HK1062642B

HK1062642B - Coated granules based on angiotensin-converting enzyme inhibitor

Info

Publication number: HK1062642B
Application number: HK04105529.5A
Authority: HK
Inventors: Philippe Chenevier
Original assignee: Ethypharm
Priority date: 2001-05-09
Filing date: 2002-05-03
Publication date: 2006-06-23

Description

The present invention relates to coated granules based on angiotensin converting enzyme (ACE) inhibitor (ACE) and their preparation process and orodispersible tablets containing such coated granules.

For the purposes of the present invention, orodispersible tablets are tablets which can disintegrate in the mouth in less than 60 seconds, preferably in less than 40 seconds on contact with saliva, forming an easily swallowed suspension.

Angiotensin converting enzyme (ACE) inhibitors are used therapeutically in the treatment of essential hypertension and following myocardial infarction in stabilised patients with signs of left ventricular dysfunction.

The most commonly used ACEs are alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, moveltopril, perindopril, quinapril, ramipril, spirapril, temocapril and tandolapril.

WO00/51593 envisages the possibility of preparing oral formulations dissolving in the mouth in less than 60 seconds containing a solid foam formed from proteins and using enalapril as the active substance.

These different IECs are available in tablet or capsule form.

For example, Ramipril is available, depending on the country, as a tablet or capsule, both marketed by Aventis under the brand name Altace®.

These forms, because of their ease of use, are well suited for outpatient treatment, but some patients, especially the elderly, have difficulty swallowing tablets or capsules, which makes it difficult and therefore unpleasant to swallow even with a fluid intake.

It is estimated that 50% of the population have difficulty swallowing tablets or capsules, which results in the failure to take the prescribed medication and thus has a significant impact on the effectiveness of treatment (H. Seager, 1998, J. Pharm. Pharmacol. 50, 375-382).

Although the capsule shape allows the outer shell (gelatin dome) to be opened and the contents to be administered into a beverage or food, the very unpleasant taste of these ECIs does not allow this mode of administration to be considered satisfactory for patients.

There is currently no pharmaceutical composition of ECI that allows easy administration to patients with swallowing problems or to those who wish to take their treatment without simultaneous fluid intake.

Rapid-release multiparticle tablets have already been described by the applicant in patents FR 99 02516, FR 97 09233, FR 98 14034, FR 92 08642 and FR 91 09245, but none of these patents describes orodispersible tablets containing an ECI.

It was therefore desirable to remedy this situation and to develop an orodispersible tablet containing a CEI with a completely acceptable taste and palatability, so that the administration of this tablet is not unpleasant.

And the Applicant Company found that these characteristics were obtained with a tablet based on IEC in the form of coated granules and a mixture of excipients including at least a disintegrant, a soluble agent and a lubricant and possibly a bulking agent, a permeabilising agent, sweeteners and flavourings.

In addition, such a tablet provides pharmacokinetic parameters equivalent to those obtained with existing tablets or capsules.

The tablets conforming to the invention have a surprisingly pleasant taste, despite the tablet's breakdown in the mouth and an equivalent release of the active substance to that of the existing forms.

Tablets conforming to the invention include coated granules based on an angiotensin converting enzyme inhibitor, pharmaceutically acceptable isomers or salts of this inhibitor.

The present invention also relates to these coated granules.

In an advantageous way of making granules in accordance with the invention, the angiotensin converting enzyme inhibitor is selected from the group comprising, inter alia, Benazepril, Captopril, Cilazapril, Enalapril, Sosinopril, Lisinopril, Perindopril, Quinapril, Ramipril, Trandolapril, their pharmaceutically acceptable isomers and salts.

The masking of the taste of IEC is achieved by coating granular micro-crystals of IEC with one or more polymers.

The granules according to the invention based on pharmaceutically acceptable micro-crystals of IEC, its isomers and salts are characterised by being coated and containing: The use of a mixture of IEC microcrystals,one or more binding agents,possibly a diluent and an antistatic agent.

Most ECIs are available as small microcrystals. For example, Ramipril is commercially available as microcrystals with an average size of less than 100 μm. The disadvantage of such a particle size is that coating by methods of spraying a solution or coating suspension on these microcrystals in a fluidized air bed is difficult and time consuming.

To address this disadvantage, according to the invention, the ECI microcrystals are granulated and coated to lead to particles with a particle size of at least 80% between 100 and 500 μm and less than 15% between 100 and 100 μm.

In coated granules conforming to the invention, the IEC maintains its physicochemical integrity, with no change in the intrinsic properties of the active substance due to granulation and coating.

According to the present invention, the granules contain a binding agent which allows the micro-crystals of IEC and other possible constituents to be bound to form granules whose size will facilitate the coating operation.

