Specification
IMATIN1B COMPOSITIONS
CROSS REFERENCE TO RELATED APPLICATIONS The present application claims the benefit of United States Provisional Patent Application No. 60/841,707, filed September 1, 2006, the contents of which is incorporated herein by reference.
FIELD OF THE INVENTION The invention relates to compositions of imatinib, methods for their preparation, and methods for treatment using the same.
BACKGROUND OF THE INVENTION Imatinib, as exemplified by the mesylate or 4-[(4-Methyl-l-piperazinyl)memyl]-N-[4-memyl-3-[[4-(3-pyridinyl)-2-pyrinidinyl]amino]-phenyl]benzamide methanesulfonate, has the following chemical structure:
It is reported to be a white to off-white to brownish or yellowish tinged
(Formula Removed)
crystalline powder. Imatinib mesylate is understood to be soluble in aqueous buffers having a pH less than or equal to 5.5, but is very slightly soluble to insoluble in neutral/alkaline aqueous buffers. In non-aqueous solvents, the drug substance is apparently freely soluble to very slightly soluble in dimethyl sulfoxide, methanol Md ethanol, but is insoluble in n-octanol, acetone and acetonitrile.
Imatinib is indicated for the treatment of newly diagnosed adult patients with Philadelphia chromosome positive chronic myeloid leukemia (CML) in chronic phase.
Imatinib is sold under the brand name Gleevec® (imatinib as mesylate)
which is marketed by Novartis Pharmaceuticals. Gleevec® is available in tablets for oral administration in 400 mg and 600 mg strength. The inactive ingredients of Gleevec® are reported to be colloidal silicon dioxide (NF); crospovidone (NF); hydroxypropyl methylcellulose (USP); magnesium stearate (NF); and microcrystalline cellulose (NF). Tablet coating: ferric oxide, red (NF); ferric oxide,: yellow (NF); hydroxypropyl methylcellulose (USP); polyethylene glycol (NF) and talc (USP).
Imatinib is generally known to be a hygroscopic material. PCT application WO 2006/048890 describes an "Alpha" form with specific hygroscopic properties, i.e., apparently the water uptake is not more than 1% w/w, preferably not more thin 0.6 % at 80% RH over a period of 90 hours. Other polymorphs of imatinib have been described including, for example, the mesylate salt. U.S. Patent 6,894,051 describes an allegedly novel non-hygroscopic form of imatmib.
There is a need in the art for stable imatinib compositions in order to achieve the desired therapeutic effect, particularly those that are chemically and physically stable.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a solid solution, preferably a stable solid solution, comprising a solid solvent and imatinib selected from amorphous and crystalline forms of imatinib and pharmaceutical acceptable salts thereof. Preferably, imatinib is selected from amorphous and crystalline forms of imatinib mesylate. Preferably, the solid solvent is a polyvinylpyrolidone (PVP), more preferably Povidone.
In another aspect, the present invention provides a stable pharmaceutical composition comprising a solid solution and at least one pharmaceutically acceptable excipient, wherein the solid solution comprises a solid solvent and imatinib selected from amorphous and crystalline forms of imatinib and pharmaceutical acceptable salts thereof. Preferably, imatinib is selected from amorphous and crystalline forms of imatinib mesylate. Preferably, the solid solvent is a polyvinylpyrolidone (PVP), more preferably Povidone.
In another aspect, the present invention provides a method of preparing a solid solution of a solid solvent and imatinib, comprising the steps of
a) coprecipitating a mixture comprising imatinib or a pharmaceutically acceptable salt thereof, and a solid solvent from a processing solvent to form a solid solution;
b) optionally combining the solid solution with at least one pharmaceutically acceptable excipient, to form a mixture; and
c) granulating the mixture to form a pharmaceutical composition.
Alternatively, a solid solution of a solid solvent and Imantinib may be
prepared by a process comprising:
a) providing imatinib selected from crystalline and amorphous forms of imatinib or pharmaceutical acceptable salts thereof;
b) dissolving a solid solvent in a processing solvent, forming a solution of the solid solvent;
c) mixing imatinib with the solution of the solid solvent, forming a mixture; and
d) removing the processing solvent, forming a solid solution.
