NOVEL FORMULATION OF INDOMETHACIN
The present invention relates to methods for producing particles of indomethacin using dry milling processes as well as compositions comprising indomethacin, medicaments produced using indomethacin in particulate form and/or compositions, and to methods of treatment of an animal, including man, using a therapeutically effective amount of indomethacin administered by way of said medicaments.
1 - 41 . (canceled)
42 . A pharmaceutical composition comprising indomethacin, wherein the median particle size of the indomethacin on a particle volume basis is less than 500 nm.
43 . The pharmaceutical composition of claim 42 wherein the median particle size on a particle volume basis is less than 400 nm.
44 . The pharmaceutical composition of claim 42 wherein the median particle size on a particle volume basis is less than 300 nm.
45 . The pharmaceutical composition of claim 42 wherein 90% of the indomethacin, on a particle volume basis, has a particle size that is less than 1500 nm.
46 . The pharmaceutical composition of claim 45 wherein 90% of the indomethacin, on a particle volume basis, has a particle size that is less than 900 nm.
47 . The pharmaceutical composition of claim 42 further comprising sodium lauryl sulfate
48 . The pharmaceutical composition of claim 42 further comprising lactose monohydrate.
49 . The pharmaceutical composition of claim 42 wherein the T max of the indomethacin when administered to a human subject is less than the T max of a conventional, non-nanoparticulate form of indomethacin administered to a human subject when the composition is administered at the same dosage as the conventional, non-nanoparticulate form.
50 . The pharmaceutical composition of claim 49 wherein the T max of the indomethacin when administered to a human subject is less than the T max of a conventional, non-nanoparticulate form of indomethacin administered to a human subject when the nanoparticulate composition is administered at a 20% lower dosage than the conventional, non-nanoparticulate form.
51 . The pharmaceutical composition of claim 49 wherein the T max is less than about 90% of the T max of a conventional, non-nanoparticulate form of indomethacin administered to a human subject when the composition is administered at the same dosage as the conventional, non-nanoparticulate form.
52 . The pharmaceutical composition of claim 42 wherein the T max of the indomethacin when administered to a human subject in the fasted state is less than the T max of a conventional, non-nanoparticulate form of indomethacin administered to a human subject in the fasted state when the composition is administered at the same dosage as the conventional, non-nanoparticulate form.
53 . The pharmaceutical composition of claim 52 wherein the T max of the indomethacin when administered to a human subject in the fasted state is less than the T max of a conventional, non-nanoparticulate form of indomethacin administered to a human subject in the fasted state when the composition is administered at a 20% lower dosage than the conventional, non-nanoparticulate form.
54 . The pharmaceutical composition of claim 42 wherein the C max of the indomethacin when administered to a human subject is greater than the C max of a conventional, non-nanoparticulate form of indomethacin administered to a human subject when the composition is administered at a 20% lower dosage than the conventional, non-nanoparticulate form.
55 . The pharmaceutical composition of claim 42 wherein the C max of the indomethacin is at least 10% greater.
56 . The pharmaceutical composition of claim 42 when tested in vitro by USP Apparatus I (Basket) method of U.S. Pharmacopoeia at 100 rpm at 37° C. in 900 ml of a 100 mM citric acid solution buffered to pH 5.5 provides a dissolution rate of indomethacin such that greater than 83% (by weight) is released at 20 minutes.
57 . The pharmaceutical composition of claim 42 wherein the T max of the indomethacin when administered to a fasted human subject is 2 hours or less.
58 . The pharmaceutical composition of claim 42 wherein the T max of the indomethacin when administered to a fed human subject is 3 hours or less.
59 . The pharmaceutical composition of claim 42 wherein the T max of the indomethacin when administered to a human subject is less than 3 hours when dosed in the fed or fasted state at 20 mg or 40 mg.
60 . A method for producing an indomethacin-containing composition, comprising:
dry milling a composition comprising indomethacin and a millable grinding matrix in a mill containing a plurality of milling bodies for a time period sufficient to produce a indomethacin-containing composition comprising particles of indomethacin having a median particle size on a particle volume basis of less than 500 nm dispersed in an at least partially milled grinding matrix.
61 . The method of claim 60 wherein the composition further comprises a surfactant.
62 . The method of claim 60 further comprising combining the indomethacin-containing composition with a facilitating agent.
63 . The method of claim 62 wherein the facilitating agent is selected from a surfactant, polymer, a binding agent, a filling agent, a lubricating agent, a sweetener, a flavoring agent, a preservative, a buffer, a wetting agent, a disintegrant, and an effervescent agent.
64 . The method of claim 60 further comprising processing the indomethacin-containing composition into a unit dosage pharmaceutical composition.
65 . The method of claim 64 wherein the unit dosage composition contains 20 mg or 40 mg of indomethacin.
66 . A unit dosage composition of indomethacin comprising the pharmaceutical composition of claim 42 wherein the unit dosage composition contain 20 or 40 mg of indomethacin.
67 . The pharmaceutical composition of claim 42 , wherein administration of the composition to a patient having undergone a surgical dental extraction procedure results in a TOTPAR-8 value of greater than 8.
68 . The pharmaceutical composition of claim 42 , wherein administration of the composition to a patient having undergone a surgical dental extraction procedure results in a visual analog scale pain intensity difference value of greater than 7 at 60 minutes after administration.
69 . The pharmaceutical composition of claim 42 , wherein administration of the composition to a patient having undergone a surgical dental extraction procedure results in a median time to onset of analgesia of less than 90 minutes.
70 . The pharmaceutical composition of claim 42 , wherein administration of the composition to a patient having undergone a surgical dental extraction procedure results in a visual analog scale pain intensity score of less than 70 at 60 minutes after administration.
71 . The pharmaceutical composition of claim 42 , wherein administration of the composition to a patient having undergone a surgical dental extraction procedure results in a median time to first perceptible pain relief of less than 90 minutes.