Pharmaceutical composition

Abstract

The invention relates to an oral pharmaceutical composition comprising coated particles of a complex of at least one active agent with an ion-exchange resin, wherein said particles are coated with a bioadhesive coating layer comprising at least one bioadhesive material. The invention also relates to a process for preparing the oral pharmaceutical composition.

Claims

1. Oral pharmaceutical composition comprising coated particles of a complex of at least one active agent with an ion-exchange resin, wherein said particles are coated with a bioadhesive coating layer comprising at least one bioadhesive material and wherein the coated particles further comprise an enteric coating layer which is placed over the bioadhesive layer and comprises at least one enteric coating material, and at least a portion of the coated particles further comprises a release modifying coating layer which is placed between the complex and the bioadhesive layer and comprises at least one release modifying material, wherein the bioadhesive material is selected from the group consisting of homopolymers of acrylic acid or an alkylacrylic acid, crosslinked homopolymers of acrylic acid or an alkylacrylic acid, copolymers of acrylic acid or methacrylic acid with a (C.sub.10-C.sub.30)alkyl acrylate, and crosslinked copolymers of acrylic or methacrylic acid with a (C.sub.10-30)alkyl acrylate.

2. The composition according to claim 1, wherein the bioadhesive material has a weight average molecular weight of at least about 10,000 Daltons.

3. The composition according to claim 1, wherein the enteric coating material is selected from the group consisting of anionic cellulose derivatives, anionic vinyl resins and anionic acrylic resins.

4. The composition according to claim 3, wherein the enteric coating material is selected from the group consisting of cellulose acetate phthalate, cellulose diacetate phthalate, cellulose triacetate phthalate, methylcellulose phthalate, hydroxypropyl cellulose phthalate, hydroxypropyl methylcellulose phthalate, cellulose acetate hexahydrophthalate, hydroxypropyl methylcellulose hexahydrophthalate, pharmaceutically acceptable salts thereof, polyvinyl acetate phthalate, poly(methacrylic acid-co-ethylacrylate) and poly(methacrylic acid-co-methylmethacrylate).

5. The composition according to claim 1, wherein the release modifying material is selected from delayed release materials and/or controlled release materials.

6. The composition according to claim 5, wherein the release modifying material is selected from the group consisting of ethyl cellulose, methyl cellulose, hydroxypropylmethylcellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, poly(methacrylic acid-co-ethylacrylate), poly(methacrylic acid-co-methylmethacrylate), polyvinylchloride, polyvinyl acetate phthalate, poly(vinylpyrrolidone-co-vinylacetate), silicone elastomers, shellac, zein, rosin esters and mixtures thereof.

7. The composition according to claim 6, wherein the release modifying material is selected from the group consisting of methyl cellulose, ethyl cellulose and mixtures thereof.

8. The composition according to claim 1 comprising at least two groups of coated particles differing in the amount and/or the composition of release modifying material.

9. The composition according to claim 1, wherein the ion exchange resin is selected from the group consisting of polymers of acrylic acid, copolymers of acrylic acid, polymers of methacrylic acid, copolymers of methacrylic acid, polymers of styrene modified with ionic groups, copolymers of styrene modified with ionic groups, cellulose modified with ionic groups, dextran modified with ionic groups and silica gel modified with ionic groups, wherein said ionic groups are selected from sulfonate groups, tertiary amine groups and quaternary ammonium groups.

10. The composition according to claim 1, wherein the ion exchange resin is a crosslinked sulfonated copolymer of styrene and divinylbenzene.

11. The composition according to claim 1, wherein the average particle size of the particles of the complex of the active agent with the ion-exchange resin is about 10 to about 3000 μm.

12. The composition according to claim 1, wherein the average particle size of the coated particles is about 20 to about 5000 μm.

13. The composition according to claim 1, wherein the coated particles have a specific gravity in the range from 1.1 to 2.0.

