HK1077023B - Spheroids, preparation method thereof and pharmaceutical compositions - Google Patents

Description

The present invention relates to gastro-resistant spheroids coated with a flexible, deformable film and multiparticle tablets containing such spheroids.

The present invention also extends to the preparation of such enteric spheroids and multiparticle tablets containing such spheroids.

Finally, the present invention relates to a new use of a mixture of mono-, di-, and triglycerides and polyethylene glycol mono- and diester.

Spherical units may vary in size from 0,1 mm to 2 mm, preferably from 0,1 mm to 2 mm.

The enteric coating allows the nucleus containing the active substance to remain intact for the duration of the stomach stay of about two hours in a medium with a pH of approximately 1 to 3. Once in the small intestine, including the duodenum, jejunum and ileum, the enteric coating will rapidly dissolve in a medium with a pH of more than 4.5 and gradually increase to a pH of about 7.2 in its distal part.

Previous art includes many examples of multiparticle tablets comprising coated granules.

However, it has been shown that film-producing agents normally used to coat granules cannot normally absorb mechanical stresses applied during compression (International Journal of Pharmaceutics, No. 143, 13-23, 1996).

The compression of coated granules is a delicate operation by changing the structure of the coating film by the appearance of cracks or rupture, it can cause partial or total loss of the properties of the film.

The cracking of the granules irreversibly alters the release profile of the active substance (s) they contain.

Films made only of enteric polymers or copolymers such as Eudragit®L30D have very poor mechanical properties, such as not being compressive.

Alternatively, other polymers with mechanical properties that make them suitable for compression may be added to the enteric film.

Drugs made in Germany 37, No 2 (1994), p.53 shows that it is possible to combine Eudragit®L30D and Eudragit®NE30D to produce multiparticle tablets containing these coated particles.

In order to preserve the characteristics of the film covering the granules after compression, another solution is to dilute the granules with auxiliary substances, the role of which is to absorb the physical stresses of compression (binding agents) and to allow the tablet to disintegrate (disintegrating agents) in liquid medium, i.e. in aqueous solution or in the digestive fluid.

International application WO 96/01624 (ASTRA ZENECA) concerns a multi-particle tablet containing gastro-resistant microgranules, the proportion of which is less than 75% by weight, preferably less than 60% by weight, of the total weight of the tablet, the supplement being a pellet protector diluent.

The addition of these auxiliary substances makes these forms unsuitable when dosage is high, complicates the process by adding mixing steps, and also increases the unit cost of formulation.

International application WO 02/19991 (ROHM) concerns a multi-particle tablet and gastro-resistant microgranules, comprising an enteric coating of a copolymer of methycrylic acid and propylene glycol, in which the proportion of such granules in the tablets is between 35 and 90%, preferably 40 to 70% by weight, of the total weight of the tablet, the complement being a binder.

The applicant's international application WO 99/26608 concerns spheroids containing one or more active ingredients which are directly compressible without the addition of a substantial part of an auxiliary substance.

These spheroids consist of a core containing the active substance, the latter being coated with a first layer containing at least one thermoplastic excipient, which is paste-like to semi-solid in consistency at a temperature of about 20°C and has a melting point between about 25°C and about 100°C, the resulting spheroid being itself coated with a flexible, deformable film, based on a polymer material.

Although particularly suitable for the preparation of gastro-resistant forms, these spheroids have the disadvantage of being made up of a plurality of successive layers of different compositions involving a long and constrictive preparation process and of using thermoplastic excipients whose paste-like consistency to semi-solid at 20°C makes them difficult to handle.

It is therefore of particular interest to obtain gastro-resistant spheroids without any protective layer of thermoplastic excipients, but resistant to compression stresses in such a way that the gastro-resistant property can be maintained without the need to add large amounts of auxiliary agents.

The applicant has found that, contrary to the evidence of previous art, it is quite possible to improve the mechanical properties of the enteric films sufficiently to enable spheroids coated with such a film, which are sufficiently flexible and deformable, to be compressed directly without the addition of more than about 5% by weight of auxiliary substances, to be made.

The use of Gelucire® in enteric polymer coatings has a surprisingly high mechanical performance, so that the spheroids coated with this coating can be compressed directly without the addition of more than about 5% by weight of auxiliary substances.

