F0RM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention.- "CONTROLLED RELEASE MULTIPLE UNIT
FORMULATION"


2. Applicant(s)
(a) NAME :
(b) NATIONALITY:
(c) ADDRESS :

ALEMBIC LIMITED
An Indian Company.
Alembic Campus, Alembic Road, Vadodara - 390 003, Gujarat, India.

3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.


FIELD OF THE INVENTION
The present invention relates to controlled release multiple unit formulations, which comprise a water-insoluble inert core, an active ingredient and one or more pharmaceutically acceptable excipients. Further, the present invention relates to processes of preparing controlled release multiple unit formulations comprising a water-insoluble inert core, an active ingredient and one or more pharmaceutically acceptable excipients.
BACKGROUND OF THE INVENTION
Numerous systems have been developed and marketed for the purpose of obtaining an extended release and for reducing the frequency of administrations. Examples of such are the matrix systems, reservoir systems, osmotic drug delivery systems and other monolithic systems.
The controlled-release dosage forms often result in the reduction or elimination of fluctuations in drug concentration in the blood, which improves disease state management. In addition, because the controlled-release dosage form reduces the maximum concentration of drug in the blood relative to an immediate release formulation of the same dose, the controlled-release formulation may minimize side effects, and may result in less potentiation or reduction in drug activity with chronic use.
For extended-release dosage forms containing very high quantities of active principle, avoiding excessively rapid release (dose dumping) is particularly very critical as it can lead to toxic effects, which are undesirable. Moreover, such systems are dependent upon gastric emptying rates and transit times and are also associated with a lot of intra- and inter-individual variations.
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These disadvantages have led to a shift in modified release technology, from the use of monolithic systems to multiple unit systems, wherein each individual unit is formulated with modified release characteristics. The final dosage form comprises a multiplicity of individual units contained in a formulation in such a form that individual units will be made available from the formulation in the gastrointestinal tract.
Multiple unit dosage forms possess large surface area, which promotes complete and uniform absorption, minimize peak plasma fluctuations and thus reduce the potential for systemic side effects, A further advantage of these dosage forms is that high local concentrations of the active substance in the gastrointestinal system is avoided, due to the units being distributed freely throughout the tract.
U.S. Patent Nos. 4,927,640 and 4,957,745 disclose a controlled release preparation containing a number of beads comprising insoluble cores coated with metoprolol. The beads have a high content of metoprolol in the range of 95-100% w/w of the soluble part of the bead. Insoluble cores, such as glass and silicon dioxide are used. U.S. Patent No. 5,001,161 discloses a pharmaceutical composition comprising metoprolol succinate together with a sustained release pharmaceutically acceptable carrier.
U.S. Patent Publication 20030185887 discloses a controlled or sustained release dosage formulation of propranolol where the inert core is coated with a solution of propranolol, water insoluble binder and filler. The active core so produced is further coated with a release-controlling layer.
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U.S. Patent Publication 20050008701 discloses a controlled release pellet comprising water-soluble or water swellable inert core and a drug layer applied to it, along with a controlled release coating surrounding the drug layer.
Several other controlled release/extended release pharmaceutical compositions are known for example, in U.S. Patent Nos. 5,399,362; 5,399,358; 5,707,656; 5,709,882; and 4,871,549; U.S. Application Nos. 20020177579; 20050266078; 20060003007; and 20040228915.
The inert cores used in prior art include one or more of water-soluble, water-insoluble or water-swellable materials. Examples include one or more of sugar, non-pareils, microcrystalline cellulose, celphere, sand, silicon dioxide, glass, plastic, polystyrene, ethyl cellulose or hydroxypropyl melhylcellulose. The sugar may include one or more of glucose, mannitol, lactose, xylitol, dextrose, and sucrose.
The water soluble inert cores have a disadvantage in that the soluble cores tend to create a great amount of osmotic pressure causing the multiple units to burst up and dump the drug. The water insoluble inert cores are too hard and brittle that the drug layers tend to crack from the surface thereby affecting the release profile. Therefore, there is still a need for the development of controlled release multiple unit formulation comprising an inert core that can be prepared using a simple process and can also be advantageously used for preparing pharmaceutical dosage forms.
