DE19536387A1 - Process for the preparation of vitamin-containing solid preparations - Google Patents

Abstract

A process for preparing vitamin-containing pharmaceutical products by extruding then moulding a vitamin-containing molten polymer is characterised in that a hydroxypropyl cellulose is used as matrix polymer.

Description

The present invention relates to a method for manufacturing of vitamin-containing solid preparations by extrusion active polymer melt and subsequent shaping and dosage forms from these preparations.

The preparation of active ingredient-containing preparations Melt extrusion is well known.

In US-A 4,801,460 the manufacture of solid medicament shape by melt extrusion of mixtures of active ingredient and thermoplastic N-vinylpyrrolidone polymers described. As Active ingredients are also called vitamins, for example.

Many vitamins are chemically labile substances that have already passed through Atmospheric oxygen, heat and water ingress are decomposed (see V. Bühler, "Vademecum for Vitamin Formulations", Scientific Publishing company Stuttgart (1988), e.g. B. page 9) and insofar for a thermal processing like melt extrusion not necessarily suitable. In US-A 4,880,585 described the processing of vitamins, but persisted with regard to the stability of the preparations, there is still room for ver improvements.

The object of the present invention was to provide an improved Ver continue to find the manufacture of vitamin preparations.

Accordingly, there has been a process for producing vitamin-containing ones solid preparations by extrusion of a vitamin-containing one Polymer melt and subsequent shaping found which is characterized in that a water-soluble as the matrix polymer Liche thermoplastic hydroxypropyl cellulose is used.

The vitamin-containing melt is produced in the extruder preferably at temperatures from 80 to 110 ° C.

As a polymeric matrix for the vitamin-containing preparations a water-soluble, thermoplastic processing according to the invention bare hydroxypropyl cellulose used, which preferably a mo laren degree of substitution of 3.0 to 4.4. "Molar sub degree of stitution "refers to the average number of  Moles of propylene oxide, which are converted per cellulose glucose unit sets are.

The hydroxypropyl celluloses can have melt viscosities DIN 53735 in the range from 0.075 to 54.8 g / 10 min.

The molecular weight of the hydroxypropyl cellulose can be broad Ranges are varied depending on whether a slower one or a faster release of active ingredient is desired. High molecular weight lare hydroxypropyl cellulose with molecular weights in the range of 200,000 to 1,500,000 are particularly suitable for production of dosage forms in which slow drug release is desired, e.g. B. in extended release forms, since the higher molecular polymers less well and only with swelling in water to solve.

However, if you want pharmaceutical forms with a faster active ingredient Establish release, use is recommended molecular polymers that are readily water-soluble, being in this Case of hydroxypropyl celluloses with a molecular weight of 60,000 to 200,000, preferably 60,000 to 100,000 who used that can.

The production of the hydroxypropylcel used according to the invention lulosen is well known. They are commercially available for example under the brand name Klucel® (from Aqualon).

The proportion of hydroxypropyl cellulose in the total amount of Dosage form can be 5 to 95% by weight, preferably 15 to 40% by weight carry.

In principle, according to the invention, all vitamins come in as vitamins Consider because of the low processing temperatures sensitive substances can also be used. Vitamins Provitamins or Vitaminderi are also within the meaning of the invention vate.

Suitable vitamins are accordingly:

• - Vitamin A group
  Retinol (A₁), dehydroretinol (A₂), retinoids such as vitamin A acid, carotenoids such as. B. β-carotene,
• - Vitamin B group
  Thiamine (B₁), riboflavin (B₂), the B₆ vitamins pyridoxal, pyridoxamine and pyridoxine, cobalamins (B₁₂) such as cyanocobalamin, bio tin, folic acid, nicotinic acid, nicotinamide, pantothenic acid,
• - Vitamin C group
  Ascorbic acid and its physioligially tolerated salts such as ascorbyl palmitate
• - Vitamin D group
  Ergocalciferol (D₂), colecalciferol (D₃), provitamin D₃ (7-dehy drocholesterol), provitamin D₂ (ergosterol)
• - Vitamin E group
  α-tocopherol, tocopherol acetate, γ-tocopherol, tocopherol succinate
• - Vitamin F (essential fatty acids)
  such as linolenic acid, linoleic acid or arachidonic acid,
• - Vitamin K group
  Phylloquinone (K₁), menaquinone 7 (K₂).