The object of the present invention is a directly compressible gastro-resistant spheroid, characterized by the inclusion of: a nucleus containing one or more active ingredients and at least one binding agent, directly coated with a flexible, deformable film, comprising an enteric polymer and a mixture of saturated and/or unsaturated polyglycosylated glycerides whose fatty acids contain at least 8 carbon atoms, a hydrodispersible outer layer containing at least one disintegrating agent.

Err1:Expecting ',' delimiter: line 1 column 47 (char 46)

The core contains one or more active substances selected from the group of gastrointestinal sedatives, antacids, analgesics, anti-inflammatories, coronary vasodilators, peripheral and brain vasodilators, anti-infectious, antibiotics, antiviral, antiparasitic, anti-cancer, anxiolytics, neuroleptics, central nervous system stimulants, antidepressants, anti-amine, antidiarrheal, laxative, hypoglycemic, immuno-depressants, hypocholesterolemic, hormonal, enzyme, herbicide, anti-diarrheal, 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-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-hypertensive, anti-

The active substances of particular preference in this application are acid-labile active substances requiring gastro-protection for oral administration, e.g. proton pump inhibitors, such as omeprazole, lansoprazole, pantoprazole, pariprazole, leminoprazole and rabéprazole in their racemic or pure enantiomeric forms, present on their own, as bases or as alkaline salts.

Other preferred active substances are stomach mucus irritants, whose ulcerogenic effects require delayed administration, such as nonsteroidal anti-inflammatory drugs, e.g. diclofenac, antibiotics such as erythromycin and its derivatives, doxycycline.

The active substance (s) are applied by mounting on the surface of a neutral core of a mixture of sucrose and starch, or microcrystalline cellulose, or by an alternative process, and are dispersed in the core mass by dry, wet or hot granulation or by extrusion-sferonisation.

The active substance, initially in powder or microcrystals, is used as a solution or suspension in an aqueous or organic solvent for mounting on neutral, and generally in the dry state in other cases.

According to the present invention, the cores also contain a binder.

The binder is selected 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 binder is present in proportions up to about 50% by weight, preferably up to about 20% by weight of the uncoated cores.

Its role is to fix the active substance to the neutrals without loss of matter, or to glue the powder or microcrystals of the active substance and the other excipients, in order to give homogeneous particles of the active substance whose size will make the coating operation easier.

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, preferably mannitol, minerals, preferably dicalcium phosphate.

The diluent is present in proportions up to about 95% by weight, preferably up to about 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, e.g. Aerosil®, preferably precipitated silica, e.g. Syloïd® FP244, micronized or unmicronized talc and mixtures thereof.

The antistatic agent is present in proportions up to about 10% by weight, preferably up to about 3% by weight of uncoated particles and improves the fluidisation of the material when using a fluidised air bed, particularly in the case of powder granulation.

An optional polymer layer may be applied between the core and the flexible, deformable polymer film to isolate the active core from the polymer layer to enhance the gastro-protection of the active substance.

In this case, the polymer is chosen from the same polymers as those used as binders, and may be the same or different from the one used as a binding agent in the active nucleus.

The amount of polymer applied is between 1 and 10% in weight gain relative to the mass of active nuclei used, preferably between 2 and 5%.

The core containing the active substance is then coated with a flexible, malleable film to provide gastro-protection of the active substance and consisting of an enteric polymer and at least one plasticizer.

The enteric polymer is chosen from the group comprising cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose succinate phthalate, polyvinyl acetate phthalate, cellulose acetate trimellitate, carboxymethylcellulose, shellac or any other enteric polymer, used alone or in combination separately. The preferred polymer is methacrylic acid copolymer, marketed under the trade name Eudragit®L100 or Eudragit®L30D.

The coating composition is applied by spraying to form a continuous film covering the entire surface of each particle, regardless of its surface condition, in sufficient quantity to provide gastro-protection of the active substance.

Gastro-protection is determined by a two-stage test, consisting of measuring the dissolution profile of the coated form, such that when the coated form is placed in a pH 1,2 solution medium, the percentage of active substance released after 120 minutes is less than 10% by weight and then when, after changing the pH of the medium from a value of 1,2 to a pH 6,8, the percentage of active substance released after 60 minutes at this pH is at least 80% by weight.

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

The solvent used to spray the enteric 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 colloidal dispersion in the solvent or mixture of solvents, preferably in colloidal dispersion in water.

