Technical Field of the Invention
The present invention relates to a controlled release multiple units and process for the preparation thereof.
Backqround of the Invention
An oral dosage form is the preferred route of administration of pharmaceutical compounds because it provides easy, low cost administration. However, patient compliance becomes an important factor to consider in conjunction with oral administration of a pharmaceutical compound, especially if the compound must be taken three or four times a day. To maximize patient compliance, one attempts to reduce the frequency of dosing to attain effective therapy, while at the same time provide an oral dosage form which is palatable to the patient.
One method of accomplishing this goal is the use of controlled release formulations which have been extensively described in the prior art. The intention of controlled release formulations is to provide an extended duration of the pharmacological response after administration of the dosage form, than is ordinarily experienced after the administration of an immediate release dosage form. The purpose of these formulations is to provide a constant concentration of the active substance in body fluids for a certain time period. However, the demand on controlled release dosage forms is immense, the maximal therapeutic effect is to be reached using a minimum amount of active substance with reduced frequency of dosing and the degree of side effects, as well as inter and intra individual effect variations. The dosage form could be single unit or multiple unit dosage form.
Single unit controlled release dosage forms of drugs have known disadvantages. Such dosage forms either pass undisintegrated through the gastrointestinal tract or release al the drug in a burst (dose dumping). These dosage forms are dependent upon gastric emptying rates and transit times and are also associated with a lot of intra and inter-individual variations.
Multiple unit dosage forms comprise a multiplicity of individual units contained within a
rapid dissolving capsule, or compressed into a tablet, and soon after ingestion upon its dissolution are available as individual units in the G.I.T.
Several advantages with multiple unit dosage forms comprising a large number of small units have been described in the literature. It is, for example, possible to obtain a reproducible emptying of the units from the stomach into the small intestine when the particles are less than 1-2 mm. Dispersion over a large area in the gastrointestinal tract can give a more reproducible time for the passage, which is of advantage for the absorption process. In addition a multiple unit preparation is preferable to one single drug unit as the dose is spread out in the intestine. The risk of local irritation and accumulation of several doses due to constriction in the alimentary canal are also considered to be lower.
A further advantage with a multiple unit preparation is that it may be divided into smaller portions all having the same absorption properties. This makes it possible to obtain a greater flexibility in selecting the size of the dose.
US 6,911,217 describes bead comprising (i) a core unit of a substantially water-soluble or water-swellable inert material, (ii) a first layer on the core unit of a substantially water-insoluble polymer, (iii) a second layer covering the first layer and containing an active ingredient, and (iv) a third layer of polymer on the second layer effective for controlled release of the active ingredient, wherein the first layer is adapted to control water penetration into the core. This formulation has substantially reduced lag phase.
US 4,927,640 and 5,246,714 describe controlled release insoluble beads coated with a membrane controlling drug release. Examples of insoluble inert material used are silicon dioxide, glass, or plastic resin particles. The core material have a standardized size and shape, preferably spherical with an even surface with size of 0.15 - 0.25mm. The preparation has several advantages, e.g. the particles contain a high percentage of active ingredient and are not contaminated by soluble inert compounds, which is the case, when cores of e.g. lactose or sugar are covered by a therapeutically active compound. By using small dense particles of e.g. silicon dioxide as the core material, it is possible to obtain highly concentrated beads (granules) of the active compound which is an advantage for high dosage preparations, e.g. magnesium chloride.
US 5,783,215 describes the multiple unit dose preparation capable of withstanding the mechanical stress, i.e. during compaction. This has been done by using inert and non-soluble cores of glass or sand particles or soluble cores such as sugar spheres capable of withstanding mechanical stress, in combination with a plasticizing layer. The active substance is dispersed in a solution of the hydrophilic polymer and applied to the core, which is again covered with controlled release membrane. These beads have excellent mechanical and release characteristics.