14. The composition according to claim 1, wherein the coated particles exhibit a specific surface area in the range of from about 1 to 200 m.sup.2/g.

15. The composition according to claim 1, wherein the active agent is selected from the group consisting of ondansetron, granisetron, tropisetron, dolasetron, palonosetron, aprepitant, sulfasalazine, doxazosin, atenolol, bisoprolol, hydrochlorothiazide, carvedilol, amlodipine, felodipine, nifedipine, verapamil, diltiazem, enalapril, lisinopril, ramipril, quinapril, cilazapril, fosinopril, trandolapril, losartan, valsartan, simvastatin, lovastatin, fluvastatin, atorvastatin, rosuvastatin, gemfibrozil, fenofibrate, cholestyramine, oxybutynin, propiverine, solifenacin, trospium, darifenacin, sildenafil, phentolamine, tamsulosin, finasteride, cyclophosphamide, chlorambucil, melphalan, busulfan, lomustin, temozolomide, methotrexate, mercaptopurine, thioguanine, cladribine, fludarabine, cytarabine, 5-fluorouracil, gemcitabine, capecitabine, vinblastine, vincristine, vindesine, etoposide, paclitaxel, docetaxel, actinomycin D, doxorubicin, daunorubicin, epirubicin, idarubicin, mitoxantrone, bleo-mycin, mitomycin, cisplatin, carboplatin, oxaliplatin, procarbazine, rituximab, trastuzumab, cetuximab, bevacizumab, sunitinib, sorafenib, dasatinib, lapatinib, nilotinib, temsirolimus, amsacrine, asparaginase, hydroxyurea, estramustine, topotecan, irinotecan, imatinib, bortezomib, erlotinib, anagrelide, megestrol, tamoxifen, flutamide, nilutamide, bicalutamide, anastrazole, letrozole, exemestane, mycophenolate mofetil, sirolimus, everolimus, cyclosporine, tacrolimus, azathioprine, etidronic acid, clodronic acid, pamidronic acid, alendronic acid, tiludronic acid, ibandronic acid, risedronic acid, zoledronic acid, morphine, hydromorphone, oxycodone, pethidine, fentanyl, pentazocine, buprenorphine, tramadol, acetylsalicylic acid, metamizole, paracetamol, sumatriptan, methylphenobarbital, phenobarbital, primidone, phenytoin, ethosuximide, clonazepam, carbamazepine, oxcarbazepine, valproic acid, vigabatrin, progabide, tiagabine, sultiame, phenacemide, lamotrigine, felbamate, topiramate, gabapentin, pheneturide, levetiracetam, zonisamide, pregabalin, stiripentol, lacosamide, beclamide, trihexyphenidyl, biperiden, levodopa, carbidopa, benserazide, entacapone, amantadine, bromocriptine, pergolide, dihydroergocryptine, ropinirole, pramipexole, cabergoline, apomorphine, piribedil, rotigotine, selegiline, rasagiline, tolcapone, entacapone, budipine, levomepromazine, chlorpromazine, promazine, fluphenazine, perazine, haloperidol, sertindole, ziprazidone, zuclopenthixol, clozapine, olanzapine, quetiapine, loxapine, sulpiride, amisulpride, lithium, prothipendyl, risperidone, clotiapine, mosapramine, zotepine, aripiprazole, paliperidone, diazepam, alprazolam, meprobamate, flurazepam, nitrazepam, midazolam, zolpidem, clomipramine, amitriptyline, maprotiline, fluoxetine, citalopram, paroxetine, sertraline, alaproclate, fluvoxamine, etoperidon, escitalopram, mirtazapine, venlafaxine, methylphenidate, modafinil, neostigmine, pyridostigmine, disulfiram, naloxone, methadone, riluzole, abacavir, aciclovir, atropine, buspirone, caffeine, captopril, chloroquine, chlorphenamine, desipramine, diphenhydramine, disopyramide, doxepin, doxycycline, ephedrine, ergonovine, ethambutol, glucose, imipramine, ketorolac, ketoprofen, labetalol, levofloxacin, metoprolol, metronidazole, minocycline, misoprostol, phenazone, phenylalanine, prednisolone, primaquine, propranolol, quinidine, rosiglitazone, salicylic acid, theophylline, zidovudine, codeine, dextromethorphan, hydrocodone, hydralazine, metaproterenol, phenylpropanolamine, pseudoephedrine and mixtures thereof.

