WO1998056354A2 - Multiple-unit delayed dosage preparations and method for producing the same - Google Patents

Abstract

The invention relates to stable multiple-unit delayed dosage forms or preparations with controlled release which can be administered orally, and to a method for producing them using a selected polymer.

Description

Multiple unit retard preparations and process for their preparation

The invention relates to orally administrable, stable multiple unit prolonged release dosage forms or. Controlled release preparations and methods for making them using a selected polymer.

Oral sustained release preparations or dosage forms release the drug F at a predetermined rate and maintain the desired plasma concentration for a longer period than conventional immediate release dosage forms. As a result, the patient does not have to take the prolonged-release dosage form as often as the conventional instant or rapid release dosage forms. This in turn improves patient compliance.

Matrix tablets containing polymers are already known as a slow-release dose type. The polymers used for retardation purposes can be either hydrophilic or hydrophobic or a mixture thereof. Hydrophilic matrix tablets have recently become very popular because the hydrophilic polymers offer obvious advantages: they are relatively cheap, comparatively non-toxic and can be processed on conventional systems. Matrix tablets are usually available in single unit dosage forms.

Multiple unit dose forms have significant advantages over single unit dose forms, since their passage in the gastrointestinal tract is not so badly affected by the hydrodynamic conditions, or in other words, multiple unit dose forms compared to the hydrodynamic loads in the stomach Intestine

Tract are less susceptible. They also distribute themselves more uniformly in the gastrointestinal tract and enable more even absorption of the drug. As a result, the inter- and intra-individual fluctuations in the pharmacokinetic profiles are reduced compared to those of the single-unit dosage forms. The multiple unit dosage forms are usually hard gelatin capsules that contain coated pellets, granules, mini tablets or pearls. The rate of release of the active ingredient is often determined by the thickness and type of coating. The previously used multiple unit dose Form applied technology is complicated, requires the use of organic solvents and is expensive compared to single unit dosage forms.

The subject of the present invention combines the advantages of multiple unit dosage forms in terms of their behavior in the gastrointestinal tract, e.g. the uniform absorption of the active ingredient and the technological advantages of single unit dosage forms through the inexpensive and simple production of mini matrices. The dose of active substance can be easily adapted to the respective medical needs by varying the number of extrudates.

Another advantage of the multiple unit dosage forms is that extrudates of different active substances can be filled into the capsule and thus mixtures of active substances can be conveniently brought to the administration. In addition, the extrudates can be pressed into tablets using conventional auxiliaries. These tablets disintegrate into the extrudates quickly after administration so that the tablet behaves like a multiple unit dosage form.

According to the invention, the easily accessible, inexpensive and non-toxic cellulose ether hydroxypropyl cellulose (HPC) is preferably chosen. Instead of the conventional granulation methods, a melt extrusion method is preferably chosen for HPC. This method is simple and economical because it does not require organic solvents. The principle of melt extrusion has been known for over 3 decades (Beckmann 1964).

Slow-release formulations have already been produced using solvent-free N-vinylpyrrolidone with a water content of at most 3.5% by weight (EP 240 904). BASF developed a special manufacturing process in which the dose form is obtained directly from the extrudate in its final form, calendering. The mixture is extruded and the warm, still deformable extrudate is pressed between two rollers / belts or a roller and a belt, which are operated in opposite directions and have mutually opposite depressions. The shape of these depressions determines the shape of the finished dose form (EP 240 906 and EP 358 105). In a later patent application (EP 544 144), various compositions are described which contain a water-insoluble and a water-soluble polymer. In order to achieve the sustained release effect, the amount of the water-insoluble polymer should be at least 6% by weight. Instead of using a combination of water-soluble and water-insoluble polymers, the desired release rate was achieved by using a mixture of at least two water-soluble polymers with low (1 - 500 cP) and high (1000 - 120,000 cP) viscosity.

It is also known to produce spherical to lenticular sustained-release matrix pellets in a single production step. These contain drug, at least one water-insoluble polymer, a lipophilic component as a plasticizer and a gel-forming polymer (DE 4 413 350).

The use of a twin-screw extruder with special blade devices on each of the two screw shafts is already known. The blades are said to improve the homogeneity of the mixture (US Pat. No. 5,456,923).