In WO 95/34291 it was described how pellets capable of being coated using a fluidized bed technique could be produced if the mixture being spray-dried contained a binder and an inert particulate carrier material, for example a calcium salt such as calcium carbonate or a calcium phosphate. The spray-dried pellets described in W095/34291 however are still relatively fragile and there still exists a need for pellets that are more robust.
U.S. Pat. No. US 4,713,248 and US 4,716,041 assigned to Kjornaes, et al describe controlled release multiple-units containing active substance and coated with substantially water-insoluble, but water-diffusible controlled release coatings. The coating possesses a sufficient plastic deformability to result in no significant changes in the release characteristics of compressed coated units relative to non-compressed coated units.
US 5,283,065 describes controlled release pharmaceutical compositions in oral dosage units comprising blends of active spherical granules and compressible spherical granules, which may or may not contain active medicament, formed into tablets. The tabletted oral dosage units provide excellent controlled release of the active medicament, particularly effective when comprised of relatively low dosage ranges of active medicament. Additionally, they can be stored for prolonged periods of time at a wide range of temperatures and humidities while retaining their potency and controlled release properties.
Regardless of several advantages found in the above mentioned prior art controlled release formulations, the insoluble core used in these formulations lack the custom based size ranges, which is generally required in regulating the drug release from the
formulations. Further the process of preparing involves time-consuming methods, in addition to being expensive.
Thus, there remains a need for improved cores for controlled release formulations that are more robust in nature, having different size ranges and relatively involving inexpensive process.
Summary of the invention
In one general aspect there is provided a controlled release multiple unit formulation for oral administration that will provide a therapeutically effective blood concentration level of active ingredient for a sustained period of time up to at least twelve hours.
In one aspect controlled release multiple unit formulation is provided in unit dosage form comprising:
(i) a inert core unit of ethyl cellulose and optionally one or more water-soluble or
water-swellable excipient(s), (ii) a layer of active ingredient on the surface of the inert core, comprising one or
more hydrophilic polymers, (iii) a polymeric layer over the active layer, effective for controlling or modifying the release of active ingredient.
The amount of water-soluble or water-swellable excipient(s) is about 0.1 to 80% w/w calculated on the total weight of the inert core.
Embodiments of the controlled release multiple unit formulation may include one or more of the following features. For example, a seal-coat may be applied over the active ingredient layer or over the polymeric layer with one or more layers of water-soluble or water-insoluble polymer.
The inert core units comprising ethylcellulose and one or more water-soluble or water-swellable excipient(s) can be formulated as a plurality of discrete or aggregated particles, pellets, bead or granules of ethyl cellulose. The process for preparing the unit can be accomplished by blending ethyl cellulose and other water-soluble or water-swellable excipient(s) and granulating with a dispersion of ethyl cellulose or in a
suitable solvent, followed by drying and sieving; or any processes known in the art, such as extrusion and marumerization or spheronization; rotogranulation; peptization; micropelletization, etc.
The solvents may be one or more of water, ketones, such as acetone; alcohols, such as methanol, ethanol, isopropyl alcohol; chlorinated hydrocarbons, such as methylene chloride or mixtures thereof.
In another one aspect of the above embodiments, the active ingredient may also be included in the core. The core containing the active ingredient may be prepared by blending the active ingredient, ethyl cellulose and other water-soluble or water-swellable excipient(s) and granulating with a dispersion of ethyl cellulose or in a suitable solvent followed by sieving; extrusion and marumerization or spheronization; rotogranulation; peptization; micropelletization, etc.
Embodiments may include an additional layer containing the active ingredient over the surface of the core. The active may be similar to that present in the core or different.
The active ingredient(s) may be selected from the therapeutic category of antiulcers, analgesics, antihypertensives, antibiotics, antipsychotics, anticancer agents, antimuscarinics, diuretics, antimigraines, antivirals, anti-inflammatory agents, sedatives, antidiabetics, antidepressants, antihistaminics, antiparasitics, antiepileptics, lipid lowering drugs, or mixtures thereof.
Embodiments for hydrophilic polymers may include one or more starch, gums, alginates, polyvinylprrolidone, polyethylene glycol, acrylic acid derivatives, cellulose derivatives or mixtures thereof.
