FI118952B - Slow-passage carrier of active ingredients for controlled release of active ingredients in the gastrointestinal tract - Google Patents

Abstract

A strip-shaped film substrate with openings and loaded with an active substance serves as the basis for the production of an active substance carrier for the controlled release of active substances in the gastro-intestinal tract with delayed passage through the pylorus.

Description

118952

The invention relates to the use of a web-shaped, film-like, opaque, and active-containing substrate for the release of active ingredients from the controlled gastrointestinal tract.

Carriers or dosage forms of sustained release active ingredients must be capable of providing a topical therapeutic effect in the stomach. In addition, they allow the release of active ingredients over a longer total time than conventional oral dosage forms and thus the frequency of administration can be reduced.

Longer stomach formulations are either of very low density and floating on the surface of the gastric fluid or unable to pass through the gastric port due to their size or space requirements.

Floating dosage forms include, for example, those rich in lipophilic, low density (DE 2 611 041). In addition, it has been described to make the second tablet or capsule buoyant to float by providing a plurality of small air closures (EP-A 0 297 978, DE-A 3 803 482). Finally, gaseous substances or mixtures such as carbon dioxide may be added. , 1; diarrhea foam formulations in a diapered dosage form with simultaneous expansion of such a device after use (US 4,996,058).

The main disadvantage of floating dosage forms is their non- • · · I .; 30 reliable stomach retention. Unless they are prevented from moving through the stomach gland by the size of the pharmaceutical form (EP-A 0 308 904), only floating persons: ***: sitting or standing. Sleeping People · «· .j. • The stomach gate can be very easily contacted • · * '. 35, whereby the floating dosage form · · · 1 is preferably transported to the small intestine. (A. J. Moes, Crit. Rev.

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Therap. Drug Carrier Syst. 10, 143 (1993). The floating of such devices requires the presence of a minimum amount of gastric fluid, which is not necessarily required of patients.

Dosage forms which, by virtue of their size or space requirements, are retained in the stomach have also long been known. Since the dosage form is first to be swallowed, and thus may not initially exceed a given maximum size, various mechanisms have been described to increase the size of the stomach after ingestion. This can be accomplished, e.g., by providing a gas phase in the device after contact with an aqueous liquid (US 4,996,058), but also by allowing hydrophilic components to swell in gastric fluid (EP 0 425 154, US 5 147 646, EP 0 310 326, US 4 207 890). , US 4,434,153). The primary disadvantage of these formulations is that they are either not strong enough to withstand the contraction forces of the stomach-wall muscles or, when they are strong enough, they can cause a harmful and potentially dangerous obstruction of the stomach, preventing stomach contents preceded by a 20-leen transition.

Known in different ways, with a lot of space • · · ί ·! • active ingredients containing • ·: .V in compressed or reduced form before use. A permanent compressed or constricted state is generally achieved by t4 * j * 25, usually by wrapping, such as encapsulation, whereby this state remains in the gastric fluid until disintegration of the capsule. After the disintegration of the shaft, the restoring forces or the swelling pressure of the hydrophilic components cause a large space-consuming structural remodeling (US 4,735,804, EP 0 202 159, * 30 US 5 002 772, EP-A 0 415 671). . Provided these structures retain sufficient mechanical stability to withstand mechanical (•. *. * ·· gastric contraction movements, they are potentially the most suitable gastrointestinal dosage forms because they are reliably prevented from passing through the stomach gland). • «· I 35 Preventing emptying of glove contents.

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Although the constructional features of various gastric retention systems have been explained in the prior art, little has been done in the engineering aspects. Because the formulation of known gastric retention formulations is mo-5, the industrial batch manufacture of such systems is considered to be extremely laborious and expensive. To date, continuous methods have not been described. Dosage formulations often contain a variety of components, each of which serves either to preserve the formulation or to release the active ingredients. In addition, there are no pharmaceutical testing methods available to assure the quality of these dosage forms during manufacture. Large and space-intensive structures with high mechanical stability are not only difficult to complete, but also have the disadvantage that they can irritate the stomach.