WO 96 11 674-A1 describes a process according to which a mixture of medicinal substance, HPC and suitable auxiliaries for thermoforming and for modifying the release rate of the medicinal substance is heated, compressed and then injection molded under pressure, which results in a product with a defined shape . Mixtures of HPC with different molecular weights are used to optimize the release.

The previously known methods and products have a number of disadvantages. In most of the above-mentioned processes relating to melt extrusion, at least two polymers (one of which is water-soluble and the other water-insoluble or both of which are water-soluble) and additionally one or more auxiliaries (often at least one) are used to produce an extrudate

Plasticizers). By using many excipients, the excipient-drug ratio is increased and the finished product becomes very bulky and also expensive. In some cases, the product with a defined shape can only be obtained in a single step after complicated manufacturing methods with specially prepared machines. When the product containing N-vinylpyrrolidone is stored as the release control polymer, the release rate decreases with time, indicating a reduced stability.

Surprisingly, it has now been found that with a specially selected single thermoplastic polymer, namely hydroxypropyl cellulose (HPC), melt extrudates with a desired linear release profile and high stability can be obtained in a simple manner. This much simpler process only requires a conventional extruder and does not require any complicated manufacturing methods.

The object of the invention is to provide orally administrable, non-porous, stable multiple-unit prolonged-release dosage forms with controlled release, in particular dosage forms which contain only a selected polymer in addition to the active ingredient.

Another object of the invention is to provide a method using a single selected polymer to make the above dosage form type. If desired, the extrudates obtained can subsequently be rounded and varnished.

Other objects of the invention will be apparent from the text below.

Description of the invention

The present invention also relates to a process for the production of non-porous multiple unit prolonged-release dosage forms, comprising at least one therapeutically active substance and a hydrophilic thermoplastic but pharmaceutically acceptable polymer and optionally other customary pharmaceutical auxiliaries which, however, do not contribute to the prolonged-release effect. The therapeutically active drug and the polymer are conveyed either simultaneously, without prior mixing, or as a mixture, after prior mixing, in a normal extruder which has previously been heated to a temperature at which the polymer softens and the drug does not degrade. The temperature range at the outlet nozzle of the extruder is 50 to 200 ° C, preferably 80 to 180 ° C, and in particular 110 to 160 ° C. In the area of product entry into the extruder, the temperature is 25 ° C., preferably 40 to 70 ° C., preferably 40 to 60 ° C., particularly preferably 50 to 60 ° C.: The temperature in the intermediate area of the extruder lies between the temperature in the product entry area of the extruder and the temperature at the exit nozzle of the extruder.

The homogeneous mixture softens during the passage through the extruder and is finally pressed through a plate which contains at least one nozzle with a defined diameter of 0.5 to 3.5 mm, preferably 0.8 to 3.0 mm.

The extruded strands, which are still soft on leaving the extruder die and quickly become solid at room temperature, are cut into cylinders with a length of 0.5 to 4 mm, preferably 1.0 to 3 mm, immediately after they exit. Alternatively, the extruded strands are granulated immediately (e.g. water-ring granulation or underwater granulation) or cut into pieces immediately (on-line). The extrudates obtained can be filled directly into hard gelatin capsules or, if necessary, rounded beforehand to improve their flow properties. As a special embodiment, it has proven advantageous to coat the extrudates obtained before they are filled into gelatin capsules, preferably with a water-insoluble but water-permeable and non-gel-forming polymer.

The coated extrudates can be coated with conventional auxiliary materials (e.g. micro-

(R) crystalline cellulose, Ac-Di-Sol, etc.) are pressed into tablets. These tablets disintegrate quickly after administration so that the tablet looks like one

Multi-unit dosage form behaves. The active ingredient can be any orally administered pharmaceuticals, such as anti-infectives, circulatory agents, antifungals, antidepressants, anti-dementics, anti-epileptics, anti-inflammatory drugs, analgesics, anti-asthmatics, anti-thrombotic agents, anti-tumor agents, anti-malarial drugs, non-steroidal anti-inflammatory drugs, anti-inflammatory drugs. Diuretics, antiarrhythmics, hypoglycemic agents, ACE

Inhibitors, sedatives, decongestants, antihistamines, lipid-lowering agents. For the purposes of the present invention, only those drugs are incorporated which do not decompose under the temperatures and processing conditions. The drugs specified in the examples are dihydropyridines. The amount of active ingredient to be administered per dose unit can be varied within wide limits depending on the type of drug and the rate of release. It has proven to be advantageous to use 0.5 to 10 parts by weight, preferably 1 to 5 parts by weight, of the gel-forming polymer per part by weight of active ingredient.