This binding agent may be chosen from the group comprising, inter alia, cellulosic polymers, povidones, polyvinyl alcohols and acrylic polymers.

The preferred choice of cellulosic polymers is ethyl cellulose, hydroxypropyl cellulose (HPC) and hydroxypropyl methyl cellulose (HPMC), alone or in combination.

The acrylic polymers are the ammonium methacrylate copolymer (Eudragit® RL and RS), polyacrylate (Eudragit® NE) and polymetacrylate (Eudragit® E), which are trademarked as Eudragit®, which are used alone or in combination.

The binding agent is present in proportions up to 15% by weight, preferably up to 10% by weight of the uncoated granules.

The advantage of using a diluent to promote granulation of the ECI is that it also increases the proportion of coated granules in the tablets and thus reduces the risk of heterogeneity due to low doses of ECI.

This diluent may be chosen from the group comprising in particular cellulosic derivatives and preferably microcrystalline cellulose, starches, lactose, polyols and preferably mannitol.

This diluent is present in proportions up to 85% by weight, preferably up to 50% by weight of the uncoated granules.

To facilitate fluidization of the material when using a fluidized air bed for granulation, an agent with antistatic properties may be used.

This antistatic agent may be selected from the group comprising colloidal silica, in particular that marketed under the brand name Aerosil®, and preferably precipitated silica, in particular that marketed under the brand name Syloïd® FP244, micronized or unmicronized talc and mixtures thereof.

This antistatic agent is present in proportions up to 10% by weight, preferably up to 3% by weight of the uncoated granules.

The granules obtained after granulation are coated by spraying a coating composition, in particular in the form of a solution or polymer suspension, which will allow the taste of the IEC to be masked.

The coating composition shall be chosen according to the physico-chemical characteristics of the IEC and shall consist of at least one coating polymer and possibly an antistatic agent, plasticizers and soluble agents, including polyols.

The coating polymer is favorably chosen from the group comprising cellulosic polymers, acrylic polymers and their mixtures.

The acrylic polymers are to be preferred as ammonium methacrylate copolymer (Eudragit® RL and RS), polyacrylate (Eudragit® NE) and polymetacrylate (Eudragit® E), Eudragit® being a registered trademark of RÖHM.

The coating polymer is present in proportions up to 30% by weight, preferably up to 15% by weight of the coated granules.

The antistatic agent may be chosen from the group comprising colloidal silica, in particular that marketed under the brand name Aerosil®, and preferably precipitated silica, in particular that marketed under the brand name Syloïd® FP244, micronized or unmicronized talc and mixtures thereof.

This agent is present in proportions up to 10% by weight, preferably up to 5% by weight of the coating polymer.

According to an advantageous embodiment of the invention, The same polymer is used as the binding agent for the granule and the coating polymer.

According to an advantageous embodiment, the coated granules of the present invention include: 10 to 95% of ECI microcrystals,0 to 85% of a diluent,0 to 10% of an antistatic agent,5% to 50% of a coating polymer,the percentages being expressed by weight in relation to the weight of the coated granule.

Diluent concentrations above 85% are not advantageous in terms of facilitating granulation and lead to a significant dilution of the ECI, resulting in large tablet sizes.

At a coating polymer concentration below 5%, the coating is not sufficient to allow a good masking of the taste.

Anti-static agent concentrations above 10% do not lead to further improvement in particle fluidization.

According to another advantageous embodiment, the coated granules of the invention include: 10 to 95% of ECI microcrystals,0 to 85% of mannitol,0 to 10% of colloidal silica, and 5 to 50% of ethyl cellulose, the percentages are expressed as weight by weight of the coated granule.

The invention also relates to the process of preparation of coated granules of IEC.

The process according to the invention consists of successive steps: The test method is to use a mixture of ECI micro-crystals with the diluent and possibly an antistatic agent,to granulate the mixture obtained at the previous step by spraying a solution or suspension of the binding agent,to coat the resulting granules by spraying a suspension of the coating composition,to dry the resulting coated granules.

According to this method, the mixing, granulation and coating steps can be carried out in different or the same apparatus and in the presence of a mixture of excipients of the same or different nature at each step.

In a first embodiment of the granulation process according to the invention, the initial dry mixing, granulation, coating and drying steps are performed in a fluidized air bed.

In this case, the initial mixture of powder of the active substance, diluent and possibly antistatic agent is first fluidised, before being granulated by spraying on the powder a solution or suspension of excipients containing at least one binding agent, the resulting grains are then coated by spraying the coating composition suspension, the coated granules formed are dried, all these steps being carried out in a fluidized bed.

