Preparations of non-steroidal analgesics

Details Preparations of non-steroidal analgesics Preparations of non-steroidal analgesics

1998-07-15

2001-06-26

Webman, Edward J. (Department: 1611)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Matrices

C424S468000, C424S457000, C424S497000

Reexamination Certificate

active

06251434

ABSTRACT:

DESCRIPTION
The present invention relates to preparations of non-steroidal analgesics with antipyretic and antiinflammatory effect, obtainable by extrusion of a melt, comprising, besides one or more active ingredients, a mixture [lacuna]
a) 40-99.5% by weight of a homopolymer of N-vinylpyrrolidone with a Fikentscher K value of 30,
b) 0.25-59.75% by weight of water-soluble N-vinyl [sic] copolymers, and
c) 0.25-10% by weight of one or more physiologically acceptable salts of sodium or potassium,
where the stated amounts are based on the total of components a), b) and c), and subsequent shaping.
The invention furthermore relates to a process for producing such preparations.
Rapid release of the active ingredient is crucially important particularly with analgesics in order to achieve a rapid onset of the pain-relieving effect.
In the case of active ingredients which have low solubility in water, like the organic acids which have analgesic activity, rapid release of adequate doses is often not simple to achieve (cf. Deutsche Apotheker Zeitung, No. 32, page 54).
EP-A 607 467 proposes promoting rapid release of ibuprofen by adding basic salts which are applied in the form of aqueous solutions during the pelleting process to the active ingredient which has been premixed with an ancillary substance. The pellets are subsequently compressed to tablets in a conventional way. This procedure is, however, relatively complicated and therefore economically unfavorable.
Recent investigations have shown that rapid release of ibuprofen can be achieved by using the corresponding lyrine [sic] salts (G. Geisslinger et al., Drug. Invest. SC4), 238-242, 1993).
It is furthermore known that drug forms can be produced in a very economic manner by extruding polymer melts which contain active ingredients, with subsequent continuous shaping.
EP-B 240 904 describes such a process for producing solid pharmaceutical forms by extruding polymer melts which contain active ingredients, the polymers used being homo- or copolymers of N-vinylpyrrolidone.
However, the basic problem in such a process is that the matrix-forming polymers on the one hand are sufficiently thermoplastic at the processing temperatures, or become processable by addition of a plasticizer, but on the other hand lead to drug forms which are stable under the usual storage conditions and with which no cold flow occurs.
This problem is all the more difficult to solve when the intention is to produce rapid release drug forms. Normally suitable for this purpose are, in particular, relatively low molecular weight polymers which rapidly dissolve in digestive fluids. However, it is precisely these which are prone to cold flow of the finished drug forms. High molecular weight polymers normally do not give rapid release and can scarcely be extruded without a plasticizer because the glass transition temperature (DIN 52324) is considerably higher.
An additional problem arises when transparent drug forms are to be produced by melt extrusion.
It is an object of the present invention to find transparent, rapid release preparations of non-steroidal analgesics which can be produced in a simple manner by melt extrusion with subsequent shaping and have a long shelf life.
We have found that this object is achieved by the preparations defined at the outset.
Suitable active ingredients according to the invention are non-steroidal analgesics with antipyretic and antiinflammatory effect, as also employed for symptomatic antirheumatic therapy.
Accordingly, suitable active ingredients are derivatives of salicyclic acid, such as acetylsalicylic acid, and derivatives of other organic acids and pyrazole derivatives and, where they exist, their physiologically tolerated salts. Thus, suitable active ingredients are aryl [sic] acid derivatives, such as diclofenac, tolmetin or zomepirac, also arylpropyl [sic] acid derivatives, such as ibuprofen, with both enantiomerically pure S(+)-ibuprofen and a racemate enriched with this enantiomer being embraced, as well as D,L-lysine salts of ibuprofen, naproxen, fenoprofen, flurbiprofen or ketoprofen, or else indole- and indeneacetic acid derivatives such as indomethacin or sulindac. Examples of suitable pyrazole derivatives are phenazone, amino-phenazone, metamizole, propyphenazone, phenylbutazone or oxy-phenbutazone.
Preferred active ingredients are ibuprofen, acetylsalicylic acid and ketoprofen, sulindac, indomethacin, flurbiprofen.
It is also possible to employ mixtures of active ingredients. Also suitable are mixtures of the analgesics with caffeine or codeine.
The preparations according to the invention comprise as component a) a homopolymer of N-vinylpyrrolidone with a Fikentscher K value of 30. This homopolymer is readily thermo- [sic] and water-solution, “water-soluble” meaning that at least 0.5 g, preferably at least 2 g, of the polymer dissolves, possibly as colloidal solution, in 100 g of water at 20° C. Preparation of the homopolymer is generally known.
Suitable as component b) are water-soluble copolymers of N-vinylpyrrolidone. Particularly suitable copolymers are those with vinyl acetate in amounts of 10-50%, particularly preferably those obtained by copolymerizing 60% by weight of N-vinylpyrrolidone and 40% by weight of vinyl acetate.
Suitable as component c) are physiologically tolerated sodium and/or potassium salts, also in the form of their hydrates, for example sodium acetate, potassium acetate, sodium carbonate, potassium carbonate, disodium [sic] bicarbonate, potassium hydroxide, sodium chloride or potassium chloride, sodium tricitrate [sic], with sodium acetate being preferred, particularly preferably as sodium acetate trihydrate.
The ratios of the amounts of components a), b) and c) are chosen according to the invention so that the preparations comprise a mixture of
a) 40-99.5% by weight, preferably 45-95% by weight, of component a),
b) 0.25-59.75% by weight, preferably 0.5-50% by weight, of component b), and
c) 0.25-10% by weight, preferably 0.5-7% by weight, of component c),
where the stated amounts are based on the total of a), b) and c).
Very particularly preferred drug forms comprise, besides the medicinal substance, a mixture of
a) 60-85% by weight of component a)
b) 5-35% by weight of component b)
c) 0.5-5% by weight of component c).
The proportionate amount of the total of components a), b) and c) in the drug form is preferably from 60 to 85% by weight. Accordingly, the drug forms preferably comprise 15 to 40% by weight of one or more active ingredients.
The drug forms may additionally comprise 0 to 5% by weight of other conventional ancillary substances in the usual amounts.
The mixing of the active ingredient or ingredients with the polymeric binders and, where appropriate, pharmaceutical additives can take place before or after the melting of the polymeric binder by conventional processes. Mixing in an extruder is preferred, preferably a twin screw extruder or a single screw extruder with mixing compartment.
The melts contain no solvent. This means that no water and no organic solvent is added.
Production takes place by extrusion at from 50 to 180° C., preferably, 60 to 150° C. with subsequent shaping of the still plastic extrudate, eg. by shaping to tablets, for example as disclosed in EP-A 240 906 by passing the extrudate between two rolls which are driven in opposite directions and have mutually opposite depressions on the surface of the rolls, whose design determines the shape of the tablets. Cold cutting is also suitable.
A hot-cut process is preferred. This entails the extrudates being cut immediately after emerging from the die arrangement on the extruder by, for example, rotating knives or another suitable arrangement, expediently into pieces whose length is approximately equal to the diameter of the extrudate. The pellets which have been cut off cool in the stream of air or gas to such an extent that the surface is tack-free even before contact with other pellets or a vessel wall but, on the other hand, the p

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