WO2002019991A1

WO2002019991A1 - Multiparticulate pharmaceutical dosage form and a method for producing the same

Info

Publication number: WO2002019991A1
Application number: PCT/EP2001/009042
Authority: WO
Inventors: Thomas Beckert; Laetitia Briand; Günter Bergmann; Manfred Assmus; Denis Wouessidijewe
Original assignee: Röhm GmbH & Co. KG
Priority date: 2000-09-07
Filing date: 2001-08-04
Publication date: 2002-03-14
Also published as: AU2001282071A1; DE10044299A1

Abstract

The invention relates to a multiparticulate pharmaceutical dosage form, produced from particles compressed with conventional binding agents. Said particles contain a pharmaceutical active ingredient and are covered with a gastric-juice resistant coating consisting of a (meth)acrylate copolymer that comprises 40 to 60 wt.- % methacryl acid and 60 to 40 wt.- % ethylacrylate. Said dosage form is characterized in that the coating contains more than 15 and up to 50 wt.- % of the plasticizer propylene glycol in relation to the (meth)acrylate copolymer and that the particle fraction of the pharmaceutical dosage form constitutes 35-90 wt.- % for an application quantity of the coating in excess of 15 and up to 38 wt.- % in relation to the particle weight. The invention also relates to the production method and to the corresponding use of propylene glycol as a plasticizer.

Description

Multiparticulate dosage form and process for its preparation

The invention relates to a multiparticulate pharmaceutical form and a process for its preparation, as well as the advantageous use of the plasticizer propylene glycol.

State of the art

EP 088 951 describes a method for coating pharmaceutical forms by means of a coating agent dispersed in water. Among other things, gastric juice-resistant (meth) acrylate copolymers are used as coating agents, which only release a coated active ingredient in the alkaline intestinal area. The release characteristic is strongly dependent on the monomer composition of the respective copolymers. Among others, EP 088 951 also describes (eth) acrylate copolymers of 50% by weight methacrylic acid and 50% by weight ethyl acrylate (EUDRAGIT® L100-55).

Multiparticulate pharmaceutical forms which are obtained by pressing a binder containing an active ingredient and pellets coated with enteric-resistant (meth) acrylate copolymers are known from Becken et al. (1996), "Compression of enteric-coated pellets to disintegrating tablets", International Journal of Pharmaceutics 143, pp. 13-23. The pressing process, in particular, proves to be problematic in the production of multiparticulate pharmaceutical forms, since high mechanical loads act on the coated pellets here. This is all the more problematic if (meth) acrylate copolymers with comparatively low film flexibility are to be used for the enteric-coated pellet coatings. Pellet coatings made from (meth) acrylate copolymers made from 50% by weight of methacrylic acid and 50% by weight of ethyl acrylate (EUDRAGIT® L100-55) with elongation at break values of less than 5% despite the addition of 10% by weight of triethyl citrate, according to Beckert et al. when pressing to form cracks. Such cracks in the pellets can cause the active ingredient from the compressed dosage units to be undesirable are already released in the stomach so that the actual gastric juice resistance of this copolymer can no longer come into play.

The BASF company brochure “Kollicoat® Who can resist?” (1999) describes enteric copolymers for use as binders and coating agents for pharmaceutical forms. The products named Kollicoat® MAE 30 DP and Kollicoat® MAE 100 P are described as copolymers of 50% by weight methacrylic acid and 50% by weight ethyl acrylate. For coating pellets and crystals in the range of 0.5 to 3.0 mm, 10 to 30% coatings are recommended. To improve the flexibility of the coating films obtained, plasticizers in concentrations of 10 to 25% by weight are recommended. 1, 2 propylene glycol, triethyl citrate, polyethylene glycols and triacetin are mentioned. In one example, 15% by weight propylene glycol, based on the dry copolymer substance, is listed. Information on the processing of coated particles into multiparticulate dosage forms is not included.

