HK1072014B

HK1072014B - Coated particles with prolonged release and tablets containing same

Info

Publication number: HK1072014B
Application number: HK05105337.6A
Authority: HK
Inventors: Philippe Chenevier; Dominique Marechal
Original assignee: Ethypharm
Priority date: 2002-04-23
Filing date: 2003-04-23
Publication date: 2009-08-28

Description

The invention relates to coated particles and, more specifically, to coated granules or pellets with extended release, their preparation process and multiparticle tablets containing the coated particles.

The extended-release multiparticle forms are well known in earlier art.

These forms exist in particular in unit forms such as capsules or multi-particle tablets.

Multiparticle tablet means a tablet comprising, on the one hand, particles containing at least one active substance, individually coated with a polymer film modulating the release of the active substance over a period of up to 8 to 24 hours, and, on the other hand, compression excipients.

The coated particles are first mixed with the compression excipients, the mixture being then compressed to lead to a homogeneous unitary shape.

During the compression step, the polymer coating is subjected to significant stresses, such that cracks or ruptures may occur, causing a leakage and the immediate release of the entire active substance.

The polymer film must therefore be sufficiently flexible and deformable to withstand compression.

To evaluate the properties and mechanical characteristics of the polymer film, parameters such as the breaking strength or the percentage of elongation can be used.

Acrylic polymers are a family of polymers with deformation properties that allow multiparticle tablets to be made.

In application EP 1032374, the applicant described spheroids containing in the core or layer a thermoplastic excipient with a consistency of a paste to a semi-solid at 20°C and a flexible, deformable film with an elongation percentage of 50% or more, which is made of a neutral copolymer of acrylic acid esters, for example Eudragit® NE30D with an elongation percentage of 600% and a compressive strength of 8N/m2.

Polymers with poor elongation or compressive strengths do not normally absorb the mechanical stresses associated with compression (International Journal of Pharmaceutics, 143, 13-23 (1996).

Many publications describe cellulosic polymers as brittle and inflexible, for example ethyl cellulose, which usually has an elongation capacity of less than 15%, making it difficult to use as a coating agent for particles intended to be compressed (Eur. J. Pharm. Biopharm., 43, 1-8 (1997)).

Studies of ethyl cellulose free films show that the addition of plasticizers or soluble agents to the coating film and the implementation of a maturation step under certain temperature and humidity conditions (Int. J. Pharm. 104, 203-213, (1994), Acta Pharm. Technol. 35(4), 232-237, (1989)) may possibly improve the properties of cellulose derivative films. FR 2 385 388 describes the use of a waxy substance, such as polyoxyethylene glycol, as an excipient in the tablet for protection against fragile particles.

This improvement is not sufficient, however, and the release profile of the active substance is directly influenced by the composition of the coating film.

It would be particularly advantageous to have means to make them systematically usable for the production of coating films without changing their composition or influencing their release profile of the active substance.

The applicant was of the opinion that that objective could be achieved and that it became possible to obtain coated, extended-release particles consisting of at least one cellulose polymer such that the release profile of a multiparticle tablet based on those particles was identical to that of pre-compression coated particles, the two release profiles being determined under similar conditions of application (dissolving medium, apparatus, method), provided that the particles were coated with a protective coating based on at least a thermoplastic agent with a melting point of 25 100 °C applied to the polymer cellulose coating.

Two release profiles are considered to be similar if the variation between the mean values measured for each of the profiles at each sampling time is less than or equal to plus or minus 15%, preferably plus or minus 10%, i.e. in the present case, between the mean value obtained for the particulate coated pre-compression and that obtained for the multiparticle tablet based on these particles.

If the change in question is greater than 15%, the release profile is considered to be significantly changed.

It follows that the extended-release coated particles conforming to the invention, including a core containing an active substance and at least one binding agent and a coating film based on at least one cellulose polymer, alone or in combination with a plasticizer, are characterised by the presence of a protective coating based on at least one thermoplastic agent with a melting point of approximately 25°C to approximately 100°C and which is applied to the coating film based on at least one cellulose polymer.

The particles according to the invention are granules or pellets, depending on the process of obtaining the active nucleus.

The granules are obtained by dry or wet granulation and the granules by mounting the active substance on a neutral.

The particle core includes at least one active substance selected from those in the group including gastrointestinal sedatives, antacids, analgesics, anti-inflammatories, coronary vasodilators, peripheral and brain vasodilators, anti-infectious, antibiotics, antivirals, antiparasitics, anti-cancer, anti-anxiety medicines, neuroleptics, central nervous system stimulants, antidepressants, antihistamines, antidiarrheals, laxatives, nutritional supplements, hypoglycaemic, anti-depressants, hypocholesteroxins, dysporiferins, enzymes, anti-depressants, anti-blood disruptors, anti-inflammatories, anti-cardiovascular, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-coagultivating, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti

This active substance, initially in the form of powder or microcrystals, is used in the dry state for the preparation of granules, and in the form of solution or suspension in an aqueous or organic solvent for mounting on neutral surfaces.

