Sustained release formulations containing tacrolimus

Details Sustained release formulations containing tacrolimus Sustained release formulations containing tacrolimus

2001-10-17

2003-06-10

Naff, David M. (Department: 1651)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Tablets, lozenges, or pills

C424S400000, C424S452000, C424S455000, C424S457000, C424S465000, C424S489000, C514S294000

Reexamination Certificate

active

06576259

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a formulation containing a macrolide compound and being endowed with an ability of an extremely excellent sustained-release, for use in a medical field.
BACKGROUND OF THE INVENTION
An oral formulation of one of macrolide compounds, namely tacrolimus with an useful immunosuppressive activity, has been prepared as a solid dispersion compositions, which possesses a rapid-release characterization by using polymers such as hydroxypropylmethyl cellulose and disintegrator (see for example EP 0 240 773). Owing to the presence of disintegrator therein, it is a rapid-release formulation. It has been appraised highly in clinical field owing to its high absorbability. In clinical practice, alternatively, the emergence of an oral tacrolimus formulation with a sufficient long action and excellent oral absorbability has been expected. However, it is the state of the art for a person skilled in the art that the absorbability of a pharmaceutically active agent given orally in a manner as sustained-release formulation is generally reduced and/or that a non-negligible variation of the absorbability is observed. The inventors of the invention have carried out a lot of investigations. Consequently, the inventors have invented sustained-release formulations of macrolide compounds, the representative of which is tacrolimus, characterized in that macrolide compound is excellently absorbed orally and/or that variation of its absorbability is suppressed.
DISCLOSURE OF THE INVENTION
The present invention relates to a sustained-release formulation of a macrolide compound, wherein the dissolution of the macrolide compound is under sustained release.
It is an object of the invention to provide a sustained-release formulation of a macrolide compound, wherein the time (T63.2%) required for 63.2% of the maximum amount of macrolide compound to be dissolved is 0.7 to 15 hours, as measured according to the Japanese Pharmacopoeia, the 13-th edition, Dissolution Test, No. 2 (Puddle method, 50 rpm) using a test solution which is an aqueous 0.005% hydroxypropyl cellulose solution, adjusted to pH 4.5.
It is the other object of the invention to provide a solid dispersion composition of a macrolide compound usable in the sustained-release formulation mentioned above, wherein the macrolide compound is present as an amorphous state in a solid base.
It is a further object of this invention to provide a fine powder of a macrolide compound characterized by a particle diameter distribution within the range of 0.1~50 &mgr;m and/or a mean particle diameter within the range of 0.2~20 &mgr;m for use in the above-mentioned sustained-release formulation.
The T63.2% value as determined by the dissolution test in accordance with this invention can be estimated from the release curve constructed by plotting test data on graph paper. However, the release profile of a drug can be generally analyzed by fitting dissolution test data to a release model and such a method can also be used in the computation of said T63.2% value. The model for fitting which can be used includes the first-order or linear model, zero-order model, cube-root model, etc. as described in Yamaoka, K. & Yagahara, Y.: Introduction to Pharmacokinetics with a Microcomputer, Nankodo, p.138 but as a model by which all kinds of release patterns can be expressed with the highest validity, there is known Weibull function, which is described in the above book and L. J. Leeson & J. T. Carstensen (ed.): Release of Pharmaceutical Products (American Pharmaceutical Society) (Chizin Shokan), p. 192-195.
Weibull function is a function such that the dissolution rate (%) in time (T) can be expressed by the following equation:
Dissolution rate (%)=
D
max
×{1−exp[−((T−Ti)
n
)/m]} where D
max
represents the maximum dissolution rate at infinite time, m is a scale parameter representing the dissolution velocity, n is a shape parameter representing the shape of the dissolution curve, Ti is a position parameter representing the lag time till start of dissolution, and the dissolution characteristic of a pharmaceutical product can be expressed by using those parameters in combination.
In order to fit dissolution test data to Weibull function and calculate the respective parameters, the nonlinear least square method described in Yamaoka, K. & Yagahara, Y.: Introduction to Pharmacokinetics with a Microcomputer, Nankodo, p.40, mentioned above, is used. More particularly, the parameters are determined at the point of time where the sum of the squares of differences between the values calculated by the above equation and the measured values at each point of time is minimal and the dissolution curve calculated by means of the above equation using those parameters is the curve which dose most faithfully represent the measured values.
The meaning of each parameter of Weibull function is now explained.
D
max
(maximum dissolution rate) is the maximum dissolution rate at infinity of time as mentioned above and generally the value of D
max
is preferably as close to 100 (%) as possible.
m (scale parameter) is a parameter representing the dissolution velocity of a pharmaceutical product, and the smaller the value of m is, the higher is the dissolution velocity and similarly the larger the value of m is, the lower is the dissolution velocity.
n (shape parameter) is a parameter representing the shape of a dissolution curve. When the value of n is 1, Weibull function can be written as dissolution rate (%)=D
max
×{1−exp[−(T−Ti)/m]}, and since this is equivalent to first-order kinetics, the dissolution curve is linear. When the value of n is smaller than 1, the dissolution curve plateaus off. When the value of n is larger than 1, a sigmoid dissolution curve prevails.
Ti (position parameter) is a parameter representing the lag time till start of dissolution.
The sustained-release formulation comprising a macrolide compound according to this invention can also be characterized by means of said Weibull function. Thus, the objective sustained-release formulation can be implemented by setting D
max
(maximum dissolution rate) at 80% or more, preferably 90% or more, more preferably 95% or more, m (scale parameter) at 0.7~20, preferably 1~12, more preferably 1.5~8, n (shape parameter) at 0.2~5, preferably 0.3~3, more preferably 0.5~1.5, and Ti (position parameter) at 0~12, preferably 0~8, and more preferably 0~4.
The value found by substituting the parameter values of m and n from the above Weibull function into the term m
1

represents the time in which 63.2% of the maximum amount of dissolution of the active ingredient is released from the formulation (T63.2%). That is to say, T63.2% (hr)=m
1

. The release characteristic of the sustained-release formulation of this invention can be evaluated by the Dissolution Test, Method 2 (Paddle method, 50 rpm) of JP XIII using a test solution which is 0.005% aqueous solution of hydroxypropyl cellulose adjusted at pH 4.5. In the sustained-release formulation comprising a macrolide compound according to this invention, the time (T63.2%) in which 63.2% of the maximum amount of the macrolide compound to be dissolved is released from the formulation is 0.7~15 hours. In the past, though the rapid-release formulation comprising macrolide compound has already been produced, any sustained-release formulations, T63.2% of which is 0.7~15 hours and which are quite useful in clinical practice, have never been produced. The present invention completed it for the first time. If the T63.2% value is shorter than 0.7 hour, the efficacy of the macrolide compound following oral administration will not be sufficiently sustained. When the formulation has a T63.2% value of more than 15 hours, the release of the active ingredient will be so retarded that the active ingredient will be eliminated from the body before the effective blood concentration is reached, thus being unsuited as the formulation of this invention. When T63.2% is 1.0~12

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