NO131864B - - Google Patents

Description

Numerous medicinal preparations which do not immediately make the active ingredient available at full height have been introduced into the market in recent years. The usual word for this, "protracted" can in this connection mean two things: 1. A temporally shifted, but rapid release of the active substance. 2. A regulated active substance release in a therapeutically sufficient amount over a longer period of time.

Corresponding to this difference, different methods for the production of solid protracted pharmaceutical forms have become known. Tablets are thus given in which the application of a coating e.g. of keratin, gelatin with formaldehyde, collodion, higher alcohols, wax, cellulose acetate phthalate or a film-forming polymer such as polymethacrylic acid or polyvinyl acetate, in the form of a solution or suspension provides a time-delayed release of the active substance. Until the coating is dissolved, no active substance is released from these tablets, but after the coating is dissolved, on the other hand, the entire active substance is immediately available.

Furthermore, so-called swelling tablets are known, such as e.g. contains agar and swellable cellulose products, which swell up in the digestive tract and slowly or incompletely release the active substance. Such swelling tablets have the disadvantage that when they are taken orally in the stomach or the intestines are formed voluminous gels or semi-viscous masses, which cause inconvenience.

An aqueous solution of a high polymer on an active substance can also delay absorption. For example, the suspension of finely ground nitrofurantoin in a 5% aqueous methylcellulose solution leads to a delayed but also considerably reduced release of the active substance (j. Pharm. Pharmac. 1968, 20, 968).

In another method, the active ingredient is pressed together

into tablets with a practically insoluble and non-swellable skeletal substance. Only the cross-section of the pores in the skeletal material is at all times available to the leaching body fluids, so that the dissolution rate of the active substance is greatly reduced. Non-swellable plasters in grain or powder form (DAS 1.258-548) or paraffins (DAS 1.258-025) can be used as skeletal materials.

In addition to the tablets with a skeletal structure where the active ingredient is embedded, the coating method is known by which different pre-treated granules are produced and these are pressed together into tablets. The different granules then release their dose of active ingredient one after the other at a specific pH or after a specific time. The so-called microcapsules also work according to this principle.

Common to all these embedding methods is that easily water-soluble active substances must be used, so that a therapeutically sufficient amount of active substance is present at all times. In the case of substances that are poorly water-soluble, e.g. nitrofurantoin, special depot forms, such as administration of larger crystals, are also possible. With a single oral administration, finely ground nitrofurantoin quickly produces high urine levels, which already fall below the therapeutically necessary level after about 5 hours. The rapid resorption occasionally leads to unacceptable conditions, which is of considerable importance in the case of medicines for long-term therapy. When, on the other hand, "macrocrystals" of the order of 20 - 100 µm are administered, the urine level likewise rises rapidly, but remains for over approx. 8 hours at a therapeutically sufficient height, without showing a distinct maximum. The effect is prolonged, and the medicine is therefore best tolerated.

Surprisingly, it has now been shown that the same prolonged effect can be achieved with the present method by producing solid, resorbable pharmaceutical preparations with a content of one or more active substances, physiologically harmless, easily water-soluble fillers and water-soluble or swellable binders, and where the release of the active substances can be regulated, by kneading and subsequent granulation, which method is characterized by kneading, calculated on the final agent, 35-50% by weight of poorly soluble active substances together with the filler and 0.5-2% by weight of binder and water into a dough and granulates this in a manner known per se by means of sieves or perforated plates. The granule particles thus obtained are filled into gelatin capsules, or with the addition of explosives, such as agar or Na-amylopectin glycolate, and other common excipients are pressed into tablets in a manner known per se, which are optionally then provided with a dragée coating.

The granulate grains can be given any desired size by usual granulation methods, but grains with a volume of approx. 1 mm. This granule can easily be used for dosing, e.g. in hard gelatin capsules. If tablets are pressed from the granulate, a suitable explosive must be added to ensure that the tablets are quickly broken up into the fine granulate grains so that the individual particles can exert their effect and not the tablet as a whole. Each grain presents a specific surface for the attack of stomach and intestinal secretions. This surface area, which after removal of the water-soluble substance is first increased by pore formation, is decisive for the protracted effect that is expected. By the quantity of the added easily water-soluble fillers, the size of the pores and thus the size of the surface of the granulate grains can be varied as desired between the usually too large surface of the fine crystalline starting material and the difficult-to-produce coarse-grained crystallized material. in the surprisingly simple way, it is now possible to vary the release rate of the active ingredient within the widest limits, thereby achieving an optimal therapeutic effect. In the case of nitrofurantoin, the granules have the advantage that you can start from ordinary commercial material and do not need a complicated process to produce "macrocrystals". The administration is thus not limited to a pharmaceutical form such as e.g. macrocrystals from suppositories, but is versatile and extends from the loose granule filling over suppositories to tablets and dragées.

