JP2013537915A - Opioid controlled release formulations - Google Patents

Abstract

Pharmaceutical formulation comprising an opioid component, each having a release profile. The components can provide immediate or controlled release of the opioid. The invention also relates to methods of controlling the release of one or more opioid compounds and methods of treating pain. The pharmaceutical formulations of the invention may comprise one or more components having one or more release profiles, at least one of which comprises a compound having opioid receptor agonist activity. In embodiments where more than one component is present, the components may have the same release profile, or the components may have different release profiles.

Description

This application claims the benefit of US Provisional Application No. 61 / 386,277, filed Sep. 24, 2010, and US Patent Application No. 13/024, filed Feb. 9, 2011. Claim priority over Issue 319. Both of these applications are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION The present invention relates to pharmaceutical formulations comprising an opioid component, each having a release profile. The components can provide immediate or controlled release of the opioid. The invention also relates to methods of controlling the release of one or more opioid compounds and methods of treating pain.

BACKGROUND OF THE INVENTION Opioids are a class of pain relieving prescription drugs frequently used in the treatment of various acute and chronic moderate to severe pain. However, opioids can be rapidly absorbed and excreted systemically by the body through metabolic inactivation. In order to treat patients, particularly those in severe pain states, administration of opioids maintains an effective steady state blood level of the opioid, thereby providing consistent analgesia. Careful dosing at frequent intervals is often required. Otherwise, the blood levels of the opioids may fluctuate, resulting in inadequate and inconsistent pain relief.

  These problems with the administration of opioids suggest the need to develop an opioid treatment that can maintain consistent levels of opioids in the blood after administration and avoid fluctuations in pain relief.

SUMMARY OF THE INVENTION The present invention relates to a pharmaceutical formulation for treating pain comprising an opioid compound and components having different release profiles. The invention also relates to methods of controlling the release of one or more opioid compounds and methods of treating pain.

  The pharmaceutical formulations of the invention may comprise one or more components having one or more release profiles, at least one of which comprises a compound having opioid receptor agonist activity. In embodiments where more than one component is present, the components may have the same release profile, or the components may have different release profiles.

  In some embodiments, compounds having opioid receptor agonist activity are mu ("μ", morphine receptor), sigma ("σ", phencyclidine receptor), kappa ("κ", ketocyclazocine receptor) Or delta (“δ”, endorphin enkephalin receptor) may have agonist activity against an opioid receptor. Such compounds may include, inter alia, morphine, codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine, oxymorphone, mixtures thereof or salts thereof. In certain embodiments, one component may comprise two opioid compounds in various ratios. In certain embodiments, one component may include morphine and oxycodone or salts thereof in a weight ratio of about 3: 2.

  In some embodiments, the component can have an immediate release profile or a controlled release profile.

  In certain embodiments, the formulation may include one or more additional components (eg, at least two, at least three, at least four or at least five components). In some embodiments, the one or more additional components can include one or more active agents. In some embodiments, the one or more active agents can be compounds having opioid receptor agonist activity. In some embodiments, the one or more active agents have one or more non-opioid analgesic compound (s), or one or more non-opioid analgesic compound (s) and opioid receptor agonist activity 1 It may be a mixture of one or more compound (s) or a pharmaceutically acceptable salt, ester or prodrug thereof. In certain embodiments, the one or more active agents comprise one or more hybrid opioid compound (s), or one or more hybrid opioid compound (s) and one or more opioid receptor agonist activities. Or a pharmaceutically acceptable salt, ester or prodrug thereof.

  In embodiments of the invention, the pharmaceutical formulation may comprise one or more opioid components, wherein at least one of the opioid components is a controlled release opioid component comprising an opioid. In certain embodiments, the opioid is selected from the group consisting of morphine, codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine, oxymorphone, mixtures thereof and salts thereof. In certain embodiments, the opioid is oxycodone or a salt thereof.

In certain embodiments, the pharmaceutical formulation provides an opioid peak plasma concentration attainment time (T _max ) of about 4.5 to about 8 hours after repeated dosing. In certain embodiments, T _max is about 5 to about 6 hours or about 6 hours after repeated dosing.

In some embodiments, the controlled release component provides an oxycodone minimum plasma concentration attainment time (T _min ) of about 13 to about 16 hours after repeated dosing. In certain embodiments, T _min is about 14 hours after repeated administration. In some embodiments, the repeated administration is through steady-state conditions.

  In some embodiments, the dissolution of the pharmaceutical formulation releases about 0 to about 20% of the opioid after 2 hours as measured at 50 rpm in water at 37 ° C. in a USP Type I device. Or release after about 4 hours about 15 to about 60% of the opioid, or after 6 hours release about 25 to about 80% of the opioid, or after 8 hours about 35 to about 85% Release the opioid or release about 45 to about 95% of the opioid after 10 hours, or release about 60 to about 100% of the opioid after 12 hours.

