Multi mineral dietary supplement with controlled release bioavailable iron

Object of the present invention are oral multi mineral preparations with sustained release, optionally with vitamins may be combined, process for producing these multi- mineral supplements and their use in the treatment of Iron deficiency.

are oral ferrous vitamin or mineral supplements as Supplement to the food ingested for the prevention or treatment of Iron deficiency. In general, the shortage is on a mineral accompanied by other symptoms of deficiency. For example, in iron deficiency anemia due to an inadequate supply of iron by inadequate iron intake from food very often a further shortage of other essential food cash equivalents share before. Such multiple deficiencies occur in particular under specific conditions such as in the Growth phase or due to exposure to pregnancy or Breastfeeding. Deficiency symptoms also occur in people who strict dietary restrictions must comply, due to chemo therapy and generally in people with non-conventional Ernährungsver keep such. as anorexia, or in general as a result of conditions recording, utilization and excretion of essential minerals materials such as iron hamper.

It is known that the uptake of iron in mineral gastrointestinal tract is not in the presence of divalent ferrous minerals such as magnesium or calcium beeinträch is taken, for example, see Goodman et al., Pharmacological Basis of Therapeutics, Third Edition 1968, pp. 1396 ff, Freeman et al., Am.J.Physiol., Vol. 137, pp. 706-709 (1942) and amines et al., N. Nutrition, Vol. 101, pages 927-936 (1971).

Many well-known iron-containing mineral preparations which during are to be taken during pregnancy, contain certain amounts of . Calcium and / or magnesium, for example, the preparation Filibon ®: Lederle (Prenatal capsules), see the Physician's Desk Reference (PDR), Medical Economics Co. (Editor), 20th edition, page 670 (1965) and the US Patent 44 31 634th

In addition, ferruginous mineral preparations Nebenerschei causing voltages as constipation, diarrhea and bloating. One has therefore developed special mineral supplements, the iron in the form ent of a depot controlled and continuous release keep, for. example, in a matrix of wax-like material, eg. as the Preparation Slow Fe ®: Ciba-Geigy. It has also proposed Mineral combinations and / or vitamin combinations in a embed porous matrix of polymeric material to this additional materials freizu decelerated in the gastrointestinal tract set, for example, see US Reissue Patent 27 107. With these novel dosage forms could en the described be mitigated or suppressed side effects, the vermin Low-made iron in the gastrointestinal tract at the same time However, the presence of magnesium and calcium remains as a problem consist.

The present invention is an object, a new and advantageous dosage form for iron-mineral combinations without the disadvantages described produce. The new Darrei tical form to the improved absorption of iron in the presence of divalent minerals such as calcium and magnesium without the disadvantages and side effects with optimal allow utilization.

The present invention is also the object of a A method for the prevention and / or treatment of iron deficiency by Application of new and advantageous dosage form for ent wrap.

The aforementioned objects are achieved by the present invention dissolved, which will be described in the following.

The invention relates to iron-mineral composite Preparations for oral use, which in a unit dosage following components:

<ul><li>a) one or more mineral components with divalent bioavailable minerals the group calcium and magnesium,</li><li>b) a bioavailable iron mineral component, which in a Depot form and from which the iron component to the delivery Component a) controlled and continuously in the wider area Gastrointestinal discharged.</li></ul>

The compositions of the invention can pharmazeutichen formulated unit dose preparations in the form of coated tablets be that in an outer layer, the divalent minerals the component a) and in a core, the bioavailable iron mineral ingredient component b) controlled and continuous release power included. The outer layer may also by a further protective layer or a film-like coating to increase the stability of the formulation or for cosmetic or Ge taste reasons be coated. In addition, between the core with the iron depot formulation and the outer layer a further protective layer are that the inner core stabilized and a possible mixing of the active ingredient parts, z. B. of the core and the outer layer, eg., during the Storage of the formulation, is prevented.

Through the delivery of bioavailable calcium and / magnesium in upper part of the gastrointestinal tract, these minerals before the controlled and continuous delivery of bioverfüg up Barem iron in the wider area of ​​the gastrointestinal tract accepted and utilized. The term controlled and conti ous discharge defines a controlled delivery, which delayed used after taking the formulation and in the therapeutic Level or in the effective area longer than a conven tional formulation such as a tablet holding. Advantageously and not an obvious way, the disruptive effect of magnesium and Calcium reduces the absorption of iron. In addition, the because this disturbing effect to maintain a sufficiently high iron levels increased dose of iron reduced will. This advantage is due to an increased iron intake occurring side effects such as constipation particularly into Weight.

In the description of the present invention comprises the Term "Upper Gastrointestinal Tract" the area of ​​the stomach and the upper duodenum. The bioavailable calcium and / or magnesium component as well as additional non-ferrous Mineralstoffkompo components and / or vitamin supplements are in the stomach and upper duodenum preferably submitted. After or the late submission of this compo components and ingredients constitutes controlled and continuous Delivery of iron a. The controlled delivery of iron and in other Part of the gastrointestinal tract, eg. As in the duodenum and jejunum causes maximum absorption and tolerability of the formulation.

