WO2004082587A2 - Stable lamotrigine pharmaceutical compositions and processes for their preparation - Google Patents
Stable lamotrigine pharmaceutical compositions and processes for their preparation Download PDFInfo
- Publication number
- WO2004082587A2 WO2004082587A2 PCT/IB2004/000820 IB2004000820W WO2004082587A2 WO 2004082587 A2 WO2004082587 A2 WO 2004082587A2 IB 2004000820 W IB2004000820 W IB 2004000820W WO 2004082587 A2 WO2004082587 A2 WO 2004082587A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- weight
- lamotrigine
- pharmaceutical composition
- sodium starch
- starch glycolate
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
Definitions
- the present invention relates to a stable pharmaceutical composition of lamotrigine and pharmaceutically acceptable acid addition salts thereof.
- the invention also relates to a process for the preparation of such a composition.
- Lamotrigine is 3,5-diamino-6-(2,3-dichlorophenyl)-l,2,4-triazine. Lamotrigine is indicated as adjunctive therapy for the treatment of partial seizures in adults with epilepsy.
- U.S. Patent No. 5,861,179 discloses a powder formulation of lamotrigine that includes lamotrigine or a pharmaceutically acceptable acid addition salt thereof with lactose, starch, crystalline cellulose and polyvinylpyrrolidone. Further specified are the specific grades, concentrations and particle size of the excipients, which are necessary to make a stable powder formulation.
- One specific formulation disclosed is (a) from 0.5 to 50% by weight of lamotrigine or a pharmaceutically acceptable acid addition salt thereof, (b) from 15 to 50% by weight of lactose, (c) from 15 to 50% by weight of starch, (d) from 0.5 to 15% by weight of crystalline cellulose, and (e) from 5 to 15% by weight of polyvinylpyrrolidone.
- the formulation is further characterized as being in the form of a free-flowing powder of granules in which (i) no granules have a particle size of greater than 850 microns, (ii) at least 90% by weight of the granules have a particle size of from 75 to 850 microns, (iii) the granules disintegrate within 30 minutes according to the Disintegration Test of The Pharmacopoeia of Japan, twelfth edition, 1991, and (iv) at least 90% by weight of the lamotrigine or lamotrigine salt in the granules dissolves within 30 minutes when the granules are subjected to the Dissolution Test, method 2 (paddle method) of The Pharmacopoeia of Japan, twelfth edition, 1991. Also disclosed is the use of spray granulation as a process to make such a powder formulation.
- Embodiments of the pharmaceutical composition may include one or more of the following features.
- the pharmaceutical composition may further include about 17% to about 70% by weight of microcrystalline cellulose, about 0.1 % to about 13% by weight of sodium starch glycolate, and about 0.1% to about 4% by weight of polyvinylpyrrolidone.
- the pharmaceutical composition may further include from about 0.1% to about 14.5% by weight of lactose.
- the pharmaceutical composition may further include about 17% to about 70% by weight of microcrystalline cellulose, about 0.1% to about 13% by weight of sodium starch glycolate, about 0.1% to about 4% by weight of polyvinylpyrrolidone, and about 0.1% to about 13% by weight of lactose.
- the pharmaceutical composition may still further include about 20% to about 70% by weight of microcrystalline cellulose, about 0.1% to about 10% by weight of sodium starch glycolate, about 0.1% to about 3% by weight of polyvinylpyrrolidone, and about 0.1% to about 10% by weight of lactose.
- the sodium starch glycolate may be intragranularand/or extragranular.
- the pharmaceutical composition may be a tablet.
- At least 80% by weight of the lamotrigine or the acid addition salt thereof may dissolve within 10 minutes. At least 90% by weight of the lamotrigine or the acid addition salt thereof may dissolve within 30 minutes.
- the pharmaceutical composition may be stable after three months storage at 40°C and 75% RH with at least 98% of the lamotrigine or acid addition salt thereof remaining after three months.
- a process for preparing a pharmaceutical composition includes wet granulating a composition that includes:
- the pharmaceutical composition may further include about 17% to about 70% by weight of microcrystalline cellulose, about 0.1% to about 13% by weight of sodium starch glycolate, and about 0.1% to about 4% by weight of polyvinylpyrrolidone.
- the pharmaceutical composition may further include from about 0.1% to about 14.5% by weight of lactose.
- the pharmaceutical composition may further include about 17% to about 70% by weight of microcrystalline cellulose, about 0.1% to about 13% by weight of sodium starch glycolate, about 0.1% to about 4% by weight of polyvinylpyrrolidone, and about 0.1% to about 13% by weight of lactose.
