Sustained release vitamin preparation.

The present invention relates to a solid sustained release vitamin unit dose for oral administration, comprising a blend of a matrix material and an effective amount of at least one active ingredient comprising at least one vitamin, according to the preamble of the first claim. Commercially available multi vitamin tablets usually take the form of tablets, which comprise multiple, different vitamin species. The problem associated with the known tablets is however that the tablet is administered in one piece, following which it is digested at once into the gastrointestinal system and the full vitamin dose is released at once into the organism. The release of a high vitamin dose at once is undesirable, in particular for water- soluble vitamins as the excess, which is not metabolized, is released from the body rather shortly after intake. This problem is less pronounced with lipophilic vitamins as they are absorbed in lipid tissue and their excretion from the lipid tissue proceeds slowly. Numerous compositions are known which provide a controlled or a sustained release of a drug into the human gastro-intestinal tract. Controlled release may be achieved by encapsulation of the active ingredient in a film, which controls the release of the drug from the composition. Controlled release may also be obtained by coating a drug-containing tablet with a water permeable coating, which permit diffusion of water into the tablet and of active ingredient dissolved in the water from the tablet. Whereas controlled or sustained release of drugs or medicaments has been widely used in the art, controlled or sustained release formulations of vitamins have hitherto not been found on the market. The present invention aims at providing a vitamin preparation which is suitable for oral administration as a solid product, which shows sustained release of the active ingredients incorporated therein with the aim of providing bioavailability of the active ingredients over a desired period of time.

This is achieved according to the present invention with a sustained release vitamin unit dose showing the technical features of the characterizing part of the first claim.

Thereto the matrix material comprises at least one material selected from the group of a cellulose derivative, an acrylic or methacrγlic acid polymer or co-polymers of those, modified gelatin or a blend of two or more of these materials, to provide a sustained release effect of the at least one active material for a time period of from about 8 to about 24 hours and in that the at least one vitamin active ingredient is present in an effective amount to render a desired effect.

In a preferred embodiment the matrix material comprises at least one material selected from the group of alkyl cellulose, gelatin, starch, cross linked starch, alginate, polyvinyl acetate, povidone, polyacrylate, polyethylene glycol polymer or a blend of two or more of these materials, although alkyl cellulose is particularly preferred. The alkyl cellulose matrix material is preferably selected from the group of methylcellulose, carboxymethyl cellulose and salts thereof, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose and or a blend of two or more of those materials. These materials have been found to show an optimal sustained release behavior and permit controlling the release period in an optimum way. Amongst those hydroxypropylmethyl cellulose has been found particularly suitable to provide the desired effect.

The term sustained or controlled release is defined as the release of the active ingredient from the unit dose of this invention, at such a rate that variation of the concentration levels of the at least one active ingredient are maintained within a desired range, to provide that the maximum concentration that can be resorbed by the organism for about 2 to 24 hours, preferably from about 4 to 18 hours, more preferably from about 8 tot 16 hours, is present. The controlled release profile can be altered by varying the amount of matrix material, but also by the inclusion of additional ingredients.

The functioning of the unit dose of this invention is based on the finding that the matrix material shows optimum solubility in the conditions prevailing in the human gastro-enteritic system, the solubility being only slightly pH dependent and depending mainly on the contact time of the unit dose

with water. This effect has been found to be particularly pronounced with alkyl cellulose, more particularly with hydroxypropymethyl cellulose. The inventors have observed that the alkyl cellulose material, in particular the hydroxypropymethyl cellulose when contacted with water, absorbs the water which causes swelling and is followed by gel formation. Following gel formation, the active ingredients partly dissolve in the gel water, after which they can migrate from the tablet and be released into the environment. Thus, release of the active ingredients from the unit dose is determined by the contact time with or residence time in the aqueous environment. Release of the matrix material into the aqueous environment and the active ingredients associated with it, has been found to be further partly determined by the erosion rate of the exposed surface layers. Thus, with the unit dose of the present invention release of the material is governed by the cooperating effects of dissolution and erosion of the matrix material, which permits to adapt the release time as desired. In particular with the present invention release may be controlled over an extended period of time for example from 4 to 24 hours or shorter or longer.

The length of the period over which the sustained release occurs may be controlled by adapting the concentration of the matrix material in the tablet, or in other words the release time may be increased by increasing the matrix material concentration in the tablet. Thereto, the amount of matrix material in one unit dose tablet will usually be 10-50 wt. % with respect to the total weight of the unit dose, preferably 20-40 wt. %, more preferably 20-30 wt. %.

The sustained release as provided by the unit dose of the present invention, ensures that the active ingredient is released in such a way that it is bio-available so that it may be effective for its intended purpose. Bio- available is defined as the total amount of active substance that is dissolved from the unit dose and available for absorption by the organism to provide the desired effect after administration of a unit dosage form. The unit dose of this invention provides release of the active ingredients over a sustained period of time in water or an aqueous medium. Within the framework of this invention "aqueous medium" means any water- containing medium, for example gastric fluid, intestinal fluid and the like.