The advantage is that the cores contain a binding agent that allows the active powder or microcrystals and other possible constituents to be bound to produce particles of sufficient size to facilitate the coating operation.

The binding agent may be chosen from the group comprising, inter alia, cellulosic polymers, acrylic polymers, povidones, copovidones, polyvinyl alcohols, alginic acid, sodium alginate, starch, pre-gelatinised starch, sucrose and their derivatives, guar gum, polyethylene glycols and mixtures thereof.

The preferred choice of cellulose polymers is ethyl cellulose, hydroxypropyl cellulose and hydroxypropyl methyl cellulose, alone or in combination.

The acrylic polymers are ammonium methacrylate copolymer, acrylic and methacrylic acid polymers and copolymers, polyacrylates and polymethylated polymers, used alone or in combination, which are the preferred choice.

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

The core shall optionally contain a diluent and an antistatic agent.

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

The core may also be a neutral mixture of starch and sucrose or microcrystalline cellulose.

The diluent is present in proportions up to 95% by weight, preferably up to 50% by weight of uncoated particles.

Its role is to increase the total mass of particles to be coated and to obtain a population of particles of homogeneous size.

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.

The antistatic agent is present in proportions up to 10% by weight, preferably up to 3% by weight of uncoated particles.

It improves the fluidisation of the material when using a fluidised air bed, especially in the case of powder granulation.

The nuclei containing the active substance are then coated with a first coating composition.

The resulting coating film allows the active substance to be released for a longer period.

It consists of at least one cellulosic polymer, alone or in combination with a plasticizer.

The preferred cellulose polymer is ethylcellulose.

This coating film is applied by spraying a solution, suspension or colloidal dispersion of this polymer in a solvent to form a continuous film covering the entire surface of each particle, irrespective of the surface condition of the particle, in sufficient quantity to allow the prolonged release of the active substance over a period of up to 8 to 24 hours.

The coating polymer is present in proportions up to 50%, preferably up to 20%, calculated as weight gain in relation to the mass of cores to be coated.

The solvent used to spray the cellulose polymer may be water, an organic solvent such as ethanol, isopropanol, acetone or a mixture of solvents.

The polymer is then in solution, suspension or dispersion in the solvent or mixture of solvents, preferably in solution in an organic solvent, preferably in isopropanol.

The coating composition also includes, optionally, a pore-forming agent, a plasticizing agent, a surfactant, an antistatic agent, a lubricant.

The pore-forming agent allows the release of the active substance to be modulated and in particular accelerated.

The agent must be soluble in pH media of 5 or less. It may be chosen from sugars, polyols, polymers or copolymers of acrylic or methacrylic acids, hydroxylated cellulose derivatives, povidones and polyvinyl alcohols.

The plasticizer shall be selected from the group comprising triethyl citrate, acetyltributyl citrate, triacetin, tributyl citrate, diethyl phthalate, polyethylene glycols, polysorbates, mono- and diacetyl glycerides and mixtures thereof.

Its function is to lower the glass transition temperature of the coating film and to improve its mechanical properties.

It is used in a proportion of not more than 40%, preferably between 15 and 30%, expressed as a percentage of the dry polymer weight.

The surfactant is chosen from anionic, cationic, non-ionic or amphoteric surfactants.

The antistatic agent, if used, is used to avoid problems with static electricity and is selected from the group comprising micronized and non-micronized talc, colloidal silica (Aerosil®200), treated silica (Aerosil® R972), precipitated silica (Syloid® FP244) and their mixtures.

It shall be applied in a proportion of not more than 10% by weight, preferably between 0 and 3%, and preferably even less than 1% by weight.

The lubricant is selected from the group comprising magnesium stearate, stearic acid, sodium stearyl fumarate, micronized polyoxyethylene glycols (Macrogol 6000 micronized), sodium benzoate and their mixtures.

An optional polymer layer may be applied between the core and the functional polymer film to isolate the core containing the active substance from the cellulose polymer layer which allows the prolonged release of the active substance.

The constituent polymer of the optional layer may be chosen from the same polymers as those used as binders; in particular, it may be identical or different from that used as binders in the active substance-containing core.

Err1:Expecting ',' delimiter: line 1 column 569 (char 568)

The amount of polymer applied is between 1 and 10% and preferably between 2 and 5% by weight of the mass of the cores containing the active substance used.

According to the invention, the cellulose polymer layer for prolonged release of the active substance is covered with a protective coating.

This protective coating shall be based on at least a thermoplastic agent with a melting point of about 25°C to about 100°C and possibly a lubricant.