WO 96/01624 describes the production of multiparticulate pharmaceutical forms for proton pump inhibitor active substances. To coat the particles containing the active ingredient, inter alia a (meth) acrylate copolymer of 50% by weight methacrylic acid and 50% by weight ethyl acrylate (EUDRAGIT® L100-55) in combination with plasticizers, in particular triethyl citrate in concentrations of 30% by weight, is used. %, used. No mention is made of propylene glycol. With the exception of one example, the application quantities of the coatings are at least 40% by weight. In Example 15, a small application amount is selected at approximately 20% by weight, but this only seems possible because the proportion of pellets in the dosage form is also selected to be low at approximately 23% by weight, so that the mechanical stress on the pellets during Pressing remains low. Task and solution

Multiparticulate drug forms generally offer the advantage of high dosing reliability, since manufacturing-related fluctuations in the coating thickness are averaged by the large number of individual particles and thus statistically balanced. Furthermore, efforts are always made to keep the proportion of substances that are added to a pharmaceutical active ingredient in the formulation of medicaments to a minimum and in particular not to place unnecessary strain on the human organism.

The advantage of high dosing security of multiparticulate pharmaceutical forms requires that the coating layers of the particles contained in the production are not damaged by pressing. To be able to guarantee this with some certainty, one must either apply comparatively thick coating layers or else reduce the particle content of the dosage forms. Thick coating layers increase the mechanical strength of the particles. In contrast, lower particle proportions reduce the probability that particles collide during the pressing process and thus mechanically damage one another, since these are then better isolated from one another by the higher proportion of binder.

(Meth) acrylate copolymers of 50% by weight methacrylic acid and 50% by weight ethyl acrylate (type EUDRAGIT® L100-55) are well suited for many applications as coating and binding agents for enteric drug forms. Because of the high brittleness of this type of copolymer, according to WO 96/01624, when applied in multiparticulate pharmaceutical forms, either application amounts of at least 40% by weight or a combination of a small application amount and at the same time a reduced particle content are selected. Ultimately, both variants represent a compromise, since they run counter to the general requirement to reduce the proportion of excipients in pharmaceutical forms. It was seen as an object to provide a multiparticulate pharmaceutical form which allows the use of (meth) acrylate copolymers of the type composed of 50% by weight of methacrylic acid and 50% by weight of ethyl acrylate with low coating application amounts and at the same time high particle proportions.

The task is solved by a

Multiparticulate pharmaceutical form, produced from particles pressed with conventional binders, which contain a pharmaceutical active ingredient and are coated with an enteric coating made from a (meth) acrylate copolymer of 40 to 60% by weight methacrylic acid and 60 to 40% by weight ethyl acrylate .

characterized,

that the coating contains more than 15 to 50% by weight of the plasticizer propylene glycol based on the (meth) acrylate copolymer and the particle fraction of the pharmaceutical form is 35-90% by weight when the coating is applied in an amount of more than 15 and up is 38% by weight based on the particle weight.

It was not foreseeable that the problem could be solved by using the plasticizer propylene glycol. Although the use of this special plasticizer in combination with the type of copolymer mentioned is known, there is no indication of the advantageous action in connection with multiparticulate pharmaceutical forms. Another unexpected advantage is that the amount of plasticizer can be significantly reduced in a preferred embodiment compared to the examples of WO 96/01624. Implementation of the invention

The invention relates to a multiparticulate pharmaceutical form, produced from particles pressed with conventional binders, which contain a pharmaceutical active ingredient and with an enteric coating made from a (meth) acrylate copolymer of 40 to 60% by weight of methacrylic acid and 60 to 40% by weight. % Are coated with ethyl acrylate, the coating containing more than 15 and up to 50, in particular 16 to 28, particularly preferably 17 to 23% by weight of the plasticizer propylene glycol, based on the (meth) acrylate copolymer, and the particle fraction of the pharmaceutical form 35 90, particularly preferably 40 to 70% by weight for an applied amount of the coating of more than 15 and up to 38, particularly preferably from 18 to 36, in particular from 20 to 30% by weight, based on the particle weight.

The multiparticulate pharmaceutical form can contain the active substance inside the coated particles in the form of active substance crystals or in the form of pellets coated with the pharmaceutical active substance.

The multiparticulate dosage form can e.g. Active substances from the active substance classes proton pump inhibitors, H2-antagonists, anti-rheumatic, pain reliever proteins, antigens, antibodies and / or hormones.