16. The composition according to claim 15, wherein the active agent is selected from the group consisting of levodopa, carbidopa, benserazide, entacapone and mixtures thereof.

17. The composition according to claim 15, wherein the active agent is selected from the group consisting of alendronate, olanzapine, risperidone and ropinirole.

18. The composition according to claim 1 comprising at least two groups of coated particles comprising different active agents.

19. The composition according to claim 1 further comprising an active agent, or a pharmaceutically acceptable salt or solvate thereof, outside the coated particles.

20. The composition according to claim 16 comprising levodopa and carbidopa or benserazide in a ratio of 20:1 to 1:1.

21. The composition according to claim 1, wherein the coated particles comprise (a) 1 to 50 wt. % of said at least one active agent; (b) 1 to 50 wt. % of said ion-exchange resin; (c) 1 to 50 wt. % of release modifying material; (d) 0.5 to 30 wt. % of said bioadhesive material; and (e) 1 to 80 wt. % of said enteric coating material; based on the total weight of the coated particles.

22. Process for preparing a composition according to claim 1, said process comprising the steps of: (i) contacting an active agent with an ion-exchange resin to obtain an active agent/ion exchange resin complex; (ii) coating the complex of step (i) with a coating layer comprising a release modifying material; (iii) coating the coated complex of step (ii) with a coating layer comprising a bioadhesive material; and (iv) coating the coated complex of step (iii) with a coating layer comprising an enteric coating material.

23. The composition according to claim 1, wherein the enteric coating layer is placed directly over the bioadhesive layer.

24. The composition according to claim 2, wherein the enteric coating layer is placed directly over the bioadhesive layer.

25. The composition according to claim 1, wherein the bioadhesive material is selected from the group consisting of homopolymers of acrylic acid, homopolymers of alkylacrylic acid, crosslinked homopolymers of acrylic acid and crosslinked homopolymers of alkylacrylic acid.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 shows the release of levodopa from 500 mg of the levodopa drug resin complex obtained in Example 1A dispersed in deionized water at room temperature under stirring with a magnetic stirrer. NaCl was added as follows: 9 min: 200 mg; 36 min: 700 mg; 52 min: 1200 mg; 61 min: 3300 mg.

(2) FIG. 2 shows the dissolution profile of coated LDRC obtained in Example 1B-1 in phosphate buffer (USP method #2, paddle rotation speed 50 rpm, 37° C., pH 5.5, ionic strength 0.075).

(3) FIG. 3 shows the dissolution profile of coated LDRC obtained in Example 1B-3 in phosphate buffer (USP method #2, paddle rotation speed 50 rpm, 37° C., pH 5.5, ionic strength 0.075)

(4) FIG. 4 shows the dissolution profiles of coated LDRC obtained in Examples 1B-2 to 1B-4 in phosphate buffer (USP method #2, paddle rotation speed 50 rpm, 37° C., pH 6.0, ionic strength 0.075).

(5) FIG. 5 shows the dissolution profile of coated LDRC obtained in Example 1C-3 in phosphate buffer (USP method #2, paddle rotation speed 50 rpm, 37° C., pH 6.0, ionic strength 0.075).

(6) FIG. 6 shows the dissolution profile of coated LDRC obtained in Example 1C-5 in phosphate buffer (USP method #2, paddle rotation speed 50 rpm, 37° C., pH 6.0, ionic strength 0.075).