- the pharmaceutical composition may still further include about 20% to about 70% by weight of microcrystalline cellulose, about 0.1% to about 10% by weight of sodium starch glycolate, about 0.1% to about 3% by weight of polyvinylpyrrolidone, and about 0.1% to about 10% by weight of lactose.
- the lamotrigine or its acid addition salt, microcrystalline cellulose, sodium starch glycolate, polyvinylpyrrolidone and/or lactose may be blended and then granulated with water.
- the lamotrigine or its acid addition salt, microcrystalline cellulose, sodium starch glycolate and/or lactose may be blended and then granulated with an aqueous solution of polyvinylpyrrolidone.
- the process may further include screening the wet mass to obtain granules.
- the process may still further include drying and sieving the granules.
- the process may still further include compressing the granules to form tablets.
- the sodium starch glycolate may be is intragranular and/or extragranular.
- a method of treating a medical condition responsive to lamotrigine includes administering a pharmaceutical composition of lamotrigine.
- the composition includes:
- the pharmaceutical composition may further include from about 0.1 % to about 14.5% by weight of lactose.
- a stable tablet of lamotrigine can be prepared by wet granulation with about 15.5% to about 70% by weight of microcrystalline cellulose, about 0.1% to about 14.5% by weight of sodium starch glycolate, and about 0.1% to about 4.5% by weight of polyvinylpyrrolidone, with or without the inclusion of lactose.
- lamotrigine refers to its free base or acid addition salt, such as, methanesulphonate and isothionate salts.
- formulations may include from about 0.1% to about 50% by weight of lamotrigine or a lamotrigine salt by weight of the tablet.
- Microcrystalline cellulose is commonly used as a filler in tablets. It is a white, odorless, tasteless, free flowing powder.
- Particularly suitable fillers include one or more of Avicel PH101, Avicel PH102, Tabulose® 101, Tabulose®102, Vivapur®102 or a combination thereof. These grades have a particle size in the range of about 50 ⁇ to about lOO ⁇ .
- the microcrystalline cellulose may be present in the tablet in an amount of from about 15.5% to about 70% by weight of the tablet, more particularly from about 17% to about 70% by weight of the tablet, and even more particularly from about 20% to about 70% by weight of the tablet.
- Sodium starch glycolate is used herein as a disintegrant. It is a white to off-white, tasteless, odorless, relatively free flowing powder. Sodium starch glycolate absorbs water rapidly, resulting in swelling, which leads to rapid disintegration of tablets and granules that include the sodium starch glycolate. It can be used intragranularly as well as extragranularly and may be present in amounts of from about 0.1% to about 14.5% by weight of the tablet, more particularly from about 0.1% to about 13% by weight of the tablet, and even more particularly from about 0.1% to about 10% by weight of the tablet.
- Polyvinylpyrrolidone is a commonly used binder. It is a white or creamy white powder and is available at different molecular weights. Suitable grades include those having molecular weights of from about 40,000 to 1,300,000 Daltons. Povidone K30 and Povidone 90 and combinations thereof are particularly suitable. Polyvinylpyrrolidone may be present in an amount of from about 0.1% to about 4.5% by weight of the tablet, more particularly from about 0.1% to about 4% by weight of the tablet, and even more particularly from about 0.1% to about 3% by weight of the tablet.
- Lactose is another commonly used filler in tablets. It is a white or almost white, free flowing powder. Lactose may include anhydrous lactose, such as Pharmatose® grades 150M, 200M, 350M, 450M, DCL21 and combinations thereof. Lactose may be present in an amount of from about 0.1% to about 14.5% by weight of tablet, in particular from about 0.1% to about 13% by weight of the tablet, and, more particularly, from about 0.1% to about 10% by weight of the tablet.
- the present pharmaceutical composition may also include one or more glidants and lubricants, such as talc, colloidal silicon dioxide, magnesium stearate and sodium stearyl fumarate.
- a pharmaceutical composition was prepared by wet granulation.
- Lamotrigine or its acid addition salt was mixed with microcrystalline cellulose, sodium starch glycolate, lactose, and polyvinylpyrrolidone. The blend was then granulated with purified water in a rapid mixer granulator.
- a blend including lamotrigine or its acid addition salt, microcrystalline cellulose, sodium starch glycolate and lactose may be granulated with an aqueous solution of polyvinylpyrrolidone. The wet mass was then screened to obtain granules.
- the granules were dried and mixed with extragranular excipients such as fillers (e.g., microcrystalline cellulose), disintegrants (e.g., sodium starch glycolate), lubricants (e.g., magnesium stearate) and glidants (e.g., talc and colloidal silicon dioxide).