All water-soluble, physiologically acceptable substances can be used as water-soluble substances, preferably sugar and sugar alcohols. However, it is also possible to use a different but easily soluble active ingredient as a filler.

•The mentioned water-soluble, respective swellable binders

must have such properties that, as the most important criterion for the dissolution rate, the surface remains a granulate grain. thus, e.g. methylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, starch, polyvinyl alcohol, swellable polyvinyl acetate, etc., are used. The binder can be used in solid form or also as an aqueous dispersion. The quantity depends on the formation of good granulate grains by the usual production methods. Too much binder naturally results in an unnecessarily delayed and possibly too little medicinal effect.

The production of the granules takes place entirely within the framework of the known wet granulation methods. The finely crystalline active substance is mixed with the additives, the binder and the required amount of water in a kneading machine. The granulate is all the better the more evenly the mass is moistened and thoroughly mixed. The correct amount of granulation liquid depends on the physical properties of the granulation mass. The moistened granulate is then granulated using suitable screens (press granulates, shaker granulates) or perforated metal plates (perforated plate granulates). The moist granules are then dried at temperatures at which the active substance and additives do not decompose. After drying, the granulate is brought to a uniform grain size, preferably by again being passed through sieves.

By adding suitable excipients, such as e.g. coarse-grained milk sugar, the granules can be mechanically filled into hard gelatin capsules. It can of course also be tableted. This includes, in addition to fillers, the necessary quantity of fast-acting explosives such as e.g. agar or sodium amylopectin glycolate, as well as lubricants, mold release agents and possibly drip control agents. The finished tablets can optionally be transferred into dragées by applying a sugar and dye coating.

The following examples will illustrate the invention in more detail.

Example 1

Production of the granulate

The nitrofurantoin is mixed well with the milk sugar in a kneader, moistened well with the polyvinylpyrrolidone solution and kneaded together. The granulation takes place through a sieve with a mesh size of 1.9 mm. The dried granules are then sieved through a sieve with a mesh size of 1.2 mm and then the dust fraction is removed through a sieve with a mesh size of 0.6 mm.

Example 2

The production of the granules takes place analogously to example 1.

Example 3

The production of the granules takes place analogously to example 1.

Example 4

The manufacture of tablets

206 g of granules prepared according to example 3 are pressed with 3.0 g of magnesium stearate and 15.0 g of sodium amylopectin glycolate into tablets with a diameter of 10 mm and a weight of 224 mg. The hardness of the tablets was 2.0 kp.

Example 5

Manufacture of dragées

200 g of granules from example 3 are pressed with 2.0 g of magnesium stearate and 15.0 g of sodium amylopectin glycolate as in example 4 into dragée cores with a diameter of 10 mm. Dragging is performed automatically

with a coating suspension according to DAS 1,184,459. After coating, the hardness of the dragees was 3.0 kp.

Example 6

Dissolution rate of different nitrofurantoin preparations

Nitrofurantoin preparations with a total nitrofurantoin content of 30 mg are introduced into a 3 l three-necked flask filled with 1500 ml of distilled water at 25°C. The water is adjusted with 2N hydrochloric acid to pH 2, and the temperature is kept constant. The suspension is then stirred with a two-bladed propeller stirrer at 50 revolutions per minute. minute. 5, 15, 30, 60 and 120 minutes after the addition of the active ingredient, 10 ml samples are taken each time. The absorption of the samples at 367 (im is compared with the absorption of a standard solution of 20 mg of nitrofurantoin. The dissolution rate calculated from the absorption is given in Table 1.

Ex empe1 8

Urine level examination

Six adult male subjects each received the preparations of nitrofurantoin listed in Table 2 in a dose of 100 mg per try. 2, 4, 6 and 8 hours after administration of the nitrofurantoin, the urine was collected and examined microbiologically for its nitrofurantoin content. The concentration values thus obtained were converted to a standard volume of 100 ml of urine.

Claims (1)

Procedure for the production of solid, resorbable medicinal preparations containing one or more active substances, physiologically harmless, easily water-soluble fillers and water-soluble or swellable binders, and where the release of the active substances is adjustable, by kneading and subsequent granulation, characterized by , calculated on the final agent, kneads 35 - 50% by weight of poorly soluble active substances together with the filler and 0.5 - 2% by weight of binder and water into a dough and granulates this in a manner known per se using sieves or perforated plates.