In a more advantageous manufacturing method, the mixture of excipients used in the granulation step and the coating suspension used in the coating step form a single mixture. In this case, the granulation step is distinguished from the coating step by varying different parameters, such as the spray flow rate of the excipient mixture and the atomisation pressure of the mixture. Thus, only part of the excipient mixture is used in the granulation step while the other part is used in the coating step.

The spray rate of the excipient suspension is higher in the granulation stage than in the coating stage, while the atomisation pressure of the excipient suspension is lower in the granulation stage than in the coating stage.

In practice, at the laboratory level in a fluidised airbed apparatus e.g. GLATT GPCG3 type, the spray rate of the excipient mixture during the granulation step is between 15 and 30 g/min and the atomisation pressure is between 1 and 2,5 bar.

During the coating step, the spray flow rate of the coating suspension is between 10 and 25 grams/minute, while the atomization pressure is between 1,5 and 3 bars.

In an advantageous manufacturing method, 10 to 30% of the excipient mixture is sprayed during the granulation step, with 100% of the supplement being sprayed during the coating step.

In this advantageous method, after dry mixing the active substance, the diluent and, preferably, the antistatic agent, a suspension of excipients comprising the coating polymer (s) and the antistatic agent is sprayed on the fluidised bed by varying the spraying rate and the atomisation pressure of the suspension, so as to obtain first a granulation and then a coating of the formed grains.

The coated granules based on IEC thus prepared are particularly suitable for use in the formulation of rapidly-decay tablets which are also the subject of the invention.

The tablets of the invention are designed to disintegrate in the mouth in saliva in less than 60 seconds, preferably less than 40 seconds, to form an easy-to-swallow suspension and are based on granules coated with CEI and a mixture of excipients including at least one disintegrant, a solvent diluent, a lubricant and possibly a blower, a permeable, sweeteners and flavourings.

The breakdown time is the time between the time when the tablet is placed in the mouth in contact with the saliva and the time when the suspension is swallowed as a result of the breakdown of the tablet in contact with the saliva without chewing.

According to an advantageous embodiment, the tablets conforming to the invention are based on coated granules of ECI, these granules having intrinsic compression characteristics and an excipient mixture, the proportion of excipient mixture to coated granules being 0.4 to 10, preferably 1 to 10 and preferably 1 to 4 parts by weight, the mixture of excipients comprising: A disintegrant,a soluble diluent with binding properties,a lubricant,a permeable agent,and possibly sweeteners, flavourings and colours.

The decomposition agent shall be selected from the group comprising in particular cross-linked sodium carboxymethylcellulose, referred to in the trade as croscarmellose, crospovidone and mixtures thereof.

Soluble diluent with binding properties, consisting of a polyol of less than 13 carbon atoms, either as a directly compressible product with an average particle diameter of 100 to 500 μm or as a powder with an average particle diameter of less than 100 μm, preferably chosen from the group consisting of mannitol, xylitol, sorbitol and maltitol, provided that sorbitol cannot be used alone and that, if the soluble diluent with binding properties is unique, it is used as the directly compressible product, whereas, if there are at least two diluent polyols with binding properties, one is in the direct form and the other in the compressible form, which may be compressed, and the proportion of the polyol is preferably 80/80, 20/80.

The respective proportions of disintegrant and solvent used to constitute the excipient are 1 to 15% by weight of the tablet, preferably 2 to 7% by weight for the former and 30 to 90% by weight, preferably 40 to 70% by weight for the latter.

The lubricant is selected from the group comprising in particular magnesium stearate, stearic acid, sodium stearylfumarate, micronized polyoxyethylene glycol (Macrogol 6000 micronized), leucine, sodium benzoate and mixtures thereof.

The amount of lubricant is between 0,2 and 20 per thousand (weight of lubricant/total weight of tablet), preferably between 5 and 10 per thousand.

The lubricating agent may be distributed within the excipient or, depending on the advantageous embodiment, the entire lubricating agent may be distributed on the tablet surface.

A selected compound is used as the permeable agent from the group comprising, in particular, silica with a high affinity for aqueous solvents, such as precipitated silica better known by the trade name Syloid®, maltodextrins, β-cyclodextrins and mixtures thereof. The permeabilising agent allows the creation of a hydrophilic network which facilitates the penetration of saliva and thus contributes to a better disintegration of the tablet.

The permeable agent ratio of the tablet to its mass is 0.5% to 5% by weight.

The sweetener may be selected from the group comprising, inter alia, aspartame, potassium acesulfame, sodium saccharinate, neohesperidin dihydrochalcone, sucralose, monoammonium glycyrrhizinate and mixtures thereof.

