TUNABLE SUSTAINED RELEASE OF A SPARINGLY SOLUBLE HYDROPHOBIC THERAPEUTIC AGENT FROM A HYDROGEL MATRIX

• US 20100291191A1
• Filed: 05/21/2010
• Published: 11/18/2010
• Est. Priority Date: 04/25/2005
• Status: Active Grant

• Current Assignee: The Governing Council of the University of Toronto (University of Toronto)
• Original Assignee: The Governing Council of the University of Toronto (University of Toronto)
• Inventors: Shoichet, Molly S., Lapitsky, Yakov, Wang, Yuanfei
• Granted Patent: US 9,205,047 B2
• Time in Patent Office: Days
• US Class Current: 424/450
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 47/38 Cellulose; Derivatives thereof
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/14 Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/02 Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 33/02 Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• CPC Class Codes: A61P 33/10 Anthelmintics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/06 Antiarrhythmics

Abstract

The incorporation of polymeric excipients into an injectable hydrogel matrix, for example, methyl cellulose in the case of a hydrogel matrix comprising hyaluronan and methylcellulose (HAMC) has been found to increase the solubility of sparingly soluble hydrophobic drugs and tune their rate of release. The hydrogel matrix may also include other sparingly soluble hydrophobic food or cosmetic agents.

Claims

1. A hydrogel matrix comprising an aqueous solution of methylcellulose or other water soluble hydrophobic cellulose derivative, in which particles of at least one selected size of at least one sparingly soluble hydrophobic agent are dispersed and solubilised, which is blended with an anionic polysaccharide or a derivative thereof to form the hydrogel matrix, the water solubility of the sparingly soluble hydrophobic agent being increased in the presence of the methylcellulose or other water soluble hydrophobic cellulose derivative, which together with the selected particle sizes determine the sustained release profile of the at least one sparingly soluble hydrophobic agent from the hydrogel matrix.

2. The hydrogel as claimed in claim 1 wherein at least one sparingly soluble hydrophobic agent is selected from sparingly soluble hydrophobic therapeutic, food and cosmetic agents.

3. The hydrogel matrix as claimed in claim 1 wherein the anionic polysaccharide or a derivative thereof comprises hyaluronan.

4. The hydrogel matrix as claimed in claim 1, wherein the anionic polysaccharide or a derivative thereof comprises from about 100 to about 7,000 kg/mol and the methylcellulose or other water soluble hydrophobic cellulose derivative comprises from about 2 to about 3,000 kg/mol.

5. The hydrogel matrix as claimed in claim 1, wherein the ratio of anionic polysaccharide or a derivative thereof to the methylcellulose or other water soluble hydrophobic cellulose derivative comprises from about 1:

20 to about 1;

1 w/w.

6. The hydrogel matrix as claimed in claim 1, wherein the amount of anionic polysaccharide or a derivative thereof comprises from about 0.5% to about 5.0% by weight and the methylcellulose or other water soluble hydrophobic cellulose derivative comprises from about 1.0% to about 20% by weight of the matrix.

7. The hydrogel matrix as claimed in claim 1, wherein the amount of hyaluronan or a derivative thereof comprises from about 0.5% to about 5.0% by weight and the methylcellulose or other water soluble hydrophobic cellulose derivative comprises from about 1.0% to about 10% by weight of the matrix.

8. The hydrogel matrix as claimed in claim 2, wherein the sparingly soluble hydrophobic therapeutic agent comprises from about 0.0001 to about 30 wt %, based on the matrix.

9. The hydrogel matrix as claimed in claim 2, wherein the particles of the at least one therapeutic agent are selected from particle sizes of from about 1 nm to about 1000 μ

m.

10. The hydrogel composite as claimed in claim 2, wherein the particles of sparingly soluble hydrophobic pharmaceutical agent are selected from particle sizes of from about 220 nm to about 37 μ

m.