The term "Bioavailable calcium" includes calcium compounds or compositions with calcium or calcium mixtures be partially or completely in the upper gastrointestinal tract can be taken, eg. as bonemeal, limestone, pure calcium carbonate, calcium sulfate, calcium gluconate, calcium lactate, calcium phosphate (mono- or polybasic) and calcium laevulinate. calcium carbonate and calcium sulfate are preferred.

The term "Bioavailable magnesium" includes analog Magnesiumver compounds or compositions with magnesium or magnesium mixtures which partially or completely in the upper Gastrotestinal tract are taken. z. B. magnesium carbonate or magnesium oxide. Magnesium oxide is preferred.

As bioavailable iron component may comprise the customary in oral Formulations contained ferrous mineral additives be used, eg., iron-II-salts, eg., iron-II-sulfate, fumarate, gluconate, succinate, glutamate, lactate, citrate, -tartat, pyrophosphate, -cholinisocitrat or carbonate. Iron II sulfate is preferred.

The multi-mineral preparations according to the invention can in particular cially in the outer layer further mineral additives included, which are contained in usual mineral supplements, z. B. copper as cupric oxide, copper sulfate or copper gluconate Phosphorus as calcium phosphate or phosphorus in bone meal, Iodine, z. B. as sodium or potassium iodide, zinc, z. B. as zinc chloride, zinc sulfate or zinc oxide, chromium as chromium-III-chloride (Very small amounts), molybdenum, z. B. sodium, selenium Sodium selenate and manganese, for. Example, as a manganese-II-sulfate or chloride. The last-mentioned metal salts are in for "trace elements" usual concentrations found.

The core of the bioavailable iron component may take the form of a Tablet or in the form of pellets or granules in a water soluble capsule present. The tablet or capsule, the Task controls the iron mineral component and continu ously release. The core, the iron mineral component in controlled amounts continuously over a period of release approximately 2 hours after taking up to eight hours. The Preparing such tablet cores or encapsulated pellets or granules is known per se.

For example, can be granules of ferrous sulfate, fumarate, gluconate, succinate, glutamate, lactate, etc. by mixing with a coating solution containing a suitable polymeric material, z. B. plastic or waxy film former, in an inert volatile solvents such as methanol, ethanol or methylene chloride, coating these ferrous granules, evaporating the Solvent and compressing the coated granules to Tablet tenkernen produce which the iron-containing mineral component in a plastic or wax-like matrix.

Suitable polymeric material with plastic or waxy Properties, the liquid contained in the gastrointestinal tract record speed and controlled amounts of iron-containing minerals ingredient component by slowed and continuous release or by producing passages using osmosis etc. submit. Suitable plastic or film-forming materials are for example, cellulose ethers such as methyl or ethyl cellulose, Hydroxypropyl cellulose, methyl or Arthylhydroxyaethylcellulose, Methyl or Aethylhydroxypropylcellulose, carboxymethylcellulose, Polymers having vinyl groups such as polyvinyl alcohol, polyvinyl acetate, Polyvinylpyrrolidone, and mixtures or copolymers thereof, Cellulose esters such as cellulose acetate, Celluloseacetatpolymere, Polyamide resins, phthalic anhydride Polyhydroxyalkoholbasis, Urethanes, shellac cellulose mentioned etc. Preference ether, polymers with vinyl groups and cellulose esters. this Materials can be added excipients that the Abgabege rate further reduced, eg. as sugar, castor oil hydrogenated, vegetable oils, higher fatty alcohols, higher fatty acids, Polyethylene glycol u. Ä.

As an alternative to embedding in the said materials, the ferrous mineral component in swellable coated Granules or beads (beads) in a water soluble capsule, z. B. in a gelatin capsule containing its z. B. as in the US Patent 32 47 066..

The outer layer with one or more mineral components from divalent bioavailable minerals the group calcium or Magnesium can besides these two minerals other mineral materials included. In a preferred embodiment, the outer layer of the dosage form normal vitamin supplements namely in the usual daily dose (US Recommended Daily Allowance: US RDA) of added vitamins each adult. at multiple dosing may halve this dose, divided into thirds, etc. will. Usual vitamin supplements are for example vitamin A (z. B. as acetate or palmitate), vitamin D (z. B. as cholecalciferol) vitamin B₁ (Z. B. as thiamine mononitrate), Vitamin B₂ (Z. B. as Riboflavin), Vitamin B₆ (Z. B. as pyridoxine hydrochloride), Vita min B₁₂ (Z. B. than Cynocobalamin), Vitamin C (for. Example, as ascorbic acid or sodium ascorbate), vitamin D, vitamin E (z. B. as dl-alpha Tocopheryl acetate), folic acid or niacin (z. B. as niacinamide). Optionally, further vitamins, such as vitamin K₁ (Z. B. as Phytonadione), biotin and pantothenic acid (z. B. as Calciumpanto naphthenate), which in the bioavailable calcium and / or magnesium -containing outer layer may be contained in a dose, the US or the RDA equivalent for these additives in the case of vitamin K₁ up to 100 mg daily dose.