In certain embodiments, when the pharmaceutical formulation comprises about 2 mg of an opioid, the pharmaceutical formulation has an average maximum plasma concentration of about 1 to about 3 ng / mL or about 2 ng / mL after repeated administration (C _max ) can be provided. In some embodiments, the repeated administration can be during steady state conditions. In certain embodiments, the area under the curve (AUC ₂₄ ) from about 0 to about 24 hours after a single dose is from about 14.7 ng · hr / mL to about 23.0 ng · hr / mL or about 15.8 ng Hr / mL to about 21.0 ng hr / mL or about 17.1 ng hr / mL to about 19.7 ng hr / mL.

In certain embodiments, when the pharmaceutical formulation comprises about 5 mg of an opioid, the pharmaceutical formulation may provide an average C _max of about 3 to about 7 ng / mL or about 5 ng / mL after repeated dosing. . In some embodiments, the repeated administration can be during steady state conditions. In certain embodiments, the AUC ₂₄ after a single dose is about 40.2 ng · hr / mL to about 62.8 ng · hr / mL or about 43.2 ng · hr / mL to about 57.2 ng · hr / mL or about 46.7 ng hr / mL to about 53.7 ng hr / mL.

In certain embodiments, when the pharmaceutical formulation comprises about 10 mg of an opioid, the pharmaceutical formulation may provide an average C _max of about 5 to about 15 ng / mL or about 10 ng / mL after repeated dosing. . In some embodiments, the repeated administration can be during steady state conditions. In certain embodiments, the AUC ₂₄ after a single dose is about 80.5 ng · hr / mL to about 125.9 ng · hr / mL or about 86.6 ng · hr / mL to about 114.8 ng · hr / mL or about 93.7 ng hr / mL to about 107.7 ng hr / mL.

In certain embodiments, when the pharmaceutical formulation comprises about 20 mg of an opioid, the pharmaceutical formulation may provide an average C _max of about 10 to about 30 ng / mL or about 20 ng / mL after repeated administration. . In some embodiments, the repeated administration can be during steady state conditions. In certain embodiments, the AUC ₂₄ after a single dose is about 166.0 ng · hr / mL to about 259.3 ng · hr / mL or about 178.5 ng · hr / mL to about 236.6 ng · hr / mL or about 193.0 ng hr / mL to about 222.0 ng hr / mL.

In certain embodiments, when the pharmaceutical formulation comprises about 40 mg of an opioid, the pharmaceutical formulation may provide an average C _max of about 25 to about 55 ng / mL or about 40 ng / mL after repeated dosing. . In some embodiments, the repeated administration can be during steady state conditions. In certain embodiments, the AUC ₂₄ after a single dose is about 338.5 ng · hr / mL to about 528.9 ng · hr / mL or about 363.9 ng · hr / mL to about 482.3 ng · hr / mL or about 393.5 ng hr / mL to about 452.7 ng hr / mL.

In certain embodiments, when the pharmaceutical formulation comprises about 80 mg of an opioid, the pharmaceutical formulation may provide an average C _max of about 50 to about 110 ng / mL or about 80 ng / mL after repeated dosing. . In some embodiments, the repeated administration can be during steady state conditions. In certain embodiments, the AUC ₂₄ after a single dose is about 868.4 ng · hr / mL to about 1356.9 ng · hr / mL or about 933.5 ng · hr / mL to about 1237.5 ng · hr / mL or about 1009.5 ng · hr / mL to about 1161.5 ng · hr / mL.

In some embodiments, the pharmaceutical formulation provides an average lowest oxycodone plasma concentration (C _min ) of about 0.5 to about 40 ng / mL or about 4 to about 15 ng / mL after repeated dosing. In some embodiments, the repeated administration is during steady state conditions.

  In certain embodiments, the pharmaceutical formulation comprises a second controlled release opioid component. In some embodiments, the second controlled release opioid component is an opioid selected from the group consisting of morphine, codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine, oxymorphone, mixtures thereof and salts thereof Including.

  In certain embodiments, the pharmaceutical formulation comprises an immediate release opioid component. In some embodiments, the immediate release opioid component comprises an opioid selected from the group consisting of morphine, codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine, oxymorphone, mixtures thereof and salts thereof. In a further embodiment, the opioid in the immediate release opioid component is morphine or a salt thereof. In still further embodiments, all morphine or a salt thereof and all oxycodone or a salt thereof in the above formulation are present in a weight ratio of morphine or a salt thereof to oxycodone or a salt thereof of about 3: 2.

  In certain embodiments, the pharmaceutical formulation comprises a second opioid component and a third opioid component, wherein: (a) the second opioid component is an immediate release opioid component, a κ agonist And (b) the third opioid component is a controlled release opioid component and includes an opioid having mu agonist activity. In some embodiments, the opioid having κ agonist activity is oxycodone or a salt thereof and the opioid having μ agonist activity is morphine or a salt thereof.

  In certain embodiments, the controlled release opioid component comprises morphine or a salt thereof. In some embodiments, the controlled release opioid component comprises morphine or a salt thereof and oxycodone or a salt thereof in a weight ratio of about 3: 2.

