MXPA99004759A - Lozenge for the modified releasing of active substances in the gastrointestinal tract - Google Patents

Abstract

A pharmaceutical sucking tablet for the modifiedreleasing of active substances in the gastrointestinal tract is described. It has particles containing active substances which have a first coating that controls the releasing, and a further, outer coating with saliva-resistant properties. The first coating, which controls the releasing of the active agents, can have retarding or gastric juice resistant properties.

Description

Lung tablet for the modified release of active substances © n - the gastrointestinal tract DESCRIPTION OF THE INVENTION The invention relates to a pharmaceutical tablet for the modified release of active substances in the intestinal tract with particles containing active substances, and having a first envelope controlling the release and another outer envelope of saliva-resistant properties »The forms of administration of peroral application with modified release of active substances can serve various therapeutic purposes. The most frequent objectives are to protect the gastric mucosa against a harmful active substance or to protect the active substance from the acid medium of the stomach, which is achieved by envelopes resistant to gastric juices; in addition to this, controlling the rate of release over a prolonged period, which can be achieved by means of various delaying measures, and which results in plasma levels of relatively low oscillations, and therefore better compatibility and a longer efficacy for the application. A formulation with modified release of active substances does not develop with equal ease REF. 30278 for all active substances that are archaeologically appropriate. It usually requires the use of a series of additional substances through which the desired effects can be achieved. These active substances therefore significantly increase the mass of the administration form. In administration forms with prolonged release of active substances, the dose to be applied is also increased, in comparison with a simple administration form. For this reason it has not been possible to develop for various active substances, and due to their dosage, forms of prolonged release of active substances, using the known possibilities, since due to the resulting dimensions could not be swallowed in the form of capsule or compressed. For example, there are several antibiotics that must be applied three or four times a day orally, although it is known that with more than two daily applications there is a reduced safety of ingestion by patients. In antibiotics, the single non-delaying dose is usually already in 500 to 1000 mg, which together are the auxiliary substances necessary to form the drug leads to capsules or tablets difficult to swallow. A retardant preparation prepared according to conventional techniques and having more than 1000 mg of active substance and a still higher proportion of auxiliary substances can practically no longer be swallowed. It is therefore desirable to obtain a form of presentation with modified release of active substance, which can be taken easily and pleasantly, and which is also suitable for active substances to be taken in large single doses. According to the invention, the problem of ingesting high doses is solved by administering a preparation of multiple-active substance pressed in the form of a suction tablet, the particles of which are present individually wrapped to achieve the modified release. The wrapped particles are released into the mouth in a finely distributed form by sucking the tablet and can be swallowed easily with saliva. The form of tablet application for sucking has been known for a long time and is frequently used to transmit active substances to the diseased oral mucosa and pharyngeal mucosa. The tablet to suck may also be suitable for substances of systemic action if the substances have an acceptable taste, their resorption must be achieved without delay. In order to solve the problem, the application form of the suction tablet is used because it has a greater capacity for accommodating mass of active substance and auxiliary substance without losing its ease of application., better than a tablet intended to be swallowed. In commerce there are tablets to suck with a mass greater than 4 g, and apparently patients accept them without problems. The current level of technology makes it possible in principle to press coated particles with modified release of active substance, despite the fact that the application according to the invention, with all its advantages - the application of the suction tablet suitable also for high doses of active substance , has not been recognized or described as a solution to the aforementioned problem. For example, patent specifications EP 153 104 and EP 355 247 describe the pressing of retardant coated particles containing active substance to form tablets, this being a process that is also described in other sources. In addition to this, US Pat. No. 5,464,632 discloses a rapid disintegration tablet intended to be swallowed or for decomposition in the mouth, containing the optional active substance in the form of coated particles for modified release. However, in the case of this tablet, it can be expected that when it decomposes in the mouth, parts of the active substance are already released through the envelope of the particles in the oral cavity, thus leaving a negative taste impression. Similarly, the method of applying the tablet to suck such a co or is required in the present invention although on the one hand solves the problem of being able to apply greater amounts of active substance and auxiliary substance substances, however on the other hand creates new problems. On the one hand, in the particles with a coating resistant to gastric juices, the envelopes are exposed to saliva of neutral pH, with which they decompose prematurely and the desired protective effect on the stomach can no longer be achieved. On the other hand, in the particles that have a retardant coating, part of the active substance is already released by diffusion into the buccal cavity, which is not acceptable especially in the case of unpleasant substances. Therefore, there is a need for an improved form of administration with modified release of active substance to administer large doses of active substance, without presenting the mentioned drawbacks. This problem that constitutes the basis of the invention is solved by a pharmaceutical administration form in accordance with one of the two main claims; In addition to its special form as compressed to suck, the tablet according to the invention overcomes the disadvantages of the current level of the technique by the fact that its active substance is present in the form of particles with double coating © coating of two layers , serving a first inner shell for 1-a modified release of active substance while another outer shell is resistant to saliva, but dissolves in the acid medium of the stomach, thus ensuring that when sucking the tablet is not released anymore active substance in the oral cavity. The first inner shell of the particles can modify the release of active substance according to one of the two main claims, either upon initiation of release only once the particles have passed through the stomach, or it can be a membrane insoluble in gastric juices. and intestinal, but through which the active substance can diffuse slowly outward, releasing delayed. According to the invention, the particles containing the active substance, together with suitable auxiliary substances, are compressed to form tablets for sucking, which due to their composition slowly erode in the mouth, giving the particles to the saliva. The saliva is then swallowed with the wrapped particles. The own tests carried out resulted in that the particles up to a diameter of approximately 100-200 μm are only perceived with a moderate discomfort when sucking. The specialist knows the polymers that can be used to obtain a saliva-resistant coating. For this purpose, a depolymerizate based on dimethylaminoethyl methacrylate and neutral esters of methacrylic acid, under the trade name Eudragit E, is frequently used. { Signature Rohm). The basic character of the di-ethylaminoethylmethacrylate facilitates the solubility in acid medium, co or for example in the gastric juices while its solubility in the saliva, which is relatively neutral, is rather poor. By choosing a suitable film thickness, a shell can be produced with this copolymer which for a long time bears decomposition in the saliva, but dissolves rapidly in the stomach. Alternatively, all the other film-forming polymers which have a distinctly higher solubility in gastric juices than in saliva can be used for this purpose. Release retardant film coatings are very widespread in the technology of solid oral administration forms. The polymers used for this purpose usually have a lower solubility in aqueous media, as well as acidic as well as neutral to basic pH values. When the coating film has sufficient thickness and mechanical strength, it does not dissolve in saliva or in gastric or intestinal juices. On the other hand, the thickness should not be excessive since the coating film has to allow the diffusion of water to the active substance deposit where the active substance is constantly dissolved, diffusing in a dissolved form outwards through the shell. Many polymers have been used for this purpose; Examples which may be mentioned are: polymers of the group of cellulose esters, for example cellulose acetate, representatives of the group of cellulose ethers, such as for example ethyl cellulose, certain poly-acid derivatives. { meth) acrylic, for example Eudragit RL or RS (Firma Rohm), certain polyvinyl derivatives such as polyvinyl acetate.

