Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1996-07-30
2001-10-30
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S474000, C424S479000, C424S480000, C424S481000
Reexamination Certificate
active
06309668
ABSTRACT:
This invention relates to abuse resistant tablets, to a process for their preparation, and to their use in therapy. More particularly, the present invention relates to abuse resistant tablets comprising a plurality of layers.
It is known that many drugs intended for legitimate oral use have the potential for abuse, whereby the drug may be extracted from a solid oral dosage form to provide a solution which may be used for unauthorised, unsupervised, illegal and/or dangerous parenteral administration. One way of substantially reducing or even eliminating this potential for drug abuse is to suppress or inhibit the extractibility of the drug from the composition comprising the drug. In U.S. Pat. No. 4,070,494 this is reported to have been achieved by incorporating in the composition an aqueous gelable material present in sufficient quantity to form a gel when combined with that volume of water otherwise necessary to dissolve all of the medicinal agent. U.S. Pat. No. 4,070,494 describes enteral compositions, including single and bilayer tablets, wherein the drug with potential for abuse is mixed with the gelling agent and in the case of a tablet is then pressed according to a conventional procedure. However, such tablets comprising a gelling layer are liable to seriously retard the release of the drug substance.
We have now found that release of the drug substance from a tablet comprising a gelling agent is improved if the drug substance and the gelling agent are present in separate layers of the tablet.
The present invention thus pertains to a tablet containing two or more layers comprising one or more drugs and one or more gelling agents, characterised in that the drug(s) and gelling agent(s) are contained in separate layers of the tablet.
For the avoidance of doubt, it should be appreciated that the tablet may comprise separate layers one stacked on top of the other in a sandwich arrangement, or may comprise a core layer of gelling agent surrounded by one or more layers comprising one or more drugs. The sandwich arrangement is generally preferred.
Optionally the tablet has a coating which may or may not be a modified or sustained release coating.
Suitable drugs which may be incorporated into the abuse resistant tablets of the present invention include those which are particularly liable to abuse, for example, analgesics, hypnotics and anxiolytics.
Specific examples of analgesic drugs which may be incorporated into tablets of this invention include commercially available analgesic drugs, such as codeine, pethidine, methadone and morphine.
Specific examples of hypnotic agents which may be incorporated into tablets of this invention include benzodiazepines such as temazepam, nitrazepam, flurazepam and loprazolam and non-benzodiazepines such as chlormethiazole, zopiclone and zolpidem, and barbiturates such as butobarbitone, phenobarbitone and amylobarbitone.
Specific examples of anxiolytic agents which may be incorporated into tablets of this invention include diazepam, medazepam, oxazepam and lorazepam.
The term “gelling agent” as used herein refers to a material which forms a gel by the action of an aqueous medium, such as water or an aqueous solution of an organic acid (e.g. aqueous citric or acetic acid), a base (e.g. sodium bicarbonate or sodium tetraborate solution) or alcohol (e.g. an aqueous lower alkanol such as aqueous ethanol or isopropanol).
Suitable gelling agents include, but are not limited to, modified celluloses such as hydroxypropylmethylcellulose, hydroxypropyl-ethylcellulose, methylcellulose, sodium carboxymethylcellulose, and hydroxyethylcellulose, sodium alginate, alginic acid, tragacanth, polyacrylic acid and xanthan, guar, locust bean and karaya gums. Mixtures of two or more gelling agents may also be used.
Hereinafter, the layer or layers of the tablet containing the drug is referred to as the “active layer” and the layer or layers containing the gelling agent is referred to as the “gelling layer”.
The viscosity of the gelling agent in the gelling layer will generally be within the range of about 1000 cp to about 100,000 cp. As used herein, the term “cp” refers to centipoise which is a standard unit of viscosity. One centipoise (cp) is equivalent to one millipascal second (mPa.s).
Preferably, the gelling agent will have a viscosity within the range of about 4,000 cp to about 100,000 cp. More preferably, the gelling agent will have a viscosity within the range of about 10,000 cp to about 100,000 cp.
It will be appreciated that the amount of gelling agent required in the tablet depends upon features such as the nature of the active constituent, the nature of the other excipients in the tablet, the weight of the tablet and the viscosity grade of the gelling agent. The amount of gelling agent present is preferably such that substantially no filterable material remains when the tablet is triturated with the minimal amount of aqueous medium needed to extract the drug. In general, the proportion of gelling agent by weight in the gelling layer is from about 10 to about 70%, preferably about 20 to about 60%, and most preferably about 30 to about 50%. The total amount of gelling layer in the tablet depends upon the relative proportion of active and gelling layers but may typically be in the range of about 20 to about 80% and preferably about 50 to about 80% by weight.
The amount of drug in the active layer depends upon the therapeutic dose required, as in conventional tablets. In general, the quantity of drug which is incorporated into each tablet is often from about 0.5 mg to about 200 mg by weight, preferably from about 1 mg to about 100 mg, and most preferably from about 1 mg to about 50 mg. In the case of zopiclone the quantity of drug which is incorporated into each tablet is preferably about 1 mg to about 10 mg.
The remainder of the active and gelling layers may consist of standard tablet excipients known to those in the art, including but not limited to diluents such as lactose, starches, cellulose and calcium hydrogen phosphate, disintegrants such as starches, modified starches, celluloses and modified celluloses, binders, glidants and lubricants.
The tablet may also contain materials known in the art intended for the modification of release characteristics of the drug.
Preferably the active layer and the gelling layer are substantially identical in colour and appearance, so that the join is not readily visible to the potential abuser.
A coating, which may or may not be a modified or sustained release coating, may advantageously be applied to a tablet according to the present invention. A coated tablet is potentially advantageous when the tablet layers are stacked in a sandwich construction in that the join between the active layer and the gelling layer is further disguised.
In tablets according to the invention with more than two layers, one surface of the active layer should be exposed to prevent retardation of release of drug substance. Since one surface of the active layer is always exposed and not in contact with the gelling layer in tablets according to the present invention, release of drug can proceed relatively uninhibited and at a rate substantially similar to that of conventional tablets which do not possess a gelling layer.
In contrast, a combination of the active drug substance and gelling agent in the same layer has the disadvantage that the gelling action is likely to retard the release of the drug in a manner similar to some known sustained release products which include water-swellable high molecular weight polymers to retard drug release. Reduction of the gelling agent concentration to a level which would not inhibit release of the drug substance severely limits the abuse resistance potential of the tablet.
Drugs which may be particularly suitable for incorporation into the active layer of a tablet according to the present invention include zopiclone, temazepam, diazepam, zolpidem, codeine, methadone, pethidine, phenytoin and phenobarbitone. A preferred drug for use according to the present invention is zopiclone.
Gelling agents which may be
Bastin Richard James
Lithgow Bruce Hamilton
Aventis Pharma Limited
Joynes R.
Oehler Ross J.
Page Thurman K.
Wang George G.
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