Flavourings and colouring agents are those commonly used in pharmacy for the preparation of tablets.

The present invention will be better understood by the following description supplement which refers to useful examples of the manufacture of rapidly deforming IEC tablets conforming to the invention.

Example 1: Preparation of coated granules based on Ramipril.

The granules are manufactured advantageously using a fluidised air bed granulator, as follows.

A polymer solution is first prepared by solubilising 109 g of ethyl cellulose in 2050 g of isopropyl alcohol.

A homogeneous mixture of powders consisting of 500 grams of Ramipril, 500 grams of mannitol and 53 grams of silica is then fluidised in a fluidised air bed.

The particle size of the various powders is less than 100 μm.

The granulation is carried out by spraying on the fluidised bed of the homogeneous powder mixture a first fraction of about 15 to 25% of the total polymer solution for about 20 minutes at a spray rate of about 20 to 25 grams/minute and at a solution atomisation pressure of 2 bar.

This results in a fluidised bed of granules with a particle size of mostly 100 to 500 μm.

The granules are then coated by spraying the remaining fraction of the polymer solution on the fluidised bed of granules, with a spraying time of approximately 2 hours, a spraying rate of approximately 15-20 g/minute and a solution atomisation pressure of 2,5 bar.

This results in a homogeneous mixture of coated granules.

The homogeneous mixture of coated granules has a statistically constant composition.

Thus, it is possible to determine the content of active substance in a given mass of this homogeneous coated granule mixture and, conversely, it is possible for a desired amount of active substance to determine the corresponding amount of homogeneous coated granule mixture.

For example, to obtain 10 mg of Ramipril, 24.62 mg of the homogeneous blend of coated granules is required. - What?

Tableau I

Principe actif	Ramipril	10 mg
Agent diluant	Mannitol	10 mg
Agent liant/Agent d'enrobage	Ethycellulose	3,12 mg
Agent antistatique	Silice précipitée	1,5 mg
	TOTAL	24,62 mg

Example 2 - Preparation of multi-particle rapid release tablets containing 10 mg of Ramipril

Ramipril 10 mg tablets are prepared in the form of tablets as shown in Table II below.

Quantities of each of the excipients identified in Table II below, taken in the respective proportions corresponding to the proportions resulting from that table, shall be screened in bulk on a sieve with a mesh size of approximately 800 μm.

Then, in a dry blender, a quantity of coated granules corresponding to the proportion of granules resulting from Table II with the filtered excipient mixture is mixed in a homogeneous manner. - What?

Tableau II


Principe actif	Granules enrobés de l'exemple 1	24,62 mg équivalent à 10 mg de Ramipril
Agent de compression	Mannitol	159 mg
Agent désintégrant	Crospovidone	22 mg
Agent perméabilisant	Silice précipitée	2,2 mg
Agent édulcorant	Aspartam	4,4 mg
Aromatisant	Arôme orange	2,2 mg
Agent lubrifiant	Stéarate de magnésium	2,2 mg

The resulting mixture is then distributed and shaped on a rotary compressor with dies and 8 mm diameter punches.

The resulting tablets are approximately 30 N hard.

The oral degradation time of the resulting tablets is less than 20 seconds.

Err1:Expecting ',' delimiter: line 1 column 218 (char 217)

The unpleasant taste of Ramipril is not detected during the time the tablet is in the mouth, i. e. between the time it is taken and the time it is swallowed.

The kinetics of dissolution is determined according to the European Pharmacopoeia 3rd edition in a type II apparatus with rotary blades.

To do this, 1 tablet is introduced into the device in a volume of 500 ml solution in 0.1 N HCl medium and agitated at a rate of 75 revolutions per minute.

The results obtained are shown in Figure 1 as a C1 curve showing the dissolution of the active substance over time.

As shown in this C1 curve, Ramipril rapid release multiparticle tablets allow for unadvanced release of Ramipril.

Example 3: Preparation of multi-particle rapid release tablets containing 7,5 mg of Ramipril

Ramipril 7.5 mg tablets are prepared in the following table III: - What?

Tableau III


Principe actif	Granules enrobés de l'exemple 1	18,53 mg équivalent à 7,5 mg de Ramipril
Agent de compression	Mannitol	119 mg
Agent désintégrant	Crospovidone	16,2 mg
Agent perméabilisant	Silice précipitée	1,6 mg
Agent édulcorant	Aspartam	3,2 mg
Aromatisant	Arôme Menthe	1,6 mg
Agent lubrifiant	Stéarate de magnésium	1,6 mg

For the preparation of these tablets, the excipients and active substance are used in the proportions shown in Table III above as in Example 2.

The tablets weigh 162 mg.