The polymers normally used for the preparation of enveloping films resistant to gastric juices but soluble in the small intestine exhibit an extremely reduced solubility in an acidic medium and remarkably better solubility in a neutral pH medium. These properties are observed mainly in those polymers that contain acid groups that are present without dissociating in the gastric juice. Examples which may be mentioned are: esters of bivalent acids such as succinic acid or phthalic acid with cellulose ethers, cellulose esters, polyvinyl derivatives, carboxymethylcelluloses or poly (eth) acrylic acids, as they are contained in Eudragit L or S ( Signature Rohm). The elasticity and 1-resistance of the enveloping films of the particles are necessary conditions for the shape of the drug to carry out its function correctly, since the envelopes must not suffer due to the intense mechanical stress to which they are subject to. press them to make the tablets; at least most of the particles contained in the sucking tablet must have two envelope layers intact in the sense of the invention. The specialist knows that the elasticity, the 1-lexibility and the resistance of the polymer films depend on the type of polymer, its molecular weight, the degree of substitution of the fi lm-ogen agents used, but also on the kind and quantity of the additional substances used. It is especially the plasticizers or other plasticizing substances used for other purposes which have a considerable influence on the mechanical characteristics of the film. For most of the polymers that can be used in the sense of this invention, the current level of the art knows suitable plasticizers to obtain certain mechanical properties; the specialist will be able to determine by suitable tests 1-the optimum amount of plasticizer necessary for the purpose of forming tablets with the wrapped particles according to the invention, which may differ perfectly from the amount recommended for other purposes. To clarify possible versions of the 1-invention, two examples can be used, which, however, are only illustrative; The specialist will be able to develop other examples with different recipes and preparation procedures.