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SUMMARY OF THE INVENTION
In one general aspect there is provided a controlled release multiple unit formulation comprising:
a) a water-insoluble inert core comprising a combination of colloidal silicon dioxide and ethyl cellulose,
b) one or more drug layers comprising the pharmaceutically active ingredient, and
c) one or more polymeric coatings surrounding the drug layer,
wherein the water-insoluble inert core has a bulk density from about 0.3 to about 0.7.
According to another embodiment there is provided a controlled release multiple unit formulation comprising:
a) a water-insoluble inert core comprising a combination of colloidal silicon dioxide and ethyl cellulose,
b) one or more drug layers comprising the pharmaceutically active ingredient, and
c) one or more polymeric coatings comprising one or more water soluble polymers and water insoluble polymers or mixtures surrounding the drug layer,
wherein the water-insoluble inert core has a bulk density from about 0.3 to about 0 J.
In yet another aspect there is provided a process for preparing a controlled release multiple unit formulation which comprises:
a) preparing a water-insoluble inert core by blending/mixing a combination of colloidal silicon dioxide and ethyl cellulose dispersion,
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b) loading/layering the material of step (a) with one or more drug layers
comprising the pharmaceutically active ingredient, and
c) coating the material of step (b) with one or more polymers;
wherein the water-insoluble inert core has a bulk density from about 0.3 to about 0.7.
A controlled release multiple unit formulation comprising:
a) a water-insoluble inert core comprising a combination of colloidal silicon dioxide and ethyl cellulose,
b) one or more drug layers comprising metoprolol or pharmaceutically acceptable salts thereof, and
c) one or more polymeric coatings surrounding the drug layer,
wherein the water-insoluble inert core has a bufk density from about 0.3 to
about 0.7,
which is obtained by the process as mentioned above.
DETAILED DESCRIPTION OF THE INVENTION
Generally provided herein is a controlled release multiple unit formulation comprising a water insoluble inert core and one or more active ingredient layers, having desirable release profiles, as well as processes to prepare same.
The phrase "contro]]ed-re\ease multiple unit formulation" as used herein, includes solid dosage forms such as tablets, capsules, pills and like. For example, tablets can be prepared by techniques known in the art and contain a therapeutically effective amount of an active and such excipients as are necessary to form the tablet.
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The phrase "controlled-release multiple unit formulation" as used herein, includes any pharmaceutical composition that achieves slow release of active ingredient over an extended period of time, and includes prolonged, modified, extended and sustained-release compositions.
The water insoluble inert core of the present invention can be prepared by using the combination of colloidal silicone dioxide and ethyl cellulose (Surelease dispersion).
Of the properties of inert cores, bulk density is of at most importance. In the case of inert cores used for release control purposes, bulk density serves as a composite indicator of shape and density.
Bulk density refers to bulk density of inert cores and can be determined by any method known in the art. For eg., bulk density can be measured by pouring an excess of inertcores through a funnel into a smooth metal vessel, scraping off the excess from the heap above the rim of the vessel, measuring the remaining mass of inert cores and dividing the mass by the volume of the vessel.
The inert cores prepared have the desired bulk density in the range of about 0.3 to about 0.7, which is also suitable for fluid bed coating and further overcomes the disadvantages of prior art water soluble and water insoluble inert cores. Since colloidal silicon dioxide has bulk density of approximately 0.1 and is not suitable as such to carry out drug layering in fluidized bed coater as it is not possible to fluidize the colloidal silicon dioxide. When colloidal silicon dioxide was granulated with general binders like starch paste or povidone solution, the desired bulk density of colloidal silicon dioxide is not achievable above 0.3. It was surprisingly found by the present inventors that
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when colloidal silicon dioxide was granulated with aqueous dispersion of ethylcellulose and after drying, it was found that bulk density of granules was 0.45 and it was possible to properly fluidize the material in fluid bed coater to perform drug layering/functional coating.