(7) FIG. 7 shows the dissolution profiles of coated LDRC obtained in Examples 1D-2 to 1D-4 in phosphate buffer (USP method #2, paddle rotation speed 50 rpm, 37° C., dissolution medium 0-1 h: 0.1 N HCl, 1-12 h: phosphate buffer pH 6.25, ionic strength 0.075).

(8) FIG. 8 shows the dissolution profiles of coated LDRC obtained in Examples 1D-1 and 1D-4 in phosphate buffer (USP method #2, paddle rotation speed 50 rpm, 37° C., dissolution medium 0-1 h: 0.1 N HCl, 1-12 h: phosphate buffer pH 6.25, ionic strength 0.075).

(9) FIG. 9 shows the dissolution profiles of uncoated ropinirole drug resin complex (RoDRC) obtained in Example 2A and coated RoDRC obtained in Example 2D before and after sieving (USP method #2, paddle rotation speed 75 rpm, 37° C., dissolution medium 0-1 h: 500 ml 0.1 N HCl, 1-10 h: buffer mixture [500 ml 0.1 N HCl+500 ml phosphate buffer], pH 5.6, ionic strength 0.075).

(10) FIG. 10 shows the dissolution profile of coated alendronate drug resin complex (AlDRC) obtained in Example 3D (USP method #2, paddle rotation speed 75 rpm, 37° C., dissolution medium 1000 ml 0.1 M NaCl).

(11) FIG. 11 shows the dissolution profile of coated risperidone drug resin complex (RiDRC) obtained in Example 4D (USP method #2, paddle rotation speed 75 rpm, 37° C., dissolution medium 0-1 h: 500 ml 0.1 N HCl, 1-12 h: buffer mixture [500 ml 0.1 N HCl+500 ml phosphate buffer], pH 5.6, ionic strength 0.075).

(12) FIG. 12 shows the dissolution profile of coated olanzapine drug resin complex (OzDRC) obtained in Example 5D (USP method #2, paddle rotation speed 75 rpm, 37° C., dissolution medium 0-1 h: 500 ml 0.1 N HCl, 1-12 h: buffer mixture [500 ml 0.1 N HCl+500 ml phosphate buffer], pH 5.6, ionic strength 0.075; 10 g of NaCl was added after 10.5 h).

EXAMPLES

(13) Release of levodopa was measured spectrophotometrically at 280 nm.

Example 1

A) Preparation of Levodopa Drug Resin Complex (LDRC)

(14) 400 g of a sodium polystyrene sulfonate cation exchange resin crosslinked with divinylbenzene (125-400 mesh) were mixed with 1200 ml of deionized water under slow stirring for 1 h. The resin was allowed to settle and the water was decanted. Diluted HCl was prepared by adding 300 ml of conc. HCl to 1200 ml of deionized water and mixing. The resin was mixed with 250 ml of the diluted HCl for 30 min and then allowed to settle, the supernatant was decanted and this step was repeated until all of the diluted HCl had been used up. The resin was washed by mixing with 500 ml of deionized water for min, allowing the resin to settle, decanting the super-natant and repeating this step 8 times or until the supernatant was neutral to litmus paper.

(15) A mixture of 300 ml of ethanol and 300 ml of deionized water was added to the resin and 250 g of levodopa were added and treated with the resin for 4 h while mixing for 1 min every 30 min. The resin was allowed to settle overnight and then the supernatant was decanted. The resin was washed by mixing with 300 ml of a water/ethanol (3:2) mixture, allowing the resin to settle, decanting the supernatant and repeating this step until no levodopa crystals were visible under a microscope after evaporating the supernatant. The obtained levodopa drug resin complex was dried in a furnace at 60° C. Moisture content (LOD [loss on drying]): 5±0.5 wt. %, levodopa content (HPLC): 40±1 wt. %. The obtained complex was found to be stable against exposure to air at room temperature for at least 6 months.

