WO1996038169A1

WO1996038169A1 - Enteric coated compressed pancreatin particles

Info

Publication number: WO1996038169A1
Application number: PCT/EP1996/002297
Authority: WO
Inventors: Herman Vromans; Werenfriedus Adrianus Faassen
Original assignee: Akzo Nobel NV
Current assignee: Akzo Nobel NV
Priority date: 1995-05-31
Filing date: 1996-05-29
Publication date: 1996-12-05
Anticipated expiration: 1997-11-30
Also published as: AU6123296A

Abstract

The invention concerns irregularly shaped enteric coated compressed pancreatin particles, which can be prepared by a method of production, characterized in that pancreatin powder without solvents, and optionally together with a lubricant, in a first step of the process is compressed by applying elevated pressure, thereafter in a second step crushed into particles, after which in a third step the particles are coated with an enteric coating. After the crushing into particles, the particles can be sieved, after which the part of the particles having a particle size larger that a pre-determined size are enteric coated, and the part of the particles having a particle size smaller than a pre-determined size areseparated from the process, and optionally are recirculated into the first step of the process.

Description

ENTERIC COATED COMPRESSED PANCREATIN PARTICLES

The invention concerns irregularly shaped enteric coated compressed pancreatin particles, a pharmaceutical composition comprising the same, a capsule comprising the pharmaceutical composition and a method of production.

Pancreatin is a versatile drug for the treatment of digestive disorders in mammals, including human beings. Pancreatin granules are commonly coated with a gastric acid resistant coating (enteric coating), which disintegrates under neutral or basic conditions, and prevents disintegration in the stomach.

Various methods of producing coated pancreatin have been disclosed, for instance US 5,302,400 comprising blending pancreatin with other ingredients among which a binder, adding organic solvents, granulating the composition, compacting the granules to spherical particles, which are subjected to drying and coating. A similar process has been disclosed by the same inventor in US 5,260,074. This type of process has been earlier disclosed in US 4,079,125, according to which pancreatin, a binding agent, a stabilizer, and a disintegrating agent are dissolved in isopropanol, granulated, extruded and formed into beads by Marumerizer compaction, after which the beads are coated with a conventional enteric coating. A method of preparation of spherical particles, not applying compaction and not using binders, but still using organic solvents (aqueous acetone), has been disclosed in WO 91/07948.

There is a need for a simple method of production, which does not require binders and preferably no other ingredients, and most importantly, does not use organic solvents. The present invention concerns such method and provides irregularly shaped enteric coated compressed pancreatin particles. Said irregularly shaped enteric coated compressed pancreatin particles can be applied in pharmaceutical compositions, which compositions can be dispensed into capsules. More specifically the invention concerns a method of producing irregularly shaped enteric coated compressed pancreatin particles, characterized in that pancreatin powder without solvents, and optionally together with a lubricant, in a first step of the process is compressed by applying elevated pressure, thereafter in a second step is crushed into irregularly shaped particles, after which in a third step each of the particles are coated with an enteric coating.

The present method is about ten times less expensive than the prior art methods, which comprise a separate granulation step, and a compaction step to provide spherical beads. The present method, moreover, can easily be scaled up. Further, no organic solvents are used, which provides a process with minimum environmental problems, whereas the coated particles have improved stability.

In a preferred embodiment of the invention the particles obtained after the crushing are sieved, after which the part of the particles having a particle size larger than a pre¬ determined size are enteric coated, and the part of the particles having a particle size smaller than the pre-determined size are separated from the process, and optionally are recirculated into the first step of the process.

Basically any pancreatin can be used, and preferably commercially available pancreatin which meets the European Pharmacopoeia, USP and DAB specifications is used.

In most instances it is not necessary to use lubricants, but to prevent sticking of the pancreatin powder to the rollers during roller compression small amounts of lubricant, preferably magnesium stearate in an amount of between 2 and 0.01 % w/w, and preferably of about 0.25 % w/w, can be added to the pancreatin powder. This is usually only required when the pancreatin powder has a very small particle size.

The pancreatin powder, and optionally the lubricant (e.g. magnesium stearate) are compressed, preferably by using roller compaction. This first step of the method is a dry granulation step in which no solvents are used and wherein the pancreatin powder is granulated into particles. This compression step should not be confused with the compaction step of the prior art methods, in which the compaction is used to make spherical beads from a pancreatin granulate. In the present method after compression a plate of pancreatin is obtained, which is crushed into irregularly shaped particles (granules). As an additional step the particles may be sieved into desired particles and into fines. The fines may then be recirculated into the hopper of the roller compactor.

During the compression of pancreatin powder the applied pressure is an important parameter. By applying pressure the temperature of the pancreatin between the rollers increases. Since the activity of enzymes like pancreatin is influenced by temperature, degradation of enzymes will take place. In general, the higher the roller compaction pressure, the higher the degradation. An increase of the roller compaction pressure also results in higher strength of the compacted plate resulting in a low friability. Furthermore, the production yield increases when the pressure increases. Suitable compaction pressures to give low friability and degradation, and high production yields, are of between about 1 and 3 MPa (megaPascal). A preferred pressure is about 1.7 MPa, giving a minimum activity loss and maximum yield.