Optionally, this polymer may be mixed with a second polymer or copolymer, which may itself be soluble or insoluble, in particular a neutral copolymer of acrylic and methacrylic acid esters, marketed under the trade name Eudragit®NE30D.

The addition of a second polymer to the coating compound improves the mechanical properties of the enteric film resulting from this mixture, in which case the second polymer is added in a quantity of not more than 100% by dry weight of the polymer in relation to the dry weight of the enteric polymer, preferably in a ratio of 10 to 30%.

The mixture of saturated and/or unsaturated polyglycosylated glycerides with at least 8 carbon atoms in the fatty acids is in particular a mixture of mono-, di- and triglycerides and polyethylene glycol (PEG) mono- and diesters, with a molecular weight of between 200 and 1500, possibly glycerol and free PEG.

This mixture is, for example, marketed under the trade name Gelucire®.

The fatty acids in the mixture of saturated and/or unsaturated polyglycosylated glycerides preferably contain 8 to 18 carbon atoms (C8-C18).

C8-C18 means mixtures in significant and variable proportions of caprylic (C8), capric (C10), lauric (C12), myristic (C14), palmitic (C16) and stearic (C18) acids, when these acids are saturated and the corresponding unsaturated acids in (C8-C18).

Among the Gelucires®, Gelucires® 50/13 is preferred, which thus predominantly contains palmitostearic acid (C16-C18) and is characterised by a melting point between 46.0 and 51.0°C and a hydrophilic/lipophil balance (HLB) value of 13.

The total proportion of the saturated and/or unsaturated polyglycosylated glycerides in the mixture shall not exceed 40%, preferably between 10 and 30%, expressed as a percentage of the dry weight of the polymer.

The function of the mix of saturated and/or unsaturated polyglycosylated glycerides is to lower the glass transition temperature of the film and to improve the mechanical properties of the coating polymer film, in particular to make it flexible and deformable.

Optionally, the coating film shall also include a plasticizer selected from the group comprising triethyl citrate, acetyltributyl citrate, triacetin, tributyl citrate, diethyl phthalate, polyethylene glycols, polysorbates, mono- and diacetyl glycerides.

The total proportion of plasticizer used shall not exceed 40%, preferably between 10 and 30%, expressed as a percentage of the dry weight of the polymer.

The function of the plasticizer is to lower the glass transition temperature of the film.

The coating composition also includes, optionally, a surfactant, an antistatic agent, a lubricant.

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

The antistatic agent, used as a preventative for problems related to static electricity, is in the group comprising micronized or non-micronized talc, colloidal silica (Aerosil®200), treated silica (Aerosil®R972), or precipitated silica (Syloid® FP244) and their mixtures.

The antistatic agent shall be used in a proportion of not more than about 10% by weight, preferably between 0 and 3%, preferably less than about 1% by weight.

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

The granularity of these spheroids allows them to be used in the manufacture of multiparticle tablets.

The advantage is that the spheroids have a diameter of between 0.1 mm and 2 mm, preferably between 0.3 mm and 1 mm.

The size is determined by conventional methods, e.g. by a calibrated mesh sieve set, or by laser diffraction.

The spheroids of the invention are advantageously coated with an outer layer which is water-dispersible.

This layer ensures the cohesion of the spheroids at the time of compression and thus the hardness of the tablet, and allows the resulting tablet to be broken up in an aqueous medium.

The outer layer of the water-dispersible material shall consist of at least one disintegrator.

The decantant is selected from the group comprising, inter alia, cross-linked sodium carboxymethylcellulose, known in the trade as croscarmellose, crospovidone, sodium carboxymethylstarch and mixtures thereof.

It may optionally include a binder selected from those used for the assembly step and water-soluble auxiliary substances such as polyols, in particular mannitol.

The invention also relates to the process of preparing gastro-resistant spheroids which can be directly compressed.

The process according to the invention consists of the following steps: preparation of a nucleus containing one or more active ingredients and at least one binder; coating of the resulting nuclei by spraying the coating composition containing an enteric polymer, a mixture of saturated and/or unsaturated polyglycosylated glycerides whose fatty acids contain at least 8 carbon atoms, preferably 8 to 18 carbon atoms (C8-C18) coating of the gastro-resistant spheroids with a hydrodispersable outer layer containing at least one disintegrating agent, and drying of the spheroids.

Depending on the method of implementation, the steps may be performed in different or the same apparatus.