The thermoplastic agent shall be selected from the group comprising partially hydrogenated oils, beeswax, carnauba wax, paraffin waxes, silicone waxes, fatty alcohols, C12-C18 fatty acids, solid semi-synthetic glycerides, glycerol monoesters, diesters or triesters, polyoxyethylene glycols, glycosylated polyoxyethylene glycerides and mixtures thereof.

The function of the protective coating is to absorb compressive stresses and to prevent deformation, alteration or rupture of the coating film consisting of the cellulose polymer, the function of which is to ensure the prolonged release of the active substance.

The thermoplastic agent shall be used in a proportion of up to 100% weight gain in relation to the mass of the granule to be coated, preferably between 10 and 50% weight gain.

It is preferably chosen from hydrophilic excipients with a hydrophilic/lipophil balance (HLB) greater than 10 so as not to alter the release profile of the active substance.

The protective coating may also include an antistatic agent.

The granulometer distribution of the particles conforming to the invention allows their use in the manufacture of multiparticle tablets.

It is preferable that the particle size is less than 700 μm, provided that at least 50%, preferably at least 70% of the particle size is between 150 and 500 μm, and that less than 15% of the particle size is less than 150 μm.

Particle size is determined by conventional methods, for example by a calibrated mesh sieve set or by laser diffraction.

The coated long-release particles thus prepared are particularly suitable for use in multi-particle tablets because of their mechanical properties.

The multiparticle tablet conforming to the invention is characterised by the fact that it is based on the coated particles conforming to the invention, this tablet also containing a mixture of excipients including: a decomposition agent and/or a bloating agent,at least one diluent agent,a lubricant and possibly an antistatic agent, a permeabilising agent, sweeteners, flavourings and colours.

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

The inflating agent is selected from the group comprising microcrystalline cellulose, starches and modified starches.

The diluent may be chosen from the group comprising cellulosic derivatives and preferably microcrystalline cellulose, lactose, polyols and preferably mannitol.

The lubricant is selected from the group comprising magnesium stearate, stearic acid, sodium stearyl fumarate, polyoxyethylene glycols (Macrogol 6000 micronized), sodium benzoate and their mixtures.

The lubricant, in whole or in part, is dispersed in the compression excipient mixture and/or sprayed on the tablet surface at the time of compression.

The permeable agent shall be selected from the group comprising, in particular, silica with a high affinity for aqueous solvents, such as the precipitated silica better known by the brand name Syloïd®, maltodextrins, β-cyclo-dextrins and mixtures thereof.

It creates a hydrophilic network that facilitates the penetration of saliva and thus helps to break down the tablet better.

The sweetener may be chosen 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.

In multiparticle tablets conforming to the invention, the proportion of the excipient mixture to the coated particles is 0.4 to 10, preferably between 1 and 5 parts by weight, the excipient mixture comprising: 1 to 15% , preferably 2 to 7% by weight of disintegrant and/or inflating agent, 30 to 90%, preferably 40 to 70% by weight of the tablet, diluent, 0.02 to 2%, preferably 0.5 to 1% by weight of lubricant, per tablet, 0.5% to 5% by weight of permeable agent, per tablet.

In a preferred embodiment, the multiparticle tablet of the invention is an orodispersible tablet which disintegrates in the mouth in contact with saliva in less than 60 seconds, preferably in less than 40 seconds, to form an easy-to-swallow suspension.

The breakdown time is the time between placing the tablet in the mouth in contact with saliva and swallowing the suspension resulting from the breakdown without chewing of the tablet in contact with saliva.

The diluent shall be chosen from soluble agents with binding properties, consisting of polyols of less than 13 carbon atoms and present 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, these polyols being preferably chosen from the group comprising mannitol, xylitol, sorbitol and maltitol, used as the directly compressible product, whereas, in the case of at least two soluble diluents with binding properties, one would be in the directly compressible form and the other in the form of a polyester, which may be the same polyester, the proportions of the directly compressible and polyester being preferably from 20/8 to 80/80, from 20/8 to 99/20.

The invention also concerns a process for preparing extended-release coated particles.

The process in question consists, in accordance with the invention, of the following steps: preparation by wet granulation or mounting on neutral materials of a core containing the active substance,coating of the cores thus obtained by spraying a coating composition consisting of at least one cellulosic polymer,coating of the coated particles thus obtained by spraying a protective coating composition based on a thermoplastic excipient,drying.

Depending on the method of implementation, successive steps of the process may be carried out in different apparatus or in the same apparatus.

In a first advantageous embodiment, the nuclei containing the active substance are prepared by granulation in the following steps: Dry mixture of the active substance in powder or microcrystals, possibly with diluent and antistatic agent,granulation of the mixture obtained by spraying a solution of the binding agent,drying.

For granulation, a high energy granulator, a planetary mixer or a fluidized air bed are advantageously used.