(16) Ionic binding of levodopa in the complex was tested by adding increasing amounts of electrolyte (NaCl) to a slurry of LDRC in deionized water. Release of levodopa is shown in FIG. 1.

B) Coating with a Release Modifying Coating Layer

(17) TABLE-US-00001 Example 1B-1 1B-2 1B-3 1B-4 Release modifying material 20% 30% 40% 50% Drug resin complex (Example) 1A 1A 1A 1A Drug resin complex (g) 74 58 58 58 Coating dispersion Ethylcellulose (g) 20 Ethylcellulose (g) 124 212 290 (pre-plasticized, 20 wt % solids) Dibutyl sebacate (g) 4 Olive oil (g) 2 Ethanol 96 vol. % (g) 374 Deionized water (g) 83 141 193 Coating conditions Nozzle diameter (mm) 0.5 0.5 0.5 0.5 Fluidizing air pressure (bar) 0.2 0.2 0.2 0.2 Fluidizing air temperature (° C.) 50 75 75 75 Nozzle air pressure (bar) 2 1.5 1.5 1.5 Product temperature (° C.) 30 37 37 37 Pump speed (g/min) 2 2.5 2.5 2.5 Yield (g) 95 80 98 110 Moisture content (wt. %, LOD) 5 5 5 5 Levodopa content (wt. %, HPLC) 29 27 23 20

(18) Levodopa drug resin complex (Ldrc) was fluidized and sprayed with coating dispersion using a Mini-Glatt coating apparatus and dried in situ to 45-50° C. The product was sifted through a 40 mesh stainless steel screen. Microscopic examination revealed uniformly coated particles with moderate agglomeration. The coated products obtained in Examples 1B-2 to 1B-4 were further cured for 2 h at 60° C.

(19) Dissolution profiles of coated LDRC obtained in Examples 1B-1 and 1B-3 in phosphate buffer (USP method #2, paddle rotation speed 50 rpm, 37° C., pH 5.5, ionic strength 0.075) are shown in FIGS. 2 and 3. Dissolution profiles of coated LDRC obtained in Examples 1B-2 to 1B-4 in phosphate buffer (USP method #2, paddle rotation speed 50 rpm, 37° C., pH 6.0, ionic strength 0.075) are shown in FIG. 4.

C) Coating with a Bioadhesive Coating Layer

(20) TABLE-US-00002 Example 1C-1 1C-2 1C-3 1C-4 1C-5 Release modifying — 30% 40% 50% 40% material Bioadhesive material 5%  5%  5%  5%  10% Drug resin complex 1A 1B-2 1B-3 1B-4 1B-3 (Example) Drug resin complex (g) 57 57 57 57 54 Coating dispersion Carboxypolymethylene* 3 3 3 3 6 (g) Ethanol 96 vol. % (g) 197 197 197 197 194 Coating conditions Nozzle diameter (mm) 0.5 0.5 0.5 0.5 0.5 Fluidizing air pressure 0.15-0.7 0.15-0.7 0.15-0.7 0.15-0.7 0.15-0.7 (bar) Fluidizing air 50 50 50 50 65 temperature (° C.) Nozzle air pressure (bar) 1.5 1.5 1.5 1.5 1.5 Product temperature 37 37 37 37 35 (° C.) Pump speed (g/min) 3 3 3 3 2.5 Yield (g) 59 59 59 59 59 Moisture content (wt. %, 5.5 5.5 5.5 5.5 4.5 LOD) Levodopa content (wt. 38 26 21 19 20 %, HPLC) *High molecular weight polymer of acrylic acid crosslinked with allyl ethers and pentaerythritol

(21) Levodopa drug resin complex (LDRC) was fluidized and sprayed with coating dispersion using a Mini-Glatt coating apparatus and dried in situ to 50° C. The product was sifted through a mesh stainless steel screen. Microscopic examination revealed uniformly coated particles with moderate agglomeration.

