WO2008065107A1

WO2008065107A1 - Storage stable tablets based on benzimidazole derivatives coated with a gastro-resistant film

Info

Publication number: WO2008065107A1
Application number: PCT/EP2007/062879
Authority: WO
Inventors: Celestino Ronchi; Giancarlo Ceschel; Manuela Astulfoni
Original assignee: Monteresearch S.R.L.
Priority date: 2006-11-28
Filing date: 2007-11-27
Publication date: 2008-06-05
Also published as: ITMI20062290A1; WO2008065107A8

Abstract

Moisture-resistant tablets containing as active principles benzimidazole derivatives and more specifically prazoles, comprising: a) a rapidly disintegrating core containing the active principle, b) a moisture-resistant rapidly disintegrating barrier layer, stabilizing and protecting of the core, applied by compression to the core (a) so as to completely envelop it, characterized in that all the operating steps for both core (a) and outer layer (b) preparation are undertaken in the dry state. Said tablet can be completely coated with a gastro-resistant film applied by conventional techniques.

Description

STORAGE STABLE TABLETS BASED ON BENZIMIDAZOLE DERIVATIVES COATED WITH A GASTRO-RESISTANT FILM

FIELD OF THE INVENTION

The present invention relates to moisture-resistant and hence storage stable tablets, containing benzimidazole derivatives as active principles. The present invention also relates to the aforesaid moisture-resistant tablets coated with a gastro-resistant film.

The present invention relates to a process for preparing said moisture-resistant tablets and the process for preparing the relative stable tablets coated with a gastro-resistant film. STATE OF THE ART

Benzimidazole derivatives such as rabeprazole sodium or potassium act by inhibiting the NaVK⁺ proton pump and are useful for treating ulcers of the digestive system as they suppress gastric acid secretion.

However, benzimidazole derivatives are not very stable and decompose rapidly, darkening in the presence of moisture or in the presence of neutral or acidic aqueous solutions.

As they are unstable in an acidic environment, preparations containing benzimidazole derivatives are commonly gastro-resistant and active principle release must take place enterically. Said preparations are normally obtained by coating the core containing the active principle with enteric coatings of acidic character (such as methacrylic acid copolymers); however, over time, and particularly in the presence of moisture, the basic active principle can migrate from the core and the gastro-resistant film-coating can be attacked, hence this type of formulation is not very stable.

The phenomenon of the basic active principle interacting with the acidic gastro- resistant film-coating and the aforesaid problem with colouration and decomposition also occur when using conventional production methods. Moreover, common methods for gastro-resistant tablet production comprise film- coating processes (for example in a pan or fluidized bed) that utilize aqueous solutions, being not very convenient when the active principle contained in the core is highly hygroscopic as in the case of benzimidazole derivatives. To overcome this difficulty, preparation methods were established which comprise for example applying, prior to the gastro-resistant coating, an intermediate layer that coats the core and contains both hardly water soluble fine components and equally hardly water soluble film-coating components (EP0342522).

According to said process however, the hardly water soluble fine components are dissolved in organic solvents such as ethanol.

Other processes for producing film-coated gastro-resistant tablets include benzimidazole derivatives and low viscosity HPC (hydroxypropyl cellulose) in the core and application of an intermediate layer containing an antioxidant. In this case, however, both layers (intermediate and enteric) are applied by means of organic solvent-based solutions/suspensions in a pan or fluidized bed or by the hot melt technique (WO2004/075881 A1 ). US 5464633 describes a tablet formed of a core within which the active principle is dispersed and a layer which envelops the entire core, prepared by a Dry-Cota (Manesty) rotary press machine which comprises two series of coupled rotating circular convex punches, of which the first series is for pressing the core and the second for the intermediate layer. Said intermediate layer consists of natural and/or synthetic polymers of re-swellable and/or erodible hydrophilic polymer classes with the function of modulating and slowing release of the active principle contained in the core, but not of protecting against moisture. Said tablet can if required be completely coated with a gastro-resistant film.

Furthermore, both the mixture forming the core and the mixture used to form the layer enveloping the core are granulated before relative compression, a granulation undertaken using an alcoholic solvent such as ethanol.

The use of organic solvents in the production processes entails problems connected to their high inflammability and toxicity and also the need to carry out drying steps on the granulate obtained to achieve their removal by evaporation. The need was therefore felt to overcome the aforesaid drawbacks. However, techniques are already known for applying moisture-resistant layers by the compression method. DE 2614020 describes the application by compression of a moisture-resistant outer layer onto a core containing the active principle. This layer is formed from a wax-based mixture and an oily component chosen from acetylated monoglycerides or a liquid mixture of acetylated triglycerides. On said layer coatings can be applied, if required, by traditional film-coating processes which comprise the use of organic solvents or water.