The polymeric layer over the active layer meant for controlling or modifying the drug release can be a pH independent or pH dependent.
The pH independent polymers may be selected from any such pharmaceutically acceptable polymers, which can control the rate of release of active ingredient, i.e. cellulose derivatives, starch, gums, alginates, acrylic acid derivatives, carbohydrate
based polymers or mixtures thereof. Particularly suitable are cellulosic derivatives such as ethyl cellulose.
The pH dependent polymers can be the enteric polymers and may be selected from any such pharmaceutically acceptable enteric polymers, which would facilitate erosion and breakdown of the pellets in the pH of the lower Gl tract. These enteric polymers may be selected from the group consisting of cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, and additional cellulose ether phthalates, any or the acrylic acid derivates phthalates (available commercially as Eudragits), shellac, zein, or mixtures thereof.
In another aspect, a process for preparing controlled release multiple unit formulation system, comprises the steps of:
(i) preparing a inert core unit of ethyl cellulose and optionally one or more water-soluble or water-swellable excipient(s); (ii) layering active ingredient onto the surface of the inert core, comprising one or
more hydrophilic polymers; (iii) applying a polymeric layer onto the active layer, effective for controlling or modifying the release of active ingredient.
In addition to the active ingredient, the units may optionally include other excipients, which act in one or more capacities as diluents, binders, lubricants, glidants, colorants or flavoring agents.
The multiple units may optionally include a non-functional coating over the polymeric layer. The units can be put into a capsule or compressed into a tablet dosage form.
Other features, objects and advantages of the present invention will become apparent from the description and claims. It should be understood however, that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various modifications within the spirit and scope of invention will become apparent to those skilled in the art in light of the description and examples.
Detailed Description of the Invention
As described in detail herein, the inventors have developed a controlled release multiple unit formulation for oral administration that are robust in nature and helps to achieve the constant release profile up to atleast about 12 hours time period.
The term "multiple unit formulation" indicates a pharmaceutical composition that includes one or more individual coated units contained in the formulation in such a form that the individual units will be available from the formulation upon disintegration of the formulation in the stomach. The multiple unit pharmaceutical composition or formulation may be a capsule or a tablet that disintegrates in the stomach to give individual units. The multiple units may be formulated as granules, pellets or beads.
The term "controlled release" as used herein includes any type of controlled release such as prolonged release, sustained release, modified release and extended release.
The inert core units comprising ethyl cellulose and one or more water-soluble or water-swellable excipient(s) can be formulated as a plurality of discrete or aggregated particles, pellets, bead or granules using a dispersion of ethyl cellulose (e.g. Surelease). The process for preparing the unit can be accomplished by processes known in the art, such as, simple granulation followed by sieving; extrusion and marumerization orspheronization; rotogranulation; peptization; micropelletization, etc.
For example the inert core units can be prepared extrusion-spheronization. The extrusion-spheronization process may include granulating the ethyl cellulose with or without water-soluble or water-swellable excipient(s) with a dispersion of ethyl cellulose (e.g. Surelease) to form a wet mass, passing the wet mass through an extruder to form extrudates, and spheronizing the extrudates.
The inert core may also be prepared by granulation. The granulation process may include wetting a dry mix of ethyl cellulose with or without water-soluble or water-swellable excipient(s) with a dispersion of ethyl cellulose, in a suitable solvent.
In addition to ethylcellulose the dispersion comprises fatty acids and medium chain triglycerides, in order to plasticize and stabilize the dispersion.
Fatty acids may be selected from the group consisting of fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral and vegetable oils, hydrogenated vegetable oils, waxes, sterols and mixtures thereof.
Suitable examples of fatty acids include, but are not limited to, stearic acid, erucic acid, palmitic acid, lauric acid, oleic acid and behenic acid; alkali metal salts of these fatty acids; sulfates of higher alcohols such as stearyl alcohol, oleyl alcohol and mixtures thereof.
