Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
1998-03-10
2004-09-07
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C424S487000, C424S488000
Reexamination Certificate
active
06787157
ABSTRACT:
The present invention relates to solid, at least two-phase active ingredient-containing formulations in which there is multiparticulate incorporation of one of the two phases into a matrix of the other phase, and at least one of the phases contains at least one active ingredient, obtainable by introducing particles of one phase into the other phase in a plastic state, and shaping the material while still plastic. The invention furthermore relates to a process for producing such forms.
A problem which frequently occurs in pharmaceutical technology is to introduce mutually incompatible active ingredients into a drug form.
This is solved in the prior art by producing laminated or multilayered tablets. These tablet forms permit not only incompatible active ingredients to be separated but also the initial and maintenance doses to be separated in controlled release drug forms. These drug forms are normally obtained by conventional compressing. However, this requires specially designed tableting machines and at least two filling and compression stations (cf. “Pharmazeutische Technologie”, Georg Thieme Verlag, 4th edition, 1993, pages 300 et seq.). This process is, however, elaborate and costly.
It is furthermore known to produce mixed granule tablets by compressing a mixture of differently pretreated granules. This entails, for example, processing untreated medicinal substances (initial dose) together with medicinal substances enveloped in fats or coated with lacquer (maintenance dose) (cf. R. Voigt, Lehrbuch der pharmazeutischen Technologie, 1987, page 225). This process is also relatively elaborate.
EP-A 580 860 discloses that it is possible to meter water or solvent in during the extrusion process. However, metering in of active ingredients is not described.
It is an object of the present invention to find a simple process for producing active ingredient-containing forms which permits the introduction of mutually incompatible active ingredients or active ingredients of different release into one drug form or the production of forms with multiphase release characteristics.
We have found that this object is achieved by the formulations defined at the outset.
It is preferred according to the invention to incorporate active ingredient-containing particles into a melt which may likewise contain active ingredient or else be free of active ingredient.
Possible particles according to the invention are granules, pellets or crystal particles, and crystal particles are preferably coated.
The particles can be obtained in a conventional way, for example by wet granulation of one or more active ingredients with conventional additives. If the active ingredient automatically results as granules in the preparation process, it can also be employed without further treatment with additives. Granules can also be obtained in a conventional way by melt extrusion of an active ingredient-containing polymer melt and subsequent shaping by hot or cold cut, prilling or drop-formation processes. Pellets can also be produced by conventional processes, for example by dry granulation. Coated or uncoated active ingredient crystals can also be obtained by processes known to the skilled worker. The particle size is not critical. For ease of handling of the particles it is advisable to use particles with a size of the order of from 0.01 to 3 mm, preferably 0.5 to 2 mm.
Particles for the purpose of this invention are also microtablets. Microtablets can likewise be produced in a conventional way.
As already mentioned, the particles can consist of pure active ingredient without containing other additives. If additive-containing particles are employed, the nature of the additives depends in particular on the release rate required for the particulate phase, ie. whether the particulate phase is to be rapid or slow release.
If coated active ingredient crystals are used, the coating may have purely stabilizing or else release-slowing properties. It is also possible to employ coatings which dissolve in particular pH ranges.
It is possible in this way to obtain combination drug forms in which the active ingredient(s) can be released from the particulate portions at various points in the digestive tract. Examples of possible coatings of this type are polyacrylates or methacrylic acid copolymers (Eudragit types).
The content of the aliquot added as particles can be from 0.01 to 90%, preferably 0.1 to 70%, particularly preferably 0.5 to 50%, of the total weight of the finished active ingredient-containing form.
In the formulation according to the invention there is multiparticulate incorporation of the particles in another phase. Thus the other phase forms the matrix for the particulate phase. The matrix phase may contain active ingredient or be free of active ingredient. An active ingredient-containing matrix phase is preferred.
It is possible in principle to employ all substances which can be melted or softened to constitute the matrix phase as long as they do not decompose under the processing conditions. The required thermoplasticity can also be brought out by adding suitable auxiliaries.
Examples of suitable constituents of the matrix are melt-processable polymeric binders. Suitable as such are uncrosslinked homo- or copolymers of N-vinylpyrrolidone with Fikentscher K values of from 12 to 120, preferably 20 to 100, with suitable comonomers preferably being vinyl esters such as vinyl propionate or vinyl butyrate or, in particular, vinyl acetate, or else N-vinylimidazole or N-vinylcaprolactam.
Further suitable binders are cellulose derivatives such as cellulose ethers, for example cellulose alkyl ethers such as methyl- or ethylcellulose or hydroxyalkylcelluloses such as hydroxypropylcellulose, also cellulose esters such as cellulose acetate, cellulose phthalate, cellulose acetate propionate, cellulose acetate phthalate or the like. Also suitable as binders are acrylate- or methacrylate-containing polymers, for example Eudragit types.
Also suitable according to the invention are matrix polymers which can be absorbed or degraded in the body. These include polylactic acid and copolymers thereof, poly(ortho)esters. Polyamides, polyphosphazenes or polyurethanes are also suitable.
Likewise suitable as matrix polymers are starch or dextrins.
Suitable matrixes according to the invention are also those composed of sugar alcohols such as erythritol, sorbitol, maltitol, mannitol, isomalt, mono- or disaccharides such as fructose or glucose.
Also suitable as matrix constituents are fatty acid glycerides and/or fatty acid polyethylene glycol esters. The latter can also be packed as semisolid extrudates with the incorporated particles into capsules. It is particularly advantageous that the softening point of these substances is relatively low and thus reliable metering in is ensured without the risk of melting the added particles. Such easily softening formulations are likewise suitable for producing suppositories and chewable compositions.
Suitable matrix polymers are also polyethylene glycols with molecular weights in the range from 1000 to 20,000.
It is furthermore possible to incorporate conventional physiologically tolerated ancillary substances into the matrix, for example bulking agents, lubricants, mold release agents, plasticizers, blowing agents, stabilizers, dyes, flavorings or flow regulators.
Examples of bulking agents are inorganic bulking agents such as the oxides of magnesium, aluminum, silicon, titanium etc. in a concentration of from 0.01 to 50, preferably from 0.20 to 20, % of the total weight of the drug form.
Examples of lubricants are stearates of aluminum, calcium and magnesium, and talc and silicones in a concentration of from 0.1 to 5, preferably from 0.1 to 3, % of the total weight of the form.
Examples of disintegration promoters which can be employed are sodium carboxymethyl starch and crospovidone. It is also possible to employ wetting agents such as sodium lauryl sulfate and sodium docusate. Salts such as Na
2
CO
3
or NaHCO
3
can also be employed.
Examples of plasticizers comprise low molecular weight poly(al
Berndl Gunther
Breitenbach Jörg
Kleinke Andreas
Rosenberg Joerg
Zeidler Jürgen
Abbott Laboratories
Keil & Weinkauf
Webman Edward J.
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