With the purpose of preparing coated chewable tablets based on cholestyramine, an active principle having a high affinity for both water and organic solvents and to which conventional coating techniques cannot be applied, a coating was conceived, described in EP 387885, having a melting point of between 55 and 60 °C comprising between 5 and 40% by weight of polyethylene glycol, 60 to 95% by weight of stearic acid and possibly between 10 and 20% of a partially hydrogenated vegetable oil. SUMMARY OF THE INVENTION The applicant has now found that tablets containing a benzimidazole derivative as active principle can be prepared, comprising: a) a rapidly disintegrating core containing the aforesaid active principle, and b) a moisture-resistant rapidly disintegrating barrier layer, stabilizing and protecting of the core, applicable by compression and which completely envelops the core (a), comprising at least one diluting agent, at least one barrier component and at least one disintegrant, in which the operating steps for both core (a) and outer layer (b) preparation are undertaken in the dry state.

A gastro-resistant coating can subsequently be applied to the tablet of the invention by conventional film-coating techniques. Therefore a further aspect of the present invention are tablets comprising in addition to the aforesaid layers (a) and (b) a further layer in the form of a gastro- resistant film (c) that completely envelops layer (b).

A further aspect of the present invention is the process for preparing the tablet of the present invention comprising a core (a) and a moisture-resistant protective layer (b).

Said process comprises the following steps:

A) The active principle, disintegrant and the possible excipients to be used for forming layer (a) are mixed and the mixture thus obtained is sieved, B) The mixture derived from step (A) is loaded into and then compressed in a suitable press machine provided with punches that enable the desired shape for the core (a) to be obtained, C) The diluting agent, the barrier component and the disintegrant are mixed and the mixture obtained is sieved,

D) The core (a) derived from (B) and the mixture derived from step (C) are loaded into a press machine and the assembly is compressed, the press machine being provided with punches enabling the desired tablet shape to be obtained. A further aspect of the present invention is a process for preparing tablets provided with a gastro-resistant coating (c) that, after the aforesaid step (D), comprises a further step (E) of gastro-resistant film-coating applicable by conventional methods. DESCRIPTION OF THE FIGURES Figure 1 shows a side section through a preferred embodiment of the tablet of the present invention coated with gastro-resistant film.

Figure 2 shows steps (B) and (D) of the process of the present invention for preparing the tablet shown in Figure 1. DETAILED DESCRIPTION OF THE INVENTION For the purposes of the present invention the definition "operating steps for core (a) and outer layer (b) preparation undertaken in the dry state" means that all the operating steps for obtaining the core (a) and the outer layer (b) are conducted in the absence of any type of organic or aqueous solvent, i.e. operating steps that neither comprise operations such as formation of solutions, suspensions nor comprise a granulation step.

For the purposes of the present invention the benzimidazole derivatives used as active principles in the tablets of the present invention are preferably prazoles, even more preferably they are rabeprazole, omeprazole, lansoprazole, pantoprazole, esomeprazole or their pharmaceutically acceptable salts, relative solvated, hydrated and polymorphic forms.

The term "diluting agent" refers to a water-soluble substance preferably chosen from sugars such as lactose, sucrose, fructose, sorbitol, mannitol, xylitol and/or low molecular weight amino acids such as: glycine, proline, isoleucine.

The term "barrier component" for the purposes of the present invention means a non-water-soluble substance chosen from:

- an inert non-water-soluble inorganic compound normally used in the pharmaceutical industry such as talc, levilite, precipitated silica, calcium phosphate, calcium silicate;

- alkyl-polysiloxanes such as dimethicone and simethicone;

- a lipid (such as a wax),

- a phospholipid such as lecithins, hydrogenated lecithins, - relative mixtures of the aforesaid barrier components.

The term "disintegrating agent" means an agent normally used in the pharmaceutical industry for this purpose such as croscarmellose sodium, crospovidone (crosslinked polyvinylpyrrolidone), microcrystalline cellulose, Ac-Di- SoI, pregelatinized starch. The diluting agent, the barrier component and disintegrant in the barrier layer (b) of the tablet of the present invention are preferably present in weight ratios between 1 :0.3:0.05 and 1 :0.05:0.001 and more preferably between 1 :0.2:0.03 and 1 :0.1 :0.01. The intermediate layer can also contain other excipients having technical functions such as antioxidants (vitamin E acetate and derivatives, ascorbyl palmitate, sodium metabisulphite), surfactants (Cremophor RH40, Poloxamer, Tween, Span), colourants (such as iron oxide, colourants supported on lacquers), lubricants (such as magnesium stearate, glycerol behenate, plasticizers (such as propylene glycol, PEG 350 up to PEG 10000), soluble polymers (such as polyvinyl alcohol, PVP, HPMC, HPC), insoluble polymers (such as methacrylates).

