Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
2001-06-22
2003-06-17
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C424S486000, C424S468000
Reexamination Certificate
active
06579536
ABSTRACT:
The invention relates to a solid sustained-release pharmaceutical composition for oral administration containing tilidine mesylate as an active ingredient.
Tilidine [ethyl-2-(dimethylamino)-1-phenyl-3-cyclohexene-1-carboxylate] represents a synthetic opioid from the group of analgesics having a morphine-like effect. It is used, just like its salts, for treating intense and very intense acute and chronic pain in cases of traumata, post-operative conditions, bone and joint ailments, pain in the region of the thoracic viscera, neuritis, neuralgia, pain caused by tumors, abdominal spasms, painful inflammations, post-traumatic pain, and pain during diagnostic and therapeutic operations.
Tilidine and its salts inhibit the neural transmission of polysynaptic pathways of the nocireceptive system. The effect is mediated through opiate receptors located on the neurons, which also serve as binding sites for naturally occurring peptides, so-called enkephalins.
Tilidine and its salts have only low analgesic activity. The actually active metabolites, nortilidine and bisnortilidine, are formed by metabolization in the liver. The two metabolites are classified as partial morphine antagonists, in that they are very similar to morphine in its pharmacokinetic properties.
Tilidine and many of its pharmaceutically acceptable salts, such as, e.g., tilidine hydrochloride (tilidine-HCl), can be prepared in solid administration forms only under great difficulty or not at all, as the stability of tilidine is very low. Tilidine in combination with solid additives very rapidly decomposes during manufacture and storage, which is indicated by discoloration. In addition, many of the tilidine salts are found to be highly hygroscopic and thus difficult to process.
Due to its stability, the tilidine dihydrogen orthophosphate described in patent specification EP 0 665 830 B1 represents the tilidine salt commonly used for the preparation of solid drugs. Manufacture of this salt, however, requires high safety standards, as quite specific conditions must be maintained in order to avoid critical situations.
It has now been found that tilidine mesylate has a sufficiently high stability and thus is very suitable for the preparation of solid drugs as it virtually does not undergo any decomposition in the solid form, i.e. in combination with solid additives. Furthermore, the high stability ensures easy processing, as there are no particular requirements to air conditioning of the work rooms and to corrosion protection of the equipment and instruments used. The preparation of tilidine mesylate may thus be carried out without any particular safety measures while using conventional laboratory equipment.
Although therapy with rapid-release drugs attempts to maintain long lasting therapeutically effective blood plasma levels of the active ingredient by frequent and at the same time regular administration of the active ingredient, the blood plasma level nevertheless varies considerably due to the instantaneous absorption, systemic excretion, and hepatic metabolization of the active ingredient. As a result, the effectivity of the active ingredient may be strongly impaired.
Considering the above, the object of the present invention is to provide a solid sustained-release pharmaceutical composition for oral administration containing tilidine mesylate as an active ingredient, so that patient compliance is improved through a reduced frequency of administration, and the effectivity of the active ingredient is optimized.
In the present context, “sustained-release” is to be understood as a release rate of the active ingredient wherein a therapeutically effective blood plasma level is achieved over a period of at least 8-12 hours and optionally of up to 24 hours. A therapeutically effective blood plasma level in particular is within the range of from 30 to 50 ng/ml of nortilidine.
It has been found that by means of the composition according to the invention a steady blood plasma level may be ensured over a period of at least 8 to 12 hours and optionally of up to 24 hours. The frequency of administration may thus be reduced to one or two doses per day.
The composition according to the invention contains an analgesically effective amount of tilidine mesylate per dosage unit corresponding to an amount of 50-500 mg of tilidine hydrochloride (tilidine-HCl), with the preferred dosage units containing an amount of tilidine mesylate corresponding to 50 mg, 100 mg, 150 mg and 200 mg of tilidine-HCl.
The composition according to the invention may be in the form of granulates, pellets, spheroids and/or extrudates. These may either be filled into capsules or sachets or pressed to form tablets. Moreover, the active ingredient and possible additives may optionally be tabletted directly.
The active ingredient used in the composition according to the invention, tilidine mesylate, may be embedded in a matrix. This matrix ensures the sustained release of tilidine mesylate over a period of at least 8 to 12 hours and optionally of up to 24 hours (matrix-controlled).
Suitable matrix-forming materials:
a) Hydrophilic or hydrophobic polymers, such as, e.g., gums, cellulose ethers, cellulose esters, acrylic resins, protein-based materials, nylon, polyvinyl chloride, starch and/or polyvinyl pyrrolidone. Suitable water-soluble polymers are, i.a., polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, poly(vinyl alcohols), alginates, polydextrose, carboxymethylene, hydrogenated hydroxyalkyl cellulose and/or hydroxypropylmethyl cellulose ether. As water-insoluble polymers polyvinyl chloride, ethyl cellulose, methyl cellulose, carboxymethyl cellulose (partly water-soluble, depending on the average degree of substitution), cellulose acetates, cellulose acetate phthalates, ethylene vinyl alcohol, alginic acid and/or its derivatives, acrylic acid and/or methacrylic acid copolymers, methyl methacrylate copolymers, ethoxy ethyl methacrylate copolymers, cyanoethyl methacrylates, aminoalkyl methacrylate copolymers, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymers, poly(methyl methacrylates), poly(methacrylic anhydrides), methyl methacrylates, polymethacrylates, poly(methyl methacrylate) copolymer, polyacrylamides, aminoalkyl methacrylate copolymers and/or glycidyl methacrylate copolymers may be used. The composition according to the invention may contain 1-90% (weight percent) of one or more of the hydrophilic or hydrophobic polymers as a matrix.
b) Digestible, substituted or unsubstituted long-chain (C
8
-C
50
, in particular C
12
-C
40
) hydrocarbons such as, e.g., fatty acids, fatty alcohols (lauryl, myristyl, stearyl, cetostearyl, ceryl or cetyl alcohol), glycerol esters of fatty acids (Witepsol, glycerol monostearate), mineral and vegetable oils (hydrogenated castor oil) and/or waxes (paraffin waxes, silicone waxes, beeswaxes, castor waxes, carnauba waxes and/or Glyco waxes). The hydrocarbons having a melting point between 25° C. and 90° C. are particularly useful. Preferred long-chain hydrocarbons are fatty alcohols. The composition according to the invention may contain at least one of the digestible, long-chain hydrocarbons, wherein their content may be up to 60% (weight percent), based on the matrix.
c) Polyalkylene glycols, wherein the composition according to the invention may contain up to 60% (weight percent) of one or more polyalkylene glycols, based on the matrix.
The preferred matrix form according to the invention may contain the active ingredient, tilidine mesylate, in a gel-forming matrix of, e.g., hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, alginate and/or polyacrylic acid, in particular hydroxypropylmethyl cellulose. The polymer hydrates to form a gel-like layer, i.e., a hydrogel matrix that slowly releases the active ingredient in a controlled manner by way of diffusion and erosion.
In another matrix form according to the invention, the active ingredient, tilidine mesylat
Hirsch Richard
Strungmann Thomas
Wesseling Martin
Fubara Blessing
Hexal AG
Nixon & Vanderhye P.C.
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