The core containing the active substance may be obtained by granulation, by mounting on a neutral surface or by extrusion-spheronisation.

In a first manufacturing process, the cores containing the active substance are prepared by granulation in the following steps: dry mixing of the active substance in powder or microcrystals, possibly with the diluent and an 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 a second method of preparation, the nuclei containing the active substance are prepared by mounting on neutrals in the following steps: spraying on neutrals of a solution or suspension of the active substance containing the solubilised binder and optionally a lubricant, an antistatic agent drying,

The mounting preparation may be in the form of suspension in aqueous or organic media, solutions, emulsions or melted form, as appropriate.

In a first variant of the assembly process, the active substance is incorporated into the assembly preparation.

In another variant of the mounting method, the active substance is applied by powdering to the neutral cores which have been previously moistened with the mounting preparation.

All steps of the process according to the invention can be carried out in a dredging turbine, a punched turbine or a fluidized air bed.

A third method is to prepare the nuclei containing the active substance by extrusion-sferonization.

The active substance is then mixed with the excipient mass, the mixture is moistened to ensure satisfactory extrusion, the resulting extrudates are calibrated and spheronized.

The resulting cores are then coated with a composition containing a filmogenic enteric polymer, a plasticizer and, optionally, a surfactant, an antistatic agent or a lubricant.

The coating composition is sprayed as a solution, suspension or colloidal dispersion of this polymer in an organic or aqueous solvent and then dried.

The water-dispersible outer layer is applied by one of the above methods, but isopropyl alcohol is preferably the solvent used.

In a preferred method of preparation of gastro-resistant spheroids, all steps of preparation of the active nucleus and coating are performed in a fluidised air bed.

Err1:Expecting ',' delimiter: line 1 column 210 (char 209)

The choice of the spraying method allows the growth kinetics of the particles to be controlled and bonding phenomena to be avoided, which are related to the nature of the active substance, the composition of the binder or coating sprayed and the various process parameters (e.g. temperature, air pressure, solution flow rate).

The present invention also applies to multiparticle tablets containing the directly compressible spheroids described above, and containing no more than approximately 5% by weight of an auxiliary substance, such as a lubricant, antistatic agent and/or permeabilising agent.

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

The antistatic agent is used to prevent problems related to static electricity and is in the group comprising micronized and non-micronized talc, colloidal silica (Aerosil®200), treated silica (Aerosil®R972) or precipitated silica (Syloid® FP244) and their mixtures.

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.

The permeabilising agent allows the creation of a hydrophilic network which thus contributes to a better disintegration of the tablet.

The multiparticle tablets of the invention disintegrate into solution in less than 60 minutes and give independent spheroids, so that the release profile of the tablet and its constituent spheroids is virtually equivalent.

The tablets of the invention allow the release of spheroids without the release profile of the active substance (s) they contain being altered by compression.

The tablets of the invention may consist only of the spheroids of the invention or of a mixture of spheroids containing one or more active ingredients and placebo steroids, i.e. steroids conforming to the present invention without an active ingredient.

The tablets of the invention may be finished with a protective coating or colouring.

The invention also relates to the process of preparing multiparticle tablets containing spheroids.

The process according to the invention consists of the following steps: mixture of gastro-resistant spheroids with not more than 5% by weight of one or more auxiliary substances, such as a lubricant, an antistatic agent and/or a permeabilising agent, compression of the mixture to a unitary shape.

The spheroid compression may be performed on an alternative or rotary compressor.

The stresses on the spheroids during the compression step may vary from 5 kN to 50 kN and preferably between 5 kN and 15 kN.

The hardness of these tablets is preferably between 1 and 10 kp, preferably between 1 and 5 kp, measured according to the European Pharmacopoeia method (2.9.8), with 1 kp being equal to 9.8 N.

Preferably, the hardness of the multi-particle tablet is adjusted to obtain a crumbliness, measured according to the European Pharmacopoeia method, of less than 2%.

The time to decomposition of the tablets in aqueous media at 37°C is less than 60 minutes.

Tablets may be 6 mm to 17 mm in diameter. They may be round, oval, oblong, flat or concave in shape, and have engravings or secatability bars.

The tablets of the invention should preferably have a mass between 0,1 g and 2 g.

The present invention will be better understood by the examples of the manufacture of gastro-resistant spheroids and multiparticle tablets conforming to the invention.

