Press coated, pulsatile drug delivery system suitable for oral administration

• US 20020164371A1
• Filed: 04/16/2002
• Published: 11/07/2002
• Est. Priority Date: 04/02/1998
• Status: Active Grant

• Current Assignee: Impax Laboratories, LLC
• Original Assignee: Impax Pharmaceuticals, Inc.
• Inventors: Ting, Richard, Hsiao, Charles
• Granted Patent: US 6,730,321 B2
• Time in Patent Office: Days
• US Class Current: 424/468
• CPC Class Codes: A61K 9/209 containing drug in at least two layers or in the core and in at least one outer layer

Abstract

A press-coated tablet suitable for oral administration, comprising an immediate-release compartment comprising a compressed blend of an active agent. The immediate-release compartment has a dissolution profile in which 10-75% of the active agent is dissolved within one hour and not less than 90% of the active agent is dissolved within 6 hours. The tablet further comprises an extended-release compartment with a dissolution profile in which 5-40% of the active agent is dissolved within one hour, 20-75% within three hours, 40-95% of the active agent within 6 hours, and not less than 60% of the active agent is dissolved within 8 hours. Additionally, the press-coated extended-release compartment substantially envelops the immediate-release compartment, and comprises a compressed blend of the active agent, a hydrophilic polymer and hydrophobic material. The tablet exhibits a first order release of the active agent interrupted by a pulsed delivery of the active agent.

Claims

1. A press-coated tablet suitable for oral administration, comprising:

(a) an immediate-release compartment comprising a compressed blend of an active agent and one or more polymers, wherein said immediate release compartment is characterized by a dissolution profile in which 10-75%0 of the active agent is dissolved within one hour and not less than 90% of the active agent is dissolved within 6 hours, based on the total amount of the active agent in the compartment, wherein the dissolution profile is measured in a type 2 dissolution apparatus (paddle) according to U.S. Pharmacopeia XXII at 37°

C.±

0.5°

C. in deionized water at 75 rotations per minute, and

(b) an extended-release compartment, wherein said extended-release compartment is characterized by a dissolution profile in which 5-40% of the active agent is dissolved within one hour, 20-75% of the active agent is dissolved within three hours, 40-95% of the active agent is dissolved within 6 hours, and not less than 60% of the active agent is dissolved within 8 hours, based on the total amount of the active agent in the compartment, wherein the dissolution profile is measured in a type 2 dissolution apparatus (paddle) according to U.S. Pharmacopeia XXII at 37°

C.±

0.5°

C. in deionized water at 75 rotations per minute, wherein the extended-release compartment is formed by press-coating to substantially envelop the immediate-release compartment, and comprises a compressed blend of the active agent, a hydrophilic polymer and hydrophobic material,

wherein the tablet exhibits a first order release of the active agent interrupted by a pulsed delivery of the active agent.

2. The tablet of claim 1, further comprising

(c) an instant-release compartment, characterized by a dissolution profile in which at least 80% of the active agent is dissolved within 15 minutes, based on the total amount of the active agent in the compartment, wherein the dissolution profile is measured in a type 2 dissolution apparatus (paddle) according to U.S. Pharmacopeia XXII at 37°

C. 0.5°

C. in deionized water at 75 rotations per minute, wherein the instant release compartment is formed by coating to substantially envelop the extended-release compartment, and comprises a compressed blend of an active agent and one or more polymers, and wherein the instant-release compartment provides a release of the active agent before the first order release.

3. The tablet of claim 2, wherein the instant-release compartment is formed by film coating.

4. The tablet of claim 1, wherein the active agent is a drug, or a pharmaceutically acceptable salt thereof.

5. The tablet of claim 4, wherein the drug is a therapeutic drug.

6. The tablet of claim 4, wherein the drug is a prophylactic drug.

7. The tablet of claim 4, wherein the drug is selected from the group consisting of diltiazem, trapidil, urapidil, benziodarone, dipyridamole, isosorbide mononitrate and lidoflazine.

8. The tablet of claim 4, wherein the drug is selected from the group consisting of a non-steroidal anti-inflammatory drug and a steroidal antiinflamatory drug.