It can e.g. B. the active ingredients acetylsalicylic acid, diclofenac, omeprazole, omeprazole salts, esomeprazole, lansoprazole, rabeprazole, enzymes, especially the enzymes bromelain, pancreatin or trypsin, lithium, rutoside, valproic acid, ZnOrotat, 5-aminodalicylic acid, bispartacidicylsulphide, bispartacidicylsulphide, , Sulfasalazine, budenoside, plant extracts or antibiotics can be included.

The invention also relates to the corresponding process for the production of multiparticulate pharmaceutical forms by pressing pharmaceutically customary binders together with particles containing active ingredient, which are coated with an enteric-resistant (meth) acrylate copolymer from 40 to 60% by weight. Methacrylic acid and 60 to 40% by weight of ethyl acrylate are characterized in that the coating comprises more than 15 and up to 50, in particular 16 to 28, particularly preferably 17 to 23% by weight of the plasticizer propylene glycol, based on the (meth) acrylate Copolymer adds, the particle proportion of the pharmaceutical form sets 35-90% by weight, particularly preferably 40 to 70% by weight, with an application amount of the coating of more than 15 and up to 38, particularly preferably from 18 to 36, in particular from 20 up to 30 wt .-% based on the particle weight.

The use of the plasticizer propylene glycol in an amount of more than 15 to 50, in particular 16 to 28, particularly preferably 17 to 23 wt .-% in combination with a (meth) acrylate copolymer, from 40 to 60, wt .-% methacrylic acid and 60 to 40% by weight of ethyl acrylate for the production of an active substance-containing, multiparticulate pharmaceutical form with a particle fraction of 35-90, particularly preferably 40 to 70% by weight, with an application amount of the coating of more than 15 and up to 38, particularly preferably of 18 up to 36, in particular from 20 to 30% by weight, based on the particle weight, is an essential element of the invention.

(Meth) acrylate copolymers of 40 to 60% by weight of methacrylic acid and 60 to 40% by weight and 60 to 40% by weight of ethyl acrylate (type EUDRAGIT® L100-55: 50% by weight of methacrylic acid and 50% by weight) -% ethyl acrylate) are commercially available e.g. B. available as 30 dispersions and well known. The production and processing by spray application is e.g. B. described in EP 088 951.

The production of multiparticulate pharmaceutical forms by pressing a pharmaceutically customary binder with particles containing active ingredient is known, for. B. Beckert et al. (1996), "Compression of enteric-coated pellets to disintegrating tablets", International Journal of Pharmaceutics 143, pp. 13-23, and described in detail in WO 96/01624.

Active substance-containing pellets can be produced by applying active substance by means of a layering process. For this purpose, the active ingredient is used together with other auxiliaries (release agents, if necessary plasticizers) homogenized and dissolved or suspended in a binder (eg EUDRAGIT L 30 D-55). The liquid can be applied to placebo pellets or other suitable carrier materials by means of a fluidized bed process, the solvent or suspending agent being evaporated (literature: International Journal of Pharmaceutics 143, pp. 13-23). After the manufacturing process, a drying step can follow. The active ingredient can be applied in several layers.

Some active ingredients, e.g. B. acetylsalicylic acid, are commercially available in the form of active ingredient crystals and can be used in this form instead of active ingredient-containing pellets.

Film coatings on active substance-containing pellets are usually applied in fluidized bed devices. Recipe examples are mentioned in this application. Film formers are usually mixed with plasticizer and release agent by a suitable method. The film formers can be present as a solution or suspension. The auxiliaries for film formation can also be dissolved or suspended. Organic or aqueous solvents or dispersants can be used. Stabilizers can also be used to stabilize the dispersion (example: Tween 80 or other suitable emulsifiers or stabilizers).

Examples of release agents are glycerol monostearate or other suitable fatty acid derivatives, silica derivatives or talc. Examples of plasticizers are propylene glycol, phthalates, polyethylene glycols, sebacates or citrates, as well as other substances mentioned in the literature.

A separating layer can be applied between the active substance-containing and gastric juice-resistant layer, which serves to separate the active substance and coating material for the purpose of preventing interactions. This layer can consist of inert film formers (for example HPMC, HPC or (meth) acrylic acid copolymers) or for example talc or other suitable pharmaceutical Substances exist. Combinations of film formers and talc or similar substances can also be used.