(22) Dissolution profiles of coated LDRC obtained in Examples 1C-3 and 1C-5 in phosphate buffer (USP method #2, paddle rotation speed 50 rpm, 37° C., pH 6.0, ionic strength 0.075) are shown in FIGS. 5 and 6.

D) Coating with an Enteric Coating Layer

(23) TABLE-US-00003 Example 1D-1 1D-2 1D-3 1D-4 Release modifying material — 30% 40% 50% Bioadhesive material  5%  5%  5%  5% Amount of enteric coating mat. 40% 40% 40% 40% Drug resin complex (Example) 1C-1 1C-2 1C-3 1C-4 Drug resin complex (g) 58 58 58 58 Coating dispersion Methacrylic acid copolymer* (g) 35 35 35 35 Triethyl citrate (g) 3.5 3.5 3.5 3.5 Ethanol 96 vol. % (g) 300 300 300 300 Coating conditions Nozzle diameter (mm) 0.5 0.5 0.5 0.5 Fluidizing air pressure (bar) 0.4-0.6 0.4-0.6 0.4-0.6 0.4-0.6 Fluidizing air temperature (° C.) 60 60 60 60 Nozzle air pressure (bar) 1.5 1.5 1.5 1.5 Product temperature (° C.) 45 45 45 45 Pump speed (g/min) 3 3 3 3 Yield (g) 95 94 96 95 Moisture content (wt. %, LOD) 5.1 5.3 5.0 4.9 Levodopa content (wt. %, HPLC) 23 16 12 11 *Commercially available methacrylic acid copolymer with dispersing agents formulated for easy dispersion in water

(24) Levodopa drug resin complex (LDRC) was fluidized and sprayed with coating dispersion using a Mini-Glatt coating apparatus and dried in situ to 55° C. The product was sifted through a mesh stainless steel screen. Microscopic examination revealed uniformly coated particles with moderate agglomeration.

(25) Dissolution profiles of coated LDRC obtained in Examples 1D-2 to 1D-4 in phosphate buffer (USP method #2, paddle rotation speed 50 rpm, 37° C., dissolution medium 0-1 h: 0.1 N HCl, 1-12 h: phosphate buffer pH 6.25, ionic strength 0.075) are shown in FIG. 7. Dissolution profiles of coated LDRC obtained in Examples 1D-1 and 1D-4 in phosphate buffer (USP method #2, paddle rotation speed 50 rpm, 37° C., dissolution medium 0-1 h: 0.1 N HCl, 1-12 h: phosphate buffer pH 6.25, ionic strength 0.075) are shown in FIG. 8.

E) Hard Gelatin Capsules Comprising Levodopa and Carbidopa

(26) TABLE-US-00004 Example 1E-1 1E-2 LDRC from Example 1D-1 (mg) 218.0 130.0 LDRC from Example 1D-4 (mg) — 635.0 Carbidopa (mg) 12.5 25.0 Magnesium stearate or talcum (mg) 10.5 20.0 Total (mg) 241.0 810.0 Levodopa content (mg) 50.0 100.0 Carbidopa content (mg) 12.5 25.0

(27) One or more levodopa drug resin complexes were dry mixed with carbidopa and magnesium stearate or talcum as indicated. The obtained mixture was filled into hard gelatin capsules.

F) Tablet Comprising Levodopa and Carbidopa

(28) TABLE-US-00005 Example 1F LDRC from Example 1D-4 (mg) 909 Carbidopa (mg) 25 Sodium carboxymethylcellulose (mg) 50 Maize starch (mg) 25 Talc (mg) 25 Magnesium stearate (mg) 41 Total (mg) 1075 Levodopa content (mg) 100 Carbidopa content (mg) 25 Tablet diameter (mm) 10 Hardness (kg/cm.sup.2) 5

(29) Levodopa drug resin complex was dry mixed with carbidopa and excipients as indicated. The obtained mixture was compressed into tablets.