The resulting tablets are approximately 30 N hard.

The oral degradation time of the resulting tablets is less than 20 seconds.

The abrasion measured as in example 2 was found to be less than 1%.

The unpleasant taste of Ramipril is not detected during the time the tablet is in the mouth, i. e. between the time the tablet is administered and the time it is swallowed.

Example 4: Preparation of coated granules of Ramipril.

The granules are manufactured by the following process.

A polymer solution is first prepared by solubilizing Eudragit® E100 in isopropyl alcohol.

A homogeneous powder mixture consisting of 500 g of Ramipril, 750 g of mannitol and 53 g of precipitated silica is then fluidised in a fluidised air bed.

The particle size of the various powders is less than 100 μm.

It is preferable to granulate the powder mixture in a fluidized air bed granulator.

The homogeneous powder mixture is granulated by spraying on the fluidized bed of a first fraction of about 15 to 25% of the polymer solution for about 30 minutes at a spray rate of about 20 to 25 g/min and a solution atomisation pressure of 1.5 bar.

This results in a fluidised bed of granules with a particle size of mostly 100 to 500 μm. The granules are then coated by spraying the remaining fraction of the polymer solution on the fluidised bed of granules, with a spraying time of about 2 hours, a spraying rate of about 15 to 20 g/minute and a solution atomisation pressure of 2 bar.

The result is a mixture of coated granules.

For example, to obtain 10 mg of Ramipril, 31.5 mg of the homogeneous blend of coated granules is required. - What?

Tableau IV

Principe actif	Ramipril	10 mg
Agent diluant	Mannitol	15 mg
Agent liant/Agent d'enrobage	Eudragit® E 100	5 mg
Agent antistatique	Silice précipitée	1,5 mg
	TOTAL	31,5 mg

Example 5: Preparation of multi-particle rapid release tablets containing 10 mg of Ramipril

Ramipril 10 mg tablets are prepared in the following table:

Tableau V


Principe actif	Granules enrobés de l'exemple 4	31, 5 mg équivalent à 10 mg de Ramipril
Agent de compression	Mannitol	231 mg
Agent désintégrant	Crospovidone	25 mg
Agent perméabilisant	Silice précipitée	1,5 mg
Agent édulcorant	Aspartam	5 mg
Aromatisant	Arôme citron	3 mg
Agent lubrifiant	Stéarate de magnésium	3mg

For the preparation of these tablets, the excipients and the active substance are used in the proportions shown in Table V above as in Example 2.

The weight of the tablets is 300 mg.

The resulting tablets are approximately 35 N hard.

The oral degradation time of the resulting tablets is less than 25 seconds.

The abrasion, measured as in example 2, was found to be less than 1%.

The unpleasant taste of Ramipril is not felt during the time the tablet is in the mouth, i. e. between the time it is taken and swallowed.

The solution kinetics are performed according to the European Pharmacopoeia 3rd edition in a type II apparatus with rotary blades.

To do this, 1 tablet is introduced into the device in a volume of 500 ml of solution in 0.1 N HCl medium and agitated at a rate of 75 revolutions per minute.

The results obtained are shown in Figure 2 as a C2 curve showing the dissolution of the active substance over time.

As shown in this C2 curve, Ramipril rapid release multiparticle tablets allow for unadvanced release of Ramipril.

Example 6: Preparation of multi-particle rapid release tablets containing 5 mg of Ramipril

The Ramipril granules described in Example 4 are formulated as rapid-release multi-particle tablets containing 5 mg Ramipril, the composition of which is given in Table VI below:

Tableau VI


Principe actif	Granules enrobés de l'exemple 4	15,75 mg équivalent à 5 mg de Ramipril
Agent de compression	Mannitol	115 mg
Agent désintégrant	Crospovidone	12 mg
Agent perméabilisant	Silice précipitée	0,7 mg
Agent édulcorant	Aspartam	3 mg
Aromatisant	Arôme Menthe	1,5 mg
Agent lubrifiant	Stéarate de magnésium	1 mg

The tablets are manufactured according to the method in Example 2 using the different excipients and the active substance in the proportions given in Table VI.

The weight of the tablets is 150 mg.

The resulting tablets are approximately 35 N hard.

The oral degradation time of the resulting tablets is less than 20 seconds.

The abrasion, measured as in example 2, was found to be less than 1%.

The taste of Ramipril is not detected during the time the tablet is in the mouth, i. e. between the time it is taken and the time it is swallowed.

Example 7: Preparation of coated granules of Captopril.

The granules are manufactured by the following process.

a homogeneous powder mixture of 750 g of Captopril, 250 g of mannitol and 53 g of precipitated silica is then fluidised in a fluidised air bed.

