FI102037B - Process for the preparation of drug granules - Google Patents

Description

102037

The present invention relates to a process for the preparation of substantially free additive-free drug granules, and to their use, for example, in the preparation of capsules and tablets.

Drug powders that can be formulated into dosage forms, such as pellets or tablets, rarely have optimal formulation properties, such as flow, bonding, and solubility properties. Thus, in order to obtain optimal dosage forms, the drug must generally be combined with various excipients and additives which, on the one hand, impart suitable and desired properties to the dosage form 15 and, on the other hand, facilitate their preparation.

In order to obtain a homogeneous product, the powder mixture containing excipients and additives is generally first granulated, either by wet or dry granulation, from which pellets are then made and / or compressed into tablets.

Excipients commonly used in pharmaceutical forms such as pellets and tablets include excipients such as lactose, mannitol, microcrystalline cellulose, starch, sucrose, etc., whose main function is to act as an excipient or diluent for the drug. Their amount from the finished dosage form can vary widely, and can be up to 99% or even more by weight of the total preparation. 30

Binders are added to bind the powders and to ensure the cohesiveness of the dosage forms. Commonly used binders include, for example, gelatin, various cellulose derivatives, polyvinylpyrrolidone, but sucrose and starch can also act as binders. Binders are generally used in an amount of about 2-10% by weight of the preparation.

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In addition, other excipients, such as lubricants, can be added to the powders, mainly to improve the flow and flow properties of the powders so that they can be fed to the equipment at a constant rate, thus enabling the production of the most homogeneous product possible. Such substances include, for example, calcium or magnesium stearates, colloidal silica, starch and talc. Lubricants are used to reduce frictional effects such as calcium or magnesium stearates, glycerol, hydrogenated vegetable oil, mineral oil, glycols such as polyethylene glycol, or silicone derivatives such as emulsions, and as surfactants such as polysorbate sulphate di However, the total amount of these optional additives generally remains below about 10% by weight of the preparation, often below as much as 2% by weight.

In addition to the substances mentioned above, other excipients can be used in the formulation, such as disintegrants and pH-20 adjusting agents.

Since the size of the unit dosage form cannot be increased without limitation for the sake of patient compliance, any addition of the above-mentioned mandatory excipients will naturally result in the amount of drug that can be included in each unit dosage form being less than desired for treatment. If treatment requires the administration of a certain dose of the drug, this should often be done by administering several unit doses at the same time. However, patients are known to be alienated from such a route of administration, which in turn impairs patient compliance.

The above is a problem, especially for certain drugs, the most important of which are ibuprofen, sucralfate and theophylline. Ibuprofen is known as an anti-inflammatory and analgesic agent, succinate as a gastric ulcer drug and theophylline as a diuretic and cardiac stimulant, respectively.

For these substances, it may be desirable to be able to administer larger amounts, for example up to 800 mg of drug per 5 single doses, either to avoid multiple sub-doses while maintaining a small tablet size to facilitate swallowing, or to ensure a uniform release profile, which is particularly important e.g. for theophylline, which has a narrow absorption window.

This object is achieved by a process according to the invention for the preparation of granules containing ibuprofen, sucralfate or theophylline, suitable for direct compression into tablets, which process consists of the following steps: - ibuprofen, sucralfate or theophylline powder by subjecting the powder in the rotor to centrifugal force and in contact with or in the vicinity of the rotor 20 with the granulation liquid fed separately to the rotor and atomized therein, - the obtained granules are dried and optionally coated and / or optionally compressed into tablets excipients and additives less than 5% by weight.

Thus, the process according to the invention makes it possible to prepare granules from drug powder and granulation liquid alone, which can be coated and / or compressed into tablets and have a very high drug content. The powder to be fed can thus consist of up to 100%, but at least more than 95, and even more than 99%, of the drug, and it is not necessary to use fillers, binders, lubricants, lubricants or other excipients in the powder.

Such excipient-free pharmaceutical preparations have not previously been able to be prepared using conventional batch-based high shear or planetary mixers.

In the process according to the invention, the extrusion and rounding step, which requires a filler, is also completely omitted, which is, of course, advantageous from a manufacturing point of view.

As the granulating liquid, for example, water or a lower alcohol such as ethanol, or mixtures thereof, may be suitably used, but preferably water. If desired, a binder, for example polyvinylpyrrolidone, may be added to the granulation liquid, which may be used in an amount of about 1 to 10, for example about 5% by weight, of the amount of solution. The drug solution itself can also be used as the granulating liquid. The amount of granulating liquid required for granulation depends, of course, on the powder to be granulated, and is generally in the range of 20 to 100% by weight, based on the dry powder mixture. If a binder-20 is added to the granulation liquid, it is generally added in such an amount that the amount of binder in the final product will be at most about 5% by weight, usually at most about 2% by weight of the total preparation.

; The process according to the invention uses a continuous rotor type granulator. In such a case, the powder and the liquid are separately ejected by the centrifugal force generated by the rapidly rotating rotor towards the circumference of the rotor, where or in the vicinity of which the finely divided (atomized) liquid encounters the powder, mixing it uniformly into a granular mass. A mixer of this type is known per se and is described, for example, in SE patent 455 672 and EP 254 791. More specifically, this type of device 35 consists of a rotor structure rotating in a housing with a common rotor rotating on a common axis, the upper surface and the upper wall of the housing wall 5102037 the powder is fed from the center of the rotor, and a lower rotor which forms a clearance with respect to the upper rotor, to which clearance the liquid is fed from the center of the rotor. The upper and lower rotors rotate at a speed of e.g. 1000-5000 rpm, with a circumferential speed of about 300-5000 m / min depending on the circumferential diameter.