The following information shall be provided in the application:

Gastro-resistance test

The dissolution profile of gastro-resistant spheroids is determined under the following conditions: Appliance: USP type II blade speed: 100 rpm volume: 750 ml pH 1.2 and 1000 ml pH 6.8 temperature: 37.0°C ±0.5°C detection: direct UV spectrophotometry at 272 nm medium of dissolution: HCl 0,1 N (pH = 1.2) for 120 minutes (t0 to t 120mn), followed by pH 6.8 for 60mn (t = 121mn to t=180mn)

Example 1: Installation of the active substance in a fluidised air bed

Err1:Expecting ',' delimiter: line 1 column 113 (char 112)

Coating

1000 grams of granules obtained after the mounting step described above are wrapped in a GLATT GPCG-3 fluidised air bed equipped with a Würster insert by spraying an aqueous dispersion of Eudragit®L30D, comprising 30% by weight of triethyl citrate (TEC), calculated on the dry polymer weight.

Apply to theophylline granules a total amount of Eudragit®L30D corresponding to 30% weight gain on the mass of the starting uncoated granules

The coated G1 granules from the coating step have the following dissolution profile:

Théophyline libérée % (w/w)
Temps
120 mn	7
135 mn	81
150 mn	81
180 mn	81

The Commission

The spheroids have a dissolution profile satisfying the specifications of the gastro-resistance test.

The following paragraphs shall apply: Overcoated

The G1 granules in example 1 are coated with an outer layer of a binding agent but without a disintegrating agent.

Spray on the G1 granules an aqueous solution containing either PEG 4000 or a mixture of PEG 4000 and HPCM 603 in a ratio of 20/80, including 20% by weight of micronized talc, calculated on the total dry weight of the polymer.

Each sub-batch of granules is compressed separately on a MANESTY F3 press with a round, convex punch of 10 mm diameter to obtain a crumbly value of less than 2% by weight.

After 60 minutes, the resulting tablets are not disintegrated.

Conclusion:

The dispersible outer layer without a disintegrator does not allow the tablet to be disintegrated according to the specifications.

The Commission has Overcoated

The G1 granules in example 1 are coated with a water-dispersible layer containing a disintegrating agent, Ac-Di-Sol®.

Ac-Di-Sol® mixed with mannitol 25 in a 50/50 ratio is applied to the G1 granules by powdering in a conventional turbine using a binding solution containing polyvinylpyrrolidone (PVP) K29 in 10% solution in isopropyl alcohol.

Apply to the granules an amount of Ac-Di-Sol® corresponding to 20% by weight, calculated from the starting granule mass G1.

The granules G1/1 thus prepared have the following dissolution profile: - What?

Théophylline libérée % (w/w)
Temps
120 mn	7
135 mn	79
150 mn	79
180 mn	80

Compression of the

The granules obtained in the previous step G1/1 are compressed on a MANESTY F3 press with a round, convex punch of 10 mm diameter to obtain a unit theophylline dose of approximately 50 mg.

The resulting tablets (C1/1) have the following characteristics: - What?

Poids (mg)	426
Dureté (kP)	2,7
Friabilité (%)	0,21
Désagrégation (mn)	50
Théophylline libérée
% (w/w)
120 mn	51
135 mn	87
150 mn	88
180 mn	88

Conclusion:

The water-dispersible layer containing Ac-Di-Sol® allows the tablet to be disintegrated in less than 60 minutes, although the compression of the granules causes the polymer film to rupture and the loss of gastro-protection.

The tablet does not meet the specifications of the gastro-resistance test.

The Commission shall adopt implementing acts. Overcoated

The G1 granules in example 1 are coated with a water-dispersible layer containing a disintegrating agent, Kollidon®CLM.

Kollidon®CLM, mixed with mannitol 25 in a 50/50 ratio, is applied to the G1 granules by powdering in a conventional turbine using a binding solution containing PVP K29 in a 10% by weight solution in isopropyl alcohol.

Apply to the granules a quantity of Kollidon®CLM equal to 20% by weight, calculated from the starting mass of the G1 granules.

The granules thus prepared (G1/2) have the following dissolution profile: - What?

Théophylline libérée %(w/w)
Temps
120 mn	5
135 mn	82
150 mn	82
180 mn	82

Compression of the

The granules obtained in the previous step are compressed on a MANESTY F3 press with a round, convex punch of 10 mm diameter to obtain a unit theophylline dose of approximately 70 mg.