In the case of fluidised air bed granulation, the powder mixture containing the active substance and, where appropriate, the diluent and the anti-static agent, is introduced into the apparatus and then granulated by spraying on the powder mixture a solution or suspension of excipients containing at least one binding agent.

Another advantageous method is that the polymer used in the granulation step and the polymer used in the coating step are identical, in which case the granulation step differs from the coating step by different parameters, such as the spray flow rate of the excipient mixture and the atomisation pressure of the mixture.

Thus, in the granulation step, the spraying rate of the excipient suspension is higher than in the coating step, while the atomisation pressure of the excipient suspension is lower in the granulation step than in the coating step.

In practice, at the laboratory level in a fluidised airbed apparatus, e.g. GLATT GPCG3, the spraying rate of the excipient mixture during the granulation stage is 15 to 30 g/min and the atomisation pressure 1 to 2.5 bar.

During the coating step, the spray flow rate of the coating suspension is 10 to 25 grams/minute, while the atomization pressure is 1.5 to 3 bars.

Preferably, 10 to 30% of the excipient mixture is sprayed during the granulation step, with 100% of the additive being sprayed during the coating step.

In a second method of manufacture, the cores containing the active substance are prepared by mounting on neutrons in the following steps: spraying on neutrals of a solution or suspension of the active substance containing the solubilised binder,drying.

The resulting cores are then coated by successive spraying of the various coating compositions and then dried.

The polymer coating consisting of a cellulose derivative is sprayed as a solution, suspension or colloidal dispersion.

The thermoplastic excipient may be applied by spraying as a solution in an aqueous or organic solvent.

In one particular embodiment, the thermoplastic excipient can be heated to a temperature above its melting point and then sprayed as a liquid without solvent.

In this case, a thermostat spraying device is installed to prevent clogging of the pipes.

All steps of the process according to the invention can be carried out in a drag-drying turbine, a perforated turbine or a fluidized air bed.

In a preferred embodiment of the process of the invention, all steps of preparation of the active core and coating are performed in a fluidised air bed.

The fluidized air bed is equipped with a spray nozzle, the position and orientation of which can be chosen.

This allows the kinetics of particle growth to be controlled and bonding phenomena to be avoided, which are linked to the nature of the active substance, the composition of the binder or coating composition sprayed, and the various parameters of the process (temperature, air pressure, solution flow rate, for example).

The invention also relates to a method for the preparation of multiparticle tablets containing coated particles with extended release.

This process consists, in accordance with the invention, of the following steps: Dry mixing of the coated particles obtained by the above process with the compression excipients,compression of the resulting mixture to form a unitary form.

The mixture may be compressed on an alternative or rotary compressor.

The stresses exerted during the compression step may vary from 5kN to 50kN, preferably from 5kN to 15kN.

The hardness of the tablets thus obtained is preferably 1 to 10 kp, more preferably 1 to 5 kp, measured according to the European Pharmacopoeia method (2.9.8), 1 kp being equal to 9.8 N.

Preferably, the hardness of the multi-particle tablet should be adjusted to achieve a fragility of less than 2% as measured by the European Pharmacopoeia method, while maintaining a dissolution profile identical to that of the coated particles, and to achieve a disintegration time in the mouth of less than or equal to 60 seconds, preferably less than or equal to 40 seconds.

The tablets may be 6 mm to 17 mm in diameter. They may be round, oval, oblong, have a flat or concave surface, and may have engravings.

In the case of orodispersible tablets, polo pins may be used, i.e. pins to produce round, flat tablets with a concave area in the centre of both sides.

The tablets have a mass that is preferably between 0.1 and 2.0 grams.

The present invention will be better understood by using the examples of the manufacture of coated particles and multiparticle tablets conforming to the invention.

Example 1

Coated granules containing oxycodone HCI as active substance.

Granulation

500 grams of oxycodone HCl are mixed with 15 grams of Syloid® 244 FP [i.e. 3% w/w by weight of oxycodone HCI].

In a global blender, the powder mixture is granulated with a wetting solution of N7 ethyl cellulose at 8% ((w/w) in isopropanol.

The resulting grain is dried in a 45°C oven for 5 hours and then sifted on a sieve with a diameter of 0.9 mm.

Coating

The coating is carried out in a GLATT GPCG-3 fluidised air bed with a Würster insert ( bottom spray ).

The resulting mass is coated by spraying the same solution as in the previous step.

A quantity of polymer of 42% (w/w) is applied, calculated as a weight gain on the mass of the original uncoated pellets.

The particle size distribution of coated particles E1 is given in Table 1. - What?

Ouverture de maille
>0.710mm	20.7%
0.600mm-0.710mm	11.5%
0.500mm-0.600mm	12.5%
0.355mm-0.500mm	17.4%
0.180mm-0.355mm	25.8%
0.075mm-0.180mm	7.9%
<0.075mm	4.2%

The mass yield is 96.32% (w/w).