Mixtures for the production of tablets from coated particles are prepared by mixing the pellets with suitable binders for tabletting, if necessary adding disintegrating substances and if necessary adding lubricants. Mixing can take place in suitable machines. Mixers that damage the coated particles are unsuitable, e.g. B. ploughshare mixer. In order to achieve suitable short disintegration times, a special sequence when adding the auxiliary substances to the coated particles may be necessary. By premixing the coated particle with the lubricant or mold release agent magnesium stearate, its surface can be made hydrophobic and thus sticking can be avoided.

Mixtures suitable for tableting usually contain 3 to 15% by weight of a disintegrant, e.g. B. Kollidon CL and z. B. 0.1 to 1 wt .-% of a lubricant and mold release agent such as magnesium stearate. The proportion of binder is determined by the required proportion of coated particles.

Typical binders are e.g. B. Cellactose ^® , microcrystalline cellulose, calcium phosphates, Ludipress ^® , lactose or other suitable sugars, calcium sulfates or starch derivatives. Substances with a low bulk density are preferred.

Typical disintegrants (disintegrants) are cross-linked starch or cellulose derivatives, as well as cross-linked polyvinylpyrrolidone. Cellulose derivatives are also suitable. By choosing a suitable binder, the use of disintegrants can be omitted.

Typical lubricants and mold release agents are magnesium stearates or other suitable salts of fatty acids or in the literature for this purpose Listed substances (e.g. lauric acid, calcium stearate, talc, etc.). When using suitable machines (e.g. tablet press with external lubrication) or suitable formulations, the use of a lubricant and mold release agent in the mixture can be omitted.

If necessary, a flow improver may be added to the mixture (e.g. highly disperse silica derivatives, talc, etc.).

Tableting can be carried out on conventional tablet presses, eccentric or rotary tablet presses, with pressing forces in the range from 5 to 40 kN, preferably 10-20 kN. The tablet presses can be equipped with systems for external lubrication. If necessary, special systems for filling the die are used, which avoid the die filling by means of stirring blades.

The amount applied means the proportion of the sprayed dry substance of the functional film-forming polymer in% by weight. It is over 15 to 38, particularly preferably 18 to 36, in particular 20 to 30% by weight, based on the particle weight.

The particle fraction is the weight fraction of the coated particles of the total weight of the pharmaceutical form, the compressed table, in% by weight. The particle proportion of the pharmaceutical form is 35-90, particularly preferably 40 to 70% by weight. Particle proportions of 70 to 90% by weight can be achieved in particular if so-called soft cores are used instead of sugar pellets.

The multiparticulate pharmaceutical forms obtained, tablets, should not be more than 10% (pharmacopoeia request), preferably not more than 7%, particularly preferably not more than 2% in the gastric release test according to USP for 2 hours in artificial gastric juice (pH 1, 0 or pH 1, 2) Release 6% of the active ingredient contained. This is achieved when the coatings are included Particles were hardly or only very slightly damaged by pressing during manufacture. A certain amount of damage to the external particles can usually not be completely avoided. However, if the internal particles are largely intact, this is of little importance. The state of the particles can e.g. B. can also be examined by scanning electron microscopy.

The release test according to USP (according to USP XXIV, method B, modified test for "enteric coated products") is known to the person skilled in the art. The main test conditions are in particular: Paddle method, 100 revolutions per minute, 37 ° C; pH 1, 0 or pH 1, 2 with 0.1 N HCl, pH 6.8 in 0.2 M phosphate buffer and adjustment with 2 N NaOH or with HCl.

EXAMPLES

In all examples, a particle content of 50% by weight was set equally. The EUDRAGIT® L 30 D-55 used for the spray application is a 30% aqueous dispersion of a copolymer of 50% by weight methacrylic acid and 50% by weight ethyl acrylate. The weight data refer to the dry matter.