The resulting tablets (C1/2) have the following characteristics:

Poids (mg)	409
Dureté (kP)	2,5
Friabilité (%)	0,51
Désagrégation (mn)	32
Théophylline libérée
% (w/w)
120 mn	41
135 mn	80
150 mn	81
180 mn	82

Conclusion:

The water-dispersible layer containing the disintegrating agent allows the tablet to disintegrate in less than 60 minutes, however, the compression of the granules causes the polymer film to rupture and the loss of gastro-protection.

The tablet does not meet the specifications of the gastro-resistance test.

The Commission shall adopt implementing acts. Installation of the active substance in a fluidised air bed (RD239)

In a GLATTGPCG-3 type Fluidised Air Bed equipped with a Würster nozzle, a suspension containing 636.9 grams of theophylline and a PVPK29/Eudragit®RS100 blend as binders, representing a total of 50% by weight of theophylline, is sprayed on 318.5 grams of neutral nuclei.

Coating

1000 grams of granules obtained after the assembly step are wrapped in a GLATT GPCG-3 fluidised air bed equipped with a Würster insert by spraying an aqueous dispersion of a mixture of Eudragit®L30D/Gelucire®50/13 in a ratio of 75/25, including 10% by weight of triethyl citrate (TEC), calculated on the dry weight of Eudragit®L30D.

Apply to the granules a total amount of Eudragit®L30D/Gélucire®50/13 corresponding to 50% of the weight gain of the original uncoated granules.

The coated granules G2 thus coated have the following dissolution profile: - What?

Théophylline libérée % (w/w)
Temps
120 mn	3
135 mn	92
150 mn	109
180 mn	110

Overcoated

The G2 granules obtained in the previous step are coated with a water-dispersible layer including Kollidon®CLM.

Kollidon®CLM, mixed with mannitol 25 in a 50/50 ratio, is applied to the granules by powdering in a conventional turbine using a binding solution containing PVP K29 in a 10% solution in isopropyl alcohol.

Apply to the granules a quantity of Kollidon®CLM corresponding to 20% by weight, calculated from the starting mass of the G2 granules.

Compression of the

The coated granules obtained in the previous step (G2/1) are compressed on a MANESTY F3 press with a round, convex punch of 12 mm diameter to obtain a unit theophylline dose of approximately 150 mg.

The resulting tablets (C2/1) have the following characteristics: - What?

Poids (mg)	400
Dureté (kP)	6.0
Friabilité (%)	Nd
Désagrégation (mn)	26
Théophylline libérée
% (w/w)
120 mn	3
135 mn	64
150 mn	89
180 mn	92

The Commission

The spheroids meet the specifications of the gastro-resistance test.

The tablet meets the specifications of the gastro-resistance and decomposition test.

Claims (22)

1. Directly tabletable gastroresistant spheroid, characterized in that it comprises:

   ➢ a core comprising one or more active principles, directly coated with

   > a flexible and deformable film comprising an enteric polymer and a mixture of saturated and/or unsaturated polyglycosylated glycerides whose fatty acids contain at least 8 carbon atoms,

