations, fish liver oils with or without vitamin A, combinations with calcium salts, and vitamin D preparations alone. Most forms of vitamin D contain either cholecalciferol (D3) or ergocalciferol (D2). 

FIGURE 5 Total peroxide (circles), catalase-resistant peroxides (squares), and H202 as the difference (triangles) were measured in three lots of oral multivitamins without riboflavin (Tri-Vi-Sol) and three lots of oral multivitamins with 0.6 mg of riboflavin (Poli-Vi-Sol) by time after the initial opening of the bottle. Compared with the preparation without riboflavin, the level of H202 was initially higher (P < 0.01) in (Poli-Vi-Sol), and that level dropped over time (P < 0.05). In both multivitamin preparations, the levels of catalase-resistant and total peroxide rose (P < 0.05) until day 8. Data represent the mean + standard error of the mean. Variations too small relative to the symbol are not shown [30]. 

Since ascorbate reduces photooxidation of lipid emulsions and multivitamin preparations (see Figure 4) [19], Lavoie et al. [34] studied the formation of oxidative by-products of vitamin C in multivitamins exposed to light. They found that the loss of ascorbic acid in photoexposed multivitamin preparations was associated with the generation of products other than dehydroascorbate and 2,3-diketogulonic acid, which are the usual products of vitamin C oxidation. The authors showed that hydrogen peroxide at concentrations found in TPN solutions induced the transformation of dehydroascorbate into new, biologically active compounds that had the potential to affect lipid metabolism. They believe that these species have peroxide and aldehyde functions [35]. 

Lavoie, J-C., Belanger, S., Spalinger, M., and Chessex, P. (1997), Admixture of a multivitamin preparation to parenteral nutrition The major contributor to in vitro generation of peroxides, Pediatrics, 99, 61-70. 

Garrett. E. R. (1956), Prediction of stabihty in pharmaceutical preparations II. Vitamin stabihty in liquid multivitamin preparations. J. Am. Pharm. Assoc. Sci. Ed., 45,171-178. 

The determination of vitamins in pharmaceutical preparations continues to receive considerable attention. The voltammetric oxidation of vitamin A at a carbon paste electrode in the presence of vitamin E, a potential source of error in the assay, has been described [142,143]. Other assays involve the polaro-graphic determination of niacinamide [144-146], menadione (vitamin K3) [147], riboflavin (vitamin B2) [148], thiamine, riboflavin, and nicotinamide in multivitamin preparations [149], and multivitamins [150]. 

Figure 1 is the ultraviolet spectrum of a 10 mcg/ml solution of vitamin D3 in methanol. The spectrum was obtained using a Cary Model 219 recording spectrophotometer (Varian Instrument Co., Palo Alto, CA). Vitamin D3 and related compounds have a characteristic UV absorption maximum at 265 nm and a minimum at 228 nm. The extinction coefficient at 265 nm is about 17,500 and 15,000 at 254 nm. An index of purity of vitamin D3 is a value of 1.8 for the ratio of the absorbance at 265 to that at 228 nm. The high absorbance at 254 nm enables one to use the most common and sensitive spectrophotometric detector used in high performance liquid chromatography (HPLC) for the analysis of vitamin D3 in multivitamin preparations, fortified milk, other food products, animal feed additives etc. 

Reverse-phase HPLC procedures for vitamin D3 in bulk drug were reported in the early 701s by William et al. (54) using a DuPont Permaphase 0DS column (DuPont, Wilmington, Del.) and 78% methanol in water as the mobile phase. A similar column and mobile phase (DuPont s Zorbax 0DS Column and 95% methanol in water) were reported to give increased resolution of the two forms of vitamin D (62) in multivitamin formulations. Complete separation of vitamins Dg and D3 by reverse-phase chromatography in model multivitamin preparations were reported by Osadca and Araujo (63). In this... 

DeVries et al. (67) reported the summary of studies by a number of collaborating laboraties for the HPLC assay of vitamin D in multivitamin preparations. Saponification and a reverse-phase Merck LiChrosorb RP-8 column were used for sample cleanup. The analytical column was a Partisil , 5 nm column (Whatman, Clifton, N.J.) with hexane-amyl alcohol (99.65 0.35%) as the mobile phase. The cleanup procedure although a deparature from the usual analytical methods, was incorporated to ensure predictable, interference-free vitamin D assays (D2 and D3 co-elute). 

S. N. El-Gizawy, A. N. Ahmed, and N. E. El-Rabbat, High performance liquid chromatographic determination of multivitamin preparations using a chemically bonded cyclodextrin stationary phase, Anal. Lett., 24 1173 (1991). 

S. P. Sood, D. P. Wittmer, S. A. Ismael, and W. G. Haney, Simultaneous high-performance liquid chromatographic determination of niacin and niacinamide multivitamin preparations reversed-phase, ion-pair approach, J. Pharm. Sci., 66 40 (1977). 

Keto-L-Gulonic acid (2-KLG) is the precursor for Vitamin C (L-Ascorbic acid). Vitamin C is used on a large scale as an antioxidant in food, animal feed, beverages, pharmaceutical formulations, and cosmetic applications. About one half of the vitamin C is used in vitamin supplements and multivitamin preparations, one quarter in food additives, 15 percent in beverages, and 10 percent in animal feed. When ascorbic acid is used in... 

Garrett ER, Prediction of stability in pharmaceutical preparations, vitamin stability in liquid multivitamin preparations. JAPhA 1956 45 171-178. 

Multivitamin products for parenteral administration are available in a variety of compositions from different manufacturers. As different formulations are available generally, valid stability information cannot be provided. Stability data obtained on vitamins, derived from studies of a single vitamin, cannot be accurately extrapolated to all multivitamin preparations because of possible vitamin, preservative, and excipient interactions. 

Dopa-decarboxylase is a pyridoxine-dependent enzyme and concomitant use of pyridoxine, e.g. in self-medication with a multivitamin preparation, can enhance peripheral conversion of levodopa to dopamine so that less is available to enter the CNS, and benefit is lost. This effect does not occur, of course, with the now usual levodopa-decarboxylase inhibitor combinations. 

Vitamin deficiencies are commonly multiple, and complex clinical pictures occur. There are numerous single and multivitamin preparations to provide prophylaxis and therapy. 

Fat-soluble vitaimns Oral intake of vitamins A, D and E is usually sufficient — as is the dosage contained in multivitamin preparations when taken daily. Biochemical evidence of deficiency or the occurrence of diseases due to deficiency usually require vitamins A, D, E and K to be supphed parenterally as a compound preparation. (t84, t85) (s. p. 47)... 

The daily food intake should be spread over five meals. However, it is almost impossible to achieve an optimum supply of water-soluble and fat-soluble vitamins. Administration of multivitamin preparations is therefore recommended. Sodium chloride intake should not exceed 7-8 g/day. (s. pp 278, 730, 734, 741)... 

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