The liquid also protrudes from the gap between the upper and lower rotors by centrifugal force towards the rotor circumference, where it exits as a mist through a narrow gap at the upper rotor circumference 10 and where it also encounters a powder ejected towards the circumference by centrifugal force, forming a very smooth granulate.

According to a particularly preferred embodiment, a mixer / granulator sold under the trade name Nica Systems, Nica System Ab, Sweden is used.

After granulation, the granule is dried, for example in a fluid bed dryer.

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According to a preferred embodiment of the invention, after drying, the granules can be coated and / or compressed into tablets in a manner known per se.

For release coating, polymer films known per se which control the rate of release and the rate of release can be used, e.g. acrylate-methacrylate copolymers (Eudragit® RS and RL, Rohm Pharma) and cellulose polymers, e.g. Suitable release-controlling (enteric) film polymers include, for example, acrylic polymers (Eudragit® S and L), cellulose acetate-phthalate and hydroxypropylmethylcellulose phthalate-polymer (Shin-Etsu) and poly (vinyl acetate) polymer (35). Colorcon).

If desired, the granules obtained can also be compressed into tablets using disintegrants (e.g. Explotab, Ac-Di-Sol) in an amount of typically 5-20% by weight of the granules. The resulting tablet disintegrates in the stomach immediately, releasing drug substances that spread over a wide area in the gastrointestinal tract.

The following examples illustrate the invention without limiting it in any way.

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Example 1

Ibuprofen is granulated with a continuous Nica granulator (Nica M6L, Nica Systems AB, Sweden) using a 5% by weight aqueous solution of Kollidon 25 (polyvinylpyrrolidone) as the ra-15 softener. The amount of granulating liquid is 25% by weight of the amount of dry matter. The substances required in the process for 2 kg of ibuprofen granules are as follows: 20 Ibuprofen 2000 g

Collidone 25 25 g

Aq. Purif. 500 g.

The colloid is dissolved in distilled water. The solution is poured into the liquid tank of the apparatus 25, the powder supply and the liquid supply are started simultaneously. The granules are collected from a continuous process (2 kg can be granulated in less than 1 minute). Wet granules can be screened to achieve the desired grain size. The granules are dried in dampers or in a fluid bed dryer. The amount of binder in the dry final product is about 1.5% by weight.

The dry granules can be compressed into tablets as such. The granules can also be compressed into tablets using 10% by weight of a disintegrant as an excipient, e.g. Explotab, whereby the tablets disintegrate rapidly, releasing the drug immediately.

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Example 2

Theophylline is granulated with an apparatus of the type mentioned in the previous example, using water as the granulating liquid in an amount of 5 to 40% by weight of the dry matter. The substances required in the process for 2 kg of theophylline granules are as follows:

Theophylline. 2000

Aq. Purif. 800 g.

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The distilled water is poured into the liquid tank of the equipment, the powder supply and the liquid supply are started simultaneously. The granules are collected from a continuous process (2 kg can be granulated in less than 1 minute). Wet granules can be monitored to achieve the desired grain size. The granules are dried in dampers or in a fluid bed dryer.

The dry granules can be tableted or encapsulated as such. The granules can also be coated with a drug release-controlling polymeric film, e.g. Eudragit, in a fluid bed granulator. The coated granules can be tableted or encapsulated. The granules can also be compressed into tablets using a 10% by weight disintegrant, e.g. Explotab, as an excipient.

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Example 3

Sucralfate is granulated with the above-mentioned continuous Nica granulator using a 5% by weight aqueous solution of Kollidon 25 (polyvinylpyrrolidone) as the granulating liquid. The amount of granulating liquid is 55% by weight of the amount of dry matter. The substances required in the process for 2 kg sucralfate granules are as follows: 35 Sucralfat. 2000

Collidone 25 55 g

Aq. Purif. 1100 g.

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The colloid is dissolved in distilled water. The solution is poured into the liquid tank of the equipment, the powder supply and the liquid supply are started simultaneously. The granules are collected from a continuous process (2 kg can be granulated in less than 1 minute).

5 Wet granules can be screened to achieve the desired grain size. The granules are dried in dampers or in a fluid bed dryer. The amount of binder in the dry final product is about 2.7% by weight.

The dry granules can be tableted or encapsulated as such. The granules can also be coated with a drug release controlling polymer film, e.g. Eudragit, in a fluid bed granulator. The coated granules can be tableted or encapsulated. The granules can also be compressed into tablets using 15% by weight of a disintegrant, e.g. Explotab.

Claims (6)

A process for the preparation of drug granules containing ibuprofen, sucralfate or theophylline and suitable for pressing directly into tablets, which comprises the following steps: - an ibuprofen, sucralfate or theophylline powder is granulated with a granulation liquid in a granulation liquid -cip working granulator by exposing the powder in a rotor to the centrifugal force and on the periphery of the rotor or in the vicinity thereof, contacting it with a separately fed and fogged granulation liquid, - the granules obtained are dried, and possibly coated and / or optionally pressed into tablets, characterized in that the drug powder to be granulated contains less than 5% by weight of adjuvants and additives. 2. A method according to claim 1, characterized in that the drug is ibuprofen. Method according to claim 1 or 2, characterized in that the drug powder is binder and filler free. 25 Process according to any one of claims 1-3, characterized in that the granulation liquid is water. Process according to any of claims 1-3, characterized in that the granulation liquid is water to which the binder has been added. 6. A process according to claim 5, characterized in that the binder is polyvinylpyrrolidone, having an amount of 1 to 10, in particular approx. 5% by weight of the amount of the granulation liquid.