The core (a) of the tablet of the present invention, in addition to the active principle and disintegrating agent chosen from those already identified above for the barrier layer, can contain other agents normally used in the preparation of tablets such as lubricants etc. The preferred weight ratio of core (a) to intermediate layer (b) is preferably from 1 :1 to 1 :6, more preferably from 1 :2 to 1 :4. When the tablets of the present invention also comprise the coating (c), the polymer used for this gastro-resistant coating is preferably chosen from: cellulose acetophthalate, cellulose acetopropionate, methacrylic acid copolymers and polymers, and acrylic acid with different molecular weights and solubility characteristics at varying pHs. In steps (B) and (D) of the process of the present invention only one rotary press machine is used such as the S250 ZS/M (Kilian), partly used in step (B) of core (a) formation and partly used in step (D) for applying by compression the barrier layer (b) around the core (a).

To obtain the preferred embodiment of the tablet of the present invention, shown in figure 1 in which the core (a) indicated by (1 ) in the figures is of cylindrical shape and the final tablet coated with the layers (b) and (c) indicated respectively by (2) and (3) in the figures is of lenticular shape, that part of the press machine used for step (B) presents punches, of which the surfaces for imparting the shape of the core (a) are flat, whereas the part used for step (D) is provided with punches of which the surfaces for imparting the final lenticular shape of the tablet are concave, as shown in figure 2. In this figure (1 ') indicates the mixture originated from step (A) which is loaded onto the punches (4) used for forming the core (a) indicated by (1 ), the mixture originating from step (C) indicated by (2') is loaded onto the punches (4'), onto which the core (1 ) is then loaded followed by the mixture (2') again, and finally the assembly is compressed. On termination of this operation the tablet is obtained formed from the core (a) completely enveloped by the outer layer (b), this latter indicated in both the figures by (2). The gastro-resistant coating is then applied to the tablet i.e. step (E) of the process of the invention, as shown in figure (2) where (5) indicates the dispensing device, preferably an atomizer, for the formulation used for the coating of the tablet, indicated in this part of the figure by (7), in the container (6) which is preferably a pan. The tablets coated in this manner are then dried by conventional devices such as temperature-controlled forced ventilation cupboards or fluidized beds, or within the coating pan itself. The following examples are given as non-limiting illustration of the formulations of the present invention. Example 1 (Gastro-resistant tablets of rabeprazole sodium 20 mg) The tablet formulation, expressed by weight, is the following: Core 1. Rabeprazole sodium 20.00 mg

2. Calcium silicate 4. 00 mg

3. Croscarmellose sodium 7. 00 mg

4. Microcrystalline cellulose 10. 00 mg 5. Talc 6. 00 mg

6. Colloidal silica 2. 00 mg

7. Magnesium stearate 1. 00 mg Intermediate layer

8. Lactose 174 .00 mg 9. Calcium silicate 20. 00 mg

10. PVP CL 4. 00 mg

1 1. Magnesium stearate 2. 00 mg Gastro-resistant coating

12. Hypromellose phthalate 10. 00 mg 13. Talc 1. 50 mg

14. Triethyl citrate 2. 00 mg

15. Brown iron oxide, 1. 00 mg

16. Colloidal silica 0. 50 mg Production method Based on three steps:

Step I: Obtaining the nucleus (a) by compression

Step II: Preparing layer (b) by press machine

Step III: Film-coating of the tablets

Description of the process: Step I

Combine the active principle 1 with the other excipients 2, 3, 4, 5, 6 and 7.

Size the powder mixture with a 600 micron mesh sieve.

Transfer the powder mixture into a cubic mixer and mix at 20 revs/minute for 15 minutes. The mixture obtained is transferred into the hopper of a Kilian (IMA) Model S250

ZS/M rotary press machine with flat punches of 4.7 mm diameter, weight of 50 mg/tablet and hardness of 5 Kp. Ster.

Mix the excipients 8, 9, 10 and 1 1 of the intermediate layer in the mixer for 15 minutes and size with a 600 micron mesh sieve.