The compactor can be any compactor, for instance being concave or convex, having straight or profilated rollers or different design of powder transport screws. The Alexander WP120 roller compactor has appeared to be a convenient compactor.

Usually the compacted powder h.ts to be crushed into smaller particles. This crushing step is important for the particle size distribution, which depends on the crushing method used. In principle any crusher can be used, for instance a pyramid or a roller crusher, preferably together with a crushing sieve of the Alexander Roller Compactor, with a Comil conical granulator, or with a Frewitt crushing sieve. By using this type of sieves, generally a production yield of about 50% is easily obtainable. The fines which cannot be used are sieved out and can be recirculated to the compression step.

The particles obtained, which are irregularly shaped and preferably larger than 1.0 mm are enteric coated. Surprisingly the irregular shape does not prevent suitable coating. Any enteric coating is suitable, usually comprising a polymer which is resistant to pH 1-5, for instance coatings comprising one or more of hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate, and methacrylate copolymers. A very suitable coating is poly(methacrylate ethylacrylate) (Eudragit), to which a plastisizer (for instance diethyl phthalate and preferably triethyl citrate) and a lubricant or glidant (for instance talc) are added. To prevent the use of organic solvents, the polymeric coat is preferably applied from an aqueous solution. Preferably the minimum amount of coat to be applied is 15 % w/w polymer (with respect to the amount of pancreatin). Methods of coating are well known in the art, for instance as disclosed in Remington's Pharmaceutical Sciences, ed. A.R. Gennaro (Mack Publ. Co.), 18th edition, page 1671-1675. After the coating process the coated particles may be dried, for instance in a vacuum plate dryer.

The coated particles can be capsuiated, for instance in hard gel capsules, such as gelatin capsules. If desired the capsules may be packed in polypropylene blisters, or in blisters of other suitable materials, and may further be packed in water vapour resistant sachets.

The following experiments further illustrate the invention.

Example 1

Irregularly shaped enteric coated compressed pancreatin particles were obtained by fblending 14.76 kg of pancreatin (supplier: Nordmark) and 36.9 g of magnesium stearate (supplier: Otto Breyer), after which the mixture was roller compressed at 1.2, 1.7, or 2.3 MPa in an Alexander Roller Compactor. The pancreatin plate obtained was crushed by the crushing sieve of the Alexander Roller Compactor, mesh size 2.5 mm, wire thickness 1.0 mm. Particles having a diameter smaller than 1.0 mm were separated, and were re-used in the next compaction step. 4.427 Kg of the particles having a diameter larger than 1.0 mm were coated in a fluid-bed process with an aqueous dispersion of 4.50 kg of Eudragit L30D (supplier: Rohm Pharma), 337.3 g of triethyl citrate (supplier: Rohm Pharma) and 337.5 g of Talcum Luzenac M1500 (supplier: Talc de Luzenac), to obtain a formulation of the enteric coated particles which contains: wt % pancreatin 78.2 magnesium stearate 0.2 poly(methacrylate ethylacrylate) 14.4 triethyl citrate 3.6 talcum 3.6

Example 2

Using four different batches of pancreatin (various suppliers) the method according to example 1 provides the following yields:

Supplier Pressure (MPa) Yield* (%)

1 1.7 53.2

2 1.7 50.7

3 (Type I) 1.7 46.6

3 (Type II) 1.5 50.6

yield as percentage of useful particles obtained after lx compression of the powder.

Example 3

The lipase enzyme activity (units per mg) as function of the roller compaction pressure was determined:

Pressure (Mpa) Lipase act. (U/mg) Degradation (%)

0 90.8 -

1.2 87.7 3.4

1.7 85.8 5.5

2.3 82.8 8.8 Example 4

The friability of the roller compaction plate and production yield as function of the roller compaction pressure was determined:

Pressure (Mpa) Friability* (%) Yield** (%;

1.2 38.0 45.7

1.7 32.1 53.2

2.3 26.7 57.4

Expressed as percentage of fines which come from the roller compaction plate during the test

The production yield is defined as percentage of useful particles which is obtained after lx compression of the powder.

Claims

Claims:

1. Irregularly shaped enteric coated compressed pancreatin particles.

2. A pharmaceutical composition comprising irregularly shaped enteric coated compressed pancreatin particles.

3. The pharmaceutical composition of claim 2 wherein the enteric coating comprises poly (methacrylate ethylacrylate).

4. A capsule comprising the pharmaceutical composition of claim 2 or 3.

5. A method of producing irregularly shaped enteric coated compressed pancreatin particles, characterized in that pancreatin powder without solvents, and optionally together with a lubricant, in a first step of the process is compressed by applying elevated pressure, thereafter in a second step is crushed into irregularly shaped particles, after which in a third step each of the particles are coated with an enteric coating.

6. The method according to claim 5, wherein the pancreatin and optionally the lubricant is compressed by means of roller compaction.

7. The method according to claim 5 or 6, wherein the applied pressure is of between about 1 and about 3 MPa, and preferably about 1.7 MPa.

8. The method according to any one of claims 5-7, wherein after the crushing into particles, the particles are sieved, after which the part of the particles having a particle size larger than a pre-determined size are enteric coated, and the part of the particles having a particle size smaller than a pre-determined size are separated from the process, and optionally are recirculated into the first step of the process.