Examples 2-5

A) Preparation of Drug Resin Complexes (DRCS)

(30) 2A) Preparation of Ropinirole Drug Resin Complex (RoDRC)

(31) 100 g of sodium polystyrene sulfonate cation exchange resin crosslinked with divinylbenzene (125-400 mesh) was added to 500 ml of deionized deaerated water and mixed occasionally under argon for 1 h. The resulting slurry was transferred to a 250 ml glass column and washed with 200 ml of deionized deaerated water. 40 g of ropinirole hydrochloride was dissolved in 300 ml deionized deaerated water and passed through the column at a rate of 10 ml per min. The column was washed with 1000 ml of deionized deaerated water. The obtained drug resin complex was taken out of the column and dried first on filter paper and then in vacuum over silica to a moisture content of 5 wt. %.

(32) The dissolution profile of the obtained uncoated ropinirole drug resin complex (RoDRC; USP method #2, paddle rotation speed rpm, 37° C., dissolution medium 0-1 h: 0.1 N HCl, 1-10 h: buffer mixture [500 ml 0.1 N HCl+500 ml phosphate buffer], pH 5.6, ionic strength 0.075) is shown in FIG. 9.

(33) 3A) Preparation of Alendronate Drug Resin Complex (AlDRC)

(34) 50 g of cholestyramine anion exchange resin (Cl.sup.−-form, 99%<100μ, 56%<50μ) was washed with 5×200 ml of deaerated water. The final portion of water was decanted after 5 h. 300 ml of deaerated water and 16.25 g of alendronate sodium were added to the resin. The resulting slurry was mixed at room temperature for 60 min, centrifuged and the solvent decanted. This was repeated three more times until a total of 65 g of alendronate sodium had been used. The obtained drug resin complex was washed with 3 l of water and dried first on filter paper and then in vacuum over silica to a moisture content of 5 wt. %.

(35) 4A) Preparation of Risperidone Drug Resin Complex (RiDRC)

(36) 100 g of polystyrene sulfonate cation exchange resin crosslinked with divinylbenzene (H.sup.+-form) was washed with 500 ml of deionized deaerated water for 30 min. The water was decanted and the resin was washed with 300 ml 96% ethanol. 100 g of risperidone was added to 300 ml of 96% ethanol. The slurry was heated to 60° C., added to the resin and mixed for 12 h under argon. The solvent was decanted and the resin was washed with 5×250 ml of 96% ethanol. The last portion of ethanol was left overnight under argon. The ethanol was decanted and the obtained drug resin complex was dried first on filter paper and then in vacuum over silica to a moisture content of 5 wt. %.

(37) 5A) Preparation of Olanzapine Drug Resin Complex (OzDRC)

(38) 100 g of polystyrene sulfonate cation exchange resin crosslinked with divinylbenzene (H.sup.+-form) was washed with 500 ml of deaerated 96% ethanol. The ethanol was decanted. 80 g of olanzapine was dispersed in 500 ml of deaerated 96% ethanol at 40° C. and added to the resin. The resulting slurry was mixed for 5 h at 40° C. under argon and then left overnight at room temperature. The solvent was decanted and the obtained olanzapine drug resin complex was washed with 10×500 ml of deaerated 96% ethanol. The obtained drug resin complex was dried first on filter paper and then in vacuum over silica to a moisture content of 5 wt. %.

B) Coating with a Release Modifying Coating Layer

(39) 2B) Coating RoDRC with a Release Modifying Coating Layer

(40) TABLE-US-00006 Release modifying material 43% Drug resin complex from 2A (g) 65 Ethylcellulose (g) 193 (pre-plasticized, 25 wt % solids) Deionized water (g) 128 Coating conditions Nozzle diameter (mm) 0.5 Fluidizing air pressure (bar) 0.25 Fluidizing air temperature (° C.) 70-75 Nozzle air pressure (bar) 1.5 Product temperature (° C.) 25 Pump speed (g/min) 3 Yield (g) 95 Moisture content (wt. %, LOD) 5

(41) Ropinirole drug resin complex (RoDRC) was fluidized and sprayed with coating dispersion using a Mini-Glatt coating apparatus analogous to Example 1B.