Example 1

Bisacodvlpellets

Placebo pellets (e.g. sugar pellets, Werner) 4500.0 g

Bisacodyl 244.0 g

EUDRAGIT® L 30 D-55 (dry substance) 270.9 g

Triethyl citrate 8.1 g

Talc 40.5 g

Purified water 1305.0 g

Gastro-resistant coating

Bisacodvl pellets 1000.0 g

EUDRAGIT® L 30 D-55 (dry substance) 250.0 g

Propylene glycol 50.0 g

Glycerol monostearate 12.5 g

Tween 80 6.3 g

Purified water 1275.0 g

tablet formulation

Enteric coated bisacodvl pellets 500.0 g

Cellactose 417.5 g

Kollidon CL 80.0 g

Magnesium stearate 2.5 g Example 2 (comparative example with slightly too low plasticizer content (15% by weight))

Enteric coating

Bisacodyl pellets from Example 1 1000.0 g

EUDRAGIT® L 30 D-55 (dry substance) 250.0 g

Propylene glycol 37.5 g

Glycerol monostearate 12.5 g

Tween 80 6.3 g

Purified water 1325.0 g

tablet formulation

Enteric coated bisacodyl pellets 500.0 g

Cellactose 417.5 g

Kollidon CL 80.0 g

Magnesium stearate 2.5 g

Example 3 (comparative example with application amount of coating too low (12.5% by weight))

Enteric coating

Bisacodyl pellets from Example 1 1000.0 g

EUDRAGIT® L 30 D-55 (dry substance) 125.0 g

Propylene glycol 25.0 g

Glycerol monostearate 6.3 g

Tween 80 3.2 g

Purified water 640.0 g tablet formulation

Enteric coated bisacodyl pellets 500.0 g

Cellactose 417.5 g

Kollidon CL 80.0 g

Magnesium stearate 2.5 g

Example 4

Enteric coating

Bisacodyl pellets from Example 1 1000.0 g

EUDRAGIT® L 30 D-55 (dry substance) 300.0 g

Propylene glycol 60.0 g

Glycerol monostearate 15.0 g

Tween 80 7.5 g

Purified water 1530.0 g

tablet formulation

Enteric coated bisacodyl pellets 500.0 g

Cellactose 417.5 g

Kollidon CL 80.0 g

Magnesium stearate 2.5 g

Example 5

Enteric coating

Bisacodyl pellets from Example 1 1000.0 g

EUDRAGIT® L 30 D-55 (dry substance) 350.0 g

Propylene glycol 70.0 g

Glycerol monostearate 17.5 g

Tween 80 8.8 g

Purified water 1785.0 g tablet formulation

Enteric coated bisacodyl pellets 500.0 g

Cellactose 417.5 g

Kollidon CL 80.0 g

Magnesium stearate 2.5 g

Example 6

(Comparative example with plasticizer not according to the invention

(Triethycitrate) in an amount not according to the invention (10% by weight))

Enteric coating

Bisacodyl pellets from Example 1 1000.0 g

EUDRAGIT® L 30 D-55 (dry substance) 250.0 g

Triethyl citrate 25.0 g

Talc 125.0 g

Purified water 1600.0 g

tablet formulation

Enteric coated bisacodyl pellets 500.0 g

Cellactose 417.5 g

Kollidon CL 80.0 g

Magnesium stearate 2.5 g

Example 7

(Comparative example with plasticizer not according to the invention

(Triethycitrate) in the amount according to the invention (20% by weight)))

Enteric coating

Bisacodyl pellets from Example 1 1000.0 g

EUDRAGIT® L 30 D-55 (dry substance) 250.0 g

Triethyl citrate 25.0 g

Glycerol monostearate 12.5 g

Tween 80 6.3 g

Purified water 1175.0 g

tablet formulation

Enteric coated bisacodyl pellets 500.0 g

Cellactose 417.5 g

Kollidon CL 80.0 g

Magnesium stearate 2.5 g

Example 8

(Comparative example with the order quantity of the

Coating (15% by weight))

