Slow-release matrix pellets and the production thereof

Details Slow-release matrix pellets and the production thereof Slow-release matrix pellets and the production thereof

1996-10-17

2001-09-18

Webman, Edward J. (Department: 1617)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

C424S457000, C424S458000, C424S468000

Reexamination Certificate

active

06290990

ABSTRACT:

The present invention relates to a solid, preferably pharmaceutical, slow-release form (pellets) in which the active substance is embedded in a mixture of a water-insoluble polymer, a lipid and a gel-forming polymer which in water forms a highly viscous colloidal solution or at least swells. Production takes place in a one-stage continuous process by melt extrusion and, preferably hot-cut shaping.
PRIOR ART
Matrix substances suitable for melt extrusion and slowing of release are polymers and lipids which can be plasticized by pressure and temperature. Speiser et al. describe in Pharm. Acta Helv. 46 (1971) 31 the use of epoxy/amino resins which are soluble in gastric fluid and vinyl acetate/crotonic acid copolymers which are soluble in intestinal fluid for injection-molded drug forms (cf. in this connection what is said about U.S. Pat. No. 3,432,592). Hüttenrauch and Schmeiss investigated the release of model active substances from a polyethylene matrix produced by ram extrusion (Pharmazie 30 (1975) 229, 536). Mank et al. describe in Pharmazie 44 (1989) 773 and ibid. 45 (1990) 592 the release of active substance from insoluble thermoplastic matrices. These methods do not allow the slowing of release to be adjusted freely, and the active substance is not completely released in particular from the polyethylene matrices. In addition, this process has the disadvantages of injection molding such as long residence time at high temperature and large material losses due to the feed channels whose contents must not be reused. In addition, the tooling costs are extremely high relative to the production rate.
N. A. El Gindy et al. describe in Acta Pharm. Technol. 33 (1987) 208-211 the production of tablets by melting mixtures of active substances with water-soluble (polyethylene glycols and polyoxyethylene/polyoxypropylene block copolymers) and insoluble polymers and subsequently compressing. Release from these forms is more or less rapid because of the choice of polymers. Production is by a batchwise process.
N. Follonier et al. report in Capsule News 1 (1991) 2 and in the Abstract of the 6th International Conference on Pharmaceutical Technology, Paris, France, Jun. 2-4, 1992, the production of sustained release pellets by melt extrusion from a single-screw extruder. The solidified extrudate was comminuted in a pelletizer. Water-insoluble polymers were used as matrix. Besides the size of the pellets, various additives were investigated to control release of the active substance. The polymer basis was principally an ethylene/vinyl acetate copolymer. However, it was not possible to achieve release by zero order kinetics of the active substance from these forms.
U.S. Pat. No. 3,432,592 describes the injection molding of polymer melts containing active substances. The polymers used therein are said to be at least partially soluble in the digestive fluids. The soluble polymer mainly described is a complex condensation product of an amino diol and an epoxide, which is not customary in the drugs sector. Slowing of release is achieved by also using thermoplastics of low solubility in digestive fluids. The polymer combinations indicated therein are unsuitable for slowing the release from pellets of active substances which are readily soluble in water because the surface area/volume ratio is unfavorable. In general it is difficult to control the slowing of release by this procedure, and when release is greatly slowed part of the active substance remains undissolved in the pellets (release of active substance obeys the {square root over (t)} law; see T. Higuchi, J. Pharm. Sci. 52 (1963) 1145-1149). Release by zero order kinetics is not possible (cf. Table I).
EP-A 240 904 and EP-A 240 906 disclose the extrusion of polymer melts, preferably of vinylpyrrolidone copolymers, which contain active substances. There is no mention therein of the adjustment of a particular profile of active substance release by means of polymer mixtures. In addition, it has emerged that the storage stability of the products produced in this way is in many cases low, and the release-slowing effect diminishes with time.
EP-B 204 596 describes the production of pellets by embedding an active substance in a matrix composed of the following components: at least one non-hydrophilic polymer and either a mixture of at least two lipid substances, of which one has polymer-dissolving or -gelling properties and the other has lubricant properties, or one lipid substance which combines the two stated properties, with or without one or more additives selected from extenders and antistatic agents. Serious disadvantages: with higher amounts (above about 20%) of non-hydrophilic polymer the release takes place too quickly for a slow-release product, and with smaller amounts the release changes greatly on storage and is incomplete.
It is an object of the present invention to produce pellets, preferably for pharmaceutical purposes, from which the active substance is released with an adjustable release profile, ie. as slow as required, but completely. The intention was to achieve this aim by matrix pellets, ie. without release-slowing film coatings applied to the pellet core.
It is another object of the present invention, besides controlling the release of active substance by the composition of the matrix (matrix slow-release pellets), to develop a technique for simple and low-cost production of these pellets. It was intended that this take place in a continuous and one-stage process without previous mixing or pregranulation of the components and without final spheronization or similar shaping/rounding of the pellets after the production process.
ACHIEVEMENT
We have found that this object is achieved in a simple manner by melt extrusion of certain polymer matrices which contain active substances and subsequent continuous shaping to produce slow-release pellets with high active substance content, even of active substances which are very readily soluble in water, it being possible to achieve release profiles which can be adjusted over wide ranges solely by the composition of the polymer matrix without diffusion-controlling polymer coatings and which have high storage stability.
The basic principle of the polymer matrix according to the invention is a matrix which is plasticized by suitable lipophilic substances and is composed of a polymer which is insoluble in water and gastrointestinal fluids. In contrast to the prior art cited above, it is now possible to adjust the release profile freely over wide ranges if the matrix of insoluble polymer and lipophilic component additionally incorporates a gel former, ie. a polymer which in water forms a highly viscous solution (hydrocolloid) or at least swells. With the prior art matrices, although the release of the active substance is controlled by the concentration of insoluble polymer, there is a risk that the administration form will disintegrate if the amount of polymer is too low, but the release of active substance may be incomplete if the amount of polymer is too large, since portions of the active substance are completely entrapped and unavailable. The addition, according to the invention, of gel former breaks up the release-slowing matrix by swelling of this polymer, and the active substance can be completely released (cf. Tab. I).
The polymer matrix according to the invention for matrix slow-release pellets is a novel combination of inert, lipophilic and hydrophilic thermoplastic matrix.
The invention therefore relates to a solid pharmaceutical slow-release form (matrix pellets) produced in a single-stage process by melt extrusion in an extruder, preferably a twin-screw extruder or a single-screw extruder with mixing section, at 50-200° C. with continuous (preferably hot-cut) shaping of a mixture of the following composition:
a) at least one biologically active compound (“active substance”; preferably in human or veterinary medicine, but also vitamins and systemic insecticides, fungicides and herbicides) in an amount of 0.1-87, preferably 1-75, in particular 45-75, % by weight,
b) at least one n

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