IES86040Y1 - A process for producing a tablet - Google Patents
A process for producing a tabletInfo
- Publication number
- IES86040Y1 IES86040Y1 IE2011/0379A IE20110379A IES86040Y1 IE S86040 Y1 IES86040 Y1 IE S86040Y1 IE 2011/0379 A IE2011/0379 A IE 2011/0379A IE 20110379 A IE20110379 A IE 20110379A IE S86040 Y1 IES86040 Y1 IE S86040Y1
- Authority
- IE
- Ireland
- Prior art keywords
- tablet
- blend
- active ingredients
- particulate
- matrix material
- Prior art date
Links
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- 235000009529 zinc sulphate Nutrition 0.000 description 1
Abstract
ABSTRACT The present invention relates to process for producing a sustained release solid vitamin tablet comprising the steps of blending one or more active ingredients in a particulate form and at least one particulate matrix material for the active ingredients to provide a blend, drying the blend and molding it into at least one tablet. The blend comprising the one or more particulate active ingredients and at least one particulate matrix material is contacted with a mixture of a wetting fluid and a binder material in a fluidised bed.
Description
A process for producing a tablet The present invention relates to a process for producing a solid vitamin tablet for oral administration, comprising the steps of blending one or more active ingredients in a particulate form and at least one particulate matrix material for the active ingredients to provide a blend, drying the blend and molding it into at least one tablet according to the preamble of the first claim.
Commercially available vitamin tablets often comprise multiple, different vitamin species. The use of sustained release vitamin tablets permits to achieve a gradual release of the vitamins into the organism over time, and to minimize the risk that a high vitamin dose is released at once into the organism. The human body tends to release an excess of vitamins which cannot be metabolized at once rather shortly after intake. Whereras the problem of an excess dose is more pronounced with lipophilic vitamins which may be absorbed by lipid tissue, it is particularly important for water-soluble vitamins which will be released from the body together with other body fluids.
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 in different ways, for example by encapsulation of the active ingredient in a film which controls the release of the drug from the composition, by coating with a water permeable coating which permits 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, commercial activity in relation to controlled or sustained release formulations of vitamins remained iimited.
WO2007/68287 discloses a solid sustained release vitamin tablet for oral administration. Sustained release of the active sfiiéotco components over a time period of from about 8 to about 24 hours is provided by the matrix material, which is selected from the group of a cellulose derivative, an acrylic or methacrylic acid polymer or co-polymers of those, modified gelatin or a blend of two or more of these materials. the active ingredients, usually in dry powder form, are mixed with matrix material and homogenized. Tablets are produced by mixing dry powdery active ingredients with dry powdery matrix material. The thus obtained blend is mixed with ethanol to form a paste. The paste is dried and alcohol is evaporated in an air based fluidized bed. Particulate material with a particle size of between 0.2 — 1.5 or 2 mm is selectively sieved off, mixed with lubricant and shaped into tablets.
In a central part of vitamin tablets, often a central groove, often V~shaped, is provided to facilitate dividing of the tablet into halves.
It has however been observed that cohesion within the known vitamin tablets is insufficient, which gives rise to breaking of the tablet during production. Often breaking occurs along the central groove.
The present invention seeks to solve this problem of unwanted breaking of the tablets during production.
This is achieved according to the present invention with a process showing the technical features of the characterizing part of the first claim.
Thereto the method of this invention is characterized in that the blend comprising the one or more particulate active ingredients and at least one particulate matrix material is contacted with a mixture of a wetting fluid and a binder material in a fluidized bed.
The person skilled in the art will be able to determine the amount of wetting fluid and binder material which is needed to and sufficient to achieve a sufficient wetting of the particulate material, to permit tabletting of the active ingredients and matrix material.
Within the scope of this invention, a mixture of a wetting fluid and a binder material includes a solution of one or more binder materials into the wetting fluid, a dispersion or emulsion of one ore more binder materials into the wetting fluid.
The inventors have found that the method of the present invention, in particular the use of a fluidized bed for applying a mixture of a wetting material and a binder material to the particulate active ingredients and particulate matrix material, permits achieving an optimized wetting of these particles. Especially, the use of a fluidized bed for applying the mixture containing the binder material permits to achieve a finer atomization and finer and more homogeneous dispersion .of the binder material containing mixture over the particles of the matrix material and active ingredients. This way the number of adhesion points created on the particulate materials may be increased, as a result of which adhesion of particles to each other upon drying and molding, may be reinforced. in other words, the optimized wetting permits achieving an improved adhesion of the active ingredient particles to the matrix particles, of the active ingredient particles amongst each other and of the matrix particles amongst each other. The improved adhesion of the particles to each other has the effect that after molding, the mechanical strength of the tablets may be improved, that the resistance to breaking of the tablets may be increased, whereas brittleness of the tablet and the risk to breaking of tablets already during production may be reduced.