11. The hydrogel composite as claimed in claim 2, wherein the delivered therapeutic agent from the encapsulated particles is in the range of from about 0.1 to about 30 wt % (drug mass as a percentage of the drug loaded particle mass).

12. The hydrogel matrix as claimed in claim 1, wherein the aqueous solution is selected from the group comprising water, saline, artificial cerebrospinal fluid, and buffered solutions.

13. The hydrogel matrix as claimed in claim 1 having an altered chemical functionality by the addition of at least one functional group to the hyaluronan or the derivative thereof or the methylcellulose or other water soluble hydrophobic cellulose derivative selected from the group consisting of carboxylic acid, primary amine, aldehyde, hydrazide, maleimide, thiol, furan, alkyne, azide, alkene, urethane, and primary alcohol.

14. The hydrogel matrix as claimed in claim 2 wherein the at least one therapeutic agent is selected from the group comprising Analgesics and anti-inflammatory agents:

aloxiprin, auranofin, azapropazone, benorylate, diflunisal, etodolac, fenbufen, fenoprofen calcim, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxyphenbutazone, phenylbutazone, piroxicam, sulindac;

anthelmintics;

albendazole, bephenium hydroxynaphthoate, cambendazole, dichlorophen, ivermectin, mebendazole, oxamniquine, oxfendazole, oxantel embonate, praziquantel, pyrantel embonate, thiabendazole;

anti-arrhythmic agents;

amiodarone HCl, disopyramide, flecamide acetate, quinidine sulphate;

anti-bacterial agents;

benethamine penicillin, cinoxacin, ciprofloxacin HCl, clarithromycin, clofazimine, cloxacillin, demeclocycline, doxycycline, erythromycin, ethionamide, imipenem, nalidixic acid, nitrofurantoin, rifampicin, spiramycin, sulphabenzamide, sulphadoxine, sulphamerazine, sulphacetamide, sulphadiazine, sulphafurazole, sulphamethoxazole, sulphapyridine, tetracycline, trimethoprim;

anti-coagulants;

dicoumarol, dipyridamole, nicoumalone, phenindione;

anti-depressants;

amoxapine, maprotiline HCl, mianserin HCL, nortriptyline HCl, trazodone HCL, trimipramine maleate;

anti-diabetics;

acetohexamide, chlorpropamide, glibenclamide, gliclazide, glipizide, tolazamide, tolbutamide, anti-epileptics;

beclamide, carbamazepine, clonazepam, ethotoin, methoin, methsuximide, methylphenobarbitone, oxcarbazepine, paramethadione, phenacemide, phenobarbitone, phenyloin, phensuximide, primidone, sulthiame, valproic acid;

anti-fungal agents;

amphotericin, butoconazole nitrate, clotrimazole, econazole nitrate, fluconazole, flucytosine, griseofulvin, itraconazole, ketoconazole, miconazole, natamycin, nystatin, sulconazole nitrate, terbinafine HCl, terconazole, tioconazole, undecenoic acid;

anti-gout agents;

allopurinol, probenecid, sulphin-pyrazone;

anti-hypertensive agents;

amlodipine, benidipine, darodipine, dilitazem HCl, diazoxide, felodipine, guanabenz acetate, isradipine, minoxidil, nicardipine HCl, nifedipine, nimodipine, phenoxybenzamine HCl, prazosin HCL, reserpine, terazosin HCL;

anti-malarials;

amodiaquine, chloroquine, chlorproguanil HCl, halofantrine HCl, mefloquine HCl, proguanil HCl, pyrimethamine, quinine sulphate;

anti-migraine agents;

dihydroergotamine mesylate, ergotamine tartrate, methysergide maleate, pizotifen maleate, sumatriptan succinate;

anti-muscarinic agents;

atropine, benzhexyl HCl, biperiden, ethopropazine HCl, hyoscyamine, mepenzolate bromide, oxyphencylcimine HCl, tropicamide;