Triglycerides may be selected from the group consisting of pharmaceutically acceptable oil, hydrogenated oil, partially hydrogenated oil, a medium chain triglyceride, a long chain triglyceride, a structured triglyceride, and mixtures thereof. Fractionated triglycerides, modified triglycerides, synthetic triglycerides, and mixtures of triglycerides are also within the scope of the invention. Preferred triglycerides include vegetable oils, fish oils, animal fats, hydrogenated vegetable oils, partially hydrogenated vegetable oils, medium and long-chain triglycerides, structured triglycerides and mixtures thereof.
Suitable examples of triglycerides include, but are limited to, almond oil, super refined almond oil, canola oil, castor oil, coconut oil, corn oil, super refined corn oil, cottonseed oil, super refined cottonseed oil, menhaden oil, super refined menhaden oil, olive oil, super refined olive oil, peanut oil, super refined peanut oil, safflower oil, super refined safflower oil, sesame oil, super refined sesame oil, shark liver oil, super refined shark liver oil, soybean oil, super refined soybean oil, wheat germ oil, super refined wheat germ oil, hydrogenated castor oil, castorwax, hydrogenated cottonseed oil, hydrogenated palm oil, hydrogenated soybean oil, hydrogenated vegetable oil, hydrogenated cottonseed and castor oil, partially hydrogenated soybean oil, partially soy and cottonseed oil, glyceryl tributyrate, glyceryl tricaproate, glyceryl tricaprylate, glyceryl tricaprate, glyceryl triundecanoate, glyceryl trilaurate, glyceryl trimyristate, glyceryl tripalmitate, glyceryl tristearate, glyceryl triarchidate, glyceryl trimyristoleate, glyceryl tripalmitoleate, glyceryl trioleate, glyceryl trilinoleate, glyceryl trilinolenate, glyceryl tricaprylate/caprate, commercially available as Captex 300; Captex 355; Miglyol 810; Miglyol 812, glyceryl tricaprylate/caprate/laurate, commercially available as Captex 350, glyceryl tricaprylate/caprate/linoleate, commercially available as Captex 810; Miglyol 818 glyceryl tricaprylate/caprate/stearate Softisan 378; glyceryl tricaprylate/laurate/stearate, glyceryl 1,2-caprylate-3-linoleate, glyceryl 1,2-caprate-3-
stearate, glyceryl 1,2-laurate-3-myristate, glyceryl 1,2-myristate-3-laurate, glyceryl 1,3-palmitate-2-butyrate, glyceryl 1,3-stearate-2-caprate, glyceryl 1,2-linoleate-3-caprylate and mixtures thereof.
To emulsify the ethylcellulose and stabilize the dispersed particles, the fatty acid should be converted to salt form, which is done by adding ionizing agent.
Ionizing agent can be any pharmaceutically acceptable base capable of deprotonating the ionizable functional groups of the ionizable fatty acids or triglycerides. Suitable examples include, but are not limited to, amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, and the like. Also suitable are bases which are salts of a pharmaceutically acceptable acid, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like. Salts of polyprotic acids, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used. When the base is a salt, the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, and the like. Preferred cations include sodium, potassium, lithium, magnesium, calcium and ammonium.
The ethyl cellulose used to prepare the inert core could be of any grade or viscosity. The inert core of ethyl cellulose and one or more water-soluble or water-swellable excipient(s) can also be prepared by blending ethyl cellulose and one or more water-soluble or water-swellable excipient(s) with the mixture of fatty acids, triglycerides, water and with or without ionizing agents, and preparing the blend into inert units by processes known in the art, such as, simple granulation followed by sieving; extrusion
and marumerization or spheronization; rotogranulation; peptization; micropelletization, etc.
The active ingredients may also be included in the core. The core containing the active ingredient may be prepared by blending the active ingredient, ethyl cellulose, with or without water-soluble or water-swellable excipient(s) and granulating with a dispersion of ethyl cellulose or in a suitable solvent, followed by sieving; extrusion and marumerization or spheronization; rotogranulation; peptization; micropelletization, etc. Embodiments may include an additional layer containing the active ingredient over the surface of the core. The active may be similar to that present in the core or different.
