Formulations and method of treatment

• US 8,637,512 B2
• Filed: 12/02/2003
• Issued: 01/28/2014
• Est. Priority Date: 07/29/2002
• Status: Active Grant

• Current Assignee: Glaxo Group Limited (GSK plc)
• Original Assignee: Glaxo Group Limited (GSK plc)
• Inventors: Buxton, Ian Richard, Karolak, Wlodzimierz, Iyer, Vijay Mohan, Maleki, Mehran
• Primary Examiner(s): Padmanabhan, Sreeni
• Assistant Examiner(s): Neagu, Irina
• Application Number:
  US10/726,752
• Publication Number:
  US 20040192690A1
• Time in Patent Office: 3,710 Days
• Field of Search: 514/241, 514/242, 424/468, 424/497
• US Class Current: 514/242
• CPC Class Codes: A61K 31/53 having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine melarsoprol A61K31/555 ; with four nitrogen atoms A61K31/495
• CPC Class Codes: A61K 9/2031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2846 Poly(meth)acrylates
• CPC Class Codes: A61K 9/2866 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants

Abstract

A sustained release formulation of lamotrigine or a pharmaceutically acceptable derivative thereof and methods of treatment and uses thereof.

Claims

1. A sustained release formulation of lamotrigine, which has a mean serum lamotrigine concentration-time profile as shown in or substantially similar to that shown in the second graph of FIG. 8, comprising a matrix tablet in which there are two phases in the release of lamotrigine, wherein the release rate in the first phase takes place in the oesophagus and stomach and said release is slower than the release rate in the second phase which takes place when the surrounding pH exceeds 5, wherein the sustained release formulation comprises:

1) a core comprising;

a) 2.5 to 80% by weight lamotrigine;

b) 17.5 to 70% by weight release retarding hydroxypropylmethylcellulose polymer which comprises Methocel E4M and Methocel K100LV;

c) 0 to 60% by weight diluent;

d) 0 to 20% by weight compression aid;

e) 0.1 to 2.5% by weight lubricants; and

2) an outer coat covering said core comprising;

f) 0.05 mm to 0.30 mm of methacrylic copolymer which is Eudragit L30 D55;

in which the thickness of said outer coating is adapted such that it is substantially impermeable to the entrance of an environmental fluid, substantially impermeable to the exit of lamotrigine, dissolves when the surrounding pH exceeds 5; and

includes one or more orifices extending from the outside of the coating substantially completely through said coating but not penetrating said core allowing the release of lamotrigine from the core into environmental fluid, said orifices having an area or combined area from about 10 to about 60 percent of the face area of said formulation, wherein the release of lamotrigine occurs substantially through said orifice.

2. A sustained release formulation as claimed in claim 1 which upon administration to a human produces AUC values within the range of 80 to 125% and a C_max being of about 30% less than an instant release tablet containing the same amount of lamotrigine.

3. A sustained release formulation of lamotrigine, which has a mean serum lamotrigine concentration-time profile as shown in or substantially similar to that shown in the second graph of FIG. 8, comprising a matrix tablet in which there are two phases in the release of lamotrigine, wherein the release rate in the first phase takes place in the oesophagus and stomach and said release is slower than the release rate in the second phase which takes place when the surrounding pH exceeds 5, wherein the formulation comprises:

1) a core comprising;

a) 2.5 to 80% by weight lamotrigine;

b) 17.5 to 70% by weight release retarding hydroxypropylmethylcellulose polymer which comprises Methocel E4M and Methocel K100LV;

c) 0 to 60% by weight diluent;

d) 0 to 20% by weight compression aid;

e) 0.1 to 2.5% by weight lubricants; and

2) an outer coat covering said core comprising;

f) 0.05 mm to 0.30 mm of methacrylic copolymer which is Eudragit L30 D55;

in which the thickness of said outer coating is adapted such that it is substantially impermeable to the entrance of an environmental fluid, substantially impermeable to the exit of lamotrigine, dissolves when the surrounding pH exceeds 5; and

includes one or more orifices extending from the outside of the coating substantially completely through said coating but not penetrating said core, allowing the release of lamotrigine from the core into environmental fluid, said orifices having an area or combined area from about 10 to about 60 percent of the face area of said formulation, wherein the release of lamotrigine occurs substantially through said orifice, and said sustained release formulation upon administration to a human produces AUC values within the range of 80 to 125% and a C_max being of about 30% less than an instant release tablet containing the same amount of lamotrigine.