anti-neoplastic agents and Immunosuppressants;

aminoglutethimide, amsacrine, azathioprine, busulphan, chlorambucil, cyclosporin, dacarbazine, estramustine, etoposide, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitotane, mitozantrone, procarbazine HCl, tamoxifen citrate, testolactone;

anti-protazoal agents;

benznidazole, clioquinol, decoquinate, diiodohydroxyquinoline, diloxanide furoate, dinitolmide, furzolidone, metronidazole, nimorazole, nitrofurazone, ornidazole, tinidazole;

anti-thyroid agents;

carbimazole, propylthiouracil;

anxiolytic, sedatives, hypnotics and neuroleptics;

alprazolam, amylobarbitone, barbitone, bentazepam, bromazepam, bromperidol, brotizolam, butobarbitone, carbromal, chlordiazepoxide, chlormethiazole, chlorpromazine, clobazam, clotiazepam, clozapine, diazepam, droperidol, ethinamate, flunanisone, flunitrazepam, fluopromazine, flupenthixol decanoate, fluphenazine decanoate, flurazepam, haloperidol, lorazepam, lormetazepam, medazepam, meprobamate, methaqualone, midazolam, nitrazepam, oxazepam, pentobarbitone, perphenazine pimozide, prochlorperazine, sulpiride, temazepam, thioridazine, triazolam, zopiclone;

beta-blockers, acebutolol, alprenolol, atenolol, labetalol, metoprolol, nadolol, oxprenolol, pindolol, propranolol;

cardiac inotropic agents;

amrinone, digitoxin, digoxin, enoximone, lanatoside C, medigoxin;

corticosteroids;

beclomethasone, betamethasone, budesonide, cortisone acetate, desoxymethasone, dexamethasone, fludrocortisone acetate, flunisolide, flucortolone, fluticasone propionate, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone;

diuretics;

acetazolamide, amiloride, bendrofluazide, bumetanide, chlorothiazide, chlorthalidone, ethacrynic acid, frusemide, metolazone, spironolactone, triamterene;

anti-parkinsonian agents;

bromocriptine mesylate, lysuride maleate;

gastro-intestinal agents;

bisacodyl, cimetidine, cisapride, diphenoxylate HCl, domperidone, famotidine, loperamide, mesalazine, nizatidine, omeprazole, ondansetron HCL, ranitidine HCl, sulphasalazine;

histamine H;

receptor antagonists;

acrivastine, astemizole, cinnarizine, cyclizine, cyproheptadine HCl, dimenhydrinate, flunarizine HCl, loratadine, meclozine HCl, oxatomide, terfenadine;

lipid regulating agents;

bezafibrate, clofibrate, fenofibrate, gemfibrozil, probucol;

nitrates and other anti-anginal agents;

amyl nitrate, glyceryl trinitrate, isosorbide dinitrate, isosorbide mononitrate, pentaerythritol tetranitrate;

nutritional agents;

betacarotene, vitamin A, vitamin B2, vitamin D, vitamin E, vitamin K;

opioid analgesics;

codeine, dextropropyoxyphene, diamorphine, dihydrocodeine, meptazinol, methadone, morphine, nalbuphine, pentazocine;

sex hormones;

clomiphene citrate, danazol, ethinyl estradiol, medroxyprogesterone acetate, mestranol, methyltestosterone, norethisterone, norgestrel, estradiol, conjugated oestrogens, progesterone, stanozolol, stibestrol, testosterone, tibolone;

stimulants;

amphetamine, dexamphetamine, dexfenfluramine, fenfluramine, mazindol; and

mixtures of hydrophobic drugs may, of course, be used where therapeutically effective.

15. The hydrogel matrix as claimed in claim 3 having an altered rate of degradation by cross-linking the hyaluronan or the derivative thereof or by increasing the hydrophobicity of the hyaluronan or the derivative thereof.