This results in a fluidized bed of granules, the bulk of which is between 100 and 500 μm in size.

The granules are then coated by spraying the remaining fraction of the polymer solution on the fluidised bed of granules, with a spraying time of approximately 2 hours, a spraying rate of approximately 15-20 g/minute and a solution atomisation pressure of 2 bar.

The result is a mixture of coated granules.

For example, to obtain 50 mg of Captopril, 76.9 mg of the homogeneous blend of coated granules is required, the composition of which is shown in Table VII below. - What?

Tableau VII

Principe actif	Captopril	50 mg
Agent diluant	Mannitol	16,7 mg
Agent liant/Agent d'enrobage	Eudragit® E 100	6,7 mg
Agent antistatique	Silice précipitée	3,5 mg
	TOTAL	76,9mg

Example 8: Preparation of multi-particle rapid release tablets containing 50 mg Captopril

Captopril 50 mg tablets are prepared in the following table VIII:

Tableau VIII


Principe actif	Granules enrobés de l'exemple 7	76,9 mg équivalent à 50 mg de Captopril
Agent de compression	Mannitol	112 mg
Agent désintégrant	Crospovidone	22 mg
Agent perméabilisant	Silice précipitée	4 mg
Agent édulcorant	Aspartam	5 mg
Aromatisant	Arôme citron	2 mg
Agent lubrifiant	Stéarate de magnésium	2 mg

For the preparation of these tablets, the excipients and active substance are used in the proportions shown in Table VIII above as in Example 2.

The tablets weigh 224 mg.

The resulting tablets are approximately 40 N hard.

The oral degradation time of the resulting tablets is less than 30 seconds.

The abrasion, measured as in example 2, was found to be less than 1%.

The unpleasant taste of Captopril is not detected during the time the tablet is in the mouth, i. e. between the time of administration and swallowing.

Example 9: Preparation of coated granules of Enalapril

The granules are manufactured by the following process.

A polymer solution is first prepared by solubilizing ethyl cellulose in isopropyl alcohol.

A homogeneous powder mixture consisting of 500 g of Enalapril, 500 g of mannitol and 50 g of precipitated silica is then fluidised in a fluidised air bed.

The homogeneous powder mixture is granulated by spraying on the fluidized bed of a first fraction of about 15 to 25% of the polymer solution for about 30 minutes at a spray rate of about 20 to 25 g/min and a solution atomisation pressure of 2 bar.

The granules are then coated by spraying the remaining fraction of the polymer solution on the fluidised bed of granules, with a spraying time of approximately 2 hours, a spraying rate of approximately 15-20 g/minute and a solution atomisation pressure of 2.5 bar.

The result is a mixture of coated granules.

For example, to obtain 10 mg of Enalapril, 23 mg of the homogeneous blend of coated granules is required, the composition of which is shown in Table IX below. - What?

Tableau IX

Principe actif	Enalapril	10 mg
Agent diluant	Mannitol	10 mg
Agent liant/Agent d'enrobage	Ethylcellulose	2 mg
Agent antistatique	Silice précipitée	1 mg
	TOTAL	23 mg

Example 10: Preparation of rapidly released multi-particle tablets containing 10 mg of Enalapril

Enalapril 10 mg tablets are prepared in the following table X:

Tableau X


Principe actif	Granules enrobés de l'exemple 9	23 mg équivalent à 10 mg d'Enalapril
Agent de compression	Mannitol	120 mg
Agent désintégrant	Crospovidone	10 mg
Agent perméabilisant	Silice précipitée	1,5 mg
Agent édulcorant	Aspartam	3 mg
Aromatisant	Arôme Menthe	2 mg
Agent lubrifiant	Stéarate de magnésium	1,5 mg

For the preparation of these tablets, the excipients and active substance are used in the proportions shown in Table X above as in Example 2.

The tablets weigh 161 mg.

The resulting tablets are approximately 30 N hard.

The oral degradation time of the resulting tablets is less than 25 seconds.

The abrasion, measured as in example 2, was found to be less than 1%.

The unpleasant taste of Enalapril is not detected during the time the tablet is in the mouth, i. e. between the time it is taken and swallowing.

Example 11: Preparation of coated granules of Lisinopril.

The granules are manufactured by the following process.

A homogeneous powder mixture of 500 g of lisinopril, 500 g of mannitol and 50 g of precipitated silica is then fluidised in a fluidised air bed.

The result is a mixture of coated granules.

For example, to obtain 20 mg of Lisinopril, 49 mg of the homogeneous blend of coated granules is required, the composition of which is given in Table XI below. - What?