Inert cores can be coated with one or more pharmaceutically active ingredient layers.
Pharmaceutically active ingredients can comprise one or more sedatives, antacids, analgesics, non-steroidal anti-inflammatory agents, 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, hormones, enzymes, antispasmodics, antianginal agents or mixtures thereof.
Preferably, the pharmaceutically active ingredients comprise one or more of lansoprazole, pantoprazole, metoprolol, propranolol, diltiazem, tamsulosin, diclofenac, itraconazole, venlafaxine, tolterodine and pharmaceutically acceptable salts or derivatives thereof.
More preferably, the pharmaceutically active ingredient is metoprolol or pharmaceutically acceptable salts thereof.
Active ingredient layers may further comprise one or more binding agents to give proper adhesion of the active ingredient layer(s) to inert core. Binding agents include, for example, water-insoluble or water-soluble binding agents that are commonly known in the art, e.g., hydroxypropyl methylcellulose,
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povidone, hydroxypropyl cellulose, polymethacrylates, ethylcellulose, or mixtures thereof.
Active ingredient layers can be layered/loaded onto the inert core by techniques, for example, spray coating in a conventional coating pan or fluidized bed processor or dip coating from a solution or dispersion of the active ingredient.
The active ingredient can be dissolved into a suitable solvent (e.g. dichloromethane, isopropyl alcohol, acetone, methanol, ethanol, water or mixture thereof), sprayed onto the insoluble core in a coating pan or in a fluidized bed, and the solvent can be dried off. The resulting multiple units can be coated with one or more polymeric layers by dissolving a polymeric mixture into a solvent (e.g., dichloromethane, isopropyl alcohol, acetone, methanol, ethanol, water or mixtures thereof) and repeating if necessary. Spraying can be done by any of the above- mentioned techniques or any other technique known to the skilled artisan.
Multiple units coated with one or more active ingredient layers can then be coated with one or more polymeric coatings, which include coating with one or more controlled release polymers (to obtain desired release profile), one or more non- functional coatings, or mixtures thereof.
Examples of controlled release polymer include water soluble polymers, water insoluble polymers or mixtures thereof.
Examples of water soluble polymers include, but are not limited to, one or more of cellulose derivatives, gums, vinyl alcohol or vinylpyrrolidone-based polymers and mixtures thereof. The cellulose derivatives may include one or
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more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose and mixtures thereof. The gums may include one or more of xanthan gum, karaya gum, locust bean gum, alginic acid, sodium alginate and mixtures thereof. The vinyl alcohol or vinylpyrrolidone-based polymers may include one or more of polyvinyl alcohol, polyvinylpyrrolidone and mixtures thereof.
Examples of water-insoluble polymers include, but are not limited to, one or more of ethyl cellulose, hydroxypropylmethyl cellulose phthalate, cellulose acetate, cellulose acetate phthalate, co-polymers of acrylate or methacrylate having low quaternary ammonium content, poly vinyl acetate or mixtures thereof.
The controlled release multiple unit formulation may further comprise one or more non-functional coatings.
Non-function coatings (e.g., polyethylene glycol) can facilitate in forming a smooth surface and better appearance of a pharmaceutical composition. Non-functional coatings can also help in overcoming common problems, including rupturing or cracking of release- controlling layers/membrane or fragmentation of the core due to mechanical stress generated during compression of cores into tablets or filling into capsules/sachets.
Coating solutions may be applied using techniques, for example, spray coating in a conventional coating pan or fluidized bed processor or dip coating. Solutions or dispersions of polymers can be prepared in solvents, for example, dichloromethane, isopropyl alcohol, acetone, methanol, ethanol, water or mixtures thereof.
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Coating solutions may further comprise other pharmaceutically acceptable ingredients, for example, plasticizers, coloring agents and surfactants.