In embodiments of the invention, the pharmaceutical formulation may comprise one or more opioid components for humans in need thereof, the one or more opioid components having one or more release profiles (Comprise), at least one of those opioid components is a controlled release opioid component comprising oxycodone or a salt thereof; when the pharmaceutical formulation comprises oxycodone or a salt thereof, having a total dose of about 2 mg, about 4.5 to about 7.5 hours or from about 5 to about 6 hours or about 6 hours of _{T max,} and single dose of about after administration 14.7ng · hr / mL~ about 23.0ng · hr / mL or about 15. to provide a _{AUC 24} that 8 ng · hr / mL to about 21.0ng · hr / mL or about 17.1ng · hr / mL~ about 19.7ng · hr / mL . The repeated administration may be during steady state conditions.

In certain embodiments, the pharmaceutical formulation is formulated for a total dose of oxycodone or a salt thereof different from about 2 mg oxycodone or a salt thereof, and has an AUC ₂₄ proportional to the AUC ₂₄ above. In some embodiments, the total dose AUC ₂₄ is linearly proportional to the 2 mg AUC ₂₄ .

In certain embodiments, the pharmaceutical formulation provides a _Cmax of about 1 to about 3 ng / mL or about 2 mg after repeated administration when comprising a total dose of about 2 mg of oxycodone or a salt thereof. In some embodiments, the repeated administration is during steady state conditions. In some embodiments, the pharmaceutical formulation, the oxycodone or salt thereof from about 2mg be formulated for oxycodone or a salt thereof with different total doses, have a C _max which is proportional to the C _max of the 2mg. In some embodiments, the total dose C _max is linearly proportional to the 2 mg C _max .

In certain embodiments, the pharmaceutical formulation provides a T _min of about 13 to about 16 hours after repeated administration when the total dose is about 2 mg. In some embodiments, the repeated administration is during steady state conditions.

In embodiments of the invention, the pharmaceutical formulation may comprise one or more opioid components for humans in need thereof, the one or more opioid components having one or more release profiles , At least one of those opioid components is a controlled release opioid component comprising oxycodone or a salt thereof; said pharmaceutical formulation comprising about a 5 mg total dose of oxycodone or a salt thereof, after repeated administration of about 4. _{Tmax of} 5 to about 7.5 hours or about 5 to about 6 hours or about 6 hours, and about 40.2 ng · hr / mL to about 62.8 ng · hr / mL or about 43.2 ng · after a single dose An AUC _{24 of} hr / mL to about 57.2 ng hr / mL or about 46.7 ng hr / mL to about 53.7 ng hr / mL is provided. The repeated administration may be during steady state conditions.

In certain embodiments, the pharmaceutical formulation, the oxycodone or salt thereof from about 5mg formulated for oxycodone or a salt thereof with different total doses, has an AUC ₂₄ that is proportional to the AUC ₂₄ for the 5mg. In some embodiments, the total dose AUC ₂₄ is linearly proportional to the 5 mg AUC ₂₄ .

In certain embodiments, the pharmaceutical formulation provides a _Cmax of about 3 to about 7 ng / mL or about 5 ng / mL after repeated administration when comprising a total dose of about 5 mg of oxycodone or a salt thereof. In some embodiments, the repeated administration is during steady state conditions. In some embodiments, the pharmaceutical formulation, the oxycodone or salt thereof from about 5mg formulated for oxycodone or a salt thereof with different total doses, have a C _max which is proportional to the C _max of the 5mg. In some embodiments, the total dose C _max is linearly proportional to the 5 mg C _max .

In certain embodiments, the pharmaceutical formulation provides a T _min of about 13 to about 16 hours after repeated administration when comprising a total dose of about 5 mg of oxycodone or a salt thereof. In some embodiments, the repeated administration is during steady state conditions.

In embodiments of the invention, the pharmaceutical formulation may comprise one or more opioid components for humans in need thereof, the one or more opioid components having one or more release profiles , At least one of those opioid components is a controlled release opioid component comprising oxycodone or a salt thereof; said pharmaceutical formulation comprising about a 10 mg total dose of oxycodone or a salt thereof, after repeated administration of about 4. _{Tmax of} 5 to about 7.5 hours or about 5 to about 6 hours or about 6 hours, and about 80.5 ng · hr / mL to about 125.9 ng · hr / mL or about 86.6 ng after a single dose. Provides an AUC _{24 of} hr / mL to about 114.8 ng hr / mL or about 93.7 ng hr / mL to about 107.7 ng hr / mL. The repeated administration may be during steady state conditions.

In certain embodiments, the pharmaceutical formulation, the oxycodone or salt thereof from about 10mg formulated for oxycodone or a salt thereof with different total doses, has an _{AUC 24} that is proportional to the _{AUC 24} for the 10mg. In some embodiments, the total dose AUC ₂₄ is linearly proportional to the 10 mg AUC ₂₄ .

In certain embodiments, the pharmaceutical formulation provides a _Cmax of about 5 to about 15 ng / mL or about 10 ng / mL after repeated administration when comprising a total dose of about 10 mg of oxycodone or a salt thereof. In some embodiments, the repeated administration is during steady state conditions. In some embodiments, the pharmaceutical formulation, the oxycodone or salt thereof from about 10mg formulated for oxycodone or a salt thereof with different total doses, have a C _max which is proportional to the C _max of the 10mg. In some embodiments, the total dose C _max is linearly proportional to the 10 mg C _max .