The composition of the coated pellets E1 is shown in Table 2: - What?

	%(w/w)
Oxycodone HCl	65.46
Syloid® 244FP	1.96
Ethylcellulose N7	32.60
Alcool isopropylique	--

Example 2:

Orodispersible multi-particle tablets containing oxycodone HCl as the active substance.

Compression of the

Err1:Expecting ',' delimiter: line 1 column 90 (char 89)

The coated pellets obtained in Example 1 are mixed with compression excipients.

Two types of tablets, C1 and C2 respectively, are available with different relative proportions of oxycodone HCl-coated granules.

The C1 and C2 tablets are dosed at 19.8 and 10 mg HCI oxycodone respectively, as indicated in Table 3: - What?



Granulés enrobés d'oxycodone HCl	19,8	10.0
Mannitol 300	33.2	37.3
Mannitol 60	33.2	37.3
Crospovidone	9.8	10.0
Arôme orange	1.0	1.0
Syloid® 244FP	1.0	0.4
Stéarate de magnésium	2.0	2.0
Aspartame	--	2

The C1 and C2 tablets have the characteristics shown in Table 4:


Proportion théorique granulés/comprimé	20%	10%
Poids (mg)	156.0	308.6
Dureté (kP)	1,5	1,5
Friabilité	non déterminé	non déterminé
Temps de désintégration en bouche	10-15 sec.	15 sec.

A comparative dissolution profile is established between the coated granules in Example 1 (designated E1) and the tablets of formula C1 and C2 under the following conditions: The device: USP type II Blade speed: 100 revolutions per minutevolume: 900 mltemperature: 37.0°C ± 0.5°C Detection: direct UV spectrophotometry at 244 nmmedium of dissolution: HCl 0.01 N (pH = 2) The device is equipped with a laser to detect the presence of a substance in the sample.

The results recorded are summarised in Table 5: - What?

Oxycodone libérée (%(w/w)
Temps (heure)
0.5	16	37	43
1	30	53	58
2	47	74	78
4	69	92	95
6	78	95	98
8	81	96	99
10	81	96	99

The Commission

It can be inferred from the results in Table 5 that compression causes the ethyl cellulose film to break, leading to an accelerated release of the active substance.

It follows that the mechanical properties of the coating film are not suitable for compression into long-release orodispersible tablet form.

Example 3:

Coated granules containing theophylline as active substance.

Mounting on neutral

The operation is performed in a GLATT GPCG-3 fluidised air bed equipped with a Würster insert ( bottom spray ).

1500 grams of theophylline are suspended in 4500 g of isopropanol in which 262.5 grams of PVP K29 i.e. polyvinylpyrrolidone or povidone, K29 have been previously soluble, the K value expressing the mean molecular weight of povidones calculated from the relative viscosity in water and defined in the European Pharmacopoeia (sections 2.2.1.2 and 2.3.2.1), used as binding agent [i.e. 17% w/w in relation to the weight of theophylline].

1500 grams of neutrals of starch and sucrose, of a size of 250-350 μm, are introduced into the fluidised air bed.

The above-mentioned alcohol suspension containing theophylline is sprayed on the neutrals.

Coating with N7 ethyl cellulose

600 grams of granules obtained in the previous step by spraying a solution of N7 ethyl cellulose in isopropyl alcohol as prepared in example 1 are coated, containing in addition micronized talc, corresponding to 10% (w/w) in relation to the dry polymer mass.

A polymer amount of 5% (w/w) is applied, calculated as a weight gain in relation to the mass of granules to be coated.

The particle size distribution of the coated particles obtained and designated by E2 is given in Table 6: - What?


>0.500mm	6.6%
0.425mm-0.500mm	46.2%
0.355mm-0.425mm	38.2%
0.250mm-0.355mm	9.0%

Protective overlay

The coated E2 granules obtained in the previous step are coated by spraying an aqueous solution of PEG 4000 containing additionally 10% micronized talc (w/w) in relation to the dry mass of PEG.

The protective coating is applied in a quantity corresponding to 20% (w/w), calculated as weight gain in relation to the mass of E2 granules.

The particle size distribution of coated E3 particles obtained by application of the protective coating on E2 granules is shown in Table 7: - What?


>0.500mm.	15.8%
0.425mm-0.500mm	41.2%
0.355mm-0.425mm	38.4%
0.250mm-0.355mm	4.6%

A comparative dissolution profile is established between coated granules E2 and E3 under the following conditions: The device: USP type II blade speed: 100 revolutions per minutevolume: 900 mltemperature: 37.0°C ±0.5°C Detection: direct UV spectrophotometry at 272 nmmedium of dissolution: HCl 0.01 N (pH = 2) The device is equipped with a laser to detect the presence of a substance in the liquid.

