Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1999-02-26
2004-03-02
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S400000, C424S490000, C424S491000, C424S492000, C424S493000, C424S494000, C424S495000, C424S496000, C424S497000, C424S498000
Reexamination Certificate
active
06699506
ABSTRACT:
The subject of the present invention relates to the development of a multiparticulate form of the controlled-release minigranule type for the oral route, allowing the administration, in a single daily dose, of a particular antidepressant, namely: Milnacipran.
The novelty of this invention rests on the design of this minigranule or minisphere form which, by a combination:
of the Milnacipran concentration per minigranule,
of the physicochemical characteristics of the coating film,
and of the thickness of this film,
makes it possible to control, surprisingly, the in-vitro release over several hours of a molecule whose aqueous solubility is close to 800 g/l, thereby making the single-dose administration of this entity possible.
Milnacipran and its Cis enantiomers exist in the form of hydrochlorides, whose aqueous solubilities are close to 800 g/l. Currently, these extremely soluble molecules, formulated with dicalcium phosphate, calcium carboxymethylcellulose and polyvinylpyrrolidone, packaged in gelatin capsules, do not allow this objective to be achieved since the in-vitro release from this 50 mg Milnacipran form is complete in thirty minutes thereby requiring the administration of a gelatin capsule in the morning and a gelatin capsule in the evening.
By contrast and surprisingly, the present invention relates to a prolonged-release galenic form, intended for oral administration in a single daily dose of 50 to 240 mg of Milnacipran, provided in a multiparticulate form combining a plurality of minigranules each containing an active minisphere comprising a sucrose and/or starch core having a particle size of between 200 and 2000 &mgr;m and containing 150 to 1000 &mgr;g of Milnacipran as well as a binding agent, each minigranule being coated with a film, based on at least one polymer insoluble in water but permeable to physiological fluids, having a thickness of between 20 and 100 &mgr;m, said galenic form allowing an in-vitro release corresponding to the following pattern:
between 10 and 55% of the dose released in 2 hours,
between 40 and 75% of the dose released in 4 hours,
between 70 and 90% of the dose released in 8 hours,
between 80 and 100% of the dose released in 12 hours.
This minigranule form containing a dose of 60 mg to 240 mg, more precisely 120 mg of Milnacipran in racemic form, or a therapeutically equivalent dose of Dextrorotatory Cis derivative, allows the therapeutic activity to be maintained over the nychthemeron while leveling the values of the plasma concentrations.
It will be recalled first of all that Milnacipran, a new antidepressant (patents Nos. FR 2,508,035-EP 200,638 and FR 2,640,972), exhibits a novel pharmacological activity since it allows a mixed inhibition of the capture of noradrenaline and serotonin, with no effect on dopamine.
Its chemical structure reveals two asymmetric carbons which confer on the molecule a Cis and Trans type isomerism, for which it has been demonstrated that the two Cis enantiomers are the active forms, preferably obtained by synthesis.
It has also been demonstrated that for these Cis derivatives the dextrorotatory form is more active than the levorotatory form.
Accordingly, the subject of the present invention applies both to the racemic molecule Milnacipran, but also to the two Cis enantiomers, since the physicochemical properties involved in the diffusional processes from the form remain identical.
Milnacipran and its Cis enantiomeric forms exhibit an absolute bioavailability greater than 85% and a biological half-life of between 7 and 9 hours, these properties being entirely compatible, from the pharmacokinetic point of view, with the design of a one-dose-per-day prolonged-release form.
In general, two distinct steps should be considered in the technical production of the prolonged-release minigranules, namely:
the active minisphere production phase,
the active minisphere film-coating phase.
Several technologies can be used for the production of the active minispheres:
mounting in a pan which consists of sprinkling the active ingredient with the aid of a binder on the sucrose or sucrose and starch cores also called nonpareils;
mounting in a fluidized air bed which consists in spraying a solution or a dispersion of active ingredient with the aid of a binder on the bed of nonpareils. This spraying may be performed from the top toward the bottom, from the bottom toward the top (Würster method) or tangentially (rotor method). In the latter case, the active ingredient may be sprayed in solid form concomitantly with the wetting liquid, with the aid of a feed hopper;
rotogranulation which makes it possible to obtain spherical grains from a suitable active agent-excipient mixture over which a binding solution is sprayed. This technology can be performed using rotogranulators combined or otherwise with a fluidized air bed;
extrusion-spheronization which allows the production of spherical grains. It involves obtaining, starting with a suitable active agent-excipient mixture, a plastic mass after mixing with a binding solution.
The plastic mass is then extruded using various systems which make it possible to convey and/or extrude this mass (barrel extruder, gear, piston, single- or twin-screw extruder, with axial or radial extrusion).
The extrudates obtained are then spheronized in a suitable spheronizer.
Conventionally, two techniques are used for the production of coated minigranules:
pan: the uncoated active minispheres are introduced into a perforated or nonperforated pan. A solution or dispersion of coating is then sprayed over the bed of minispheres with the aid of a gun or nozzle and any other suitable system allowing the production of a continuous, uniform and reproducible film;
fluidized air bed: depending on the spraying mode chosen, the film-coating of the active minispheres may be carried out by “top-spray”, by “bottom-spray” or by “tangential-spray”. The latter two techniques give a more uniform, more continuous and more reproducible coating than the first technique.
The major problem with which persons skilled in the art are confronted for the development of a prolonged-release form in general and of the minigranule type in particular, is the aqueous a solucility of the molecule.
In the present case, Milnacipran as well as its active enantiomers are very easily soluble in water (solubility=800 g/l). It should be recalled that it is impossible to use the base forms for reasons of stability.
Indeed, it is known to persons skilled in the art that with such molecules, the formulator who has to develop a prolonged-release form is confronted with the following antinomic problem:
avoiding the phenomenon of sudden discharge which is very frequent with this type of molecule and which, in some cases, is synonymous with side effects,
and ensuring a perfect control of the release of the entire administered dose so as to avoid any loss of product.
Some formulators have solved this problem:
by combining within the same formulation several minigranule fractions (DE-3,941,703), an uncoated fraction providing the release during the first few minutes, and a fraction coated with a large amount of polymer controlling the diffusion during the subsequent hours,
or by combining within the same formulation minigranules with multilayer film-coatings (U.S. Pat. No. 4,894,240-WO-9 3097 67) or chemical compositions of coating polymers of a heterogeneous nature (EP-508 653-EP-0 322 277).
The present invention provides, through the design of this minigranule form for prolonged release of Milnacipran, having an aqueous solubility equal to 800 g/l, a solution which is less constraining for the developer.
Indeed, the formulas which are the subject of the present invention make it possible, through their design (content of active ingredient per minigranule, thickness of the film and composition of the film), to achieve an in-vitro release which is compatible with the therapeutic objective while using only one type of minigranules per formula.
It is very difficult, because of the absence of references, to describe, for a molecule with a solubilit
Avan Jean-Louis
Bougaret Joël
Goutay Eric
Paillard Bruno
Pierre Fabre Medicament
Pulliam Amy E
The Firm of Hueschen and Sage
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