NO157964B - PROCEDURE FOR THE MANUFACTURING OF QUICK-EXTENSIBLE PHARMACEUTICAL PRESSURES. - Google Patents

Abstract

Quick-disintegrating pressed shapes e.g. tablets containing pharmaceutical active substances, which shapes consist essentially of a compressed mixture of a) a pharmaceutical active substance in a granular delayed-release form, and b) a disintegrating agent having a high disintegrating capacity as well as good binding properties. The pharmaceutical active substance is coated with a mixture of ethyl cellulose and a polyacrylate to provide the delayed-release form.

Description

The invention relates to a method for the production of rapidly degradable pharmaceutical compacts, which contain pharmaceuticals in granulated retarded form.

It is known to mix resp. to coat medicinally active substances with active substance release-delaying excipients and process into granules, which can then be administered directly in this granular form or after filling in capsules, or only after further processing into tablets to be used in therapy. Hitherto known granulated retard drugs have many disadvantages. Difficulties arise in connection with the production. Either the preparation was cumbersome, or it was necessary to use organic solvents, or the excipients were not ideal with regard to the intended effect, namely the correct delayed release of the active substance. Difficulties also arose with the external properties of these grains, i.e. e.g. with free-flowing ability or moisture sensitivity in properties that appeared unfavorably either by direct administration, i.e. by dosing and possibly with simultaneous intake with food and pleasure products, or by filling in capsules. Also, single doses of over 600 mg packed in capsules are not appropriate, as the capsules are too large to swallow.

DE-AS 2 336 218 mentions coated drug cores where the coating material contains a combination of a) ethyl cellulose and b) methacrylic acid-methacrylic acid ester mixture polymer. Also mentioned in this DE-AS is polyvinylpyrrolidone (PVP), which, when active substances are applied in moderate and lower dosages to inert small carrier spheres, serve as adhesives. After application of active substance in mixture with PVP on e.g. sugar pellets, the intraperiticular polyvinylpyrrolidone-containing pellets are coated with the film, consisting of the above-mentioned components a) and b).

The present invention relates to a method for the production of rapidly degradable pharmaceutical compacts, in which the method is characterized by pressing a mixture which essentially consists of

a) a medicinal product in granulated retard form consisting of a granulated or crystalline medicinal active substance, which is

coated with a coating material, which essentially consists of a homogeneous mixture of a water-insoluble but water-dispersible poly(H+meth)-acrylic acid (methyl+ethyl)ester and a water-insoluble but water-dispersible ethyl cellulose, in which the weight ratio is between 2.5:1 and 5:1,

and

b) cross-linked polyvinylpyrrolidone as an explosive with high explosive power and binder properties.

The two covering materials preferably used according to the invention are known as such. They are suitable for use alone, however not for purposes according to the invention. The former is very thermoplastic and thus produced sheathed grains tend to coalesce. The latter, on the other hand, in usual quantities and processing methods in the present application, provides a too little effective retarding coating. Thus, it could not be expected that the combination of the covering materials which are not individually suitable for the purposes at hand would give a very good result in every respect. Thus, in the first place, the drug grains produced are free-flowing, insensitive to moisture, taste neutral, and they achieve the desired delayed effective drug release with great uniformity. During microscopic examinations, it was also determined that the individual active substance grains are very; coated, so that it essentially retains its original shape. Thus, a homogeneous intermediate product can easily be obtained with homogeneous starting material.

Granular or crystalline substances are particularly suitable as active substances for a granular drug retardation form according to the invention. Particularly suitable are solid grains or monocrystals in the size range 0.3-2 mm (diameter), which have a certain mechanical strength which is of particular importance in the subsequent processing into compacts.

On the one hand, polyacrylic acid esters with the formula f are particularly suitable as wrapping materials

Such substances are produced by emulsion polymerization, and contain copolymers with a molecular weight of some 100,000 in the form of latex particles with a diameter of around or below 1 pm. A corresponding particularly suitable product is marketed by Rohm Pharma GmbH, Darmstadt (BRD) under the name "Eudragit" E30D, as an aqueous dispersion and is an acrylic acid ethyl ester with an acrylic acid methyl ester 70:20 copolymer with a molecular weight of 800,000.

On the other hand, ethyl cellulose is preferably used as wrapping material. Particularly suitable is a product marketed by FMC Corporation Philadelphia, U.S.A., under the designation "Aquacoat" ECD-30, namely as a 305 µg aqueous polymer dispersion of small particle size (latex form) and narrow particle size distribution.