Examples of suitable plasticizers include acetyl triethyl citrate, dibutyl phthalate, tributyl citrate, triethyl citrate, acetyl tributyl citrate, propylene glycol, triacetin, polyethylene glycol, diethyl phthalate or mixtures thereof.
The thickness and number of polymeric coatings can vary widely to give the desired release characteristics of the cores and will depend on the particular polymer or mixture thereof chosen. The thickness and number of polymeric coatings can be readily determined by one skilled in the art using dissolution profile data.
The controlled-release multiple unit formulation may also be formulated as granules filled into hard gelatin capsules or sachets, or formed into tablets.
Embodiments of the controlled release multiple unit formulation comprise one or more of the following features. For example, the controlled release multiple unit formulation comprises other pharmaceutically acceptable excipients.
The controlled release multiple unit formulation can be processed into a solid dosage form selected from a tablet, a capsule or a sachet.
The coated multiple units can be processed into tablet dosage forms by various techniques.
For example, the coated multiple units can be processed into tablet dosage form comprising the steps of blending pharmaceutically inert excipient; granulating with a granulating fluid or solution/dispersion of binder; drying and
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sizing the granules; optionally blending with other pharmaceutically inert extragranular excipients; blending with active ingredient coated multiple units; lubricating the granules/blend; compressing the lubricated blend into suitable sized tablets and; optionally coating with film forming polymer and coating additives.
The coated multiple units can also be processed into tablet dosage form, comprising the steps of blending pharmaceutically inert excipient; compacting the blend by roller compactor or slugging; sizing the compacts to obtain granules and blending the slugs of inert excipients with active ingredient coated multiple units; lubricating the granules/blend; compressing the lubricated blend into suitable sized tablets and; optionally coating with film forming polymer and coating additives.
The coated multiple units can also be processed into tablet dosage form by direct compression technique, comprising the steps of blending active ingredient coated multiple units and pharmaceutically inert excipient; lubricating the blend; directly compressing the lubricated blend into suitable sized tablets and; optionally coating with film forming polymer and coating additives.
The phrase 'pharmaceutically acceptable inert excipients," as used herein, includes all excipients used in the art of manufacturing solid dosage forms. Examples of pharmaceutically acceptable inert excipients include binders, diluents, surfactants, lubricants/glidants, cushioning agents, coloring agents, and the like.
Suitable binders include, for example, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum
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arable, ethyl cellulose, polyvinyl alcohol, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and the like, or mixtures thereof.
Suitable diluents include, for example, calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, cellulose-microcrystalline, cellulose powdered, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactito!, lactose, mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners, and the like or mixtures thereof.
Suitable surfactants include, for example, both non-'ionic and ionic (cationic, anionic and zwitterionic) surfactants suitable for use in pharmaceutical dosage forms. Such surfactants include, for example, polyethoxylated fatty acids and its derivatives, e.g. polyethylene glycol 400 distearate, polyethylene glycol - 20 dioleate, polyethylene glycol 4 mono dilaurate, polyethylene glycol - 20 glyceryl stearate; alcohol - oil transesterification products, e.g. polyethylene glycol - 6 corn oil; polyglycerized fatty acids, e.g. polyglyceryl - 6 pentaoleate; propylene glycol fatty acid esters, e.g. propylene glycol monocaprylate; mono and diglycerides, e.g., glyceryl ricinoleate; sterol and sterol derivatives; sorbitan fatty acid esters and its derivatives, e.g. polyethylene glycol - 20 sorbitan monooleate, sorbitan monolaurate; polyethylene glycol alkyl ether or phenols, e.g. polyethylene glycol - 20 cetyl ether, polyethylene glycol -10 -100 nonyl phenol; sugar esters, e.g., sucrose monopalmitate; polyoxyethylene - polyoxypropylene block copolymers letdown as 'poloxamer"; ionic surfactants, e.g., sodium caproate, sodium glycocholate, soy lecithin, sodium stearyl fumarate, propylene glycol alginate, octyl sulfosuccinate disodium, palmitoyl carnitine; and the like.
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Suitable lubricants/glidants include, for example, colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and the like.
