STABLE MULTI-VITAMIN FORMULATIONS
FIELD OF THE INVENTION
The present invention relates to a stable, freeze dried, sterile parenteral formulation of multivitamins produced thereby for patients in need thereof. The invention presents a freeze dried sterile composition of vitamins along with pharmacologically accepted excipients which is reconstituted before administration for injection or through infusion.
More specifically the invention relates to a freeze dried sterile composition of multivitamins which is contained in a single vial for parenteral administration.
BACKGROUND OF THE INVENTION
Multivitamin parenteral formulations have been prescribed for providing total parenteral nutrition or TPN. For catering to all types of patient population inclusive of children below 11 years a complete spectrum of fat soluble and water soluble vitamins including vitamin K are required.
Depending on the solubility characteristics vitamins are broadly classified in to two categories. Water soluble and fat soluble vitamins. Vitamin C and vitamins of B-Complex fall under water soluble category and other vitamins fall under Fat soluble category.
Water Soluble Vitamin C (ascorbic acid) is involved in collagen metabolism, and is thus a necessary cofactor for adequate wound healing. Its effects on immune function include improved polymorphonuclear cell adherence, delivery and motility, increased antibody production and enhanced

lymphoproliferative responses. Vitamin C is an important component of oxidation reduction and hydrogen ion transfer reactions, as well as a powerful antioxidant for Folic acid.
Folic acid deficiency may result in megaloblastic anemia after as little as 4 weeks without multivitamin supplementation. Folic acid is a cofactor in numerous metabolic pathways, especially those of amino acid and nucleotide metabolism, and is necessary for DNA synthesis. Folic acid deficiency has been shown to be related to certain birth defects, especially anencephaly.
Niacin (nicotinic acid, vitamin B3) deficiency can result in pellagra, which is characterized by dermatitis, diarrhea, and dementia. Niacin is an important component of nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP), cofactors of dehydrogenase enzymes involved in many important metabolic pathways.
A deficiency of thiamine (vitamin Bl) can develop quite rapidly. This is often manifested with symptoms characteristic of peripheral neuritis, known as "dry beriberi." In severe cases, cardiac dysfunction from high output failure can occur, and is referred to as "wet beriberi." The occurrence of severe, sometimes fatal, clinical thiamine deficiency in patients receiving TPN" demonstrates the need to insure that all parenteral nutrition contain thiamine in adequate quantities. Thiamine may be deficient in apparently well nourished alcoholics. Immediate, appropriate, and daily multivitamin supplementation is especially important in these patients. Severe alcoholism is the most common factor predisposing to the development of Wernicke's encephalopathy. The need for thiamine increases as carbohydrate intake increases. Thiamine is a cofactor in various metabolic reactions. It also plays a role in nerve transmission.

Riboflavin (vitamin,|B2 deficiency is characterized by stomatitis, glossitis, and seborrheic dermatitis. Riboflavin is an important component of flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN), cofactors of enzymes involved in biological oxidation reduction reactions, including those involved in glucose oxidation, amino acid deamination, and free fatty acid breakdown.
Vitamin B6 (pyridoxine) is required for amino acid metabolism and protein
synthesis. Transamination and decarboxylation are essential biochemical processes
i that require vitamin B6 or its metabolites. Metabolites of vitamin B6 are involved
in the biosynthesis of porphyrins and heme. Deficiency of pyridoxine produces
glossitis and stomatitis. Peripheral neuritis and seizures can also occur.
Deficiency of vitamin B12 (cyanocobalamin) can result in pernicious anemia. Vitamin B12 is essential for thymidylate synthesis and, therefore, for DNA synthesis. Any abnormality of the distal ileum, where its metabolic receptor is found, can reduce vitamih B12 absorption.
Clinical signs of pantothenic acid deficiency include nausea, vomiting, headache, muscle cramps, fatigue, and paresthesia of the hands and feet. Pantothenic acid is used as a building block in the synthesis of coenzyme A (essential for glucose, protein, and fat metabolism) and acyl carrier protein (essential for fatty acid synthesis).
Biotin deficiency may result in dermatitis, as well as in paresthesia. Biolin is an important cofactor for many enzymes involved in carbohydrate, fat, and protein metabolism.
Fat Soluble Vitamin A has numerous fiinctions. Besides its well known role in vision, it is important for cellular differentiation and for the functioning of the

immune systems. Vitamin A has effects on cell mediated immunity and lymphoproliferation in vitro. A correlation exists between vitamin A deficiency and an increased susceptibility to infections. Vitamin A may also reverses the inhibitory effect of corticosteroids on the healing of intestinal anastomoses.
The major function of vitamin D is maintenance of plasma calcium and phosphate homeostasis. Vitamin D deficiency results in inadequate intestinal absorption and renal reabsorption of calcium and phosphorus and hyperparathyroidism. Laboratory findings include low levels of calcium and phosphorus and increased serum alkaline phosphatase activity.
Vitamin E (tocopherol) is an antioxidant and protects cell membranes from the deleterious effects of the products of fat oxidation. Vitamin E is derived from a series of dietary tocopherols and tocotrienols, the most potent of which is D alpha tocopherol.
Commercially prepared adult vitamin solutions do not contain vitamin K because it may interfere with anticoagulation therapy. The long term TPN patient may require weekly injections of vitamin K.
There are numerous patents and applications in the art over different composition of different patents. US patent 3,626,065 assigned to Meakawa and Egawa, discloses stable aqueous multivitamins preparations. The patent points out the known fact that Vitamin Bl, Vitamin C and Vitamin A are unstable together in aqueous preparations. This patent teaches an aqueous preparation of multivitamins such that they are made at two different pH concentrations and stored in separate compartments. The two phases are admixed before administration.