In yet another aspect, the present invention provides a method of preparing a pharmaceutical composition comprising a solid solution of a solid solvent and imatinib, comprising the steps of
a) providing imatinib, selected from amorphous and crystalline forms of imatinib and pharmaceutical acceptable salts thereof;
b) mixing imatinib, a solid solvent and a processing solvent, forming a mixture;
c) removing the process solvent, preferably thereby co-precipitating imatinib and a solid solvent from the processing solvent, forming a solid solution of imatinib, preferably by evaporation,
d) optionally mixing the solid solution with at least one pharmaceutical acceptable excipient, forming a solid solution mixture; and
e) granulating the solid solution forming a stable pharmaceutical composition.
The present invention also provides a method of treating a patient suffering
from a disease comprising administering to a patient in need thereof a therapeuticaoy effective amount of a stable pharmaceutical composition comprising a solid solution, wherein the solid solution comprises a solid solvent and imatinib selected from amorphous and crystalline forms of imatinib and pharmaceutical acceptable salts
thereof. Preferably, imatinib is selected from amorphous and crystalline forms of imatinib mesylate.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1. Shows the morphology of imatinib particles in a solid solution of PVP,
at a ratio of imatinib:PVP of 1:0.5 (wt/wt)
Figure 2. Shows the morphology of imatinib particles in a solid solution of PVP,
at a ratio of imatinib:PVP of 1:2 (wt/wt).
Figure 3. First row: Slugs prepared according to Example 5 after storage for 28
days at 40°C and 75% relative humidity, stored (a) without silica gel inserts or (b) with silica gel inserts. Second row: crystalline raw material after storage for 28 days at 40°C and 75% relative humidity, stored (a) without silica gel inserts or (b) with silica gel inserts.
DETAILED DESCRIPTION OF THE INVENTION
As used herein the term "room temperature" refers to the ambient temperatfire of an typical laboratory, which is usually about that of Standard Temperature and Pressure (STP).
The term "solid solvent" as used herein describes a solid carrier that is capable of forming a solid solution with one or more additional solids described herein. A "solid solution" is a homogeneous solid that can exist over a range of component 20 chemicals.
The term "stable" as used herein relates to a substance which is chemically and/or physically stable.
The term "chemical stability" as used herein relates to the presence or absence of degradation products of the active pharmaceutical ingredient (API) as measurea5 over time. Chemical stability is measured as the Assay of the material and/or the level of degradants. Stability is defined as having an Assay of at least about 90%, as determined by an HPLC assay method and/or having a minimum level of degradants, as determined by an HPLC Impurities and Degradation Determination (IDD) method over time. Preferably, a chemically stable composition as in the present inventioriSOas an assay of at least 95%, more preferably at least 98%, as determined by an HPLC assay over time (storage time).
As used herein the term "physical stability" of a composition means the appearance of the composition is substantially unchanged and/or the hygroscopicity is low.
The term "appearance" as used herein describes the color and texture of a composition. The color of a composition according to a scored scale, as assessed byj one of ordinary skill in the art in view of the following guidelines. A discoloration score of 1 indicates material without discoloration, whereas a discoloration score of'. indicates severe discoloration (almost complete discoloration) relative to the color of the material as obtained after preparation and prior to storage. In the present invention the composition preferably has a white color immediately after processing and generally remains white if stable. Discoloration to a yellow color is typical when the composition is unstable. Similarly, a texture score of 1 indicates material having an uniform and smooth texture, whereas a texture score of 5 indicates a nonuniform and rough texture. The texture may be determined by visual inspection by one of ordinary skill in the art. For both discoloration and texture, scores 2 to 4 represents "some or slight (change)" for a score of 2, "medium (change)" for a score of 3, and "substantial (change)" for a score of 4.
Texture is often highly correlated with hygroscopicity. Water/moisture absorption tends to reduce shine, for example. Water hygroscopicity can be determined by weight gain analyses.
Preferred embodiments of the invention have the following stability characteristics: (a) a coloration score of 4 or less and/or 3 or less and/or 2 or less, and/or a.texture score of 3 or less and/or 2 or less after storage (i) at a temperature of about 55°C and about 75% relative humidity for 5 days, and/or (ii) at a temperature of about 40°C and about 75 % relative humidity for 30 days. Preferably, a solid sohHSon of the invention has a coloration score of 3 or less, and preferably a pharmaceutical composition of the invention has a coloration score of 4 or less.