Tableau XI

Principe actif	Lisinopril	20 mg
Agent diluant	Mannitol	20 mg
Agent liant/Agent d'enrobage	Eudragit® E100	5,2 mg
Agent antistatique	Silice précipitée	2 mg
	TOTAL	47,2 mg

Example 12: Preparation of multi-particle rapid release tablets containing 20 mg of Lisinopril

20 mg Lisinopril tablets are prepared in the form of tablets as shown in Table XII below.

Tableau XII


Principe actif	Granules enrobés de l'exemple 11	47,2 mg équivalent à 20 mg de Lisinopril
Agent de compression	Mannitol	120 mg
Agent désintégrant	Crospovidone	12 mg
Agent perméabilisant	Silice précipitée	2 mg
Agent édulcorant	Aspartam	3 mg
Aromatisant	Arôme Menthe	2 mg
Agent lubrifiant	Stéarate de magnésium	1,8 mg

For the preparation of these tablets, the excipients and active substance are used in the proportions shown in Table XII above as in Example 2.

The weight of the tablets is 188 mg.

The resulting tablets are approximately 35 N hard.

The oral degradation time of the resulting tablets is less than 25 seconds.

The abrasion, measured as in example 2, was found to be less than 1%.

The unpleasant taste of Lisinopril is not detected during the time the tablet is in the mouth, i. e. between the time it is taken and swallowed.

Example 13: Preparation of coated granules of Trandolapril.

The granules are manufactured by the following process.

A homogeneous powder mixture consisting of 250 g of trandolapril, 750 g of mannitol and 50 g of precipitated silica is then fluidised in a fluidised air bed.

The result is a mixture of coated granules.

For example, to obtain 4 mg of trandolapril, 18.4 mg of the homogeneous mixture of coated granules will be required. - What?

Tableau XIII

Principe actif	Trandolapril	4 mg
Agent diluant	Mannitol	12 mg
Agent liant/Agent d'enrobage	Eudragit® E100	1,6 mg
Agent antistatique	Silice précipitée	0,8 mg
	TOTAL	18,4 mg

Example 14: Preparation of multi-particle rapid release tablets containing 4 mg of trandolapril

4 mg Trandolapril tablets are prepared in the following table XIV:

Tableau XIV


Principe actif	Granules enrobés de l'exemple 13	18,4 mg équivalent à 4 mg de Trandolapril
Agent de compression	Mannitol	117,6 mg
Agent désintégrant	Crospovidone	16 mg
Agent perméabilisant	Silice précipitée	1,5 mg
Agent édulcorant	Aspartam	3 mg
Aromatisant	Arôme Menthe	2 mg
Agent lubrifiant	Stéarate de magnésium	1,5 mg

For the preparation of these tablets, the excipients and active substance are used in the proportions shown in Table XIV above as in Example 2.

The tablets weigh 160 mg.

The resulting tablets are approximately 35 N hard.

The oral degradation time of the resulting tablets is less than 15 seconds.

The abrasion, measured as in example 2, was found to be less than 1%.

The unpleasant taste of Trandolapril is not detected during the time the tablet is in the mouth, i. e. between the time it is taken and swallowed.

Claims

Granules based on angiotensin converting enzyme inhibitor, its isomers or its pharmaceutically acceptable salts (IEC), characterized in that they are coated and in that they contain:
- microcrystals of IEC,

- one or more binders selected from the group comprising especially cellulosic polymers, particularly ethyl cellulose, hydroxypropyl cellulose and hydroxypropyl methyl cellulose, acrylic polymers, povidones, polyvinyl alcohols and mixtures thereof,

- optionally a diluent selected from the group comprising especially cellulosic derivatives, starches, lactose and polyols, particularly mannitol, and an antistatic agent selected from the group comprising especially colloidal silica, precipitated silica and micronized or non-micronized talcum.
Granules according to Claim 1, characterized in that the IEC is selected from the group comprising especially benazepril, captopril, cilazapril, enalapril, sosinopril, lisinopril, perindopril, quinapril, ramipril, trandolapril, their isomers and their pharmaceutically acceptable salts.
Granules according to Claim 2, characterized in that the IEC is selected from the group comprising ramipril, captopril, enalapril, lisinopril, trandolapril, their isomers and their pharmaceutically acceptable salts.
Granules according to any one of Claims 1 to 3, characterized in that they have a particle size distribution such that at least 80% of the granules have a size of between 100 and 500 µm, and less than 15% of the granules have a size below 100 µm.
Granules according to any one of Claims 1 to 4, characterized in that:
- the amount of binder is at most 15% by weight, preferably at most 10% by weight, based on the weight of the uncoated granules,

- the amount of diluent is at most 85% by weight, preferably at most 50% by weight, based on the weight of the uncoated granules, and