In certain embodiments, the pharmaceutical formulation provides a T _min of about 13 to about 16 hours after repeated administration when comprising a total dose of about 10 mg of oxycodone or a salt thereof. In some embodiments, the repeated administration is during steady state conditions.

In embodiments of the invention, the pharmaceutical formulation may comprise one or more opioid components for humans in need thereof, the one or more opioid components having one or more release profiles , At least one of those opioid components is a controlled release opioid component comprising oxycodone or a salt thereof; said pharmaceutical formulation comprising about a 20 mg total dose of oxycodone or a salt thereof, after repeated administrations of about 4. _{Tmax of} 5 to about 7.5 hours or about 5 to about 6 hours or about 6 hours, and after single administration about 166.0 ng · hr / mL to about 259.3 ng · hr / mL or about 178.5 ng · An AUC _{24 of} from hr / mL to about 236.6 ng hr / mL or from about 193.0 ng hr / mL to about 222.0 ng hr / mL is provided. The repeated administration may be during steady state conditions.

In certain embodiments, the pharmaceutical formulation, the oxycodone or salt thereof from about 20mg formulated for oxycodone or a salt thereof with different total doses, has an _{AUC 24} that is proportional to the _{AUC 24} for the 20mg. In some embodiments, the total dose AUC ₂₄ is linearly proportional to the 20 mg AUC ₂₄ .

In certain embodiments, the pharmaceutical formulation provides a _Cmax of about 10 to about 30 ng / mL or about 20 ng / mL after repeated administration when comprising a total dose of about 20 mg of oxycodone or a salt thereof. In some embodiments, the repeated administration is during steady state conditions. In some embodiments, the pharmaceutical formulation, the oxycodone or salt thereof from about 20mg formulated for oxycodone or a salt thereof with different total doses, have a C _max which is proportional to the C _max of the 20mg. In some embodiments, the total dose C _max is linearly proportional to the 20 mg C _max .

In certain embodiments, the pharmaceutical formulation provides a T _{min of} about 8 hours after repeated administration when comprising a total dose of about 20 mg of oxycodone or a salt thereof. In some embodiments, the repeated administration is during steady state conditions. In some embodiments, the pharmaceutical formulation, the oxycodone or salt thereof from about 20mg formulated for different total doses, has a _{C min} that is proportional to the _{C min} of the 20mg. In some embodiments, the total dose C _min is linearly proportional to the 20 mg C _min .

In embodiments of the invention, the pharmaceutical formulation may comprise one or more opioid components for humans in need thereof, the one or more opioid components having one or more release profiles , At least one of those opioid components is a controlled release opioid component comprising oxycodone or a salt thereof; said pharmaceutical formulation comprising about a 40 mg total dose of oxycodone or a salt thereof, after repeated administration of about 4. T _{max of} 5 to about 7.5 hours or about 5 to about 6 hours or about 6 hours, and after single administration, about 338.5 ng · hr / mL to about 528.9 ng · hr / mL or about 363.9 ng · An AUC _{24 of} from hr / mL to about 482.3 ng · hr / mL or from about 393.5 ng · hr / mL to about 452.7 ng · hr / mL is provided. The repeated administration may be during steady state conditions.

In certain embodiments, the pharmaceutical formulation, the oxycodone or salt thereof from about 40mg formulated for oxycodone or a salt thereof with different total doses, has an _{AUC 24} that is proportional to the _{AUC 24} for the 40mg. In some embodiments, the total dose AUC ₂₄ is linearly proportional to the 40 mg AUC ₂₄ .

In certain embodiments, the pharmaceutical formulation provides a _Cmax of about 25 to about 55 ng / mL or about 40 ng / mL after repeated administration when comprising a total dose of about 40 mg of oxycodone or a salt thereof. In some embodiments, the repeated administration is during steady state conditions. In some embodiments, the pharmaceutical formulation, the oxycodone or salt thereof from about 40mg formulated for oxycodone or a salt thereof with different total doses, have a C _max which is proportional to the C _max of the 40mg. In some embodiments, the total dose C _max is linearly proportional to the 40 mg C _max .

In certain embodiments, the pharmaceutical formulation provides a T _min of about 13 to about 16 hours after repeated administration when comprising a total dose of about 40 mg of oxycodone or a salt thereof. In some embodiments, the repeated administration is during steady state conditions.

In embodiments of the invention, the pharmaceutical formulation may comprise one or more opioid components for humans in need thereof, the one or more opioid components having one or more release profiles , At least one of those opioid components is a controlled release opioid component comprising oxycodone or a salt thereof; said pharmaceutical formulation comprising about a 80 mg total dose of oxycodone or a salt thereof, after repeated administration of about 4. _{Tmax of} 5 to about 7.5 hours or about 5 to about 6 hours or about 6 hours, and after single administration, about 868.4 ng · hr / mL to about 1356.9 ng · hr / mL or about 933.5 ng · hr / mL to about 1237.5ng · hr / mL or Hisage about 1009.5ng · hr / mL~ _{AUC 24} of about 1161.5ng · hr / mL To. The repeated administration may be during steady state conditions.

