IE81025B1 - Processing of active agents - Google Patents

Abstract

A process and formulation is provided for the manufacture of tablets comprising the active agents selegiline and betahistine wherein dissolution of these active agents in water prior to processing yields tabletted formulations having improved properties.

Description

PROCESSING OF ACTIVE AGENTS The present invention relates to the processing of active agents prior to formulation in pharmaceutical compositions.

Compressed tablets are defined as solid-unit dosage forms made by compaction of a formulation containing the drug and certain fillers or excipients selected to aid in the processing and properties of the drug product. They are the most widely used of all pharmaceutical dosage forms administered today.

Whatever method of manufacture is used, the resulting tablets must meet physical standards of shock and abrasion resistance, uniformity in weight and drug content, and acceptability of appearance, in addition to biological standards such as bioavailability of the drug content of the tablet, drug stability and drug efficacy.

All formulations are highly dependent on the properties of the raw materials concerned, including the drug substance itself. Many physicochemical factors, such as fluidity, compressibility, hygroscopicity and solubility influence the process of manufacture and must be taken into account when selecting processing conditions.

For example, if a drug substance is judged to be physically or chemically unstable when exposed to moisture, a directcompression or nonaqueous solvent granulation procedure is usually recommended for the preparation of tablets.

Moisture has been recognised by formulators as the primary cause of instability in tablets, affecting not only drug stability but flow and compression characteristics of powders and the hardness of final tablets and granulations. Since many drug substances have a tendency to absorb moisture, recent developments have been towards dry formulation processes, e.g. using selected excipients which absorb the maximum amount of free moisture, such as sorbitol and sucrose, or melt processes which rely on the use of solids having a low softening or melting point such as polyethylene glycols and waxes which, when mixed with a powder formulation and heated, liquefy to act as binders. Upon cooling, the mixture forms a solid mass in which the powders are bound together by the binder returning to the solid state.

It is an object of the present invention to provide pharmaceutical formulations having improved properties for tabletting.

It has been found that dissolving the pharmaceutical active principles betahistine and selegiline in aqueous solution prior to processing yields tabletted formulations with surprisingly improved dispersion properties, content uniformity and stability. This procedure has not previously been applied to these substances, which are used as a vasodilator and anti-Parkinsonian respectively.

Betahistine in particular is known to be highly hygroscopic and so has conventionally been stored and processed in a dry environment.

In a first aspect, the present invention provides a process for the production of a tabletted formulation comprising an active agent in which the active agent is dissolved in an aqueous medium prior to processing, and in which the active agent is betahistine, selegiline or a pharmaceutically acceptable salt of either of the above.

In a preferred process, the selegiline or betahistine, typically in the form of a salt such as the dihydrochloride, is dissolved completely in the appropriate quantity of water.

The solution may then be granulated. This term refers to any process of size enlargement, or agglomeration, whereby small particles are gathered together into-larger, permanent aggregates to render them into a free-flowing state. Typically, the solution is agitated to form a granular mass, which is then dried and compressed on a suitable tabletting press.

At any of the above formulation stages, suitable excipients may be added to the mixture.

Excipients are inert substances used as diluents or vehicles for a drug. The term includes various groups comprising diluents or fillers, binders or adhesives, disintegrants, lubricants, glidants or flow promoters, colours, flavours, fragrances and sweeteners.

In a further aspect, the present invention provides a tabletted formulation produced by a process as above described.

The invention will now be further illustrated by the following Examples: Example 1 1. Selegiline Hydrochloride is dissolved in 500ml of the water in order to yield a clear solution. 2. This solution is then added to mannitol and cellulose in a planetary mixer and the mass is mixed for 5 minutes. 3. An additional 200ml of water is then added and mixing continued for a further 5 mins, in order to form a granular mass. 4. The granulate is fluid bed dried at 60°C for 30 mins.; granulated through a 20 mesh stainless steel screen and dried for a further 45 mins, at 60°C.

. . Talc and magnesium stearate are then mixed with a small quantity of the granulate in a polythene bag. 6. The pre-mix from 5 is blended with the remaining granulate for 5 mins, in the mixer.

The lubricated granules formed above are compressed on a rotary tabletting press using 6mm normal concave tooling. Cutting weight of the granulate may be calculated from the formula as 100.Omg per tablet and in process checks are made to ensure that the mean tablet weight remains at this level plus or minus 2%. Also the compression pressure of the press is set so that tablets are well formed, free from pits and blemishes and with a hardness value of at least 3 units when assessed using a Manesty hardness tester.

The finished tablets are finally packed within blister packs on a semi-automatic line. Clear, uncoloured PVC sheet is thermoformed into blisters using tooling appropriate for the tablet size. Tablets are then filled into the blisters which are in turn sealed onto a backing strip of aluminium foil, prior to cutting to appropriate pack size.

Example 2 Formula Unit Reference to Names of Ingredients Formula (mq/tab) Function Standards Active Ingredients: Selegiline Hydrochloride 5.00 Anti-Parkinsonian HSE Other Ingredients: Microcrystalline Cellulose 72.50 Diluent EP Mannitol 20.00 Binder EP Talc 2.00 Flow Promoter EP Magnesium Stearate 0.50 Lubricant EP Example 3 1. Betahistine Dihydrochloride is dissolved in 500ml of water and filtered if necessary in order to yield a clear solution. 2. ' This solution is then added to mannitol and cellulose in a planetary mixer and the mass is mixed for 5 minutes. 3. An additional 300ml of water is then added and mixing continued for a further 5 mins, in order to form a granular mass. 4. The granulate is fluid bed dried at 60°C for 30 mins.; granulated through a 20 mesh stainless steel screen and dried for a further 60 mins, at 60°C.

. Talc, magnesium stearate and fumed silica are then mixed with a small quantity of the granulate in a polythene bag. 6. The pre-mix from 5 is blended with the remaining granulate for 5 mins, in the mixer.

The lubricated granules formed above are compressed on a rotary tabletting press using 6mm normal concave tooling. Cutting weight of the granulate may be calculated from the formula as 100.5mg per tablet and in process checks are made to ensure that the mean tablet weight remains at this level plus or minus 2%. Also the compression pressure of the press is set so that tablets are well formed, free of pits and blemishes and with a hardness value of at least 3 units when assessed using a Manesty hardness tester.

Example 4 Formula Unit Names of Incredients Formula (mcj/tab) Function Reference Standard Active Ingredients: Betahistine Dihydrochloride 8.00 Vasodilator HSE Other Ingredients: Microcrystalline Cellulose 69.00 Diluent EP Mannitol 20.00 Binder EP Fumed Silica 1.00 Desiccant EP Talc 2.00 Flow Promoter EP Magnesium Stearate 0.50 Lubricant EP It will be understood that the above Examples are by way of illustration only and modifications of detail can be made within the scope of the invention as defined in the appended claims.

Claims (5)

1. A process for the production of a tabletted formulation comprising an active agent in which the active agent is dissolved in an aqueous medium prior to processing, 5 and in which the active agent is betahistine, selegiline or a pharmaceutically acceptable salt of either of the above

2. A process according to Claim 1 comprising the steps of dissolving selegiline dihydrochloride or betahistine dihydrochloride completely in water, granulating the 10 solution so obtained, and drying and compressing the granulate.

3. A process, substantially as hereinabove described, with reference to Examples l or 3.

4. A tabletted formulation produced by a process 15 according to any one of Claims 1 to 3.

5. A tabletted formulation, substantially as hereinabove described, with reference to Examples 2 or 4.