- extragranular excipients such as fillers (e.g., microcrystalline cellulose), disintegrants (e.g., sodium starch glycolate), lubricants (e.g., magnesium stearate) and glidants (e.g., talc and colloidal silicon dioxide).
- fillers e.g., microcrystalline cellulose
- disintegrants e.g., sodium starch glycolate
- lubricants e.g., magnesium stearate
- glidants e.g., talc and colloidal silicon dioxide
- Lamotrigine raw material and tablets have been reported to have two impurities (A) 3-amino-6-(2,3-dichlorophenyl)-l,2,4-triazine-5-(4H)-one; and (B) N-(5- amino-6-(2,3-dichloropneyl)-l 5 2 3 4-triazine-3-yl)-2,3-dichlorobenzamide (B).
- the impurity A is a degradation product produced during the hydrolysis of lamotrigine and impurity B is a process impurity formed during the synthesis of lamotrigine.
- the degradation products are either not formed or are below the level of quantification.
- Example 1 The tablets of Example 1 were prepared as follows:
- Lamotrigine, lactose, polyvinylpyrrolidone, iron oxide (yellow), a portion of microcrystalline cellulose (i.e., the intragranular portion), and a portion of sodium starch glycolate (i.e., the extragranular portion) were sifted through a suitable mesh and mixed for 10 minutes.
- Step 2 The blend of Step 1 was granulated with purified water.
- Example 1 The tablets of Example 1 were subjected to accelerated studies for three months at 40°C and 75% relative humidity (RH) and the results are shown in Table 1.
- Example 1 The tablets of Example 1 were also subjected to dissolution studies in USP 2 apparatus at 50 RPM in 900 mL of 0.1N HCl. The dissolution profile of the tablets at the initial and 3 months period is given in Table 2.
- Table 2 Dissolution profile of tablets prepared as per the composition of Example 1 (in USP 2 apparatus at 50 RPM in 900 mL of 0.1N HCl).
- Example 2 The tablets of Example 2 containing lamotrigine (5 mg) were prepared as described above with respect to the process of Example 1. In Example 2, the microcrystalline cellulose is present at about 60% by weight of tablet.
- Example 3 The tablets of Example 3 containing lamotrigine (5 mg) were prepared as described above with respect to the process of Examples 1 and 2, although without lactose being present. The tablets of Example 3 were subjected to accelerated studies for three months at 40°C and 75% relative humidity. The results of these studies are reported in Table 3. Table 3: Stability data of lamotrigine tablets prepared as per Example 3 and subjected to accelerated studies.
Abstract
Description
Claims
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP04721960A EP1608342A2 (en) | 2003-03-21 | 2004-03-19 | Stable lamotrigine pharmaceutical compositions and processes for their preparation |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN355/DEL/2003 | 2003-03-21 | ||
IN355DE2003 | 2003-03-21 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2004082587A2 true WO2004082587A2 (en) | 2004-09-30 |
WO2004082587A3 WO2004082587A3 (en) | 2004-12-02 |
Family
ID=33017827
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2004/000820 WO2004082587A2 (en) | 2003-03-21 | 2004-03-19 | Stable lamotrigine pharmaceutical compositions and processes for their preparation |
Country Status (2)
Country | Link |
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EP (1) | EP1608342A2 (en) |
WO (1) | WO2004082587A2 (en) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1992013527A1 (en) * | 1991-01-30 | 1992-08-20 | The Wellcome Foundation Limited | Water-dispersible tablets |
US5861179A (en) * | 1994-12-07 | 1999-01-19 | The Wellcome Foundation Limited | Pharmaceutical composition of lamotrigine |
-
2004
- 2004-03-19 EP EP04721960A patent/EP1608342A2/en not_active Withdrawn
- 2004-03-19 WO PCT/IB2004/000820 patent/WO2004082587A2/en not_active Application Discontinuation
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1992013527A1 (en) * | 1991-01-30 | 1992-08-20 | The Wellcome Foundation Limited | Water-dispersible tablets |
US5861179A (en) * | 1994-12-07 | 1999-01-19 | The Wellcome Foundation Limited | Pharmaceutical composition of lamotrigine |
Non-Patent Citations (1)
Title |
---|
GLAXO WELLCOME INC.: "Lamictal tablets - FDA approved labeling text" INTERNET CITATION, [Online] 2001, XP002296818 Retrieved from the Internet: URL:http://www.fda.gov/cder/foi/label/2001 /20764s5lbl.pdf> [retrieved on 2004-09-15] * |
Also Published As
Publication number | Publication date |
---|---|
WO2004082587A3 (en) | 2004-12-02 |
EP1608342A2 (en) | 2005-12-28 |
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