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Details for Patent: 5,879,705

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Details for Patent: 5,879,705

Title: Sustained release compositions of morphine and a method of preparing pharmaceutical compositions
Abstract:Sustained release pharmaceutical formulations containing morphine, or a pharmaceutically acceptable salt thereof, as active ingredient, suitable for administration on a once daily basis, are disclosed. In a first aspect, an orally administrable sustained release unit dosage form gives a peak plasma level at 1.0 to 6 hours after administration. In a second aspect, the formulation provides a W.sub.50 for the M-6-G metabolite for morphine of between 4 and 12 hours. A third aspect concerns the pharmaceutical unit dosage form obtained by compressing multiparticulates comprising a pharmaceutically active substance in a matrix of hydrophobic fusible material having a melting point of from 35.degree. to 150.degree. C.
Inventor(s): Heafield; Joanne (Fenstanton, GB2), Knott; Trevor John (Bishop's Stortford, GB2), Leslie; Stewart Thomas (Cambridge, GB2), Malkowska; Sandra Therese Antoinette (Ely, GB2), Miller; Ronald Brown (Basel, CH), Prater; Derek Allan (Milton, GB2), Smith; Kevin John (Histon, GB2)
Assignee: Euro-Celtique S.A. (Luxembourg, LU)
Filing Date:Apr 18, 1997
Application Number:08/843,571
Claims:1. An oral sustained release pharmaceutical unit dosage form containing a therapeutically effective amount of morphine or a pharmaceutically acceptable salt thereof, the unit dosage form comprising a tablet formed from, or a capsule containing granules, spheroids or pellets, and containing an amount from about 10 mg to about 500 mg of morphine or a pharmaceutically acceptable salt thereof, said amount calculated as morphine sulfate, the granules, spheroids or pellets comprising a matrix of a natural or synthetic wax or oil with a melting point of from about 35.degree. C. to about 100.degree. C. and 10% to 60% by weight of morphine or pharmaceutically acceptable salt thereof, such that the unit dosage form provides a time to peak plasma level of morphine in about 1.0 to about 6.0 hours after administration, and provides morphine plasma levels which are effective for 24 hourly dosing, characterized by a width of the plasma profile at 50% C.sub.max (W.sub.50) for the morphine-6-glucoronide metabolite of morphine of between 4 and 12 hours, said granules, spheroids or pellets being prepared by mixing together said morphine or salt thereof and said natural or synthetic wax or oil at a rate and energy input sufficient to cause said natural or synthetic wax or oil to melt or soften whereby it forms said granules, spheroids or pellets containing said morphine or salt thereof.

2. An oral sustained release pharmaceutical unit dosage form containing a therapeutically effective amount of morphine or a pharmaceutically acceptable salt thereof, the unit dosage form comprising a tablet formed from, or a capsule containing, granules, spheroids or pellets, and containing an amount from about 10 mg to about 500 mg of morphine or a pharmaceutically acceptable salt thereof, said amount calculated as morphine sulfate, the granules, spheroids or pellets comprising a matrix of a natural or synthetic wax or oil with a melting point of from about 35.degree. C. to about 100.degree. C. and 10% to 60% by weight of morphine or pharmaceutically acceptable salt thereof, said unit dosage form having in vitro release characteristics such that the formulation, when assessed by the modified European Pharmacopeia Basket Method at 100 rpm in 900 ml aqueous buffer at pH 6.5 containing 0.5% polysorbate at 37.degree. C., releases from 5 to 30% of morphine two hours after start of test, 15 to 50% at 4 hours after start of test; 20% to 60% at 6 hours after start of test; 35 to 75% at 12 hours after start of test, from 45 to 100% at 18 hours after start of test and 55 and 100% at 24 hours after start of test such that the unit dosage form provides a time to peak plasma level of morphine in about 1.0 to about 6.0 hours after administration, and provides morphine plasma levels effective for 24 hourly dosing, characterized by a width of the plasma profile at 50% C.sub.max (W.sub.50) for the morphine-6-glucoronide metabolite of morphine of between 4 and 12 hours, wherein said granules, spheroids or pellets are prepared by a process comprising the steps of

a) mixing together a particulate form of said morphine or pharmaceutically acceptable salt thereof, a particulate form of said natural or synthetic wax or oil, and optionally a release control component comprising a material selected from the group consisting of a water soluble fusible material, a particulate soluble organic material, a particulate insoluble organic material, a particulate inorganic soluble material, a particulate inorganic insoluble material and mixtures thereof, at a speed and energy input which allows the carrier to melt or soften whereby it forms agglomerates; and

(b) breaking down the agglomerates to give said granules, spheroids or pellets.

3. The sustained release dosage form of claim 2 wherein said dosage form further comprises a pharmaceutically acceptable inert diluent.

4. An oral sustained release pharmaceutical unit dosage form prepared by a process comprising the steps of compressing granules, spheroids or pellets comprising morphine or a salt thereof dispersed in a matrix comprising a natural or synthetic wax or oil having a melting point from 35.degree. to 100.degree. C., wherein said dosage form is characterized by a width of the plasma profile at 50% C.sub.max (W.sub.50) for the morphine-6-glucoronide metabolite of morphine of between 4 and 12 hours.

5. The unit dosage form of claim 4, wherein said granules, spheroids or pellets are prepared by a process comprising the steps of mixing together a particulate form of said morphine or salt thereof and a particulate form of said natural or synthetic wax or oil at speed and energy input sufficient to melt or soften said hydrophobic material and to form said granules, spheroids or pellets.

6. The unit dosage form of claim 4, wherein said granules, spheroids or pellets are obtained by a process comprising the steps of mixing together said morphine or salt thereof and said natural or synthetic wax or oil at a rate and energy input sufficient to cause the natural or synthetic wax or oil to melt or soften whereby it forms said granules, spheroids or pellets and thereafter separating said granules, spheroids or pellets having a size range from about 0.1 mm to about 3 mm.

7. An orally administrable sustained release once-a-day unit dosage form comprising a plurality of granules, spheroids or pellets comprising morphine or a pharmaceutically acceptable salt thereof and a natural or synthetic wax or oil, said composition characterized by a width of the plasma profile at 50% C.sub.max (W.sub.50) for said morphine of between 4 and 12 hours after administration and providing sufficient analgesia for about 24 hours after administration of said unit dosage form to a human patient.

8. The unit dosage form of claim 7, wherein said granules, spheroids or pellets are prepared by a process comprising the steps of mixing together said morphine or salt thereof and said natural or synthetic wax or oil at a rate and energy input sufficient to cause said natural or synthetic wax or oil to melt or soften whereby it forms said granules, spheroids or pellets containing said morphine and thereafter separating said granules, spheroids or pellets having a size range from about 0.1 mm to about 3 mm.

9. The unit dosage form as claimed in claim 1 which provides a time to peak plasma level of morphine in about 1.0 to about 3.5 hours after administration.

10. The unit dosage form as claimed in claim 2 which provides a time to peak plasma level of morphine in about 1.0 to about 3.5 hours after administration.

11. The unit dosage form of claim 6, wherein the mixing step incudes mixing together the morphine or salt thereof, the natural or synthetic wax or oil, and a release modifier.
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