Hydroxypropyl cellulose is the preferred polymer for retardation. The molecular weight of the polymer and its degree of substitution play an important role. HPC is preferably used, with an average molecular weight of approximately 100,000 to 1,000,000, in particular approximately 300,000 to 1,000,000. The degree of substitution should be at least 3. If the drug is temperature sensitive, the use of low molecular weight HPC is recommended.

In contrast to the previously known techniques, only a single polymer is used for the retardation according to the present invention. The desired release rate is obtained either by selecting a suitable type of polymer and / or by varying the production parameters. The drug release rate is e.g. influenced by the drug concentration in the end product or by process parameters of the extrusion, such as the screw geometry, the extrusion rate, the extrusion temperature, the diameter and the surface of the extrudate, the viscosity of the polymer, etc.

As already mentioned, it is also possible to use other customary auxiliaries which are customary in the manufacture of solid dosage forms in pharmacy and from which Literature are known. However, none of these auxiliaries is necessary in order to significantly influence the delay in the release of the pharmaceutical substance desired according to the invention. Rather, these auxiliaries only serve to make the process more flexible.

If necessary, the extrudates are lacquered e.g. with pH-independent aqueous dispersions such as an ethyl cellulose dispersion (e.g. Aquacoat EC 30 Trademark of FMC) or a polyacrylate derivative (e.g. Eudragit NE 30 D Trademark of Röhm Pharma). In order to promote rapid penetration of water through the lacquer into the matrix, certain water-soluble polymers called "pore formers", such as low-viscosity hydroxypropylmethyl cellulose (HPMC), low-viscosity HPC or low-viscosity hydroxyethyl cellulose, etc. can be used. A plasticizer such as triethyl citrate or Tween 20 can also be used to prevent the paint film from becoming brittle during storage. Magnesium stearate can also be incorporated into the paint suspension as an anti-adhesive.

The varnish has essentially no effect on the release rate, except that there may be a delay in the onset of release during the first two hours after administration (lag time).

Typical varnish suspensions are:

A. 30-60% (preferably 40%) Eudragit NE 30 D dispersion; 3-10% (preferably 5%) HPMC 3 cP; 0.05-0.5% (preferably 0.1%) Tween 20; 1 - 7.5% (preferably 2.5%) magnesium stearate and demineralized water up to 100%.

B. 15-30% (preferably 25%) Aquacoat EC 30 D dispersion; 3-10% (preferably 4-5%) HPMC 15 cP; 0.5 - 4% (preferably 2%) triethyl citrate and demineralized water up to 100%.

The lacquer suspensions, for example, are produced by first dissolving HPMC and the plasticizer separately in water and then using the dispersion of the film former mixes. In the presence of magnesium stearate, it is dispersed in the aqueous solution of HPMC and plasticizer before the addition of the Eudragit NE 30-D dispersion.

The invention is illustrated by the following examples.

example 1

3 kg of the drug nifedipine are mixed with 7 kg of highly viscous HPC (MW 800,000). The mixture is processed on a twin-screw extruder with two outlet nozzles with a diameter of 2 mm. The material is used in a

Extruded die temperature of 150 ° C. The temperature of the various subunits in the extruder barrel is set to a temperature which is at least about 10 ° C below the die temperature. The extrudate is cut into approximately 2 mm long cylinders and painted in a fluidized bed coating system. 0.6 kg of lacquer suspension A is sprayed on per kg of extrudate. The painting is carried out under normal conditions.

Example 2

Analogous to Example 1, but 2 kg of nifedipine are mixed with 8 kg of the same type of polymer.