The two enveloping substances just mentioned [poly(H+meth)-acrylic acid (methyl+ethyl)ester and ethyl cellulose] are preferably used in a weight ratio of 2.5 to 5:1, but especially in a ratio of 3:1.

It is advantageous to put smaller quantities, e.g. from 0.5 to 156 colloidal silicon oxide, e.g. that of Degussa Frankfurt (BRD) marketed "Aerosil". With this addition, the free-flow duration of the grain is further improved. Furthermore, it is of course also possible to add other auxiliary substances in smaller quantities to the wrapping fabric treatment, such as e.g. dyes or flavorings.

The production of the medicinal granules used according to the invention can take place in a manner known per se. This also applies to the enveloped grains. These are produced in the fluidized bed atomization devices known for this purpose or in coating boilers. The coating material mixture is supplied as an aqueous dispersion at room temperature. The atomization is best carried out with air of a temperature of 25 to 30"C. In this way, the individual grains are easily obtained, i.e. an unwanted agglomeration of the granules does not occur.

Surprisingly, the drug grains used according to the invention can be pressed together with explosives with high explosive power and binder properties and with the otherwise usual excipients for tableting within a wide dose range easily pressed into shaped bodies, such as e.g. tablets or capsules, or small rod-shaped compacts. These shaped bodies produced in this way have the property that already in the stomach of the person treated in this way, they quickly break down again into single grains and thus distribute themselves well. In this way, a local overconcentration of the active substance in the digestive tract is prevented, and an even, slow and distributed active substance release over a large resorption area is ensured. Upon microscopic examination, it was established that the individual grains are hardly damaged by the compression, so that when the active substance is released from it, it can then fully unfold its original beneficial properties. If a pressing body is to be produced with two or more active substances, then individually colored drug grains can be produced separately, which improves the characterization and then also makes the patient aware that they have in front of them a drug with two or more active substances.

As explosives with high explosive power and binding agent properties for the compacts that can be produced according to the invention, cross-linked polyvinylpolypyrrolidone (PVPP), such as that of GAF Corporation, New York, N.Y., is particularly suitable. (USA) stated "Polyplasdone" XL, resp. "Kollidon" CL (BASF, Ludwigshafen/Rhein, BRD), or sodium carboxymethyl starches, such as e.g. that of W.A. Scholten's Chemiche Fabriken, N.V. Foxhol (NL) marketed "Primojel", or one of the E. Mendell Co. INC., New York (U.S.A) marketed "Explotab".

In the case of the excipients that are otherwise common for tableting, it is above all about binding and lubricating or anti-adhesives.

For the production of the rapidly degradable medicinal press bodies that can be produced according to the invention, the usual tablet presses can be used.

As the mechanical strength of the pressing bodies is surprisingly good, it is also possible to produce all desired common shapes such as e.g. tablets, capsules or rod-shaped compacts with or without instructions for breaking. These pressing bodies can, if desired, also be equipped with a protective varnish known for this purpose.

As, according to the invention, processable pharmaceutical active substances in granule form or crystals of a suitable size, it is in principle suitable for all that are suitable for peroral administration and why an increased release in the gastrointestinal tract is desired. However, the invention is particularly advantageous when using active substances, which at higher concentrations can cause local irritation of the mucous membrane in the gastrointestinal tract, and which are administered in larger single doses. This is e.g. case for potassium chloride which is administered in potassium deficiency conditions or for lithium salts in psychotherapy.

Example 1

Manufacturing

A) Enveloped grains

1) Callum chloride is presented,

2) "Eudraglt" E30D and "Aquacoat" EDC30 are mixed under gentle stirring, 3) 1. meet with 2. 1 fluidized bed granulate (fluidized bed granulator Aeromatik ST 7)

Syringe 1 direct current,

The mixture of the dispersion is stirred during the spraying process,

Supply air temperature 28°C,

Performance approx. 80 g/min,

4) Drying at 28"C to air temperature (fluidized bed dryer Aeromatik ST 7) approx. 10 min., 5) Dry coated grains are mixed with "Aerosil" 200 for 10 minutes,

6) Mixture 5 is sieved, sieve 1.5-2.0 mm.

Properties:

Free-flowing, tasteless.