9. The tablet of claim 4, wherein the drug is selected from the group consisting of acetaminophen, aldosterone, alprenolol, amitryptyline, aspirin, beclomethasone, diproprionate, bromocriptine, butorphanol tartrate, chlormethiazole, chlorpheniramine, chlorpromazine HCl, cimetidine, codeine, cortisone, cyclobenzamine HCl, desmethylimipramine, dextropropoxyphene, dihydroergotamine, diltiazem HCl, dobutamine HCl, domperidone, dopamine HCl, doxepin HCl, epinephrine, ergoloid mesylates, ergotamine tartrate estradiol, ethinylestradiol, flunisolide, fluorouracil, flurazepam HCl, 5-fluoro-21-deoxyuridine, furosemide, glipizide, glyburide, glyceryl trinitrate, guanethidine sulfate, hydralazine HCl, imipramine HCl, indoramin, isoethorine HCl, isoethrine mesylate, isoprenaline, isoproterenol sulfate, isosorbide dinitrate, levallorphan tartrate, levodopa, lidocaine HCl, lignocaine, lorcainide, meperidine HCl, 6-mercaptopurine, metaproterenol sulfate, methoxamine HCl, methylphenidate, methylpreonisolone, methyltestosterone mesylate, metoclopramide, metoprolol tartrate, morphine sulfate, nalbuphine HCl, naloxone HCl, neostigmine, nifedipine, nitrendipine, nitroglycerin, norepinephrine bitartrate, norethindrone, nortriptylene HCl, oxprenolol, oxyphenbutazone, penicillamine, pentazocine HCl, pentazocine lactate, pentobarbital, petnidine, phenacetin, phentolamine HCl, phentolamine mesylate, phenylephrine HCl, phenylephrine bitartrate, phenytoin, pindolal, prazosin, prednisone, progesterone, propoxyphene HCl, propoxyphene napsylate, propranolol HCl, quinidine, reserpine, ritodrine HCl, salicylamide, salbutamol, secobarbital, testosterone, terbutaline, timolol maleate, tolbutamide, and verapamil HCl.

10. The tablet of claim 4, wherein the drug is isosorbide-5-mononitrate.

11. The tablet of claim 1, wherein the active agent exhibits the following in vitro dissolution profile when measured in a type 2 dissolution apparatus (paddle) according to U.S. Pharmacopeia XXII at 37°

C.±

0.5°

C. in deionized water at 75 rotations per minute;

from about 0% to about 90% of the active agent is released between 1 hour and 16 hours of measurement in the apparatus; and

from about 0% to about 100% of the active agent is released between 1.5 hours and 28 hours of measurement in the apparatus.

12. The tablet of claim 1, wherein the active agent exhibits the following in vitro dissolution profile when measured in a type 2 dissolution apparatus (paddle) according to U.S. Pharmacopeia XXII at 37°

C.±

0.5°

C. in deionized water at 75 rotations per minute;

from about 10% to about 75% of the active agent is released between 1 hour and 5 hours of measurement in the apparatus; and

not less than 90% of the active agent is released after 6 hours of measurement in the apparatus.

13. The tablet of claim 1, wherein the active agent exhibits the following in vitro dissolution profile when measured in a type 2 dissolution apparatus (paddle) according to U.S. Pharmacopeia XXII at 37°

C.±

0.5°

C. in deionized water at 75 rotations per minute;

from about 0% to about 50% of the active agent is released after 1 hour of measurement in the apparatus;

from about 0% to about 90% of the active agent is released between 1 hour and 16 hours of measurement in the apparatus; and

from about 0% to about 100% of the active agent is released between 1.5 hours and 28 hours of measurement in the apparatus.

14. The tablet of claim 1, wherein the active agent exhibits the following in vitro dissolution profile when measured in a type 2 dissolution apparatus (paddle) according to U.S. Pharmacopeia XXII at 37°

C.±

0.5°

C. in deionized water at 75 rotations per minute;

from about 0% to about 35% of the active agent is released after 1 hour of measurement in the apparatus;

from about 10% to about 90% of the active agent is released between 1 hour and 5 hours of measurement in the apparatus; and

no less than 90% of the active agent is released after 6 hours of measurement in the apparatus.

15. The tablet of claim 1, wherein the one or more polymers are selected from the group consisting of alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminum silicate, magnesium stearate, methylcellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate, starch, ethylcellulose, gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polymethacrylate, povidone, shellac and zein.

16. The tablet of claim 15, wherein the one or more polymers are selected from the group consisting of colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose and hydroxypropylmethyl cellulose.

17. The tablet of claim 1, wherein the hydrophilic polymer is at least one member selected from the group consisting of carboxymethylcellulose, guar gum, gum acacia, gum tragacanth, gum xanthan, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methylcellulose, povidone, sodium carboxymethycellulose, hydroxymethyl cellulose, polyethelene oxide, hydroxyethyl methyl cellulose, carboxypolymethylene, polyethelene glycol, alginic acid, gelatin, polyvinyl alcohol, polyvinylpyrrolidones, polyacrylamides, polymethacrylamides, polyphosphazines, polyoxazolidines, poly(hydroxyalkylcarboxylic acids), an alkali metal, alkaline earth metal, carageenate alginates, ammonium alginate, sodium alganate.

18. The tablet of claim 17, wherein the hydrophilic polymer comprises hydroxypropylmethyl cellulose.

19. The tablet of claim 1, wherein the hydrophobic material is at least one member selected from the group consisting of carbomer, carnauba wax, ethylcellulose, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, microcrystalline wax, polacrilin potassium, polymethacrylate, stearic acid, a pharmaceutically acceptable acrylic polymer, including, but not limited to acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolyer, poly(methyl methacrylate), poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.

20. The tablet of claim 19, wherein the hydrophobic material comprises hydrogenated vegetable oil.