The results recorded are summarised in Table 8: - What?

	Théophylline libérée (%(w/w)
Temps (heure)
1	12	10
2	21	16
4	36	34
6	48	49
8	57	60
10	63	68

The Commission

Examination of the results in Table 8 shows that the application of the protective coating on E2 coated granules does not significantly alter the dissolution profile.

Example 4:

Oral dispersible tablets containing theophylline as active substance.

Compression of the

Err1:Expecting ',' delimiter: line 1 column 90 (char 89)

The coated granules obtained in Example 3 are mixed with compression excipients, in the two compositions shown in Table 9, giving after compression C3 and C4 tablets.



35	35
Mannitol 300	26.5	26.5
Mannitol 60	26.5	26.5
Crospovidone	10.0	10.0
Arôme	--	--
Syloid® 244FP	0.5	0.5
Stéarate de magnésium	1.0	1.0
Aspartame	--	--

The characteristics of C3 and C4 multiparticle orodispersible tablets are given in Table 10: - What?

Caractéristiques
Dosage en substance active du comprimé (mg)	80	70
Poids du comprimé (mg)	588.0	622.0
Dureté (kP)	3.8	3.1
Friabilité (%)	5.6	0.5
Temps de désintégration en bouche (secondes)	29	35

A comparative dissolution profile is established under the conditions of Example 3 between multi-particle orodispersible tablets C3 and C4, containing coated granules E2 and E3 respectively.

The results recorded are summarised in Table 11:

	Théophylline libérée (%(w/w)
Temps (heures)
1	51 (12)	16 (10)
2	67 (21)	24 (16)
4	83 (36)	43 (34)
6	91 (48)	55 (49)
8	95 (57)	63 (60)
10	98 (63)	69 (68)

The Commission

The results of the analysis in Table 11 show that the protective coating significantly improves the mechanical properties of N7 ethyl cellulose film in terms of compressive strength.

Example 5

Oral tablets are prepared with theophylline as the active substance.

Compression of the

Err1:Expecting ',' delimiter: line 1 column 90 (char 89)



Granules enrobés de théophylline E3	20
Mannitol 300	32.8
Mannitol 60	32.8
Crospovidone	10.0
Arôme	1.0
Syloid® 244FP	0.5
Stéarate de magnésium	1.0
Aspartame	2.0

The characteristics of C5 multiparticle orodispersible tablets are as shown in Table 13: - What?


Dosage du comprimé (mg) en substance active	25mg
Poids (mg)	555.0
Dureté (kP)	2.5
Friabilité (%)	0.6
Temps de désintégration en bouche (secondes)	26

A comparative dissolution profile is established under the conditions of Example 3 between coated granules E3 and C5 multiparticle orodispersible tablets containing these coated granules.

The results recorded are summarised in Table 14: - What?

	Théophylline libérée (%(w/w))
Temps (heures)
1	21 (12)
2	30 (21)
4	43 (36)
6	52 (48)
8	60 (57)
10	65 (63)

A comparative dissolution profile of C5 multiparticle orodispersible tablets is established in different solution media at pH 1.2, 4.5 and 6.8 respectively: - What? The results recorded are summarised in Table 15:

15

	Théophylline libérée (%(w/w))
Temps (heures)
1	(21)	21	22
2	(30)	31	31
4	(43)	44	44
6	(52)	53	54
8	(60)	60	62
10	(65)	66	68

The Commission

The results of the analysis in Table 15 show that the protective coating significantly improves the mechanical properties of N7 ethyl cellulose film in terms of compressive strength.

It can also be seen that the resulting profiles are independent of the pH of the medium in which the dissolution is carried out.

Example 6

To assess the differences in compressive strength between cellulosic polymers and acrylic polymers, the same test as in examples 3 and 4 is performed using a polyacrylate known as Eudragit® NE30D and marketed by RÖHM as the coating polymer.

The following shall be applied to the product:

750 grams of granules obtained after mounting on neutrals of example 3 are coated by spraying an aqueous dispersion of Eudragit®NE30D, diluted to 20% (w/w), containing in addition micronized talc, in an amount corresponding to 10% (w/w) of the dry polymer mass.

At the end of the coating, an additional stage of maturation of the film at 60°C is carried out for 2 hours.

This gives particles designated E4 and the particle size distribution is given in Table 16: - What?


>0.500mm	20.6%
0.425mm-0.500mm	46.2%
0.355mm-0.425mm	26.4%
0.250mm-0.355mm	6.8%

The application of a protective coating

The E4 coated granules obtained in the previous step are coated by spraying an aqueous solution of PEG 4000 containing additionally micronized talc in a proportion of 10% (w/w) to the dry mass of PEG.

