Colchicine formulations methods of making and methods of use thereof

Our pharmacokinetics department offers the clients a broad spectrum of high quality of services in the areas of in vitro ADME, in vivo pharmacokinetics studies and bioanalysis services, ranging from small molecules to large molecules, such as protein and antibody. The animal species involved in our services are non-human primate, canine, mice, rat, rabbit and hamster. Meanwhile, non-human primate experimental platform and isotope platform for protein/antibody are certified by the Shanghai Government. Email:marketing@medicilon.com.cn Web:www.medicilon.com

"Bioavailability" means the extent or rate at which an active agent is absorbed into a living system or is made available at the site of physiological activity. For active agents that are intended to be absorbed into the bloodstream, bioavailability data for a given formulation may provide an estimate of the relative fraction of the administered dose that is absorbed into the systemic circulation. "Bioavailability" can be characterized by one or more pharmacokinetic parameters.

In one embodiment, the solid, oral colchicine formulation is bioequivalent to a reference drug. In one embodiment, bioequivalence is any definition thereof as promulgated by the U.S. Food and Drug Administration or any successor agency thereof. In a specific embodiment, bioequivalence is determined according to the Federal Drug Administration's (FDA) guidelines and criteria, including "GUIDANCE FOR INDUSTRY BIOAVAILABILITY AND BIOEQUVALENCE STUDIES FOR ORALLY ADMINISTERED DRUG PRODUCTS— GENERAL CONSIDERATIONS" available from the U.S. Department of Health and Human Services (DHHS), Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER) March 2003 Revision 1; and "GUIDANCE FOR INDUSTRY STATISTICAL APPROACHES TO ESTABLISHING BIOEQUIVALENCE" DHHS, FDA, CDER, January 2001, both of which are incorporated herein in their entirety.In another embodiment, bioequivalence is determined according to the European Medicines Agency (EMEA) document "Note for Guidance on the Investigation of Bioavailability and Bioequivalence", issued July 26, 2001, available from EMEA.

"Reference drug" means the oral colchicine tablet product as described in U.S. Federal Food and Drug Administration's New Drug Application No. 022352 approved on July 29, 2009 (0.6 mg colchicine) and by its brand name Colcrys®. Colcrys® tablets are supplied for oral administration as purple, film-coated, capsule-shaped tablets (0.1575" x 0.3030") containing 0.6 mg of the active ingredient colchicine USP; inactive ingredients: carnauba wax, FD&C blue #2, FD&C red #40, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, pregelatinized starch, sodium starch glycolate, titanium dioxide, and triacetin. Colcrys® is formulated for immediate-release.

In one embodiment, the colchicine formulation is bioequivalent to a reference drug according to New Drug Application No. 022352 (Colcrys® 0.6 mg) when tested in a group of five or more healthy humans in the fasted or fed state.

In an embodiment, bioequivalence of the colchicine formulation to a reference drug is determined by an in vivo bioequivalence study to determine a pharmacokinetic parameter for the colchicine formulation. Specifically, bioequivalence can be determined by an in vivo bioequivalence study comparing a pharmacokinetic parameter for the two compositions. A pharmacokinetic parameter for the colchicine formulation or the reference drug can be measured in a single or multiple dose bioequivalence study using a replicate or a nonreplicate design. For example, the pharmacokinetic parameters for a colchicine formulation of the present invention and for a reference drug can be measured in a single dose bioequivalence study using a two-period, two-sequence crossover design. Alternately, a four-period, replicate design crossover study may also be used. Single doses of the test colchicine formulation and reference drug are administered and blood or plasma levels of the active agent are measured over time. Pharmacokinetic parameters characterizing rate and extent of active agent absorption are evaluated statistically.

The area under the plasma concentration-time curve from time zero to the time of measurement of the last quantifiable concentration (AUCo-t) and to infinity (AUCo-∞), Cmax, and Tmax can be determined according to standard techniques. Statistical analysis of pharmacokinetic data is performed on logarithmic transformed data (e.g., AUCo-t, AUCo∞, or Cmax data) using analysis of variance (ANOVA). [0086] In some embodiments a single dose pharmacokinetic study is performed under non-fasted ("fed") or fasted conditions. When tested under fed conditions, the formulation is administered with a high fat meal. The exemplary high-fat meal contains approximately 50 percent of the total caloric content of the meal as fat and contains approximately 800 to 1000 calories; 500-600 calories from fat. As used herein, the term "fat" is used in its conventional, art-recognized meaning.

Under U.S. FDA guidelines, two products (e.g. an inventive formulation and Colcrys®) or methods (e.g., dosing under fed versus fasted conditions) are bioequivalent if the 90% Confidence Interval (CI) limits for a ratio of the geometric mean of logarithmic transformed AUCo-∞, AUCo-t, and Cmax for the two products or two methods are about 0.80 to about 1.25.

To show bioequivalence between two products or methods pursuant to Europe's EMEA guidelines, the 90% CI limits for a ratio of the geometric mean of logarithmic transformed AUCo∞ and AUCo-t for the two products or methods are about 0.80 to about 1.25. The 90% CI limits for a ratio of the geometric mean of logarithmic transformed Cmax for the two products or methods can have a wider acceptance range when justified by safety and efficacy considerations. For example the acceptance range can be about 0.70 to about 1.43, specifically about 0.75 to about 1.33, and more specifically about 0.80 to about 1.25.

In one embodiment, in a given experiment, a colchicine formulation is considered to be bioequivalent to Colcrys® if both the Test/Reference ratio for the geometric mean of logarithmic transformed AUCo-∞, AUCo-t, or Cmax ratio along with its corresponding lower and upper 90% CI limits are within a lower limit of about 0.80 and an upper limit of about 1.25. Thus, for direct comparison between a colchicine formulation and Colcrys®, it is sometimes preferred to determine the pharmacokinetic parameters for the colchicine formulation and Colcrys® side-by-side in the same pharmacokinetic study.

In another embodiment, the 90% confidence limits of a ratio of a geometric mean of logarithmic transformed AUCo-∞ of the colchicine formulation to a geometric mean of logarithmic transformed AUCo-∞ of a reference drug according to New Drug Application No. 022352 is about 0.80 to about 1.25 when tested in a group of five or more healthy humans in the fasted or fed state.

In yet another embodiment, the 90% confidence limits of a ratio of a geometric mean of logarithmic transformed AUCo-t of the colchicine formulation to a geometric mean of logarithmic transformed AUCo-t of a reference drug according to New Drug Application No. 022352 is about 0.80 to about 1.25 when tested in a group of five or more healthy humans in the fasted or fed state.

In yet another embodiment, the 90% confidence limits of a ratio of a geometric mean of logarithmic transformed Cmax of the colchicine formulation to a geometric mean of logarithmic transformed Cmax of a reference drug according to New Drug Application No. 022352 is about 0.80 to about 1.25 when tested in a group of five or more healthy humans in the fasted or fed state.