The movement to which the matrix material and active ingredients are subjected in the fluidized bed has been found to - positively influence their mixing and has a more intensive mixing and improved blending of these materials as a result. Thus a more homogeneous distribution of the active ingredients and matrix material over the tablet may be achieved.
The amount of wetting fluid mixture containing the binding material applied should be sufficiently high to achieve sufficient and sufficiently homogeneous wetting of the particles of the particulate matrix material. Therefore, the amount of wetting fluid mixture will usually be at least .0, preferably at least 10.0, more preferably at least 15.0 I per 100 kg of blend of particulate matrix material and active ingredients.
The amount of wetting fluid mixture containing the binding material applied is preferably not above 35.0 i per 100 kg of blend, preferably not above 30.0 i, preferably less than 25.0 I per 100 kg of blend.
The concentration of the binder material in the wetting fluid mixture is not critical to the invention and may vary within wide ranges. Preferably however the binder material is applied in such an amount that the concentration of the binder material in the tablet is at least 0.01 wt. %, preferably at least 0.10 wt. %, more preferably at least 0.50 wt. % with respect to the weight of the tablet. Preferably the binder material is applied in such an amount that the concentration of the binder material in the tablet is less than .0 wt. %, preferably less than 10.0 %,aVmore preferably less than 5.0 wt. %, most preferably less than 2.0 wt. %.
After having been subjected to wetting with a mixture of wetting fluid and binder material, the wetted blend of particulate. material is dried. Drying is preferably carried out in the fluidized bed, at a temperature of at least 30°C and below 100°C, more preferably at least 30°C and below 75°C, most preferably at least 40°C and below 60°C.
Drying is preferably carried out until the fluid content of. the dried tablets is less than 5.0 wt. %, preferably less than 2.5 wt. %, more preferably-maximum 2.0 wt. %. Fluid is considered to comprise water as well as wetting fluid. The above given ranges provide an optimum compromise between a sufficiently high fluid content to guarantee adhesion of the particles and to reduce the risk to unwanted brittleness and disintegration of the tablets after moulding, and a sufficiently small fluid content after drying, as this would hamper the moulding of tablets and result in disintegration of the tablets.
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 —~ 2.0 mm, preferably between 0.2 and 2.0 mm.
The blend of one or more particulate active ingredients and particulate matrix material for the active ingredients is introduced into a fluidizing bed, where a wetting fluid is supplied in an amount sufficient to wet the active ingredients and matrix material. As wetting fluid preferably use is made of an alcohol or a mixture of two or more alcohols. The preferred alcohol is ethanol, because of its relatively low boiling point and high volatility, certainly in a fluidizing bed. Thus the 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.
To operate the fluidized bed, any gas may be used that is not reactive with the wetting fluid, the particulate matrix material and the active ingredients. Suitable gases include air, nitrogen, a noble gas for example argon, neon, helium. Preferably however air is used. . ' Within the scope of the present invention, a wide variety of matrix materials in particulate form may be used. Thereby the matrix material may be a material which provides a time controlled or sustained release of the active ingredients contained in the tablet. The matrix material may however also be a conventional matrix materiai, which does not provide sustained release. Examples of suitable particulate matrix materials which. provide controlled release of the active ingredient include cellulose derivatives, acrylic or methacrylic acid polymers or co-polymers of those, modified gelatin or a blend of two or more of these materials. Preferred matrix materials include ‘ alkyl cellulose, natural cellulose, microcrystalline cellulose, 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.
The vitamin tablet of the present invention may be a tablet capable of providing sustained, controlled or retarded release of the vitamins contained therein. Within the scope of the present invention sustained or controlled release is defined as the release of the active ingredient from the tablet 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 matrix materials listed above present the additional advantage that they ensure a release of the active ingredient in such a way that it is immediately bio-available for absorption by the organism to provide the desired effect. Hydroxypropylmethyl cellulose has been found particularly suitable to provide the desired effect of sustained release behavior and permits controlling the release period in an optimum way. Therefore it is a particularly preferred matrix material. The controlled release behavior of certain active ingredients as a function of time, may further be adapted by the inclusion of additional ingredients. l The vitamin tablet of the present invention may be a tablet capable of providing direct release or non-sustained release. Examples . of suitable matrix materials include gelatin, starch, cross linked starch, alginate, lactose, cellulose, caiciumhydrogenphosphate dihydrate, calcium phosphate, calcium sulphate, sorbitol, other polyols, saccharose.
If so desired a mixture of one or more particulate matrix materials providing sustained release of active ingredients and one or more particulate materials providing direct release of active ingredients may be used as well.
The functioning of a controlled or sustained release tablet that may be obtained with the method of this invention is based on the finding that the matrix material shows optimum solubility in the conditions prevailing in the human gastro-enteric system, the solubility being only slightly pH dependent and depending mainly on the contact time of the tablet with water. This effect has been found to be particularly pronounced with alkyl cellulose, more particularly with hydroxypropymethyl cellulose as matrix material. The inventors have observed that these matrix materials absorb water, which causes swelling and is followed by gel formation. The active ingredients partly dissolve in the aqueous gel, after which they can migrate from the tablet and be released into the environment. Thus, release of the active ingredients from the tablet 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 at least partly determined by the erosion rate of the exposed surface layers. Thus, with the tablet. of the present invention release of the material is governed by the co-operating effects of dis and erosion of the matrix material, which permits to adapt the release time as desired.