It was determined that the physical state, in particular hygroscopicity, of imatinib depends to a certain degree on the physical structure of the active drug, e.g. its polymorphism. As an example, amorphous API material tended to be much m8te hygroscopic when compared to crystalline material. It is known in the art that hygroscopic active materials will sometimes tend to be chemically and physically unstable as compared to the corresponding crystalline material. Therefore, in one embodiment the present invention provides processes and compositions that will
enable development and/or manufacture imatinib formulations where the physical state of the active drug has less effect on the product's chemical stability and/or physical stability.
Stability of an active pharmaceutical ingredient such as imatinib in the present invention may be improved, for example, by processes that use stabilized solid solutions of imatinib as a "drug source" in imatinib formulations; that use a different granulation process; or both. A product can be further optimized using packaging materials such as dessicants.
In one aspect, the present invention provides a solid solution comprising a solid solvent and imatinib selected from amorphous and crystalline forms of imatMlb and pharmaceutical acceptable salts thereof. Preferably, the solid solution is a stable solution. Preferably, imatinib is selected from amorphous and crystalline forms of imatinib mesylate. Preferably, the solid solvent is a polyvinylpyrolidone (PVP), more preferably Povidone.
A preferred solid solution of the present invention provides greater stabilit%5in solutions comprising at least about 50% of the solid solvent by weight. Accordingly, solid solutions comprising imatinib of the present invention may have a weight/weight ratio of imatinibrSolid Solvent (preferably imatinib :Povidone) in the range from about 1:0.17 to about 1:4, preferably about 1:0.5 to about 1:4, more preferably from about 1:1 to about 1:2.
In another aspect, the present invention provides a stable pharmaceutical composition comprising a solid solution and at least one pharmaceutically acceptable excipient, wherein the solid solution comprises a solid solvent and imatinib selected from amorphous and crystalline forms of imatinib and pharmaceutical acceptable salts thereof. Preferably, the solid solvent is a polyvinylpyrolidone (PVP), more prefefSbly the solid solvent is Povidone.
In another embodiment of the present invention there is provided a stable pharmaceutical composition comprising a solid solution of a solid solvent and imatinib, which has at least one pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient is selected from the group consisting of taH9t and capsule fillers and diluents (such as microcrystalline cellulose, lactose, starch and tri-basic calcium phosphate), disintegrants (such as starch, croscarmellose sodium, crospovidone and sodium starch glycolate), and glidants (such as colloidal silicon dioxide and talc), lubricants (such as magnesium stearate, sodium lauryl sulfate,
stearic acid and sodium stearyl fumarate), binders (such as starch and pregelatinized starch).
More particularly, suitable diluents and fillers for use in the pharmaceutical composition of the present invention include microcrystalline cellulose (e.g. Avicel®), lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, powdered cellulose, sodium chloride, sorbitol and talc.
Solid pharmaceutical compositions of the present invention that are compacted into a dosage form, such as a tablet, may include the addition of a disintegrant to IlKfe composition. Disintegrants include croscaimellose sodium (e.g. Ac Di Sol , Primellose®), crospovidone (e.g. Kollidon®, Polyplasdone®), microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium starch glycolate (e.g. Explotab®, Prirnoljel®) and starch.
Glidants can be added to improve the flowability of a solid composition bifbre compaction and to improve the accuracy of dosing especially during compaction and capsule filling. Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, and talc.
A lubricant can be added to the composition to reduce adhesion and/or ease the release of the product from e,g. the dye. Lubricants include magnesium stearaMJ calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.
Binders may be incorporated into the formulation. Binders are typically utilized if the manufacture of the dosage form uses a granulation step. Examples <26 suitable binders include povidone, polyvinylpyrrolidone, xanthan gum, cellulose gums such as carboxymethylcellulose, methyl cellulose,
hydroxypropylmethylcellulose, hydroxycellulose, gelatin, starch, and pregelatinized starch. Also, binders are often the same polymers as the polymers used to control the release of the active ingredient from the formulation.
