HRP960436A2 - Process for producing solid vitamin preparations - Google Patents

Description

The proposed invention relates to a process for the production of solid preparations containing vitamins by extrusion of a polymer melt containing an active substance and final shaping, as well as forms of medicine from these preparations.

The production of compositions containing active substances by melt extrusion is generally known.

US-A 4,801,460 describes the production of solid drug forms by melt extrusion from a mixture of active substance and thermoplastic N-vinylpyrrolidone polymers. Vitamins are also listed as active substances.

Many vitamins are chemically unstable substances that break down on contact with oxygen from the air, heat and water (compare V. Bühler, "Vademecum for Vitamin Formulations", Wissenschaftliche Verlagsgesellschaft Stuttgart (1988), p. 9) and are therefore not unconditionally suitable for a thermal processing process such as melt extrusion. In US-A 4,880,585 the processing of vitamins is described, however, with regard to the stability of the preparations, there is still room for improvement.

The task of the proposed invention was to find an improved process for the production of vitamin preparations.

Accordingly, a process was found for the production of solid preparations containing vitamins, extrusion of a polymer melt containing vitamins, and final molding, which is characterized by the use of water-soluble thermoplastic hydroxypropyl cellulose as a matrix polymer.

The production of the melt containing vitamins in the extruder takes place primarily at temperatures from 80 to 110°C.

Water-soluble, thermoplastically processable hydroxypropyl cellulose, which preferably has a molar degree of substitution of 3.0 to 4.4, is used as a polymer matrix for vitamin preparations according to the invention. "Molar degree of substitution" refers to the average number of moles of propylene oxide that can be exchanged per glucose unit of cellulose.

Hydroxypropyl cellulose according to DIN 53735 can have a melt viscosity in the range of 0.75 to 54.8 g/10 minutes.

The molecular weight of hydroxypropylcellulose can vary widely depending on whether a longer or slower release of the active substance is desired. High-molecular hydroxypropylcelluloses with molecular weights in the range of 200,000 to 1,500,000 are particularly suitable for the production of drug forms in which a slower release of the active substance is desirable, e.g. in retard forms, because high-molecular polymers are less soluble in water, and that only with swelling.

If, however, it is desired to produce drug forms with a faster release of the active substance, then the use of low-molecular polymers that have good solubility in water is recommended, in which case hydroxypropylcelluloses with a molecular weight of 60,000 to 200,000, preferably 60,000 to 100,000, can be used.

The production of hydroxypropyl cellulose used according to the invention is known. It is commercially available, for example under the commercial name Klucel® (manufactured by Aqualon).

The proportion of hydroxypropylcellulose in the total amount of the drug form can be from 5 to 95 wt. %, preferably 15 to 40 wt. %.

In principle, all vitamins can be considered as vitamins according to the invention, because sensitive substances can also be used on the basis of low processing temperatures. Vitamins in the sense of the invention are also provitamins or vitamin derivatives.

Accordingly, suitable vitamins are:

- vitamin A group

retinol (A1), dehydroretinol (A2), retinoids such as vitamin A-acid, carotenoids such as β-carotene,

- vitamin B group

thiamine (B1), riboflavin (B2), B6 vitamins pyridoxal, pyridoxamine and pyridoxine, cobalamin (B12) as cyanocobalamin, biotin, folic acid, nicotinic acid, nicotinamide, pantothenic acid,

- vitamin C group

ascorbic acid and its physiologically tolerable salts, such as ascorbyl palmitate,

- vitamin D group

ergocalciferol (D2), cholecalciferol (D3), provitamin D3 (7-dehydrocholesterol), 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).

Combined preparations can also be produced.

Drug forms can contain vitamins in amounts from 0.1 to 95% by weight. %, whereby the dosage is adjusted on the one hand according to the type of vitamin, and on the other hand according to use.

