Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1999-01-04
2003-04-29
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S489000, C424S484000, C424S486000, C424S481000, C424S465000, C424S485000, C514S108000, C514S102000, C514S018700, C514S609000
Reexamination Certificate
active
06555138
ABSTRACT:
This application is a 35 U.S.C. §371 national phase application of PCT international application PCT/SE 98/02090 filed on Nov. 18, 1998 which claims priority to Swedish application 9704401-0, filed Nov. 28, 1997.
FIELD OF THE INVENTION
This invention relates to a pharmaceutical dosage form comprising solid, polymeric matrix beads for oral administration comprising considerable amounts of greasy, oily or sticky (greasy/oily/sticky) substances and a pharmaceutically active substance alternatively considerably amounts of greasy, oily or sticky pharmaceutically active substances and where the new dosage form is further characterized by having fast release characteristics.
BACKGROUND OF THE INVENTION
In many therapeutic areas the need for incorporating absorption enhancers (e.g. glycerol esters for increased absorption of heparin or heparin fragments or derivatives as described in WO 95/00152 to Pharmacia), solubilizing agents (like polyethoxylated hydrogenated castor oils for felodipine as disclosed in EP 0249587 to AB Hässle), suspending agents (e.g. soybean oil or fractionated coconut oil for 1,2,4-benzotriazine oxide as disclosed in U.S. Pat. No. 5,597,582 to Sanofi), or the like into the dosage forms for drug delivery has arisen.
In many cases the above substances are greasy, sticky or oily products. Incorporation of large amounts of such substances into pharmaceutical dosage forms have since long been known to cause technical problems. One of the problems has been to get pharmaceutically acceptable dry materials that are easy to handle and use as such or in later process steps.
Earlier ways to circumvent the problem include filling the greasy, oily or sticky substances as such into soft gelatin capsules, as for instance described in U.S. Pat. No. 5,589,455 (Han Mi Pharm.) where a concentrate for soft gelatin capsule filling comprising a cyclosporin and an oily component for improving the bioavailability is disclosed.
Many researchers have during the years described the advantage of using many small pellets (multiple unit) as a dosage form, with respect to their behaviour in vivo, i.e. especially with respect to their gastric emptying properties, see for instance Bogentoft et al, J. Clin. Pharmacol. 1978, 14, 351-5. Also e.g. Edgar et al describes advantages obtained with the use of a large number of pellets compared to a single unit, see Biopharmaceutics & Drug Disposition 1984, 5, 251-60. Risk for local irritation and accumulation of several doses due to constriction in the alimentary canal are also considered to be reduced, see McMahon F. G. et al. in The Lancet, Nov. 13, 1982, 1059-61.
To use complex coacervation microencapsulation is one way to circumvent the problem in line with the above findings. This method has been described by Jizomoto et al in Pharmaceutical Research vol. 10, No. 8, 1115-22. The method comprising formation of a surrounding coating layer consisting of two oppositely charged polymers forming an uncharged complex, is often associated with technical problems e.g. with respect to scaling-up, removal of residual reagents like hardening agents (e.g. glutaraldehyde) and solvents (e.g. isopropanol). The method may also be expensive due to many and complicated process steps, among other things necessiated by need of pH-adjustment, need of addition of antiadherents, need of particle separation step and need of solvent removal and enviromental considerations with regard to solvent handling, etc.
When administrering active drug together with absorption enhancers, it has earlier been proposed to fill the oily enhancer or enhancer dissolved in oil, together with drug in soft gelatin capsules, as by Adusumilli et al in U.S. Pat. No. 5,595,758.
Another more sofisticated way has been proposed by designing the dosage forms to have synchronized controlled release, i.e. sustained release, formulations to acertain that two components arrive at the absorption site at the right time, i.e. approximately simultaneously. See for instance Rubinstein et al in WO 95/34294 (Hamilton, Brook, Smith & Reynolds, P.C.) where an erodible hydrogel is used to serve as sustained oral delivery system, releasing small portions of drug and enhancer at the same time during a prolonged time intervall.
DESCRIPTION OF THE INVENTION
It has now been found that a drug delivery system for oral administration in solid dry form of greasy, oily or sticky (henceforward g/o/s) substance(s) and pharmaceutically active substance(s) or a pharmacetically active substance(s) which itself is/are g/o/s characterized by having a plurality of solid, polymeric matrix beads comprising considerable amounts of g/o/s substances and having fast release characteristics can overcome the drawbacks associated with previous systems and (when applicable) facilitate simultaneous administration of two components.
Thus, the present invention provides a new dosage form principle for incorporation of g/o/s materials and/or including pharmaceutically active substances, into particles of small up to moderate size which are easy to handle. The invention also enables the possibility to make multiple unit dosage systems thereof.
The present invention is directed to the approach of fast release, which will ensure that drug and absorption enhancer/solubilty enhancer is delivered to the desired site simultaneously and in as high concentration as possible, and to accomplish a better concentration gradient giving high drive force and enforcing the drug absorption possibilities. This is accomplished by using solid easily soluble polymers of polyethylene glycol, that will dissolve rapidly in the gastrointestinal system at the desired locus.
It is also one characteristic of the invention to have a considerable content of the greasy, oily or sticky materials in the produced particles, to ensure locally high concentrations in vivo.
By transforming the used polymer from the solid state to the liquid one, it is possible to emulsify or suspend drug and enhancers therein. After this procedure a suitable aliquot of the emulsion/suspension is separated and transferred back to solid state. This is done with all aliquots assuring transfer of all material to the solid state. If necessary, the emulsions may be stabilized by the addition of surfactants.
As fast release is required, all chemical treatment with hardening agents of the polymers, is outside the scope of this invention.
It has now been found that the disadvantages usually associated with particles having g/o/s materials incorporated in them have been overcome.
The oily substances incorporated may be but are not restricted to, pharmaceutically active agents, absorption enhancers or solubilizers.
DETAILED DESCRIPTION OF THE INVENTION
The pharmaceutical, solid, polymeric matrix beads for oral administration comprising considerable amounts of g/o/s pharmaceutically active substance(s) or pharmaceutically active substance(s) [g/o/s or not] plus such g/o/s substances, with fast release characteristics according to the invention are in this patent application considered to have fast release characteristics when they with an in-vitro dissolution test release not less than 60% w/w (preferably 70% w/w) of pharmaceutically active substance and g/o/s substance, or pharmaceutically active substance when the pharmaceutically active substance is the g/o/s substance, within 30 minutes or shorter. The calculation is based on water-free beads. For the g/o/s substances the dissolution rate is determined using USP apparatus No. 2 (paddle), operated at 100 rpm. The dissolution medium has a temperature of 37±0.5° C. Further there is a demand on the amount and art of dissolution medium, that it enables for the whole dose to be tested a non-retarded homogenous distribution of liberated g/o/s substance within the medium.
For the specific g/o/s substances shown in the examples, the medium disclosed in each example is the appropriate one.
For the pharmaceutically active substances the dissolution rate is determined using USP apparatus No. 2 (paddle), operated at 100 rpm. The dissolution medium has a t
Karlsson Christer
Lundberg Per Johan
Rosinski Adam
Söderbom Malin
AstraZeneca AB
Sharareh S
Travers Russell
White & Case LLP
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