The components of the outer mineral layer can use the be added to conventional carriers and excipients, such. as binding Materia lien as gelatin, gelatine starch, lubricants such as Vegetable oils, stearic acid, etc., diluents such as lactose, mannitol or sucrose, disintegrating agents such as crosslinked carboxymethylcellulose, cross-linked polyvinylpyrrolidone or Carboxymethalstärke (Na-form) Swelling agents such as polyvinylpyrrolidone or polyvinyl alcohol, or Flies regulators such as silica.

The unit dose formulation containing essentially the iron-containing Mineral component and divalent in the shell mineral components of the group formed by calcium and / or magnesium as well as the further front-called non-ferrous mineral components and / or Vitamin supplements produced by methods known per se, z. B. by compressing the components of the core and the core the outer layer covers and, if necessary, this to formulation tion covered with a protective layer. The preparation of capsules is analogous.

For example, one of the core of the formulation in accordance with conventional Tabletting methods, eg., By direct compression or by Kompri ming of granules ago and transferred to the core with the iron containing mineral component in a for pressing of Tablets suitable and pre-pressed with the constituents of outer layer one side filled moldings and surrounds by pressing with constituents of the outer layer, eg. as a Granules, the core. These press-coated tablet may then with sugary dye paint are coated.

Other coatings may the formulation from moisture, Sauer fuel, protect the action of light or the taste or appearance improve the formulation. Suitable coating agents are in for example cellulose, gelatin, Hydroxypropylcellu loose, hydroxypropyl cellulose phthalate, methacrylic acid polymers and shellac.

Instead of such coatings thin enteric coatings may aufgetra be gen and colorants for better differentiation of Formu lation. The formulation can with wax-like material such as Carnauba wax polished.

The preferred embodiments are so dosed that these the for one or two applications, preferably two applications contain the necessary ingredients, the preferred total weight of the formulation is between about 600 and 1200 mg. at Application of two tablets each containing at least about 50% US RDA iron components, eg., Between about 15 and 60 mg, in particular ticular about 20 to 40 mg iron. Preferred amounts of calcium, preferably in the form of calcium carbonate, calcium sulfate, gluconate, phosphate, etc. will be approximately 50 to 200 mg per tablet, in particular about 75 to 150 mg per tablet. Preferred amounts of Magnesium, preferably in the form of magnesium carbonate, oxide or hydroxide be about 8 to 20 mg per tablet. The Usage the formulation for controlling diseases and / or conditions, which are based on iron deficiency, is also the subject of present invention.

The following example illustrates the invention. Unless otherwise stated the amounts are stated in parts by weight.

example

It is a mixture of 96 parts by weight of ferrous sulfate, 75.9 parts lactose, 5.4 parts of hydroxypropyl methyl cellulose and 0.9 parts cetostearyl and 30 parts of methylene chloride ago mixing the ingredients thoroughly, dried and granulated in a granulator with 1.5 mm mesh size. The granulate is mixed with 3.6 parts of magnesium stearate and formed into tablets with a Weight of about 181.8 mg pressed. It covers the tablets a thin film by immersion in a colored coating solution consisting of Opadry ® Light Orange formulation of Colorcon Co., dissolved in 251 parts of methylene chloride and 151 parts of methanol. The so available formulation which the ferrous core of Darrei represents tical form, is dried to provide a sheet coated Tablet core with a total weight of approximately 202.8 mg and a Content of about 30 mg bioavailable iron is replaced.

To prepare the shell of the coated tablet are 343 parts Calcium sulfate, 1.38 parts of copper oxide, 37.8 parts of zinc sulfate, 22.8 parts magnesium oxide, 0.216 parts of potassium iodide and 8 parts mixed polyvinylpyrrolidone (povidone). The mixture is mixed with 1.2 parts of water and 25 parts of methanol, the granulated Mixture dries and grinds this, so that a fine powder Granules obtained. For granules is given to 66 parts ascorbic acid, 10.8 parts of vitamin A acetate and vitamin D mixture (500 IU = Interna tional Units: 50 IU), 33 parts of vitamin E as dl-alpha-tocopheryl acetate, 11 parts of niacinamide, 1.88 parts of riboflavin, 1.728 parts Thiamine mononitrate, pyridoxine hydrochloride 2.2 parts, 0.63 parts Folic acid, 0.75 parts of vitamin B₁₂ (19% SD) and as excipients 65.2 parts of lactose, 42.5 parts of starch, 3.4 parts of silica, 50 parts hydrogenated vegetable oil and 29.2 parts Carboxymethylstärke- Sodium salt. When mixing these ingredients are still 17 parts of stearic acid added. Approximately 749 mg of this mixture are for each formulation for the manufacture of the outer Layer required. The preparation of the coated tablet is made by Compression along with the core in suitable molds, whereupon gives a formulation with about 952 mg total weight. The Tablet with coating solution "Opadry ®" -Farblos, 2.3 parts in 28.3 parts of methanol and 47 parts of methylene chloride, coated and dried, followed by a formulation containing 954 mg total weight receives.