In certain embodiments, the pharmaceutical formulation, the oxycodone or salt thereof from about 80mg formulated for oxycodone or a salt thereof with different total doses, has an _{AUC 24} that is proportional to the _{AUC 24} for the 80mg. In some embodiments, the total dose AUC ₂₄ is linearly proportional to the 80 mg AUC ₂₄ .

In certain embodiments, the pharmaceutical formulation provides a _Cmax of about 50 to about 110 ng / mL or about 80 ng / mL after repeated dosing when comprising a total dose of about 80 mg of oxycodone or a salt thereof. In some embodiments, the repeated administration is during steady state conditions. In some embodiments, the pharmaceutical formulation, the oxycodone or salt thereof from about 80mg formulated for oxycodone or a salt thereof with different total doses, have a C _max which is proportional to the C _max of the 80mg. In some embodiments, the total dose C _max is linearly proportional to the 80 mg C _max .

In certain embodiments, the pharmaceutical formulation provides a T _min of about 13 to about 16 hours after repeated administration when comprising a total dose of about 80 mg of oxycodone or a salt thereof. In some embodiments, the repeated administration is during steady state conditions.

  A method for controlling the release of one or more compounds having opioid receptor agonist activity for absorption in humans comprises administering a pharmaceutical formulation comprising one or more components, the one or more The opioid component of has one or more release profiles, at least one of which is a controlled release opioid component comprising an opioid. In certain embodiments, the pharmaceutical formulation administered to a human is according to the pharmaceutical formulation of the present invention.

  The method of treating pain in humans comprises administering a pharmaceutical formulation comprising one or more components, wherein the one or more opioid components have one or more release profiles and their opioid components At least one of which is a controlled release opioid component, including an opioid. In certain embodiments, the pharmaceutical formulation administered to a human is according to the pharmaceutical formulation of the present invention.

Figures 1a and 1b provide schematic images of two embodiments of the opioid formulations of the present invention. FIG. 2 provides the targeted release profile for oxycodone coated pellets for use in the opioid formulations of the present invention. FIG. 3 provides the targeted release profile for morphine-coated pellets used in the opioid formulations of the present invention. FIG. 4 provides a targeted release profile for Eudragit L30D-55 coated oxycodone granules for use in the opioid formulations of the present invention. FIG. 5 provides a targeted release profile for the release of total oxycodone in the opioid formulations of the present invention. FIG. 6 provides a targeted release profile for the release of total oxycodone and morphine used in dual opioid coated tablets of the present invention. FIG. 7 provides a schematic showing the method used to produce the oxycodone granules used in the present invention. FIG. 8 provides a schematic showing the method used to generate the oxycodone core pellet used in the present invention. FIG. 9 provides a schematic showing the method used to produce the morphine core pellet used in the present invention. FIG. 10 provides a schematic showing the method used to coat either the morphine core pellet or the oxycodone core pellet used in the present invention. FIG. 11 provides a schematic showing the method used to produce dual opioid coated tablets used in the present invention. FIG. 12 provides a flow diagram for preparing a sustained release intermediate oxycodone pellet used in clinical studies (Example 2). Figure 13 shows two opioid formulations of the present invention (Formulation A and Formulation B) and a reference formulation (MS Contin ® 30 mg (morphine CR) co-administered with OxyContin ® 20 mg (Oxycodone CR)) , Providing a plasma concentration profile of oxycodone for 72 hours after treatment. Figure 14 shows two opioid formulations of the invention (Formulation A and Formulation B) and a reference formulation (MS Contin ® 30 mg (morphine CR) co-administered with OxyContin ® 20 mg (Oxycodone CR)) , Provides a plasma concentration profile of oxycodone for 24 hours after treatment. FIG. 15 provides the predicted plasma profile of oxycodone from multiple dose administration at 12 hour intervals of the opioid formulations of the present invention. FIG. 16 provides the predicted plasma profile of oxycodone from the administration of multiple doses of the opioid formulations of the present invention having different dosage strengths. Figure 17 provides the predicted plasma profile of oxycodone from the administration of multiple doses at 12 hour intervals of the opioid combination formulation of the present invention (immediate release + controlled release). FIG. 18 provides predicted plasma profiles of oxycodone from administration of multiple doses of the inventive opioid combination formulation (immediate release + controlled release) with different dosing strengths. Figure 19: Various% Coatings of Ammonio Methacrylate Copolymer Type B (RS) and Type A (RL) Coating Ratios, (a) RS / RL = 90/10 and (b) RS / RL = 80/20 Figure 21 provides the release profile of morphine sulfate from coated beadlets containing morphine sulfate and oxycodone hydrochloride used at the level. Figure 20: Various% Coatings of Ammonio Methacrylate Copolymer Type B (RS) and Type A (RL) Coating Ratios, (a) RS / RL = 90/10 and (b) RS / RL = 80/20 Figure 21 provides the release profile of oxycodone hydrochloride from coated beadlets containing morphine sulfate and oxycodone hydrochloride used at the level. Figure 21: Enteric coated tablets (50% coated Ammonio methacrylate copolymer type B (RS) and type A (RL) 50% coated small beads at various% enteric coating levels Provided the release profile of morphine sulfate in Figure 22: Enteric coated tablets (50% coated Ammonio methacrylate copolymer type B (RS) and type A (RL) 50% coated small beads at various% enteric coating levels Provided the release profile of oxycodone hydrochloride in Figure 23 provides release profiles for morphine sulfate in enteric coated tablets (10% and 15% coating levels) at low, medium or high hardness levels. FIG. 24 provides the release profile for oxycodone hydrochloride in enteric coated tablets (10% and 15% coating levels) at low, medium or high hardness levels. FIG. 25. Coated small beads containing oxycodone hydrochloride, using Ammonio methacrylate copolymer type B (RS) and type A (RL) coating ratios, RS / RL = 85/15, at various% coating levels Provided a release profile of oxycodone hydrochloride from FIG. 26 shows coated small beads containing oxycodone hydrochloride, using Ammonio methacrylate copolymer type B (RS) and type A (RL) coating ratios, RS / RL = 80/20, at various% coating levels Provided a release profile of oxycodone hydrochloride from FIG. 27 shows hydrochloric acid using Ammonio methacrylate copolymer type B (RS) and type A (RL) coating ratios, RS / RL = 80/20 and RS / RL = 85/15 at various% coating levels It provides a release profile of oxycodone hydrochloride from coated small beads containing oxycodone.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to pharmaceutical formulations and methods for reducing acute or chronic pain by controlling the release of compounds having opioid agonist activity for absorption in humans. The pharmaceutical formulations and methods of the present invention can provide effective analgesia to patients while generally reducing or eliminating the unwanted side effects experienced with administration of opioid analgesic compounds. Due to the controlled release of the vapor compound (s) it is possible to obtain a substantially constant release rate of the compound (s) (corresponding to the dose required for the treatment) over a specific period of time As a result, adherence to strict dosing regimens, eg, the need to administer the drug several times daily at designated intervals, may not be necessary.