Suitable solvents may include one or more of water, ketones, such as acetone; alcohols, such as methanol, ethanol, isopropyl alcohol; chlorinated hydrocarbons, such as methylene chloride and mixtures thereof.
The water-soluble or water-swellable excipient(s) may be one or more of water soluble salts of inorganic acids, water soluble salts of organic acids, non ionic organic compounds having high water solubility, water-soluble amino acids, polymers such as starch, gums, alginates, acrylic acid derivatives, polyvinylpyrrolidone, polyalkaylene glycol, polyethylene glycol, gelatin, polyvinyl alcohol, urea and urea derivatives, cellulose derivatives like hydroxypropyl cellulose or hydroxypropyl methylcellulose.
The active ingredient layered on to the inert core may include one or more of antidepressants, antidiabetics, antiulcers, analgesics (opioids and non-opioids), antihypertensives, antibiotics, antipsychotics, antineoplastics, antimuscarinics, diuretics, antimigraine agents, antivirals, anti-inflammatory agents, sedatives, antihistaminics, antiparasitic agents, antiepileptics, lipid lowering agents and mixtures thereof.
Suitable examples of active ingredient include, but are not limited to, enalapril, captopril, benazepril, lisinopril, ranitidine, famotidine, ranitidine bismuth citrate, diltiazem, propranolol, verapamil, nifedipine, acyclovir, ciprofloxacin, tolterodine, tamsulosin, simvastatin, atorvastatin, lovastatin, venlafaxine, citalopram, paroxetine, selegiline, midazolam, fluoxetine, acarbose, buspirone, nimesulide, tramadol, fentanyl, oxycodone, captopril, nabumetone, glimepiride, glipizide, etodolac, nefazodone and their pharmaceutical^ acceptable salts.
Particularly the active ingredient is an antimuscarinic agent, and more particularly the active ingredient used is tolterodine.
The hydrophilic polymer used along with the active ingredient layer gives plastic properties to the controlled release units and even acts as a binder.
Suitable hydrophilic polymers may include, but are not limited to, pharmaceutically
acceptable materials like starch, gums, alginates, polysaccharides, polyvinylprrolidone,
polyethylene glycol, acrylic acid derivatives, and cellulose derivatives like hydroxypropyl
cellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose,
hydroxymethylcellulose, carboxymethylcellulose, methylcellulose, sodium carboxy methylcellulose and mixtures thereof.
The core particles may be coated with the active substance dispersed in the hydrophilic polymers by powder layering technique, i.e. the active substance is applied to the core in dry form as powder. The polymer is sprayed onto the mixture of cores and active substance as a solution in such a way that solvent is evaporated, and the polymer is applied to the cores together with the active substance, i.e. forming a homogenous dispersion. Alternatively, the active substance may be dispersed/dissolved in polymeric solution and coated on the cores.
The solvents used for making a solution, dispersion, or suspension may be selected from, one or more of methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water and mixtures thereof. In general, the solvent should adequately dissolve, disperse, or suspend the active ingredient and hydrophilic polymers used.
The coating may be done using a conventional coating pan, a spray coater, a rotating perforated pan, or an automated system, such as a centrifugal fluidizing (CF) granulator, a fluidized bed process, or any other suitably automated coating equipment.
The polymeric layer controlling or modifying the drug release can be a pH independent or pH dependent.
The pH independent polymers may be selected from any such pharmaceutically acceptable polymers, which can control the rate of release of active ingredient, i.e.
cellulose derivatives, starch, gums, alginates, acrylic acid derivatives and carbohydrate based polymers. Particularly suitable are cellulosic derivatives such as ethyl cellulose.