Enteric coating

Acetylsalicylic acid crystals 1000.0 g

EUDRAGIT® L 30 D-55 (dry substance) 150.0 g

Propylene glycol 30.0 g

Glycerol monostearate 7.5 g

Tween 80 3.8 g

Purified water 765.0 g tablet formulation

Enteric coated acetylsalicylic acid crystals 500.0 g

Cellactose 417.5 g

Kollidon CL 80.0 g

Magnesium stearate 2.5 g

Example 9

Enteric coating

Acetylsalicylic acid crystals 1000.0 g

EUDRAGIT® L 30 D-55 (dry substance) 200.0 g

Propylene glycol 40.0 g

Glycerol monostearate 10.0 g

Tween 80 5.0 g

Purified water 1020.0 g

tablet formulation

Enteric coated acetylsalicylic acid crystals 500.0 g

Cellactose 417.5 g

Kollidon CL 80.0 g

Magnesium stearate 2.5 g

Example 10

Enteric coating

Acetylsalicylic acid crystals 1000.0 g

EUDRAGIT® L 30 D-55 (dry substance) 250.0 g

Propylene glycol 50.0 g

Glycerol monostearate 12.5 g

Tween 80 6.3 g

Purified water 1175.0 g tablet formulation

Enteric coated acetylsalicylic acid crystals 500.0 g

Cellactose 417.5 g

Kollidon CL 80.0 g

Magnesium stearate 2.5 g

Example 11

Enteric coating

Acetylsalicylic acid crystals 1000.0 g

EUDRAGIT® L 30 D-55 (dry substance) 350.0 g

Propylene glycol 70.0 g

Glycerol monostearate 17.5 g

Tween 80 8.8 g

Purified water 1785.0 g

tablet formulation

Enteric coated acetylsalicylic acid crystals 500.0 g

Cellactose 417.5 g

Kollidon CL 80.0 g

Magnesium stearate 2.5 g

Results in the release test according to USP:

Pharmacopoeia request: Less than 10% drug release after 2 hours in 0.1 N HCI.

ASS = acetylsalicylic acid

GMS = glycerol monostearate

PG = propylene glycol

TEC = triethyl citrate

WM = plasticizer

Application amount:

Polymer dry substance based on the particles used

WM / parting agent: based on dry polymer substance

Pellet content: 50% based on final tablet mass as standard

Claims

1. Multiparticulate pharmaceutical form produced from particles compressed with conventional binders, which contain a pharmaceutical active ingredient and are coated with an enteric coating made from a (meth) acrylate copolymer of 40 to 60% by weight of methacrylic acid and 60 to 40% by weight of ethyl acrylate are,

characterized,

that the coating contains more than 15% and up to 50% by weight of the plasticizer propylene glycol based on the (meth) acrylate copolymer and the particle fraction of the pharmaceutical form is 35-90% by weight when the coating is applied in an amount of more than 15% and is up to 38 wt .-% based on the particle weight.

2. Multiparticulate pharmaceutical form according to claim 1, characterized in that the coated particles contain the active ingredient inside in the form of active ingredient crystals or in the form of pellets coated with the pharmaceutical active ingredient.

3. Multiparticulate pharmaceutical form according to claim 1 or 2, characterized in that active substances from the active substance classes of the proton pump inhibitors, H2 antagonists, antirheumatic agents, pain relievers, plant extracts, antibiotics, proteins, antigens, antibodies and / or hormones are contained.

4. Multiparticulate pharmaceutical form according to one or more of claims 1 to 3, characterized in that the active ingredient is acetylsalicylic acid, diclofenac, omeprazole, omeprazole salts, esomeprazole, lansoprazole, rabeprazole, enzymes, in particular the enzymes bromelain, pancreatin or trypsin, lithium, rutoside , Valproic acid, ZnOrotat, 5-aminosalicylic acid, aspartate, garlic, bisacodyl, sodium fluoride, sulfasalazine, budenoside, plant extracts or antibiotics are included.

5. A process for the preparation of multiparticulate pharmaceutical forms according to one or more of claims 1 to 4, by pressing pharmaceutically customary binders together with particles containing the active ingredient, which contain an enteric-resistant (meth) acrylate copolymer of 40 to 60% by weight of methacrylic acid and 60 to 40% by weight of ethyl acrylate are characterized in that more than 15 and up to 50% by weight of the plasticizer propylene glycol, based on the (meth) acrylate copolymer, are added to the coating, the particle fraction of the pharmaceutical form 35-90% by weight .-% sets with an application amount of the coating of more than 15 and up to 38 wt .-% based on the particle weight.

6. Use of the plasticizer propylene glycol in an amount of more than 15 and up to 50 wt .-% in combination with a (meth) acrylate copolymer, from 40 to 60 wt .-% methacrylic acid and 60 to 40 wt .-% Ethyl acrylate for the production of an active ingredient-containing, multiparticulate pharmaceutical form with a particle content of 35-90% by weight with an application amount of the coating of more than 15 and up to 38% by weight based on the particle weight.