Apply a 20% protective coating calculated as a weight gain on the mass of E4 granules.

This results in E5 coated particles with the particle size distribution given in Table 17: - What?


>0.600mm	4.2%
0.500mm-0.600mm	23.6%
0.425mm-0.500mm	43.2%
0.355mm-0.425mm	24.2%
0.250mm-0.355mm	4.8%

A comparative dissolution profile is established between coated granules E4 and E5 under the conditions of example 3. The results recorded are summarised in Table 18:

	Théophylline libérée (%(w/w)
Temps (heure)
1	34	40
2	49	57
4	66	74
6	75	84
8	81	90
10	86	94

The Commission

An examination of the data in Table 18 shows that the application of a protective coating on E4 granules does not significantly alter the dissolution profile.

Example 7:

Orodispersible multiparticle tablets containing theophylline as active substance

Compression of the

Err1:Expecting ',' delimiter: line 1 column 90 (char 89)

The coated granules E4 and E5 obtained in Example 6 are mixed with compression excipients according to the composition in Table 19 and C6 and C7 tablets corresponding to the coated granules E4 and E5 are obtained: - What?


	% en poids	% en poids
Granules enrobés de théophylline	35	35
Mannitol 300	26.5	26.5
Mannitol 60	26.5	26.5
Crospovidone	10.0	10.0
Arôme	--	--
Syloid® 244FP	0.5	0.5
Stéarate de magnésium	1.0	1.0
Aspartame	--	--

The characteristics of C6 and C7 tablets are summarised in Table 20: - What?


Dosage du comprimé (mg) en substance active	100	70
Poids (mg)	680.0	583.0
Dureté (kp)	4.2	3.3
Friabilité (%)	0.8	0.5
Temps de désintégration en bouche (secondes)	14	35

A comparative dissolution profile is established under the conditions of Example 3 between multi-particle orodispersible tablets C6 and C7, containing coated granules E4 and E5 respectively: - What? The results recorded are summarised in Table 21: - What?

	Théophylline libérée (%(w/w)
Temps (heures)
1	46 (34)	48 (40)
2	65 (49)	66 (57)
4	82 (66)	83 (74)
6	90 (75)	92 (84)
8	94 (81)	98 (90)
10	97 (86)	100 (94)

The Commission

Examination of the data in Table 21 shows that the protective coating does not improve the mechanical properties of the film formed by Eudragit®NE30D, which is already flexible and deformable.

Example 8 Compression of the

Err1:Expecting ',' delimiter: line 1 column 90 (char 89)

The E5 coated granules obtained in Example 6 are mixed with compression excipients according to the composition in Table 22 where the obtained multiparticle tablets are designated by C8: - What?


	% en poids
20
Mannitol 300	32.8
Mannitol 60	32.8
Crospovidone	10.0
Arôme	1.0
Syloid® 244FP	0.5
Stéarate de magnésium	1.0
Aspartame	2.0

The characteristics of C8 multiparticle orodispersible tablets are summarised in Table 23: - What?


Dosage du comprimé (mg) en substance active	40
Poids (mg)	580.0
Dureté (kP)	2.7
Friabilité (%)	0.4
Temps de désintégration en bouche (secondes)	27

A comparative dissolution profile is established under the conditions of Example 3 between E5 coated granules and C8 orodispersible tablets containing the said E5 coated granules: - What? The results recorded are summarised in Table 24: - What?

	Théophylline libérée (%(w/w))
Temps (heures)
1	45 (40)
2	65 (57)
4	85 (74)
6	95 (84)
8	100 (90)
10	100 (94)

A comparative dissolution profile of C8 multiparticle orodispersible tablets is also established in three dissolution media at pH 1.2, 4.5 and 6.8 respectively: - What? The results are given in Table 25: - What?

	Théophylline libérée (%(w/w))
Temps (heures)
1	(45)	45	46
2	(65)	64	65
4	(85)	84	84
6	(95)	94	93
8	(100)	100	99
10	(100)	100	100

The Commission

Examination of the results in Table 25 shows that the dissolution profile is not significantly altered by compression and that the obtained profiles are independent of the pH of the medium in which the dissolution is carried out.