The amount of matrix material in a tablet of the present invention will usually vary between -10.0-50.0 wt. % with respect to the total weight of the tablet, preferably 20.0-40.0 wt. %, more preferably 20.0-30.0 wt. %. 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.
Within the scope of this invention, a wide variety of binder materials may be used. Suitable binder materials include those which are soluble in water or the fluid used as wetting fluid, and which remain behind as a solid powder upon drying. The person skilled in the art will be capable of identifying the most appropriate binding material in relation to the nature of the matrix material and the active ingredients. Examples of suitable binder materials include cellulose derivatives, gelatin, synthetic materials, in particular alkyl cellulose, natural cellulose, microcrystalline cellulose, polyvinyl acetate, povidone, polyacrylate, polyethylene glycol polymer or a blend of two or more ‘ of thesematerials, although alkyl cellulose, in particular hydroxypropylcellulose is particularly preferred.
The concentration of the binder material in the wetting fluid may vary within wide ranges, but preferably ranges between 0.5 and 10.0 kg binder per 100 l of wetting fluid, preferably between 1.0 and 10.0 kg binderl 100 I wetting fluid, more preferably between 2.5 and 7.5 kg / 100 l.
The permeability of the vitamin tablet of this invention to water or water vapor may be further controlled 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. Within the scope of the present invention a wide variety of coating materials may be used, for example natural cellulose, microcrystalline 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 coating may also fulfil other functions and for example provide a certain flavour or provide moisture protecting properties. in the vitamin tablet of the present invention a wide variety of active ingredients may be used. Preferably the at least one active ingredient is 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 (=B1), pyridoxine (=B6),. 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 A 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.HC|, 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, molybdene, 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 above-listed active ingredients include water soluble compounds as well as lipophilic compounds.
The concentration of the active ingredient in the tablet 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. in addition to the above-described ingredients a vitamin tablet according to the invention 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 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.
Blending of the one or more particulate active ingredients and the at least one particulate matrix material for the active ingredients may be done in advance of introducing the blend into a fluidizing bed, or it may be done in the fluidizing bed.- Molding of tablets will usually be done by adding to the thus obtained mixture an amount of a lubricant, blending these ingredients and introducing the blend into a dye and shaped using punches.
Preferably the composition has a geometric shape, which assists in providinga 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.
The tablet of this invention provides release of the active ingredients 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 present invention also relates to a vitamin tablet. The tablet will usually comprise a particulate matrix material, at least one lipophilic active ingredient, at least one water soluble active ingredient and at least one binder material, applied in a fluid bed. Thereby the concentration of the components will be as described above. The vitamin tablet may further comprise the usual active ingredients and additives described above.
The present invention further relates to a sustained release vitamin tablet, wherein the matrix material comprises at least one material selected from the group of a cellulose derivative, an acrylic or rnethacrylic 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 lease 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.
The above described vitamin tablets, with or without sustained release matrix, may be coated with a coating comprising at least one alkyl cellulose. The alkyl cellulose material may be selected from the group of natural cellulose, microcrystalline cellulose, methyl cellulose, carboxymethyl cellulose and salts thereof, hydroxyethyl cellulose, hydroxypropyl cellulose and hydroxypropylmethyl cellulose or a blend of two or more of those materials. -
Claims (5)
1. A process for producing a solid vitamin tablet for oral administration, the process comprising the steps of blending one or . more active ingredients in a particulate form and at least one particulate matrix material for the active ingredients to provide a blend, drying the blend and ‘ molding it into at least one tablet, characterized in that the blend comprising the one or more particulate active ingredients and at least one particulate matrix material is contacted with a mixture of a wetting fluid and a binder material in a fluidized bed.
2. A process according to claim 1, wherein at least 5.0 and less than 35.0 I of wetting fluid mixture is applied per 100 kg of blend.
3. A process according to any one of claims 1-3, wherein the binder material is applied in such an amount that the concentration is at least 0.01 wt. % and maximum 15.0 wt. % with respect to the weight of the tablet.
4. A monolayer vitamin tablet comprising a particulate matrix material, -at least one lipophilic active ingredient, at least one water soluble active ingredient and at least one binder material.
5. A vitamin tablet according to claim 4, wherein the matrix material comprises at least one material selected from the group of a cellulose derivative, an acrylic or methacrylic 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 lease 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.
Publications (2)
Publication Number | Publication Date |
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IES86040Y1 true IES86040Y1 (en) | 2012-08-01 |
IE20110379U1 IE20110379U1 (en) | 2012-08-01 |
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