It has been the object of the invention to provide a carrier of the active ingredients for controlled release of the active ingredients through the gastrointestinal tract which passes through the stomach gland 20 times and which prevents or overcomes the above-described disadvantages which allow the gastric or ii: gastric mucosa to be significantly prolonged. • stomach dwell time and release of active ingredients, which • provides the best possible oral • j * 25 administration and is suitable for serial production with commercially available:: · line.

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In order to solve this problem, it is proposed to use the active ingredient carrier in the form of a web with openings and a substrate containing the active ingredient as a starting material for the slow delivery of active ingredient carrier through the gastric port. sexually active substances in the gastrointestinal tract.

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The carrier material for the active ingredients is • · «; . 35 for very good reasons. It allows for economical manufacturing of known continuous, 4,118,952 continuous sheet-forming processes, such as spinning and unrolling, plating and stamping, and diaphragm curing. -5 with material. The gastric retention formulations prepared in this way have other advantageous properties. Due to the membrane form of the active ingredient carrier, for example, gastric irritation due to the carrier of the active ingredients, which occurs with known three-dimensional, space-consuming structures which, due to their size or their large space requirements, are unlikely to be expected. In particular, when the device has a mechanically sufficient stability after the erosion of the diaper in the stomach, gastric retention can be considered very reliable. When reached, the minimum expansion of 5 cm 2 exceeds the size of the opening of the active substance carrier in the human gastric gland, thus preventing the penetration of the gastric gland even more strongly when the maximum expansion is up to 8 cm 2. In addition, the desired stomach residence time of the active ingredient carrier can be better controlled than most current systemic systems, which are able to • • ϊ.port, ϊ his muscles have been able to refine the device: V: extent. However, gastric contraction depends on many factors, ··· 25 that can hardly be controlled in practice, e.g. The duration of retention of previously proposed dosage forms of the tonic nervous system, particularly of the parasympathetic nervous system, is likely to be associated with large inter-individual variations. In contrast, the retention time of the active compounds of the invention can be controlled with much greater certainty by galenic formulation, i.e. the composition determines the rate at which the device is absorbed in gastric fluid, mainly because of erosion,

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their properties.

• · · *; * | 35 The presence of active substance carrier in the openings prevents inadvertent obstruction of the gastric port 5 118952. The gastric port normally permits the passage of fluid material of low to medium viscosity and particulate matter of particulate matter. The size is up to about 2 mm By equipping the active agent carrier with, for example, openings with a diameter of 3 mm or more, it can be prevented from accidentally blocking the stomach gate.

According to one embodiment of the invention, the active ingredient carrier comprises at least one active ingredient that acts locally on the stomach. This may be an active ingredient which is preferably absorbed through the gastric mucosa. But it can also be an active substance for which the absorption window can be found in 15 of the upper small intestine. The subject of the invention is therefore suitable for the administration of active substances which affect the upper small intestine. This does not previous conventional oral sustained release dosage forms agreed, because they supply a large part of the dose counter pharmaceutical form of over-20 tettua the upper part of the small intestine. the applicant of the invention, the active agents can be released from the active substance: dissolved form to move securely and steadily pitkäh- • · .V KOJA times the upper part of the small intestine!.

: Y: The invention has several therapeutic benefits. On the other hand, ·· 25 can be used to treat locally stomach ailments

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. It is significantly better than traditional pharmaceutical formulations. These diseases include in particular hyperacidity, microbial infections, gastritis and ulcer. These and. . for the treatment of other gastric diseases, there are effective drugs which may be improved by their efficacy or therapeutic index by the administration of the active ingredient carrier of the invention. In this way, a special * · l ** l large proportion of the active ingredient carrier used ··· is directly contacted with diseased tissue. The local action time of active drug concentrations increases with time. Examples of such active ingredients are 118,952e inorganic antacids, H2 receptor blockers such as simethidine, ranitidine, famotidine, nicatidine, roxatidine and their salts, muscarinic receptor blockers such as pirenzipine, so-called. proton pumps such as omeprazole and mi-5 soprostol; drugs that are active against Helicobacter pylorii and other microbial pathogens, proglmid and carbenoxolone.

In one embodiment, the active ingredient carrier further comprises gaseous substances, gaseous substances or mixtures thereof, or liquid or solid substances and / or mixtures thereof having a relative density less than 1. In this way, the gastric retention of the active ingredient carrier can be promoted. in addition to surface area, buoyancy.