The permeability of the unit dose of this invention to water vapor may be limited and the resistance to humidity prevailing in the environment be optimized by coating the tablet with a coating comprising an amount of stearic acid, polyvinyl alcohol or any other suitable ingredient. The coating preferably comprises an alkyl cellulose material selected from the group of natural cellulose, microcrγstalline cellulose, methylcellulose, carboxymethyl cellulose and salts thereof, hydroxyethyl cellulose, hydroxypropyl cellulose and hydroxypropylmethyl cellulose or a blend of two or more of those materials. The active ingredient to be released from the composition in a sustained manner is preferably at least one active ingredient selected from the group of vitamins, minerals, enzymes, essential amino acids, non-essential amino acids, proteins, hormones, plant extracts or a blend of two or more of those. Suitable examples of vitamins include the water-soluble vitamins for example vitamin C, vitamin B1, B2, B6, B5, B12, biotin, folic acid, thiamine nitrate, pyridoxine, nicotinamide and lipophilic or fat soluble vitamins for example vitamin A, D, E. They may be incorporated in the tablet as such or using a derivative or a salt thereof. For example vitamin And E may be incorporated as their acetate, vitamin B6 as its hydrochloric acid salt, vitamin B5 as its calcium salt. Suitable examples of essential amino acids include isoleucine, leucine, lysine, methionin, phenylalanin, threonin and valin. Suitable examples of non-essential amino acids include cystein, hystidin and tyrosine. The amino acids may be incorporated as such or as salts thereof, for example leucine.HCI, the hydrochloride of lysine, cystein, methionin and histidin. Suitable minerals to be included in the composition of this invention comprise salts of magnesium, iron, zinc, manganese, pyridoxine, copper, for example magnesium oxide, iron fumarate, zinc sulphate, manganese sulphate, copper sulphate although other suitable salts known to the person skilled in the art may be used as well.

The concentration of the active ingredient in the unit dose of this invention may vary within wide ranges, but preferably equals at least the recommended daily allowance (RDA). Thereby however care will be taken that the concentration of the active ingredient is not such as to adversely affect the dissolution of the matrix material.

The active ingredient will usually be present as a fine solid dispersed distribution of one or more active ingredients in the matrix material. The active ingredient may be dispersed as a solid solution, a fine crystalline form, a glassy amorphous phase or fine amorphous powder. In may cases it will be preferred to have a substantially homogeneous distribution of the active ingredients over the matrix material. A unit dose of this type will be simple to produce and a simple release profile obtained in this manner will usually be sufficient. It may however be desirable to have at least two matrix profiles, for example a non-controlled release and a controlled release zone, or two zones with different sustained release profiles, or any other variation contemplated. Within the framework of this invention different release patterns can be combined in one tablet so that a uniform release of one active substance alternates with the release in bursts of the same or another active ingredient. Other variations will be apparent to the person skilled in the art.

Examples of matrix materials providing direct or non- sustained release include lactose, cellulose, calciumhydrogenposphate dehydrate, calciumphosphate, calciumsulphate, sorbitol, other polyols, saccharose.

In addition to the above-described ingredients a sustained-release unit dose may contain other ingredients conventionally used in the field, such as for example one or more lubricants, binders, granulating aids, colorants, flavorings, release agents, in a concentration, which is adapted and sufficient to obtain the desired effect.

The present invention also relates to a process for producing the above-described unit dose.

According to the present invention, the active ingredients, usually in dry powder form, are mixed with matrix material and homogenized. The thus obtained mixture is mixed with a liquid, preferably alcohol, preferably ethanol, in an amount sufficient to wet the surface of the particles and to obtain a paste. The paste is dried using an air based fluidized bed, to evaporate the alcohol, as a result of which a dry powder is obtained. The use of a fluidized bed presents the advantage over the known art of melting and extrusion that heating of the mixture and the ensuing risk to decomposition or reaction of the active ingredients may be minimized, while good evaporation of the solvent is

achieved at relatively fast drying rates. Preferably drying is continued until the remaining moisture content is not more than 1wt. % with respect to the total weight of the composition. To guarantee homogeneous size distribution of the active ingredients over the tablet and to provide optimum cohesion within the tablet, the powder dried in the fluidized bed is sieved over a sieve, to obtain a powder with particle size of between 0.2 -1.5 or 2 mm. To the thus obtained mixture an amount of a lubricant is added, an amount of the mixture is introduced into a dye and shaped using punches.

Preferably the composition has a geometric shape, which assists in providing a homogeneous release of the active ingredient over the desired period of time. The composition may for example be ball shaped or take the shape of a cylindrical rod or an oval rod.