Pelletized pharmaceutical composition

• US 5,800,836 A
• Filed: 02/06/1995
• Issued: 09/01/1998
• Est. Priority Date: 08/05/1992
• Status: Expired due to Term

• Current Assignee: Mayne Pharma International Pty Limited (Mayne Pharma)
• Original Assignee: F H Faulding & Co Limited (Mayne Pharma)
• Inventors: Morella, Angelo Mario, Heinicke, Grant Wayne
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Benston, Jr., William E.
• Application Number:
  US08/398,744
• Time in Patent Office: 1,303 Days
• Field of Search: 424/489, 424/495, 424/497, 424/494
• US Class Current: 424/489
• CPC Class Codes: A61K 9/5042 Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/5047 Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/5078 with drug-free core

Abstract

A pelletized sustained release pharmaceutical composition including a core element including approximately 0.1 to 95% by weight, based on the total weight of the core element, of an active ingredient of low aqueous solubility; approximately 0.1 to 55% by weight of a core seed; and a core coating for the core element, including approximately 30 to 97% by weight, based on the total weight of the core coating, excluding filler, of an enteric polymer; approximately 3 to 50% by weight of an insoluble polymer; and 0 to approximately 50% by weight of plasticizer, the enteric polymer comprising at least approximately 70% by weight of the total weight of the enteric polymer and insoluble polymer; the core coating being such that the active ingredient is released in a controlled fashion over an extended period in the intestine but substantially no release occurs in the acid environment of the stomach and blood levels of active ingredient are maintained within the therapeutic range over an extended period of time.

Claims

1. A pelletized sustained release pharmaceutical composition comprising

a core element comprising

approximately 0.1 to 95% weight, based on the total weight of the core element of an active ingredient of low aqueous solubility,

approximately 0.1 to 55% by weight weight binding agent;

approximately 5 to 99% weight of a core seed; and

a core coating for the core element, comprising

approximately 30 to 97% by weight, based on the total weight of the core coating, excluding filler, of an enteric polymer;

approximately 3 to 50% by weight of an insoluble polymer; and

0 to approximately 50% by weight of plasticizer, the enteric polymer comprising at least approximately 70% by weight of the total weight of the enteric polymer and insoluble polymer;

the core coating being such that the active ingredient is released in a controlled fashion over an extended period in the intestine but substantially no release occurs in the acid environment of the stomach and blood levels of active ingredient are maintained within the therapeutic range over an extended period of time.

2. The pelletized pharmaceutical composition of claim 1 wherein the active ingredient is erythromycin.

3. The pelletised pharmaceutical composition of claim 1 wherein the active ingredient is a non-steroidal anti-inflammatory drug (NSAID) or an acid or salt thereof.

4. The pelletised pharmaceutical composition of claim 3 wherein the active ingredient is selected from a low aqueous solubility form of Diclofenac, Ketorolac and Indomethacin.

5. The pharmaceutical composition of claim 4 wherein the active ingredient comprises Diclofenac.

6. The pharmaceutical composition of claim 1 wherein the core coating further comprises

up to 75% by weight of a filler;

and

up to 60% by weight of a water soluble component.

7. The pelletised pharmaceutical composition of claim 1, wherein the core element includes approximately 0.1 to 45% by weight of a binding agent selected from the group consisting of polyvinylpyrrolidone (povidone), hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, hydroxyethyl cellulose, sugars and mixtures thereof.

8. The pelletised pharmaceutical composition of claim 7 wherein the core coating comprises

approximately 70 to 87% by weight of an enteric polymer selected from the group consisting of cellulose butyrate phthalate, cellulose hydrogen phthalate, cellulose propionate phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetates, dioxypropyl methyl cellulose succinates, acrylic methacrylic acid copolymers, shellac, copal collophorium, cellulose acetate phthalate and mixtures thereof;

and

approximately 3 to 50% by weight of an insoluble polymer component selected from the group consisting of ethyl cellulose, cellulose acetates and their esters, acrylic methacrylic acid copolymers, hydroxypropyl methyl cellulose acetate and mixtures thereof.

9. The pelletised pharmaceutical composition of claim 8 wherein the core coating comprises approximately 2.5 to 30% by weight of a plasticiser selected from diethyl phthalate, triethyl citrate, triethyl acetyl citrate, triacetin, tributyl citrate, polyethylene glycol, glycerol and mixtures thereof.

10. A method for preparing a pelletized sustained release pharmaceutical composition, which method comprises providing

a core element comprising

approximately 0.1 to 95% weight, based on the total weight of the core element of an active ingredient of low aqueous solubility,

approximately 0.1 to 55% by weight of a binding agent;

approximately 5 to 99% weight of a core seed; and

a core coating for the core element, including

approximately 30 to 97% by weight, based on the total weight of the core coating, excluding filler, of an enteric polymer;

approximately 3 to 50% by weight of an insoluble polymer, the enteric polymer comprising at least approximately 70% by weight of the total weight of the enteric polymer and insoluble polymer; and

spraying the core coating composition onto the core element.

11. The method of claim 10, further comprising the preliminary steps of

providing

an active ingredient of low aqueous solubility;

a binding agent; and

a core seed; and

coating the core seed with the active ingredient and binding agent to form a core element.

12. The method according to claim 10 further comprising the preliminary steps of

providing

at least one active ingredient of low aqueous solubility;

an effective amount of a solvent or granulating liquid, mixing the ingredients; and

subjecting the ingredients to an extrusion followed by marumerisation to form a core element.

13. A method for the therapeutic or prophylactic treatment of conditions in patients requiring treatment, which method includes administering to a patient an effective amount of a pelletized sustained release pharmaceutical composition comprising

a core element comprising

approximately 0.1 to 95% weight, based on the total weight of the core element of an active ingredient of low aqueous solubility selected from diclofenac, ketorolac and indomethacin,

approximately 0.1 to 55% by weight weight binding agent;

approximately 5 to 99% weight of a core seed; and

a core coating for the core element, including

approximately 30 to 97% by weight, based on the total weight of the core coating, excluding filler, of an enteric polymer;

approximately 3 to 50% by weight of an insoluble matrix polymer; and

0 to approximately 50% by weight of plasticizer, the enteric polymer comprising at least approximately 70% by weight of the total weight of the enteric polymer and insoluble matrix polymer;

the core coating being such that the active ingredient is released in a controlled fashion over an extended period in the intestine but substantially no release occurs in the acid environment of the stomach and blood levels of active ingredient are maintained within the therapeutic range over an extended period of time.

14. A sustained release pharmaceutical composition comprising pellets from about 0.5 mm to about 2 mm in size which include:

a core element comprising, based on the total weight of the core element;

about 0.1 to 95% weight of an active ingredient of low aqueous solubility;

about 0.1 to 55% by weight of a binding agent;

about 5 to 99% weight of a core seed; and

a core coating for the core element, based on the total weight of the core coating, excluding filler, comprising;

about 3 to 50% by weight of an insoluble polymer

about 30 to 97% by weight of an enteric polymer, the enteric polymer comprising at least about 70% by weight of the total weight of the enteric polymer and insoluble polymer; and

up to about 50% by weight of plasticizer;

wherein the core coating is such that the active ingredient is released in a controlled fashion in the intestine so that the blood level of the active ingredient is maintained within a therapeutically effective range over an extended period and is not substantially released in the stomach.