Other excipients that may be incorporated into the formulation include preservatives, surfactants, antioxidants, or any other excipient commonly used in the pharmaceutical industry. An optional tablet coat is preferably cosmetic and may be prepared from, for example, commercially available powders for coating suspensions
based on either Hypromellose or Polyvinyl alcohol, together with polyethylene Glycol and colorants etc.
In a preferred embodiment of the present invention, the stable pharamceutical composition comprises in addition to a solid solution of a solid solvent and imatinib Croscarmellose sodium, Pregelatinized starch (1500), Lactose, and Magnesium Stearate.
The solid stable pharmaceutical compositions of the present invention include powders, granulates, aggregates and compacted, compositions. The dosages include dosages suitable for oral, buccal, and rectal administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral. The dosages may be conveniently presented in unit dosage form and prepared by any of the methods well known in the pharmaceutical arts. Preferably, the dosage form comprises about 50mg to about 500mg imatinib, more preferably about lOOmg to about 400mg imatinib.
The pharmaceutical composition of the present invention may be prepared in any dosage form such as a compressed granulate in the form of a tablet for example. Also, uncompressed granulates and powder mixes that are obtained by the method of the present invention in the pre-compression steps can be simply provided in a dosage form of a capsule or sachet. Therefore, dosage forms of the pharmaceutical composition of the present invention include solid dosage forms like tablets, powders, capsules, sachets, etc. The dosage form of the present invention may also be a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or soft shell. The shell may be made from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.
Embodiments of the invention are preferably packaged with a desiccant, such as silica. The container preferably has a high moisture barrier, examples of which are known in the art. In a preferred packaged pharmaceutical composition of the present invention an amount of desiccant which will assure a weight gain due to moisture3
Documents
Application Documents
| # |
Name |
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| 1 |
1220-delnp-2009-abstract.pdf |
2011-08-21 |
| 1 |
1220-delnp-2009-pct-308.pdf |
2011-08-21 |
| 2 |
1220-delnp-2009-pct-304.pdf |
2011-08-21 |
| 2 |
1220-delnp-2009-claims.pdf |
2011-08-21 |
| 3 |
1220-delnp-2009-pct-237.pdf |
2011-08-21 |
| 3 |
1220-delnp-2009-correspondence-others.pdf |
2011-08-21 |
| 4 |
1220-delnp-2009-pct-210.pdf |
2011-08-21 |
| 4 |
1220-delnp-2009-description (complete).pdf |
2011-08-21 |
| 5 |
1220-delnp-2009-gpa.pdf |
2011-08-21 |
| 5 |
1220-delnp-2009-drawings.pdf |
2011-08-21 |
| 6 |
1220-delnp-2009-form-5.pdf |
2011-08-21 |
| 6 |
1220-delnp-2009-form-1.pdf |
2011-08-21 |
| 7 |
1220-delnp-2009-form-3.pdf |
2011-08-21 |
| 7 |
1220-delnp-2009-form-18.pdf |
2011-08-21 |
| 8 |
1220-delnp-2009-form-2.pdf |
2011-08-21 |
| 9 |
1220-delnp-2009-form-3.pdf |
2011-08-21 |
| 9 |
1220-delnp-2009-form-18.pdf |
2011-08-21 |
| 10 |
1220-delnp-2009-form-1.pdf |
2011-08-21 |
| 10 |
1220-delnp-2009-form-5.pdf |
2011-08-21 |
| 11 |
1220-delnp-2009-gpa.pdf |
2011-08-21 |
| 11 |
1220-delnp-2009-drawings.pdf |
2011-08-21 |
| 12 |
1220-delnp-2009-pct-210.pdf |
2011-08-21 |
| 12 |
1220-delnp-2009-description (complete).pdf |
2011-08-21 |
| 13 |
1220-delnp-2009-pct-237.pdf |
2011-08-21 |
| 13 |
1220-delnp-2009-correspondence-others.pdf |
2011-08-21 |
| 14 |
1220-delnp-2009-pct-304.pdf |
2011-08-21 |
| 14 |
1220-delnp-2009-claims.pdf |
2011-08-21 |
| 15 |
1220-delnp-2009-pct-308.pdf |
2011-08-21 |
| 15 |
1220-delnp-2009-abstract.pdf |
2011-08-21 |