The pharmaceutical forms according to the invention may also contain conventional pharmaceutical excipients if they are heat-stable under the processing conditions and if they are compatible with the vitamins used, e.g. fillers, lubricants, softeners, stabilizers, dyes or pigments, dispersants, preservatives, agents to improve taste. Suitable fillers are, for example, organic compounds such as lactose, sorbitol or mannitol or inorganic substances such as citric acid or silicates. Fillers with good water solubility such as xylitol, isomalt, lactose, sorbitol or mannitol are suitable, for example, for the production of preparations with an accelerated release of the active substance.

The proportion of filler in the preparation is adjusted according to the dosage of the active substance. In the case of low-dosage active substances, a higher tablet weight can be achieved according to the invention with a higher proportion of filler, without thereby worsening the thermoplastic processability. With active substances of very low dosages, the amount of filler can be up to approx. 90 wt. %.

As further pharmaceutical excipients, flow control agents such as mono-, di- and triglycerides of long-chain fatty acids such as C12-, C14-, C16- and C18-fatty acids or waxes such as carnauba wax in customary amounts can be used.

Softeners include, for example, low molecular weight polyalkylene oxides such as polyethylene glycol, polypropylene glycol and polyethylene propylene glycol, as well as multivalent alcohols such as propylene glycol, glycerin, pentaerythritol and sorbitol, as well as sodium diethylsulfosuccinate, glycerin mono-, di- and triacetate and polyethylene glycol stearic acid ester, if these substances are not show incompatibility with the vitamins used. At the same time, the amount of softener ranges from approx. 0.5 to 15, preferably from 0.5 to 5 wt. %.

Gliding agents include, for example, glycerin monostearate and other glycerin mono- and diesters, as well as stearates of aluminum, magnesium or calcium, as well as talc and silicones, with their amount ranging from approx. 0.1 to 5, preferably from 0.1 to 3 wt. %.

Especially useful are the forms of medicines that contain vitamins, and which contain lipids as agents for separation from the mold and auxiliary agents for influencing the plasticity of the melt.

As lipids, mono-, di- and triglycerides of available natural fatty acids come into consideration, for example glycerol monostearate, glycerol distearate, glycerol tristearate, glycerol tripalmitate, glycerol trimyristate, glycerol tribehenate, glycerol palmitylstearyl ester or glyceride mixtures as they appear in natural oils, preferably hydrogenated Castor oil.

Ceramides are also suitable for this purpose.

Useful lipids are primarily phospholipids, with phosphoglycerides such as lecithin being given special preference. Particular preference is given to hydrated lecithins such as soy and egg lecithin

Lipids can be used in an amount of 0.1 to 10 wt. % in relation to the total amount of the preparation containing the active substance, preferably from 1 to 5 wt. %.

Examples of stabilizers include light stabilizers, antioxidants, radical scavengers and stabilizers against microbial attack, which can be used in the usual amounts.

For flavoring and sweetening, for example, agents that are used as lozenges, natural, similar to natural or artificial flavors and sweeteners such as cyclamate, aspartame, neohesperidin or saccharin sodium or their mixtures can be used.

To carry out the process according to the invention, the vitamins can be melted directly or as a physical mixture with the matrix polymer or mixed with an already existing polymer melt. The last procedure is especially recommended for temperature-sensitive vitamins.

Auxiliary substances can also be added to the melt of active substances and polymers. Furthermore, excipients can be mixed into the polymer melt together with the active substance. In addition, the mixture of excipients, active substance and polymer can be melted directly.

According to the process according to the invention, melting of matrix polymers and mixing of active substances and auxiliary substances is carried out at temperatures from 50 to 150°C, preferably from 80 to 110°C in a twin-screw extruder.