Cushioning agents may comprise one or more of polyethylene glycol, colloidal silicon dioxide or mixtures thereof.
Coloring agents include any FDA approved colors for oral use.
The tablet dosage form may optionally be coated with one or more functional and/or non-functional layers comprising film-forming polymers, if desired, for eg. Opadry.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention.
The example mentioned below demonstrates some illustrative procedures for preparing the controlled-release multiple unit formulation as described herein. The example is provided to illustrate particular aspect of the disclosure and do not limit the scope of the present invention.
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- Example 1

Ingredients % w/w
Inert core
Colloidal Silicone Dioxide 1.56
Ethyl Cellulose Dispersion 1.64
Drug layered/loaded inert cores
Metoprolol succinate 15.22
Polivinylpyrrolidone 0.76
Dichloromethane q.s
Ethanol 99.5%v/v q.s
Purified water q.s
Functionally coated multiple units
Ethylcellulose 6.29
Hydroxypropyl methylcellulose 1.48
Acetyltributyl citrate 0.86
Dichloromethane q.s
Isopropyl alcohol q.s
Seal coated multiple units
Hydroxypropyl methylcellulose 1.32
Acetyltributyl citrate 0.07
Isopropyl alcohol q.s
Dichloromethane q.s
Compression
Microcrystalline Cellulose 53.49
Hydroxypropyl cellulose 6.41
Polyethylene glycol 6.41
Sodium stearyl fumarate 0.64
Film coating
Opadry 3.85
Purified water q.s
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Process:
(A) Preparation of inert core:
1. Colloidal silicone dioxide was blended/mixed with ethyl cellulose.
2. Material of step (1) was dried to get the granules of desired bulk density.
(B) Preparation of drug loaded/layered inert cores:
1. Metoprolol succinate was dissolved/dispersed in mixture of Dicholoromethane, ethanol and purified water.
2. Material of step (1) was loaded/layered on the inert cores.
(C) Functional coating of multiple units of metoprolol succinate:
1. Ethyl cellulose, hydroxypropyl methylcellulose and acetyltributyl citrate was dissolved/dispersed in mixture of isopropyl alcohol and dichloromethane.
2. Drug loaded multiple units of step (B) were coated with material of step
(1)-
(D) Seal coating of multiple units:
1. Hydroxypropyl methylcellulose was dissolved/dispersed in mixture of isopropyl alcohol and acetyltributyl citrate.
2. Dichloromethane was added to material of step (1).
3. Functional coated multiple units of step (C) were coated with the material of step (2).
(E) Compression:
1. Functionally coated multiple units were blended/mixed with microcrystalline Cellulose, polyethylene glycol and hydroxypropyl cellulose.
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2. Material of step (1) was lubricated with sodium stearyl fumarate.
3. Material of step (2) was compressed.
The controlled release multiple unit formulation prepared by the above process was further coated with opadry.
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We Claim:
1. A controlled release multiple unit formulation comprising:
a) a water-insoluble inert core comprising a combination of colloidal silicon dioxide and ethyl cellulose,
b) one or more drug layers comprising the pharmaceutically active ingredient, and
c) one or more polymeric coatings surrounding the drug layer,
wherein the water-insoluble inert core has a bulk density from about 0.3 to about 0.7.
2. A controlled release multiple unit formulation comprising:
a) a water-insoluble inert core comprising a combination of colloidal silicon dioxide and ethyl cellulose,
b) one or more drug layers comprising the pharmaceutically active ingredient, and
c) one or more polymeric coatings comprising one or more water soluble polymers and water insoluble polymers or mixtures surrounding the drug layer,
wherein the water-insoluble inert core has a bulk density from about 0.3 to about 0.7.