  One aspect of the invention relates to a pharmaceutical formulation comprising one or more components having one or more release profiles, at least one of the components comprising a compound having opioid receptor agonist activity, and a controlled release profile Have. Another aspect of the invention relates to the administration of a pharmaceutical formulation of the invention to a human in need of the pharmaceutical formulation of the invention.

  The formulations and methods described herein are used to treat various types of pain, including neuropathic and nociceptive pain, somatic pain and visceral pain. In various embodiments, the formulations and methods described herein are used to treat diabetic neuropathy, trigeminal neuralgia, post-herpetic pain and thalamic pain syndrome (central pain). Neuropathic pain is often present at the same time as nociceptive pain, and the compounds and salts of the invention are used to treat mixed pain states, ie a combination of neuropathic pain and nociceptive pain obtain. For example, trauma that damages tissues and nerves, burns (which burns the skin and nerve endings) and external nerve compression can cause both neuropathic and nociceptive pain. Examples of external nerve compression include tumor nerve compression and sciatica with a prolapsed disc that compresses the nerve. In other embodiments, the formulations and methods are used to treat lower back pain, cancer pain, osteoarthritic pain, fibromyalgia pain and post-operative pain. In various other embodiments, the present formulations and methods are used to treat pain associated with inflammation, bone pain and joint disease. The formulations and methods of the invention can be used to treat pain caused by various conditions, including but not limited to pain post surgery or post trauma, pain associated with medical illness, and the like.

  The present invention includes formulations that can be administered to provide two opioids. The object of the present invention is to activate a specific opioid receptor in the brain by one opioid and to arrive at a second opioid at a time after the receptor is occupied by the first opioid . To achieve this, dual opioid sustained release tablets are designed. For example, in formulations containing oxycodone and morphine, it is necessary to delay the release of morphine for at least half an hour, preferably more than one hour, until oxycodone arrives at its receptor. It is also necessary to re-supply oxycodone at approximately the same rate as the rate of elimination from the CNS compartment for brain uptake. The delayed, modified-release pellet component, as described herein, with both its delay and oxycodone release rate, and its pellets (such as, but not limited to, tablets and capsules) Are expected to be close together in formulations incorporating

Compounds Having Opioid Receptor Agonist Activity The components of the present pharmaceutical formulations may comprise compounds having opioid receptor agonist activity. Such compounds may have agonist activity at mu-, kappa-, sigma- or delta-opioid receptors, including other classified receptor subtypes. Compounds having opioid receptor agonist activity may be naturally occurring, semi-synthetic or fully synthetic opiate compounds, derivatives or analogs thereof, or pharmaceutically acceptable salts, esters or prodrugs thereof. Naturally occurring opiates are alkaloid compounds found in poppy resin, which include morphine, codeine and thebaine. Examples of semisynthetic or completely synthetic opiates include dihydromorphine, heterocodeine, dihydrocodeine, dihydromorphinone, dihydrocodeinone, 3,6-diacetylmorphine, morphinone, 6-desoxymorphin, heroin, Examples include, but are not limited to, oxymorphone, oxycodone, 6-methylene-dihydromorphine, hydrocodone, etorphin, bupremorphine, naloxone or naltrexone.

