Process for preparing pellets containing up to 90 wt.% of a...

Details Process for preparing pellets containing up to 90 wt.% of a... Process for preparing pellets containing up to 90 wt.% of a...

2000-01-18

2003-05-06

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

C424S489000, C424S490000, C424S499000, C424S502000, C424S464000, C424S451000

Reexamination Certificate

active

06558704

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to a process for the preparation of pellets with a content of up to 90 wt. % of a pharmaceutical active ingredient having an extremely high solubility in water, by aqueous moist extrusion and subsequent spheronization.
Extrusion and subsequent spheronization is a long-known method for the preparation of granules having a defined shape and particle size which has also gained great importance in the production of pharmaceutical pellets (J. W. Conine et al., Drug & Cosmetic Ind. 106, 38-41 (1970)). At the same time the processing of numerous pharmaceutical active ingredients has also been described. Such multiparticulate forms of administration are often preferred to monolithic dosage forms due to improved bioavailability, pharmaceutical safety and reliability of action. Moreover, there exists a comprehensive body of literature dealing with optimizing the conditions of preparation, with the effect of the composition of the formulation and with the differences between various types of extruder as well as with the principles of extrusion/spheronization (L. Hellen et al.,
Int. J. Pharm.,
95, 197-204 and 205-216 (1993); L. Baert et al.,
Int. J. Pharm.,
96, 225-229 (1993) and
Int. J. Pharm.,
81, 225-223 (1992) and
Int. J. Pharm.,
97, 79-92 (1993); K. Thoma et al.,
Drug Dev. Ind. Pharm.,
24 (5), 401-411 (1998)).
The advantages of extrusion/spheronization over pelletizing in the preparation of pellets include, among other factors, a greater compression of the pellets. Because of this, homogeneous pellets having a high content of active ingredients, that is, a content of active ingredients of up to 90 wt. %, can be obtained by the aforementioned method. Moreover, the pellets prepared by extrusion/spheronization are not only denser, but the surface of the pellets also has a lower porosity, so that the amount of functional films applied to the pellets can be distinctly decreased and more even release profiles can be achieved (G. Zhang et al.,
Drug Dev. Ind. Pharm.,
16 (7), 1171-1184 (1990)). For this reason the preferred method for the preparation of pellets, in particular for the preparation of high-dosage pellets which are provided with coatings having a controlled-release action, is by extrusion/spheronization.
Besides the so-called melt extrusion, extrusion of granules moistened with water is one of the most common extrusion methods. In this process the active ingredients together with the auxiliary substances are granulated with the addition of water and then extruded, after which the extrudates are rounded in a spheroniser and dried. This method has the advantage over melt extrusion that it avoids undesirable heat load on the mixtures containing the active ingredients.
While pellets having a high content of active ingredients of up to 90 wt. %, even for active ingredients with a good to very good solubility in water, can be prepared by melt extrusion (WO 96/14059), the limit on the content of active ingredients in pellets prepared by the aqueous extrusion methods depends critically on the degree of water-solubility of the active ingredient. Thus, for example, for active ingredients having low to poor solubility in water, pellets are known with active ingredient contents of more than 80 wt. %, the pellets still being sufficiently round and having a narrow particle size distribution despite the low content of auxiliary substances (G. A. Hileman et al.,
Drug Dev. Ind. Pharm.,
19 (4), 483-491 (1993)). However, it is well known in the art that the higher the water-solubility of the active ingredients, the lower the quantity of active ingredient which can be incorporated into the pellets (J. M. Newton et al.,
Pharm. Research,
509-514 (1998); P. H. Harrison,
J. Pharm. Pharmacol.,
37, 686-691 (1985)). Accordingly, in the case of readily water-soluble active ingredients having a solubility in water of 0.3 g/ml, generally only pellets having an active ingredient content of at most 60 wt. % can be satisfactorily prepared by means of aqueous moist extrusion.
SUMMARY OF THE INVENTION
Accordingly, it is the object of the present invention to provide pellets containing very highly water-soluble, pharmaceutical ingredients, that is, those having a solubility in water of ≧0.5 g/ml, preferably ≧1 g/ml, which pellets are prepared by means of the aqueous moist extrusion process and, advantageously, have not only a defined particle size and very good roundness, but also a relatively narrow particle size spectrum.
This object is achieved by the process according to the invention for the preparation of pellets containing ≧50 wt. % of a pharmaceutical active ingredient having a solubility in water of ≧0.5 g/ml, by granulating the mixture containing the active ingredient with water, extruding, rounding and drying the resulting moist pellets, which is characterised in that the mixture containing the active ingredient consists of:
A) at least 50 wt. %, preferably at least 65 wt. %, of at least one active ingredient having a solubility in water of >0.5 g/ml, preferably >1 g/ml, and
B) at most 50 wt. %, preferably at most 35 wt. %, of the combination of
a) microcrystalline cellulose having an average particle size of 15 to 25 &mgr;m, determined by laser diffraction (Malvern Master Sizer) and
b) low-substituted hydroxypropyl cellulose having an average particle size in the range of 10 to 25 &mgr;m, measured by laser diffraction,
the weight ratio of a):b) being in the range of 4:6 to 6:4 and the amount of water worked into the mixture being only so much that the mixture has an adequate plasticity for extrusion and spheronization.
The term “low-substituted hydroxypropyl cellulose” is used as as defined in
U.S. Pharmacopeia
&
National Formulary
, USP 24—NF 19, page 2466 (1999) and refers to a substituted hydroxypropyl ether of cellulose which when dried at 105° for one hour contains not less than 5% nor more than 16% hydroxypropoxy groups.
The process according to the invention makes it possible to prepare pellets containing up to 90 wt. % of an active ingredient having extremely high solubility in water, that is, a solubility in water of at least 0.5 g/ml, such as, for example, tramadol hydrochloride (solubility>3.0 g/ml), chlorpromazine hydrochloride (solubility 2.5 g/ml), metamizol-Na (solubility>1 g/ml), or diphenhydramine hydrochloride (solubility 860 mg/ml).
It is essential to the process according to the invention that the auxiliary substances used, namely, microcrystalline cellulose and low-substituted hydroxypropyl cellulose, have a certain average particle size and are used in a certain weight ratio to one another. Thus one must use a microcrystalline cellulose having an average particle size of 15 to 20 &mgr;m, such as, for example, Avicel™ PH 105 or Emcocel SP 15™, or low-substituted hydroxypropyl cellulose having an average particle size in the range of 10 to 25 &mgr;m, such as, for example, 1-HPC LH 31™, 1-HPC LH 32™ or 1-HPC LH 41™, preferably having a particle size of ≦20 &mgr;m (for example, 1-HPC LH 32™, 1-HPC LH 30™ or 1-HPC LH 41™) and a hydroxypropyl content of 10 to 13 wt. % (1-HPC LH 31).
The comparison tests show that when the hitherto preferably used microcrystalline cellulose having a particle size of approximately 50 &mgr;m is used in the preparation, moist extrusion of pellets containing very readily water-soluble active ingredients such as tramadol hydrochloride, can produce only pellets with an active ingredient content of at most 40 to 45 wt. % in useful yield. Higher contents of active ingredients result in agglomeration or scarcely roundable rods of extrudate (dumb-bells) having a high dust content, depending on the quantity of water present. Surprisingly, this disadvantage can successfully be surmounted by the auxiliary substances used according to the invention.
The proportion of these auxiliary substances in the mixture containing active ingredients should be 10 to 50 wt. %, preferably from 20 to 30 wt. %, and a ratio of microcrystalline cellulose to low-substituted hydroxypr

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