Example 3

Analogous to Example 1, but equal amounts of the drug and the polymer are mixed and processed.

Example 4

Analogous to example 1, but the nozzle temperature is 160 ° C.

Example 5

Analogous to example 1, but the nozzle diameter is 1.4 mm. Example 6

Analogous to example 1, but the nozzle diameter is 0.8 mm.

Example 7

Analogous to Example 1, but the extruded strands were first cut into approximately 4 mm long cylinders.

Example 8

Analogous to Example 1, but the approximately 2 mm long cut cylinders were not painted.

Example 9

Analogous to example 1, but the nozzle temperature is 120 ° C.

Example 10

Analogous to Example 1, but HPC with an average molecular weight of approximately 150,000 is used as the polymer.

Example 11

Analogous to Example 1, but HPC with an average molecular weight of approximately 1,000,000 is used as the polymer.

Example 12

Analogous to Example 1, but nisoldipine is used as the drug. Example 13

Analogously to Example 1, but nimodipine is used as the drug, low-viscosity HPC (MW 150,000) is used, and the nozzle temperature is 110 ° C.

Example 14

The same composition as in Example 1 is in a commercially available extrusion and granulation device (Leistritz) under the same

Extrusion conditions extruded and then immediately granulated and dried by the water-ring method. The resulting extrudates were slightly rounded and therefore easier to process.

Example 15

The same composition as in Example 1 is extruded under the same extrusion conditions in a commercially available extrusion and granulation device (company Gala) and then immediately granulated and dried by underwater granulation. The resulting extrudates were slightly rounded and therefore easier to process.

Example 16

The same composition as in Example 1 is extruded through an extruder with outlet nozzles with a diameter of 1 mm, the extruded strand is cooled by spraying with water and immediately granulated and dried. The extrudates obtained are processed as described in Example 1.

Claims

Claims 1. Orally administrable, stable multiple-unit prolonged-release dosage forms with controlled release, containing at least one active ingredient and only one hydrophilic thermoplastic, pharmaceutically acceptable polymer, which brings about the sustained release effect. 2. Preparation according to claim 1, characterized in that it contains hydroxypropyl cellulose as the retarding polymer. 3. Preparation according to claim 2, characterized in that it contains hydroxypropyl cellulose with an average molecular weight of about 100,000 to 1,000,000 and a degree of substitution of at least 3. 4. Preparation according to claim 1, characterized in that it is based on 1 wt. Part of active ingredient contains 0.5 to 10 parts by weight of the gel-forming polymer. 5. Preparations according to claims 1 to 4, characterized in that the multiple unit dosage forms are in the form of pellets, granules, mini-tablets or pearls, which optionally with a water-insoluble but water-permeable, non-gel-forming polymer which practically does not contribute to the retarding effect, are painted. 6. A process for the preparation of preparations according to claim 1, characterized in that a mixture of at least one active ingredient and only one selected hydrophilic thermoplastic polymer and, if appropriate, other conventional pharmaceutical auxiliaries which do not contribute to the retarding effect, is mixed and the mixture is passed through an extruder , which has a temperature of 25 ° C., preferably 40 to 70 ° C. at the point of product entry and a temperature of 50 to 200 ° C. at the outlet nozzle, the outlet nozzle (s) having a diameter of 0.5 to 3.5 mm and the still soft extruded strands immediately after their exit in Cylinders with a length of 0.5 to max. 4 mm cuts or granulated by water-ring / underwater granulation and the optionally rounded extrudate obtained is filled directly into gelatin capsule, or the optionally rounded extrudate obtained is pressed together with conventional auxiliaries to form a tablet. 7. The method according to claim 6, characterized in that the polymer used is hydroxypropyl cellulose with an average molecular weight of approximately 100,000 to 1,000,000. 8. The method according to claim 6, characterized in that the extrudates obtained are coated with water-insoluble but water-permeable, non-gel-forming polymers. 9. The method according to claim 8, characterized in that the coating of the extrudates with aqueous dispersions of ethyl cellulose derivatives or polyacrylate derivatives are carried out. 10. Use of the extrudates produced according to claim 6 in lacquered or unpainted form in the production of sustained-release medicinal preparations with controlled release.