The core, obtained in step I via a suitable loading system, is coated with the mixture obtained in step Il by a suitable Kilian rotary press (IMA) with lenticular punches of 7 mm diameter, final weight of 250 mg/tablet and hardness of 5 Kp.

Step III

Transfer the tablets thus obtained into a Nicomac model VNF 50 pan with

COMPAQ 386 computerized system and film-coat with gastro-resistant solution prepared thus:

12. Hypromellose phthalate

14. Triethyl citrate dissolved in ethyl alcohol at 95 °C. Add and suspend the components 13, 15 and

16 to the solution thus obtained. Example 2 (Gastro-resistant tablets of rabeprazole sodium 10 mg)

The formulation of the tablets, expressed by weight, is as follows:

Core

1. Rabeprazole sodium 10 .00 mg

2. Calcium silicate 4 .00 mg 3. Croscarmellose sodium 7 .00 mg

4. Microcrystalline cellulose 20 .00 mg

5. Talc 5. 00 mg

6. Colloidal silica 2. 00 mg

7. Glycerol behenate 2. 00 mg Intermediate layer

8. Xylitol 174. .00 mg

9. Croscarmellose Sodium 4. 00 mg

10. Levilite 20 .00 mg

1 1. Glycerol behenate 2 .00 mg Gastro-resistant coating

12. Cellulose acetophthalate 10 .00 mg

13. Diethylphthalate 2. 00 mg 14. Talc 7.50 mg

15. Colouring E 172 0.50 mg

The operations for obtaining the tablets are conducted in a similar manner to that described in Example 1. Example 3 (Gastro-resistant tablets of esomeprazole magnesium trihydrate 20 mg)

The formulation of the tablets, expressed by weight, is as follows: Core

1. Esomeprazole magnesium trihydrate 20.00 mg 2. Magnesium oxide 20.00 mg

3. PVP CL 10.00 mg

4. Microcrystalline cellulose 42.00 mg

5. Glycerol behenate 5.00 mg

6. Talc 3.00 mg Intermediate layer

7. Saccharose 340.00 mg

8. Dimethicone 20.00 mg

9. Precipitated silica 20.00 mg

10. PVP CL 10.00 mg 1 1. Gycerol behenate 10.00 mg

Gastro-resistant coating

12. Eudragit S- 100 15.00 mg

13. PEG 4000 3.00 mg

14. Talc 1.90 mg 15. Iron oxide 0.10 mg

The operations for obtaining the tablets are conducted in a similar manner to that described in Example 1.

Example 4 (Gastro-resistant tablets of esomeprazole magnesium trihydrate 40 mg) The formulation of the tablets, expressed by weight, is as follows: Core 1. Esomeprazole magnesium trihydrate 40.00 mg 2. Microcrystalline cellulose 12.00 mg

3. Spray dried lactose 43. 00 mg

4. Magnesium stearate 5. 00 mg Intermediate layer 5. Mannitol 250 .00 mg

6. Calcium phosphate 20. 00 mg

7. Calcium silicate 20. 00 mg

8. Ac-di-sol 5. 00 mg

9. Magnesium stearate 5. 00 mg Gastro-resistant coating

10. Cellulose acetophthalate 10.00 mg

1 1. Triethyl citrate 2.00 mg

12. PEG 6000 2.00 mg

13. Titanium dioxide 0.50 mg 14. Talc 5.50 mg

Studies on the comparative stabilities of cores and cores with qastro- resistant coatings The aim of the following stability studies is to verify the effectiveness of the intermediate coating compared with the unprotected core.

The comparative studies were carried out by subjecting the rabeprazole sodium core and comparing with the coated core, described in examples 1 and 2, to an accelerated stability programme at a temperature of 40 °C and 75% RH for 1 and 3 months of observation.

The results clearly show that the coating with the intermediate layer increases stability of the active principle.

The compositions of the uncoated and coated cores of the tablets under examination are given in Tables 1 and 2. The stability results are respectively summarized in Tables 3 and 4. TABLE 1. Composition of Example 1 of cores coated and not coated with the intermediate layer

TABLE 2. Composition of Example 2 of cores coated and not coated with the intermediate layer

TABLE 3. Results of stability studies after periods of 1 and 3 months at 40°C/75% RH of the cores of Example 1 , coated and not coated with the intermediate layer

TABLE 4. Results of stability studies after periods of 1 and 3 months at 40°C/75% RH of the cores of example 2 coated and not coated with the intermediate layer

Claims

1. Tablet containing as active principle a benzimidazole derivative comprising: a) a rapidly disintegrating core containing the aforesaid active principle, and b) a rapidly disintegrating moisture-resistant barrier layer applicable by compression to the core (a), being stabilizing and protecting of the core and which completely envelops the core (a), comprising at least one diluting agent, at least one barrier component and at least one disintegrant, characterized in that the operating steps for both core (a) and outer layer (b) preparation are carried out in the dry state.