  As compounds having μ-opioid receptor agonist activity, morphine (and structurally related analogs and derivatives), albimopane, buprenorphine, codeine, 6-desomorphine, dihydromorphine, dihydromorphinone, dihydrocodeine, dihydrocodeinone, 3,6-diacetylmorphine, 6-methylene-dihydromorphine, diphenoxylate, drotebanol, esseroline, etorphine, fentanyl, hydrocodone, levophenacylmorphan, methadone, oxymorphone, nicomorphin, Pethidine, picenadol (picenadol), tapentadol, thebaine and trimebutine (trim butane) may include, but is not limited thereto.

  Compounds having κ-opioid receptor agonist activity include asimadoline, butorphanol, bremazocine, cyclazocine, dextromethorphan, dynorphin, enadoline, enadoline, ketazocine, nalbuphine, nalfurafine, norbuprenorphine, oxycodone, pentazocine Salvinorin A, 2-methoxymethyl salvinorin B and its ethoxymethyl and fluoroethoxymethyl homologs, spiradoline and tifluadom may be included, but are not limited thereto.

  As compounds having δ-opioid receptor agonist activity, deltorphine, ethoxymethopon, leu-enkephalin, met-enkephalin, mitragyna speciosa (kratom), mitraginin (mitragynine), mitraginin-pseudoindoxyl, N-phenethyl-14-norbuprenorphine, norclozapine and 7-spiroindanyloxymorphone may be included, but is not limited thereto.

  In certain embodiments, the compound is selected from morphine, codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine, oxymorphone, mixtures thereof and pharmaceutically acceptable salts thereof.

  As a salt, hydrochloride, sulfate, bisulfate, tartrate, nitrate, citrate, hydrogen tartrate (bitratrate), phosphate, malate, maleate, hydrobromide, iodination Examples include, but are not limited to, hydrogen salts, fumarates, succinates and the like.

  The components of the pharmaceutical formulation may comprise two or more compounds present in a weight ratio. For example, the component may comprise two compounds present in a weight ratio of 2: 1, 2: 2, 2: 3, 2: 5, 3: 1, or 3: 4.

  In certain embodiments, the compounds are morphine and oxycodone or pharmaceutical salts thereof in a weight ratio of about 3: 2. A pharmaceutical formulation comprising a compound comprising morphine and oxycodone or a pharmaceutical salt thereof in a weight ratio of about 3: 2 may administer a total of up to 18 mg morphine and 12 mg oxycodone per dose. In some embodiments, a pharmaceutical formulation comprising a compound comprising morphine and oxycodone or a pharmaceutical salt thereof in a weight ratio of about 3: 2 comprises up to about 600 mg morphine or a pharmaceutical salt thereof and about An amount of 400 mg oxycodone or a pharmaceutical salt thereof may be administered.

Release Profiles and Characteristics of Ingredients At least one of the ingredients in the pharmaceutical formulation comprises a compound having opioid receptor agonist activity and has a controlled release profile.

  The formulation may comprise additional components, wherein the additional components may have an immediate release profile or a controlled release profile for the compound.

  As used herein, the term "immediate release" refers to a release profile that does not substantially delay release of the compound for absorption.

  As used herein, the term "controlled release" refers to a release profile in which the release of the compound is modified as compared to the immediate release profile. Types of controlled release profiles include delayed release profiles, sustained release profiles and pulsatile release profiles.

  As used herein, the term "delayed release" refers to a release profile in which the release of the compound for absorption is delayed.

  As used herein, the term "sustained release" refers to about 8 hours or about 10 hours or about 12 hours or about 15 hours or about 20 hours or about 24 hours or about 30 hours or about 35 hours or It refers to a release profile in which the active compound is released at such a rate that the blood concentration is maintained within the therapeutic range but below the toxic level over a longer period of time. The term "controlled release" is intended to distinguish the release profile according to the invention from "immediate release" and "release delayed" release profiles. As used herein, "delayed sustained release" refers to a release profile in which the release of the active compound is delayed but is further extended than the "immediate release" release profile.

  As used herein, the term "pulsatile release" refers to a release profile in which the compound is released at intervals for absorption.

Immediate Release Component The immediate release component may provide about 1% to about 50% of the total dose of the compound (s) delivered by the present pharmaceutical formulation. For example, the immediate release component may provide at least about 5%, or about 10% to about 30%, or about 45% to about 50% of the total dose of the compound (s) delivered by the present formulation. In an alternative embodiment, the immediate release component is about 2%, about 4%, about 5%, about 10%, about 15%, about 15% of the total dose of the compound (s) delivered by the present formulation. Provide 20%, about 25%, about 30%, about 35%, about 40%, about 45% or about 50%.

  The immediate release component may be a mixture of components that degrade immediately after administration to release the opioid compound. This may take the form, for example, of granules, particles, powders, liquids and pellets.

Controlled Release Component The controlled release component may provide about 30 to 95% of the total dose of the compound (s) delivered by the present pharmaceutical formulation. For example, the immediate release component may provide about 70-90% or about 80% of the total dose of the compound (s) delivered by the present pharmaceutical formulation. In an alternative embodiment, the controlled release component is about 30%, about 35%, about 40%, about 45%, about 50%, about 55% of the total dose of the compound (s) delivered by the present formulation. %, About 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90% or about 95%.