Claims

A multiparticulate tablet comprising
- a disintegrant and/or a swelling agent,

- at least one diluent,

- a lubricant, and

- optionally, an antistatic agent, a permeabilizer, sweeteners, flavorings and colorants,
characterized in that it is based on sustained-release coated particles comprising
- a core comprising an active principle and at least one binder, and

- a coating film consisting of at least one cellulosic polymer, alone or as a mixture with a plasticizer, and

- a protective coating based on at least one thermoplastic agent with a melting point of from about 25°C to about 100°C and which is applied to the coating film based on at least one cellulosic polymer, said thermoplastic agent being chosen from the group comprising partially hydrogenated oils, beeswax, carnauba wax, paraffin waxes, silicone waxes, fatty alcohols, C₁₂-C₁₈ fatty acids, solid semisynthetic glycerides, glyceryl monoesters, diesters or triesters, polyoxyethylene glycols and polyoxyethylenated glycosyl glycerides, and mixtures thereof.
The multiparticulate tablet as claimed in claim 1, characterized in that the protective coating of the sustained-release coated particle is chosen from excipients chose hydrophilic/lipophilic balance (HLB) is greater than 10.
The multiparticulate tablet as claimed in either of claims 1 and 2, characterized in that it comprises a binder, a permeabilizer, sweeteners, flavorings and colorants and in that the protective coating of the coated particles comprises an antistatic agent and a lubricant.
The multiparticulate tablet as claimed in either of claims 1 and 3, characterized in that the proportion of excipients mixture relative to the coated particles is from 0.4 to 10 and preferably from 1 to 5 parts by weight.
The multiparticulate tablet as claimed in either of claims 1 and 4, characterized in that it disintegrates in the mouth on contact with the saliva in less than 60 seconds and preferably in less than 40 seconds, forming a suspension that is easy to swallow.
The multiparticulate tablet as claimed in claim 5, characterized in that it comprises at least one disintegrant, a diluent, a lubricant and optionally a swelling agent, a permeabilizer, sweeteners and flavorings.
The multiparticulate tablet as claimed in either of claims 5 and 6, characterized in that the diluent is chosen from soluble agents with binding properties, consisting of a polyol of less than 13 carbon atoms and being either in the form of a directly compressible product with a mean particle diameter of from 100 to 500 µm, or in the form of a powder with a mean particle diameter of less than 100 µm, this polyol preferably being chosen from the group comprising mannitol, xylitol, sorbitol and maltitol, used in the form of a directly compressible product, whereas, in the case where there are at least two soluble diluents with binding propertied, one is present in the directly compressible form and the other in the form of a powder, the polyol possibly being the same, the proportions of directly compressible polyol and of polyol powder being from 99/1 to 20/80 and preferably from 80/20 to 20/80.
The multiparticulate tablet as claimed in one of claims 1 to 7, characterized in that the coated particles comprise at least one active principle chosen from those of the group comprising gastrointestinal sedatives, antacids, analgesics, antiinflammatories, coronary vasodilators, peripheral and cerebral vasodilators, antiinfectives, antibiotics, antiviral agents, antiparasitic agents, anticancer agents, anxiolytics, neuroleptics, central nervous system stimulants, antidepressants, antihistamines, antidiarrheal agents, laxatives, dietary supplements, immunodepressants, hypocholesterolemiants, hormones, enzymes, antispasmodics, antianginal agents, medicinal products that affect the heart rate, medicinal products used in the treatment of arterial hypertension, antimigraine agents, medicinal products that affect blood clotting, antiepileptics, muscle relaxants, medicinal products used in the treatment of diabetes, medicinal products used in the treatment of thyroid dysfunctions, diuretics, anorexigenic agents, antiasthmatics, expectorants, antitussive agents, mucoregulators, decongestants, hypnotics, antinausea agents, hematopoietic agents, uricosuric agents, plant extracts and contrast agents.
The multiparticulate tablet as claimed in one of claims 1 to 8, characterized in that the binder included in the constitution of the coated particles is chosen from the group comprising cellulosic polymers, acrylic polymer, povidones, copovidones, polyvinyl alcohol, alginic acid, sodium alginate, starch, pregelatinized starch, sugars and derivative thereof, guar gum and polyethylene glycols, and mixtures thereof.
The multiparticulate tablet as claimed in one of claims 1 to 9, characterized in that:
- the core of the coated particles comprises a diluent and an antistatic agent,

- the cellulosic polymer borne by the coated particles is ethylcellulose,

- the coating film of the coated particles comprises a pore-forming agent, a plasticizer, a surfactant, an antistatic agent and a lubricant, and

- a polymer layer is applied between the core and the functional polymer film borne by the coated particles.
The multiparticulate tablet as claimed in one of claims 1 to 10, characterized in that the diameter of the coated particles is from 150 to 700 µm, given that the diameter of at least 50% and preferably of at least 70% of the particles is between 150 and 500 µm, and that the diameter of less than 15% of the particles is less than 150 µm.
A process for preparing coated particles borne by the multiparticulate tablet as claimed in one of claims 1 to 11, characterized in that it comprises the following steps:
- preparation by wet granulation or mounting on neutral supports, of a core comprising the active principle,

- coating of the cores thus obtained by splaying the coating composition consisting of at least one cellulosic polymer,

- coating of the coated particles thus obtained by spraying with a protective coating composition consisting of an excipient of thermoplastic type, dissolved in an aqueous solvent devoid of organic solvent,

- drying.