Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
1998-12-17
2003-10-14
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C514S960000, C424S465000, C424S452000
Reexamination Certificate
active
06632455
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to compositions having enhanced or improved bioavailability for a novel tricyclic amide compound.
WO 97/23478, published Jul. 3, 1997, discloses tricyclic amides useful for inhibition of G-Protein function and for treatment of proliferative diseases. One particular compound (+)-4-[4-(8-chloro-3,10-dibromo-6,11-dihydro-5H-benzo [5,6cyclohepta[1,2-b]pyridin-11-yl)-1-piperidinyl]-2-oxoethyl]-1-piperidinecarboxamide (Compound I)
was found to have potent activity for inhibiting the abnormal growth of cells, and for inhibiting farnesyl protein transferase.
WO 97/23478 discloses that examples of suitable compositions of this compound include solid compositions such as tablets and capsules.
In developing a solid dosage form, e.g. a tablet or capsule, it was observed that crystalline Compound I had very poor bioavailability, did not seem suitable for development as a tablet or capsule.
The oral bioavailability of active compounds can vary with the dosage form of the active compound. For example, it is known that solution dosages and suspensions generally give rise to higher bioavailability than capsules or tablets (see Pharmacokinetics Process and Mathematics, ACS Monograph 185, Chapter 5, page 57 (1986), and J. G. Nairn, Remington's Pharmaceutical Sciences, 18th edition (1990)). However, tablets and capsules are more convenient dosage forms, and it would be preferable to have a tablet or a capsule dosage form of an active compound that has comparable bioavailability as that of solution or suspension.
A formulation of compound I that provides enhanced bioavailability of the compound would be a welcome contribution to the art. A formulation of the above compound that can be manufactured in a tablet or capsule form that has greater bioavailability, or comparable to that of a suspension would also be a welcome contribution to the art. This invention provides these contributions to the art. Thus, this invention overcomes the problem of making active compounds that have a very-low bioavailability into more bioavailable form.
SUMMARY OF THE INVENTION
The present invention provides a pharmaceutical composition comprising:
a molecular dispersion, said molecular dispersion comprising a compound having the formula
molecularly dispersed in a polymer matrix.
This invention also provides solid dosage forms comprising the molecular dispersion described above. Solid dosage forms include tablets, capsules and chewable tablets. Known excipients can be blended with the molecular dispersion to provide the desired dosage form. For example, a capsule can contain the molecular dispersion blended with (a) a disintegrant and a lubricant, or (b) a disintegrant, a lubricant and a surfactant. A tablet can contain the molecular dispersion blended with at least one disintegrant, a lubricant, a surfactant, and a glidant. The chewable tablet can contain the molecular dispersion blended with a bulking agent, a lubricant, and if desired an additional sweetening agent (such as an artificial sweetener), and suitable flavors.
DETAILED DESCRIPTION OF THE INVENTION
The compound of Formula I is a tricyclic amide compound described in WO 97/23478, published Jul. 3, 1997.
Reference to the “compound of Formula I” also includes reference to the enantiomers of the compound.
As used herein, the term “molecularly dispersed” or “molecular dispersion” refers to a condition in which: (a) compound (I) is in a substantially amorphous form and is dispersed in a polymer matrix (also known as a “solid solution”), or (b) compound (I) is in crystalline form and is dispersed in a polymer matrix, the crystals being so fine, that they can not be detected by x-ray diffraction analysis.
As used herein, the term “substantially amorphous” refers to a condition in which greater than 90% of compound (I) is in amorphous form.
When the molecular dispersion is a dispersion of compound (I) in substantially amorphous form, such molecular dispersions may be prepared by dissolving the compound and a polymer in a suitable organic solvent, or mixture of organic solvents, and then removing the solvent to produce a molecular dispersion. The molecular dispersions formed in this manner are such that compound (I) is in substantially amorphous form, and homogeneously dispersed in the polymer matrix. Preferably, the polymer is a water soluble polymer. When water insoluble polymers are employed instead of water soluble polymers, the resulting molecular dispersions have enhanced bioavailability, but will exhibit a sustained release profile.
Alternatively, the molecular dispersions may be prepared by dissolving the compound of formula (I) in an organic solvent that will swell a polymer matrix instead of dissolving the polymer. The polymer matrix will absorb the active solution, rendering compound (I) in a fine crystalline or amorphous state dispersed throughout the matrix, upon subsequent evaporation of the solvent.
The preparation of solid solutions from soluble polymers is well known in the art—see, for example, page 173 in Kollidon—polyvinylpyrrolidone for the pharmaceutical industry by BASF. The preparation of solid solutions from insoluble polymeric matrices are also known in the art, and such preparations are similar to those for drug loading into crosslinked hydrogels—see for example, U.S. Pat. No. 4,624,848 and Lee, P. I., Kinetics of Drug Release from Hydrogel Matrices, Journal of Controlled Release, Vol. II, pages 277 to 288 (1985).
Suitable water soluble polymers for use as the polymer matrix include, but are not limited to: polyvinylpyrrolidone (Povidone); hydroxypropyl methylcellulose, hydroxypropyl-cellulose; polyethylene glycol; polyethylene oxide; gelatin; carbomer; carboxymethyl-cellulose; methyl cellulose; methacrylic acid copolymer; ammonio methacrylate copolymer; hydroxy ethyl cellulose; polyvinyl alcohol; cellulose acetate phthalate; hydroxypropyl methylcellulose phthalate; and polyvinyl alcohol phthalate.
Suitable water insoluble polymers for use as the polymer matrix include, but are not limited to: crospovidone; sodium starch glycolate; and croscarmellose.
Preferably, the polymer used for the polymeric matrix is selected from the group consisting of polyvinylpyrrolidone (Povidone), hydroxypropyl methylcellulose, hydroxypropyl-cellulose, and polyethylene glycol. Polyvinylpyrrolidone is particularly preferred. When a water isoluble polymer is employed, crospovidone is preferred.
All of the foregoing polymers are well known in the art.
Polyvinylpyrrolidone represents polymers of 1-vinyl-2-pyrrolidone. It is available commercially as Povidone or Kollidon having a weight average ranging from about 12,000 to about 150,000. Generally, the polyvinylpyrrolidone used has a weight average in the range of about 7000 to about 54,000, with about 28,000 to about 54,000 being preferred, and about 29,000 to about 44,000 being more preferred.
Crospovidone represents water insoluble synthetic cross-linked homopolymers of N-vinyl-2-pyrrolidone. Generally, the crospovidone has a particle size of about 20 &mgr;M to about 250 &mgr;M, and preferably about 50 &mgr;M to about 250 &mgr;M (see, for example, Kollidon, polyvinylpyrrolidone for the pharmaceutical industry, by BASF).
Preferably, the ratio of the compound of formula (I) to polymer is about 1:0.5 to about 1:4, more preferably about 1:1 to about 1:3, and most preferably, about 1:1.
When the molecular dispersions of the present invention are prepared by dissolving the compound of formula I and the polymer in an organic solvent or mixture of organic solvents, suitable organic solvents include, but are not limited to methylene chloride, methanol, ethanol, isopropanol, tetrahydrofuran, or mixtures thereof.
The solvent may be removed by conventional means: e.g., evaporating the solvent under a hood; use of a double drum dryer, or spray dryer or supercritical fluid extraction process.
The composition comprising the molecular dispersion can, optionally, further comprise excipients selected from the group consisting of:
Lee Ping I.
Nomeir Amin A.
Sangekar Surendra A.
Hoffman Thomas D.
Kutzenco Alan N.
Schering Corporation
Webman Edward J.
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