16. The hydrogel matrix as claimed in claim 3, wherein the particles of the at least one sparingly soluble hydrophobic therapeutic agent are microspheres or liposomes.

17. The hydrogel matrix as claimed in claim 3 wherein a charge stabilizer is added to promote an interaction between the blend and the therapeutic agent or the therapeutic agent is covalently bonded to the hyaluronan, methyl cellulose or derivatives thereof.

18. The hydrogel matrix as claimed in claim 1 wherein the other hydrophobic water soluble cellulose derivatives are selected from the group comprising hydroxypropyl methylcellulose, ethylcellulose, 3-O-ethylcellulose, hydroxypropyl methylcellulose phthalate, hydrophobically modified hydroxyethyl cellulose selected from ethyl(hydroxyethyl)cellulose, 6-O-alkylated cellulose, cellulose octanoate sulfate, cellulose lauroate sulfate, cellulose stearoate sulfate, and cationic derivatives thereof, 6-O-benzylcellulose, 2,3-di-O-methyl-6-O-benzylcellulose, 2,3-di-O-benzylcellulose, 2,3-di-O-benzyl-6-O-methylcellulose, 2,3,6-tri-O-benzylcellulose, hydroxypropyl methylcellulose acetate succinate, O-2-[2-(2-methoxyethoxy)ethoxy]acetyl cellulose.

19. The hydrogel matrix as claimed in claim 1 wherein the derivatives of hyaluronan are esters of hyaluronan resulting from esterification with different classes of alcohols such as aliphatic, cycloaliphatic and heterocyclic.

20. A method for the manufacture of a hydrogel matrix as claimed in claim 1, wherein the matrix has a tunable agent release profile comprising the steps ofproviding particles of the at least one selected size of the at least one sparingly soluble hydrophobic agent;

2) dispersing and solubilising the particles in an aqueous solution of methylcellulose or other water soluble hydrophobic cellulose derivative; and

3) blending the thus formed dispersion with an anionic polysaccharide or a derivative thereof to form the hydrogel matrix containing the at least one solubilised sparingly soluble hydrophobic agent;

wherein, the solubility of the sparingly soluble hydrophobic agent is increased in the presence of the methylcellulose or other water soluble hydrophobic cellulose derivative which together with the selected particle sizes of the sparingly soluble hydrophobic agent determine the sustained release profile of the at least one agent from the hydrogel matrix.

21. A hydrogel matrix comprising an aqueous solution of methylcellulose or other water soluble hydrophobic cellulose derivative, in which particles of at least one selected size of at least one sparingly soluble hydrophobic agent are dispersed and solubilised, the solubility of the sparingly soluble hydrophobic agent being increased in the presence of the methylcellulose or other water soluble hydrophobic cellulose derivative, which together with the selected particle sizes determine the sustained release profile of the at least one sparingly soluble hydrophobic agent from the hydrogel matrix.

22. The hydrogel matrix of claim 21, wherein the sparingly soluble hydrophobic agent is selected from therapeutic agents, cosmetic agents and food agents.

23. A method for the manufacture of a hydrogel matrix as claimed in claim 21, wherein the matrix has a tunable agent release profile comprising the steps of 1) providing particles of at least one selected size of the at least one sparingly soluble hydrophobic agent;

2) dispersing and solubilising the particles in an aqueous solution of methylcellulose or other water soluble hydrophobic cellulose derivative; and

     3). increasing the temperature of the solution to form the hydrogel matrix containing the at least one solubilised sparingly soluble hydrophobic agent;

wherein, the solubility of the sparingly soluble hydrophobic agent is increased in the presence of the methylcellulose or other water soluble hydrophobic cellulose derivative which together with the selected particle sizes of the sparingly soluble hydrophobic agent determine the sustained release profile of the at least one agent from the hydrogel matrix.

24. The method of claim 23, wherein the sparingly soluble hydrophobic agent is selected from therapeutic agents, cosmetic agents and food agents.