- the amount of antistatic agent is at most 10% by weight, preferably at most 3% by weight, based on the weight of the uncoated granules.
Granules according to any one of Claims 1 to 5, characterized in that they are coated with a coating composition comprising a coating polymer selected from the group comprising cellulosic polymers, particularly ethyl cellulose, hydroxypropyl cellulose and hydroxypropyl methyl cellulose, acrylic polymers and mixtures thereof, and optionally an antistatic agent, plasticizers and soluble agents, especially polyols.
Granules according to any one of Claims 1 to 6, characterized in that one and the same polymer constitutes the binder of the uncoated granule and the coating polymer.
Granules according to Claim 7, characterized in that they comprise:
- from 10 to 95% of microcrystals of IEC,

- from 0 to 85% of a diluent, preferably mannitol,

- from 0 to 10% of an antistatic agent, preferably colloidal silica, and

- from 5 to 10% of coating polymer or binder, preferably ethyl cellulose,
the percentages being expressed by weight, based on the weight of the coated granule.
Process for the preparation of coated granules according to any one of Claims 1 to 8, characterized in that it comprises the following successive steps:
- dry mixing of the microcrystals of IEC with the diluent and optionally an antistatic agent,

- granulation of the mixture obtained in the previous step by spraying with a solution or suspension of the binder,

- coating of the granules obtained by spraying with a suspension of the coating composition, and

- drying of the coated granules obtained.
Process according to Claim 9, characterized in that the different steps are carried out in a fluidized air device.
Process according to Claim 9 or 10, characterized in that the spraying rate of the solution or suspension of binder in the granulation step is higher than the spraying rate of the suspension of coating composition in the coating step, and the atomization pressure is lower in the granulation step than in the coating step.
Rapidly disintegrating tablet of the kind intended to disaggregate in the mouth on contact with the saliva in less than 60 seconds, preferably in less than 40 seconds, to form a suspension that is easy to swallow, characterized in that it is based on coated granules according to any one of Claims 1 to 8 or coated granules as prepared by the process of Claims 9 to 11 and a mixture of excipients comprising at least one disintegrating agent, a soluble diluent, a lubricant and optionally a swelling agent, a permeabilizing agent, sweeteners and flavourings.
Tablet according to Claim 12, characterized in that the disintegrating agent is selected from the group comprising especially croscarmellose, crospovidone and mixtures thereof.
Tablet according to Claim 12 or 13, characterized in that the soluble agent has binding properties and consists of a polyol having fewer than 13 carbon atoms which takes the form either of the directly compressible product having a mean particle diameter of 100 to 500 µm, or of a powder having a mean particle diameter below 100 µm, this polyol preferably being selected from the group comprising mannitol, xylitol, sorbitol and maltitol, it being understood that sorbitol cannot be used on its own and that, in the case where there is only one soluble diluent with binding properties, it is used in the form of the directly compressible product, whereas in the case where there are at least two soluble diluents with binding properties, one is present in directly compressible form and the other in powder form, it then being possible for the polyol to be the same, the proportions of directly compressible polyol and powdered polyol being from 99/1 to 20/80, preferably from 80/20 to 20/80 and particularly preferably from 80/20 to 50/50.
Tablet according to any one of Claims 12 to 14, characterized in that the proportion of excipient mixture relative to coated granules of IEC is from 0.4 to 10, preferably from 1 to 10 and particularly preferably from 1 to 4 parts by weight.
Tablet according to any one of Claims 12 to 15, characterized in that the proportion of disintegrating agent relative to the weight of the tablet is from 1 to 15% by weight, preferably from 2 to 7% by weight, and the proportion of soluble agent relative to the weight of the tablet is from 30 to 90% by weight, preferably from 40 to 70% by weight.
Tablet according to any one of Claims 12 to 16, characterized in that the permeabilizing agent is selected from the group comprising especially silicas having a high affinity for aqueous solvents, such as precipitated silica, maltodextrins, β-cyclodextrins and mixtures thereof.
Tablet according to any one of Claims 12 to 17, characterized in that the lubricant is selected from the group comprising especially magnesium stearate, sodium stearylfumarate, stearic acid, micronized polyoxyethylene glycol and mixtures thereof.
Tablet according to any one of Claims 12 to 18, characterized in that the sweetener is selected from the group comprising especially aspartame, acesulfame potassium, potassium saccharinate, neohesperidine dihydrochalcone, sucralose, monoammonium glycyrrhizinate and mixtures thereof.
Tablet according to any one of Claims 12 to 19, characterized in that the lubricant is in powder form, at least the major part of it being distributed over the surface of the tablet.