Ethyl cellulose is available in grades having different viscosities. Water-based dispersions of ethyl cellulose is suitable and is commercially available as Surelease®. Ethyl cellulose can be used alone or in a combination with e.g. a water soluble polymer such as hydroxypropylmethyl cellulose to adjust the permeability of the coating layer. Even the copolymerisate of acrylic and methacrylic acid esters or other film-formers mentioned herein may be used in combination with a water-soluble polymer.
The pH dependent polymers can be the enteric polymers and may be selected from any such pharmaceutically acceptable enteric polymers, which would facilitate erosion and breakdown of the pellets in the pH of the lower Gl tract. These enteric polymers may be selected from the group consisting of cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, and additional cellulose ether phthalates, any or the acrylic acid derivates phthalates (available commercially as Eudragits), shellac, zein, or mixtures thereof.
In addition to the active ingredient, rate controlling or enteric polymers, the units may optionally include other pharmaceutically acceptable excipients, which act in one or more capacities as fillers, binders, lubricants, glidants, plasticizers, colorants or flavoring agents.
Suitable examples of fillers include, but are not limited to, corn starch, lactose, white sugar, sucrose, sugar compressible, sugar confectioners, glucose, sorbitol, calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose, fructose, kaolin, lactitol, mannitol, sorbitol, starch, starch pregelatinized, sucrose, and mixtures thereof.
Examples of binders include, but are not limited to, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, poloxamer, gelatin, gum Arabic, ethyl cellulose, polyvinyl alcohol, pullutan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and mixtures thereof.
Examples of lubricants and glidants include, but are not limited to, colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acids, microcrystalline wax, yellow beeswax, white beeswax, and mixtures thereof.
Examples of plasticizers include, but are not limited to, polyethylene glycol, triethylene glycol, oleic acid, ethyleneglycol monooleate, triethyl citrate, triacetin, diethyl phthalate, glyceryl monostearate, acetyl triethylcitrae, castor oil, dibutyl sebacate and the like.
The coloring agents of the present invention may be selected from any FDA approved color for oral use.
The multiple units may optionally include a non-functional coating using film forming agents over the polymeric layer.
The units can be filled into capsules or compressed into tablets that disintegrate in the stomach to make available a multiplicity of individually coated units.
The following examples illustrate various aspects of the present inventions. These examples are for illustration only and do not limit the scope of the inventions.
Preparation of Inert core Example 1:
(TABLE REMOVED)

Ethyl cellulose was granulated with aqueous dispersion of ethyl cellulose (Surelease®, comprising mixture of Ethylcellulose, Ammonium hydroxide, Medium chain triglycerides and Oleic acid).
The wet mass was extruded, spheronized, dried and sieved to get inert core of desired particle size.
Example 2:
(TABLE REMOVED)

1. Ethyl cellulose and microcrystalline cellulose were granulated with aqueous
dispersion of ethyl cellulose (Surelease®, comprising mixture of Ethylcellulose,
Ammonium hydroxide, Medium chain triglycerides and Oleic acid).
2. The wet mass of step 1 is extruded, spheronized, dried and sieved to get inert
core of desired particle size.
Example 3:
(TABLE REMOVED)

1. Ethyl cellulose and sugar were granulated with aqueous dispersion of ethyl
cellulose (Surelease®, comprising mixture of Ethylcellulose, Ammonium
hydroxide, Medium chain triglycerides and Oleic acid)..
2. The wet mass of step 1 is extruded, spheronized, dried and sieved to get
inert core of desired particle size.
Example 4:
(TABLE REMOVED)

1. Ethyl cellulose, microcrystalline cellulose and lactose were granulated with
aqueous dispersion of ethyl cellulose (Surelease®, comprising mixture of
Ethylcellulose, Ammonium hydroxide, Medium chain triglycerides and Oleic
acid).
2. The wet mass of step 1 is extruded, spheronized, dried and sieved to get
inert core of desired particle size.
(TABLE REMOVED)

1. Ethyl cellulose, sugar, starch and talc were granulated with mixture of
isopropyl alcohol and water.
2. The wet mass of step 1 is extruded, spheronized, dried and sieved to get
inert core of desired particle size.