(42) 3B) Coating AlDRC with a Release Modifying Coating Layer

(43) 25 g of ethylcellulose was thoroughly mixed with 30 ml of 99% ethanol and 0.5 g glycerin used as a plasticizer. The obtained mixture was added to 40 g of the alendronate drug resin complex prepared in Example 3A and mixed until the mixture was homogeneous. The wet mass was forced through a 425 p sieve and dried at 60° C. for 2 h. The obtained granulate was sieved through a 425 p sieve.

C) Coating with a Bioadhesive Coating Layer

(44) TABLE-US-00007 Example 2C 3C 4C 5C Release modifying material 39% 35% — — Bioadhesive material  9%  9% 10.6% 13% Drug resin complex (Example) 2B 3B 4A 5A Drug resin complex (g) 100 100 84 67 Coating dispersion Carboxypolymethylene* (g) 10 10 10 10 Ethanol 96 vol. % (g) 90 90 90 120 Water (g) 4 4 4 4 Coating conditions Nozzle diameter (mm) 0.5 0.5 0.5 0.5 Fluidizing air pressure (bar) 0.22 0.22 0.2-0.3 0.2-0.25 Fluidizing air temperature (° C.) 60 60 60 60 Nozzle air pressure (bar) 1.5 1.5 1.5 1.5 Product temperature (° C.) 38 36 30-38 23-40  Pump speed (g/min) 1-3 3 3 3 Peristaltic pump hose internal 2 2 2 2 diameter (mm) *High molecular weight polymer of acrylic acid crosslinked with allyl ethers and pentaerythritol

(45) Drug resin complexes were fluidized and sprayed with coating dispersion using a Mini-Glatt coating apparatus analogous to Example 1C.

D) Coating with an Enteric Coating Layer

(46) TABLE-US-00008 Example 2D 3D 4D 5D Release modifying material 28% 25% — — Bioadhesive material  6%  6%  7%  9% Amount of enteric coating mat. 29% 29% 31% 31% Drug resin complex (Example) 2C 3C 4C 5C Drug resin complex (g) 100 100 94 77 Coating dispersion Methacrylic acid copolymer* (g) 35 35 35 35 Triethyl citrate (g) 5 5 5 4 Ethanol 96 vol. % (g) 300 300 300 300 Coating conditions Nozzle diameter (mm) 0.5 0.5 0.5 0.5 Fluidizing air pressure (bar) 0.3-0.4 0.2 0.3 0.3 Fluidizing air temperature (° C.) 60 60 60 60 Nozzle air pressure (bar) 1.5 1.2 1.5 1.5 Product temperature (° C.) 27-42 30-48 35-37 35-37 Pump speed (g/min) 5 5 5 5 Peristaltic pump hose internal 2 2 2 2 diameter (mm) Active agent content (wt. %, HPLC) 9.3 22 20.3 10.8 *Commercially available methacrylic acid copolymer with dispersing agents formulated for easy dispersion in water

(47) Drug resin complexes were fluidized and sprayed with coating dispersion using a Mini-Glatt coating apparatus analogous to Example 1D.

(48) Dissolution profiles of coated ropinirole drug resin complexes obtained in Example 2D before and after sieving in phosphate buffer (USP method #2, paddle rotation speed 75 rpm, 37° C., dissolution medium 0-1 h: 500 ml 0.1 N HCl, 1-10 h: buffer mixture [500 ml 0.1 N HCl+500 ml phosphate buffer], pH 5.6, ionic strength 0.075) are shown in FIG. 9.

(49) Dissolution profiles of coated drug resin complexes obtained in Examples 3D, 4D and 5D are shown in FIGS. 10 to 12.