3. The formulation of claim 1 or 2 , wherein the pharmaceutically active
ingredient comprises one or more of sedatives, antacids, analgesics, non¬
steroidal anti-inflammatory agents, coronary vasodilators, peripheral and
cerebral vasodilators, anti infectives, antibiotics, antiviral agents, antiparasitic
agents, anticancer agents, anxiolytics, neuroleptics, central nervous system
stimulants, antidepressants, antihistamines, antidiarrheal agents, laxatives,
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dietary supplements, immunodepressants, hypocholesterolemiants, hormones, enzymes, antispasmodics, antianginal agents or mixtures thereof.
4. The formulation of claim 3, wherein the pharmaceutically active ingredient
comprises one or more of one or more of lansoprazole, pantoprazole,
metoprolol, propranolol, diltiazem, tamsulosin, diclofenac, itraconazole,
venlafaxine, tolterodine and pharmaceutically acceptable salts or derivatives
thereof.
5. The formulation of claim 4, wherein the pharmaceutically active ingredient comprises metoprolot or pharmaceutically acceptable salts or derivatives thereof.
6. The formulation of claim 1, wherein the one or more polymeric coatings comprise one or more controlled release polymers selected from one or more water soluble polymers, one or more water insoluble polymer or mixtures thereof.
7. The formulation of claim 2 or claim 6, wherein the one or more water-soluble polymers comprises one or more of cellulose derivatives, gums, vinyl alcohol or vinylpyrrolidone based polymers and mixtures thereof.
8. The formulation of claim 2 or claim 6, wherein the one or more water-insoluble polymer comprises one or more of ethyl cellulose, hydroxypropylmethyl cellulose phthalate, cellulose acetate, cellulose acetate phthalate, co-polymers of acrylate or methacrylate having a low quaternary ammonium content poly vinyl acetate or mixtures thereof.
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9. The formulation of claim 1 or 2, further comprising one or more pharmaceutically inert excipients.
10. The formulation of claim 9, wherein one or more pharmaceutically inert excipients is selected from the group consisting of binders, diluents, surfactants, lubricants/glidants, cushioning agents, coloring agents or mixtures thereof.
11. The formulation of claim 1 or 2, further comprising one or more non functional coatings.
12. The formulation according to claim 1 or 2, wherein the multiple units are processed into a solid dosage form selected from a tablet, a capsule or a sachet.
13. A process for preparing a controlled release multiple unit formulation which comprises:

a) preparing a water-insoluble inert core by blending/mixing a combination of colloidal silicon dioxide and ethyl cellulose,
b) loading/layering the material of step (a) with one or more drug layers comprising the pharmaceutically active ingredient, and
c) coating the material of step (b) with one or more polymers,
wherein the water-insoluble inert core has a bulk density from about 0.3 to about 0.7.
14. The process for preparing a controlled release multiple unit formulation
according to claim 13, wherein the pharmaceutically active ingredient
comprises one or more of sedatives, antacids, analgesics, non- steroidal anti¬
inflammatory agents, coronary vasodilators, peripheral and cerebral
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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 or mixtures thereof.
15. The process for preparing a controlled release multiple unit formulation according to claim 14, wherein the pharmaceutically active ingredient comprises one or more of lansoprazole, pantoprazole, metoprolol, propranolol, diltiazem, tamsulosin, diclofenac, itraconazole, venlafaxine, tolterodine and pharmaceutically acceptable salts or derivatives thereof.
16. The process for preparing a controlled release multiple unit formulation according to claim 15, wherein the pharmaceutically active ingredient comprises metoprolol or pharmaceutically acceptable salts or derivatives thereof.
17. A controlled release multiple unit formulation comprising:

a) a water-insoluble inert core comprising a combination of colloidal silicon dioxide and ethyl cellulose,
b) one or more drug layers comprising metoprolol or pharmaceutically acceptable salts thereof, and
c) one or more polymeric coatings surrounding the drug layer,
wherein the water-insoluble inert core has a bulk density from about 0.3 to
about 0.7,
which is obtained by the process according to claim 12.
18. A controlled release multiple unit formulation substantially as herein
described and illustrated with respect to the examples.
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19. The process for preparing a controlled release multiple unit formulation substantially as herein described and illustrated with respect to the examples.
Dated this 23rd day of January 2009

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