Combination preparations can also be produced.

The dosage forms can the vitamins in amounts from 0.1 to Contain 95 wt .-%, the dosage depending on the one hand Type of vitamins, the other depends on the use.

Furthermore, the pharmaceutical forms according to the invention can still be conventional contain pharmaceutical excipients, provided that they fall under the ver working conditions thermally stable and with the used Vitamins are compatible, e.g. B. fillers or extenders, Lubricants, plasticizers, stabilizers, dyes or pig elements, disintegrants, preservatives of flavorings. Suitable fillers are, for example, organic compounds such as lactose, sorbitol or mannitol or inorganic substances such as Kie silica or silicates. Well water soluble fillers like Lactose, sorbitol or mannitol are, for example, suitable for the manufacture provision of preparations with accelerated release of active ingredient tongue.

The proportion of fillers in the preparation depends on the active ingredient dosage. For active ingredients with a low dosage can, according to the invention, have a higher proportion of filler Tablet weight can be achieved without the thermoplastic  Processability is impaired. At very low to dose materials, the amount of filler can be up to approx. 90% by weight be.

Flow regulators can be used as further pharmaceutical adjuvants agents such as the mono-, di- and triglycerides long-chain fatty acids such as C₁₂-, C₁₄-, C₁₆- and C₁₈-fatty acid or Waxes such as carnauba wax can be used in the usual quantities.

As plasticizers such. B. in addition to low molecular weight polyalkylene oxides such as polyethylene glycol, polypropylene glycol and polyethylene propylene glycol also polyhydric alcohols such as propylene glycol, Gly cerin, pentaerythritol and sorbitol and sodium diethylsulfosucci nat, mono-, di- and triacetate of glycerin and polyethylene glycol called stearic acid esters, provided these substances are not incompatible Show lity with the vitamins used. Here lies the amount of plasticizer at about 0.5 to 15, preferably 0.5 to 5% by weight.

As a lubricant such. B. Stearates of aluminum, magnesium or calcium as well as talc and silicones called, their amount is about 0.1 to 5, preferably 0.1 to 3% by weight.

Particularly preferred are vitamin-containing medicinal forms which are used as Mold release agents and aids for influencing the plastic act of the melt contain lipids.

According to the invention, mono-, di- and triglycerides come from as lipids naturally occurring fatty acids, for example Glycerol monostearate, glycerol mono- and distearate, glycerol tri stearate, glycerol tripalmitate, glycerol trimyristate, glycerol tribe henate, Glycerolpalmitylstearylester or glyceride mixtures like them occur in natural oils, preferably hydrogenated castor oil.

Ceramides are also suitable for this purpose.

Preferred lipids are especially phospholipids, with phosphogly cerides such as lecithins are particularly preferred. Especially be hydrogenated lecithins such as soy and egg lecitin are preferred.

The lipids can be present in amounts of 0.1-10% by weight, based on the Total amount of preparations containing active ingredient, who used 1 to 5% by weight are preferred.  

Examples of stabilizers are light stabilizers, Antioxidants, radical scavengers and anti-microbial stabilizers len called infestation, which are used in the usual amounts can.

For flavoring and sweetening, for example for use as a lozenge, can be natural, nature-identical or artificial flavors and sweeteners such as B. Cyclamate, Aspartame, Neo hesperidin or saccharin sodium or mixtures thereof will.

To carry out the method according to the invention, the Vi tamine either directly as a physical mixture with the matrix polymer melted or with the already existing Polymer melt can be mixed. The latter approach emp is particularly suitable for very temperature-sensitive vitamins.