us patent 3,914,419 patent teaches an injectable liquid composition of multivitamins in a two chambered one unit consecutively administrable package. The disclosed invention gives stable aqueous multivitamin preparation in two phases at two different pH. Each incompatible phase is stored in two different compartments of a single hypodermic syringe. The composition however does not include Vitamin K.
US patent 4,740,373 teaches stable aqueous multivitamin/trace elements preparation for parenteral administration. The patent discloses the use of unsaturated organic acids prevent the rapid inter-reaction between vitamins and trace elements and act as potential stabilizers. However the incompatibility between the different vitamins is not dealt and the composition is filled in two compartment one unit vial or syringe.
US patent 5,770,233 teaches a container with two compartments each filled with infusion liquids. Further one of the compartments in the container comprises of vitamin C, vitamin Bl, vitamin B2, vitamin A, vitamin D, vitamin E, vitamin K in fat emulsion and sugar; the second compartment comprises of amino acid, electrolyte, vitamin B6, vitamin B12 and folic acid. The patent recites that vitamins are usually unstable and a certain combination of vitamins can cause decomposition of one of the vitamins or can make the liquid turbid. To avoid the same a two compartment container is devised for the composition.
US patent 6,129,925 which is a continuation of 5,770,233 recites an infusion preparation comprising amino acid, electrolytes, fat emulsion, sugar and vitamins. The preparation is filled in a two compartment container to avoid any mixing of the content in each.

wo application 98/08522 discloses a composition of multivitamins and other essential elements wherein the actives are mixed in dry state and put into a suitable unit dose delivery device such as a capsule, sachet or other unit dose which does not involve significant compaction. This patent discloses a nutrient composition targeted to achieve better autonomic balance and enhanced performance in the patient.
However a need has been felt for stable parenteral multivitamin formulation comprising oil soluble and water soluble components including Vitamin K which can be used for adult as well as paediatric patient population for TPN.
OBJECTIVES OF THE INVENTION
The primary objective of the present invention is to provide a combination of water soluble and fat soluble vitamins in a physiological micellar system contained in a unitary container closure pack.
Another objective of the present invention is to provide a product under proper dilution that would contribute intake of necessary vitamins including vitamin K for maintaining the body's normal resistance and repair processes (not only as daily maintenance dose but also in situations like surgery, extensive burns, trauma, fractures and severe infections).
Yet another objective of the present invention is to provide a lyophilized formulation of multivitamins that is stable.

SUMMARY OF THE INVENTION
The present invention relates to a parenteral formulation comprising 13 water soluble and oil soluble vitamins including Vitamin K in physiologic micellar system containing soybean lecithin, glycocholicacid and glycine as adjuants to produce a lyophilized product in a unitary container closure system which is stable.
DESCRIPTION OF THE INVENTION
■r
The present invention is a stable parenteral formulation comprising 13 vitamins including Vitamin K and lyophilized to achieve stability. It has now been unexpectedly found that during the process of manufacture of this lyophilized formulation involving glycine, glycocholicacid, soybean lecithin and sodium hydroxide, the lyophilized parenteral formulation is stable.
The invention which is a stable lyophilized parenteral formulation
comprising of vitamins is formulated using a four step process.
Step I (Aqueous phase): Water soluble vitamins like Ascorbic acid, Thiamine HCl,
Pyridoxin HCI, Dexpanthenol, Biotin, Cyanocobalamin, Nicotinamide, Riboflavin
5 Phosphate and Glycine are dissolved in sufficient quantity of WFI to obtain a
clear solution. Folic acid is dissolved in WFI separately and made alkaline using
NaOH solution to obtain clear solution.
Step II (Oily phase): Glycocholic acid is dispersed in WFI and solubilized using
sufficient quantity of NaOH solution. Lecithin is emulsified in WFI and oil soluble
vitamins like A, D3, E and K are added to it. The bulk is homogenized by adding
i the glycocholic acid solution till a uniform smooth emulsion containing micelles is
obtained.

under continuous homogenization at a speed of about 1000 to 10000 rpm to
control the particle size. pH of the bulk observed at this stage is in the range of 3.8
to 4.5. pH is then adjusted between 5 and 6 using NaOH solution and FoMc acid
solution is added to the bulk under continuous homogenization. pH of the final
solution is made up to 5.5 -6.5 using NaOH solution.
Step IV (Lyophilization):j Filled vials (5mL fill in lOmL amber vials) are
iyophilized to obtain lyophilized powder / cake.
The following non-limiting example is intended to demonstrate the preferred
i embodiment of the invention. One skilled in the art will readily recognize that
numerous embodiments of the invention can be practiced to achieve the stabilizing
effect.
Example 1
. The process as per the description.

What is claimed is
1. A parenteral multivitamin lyophilized formulation comprising Retinol palmitate, Cholecalciferol, Tocopherol, Ascorbic acid, Nicotinamide, Panthenol, Pyridoxine, Riboflavin, Thiamine, Folic acid, Biotin, Cyanocobalamine, including Vitamin K which is stable.
2. A parenteral multivitamin lyophilized formulation according to claim 1 which is stable at room temperature and also at 2 to 3. A parenteral multivitamin lyophilized formulation according to claim 1 which is a combination of water soluble and fat soluble vitamins in a physiological micellar system contained in unitary container closure pack.
4. A process for manufacture of a stable parenteral multivitamin lyophilized
formulation according to claim 1 wherein the said process comprises
(i) Formation of a micellar system to solubilize hydrophobic drugs in an
aqueous environment (ii) Homogenizing the mixture containing aqueous and oily phase to
monitor particle size
(iii) Lyophilizing the product to obtain lyophilized powder/ cake.
i I
Signature of First Inventor