The vitamin-containing melt exiting the extruder, as described in US-A 4,880,585, is pressed directly into tablets with a pair of counter-rotating rollers. Otherwise, procedures for the production of smaller particles (pills) are also possible, e.g. by applying the hot cutting process (extrusion of the melt through narrow holes; shredding the strip of extrudate directly in front of the perforated plate of the nozzle with a rotating knife into pills). It is also possible to cool the melt after exiting the extruder and only after cooling and hardening can it be crushed with a suitable mill into granulate or powder. Pills, granules or powder of this type are suitable, for example, for filling in hard gelatine capsules, but also as a preliminary step for a subsequently connected tablet pressing device.

The methods according to the invention are particularly suitable for the production of vitamin preparations containing vitamins sensitive to oxidation and temperature, provitamins or vitamin derivatives. By melting vitamins in the polymer matrix, oxidative decomposition (oxygen from the air) is minimized, because the cooled melt is not porous.

Thus, ascorbic acid can be processed largely without decomposition, which was surprising given the known temperature sensitivity of this substance. Also, β-carotene can be processed very well without noticeable isomerization. The storage stability of the formulations according to the invention was also good; after three months of storage at 30°C, no vitamin losses were found.

Vitamin preparations produced according to the invention can be used for pharmaceutical or veterinary medical purposes. They are also suitable for "vitaminizing" foodstuffs, for example as drinking solutions by pouring the appropriate granulate or powder into water, other drinks or food. Furthermore, compositions containing carotenoids can also be used for coloring foodstuffs. Further area application is animal feed.

Examples 1 to 10

All experiments were carried out on a twin-screw extruder (extruder ZSK-40, manufactured by Werner & Pfleiderer, Stuttgart). The extruder had 4 heating zones, and a head and nozzle with a wide gap with separate heating. The set temperatures are listed in the table. The extruded melt was drawn in the form of a 12 to 14 cm wide strip through a wide gap nozzle and then directly pressed into tablets in a press calender, which consisted of a pair of counter-rotating rolls (which could be cooled). The tablets were oblong, rod-shaped (oblong tablets). The raw materials listed in the table were pre-mixed in a Rhönrad mixer and fed as a mixture into the extruder via a dosing path with an output of 20 to 30 kg/h. The number of revolutions of the extruder screw was in all cases 100 to 150 rpm.

In the examples, among others, the following materials were used:

a) Klucel® EF. hydroxypropylcellulose (manufactured by Aqualon), molar degree of substitution 3.0 - 4.4,

b) ascorbic acid: vitamin C (crystalline product), manufacturer BASF AG,

c) tocopherol acetate: preparation of vitamin E "SD-50" (manufacturer BASF AG; 50% formulation of tocopherol acetate on a water-soluble carrier),

d) beta-carotene: pure substance (powder), manufacturer Merck or 10% wt. CWD formulation (BASF AG),

e) mannitol: manufacturer Merck,

f) pure lecithin: Sternpur PM (manufacturer Stern),

g) isomalt: Palatinit®, manufacturer Palatinit, Mannheim.

Example 11

The content of vitamin C in the sample according to example 3 was analyzed a few days after production using the HPLC method (isocratic system). The actual value found was 41.46 wt. % (required value: 41.66 wt. %), no side products were observed. The actual values found for beta-carotene were 3.8 wt. % (required: 3.34 wt. %), of which all trans-beta-carotenes were 90.7%.

Example 12

Analogously to examples 1-10, the following mixtures were processed (numerical data always represent the respective mass percentages).

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Tablets containing vitamins according to example 12 were tested using reverse phase high pressure liquid chromatography.

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No typical thermal decomposition products of vitamins were found in the chromatogram.

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Claims (4)

1. Process for the production of drug forms containing vitamins by extrusion of a polymer melt containing vitamins and final shaping, characterized by the fact that hydroxypropyl cellulose is used as the matrix polymer. 2. The method according to claim 1, characterized in that the melt containing the vitamin is created at temperatures from 80 to 110°C. 3. The method according to claim 1 or 2, characterized in that hydroxypropyl cellulose is used with a molar degree of substitution of 3.0 to 4.4. 4. Forms of medicines, characterized by the fact that they are obtained by the process according to claims 1 to 3.