It is possible to melt the excipients from active ingredients and to mix polymers. The auxiliaries can also be used together be incorporated into the polymer melt with the active ingredient. Mixtures of excipients, the active ingredient and the Polymers are fused directly.

According to the inventive method, the Matrix polymers and mixing with active ingredients and auxiliaries at temperatures of 50 to 150 ° C, preferably 80 to 110 ° C in a twin screw extruder.

The vitamin-containing melt leaving the extruder can, as in the US-A 4,880,585 described, directly over counter-rotating form whale Zen pairs are pressed into tablets. On the other hand, Ver drive to the production of small particles (pellets) possible, for. B. by using the hot cut process (extrusion of the melt through thin holes; Cut the extrudate strands directly in front of the perforated nozzle plate by rotating knives to pellets). It is also possible to melt after leaving the extru Allow to cool and only after cooling and curing ground into granules or powders using suitable mills. Such pellets, granules or powders are suitable for. B. to Ab fill in hard gelatin capsules, but also as a preliminary stage for a downstream tableting pressing process.

The method according to the invention is particularly suitable for manufacturing development of vitamin preparations, the oxidation and temperature contain sensitive vitamins, provitamins or vitamin derivatives By melting the vitamins into the polymer matrix  oxidative decomposition (atmospheric oxygen!) is minimized because the cooled melt is not porous.

Ascortoic acid can be processed largely without decomposition ten what in terms of temperature sensitivity of this Substance was surprising. Β-Carotene is also excellent process without significant isomerization taking place det. The storage stabilities of the formulations according to the invention were also good; after three months of storage at 30 ° C for example, no loss of vitamins.

The vitamin preparations produced according to the invention can for pharmaceutical or veterinary purposes the. They are also suitable for "vitaminizing" foods, for example as a drinking solution by sprinkling appropriate Granules or powder in water, other drinks or in food. Compositions containing carotenoids can also be used be used for coloring food. Another thing The area of application is animal nutrition.

Examples 1 to 10

All experiments were carried out in a twin screw extruder (ZSK-40 extruder, Werner and Pfleiderer, Stuttgart) leads. The extruder contained 4 heatable shots, also the The extruder head and the slot die could be heated separately. The set temperatures can be found in the table. The extruded melt was in the form of a 12 to 14 cm wide Tape is discharged through a slot die and then in a form calender that consists of a counter rotating mold There is a pair of rollers (coolable), pressed directly into tablets. The Tablets had an elongated, rod-like shape (oblong Tablets). The raw materials listed in the table have become before mixed in a wheel mixer and as a mixture in the Ex truder on a dosing scale with capacities from 20 to 30 kg / h registered. The speed of the extruder screw was in al len cases at 100 to 150 rpm.

In the examples, among others, the following use was made fabrics used:

• a) Klucel EF. Hydroxypropyl cellulose (Aqualon)
• b) Ascorbic acid: Vitamin C (crystalline goods), from BASF AG
• c) Tocopherol acetate: Vitamin E preparation "SD-50" (from BASF AG; 50% formulation of toxopherol acetate on water soluble Carrier)  
• d) Beta carotene: pure substance (powder), from Merck or 10% by weight CWD formulation (BASF AG)
• e) Mannitol: Merck
• f) Reinlecithin: Sternpur PM (from Stern)
• g) Isomalt: Palatinit®, Palatinit, Mannheim

Example 11

The vitamin C content of a sample according to Example 3 became few Days after production using an HPLC method (isokrati system) analyzed. The actual value found was 41.46 wt .-% (target value: 41.66 wt .-%), there were no secondary products observed. The actual values found for the beta caro tin was 3.8% by weight (target: 3.34% by weight), of which 90.7% all-trans beta-carotene.

Claims (2)

1. A process for the production of vitamin-containing medicinal forms by extrusion of a vitamin-containing polymer melt and subsequent shaping, characterized in that a hydroxypropyl cellulose is used as the matrix polymer. 2. The method according to claim 1, characterized in that one the vitamin-containing melt at temperatures from 80 to 110 ° C generated.