   ➢ a water-dispersible outer layer comprising at least one disintegrant.
2. Spheroid according to Claim 1, characterized in that the core comprises one or more active principles selected from those from the group consisting of gastrointestinal sedatives, antacids, analgesics, antiinflammatories, coronary vasodilators, peripheral and cerebral vasodilators, antiinfection agents, antibiotics, antivirals, antiparasitics, anticancer agents, anxiolytics, neuroleptics, central nervous system stimulants, antidepressants, antihistamines, antidiarrheals, laxatives, nutritional supplements, immuno-depressants, hypocholesterolemics, hormones, enzymes, antispasmodics, antianginal agents, medicinal products which influence heart rate, medicinal products used in the treatment of arterial hypertension, antimigraine agents, medicinal products which influence blood clottability, 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, antitussives, muco-regulators, decongestants, hypnotics, antinausea agents, hematopoietic agents, uricosuric agents, plant extracts, and contrast agents.
3. Spheroid according to either of Claims 1 and 2, characterized in that the active principle is selected from proton pump inhibitors, preferably omeprazole, lansoprazole, pantoprazole, pariprazole, leminoprazole or rabeprazole, in their racemic form or in the form of pure enantiomers, themselves in base form or in the form of alkali metal salts; nonsteroidal antiinflammatories, preferably diclofenac, in the form of bases or of salts; antibiotics, preferably erythromycin and its derivatives, in the form of bases or of salts.
4. Spheroid according to one of Claims 1 to 3, characterized in that the binder is selected from the group consisting of cellulosic polymers, acrylic polymers, povidones, copovidones, polyvinyl alcohols, alginic acid, sodium alginate, starch, pregelatinized starch, sucroses and derivatives thereof, guar gum, polyethylene glycols, and mixtures thereof.
5. Spheroid according to one of Claims 1 to 4, characterized in that the core optionally comprises a diluent, an antistat and/or a lubricant.
6. Spheroid according to one of Claims 1 to 5, characterized in that the enteric polymer is selected from the group consisting of cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose succinate phthalate, polyvinyl acetate phthalate, cellulose acetate trimellitate, carboxymethylcellulose and shellac, which are used alone or in a mixture.
7. Spheroid according to Claim 6, characterized in that the enteric polymer is a methacrylic acid copolymer.
8. Spheroid according to one of Claims 1 to 7, characterized in that the fatty acids of the mixture of saturated and/or unsaturated polyglycosylated glycerides contain from 8 to 18 carbon atoms (C8-C18).
9. Spheroid according to Claim 8, characterized in that said mixture is a mixture of mono-, di- and triglycerides and of polyethylene glycol monoester and diester, with a molecular weight of between 200 and 1500, and optionally of glycerol and of free PEG, and predominantly comprises palmitostearic acid, said mixture being characterized by a melting point of between 46.0°C and 51.0°C and a hydrophilic/lipophilic balance (HLB) of 13.
10. Spheroid according to Claim 8, characterized in that said mixture is Gélucire®, in particular Gélucire 50/13.
11. Spheroid according to Claims 1 to 10, characterized in that the flexible and deformable film optionally comprises a plasticizer selected from the group consisting of triethyl citrate, acetyl tributyl citrate, triacetin, tributyl citrate, diethyl phthalate, polyethylene glycols, polysorbates, and monoacetylated and diacetylated glycerides, preferably triethyl citrate.
12. Spheroid according to Claims 1 to 11, characterized in that the coating composition optionally comprises a surfactant, an antistat and/or a lubricant.
13. Spheroid according to Claims 1 to 12,characterized in that the disintegrant is selected from the group consisting of the crosslinked sodium carboxymethylcellulose denoted in the art by the term croscarmellose, crospovidone, sodium carboxymethyl starch, and mixtures thereof.
14. Spheroid according to Claims 1 to 13, characterized in that the dispersible outer layer optionally comprises a binder and an auxiliary substance, in particular mannitol.
15. Method of preparing the spheroids according to Claims 1 to 14, characterized in that it comprises the following steps:

    ➢ preparing a core comprising one or more active principles and at least one binder;

    ➢ coating the cores thus obtained by spraying the coating composition comprising an enteric polymer and a mixture of saturated and/or unsaturated polyglycosylated glycerides whose fatty acids contain at least 8 carbon atoms, preferably from 8 to 18 carbon atoms (C8-C18);

    ➢ coating the gastroresistant spheroids with a water-dispersible outer layer comprising at least one disintegrant; and

    ➢ drying the spheroids.
16. Method of preparing according to Claim 15, characterized in that the core comprising the active principle is prepared by granulation, by application to neutral substance, or else by extrusion with spheronization.
17. Method of preparing according to Claims 15 and 16, characterized in that the spheroids are prepared in a fluidized-air bed.
18. Multiparticulate tablet comprising the spheroids according to one of Claims 1 to 17.
19. Multiparticulate tablet according to Claim 18, characterized in that it contains not more than approximately 5% by total weight of one or more auxiliary substances.
20. Multiparticulate tablet according to either of Claims 18 and 19, characterized in that the auxiliary substance is a lubricant, an antistat and/or a permeabilizing agent.
21. Multiparticulate tablet according to one of Claims 18 to 20, characterized in that it comprises a mixture of spheroids comprising one or more active principles and of placebo spheroids.
22. Method of preparing the multiparticulate tablets according to either of Claims 18 and 19, characterized in that it comprises the following steps:

    ➢ mixing the gastroresistant spheroids with not more than approximately 5% by weight in total of one or more auxiliary substances;

    ➢ tableting the mixture to give a unitary form.