Drug – bio-affecting and body treating compositions – Designated organic nonactive ingredient containing other... – Solid synthetic organic polymer
Reexamination Certificate
2000-01-31
2003-04-15
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Designated organic nonactive ingredient containing other...
Solid synthetic organic polymer
C424S488000, C424S484000, C424S486000
Reexamination Certificate
active
06548555
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to compositions of basic drugs, zwitterionic drugs, or salts of either that have improved solubility, hence bioavailability, in the small intestine, to processes for testing such compositions, and to methods of using such compositions. In particular, it relates to compositions comprising a basic or a zwitterionic drug and a polymer selected from hydroxypropylmethylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate (CAT), cellulose acetate phthalate (CAP), hydroxypropylcellulose acetate phthalate (HPCAP), hydroxypropylmethylcellulose acetate phthalate (HPMCAP), and methylcellulose acetate phthalate (MCAP). The invention further relates to a method for increasing the bioavailability of a basic or a zwitterionic drug comprising co-administering the basic or zwitterionic drug with any one or more of the aforementioned polymers.
BACKGROUND OF THE INVENTION
It is known in the pharmaceutical arts that low-solubility drugs often show poor bioavailability or irregular absorption, the degree of irregularity being affected by factors such as dose level, fed state of the patient, and form of the drug. A drug which forms a zwitterion can also exhibit poor solubility, depending on its pK
a
s and on the pH of its aqueous use environment.
Many basic drugs are quite bioavailable, although bioavailability can be dose-dependent. In the low pH environment of the stomach (pH 1-2, usually about 1.2), a basic drug may be soluble. When the drug solution passes into the higher pH environment of the small intestine where the pH is 5 to 7, usually about 6.5, the drug may be above its equilibrium solubility at that pH. However, if the dose is relatively low and if the drug has the capacity to temporarily supersaturate, the drug may maintain supersaturation in the small intestine for a time, thus permitting absorption of the dissolved drug across the intestinal wall. In general, the residence time in the small intestine of humans is around 4 hours. Thus, a drug which can maintain supersaturation at intestinal pH will, in general, be better absorbed than one which does not.
Zwitterionic drugs can be affected by the same considerations. That is, even though a drug forms ions in aqueous use environments having acid and/or basic pHs, and thereby exhibits good solubility in such use environments, the same drug may be poorly soluble in an aqueous use environment having a pH at which the drug assumes its neutral form and the neutral form intrinsically exhibits poor aqueous solubility at that pH.
Some basic and zwitterionic drugs exhibit “dose/solubility-limited exposure”. As the dose is increased, the systemic drug exposure increases until a limiting dose is achieved, above which dose the increase in systemic exposure with increasing dose is less than that observed at doses lower than this dose. Since basic and zwitterionic drugs are generally soluble at gastric pH, this effect may be due to precipitation of drug in the small intestine above the limiting dose.
Some basic drugs exhibit little or no capacity to be supersaturated at neutral pH; such drugs precipitate quickly in the small intestine even if reasonably soluble in the stomach, and are poorly bioavailable.
It is not generally possible to predict the propensity of a basic drug to supersaturate the small intestinal lumen.
Miyajima et al., U.S. Pat. No. 4,983,593 relates to the destruction of drug crystallinity by drying a solution of drug and polymer. Miyajima discloses, inter alia, formulating HPMCAS with a drug designated as NZ-105. The patent disclosed that there is formed “. . . a composition having a remarkably enhanced bioavailability and easily prepared into tablets, capsules, granules, powders, and the like . . . ” The patent teaches that the formulations can be prepared by dissolving NZ-105 and HPMCAS in an organic solvent and removing the solvent by means of vacuum-drying, spray-drying, freeze-drying, or the like, or by coating a filler such as an inorganic salt (e.g., calcium hydrogen phosphate) or a sugar (e.g., lactose, sucrose, and so forth) and the like by means of a fluidized bed granulation method, a centrifugal coating method, or a pan coating method to produce granules.
