Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2001-12-17
2003-05-06
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S468000, C424S469000, C424S474000, C424S480000, C424S482000, C514S772300, C514S781000, C514S784000, C514S786000
Reexamination Certificate
active
06558701
ABSTRACT:
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a continuation of international patent application no. PCT/EP00/05385, filed Jun. 13, 2000, designating the United States of America, the entire disclosure of which is incorporated herein by reference. Priority is claimed based on Federal Republic of Germany patent application no. DE 199 27 688.9, filed Jun. 17, 1999.
BACKGROUND OF THE INVENTION
The present invention relates to a multilayer tablet containing the active substances Tramadol and Diclofenac and/or their in each case physiologically compatible salts, with the active substances being separated from one another by a separating layer.
Tramadol is an analgesic used to treat severe and moderately severe pain, whose mode of action is not based on a pure opioid mechanism. Tramadol does not exhibit the characteristic side effects of an opioid. In some cases nausea is observed as an undesirable accompanying symptom.
Other known, non-opioid analgesics suitable for treating less severe pain include steroid-free analgesics such as Diclofenac-Na, acetylsalicylic acid or Ibuprofen.
Furthermore, for the treatment of moderate to severe pain, the World Health Organization (WHO) recommends combining opioid analgesics with non-steroidal analgesics in order to produce a more effective pain relief and possibly reduce amounts of analgesic which are necessary to administer.
Raffa, European Patent no. EP-B 546 676 discloses, for example, that the combination of Tramadol-HCl with non-steroidal anti-inflammatories, such as for example Ibuprofen, in a composition ratio of 1:1 to 1:200 produces a synergistically enhanced analgesic action and reduces the undesired accompanying symptoms. Tramadol-HCl and Diclofenac-Na form a sparingly soluble compound however. It is therefore to be expected that the bioavailability of the two active substances is reduced and that higher dosages are required in order to compensate for this.
SUMMARY OF THE INVENTION
The object of the present invention was accordingly to combine the two active substances Tramadol and Diclofenac and/or physiologically compatible salts thereof, respectively, in a common administration unit without however impairing the release profiles of the two active substances or reducing their bioavailability.
This object is achieved in accordance with the invention by providing a multilayer tablet to be administered orally that contains in at least one layer Tramadol and/or a physiologically compatible salt thereof and in at least one further layer Diclofenac and/or a physiologically compatible salt thereof, with a separating layer being present in each case between the layers containing the active substances.
Preferably the tablet consists of seven layers, particularly preferably of five layers and most particularly preferably of three layers.
Preferred physiologically compatible salts of Tramadol include Tramadol hydrochloride, Tramadol hydrobromide, Tramadol sulfate, Tramadol phosphate, Tramadol fumarate, Tramadol succinate, Tramadol maleate, Tramadol nitrate, Tramadol acetate, Tramadol propionate, Tramadol malonate, Tramadol citrate, Tramadol tartrate, Tramadol benzoate, Tramadol salicylate, Tramadol phthalate and/or Tramadol nicotinate. Particularly preferably Tramadol hydrochloride is used.
Preferred physiologically compatible salts of Diclofenac include Diclofenac-sodium, Diclofenac-potassium, Diclofenac-calcium, Diclofenac-magnesium and/or Diclofenac-cholestyramine. Particularly preferably Diclofenac-sodium is used.
The multilayer tablet to be used according to the invention may contain the conventional auxiliary substances and additives in the Tramadol-containing layer as well as in the Diclofenac-containing layer.
Preferably the multilayer tablet includes one or more layers each respectively containing one of the two active substances, preferably uniformly divided, in a retarding (delayed release) matrix, whereby optimal, individually matched release values can be achieved. By combination with the immediately released active substance an initial dose for a rapid pain relief can be achieved. The slow release from the retarded form permits the maintenance of therapeutic blood levels over an extended time.
The layers may also contain a retarded, particulate form of the respective active substance, preferably granules and/or pellets, particularly preferably pellets produced by extrusion and/or spheronisation. Particularly preferably in this connection the release of the active substance or active substances will be adjusted so that the tablet has to be administered at most twice, and preferably only once per day.
The proportion of the two analgesics in relation to auxiliary substances in the multilayer tablet may be adjusted depending on the desired release duration and amount of the analgesics to be released. Preferably the content of Tramadol is 2 to 60 wt. %, more preferably 5 to 45 wt. %, and most particularly preferably 10 to 35 wt. %, relative to the total weight of the multilayer tablet. Preferably the proportion of Diclofenac is 2 to 30 wt. %, particularly preferably 5 to 25 wt. %, and most particularly preferably 6 to 20 wt. %, relative to the total weight of the multilayer tablet. Based on the known activities of the analgesics, persons skilled in the art know what quantitative ratios of these analgesics should be used in order to achieve the desired effect of the active substances.
Suitable matrix materials useful in the invention include physiologically compatible, hydrophilic materials that are known to persons skilled in the art. Preferred hydrophilic matrix materials include polymers, particularly preferably cellulose ethers, cellulose esters and/or acrylic resins. Most particularly preferred matrix materials include ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose, poly(meth)acrylic acid and/or derivatives thereof such as its salts, amides or esters.
Particularly preferably there is used as physiologically compatible material for a retarding matrix at least one cellulose ether and/or cellulose ester whose 2 wt. % aqueous solution at 20° C. has a viscosity of 3,000 to 150,000 mP·as, preferably 10,000 to 150,000 mP·as, optionally in combination with a filler that is not swellable in an aqueous medium, such as for example calcium hydrogen phosphate, or with an insoluble filler that is swellable in an aqueous medium, such as for example microcrystalline cellulose, or a filler that is soluble in aqueous media, such as for example lactose.
Also preferred is a matrix material of hydrophobic materials such as hydrophobic polymers, waxes, fats, long-chain fatty acids, fatty alcohols or corresponding esters or ethers or their mixtures. Particularly preferably monoglycerides or diglycerides of C
12
-C
30
fatty acids and/or C
12
-C
30
fatty alcohols and/or waxes or their mixtures are used as hydrophobic materials.
It is also possible to use mixtures of the aforementioned hydrophilic and hydrophobic materials as a retarding matrix material.
In one preferred embodiment the separating layer is slightly permeable with respect to the two active substances also on contact with aqueous body fluids. This separating layer is preferably composed of a polymer, a wax, a fat, a fatty acid, a fatty alcohol or a corresponding ether or ester or a mixture thereof, and has a melting point of ≧40° C.
Preferred physiologically compatible polymers which may be used in the invention include cellulose acetate, ethylcellulose, cellulose butyrate, polyethylene or ethylene/vinyl acetate copolymers.
In a further preferred embodiment the separating layer is more specifically readily permeable with respect to the two active substances per se on contact with aqueous body fluids, the thickness of the separating layer then being adjusted however so that the two active substances do not come into contact with one another during the duration of the release.
To this end a permeable separating layer of the tablet may consist of hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose and/or h
Bartholomaeus Johannes
Ziegler Iris
Crowell & Moring LLP
Gruenenthal GmbH
Spear James M.
LandOfFree
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