2. Tablet as claimed in claim 1 characterized by presenting a further layer (c) consisting of a gastro-resistant coating applicable by conventional film-coating methods.

3. Tablet as claimed in claim 1 or 2 characterized in that the core (a) has a cylindrical form while the layer (b) has a lenticular form.

4. Tablet as claimed in any of claims 1 to 3 characterized in that the benzimidazole derivatives belong to the prazole class.

5. Tablet as claimed in claim 4 characterized in that the prazoles are chosen from the class consisting of rabeprazole, omeprazole, lansoprazole, pantoprazole, esomeprazole or their pharmaceutically acceptable salts, relative solvated, hydrated and polymorphic forms.

6. Tablet as claimed in any of claims 1 to 5 characterized in that the diluting agent is a water-soluble substance chosen from sugars and/or low molecular weight amino acids.

7. Tablet as claimed in claim 6 characterized in that said sugars are chosen from lactose, sucrose, fructose, sorbitol, mannitol, xylitol.

8. Tablet as claimed in any of claims 1 to 7 characterized in that the barrier component is chosen from: an inert non-water-soluble inorganic compound normally used in the pharmaceutical industry, alkyl-polysiloxanes, lipids and phospholipids and relative mixtures of the aforesaid components.

9. Tablet as claimed in claim 8 characterized in that said barrier component is chosen from the class consisting of: talc, levilite, precipitated silica, calcium phosphate, calcium silicate, dimethicone and simethicone, waxes, lecithins or hydrogenated lecithins and relative mixtures of said components.

10. Tablet as claimed in any of claims 1 to 9 characterized in that the disintegrating agent is chosen from the class consisting of croscarmellose sodium, crospovidone (crosslinked polyvinylpyrrolidone), microcrystalline cellulose, Ac-Di- SoI, pregelatinized starch.

1 1. Tablet as claimed in any of claims 1 to 10 characterized in that the diluting agent, the barrier component and the disintegrant are present in layer (b) in weight ratios between 1 :0.3:0.05 and 1 :0.05:0.001.

12. Tablets as claimed in claim 1 1 wherein said weight ratios are between 1 :0.2:0.03 and 1 :0.1 :0.01.

13. Tablets as claimed in any of claims 1 to 12 characterized in that the weight ratio of the core (a) to layer (b) is between 1 :1 and 1 :6.

14. Tablets as claimed in claim 13 characterized in that said weight ratio is between 1 :2 and 1 :4.

15. Tablets as claimed in any of claims 2 to 15 characterized in that the polymer used for the gastro-resistant coating (c) is chosen from: cellulose acetophthalate, cellulose acetopropionate, methacrylic acid copolymers and polymers and acrylic acid with different molecular weights and solubility characteristics at varying pHs.

16. Process for preparing the tablets as claimed in any of claims 1 , 4 to 15, comprising the following steps:

A) The active principle, disintegrant and the possible excipients to be used for forming layer (a) are mixed and the mixture thus obtained is sieved,

B) The mixture derived from step (A) is loaded into and then compressed in a suitable press machine provided with punches that enable the desired shape for the core (a) to be obtained,

C) The diluting agent, the barrier component and the disintegrant are mixed and the mixture obtained is sieved,

D) The core (a) derived from (B) and the mixture derived from step (C) are loaded into a press machine and the assembly is compressed, the press machine being provided with punches enabling the desired shape of the tablet to be obtained.

17. Process as claimed in claim 16 for preparing the tablet claimed in any one of claims 3-15 further comprising, after step (D), a further step (E) of film-coating applicable by conventional methods.

18. Process as claimed in claim 16 or 17 characterized in that in steps (B) and (D) a single rotary press machine is preferably used, partly used in step (B) for formation of the core (a) and partly used in step (D) for application by compression of the barrier layer (b) enveloping the core (a).

19. Process as claimed in claim 18 for preparing the tablet claimed in claim 3 characterized in that said part of the machine used for step (B) presents punches whose surfaces, able to impart the shape of the core (a), are flat, whereas the part used for step (D) is provided with punches whose surfaces, able to impart the final lenticular shape to the tablets, are concave.