Release properties of callum chloride (Van der Kamp decomposition tests in water at 37°C).

A) Press body:

Coated grains "Aerosil" 200, "Polyplasdone" XL and magnesium stearate "are mixed for 1 15 minutes. The mixture is pressed on a commercial tableting machine for small bars (e.g. Korsch EKO) punch size 20.7 x 8.6 mm.

Properties:

Decomposition in water of 37 °C < 5 min.

Release properties of callum chloride (Van der Kamp decomposition tests in water of 37°C): Example 2

Manufacturing

A) Coated grains:

1) Callum chloride is presented.

2) "Eudragit" E30D and "Aquacoat" ECD30 are mixed under gentle stirring. 3) 1. is sprayed with 2. in fluid bed granules (fluid bed granules Aeromatik Strea 1).

Spray in direct current.

The mixture of the dispersion is stirred during the atomization process.

Supply air temperature 28°C.

Performance approx. 8 g/min.

4) Drying at 28°C supply air temperature (fluidized bed dryer Aeromatik ST 7) approx. 10 minutes. 5) Dry coated grains are mixed with "Aerosil" 200 for 10 minutes.

6) Mixture 5. is sieved with a sieve of 1.5-2.0 mm.

B) Press body:

Coated grains., cross-linked polyvinyl polypyrrolidone and magnesium stearate are mixed for 15 minutes. The mixture is pressed on a commercial tableting machine for small bars (e.g. Korsch EKO), punch size 20.7x8.6mm.

Properties:

Decomposition in water of 37'C < 5 minutes.

Release properties of callum chloride (Van der Kamp decomposition tests in water of 37°C):

Example 3

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Manufacturing

A) Enveloped grains

1) Pirprofen is presented.

2) "Eudragit" E30D and "Aquacoat" ECD30 are mixed under gentle stirring.

3) 1. sprayed with 2. fluid bed granulator

Aeromatik Strea 1:

Sprayed in direct current.

The dispersion is stirred.

Supply air temperature 35'C.

Performance approx. 8 g/min.

4) Drying at 35°C supply air temperature (fluidized bed dryer Strea 1) approx. 10 minutes mixing with "Aerosil". 5) Dry coated grains are mixed with "Aerosil" 200 for 10 minutes.

6) Mixture 5. is sieved through sieve 2.0 mm.

B) Press body

5. mix with "Polyplasdone" XL and hydrogenated cottonseed oil for 15 minutes in a tumble mixer of the "Turbual" type.

Homogeneous mixture 6. is pressed on a tablet press EKO into small stick-shaped tablets 16.4 x 8.6 mm.

Survey data:

Decomposition in water (37°C) in single- 30 sec. Decomposition in gastric juice ( 37°C)} particles 1 min. Example 4

Manufacturing:

"Zerolit" 225 (cationic ion exchanger of diaproxim Ltd., England), "Polyplasdone" XL and "Avicel PH 102" (granulated microcrystalline cellulose of FMC, U.S.A) are sieved through a sieve with a mesh size of 0.8 mm.

The sieved components are mixed for 10 minutes in a Turbula mixer.

The homogeneous mixture is pressed on a tableting machine, e.g. Korsch EKO for round tablets.

Properties:

Tablet diameter 9.0 mm

Tablet hardness approx. 80 Newtons

Decomposition (water 37'C) approx. 15 seconds.

Claims (5)

1. Process for the production of rapidly degradable pharmaceutical press bodies, characterized in that a mixture is pressed which essentially consists of a) a medicinal product in granular retard form of a granular or crystalline medicinal active substance, which is enveloped with an enveloping substance, which essentially consists of a homogeneous mixture of a water-insoluble, but in water-dispersible poly(H+meth)-acrylic acid (methyl+ethyl)ester and a water-insoluble, but water-dispersible ethyl cellulose, in a weight ratio between 2.5:5:1, and b) cross-linked polyvinylpyrrolidone as explosive with high explosive power and binder properties. 2. Method according to claim 1, characterized in that the mixing ratio of the covering materials is 3:1. 3. Method according to claim 1, characterized in that the coating material mixture also contains colloidal silicon dioxide. 4. Method according to claim 1, characterized in that the medicinal substance is callum chloride in the order of 0.2-1.2 mm in diameter. 5. Method according to claim 1, characterized in that the medicinal substance is pirprofen in the size range of 0.5-1.2 mm in diameter.