Nakamichi et al., U.S. Pat. No. 5,456,923, disclose, inter alia, a process for producing solid dispersions by passing a mixture of a drug and a polymer carrier through a twin screw compounding extruder. A large list of polymers which can be used is disclosed.
Miyamoto, PCT/JP96/02246, discloses hydroxypropylmethylcellulose (HPMC), HPMCAS, and poly(vinyl acetate) (PVA) as part of an extensive list of amorphous stabilizers. Miyamoto discloses amorphous dispersions of drug plus amorphism inducing agent plus amorphism stabilizer, formed by heating, milling, or precipitation from a solvent.
U.S. Pat. No. 5,456,923 to Shogo et al. discloses an extrusion method for making solid dispersions. HPMCAS is included in a list of polymeric materials, including materials such as starch or gelatin, that can be used as matrix materials.
Takeichi et al., Chem. Pharm. Bull, 38 (9), 2547-2551 (1990) relates to the destruction of drug crystallinity by co-grinding with other agents. Takeichi attempted to use a solid dispersion of HPMCAS and uracil made by grinding in a ball mill to enhance rectal absorption, but concluded that uracil absorption was lower than for low molecular weight matrix materials such as sodium caprate. The use of HPMCAS was not recommended.
Baba et al., Chem. Pharm. Bull, 38 (9), 2542-2546 (1990) relates to the destruction of drug crystallinity by co-grinding with other agents. Baba made ground mixtures of uracil and HPMCAS along with 50 other matrix materials. Although some enhancement (about a factor of 2) in the dissolution of uracil was observed in the co-ground HPMCAS material relative to a simple mixture of crystalline drug and HPMCAS, the enhancement decreased as the polymer-to-drug ratio was increased. This led the researchers to conclude that HPMCAS adsorbed on the surface of the uracil thereby hindering the dissolution of uracil. Its use was not recommended.
T. Yamaguchi et al., Yakuzaigaku, 53 (4), 221-228 (1993) relates to the destruction of drug crystallinity by spray-drying drug and polymer to form: a dispersion. Yamaguchi prepared solid amorphous dispersions of 4″-O-(4-methoxyphenyl)acetyltylosin (MAT) in HPMCAS as well as carboxymethylethylcellulose (CMEC). Dissolution tests at pH 4.0 showed supersaturated concentrations of MAT 9-fold that of crystalline MAT with HPMCAS dispersions. This concentration was comparable to that obtained with the dissolution of amorphous drug alone. However, the presence of HPMCAS sustained the supersaturation longer than the amorphous drug alone. The authors report that even better results were obtained with the CMEC dispersions, however, causing the authors to conclude that CMEC is the preferred dispersion matrix.
SUMMARY OF THE INVENTION
In a first aspect, this invention provides a composition comprising
a) a basic drug, a drug which forms a zwitterion, or a salt of either, admixed with
b) a polymer selected from the group consisting of hydroxypropylmethyl-cellulose acetate succinate (HPMCAS), cellulose acetate trimellitate (CAT), cellulose acetate phthalate (CAP), hydroxypropylcellulose acetate phthalate (HPCAP), hydroxypropylmethylcellulose acetate phthalate (HPMCAP), and methylcellulose acetate phthalate (MCAP);
wherein, in the absence of said polymer, said basic drug, zwitterionic drug or salt has a solubility in a first aqueous use environment having a pH of 1.0 to 2.0 which is at least 3-fold the solubility of said drug in a second aqueous use environment having a pH in the range of 5.0 to 7.0;
and wherein, in said composition, said polymer is present in an amount such that, at any time during the first two hours following the time at which said composition has been introduced from said first use environment into said second use environment, the concentration of said dissolved basic drug, zwitterionic drug, or salt of either in said second use envir
Curatolo William J.
Nightingale James A. S.
Shanker Ravi M.
Sutton Steven C.
Benson Greg C.
Fubara Blessing
Jones James T.
Page Thurman K.
Pfizer Inc
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