(TABLE REMOVED)

1. Ethyl cellulose, oleic acid and medium chain triglycerides were mixed well
and granulated with ammonium hydroxide and water.
2. The wet mass of step 1 is extruded, spheronized, dried and sieved to get
inert core of desired particle size.
Example 7:
Preparation of Controlled Release Tolterodine multiple units using inert cores
of examples 1-6
(TABLE REMOVED)

Tolterodine tartrate, hydroxypropyl methylcellulose and water were dissolved in water to form a solution.
The solution of step 1 is sprayed over the inert cores using fluidized bed coater.
The tolterodine layered cores of step 2 were dried in an oven or in a fluidized bed.
The tolterodine layered cores were coated with the coating composition containing ethyl cellulose, hydroxypropyl methylcellulose, a plasticizer to a weight build up of about 7.1 %.

WE CLAIM:
1. A controlled release multiple unit formulation in unit dosage form comprising:
(i) a inert core unit of ethyl cellulose and optionally one or more water-soluble or
water-swellable excipient(s), (ii) a layer of active ingredient on the surface of the inert core, comprising one or
more hydrophilic polymers, (iii) a polymeric layer over the active layer, effective for controlling or modifying
the release of active ingredient.
2. The formulation according to claim 1 wherein the inert core additionally comprises active ingredient in the core.
3. The formulation according to claim 1 or 2 wherein the inert core units are formulated by blending ethyl cellulose and water-soluble or water-swellable excipient(s) with a dispersion of ethyl cellulose in a suitable solvent, followed by granulation and sieving; or extrusion and marumerization or spheronization; rotogranulation; pelletization; and micropelletization.
4. The formulation according to claim 1 or 2 wherein the inert core units are prepared by blending ethyl cellulose and one or more water-soluble or water-swellable excipient(s) with the mixture of fatty acids, triglycerides, water and with or without ionizing agents, followed by granulation and sieving; or extrusion and marumerization or spheronization; rotogranulation; pelletization; and micropelletization.
5. The formulation according to claim 1 or 2 wherein the water-soluble or water-swellable excipient(s) comprises one or more of water soluble salts of inorganic acids, water soluble salts of organic acids, non ionic organic compounds having high water solubility, water-soluble amino acids, polymers such as starch, gums, alginates, acrylic acid derivatives, polyvinylpyrrolidone, polyalkaylene glycol, polyethylene glycol, gelatin, polyvinyl alcohol, urea and urea derivatives, cellulose derivatives like hydroxypropyl cellulose and hydroxypropyl methylcellulose.
6. The formulation according to claim 1 or 2 wherein the active ingredient comprises one or more of therapeutic agents of antiulcer, analgesic, antihypertensive, antibiotic, antipsychotic, anticancer, antimuscarinic, diuretic, antimigraine, antiviral, antiinflammatory, sedatives, antidiabetic, antidepressant, antihistaminic, antiparasitic, antiepileptic and lipid lowering drugs.
7. The formulation according to claim 1 wherein hydrophilic polymers comprises one or more of starch, gums, alginates, polysaccharides, polyvinylprrolidone, polyethylene glycol, acrylic acid derivatives, and cellulose derivatives like hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, carboxymethylcellulose, methylcellulose, sodium carboxy methylcellulose and mixtures thereof.
8. The formulation according to claim 1 wherein the polymeric layer for controlling or modifying the drug release comprises pH independent polymers and pH dependent polymers.
9. The formulation according to claim 1 wherein the formulation further comprises one or more pharmaceutically acceptable excipients of fillers, binders, lubricants, glidants, plasticizers, colorants and flavoring agents.
10.A process for preparing controlled release multiple unit formulation system, comprising steps of: (i) preparing a inert core unit of ethyl cellulose and optionally one or more water-soluble or water-swellable excipient(s); (ii) layering active ingredient onto the surface of the inert core, comprising one or
more hydrophilic polymers; (iii) applying a polymeric layer onto the active layer, effective for controlling or modifying the release of active ingredient.