The invention further relates to a carrier for active substances consisting of or containing erodible material in biological fluids. The composition of the material used essentially determines the residence time in the stomach of the device retained by the stomach. It preferably consists of one or more pharmaceutically acceptable polymers and other pharmaceutical excipients such as plasticizers. · Roads, wetting agents, hydrophilizing agents, stabilizing agents: Y: Waves, dyes, release agents, buffer salts, etc. Examples of polymers used are polysaccharides, such as gums, starches or cellulose derivatives, ····. . ·. polyacrylates and methacrylates, polylactides, polyglycol • · ·. ···. Lidis, polyoxyethylenes and polyoxypropylenes, proteins, · · · · · · · · · · · · · · · · · · · · ·, polyvinyl alcohol, polyvinyl acetate, polyvinyl. . chloride or polyvinylpyrrolidone, silicone elastomers and copolymers. With suitable mixtures, the rate of erosion • · '··· * can be adjusted to achieve the desired retention time in the stomach. After this time, the device manufactured according to the invention has lost so much mechanical strength that stomach contractions are able to crush it and pass through the gastric port. After this *. ** time, the active ingredient carrier prepared according to the invention has lost so much mechanical strength that it is capable of being comminuted by gastric contractions and that the carrier is able to pass through the gastric port.

The dimensions of the active ingredient carriers prepared according to the invention are altered by rolling or folding so that they are suitable for oral administration. This requires that the membrane material be flexible and not brittle. After wrapping or folding, the devices are preferably provided with a suitable sheath 10 for attaching the devices to this space until use. Such a diaper may be, for example, a hard gelatin capsule, but any diaper which engages the device in a rolled or folded state which is degradable in gastric fluid and which is physiologically acceptable is suitable.

15 Compared to the state of the art, the active ingredient as a whole carries many advantages. These have the potential to reduce the frequency of intake in chronic therapy compared to traditional sustained release formulations. Sustained-release drugs are usually sensible in long-term therapy if the active substance is rapidly eliminated from the body, i.e., the elimination half-life is less than about 10 to 20 hours. If sustained-release formulations can reduce the frequency of intake, 1 · 1. large blood concentration variations can be avoided and thus adverse side effects can be improved and patient compliance improved. When using the active ingredient carrier of the invention, the intake frequency of many active ingredients can be reduced once a day, which,. marks a further step forward in therapeutic safety.

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Claims (10)

8 118952 Use of a web-shaped, film-like, apertured, and active-containing substrate 5 as a starting material for the manufacture of a sustained-release, film-like, apertured carrier for the release of active ingredients in the gastrointestinal tract. 2. Starting material for the slow release of active ingredients in the gastrointestinal tract through the gastrointestinal tract 10 for the controlled release of active ingredients in the gastrointestinal tract, characterized in that it contains at least one active ingredient which acts locally on the stomach. The starting material according to claim 2, characterized in that it contains at least one active ingredient which is preferably absorbed through the gastric mucosa. 4. A slow-acting, transmembrane, transmembrane carrier with active ingredients for the controlled release of active ingredients in the gastrointestinal tract, characterized in that it contains at least one active ingredient, is being absorbed • · s window of the small intestine upper end of the range. • · Active ingredient carrier according to Claim 4, characterized in that it further contains gaseous substances, gaseous substances or S · · amine mixtures or liquid or solid substances and / or mixtures thereof, having a relative density of less than 1. 6. The active ingredient carrier according to claim 4 or 5, characterized in that it consists of: a material which is eroded in biological fluids; ···, contains such. * · 118952 that it is in a compact form for oral administration in the form of a roll or a folding press. Active ingredient carrier according to one or more of Claims 4 to 7, characterized in that it is encapsulated in its compact form, for example, by a capsule which is rapidly disintegrated in gastric fluid. Active ingredient carrier according to one or more of Claims 4 to 8, characterized in that it has a surface area of at least 5 cm 2 in the unfolded or opened state. Process for preparing the active ingredient carrier according to one or more of Claims 4 to 9, characterized in that the starting material is a film-shaped, apertured film-like material and the process is carried out continuously. * • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • 1 «·» • 1 ·•••••• I * ····················································••• · • 1 · e · • · · • ♦ · 2 • ♦ 10 1 1 8952