Example 1: Tablet to suck with ibuprofen particles, with gastric juice-resistant casing, with 600 mg of ibuprofen. First, ibuprofen micropelets are prepared by granulation, extrusion and spheronization. For this, 700 g of ibuprofen®, 180 g of microcrystalline cellulose and 120 g of lactose monohydrate are mixed in a powder mixer, and then a dough of modelable consistency is formed by adding n g of water. The dough is extruded by means of an extruder, for example a single-screw extruder of the type E 40/10 D (Gabler firm) through a specially prepared orifice disc with a hole diameter of 300 μm, cut and rounded ideally in an online procedure, for example in a spheronizer of type R 250. { Gabler firm). The micropelets are then dried in a dryer until a residual moisture of approx. 2-3%, 1 which can be carried out in a suitable fluidized bed equipment, but preferably already in the same equipment provided for the coating of the pellets, for example the fluidized leeger © / dryer / coater Uni-Glatt type (Glatt signature). i: In order to produce the first coating resistant to gastric jugs, the pellets in the fluidized bed were fed through a binary nozzle with a pressure of approx. 1-2 bar in T © p-Spray arrangement, and a spray rate of 10 ml / min., With a dispersion based on 95 g of Eudragit 'L30 D-55, 45 g of Eudragit' NE30 D ( both from the Rohm Firm), 8 g of triethylcitrate, 12 g of p-lietilengliool 6000, 20 g of talc and 90 g of water, until an increase of weight in sec © of 12% was reached. A suitable treatment temperature is 38-43 C, after which a subsequent drying should be carried out at 30-35 G. The coated, gastric juice-resistant particles prepared in this manner are then coated in accordance with the invention with a second saliva-resistant coating. Alternatively, the preparation of the saliva resistance in the previous process can also be carried out by changing the spray medium. A spray solution suitable for this purpose is composed of 240 g of Eudragit® E 12.5, 18 g of polyethylene glycol 6000, 12 g of microcrystalline cellulose, 12 g of magnesium stearate and 220 g of acetone. . It can be sprayed on the above-described apparatus at the same pressure and at the same spray rate, but preferably at a reduced temperature of about 30 ° C. The spraying process is completed when a pellet weight increase of 11% has been reached. After the subsequent drying, the particles which are now provided with two coatings can be pressed to form the tablets to suck. To do this, 1066 g of pellets, containing 600 g of ibuprofen, are mixed in a powder mixer, with 260 g of sorbitol (a quality is needed with which tablets can be directly formed), 2 g of colloidal silicon dioxide, 28 g of stearic acid and 11 g of magnesium stearate, and pressed in a tablet press to form tablets of 1367 mg in weight, for example with a diameter of 18 mm.

Example 2: Tablets for sucking with ibuprofen particles with 600 mg of ibuprofen, with release retardant coating. The preparation is carried out analogously to Example 1 with the exception that a dispersion is used to obtain the coating that modifies the release. based on 110 g of Euradit RS 30 D, 25 g of talc, 28 g of triethylcitrat © and 15 g of p © lietilenglic © l 6000.

These exemplary embodiments manifest the principle of the invention; according to the priority given to the various properties of the product, for example reduced particle size to improve the taste of the sucking or decomposing properties of the tablet or lesser use of auxiliary substances to reduce production costs, they will be able to optimize clearly in the direction towards one of the parameters of the objective. It should be noted that in relation to this date, the best choice for the bidder to carry out the aforementioned invention is the conventional one for the manufacture of the objects or products to which it refers.

Claims (7)

CLAIMS Having described the invention as above, the contents of the following claims are claimed as co or properties:

1. A suction compressed tablet pressed from a powder or granular mass, characterized in that the pressing material contains, in addition to the usual auxiliary substances suitable for 1-manufacture of sucking tablets, a preparation of active substances in the form of particles with a two-layer coating liner, being an outer coating layer resistant to saliva but soluble in gastric juices, and an inner lining layer remarkably resistant to decomposition in aqueous medium, but allowing a delayed release of active substance by diffusion.

2. Pharmaceutical tablet for sucking pressing from a powder or granular mass, characterized in that the pressing material contains, in addition to the usual auxiliary substances suitable for the manufacture of tablets for sucking, a preparation of active substances in the form of particles with a minimum of two layers of coating, being an outer coating layer resistant to saliva but soluble in gastric juices, and a layer of coating inward resistant to gastric juices, per ¬ soluble in the intestine © thin.

Pharmaceutical suction tablet according to claims 1 or 2, characterized in that the coating layer resistant to saliva but soluble in gastric juices contains as a film-forming agent one or more polymers of the group of dimethylaminoethyl methacrylates and methacrylic acid esters .

4. Pharmaceutical suction gum according to claim 1, characterized in that the coating layer which delays the release of the active substance contains a film-forming agent © a © various polymers of the group of cellulose ethers, cellulose esters, derivatives of polyacrylic acid, polymethacrylic acid derivatives and polyvinyl derivatives.

5. Pharmaceutical suction tablet according to claim 1, characterized in that the gastric juice-resistant coating layer contains one or more polymers from the group of phthalates or succinates of cellulose ether, cellulose ester, polyvinyl acetate as the smoke agent. , of the carboxy ethylethylcelluloses, of the derivatives of the polyacrylic acid and of the derivatives of the acid pslimetaeríJLic ©.

6. Pharmaceutical suction tablet according to one of the preceding claims, characterized in that the coating films also have, in addition to the film-forming film, a content of therapeutically acceptable auxiliary substances which are able to increase the flexibility of the coating films.

7. PROCESS FOR THE PREPARATION OF SUCTION TABLETS according to one of the preceding claims, characterized in that in a first stage of the process a preparation is prepared by an agglomeration method and from a mixture of active substance and suitable auxiliary substances, a preparation of multiple particles, whose particles are coated in a second phase of the process and by a spray application procedure, firstly with a film layer that retards the release of active substances or is resistant to gastric juices, and then with a layer of resistant film to saliva per resistente resistant to gastric juices, and in a third case of the © © © press junt © with after auxiliary substances in a tabletting machine to obtain suction pads.