# US 2014/0154328 A1 · Pharmaceutical Composition

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- Number: US 2014/0154328 A1
- Document ID: US20140154328A1
- Status: Published application
- Kind: A1
- Application number: 14/009,996
- Filed: 2012-04-05
- Published: 2014-06-05
- Earliest claimed: 2011-04-06
- Assignees: Cvjetko Brkicic
- Inventors: Ljiljana Sovic Brkicic; Zdravko Dokuzovic
- Web page: https://patentgrep.com/patent/US20140154328A1

## CPC

- B05D 1/22: using fluidised-bed technique (fluidised-bed technique in general B01J8/24)
- A61K 9/2081: {with microcapsules or coated microparticles according to A61K9/50}
- A61K 9/4808: {characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release (capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084)}
- A61K 9/5026: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/5047: {Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose}
- A61K 9/5073: {having two or more different coatings optionally including drug-containing subcoatings}
- A61K 9/5084: {Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs (tablets containing such a mixture A61K9/2077)}
- A61K 31/198: Alpha-amino acids, e.g. alanine or edetic acid [EDTA] (betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00)
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/585: {Ion exchange resins, e.g. polystyrene sulfonic acid resin}
- A61P 25/16: Anti-Parkinson drugs
- B05D 1/02: performed by spraying
- B05D: PROCESSES FOR APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL (conveying articles or workpieces through baths of liquid B65G, e.g. B65G49/02)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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

### Claim 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, wherein the bioadhesive material is selected from the group consisting of optionally crosslinked homopolymers of acrylic acid or an alkylacrylic acid and optionally crosslinked copolymers of acrylic acid or methacrylic acid with a (C10-C30)alkyl acrylate.

### Claim 2 (depends on 1)

Composition according to claim 1, 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.

### Claim 3 (depends on 1)

Composition according to claim 1, wherein 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.

### Claim 4 (depends on 1)

Composition according to claim 1, wherein the bioadhesive material has a weight average molecular weight of at least about 10,000 Daltons, preferably at least about 50,000 Daltons, more preferably at least about 100,000 Daltons, still more preferably at least about 1,000,000 Daltons, and most preferably from about 1,000,000 to about 10,000,000 Daltons.

### Claim 5

(canceled)

### Claim 6 (depends on 2)

Composition according to claim 2, wherein the enteric coating material is selected from the group consisting of anionic cellulose derivatives, anionic vinyl resins and anionic acrylic resins.

### Claim 7 (depends on 6)

Composition according to claim 6, 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 and pharmaceutically acceptable salts thereof, polyvinyl acetate phthalate, poly(methacrylic acid-co-ethylacrylate) and poly(methacrylic acid-co-methylmethacrylate).

### Claim at position 8

8-15. (canceled)

### Claim 16 (depends on 3)

Composition according to claim 3, wherein the release modifying material is selected from delayed release materials and/or controlled release materials.

### Claim 17 (depends on 16)

Composition according to claim 16, 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.

### Claim 18 (depends on 17)

Composition according to claim 17, wherein the release modifying material is selected from the group consisting of methyl cellulose, ethyl cellulose and mixtures thereof.

### Claim 19 (depends on 3)

Composition according to claim 3 comprising at least two groups of coated particles differing in the amount and/or the composition of release modifying material.

### Claim 20 (depends on 1)

Composition according to claim 1, wherein the ion exchange resin is selected from the group consisting of polymers and copolymers of acrylic acid, methacrylic acid and 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.

### Claim 21 (depends on 20)

Composition according to claim 20, wherein the ion exchange resin is a crosslinked sulfonated copolymer of styrene and divinylbenzene.

### Claim 22 (depends on 1)

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 preferably about 10 to about 3000 μm, particularly about 30 to about 2000 μm, and most preferably about 50 to about 1000 μm.

### Claim 23 (depends on 1)

Composition according to claim 1, wherein the average particle size of the coated particles is preferably about 20 to about 5000 μm, particularly about 50 to about 4000 μm, and most preferably about 70 to about 3000 μm.

### Claim 24 (depends on 1)

Composition according to claim 1, wherein the coated particles have a specific gravity in the range from 1.1 to 2.0, preferably from 1.2 to 1.8.

### Claim 25 (depends on 1)

Composition according to claim 1, wherein the coated particles exhibit a specific surface area in the range of from about 1 to 200 m2/g.

### Claim 26

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, 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, bleomycin, 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, phenyloin, 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, disulfuram, 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.

### Claim 27 (depends on 26)

Composition according to claim 26, wherein the active agent is selected from the group consisting of levodopa, carbidopa, benserazide, entacapone and mixtures thereof.

### Claim 28 (depends on 26)

Composition according to claim 26, wherein the active agent is selected from the group consisting of alendronate, olanzapine, risperidone and ropinirole.

### Claim 29 (depends on 1)

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

### Claim 30 (depends on 1)

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

### Claim 31 (depends on 1)

Composition according to claim 1 comprising levodopa and carbidopa or benserazide in a ratio of 20:1 to 1:1, preferably 15:1 to 2:1, and most preferably 10:1 to 4:1.

### Claim 32 (depends on 1)

Composition according to claim 1, wherein the coated particles comprise
(a) 1 to 50 wt. %, particularly 5 to 40 wt. % and preferably 10 to 20 wt. % of said at least one active agent;
(b) 1 to 50 wt. %, particularly 10 to 35 wt. % and preferably 15 to 25 wt. % of said ion-exchange resin;
(c) 0 to 50 wt. %, particularly 1 to 50 wt. %, preferably 10 to 40 wt. % and more preferably 15 to 30 wt. % of said release modifying material;
(d) 0.5 to 30 wt. %, particularly 1 to 10 wt. % and preferably 2 to 8 wt. % of said bioadhesive material; and
(e) 0 to 80 wt. %, particularly 1 to 80 wt. %, preferably 10 to 60 wt. % and more preferably 30 to 50 wt. % of said enteric coating material;
based on the total weight of the coated particles.

### Claim 33 (depends on 1)

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) optionally coating the complex of step (i) with a coating layer comprising a release modifying material;
(iii) coating the complex of step (i) or the coated complex of step (ii) with a coating layer comprising a bioadhesive material; and
(iv) optionally coating the coated complex of step (iii) with a coating layer comprising an enteric coating material.