The controlled release component may be about 1 to about 25 hours after repeated administration or after a single dose, or about 20 hours, about 17 hours, about 15 hours, about 12 hours, about 11 hours, about 8 hours, about 6 hours after administration. , May have a T _max of about 5 hours, about 4 hours, about 3 hours, about 2 hours or about 1 hour.

In certain embodiments, the controlled release component may have a T _max of about 4.5 to about 8 hours after repeated dosing, or about 5 to about 6 hours after repeated dosing, or about 6 hours after repeated dosing.

The controlled release component may be about 10 to about 25 hours after repeated dosing or about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours or about about 12 hours. It may have a T _min of 20 hours.

In certain embodiments, the controlled release component may have a T _min of about 13 to about 16 hours after repeated dosing or about 14 hours after repeated dosing.

  The release of the controlled release component, as measured at 50 rpm in water at 37 ° C. in a USP Type I device, releases about 0 to about 20% of the compound or its salt after 2 hours, or after 4 hours. Release about 15 to about 60% of the compound or salt thereof, or release about 25 to about 80% of the compound or salt thereof after 6 hours, or about 35 to about 5% of the compound or salt thereof after 8 hours It releases about 85%, or releases about 45 to about 95% of the compound or its salt after 10 hours, or releases about 60 to about 100% of the compound or its salt after 12 hours.

The controlled release component may comprise about 2 mg to about 80 mg of the above compound. When the controlled release component comprises about 2 mg, the controlled release component may provide an average C _max of about 1 to about 3 ng / mL or about 2 ng / mL after repeated dosing. The above AUC ₂₄ after a single dose is about 14.7 ng · hr / mL to about 23.0 ng · hr / mL or about 15.8 ng · hr / mL to about 21.0 ng · hr / mL or about 17.1 ng Hr / mL to about 19.7 ng hr / mL.

When the controlled release component comprises about 5 mg, the controlled release component may provide an average C _max of about 3 to about 7 ng / mL or about 5 ng / mL after repeated dosing. The above AUC ₂₄ after a single dose is about 40.2 ng · hr / mL to about 62.8 ng · hr / mL or about 43.2 ng · hr / mL to about 57.2 ng · hr / mL or about 46.7 ng Hr / mL to about 53.7 ng hr / mL.

When the controlled release component comprises about 10 mg, the controlled release component may provide an average C _max of about 5 to about 15 ng / mL or about 10 ng / mL after repeated dosing. The above AUC ₂₄ after a single dose is about 80.5 ng · hr / mL to about 125.9 ng · hr / mL or about 86.6 ng · hr / mL to about 114.8 ng · hr / mL or about 93.7 ng Hr / mL to about 107.7 ng hr / mL.

When the controlled release component comprises about 20 mg, the controlled release component may provide an average C _max of about 10 to about 30 ng / mL or about 20 ng / mL after repeated dosing. The above AUC ₂₄ after a single dose is about 166.0 ng · hr / mL to about 259.3 ng · hr / mL or about 178.5 ng · hr / mL to about 236.6 ng · hr / mL or about 193.0 ng Hr / mL to about 222.0 ng hr / mL.

When the controlled release component comprises about 40 mg, the controlled release component may provide an average C _max of about 25 to about 55 ng / mL or about 40 ng / mL after repeated dosing. The above AUC ₂₄ after a single dose is about 338.5 ng · hr / mL to about 528.9 ng · hr / mL or about 363.9 ng · hr / mL to about 482.3 ng · hr / mL or about 393.5 ng Hr / mL to about 452.7 ng hr / mL.

When the controlled release component comprises about 80 mg, the controlled release component may provide an average C _max of about 50 to about 110 ng / mL or about 80 ng / mL after repeated dosing. The above AUC ₂₄ after a single dose is about 868.4 ng · hr / mL to about 1356.9 ng · hr / mL or about 933.5 ng · hr / mL to about 1237.5 ng · hr / mL or about 1009.5 ng Hr / mL to about 1161.5 ng hr / mL.

In some embodiments, the controlled release component provides an average C _min of about 0.5 to about 40 ng / mL or about 4 to about 15 ng / mL after repeated dosing.

In certain embodiments, T _max , T _min , mean C _max and C _min may be determined after repeated dosing that is during steady state conditions. As used herein, the term "steady state" means that the plasma level for a given drug is above the lowest effective therapeutic level for the compound and below the lowest toxic plasma level, depending on the subsequent dose of the drug It means that the level is achieved and it is maintained. In the case of opioid analgesics such as oxycodone, the minimum effective therapeutic level may be determined in part by the amount of pain relief achieved in a given patient. It is well understood by those skilled in the medical art that pain measurements are very subjective and large individual differences can occur between patients. It is clear that after administration of each dose, the concentration passes the maximum and then drops again to the minimum.

  The steady state may be described as follows: At time t = 0, which is the time when the first dose was administered, the concentration C is also zero. The concentration then passes through the first maximum and then falls to the first minimum. Another dose is administered before the concentration drops to zero, so that the second rise in concentration does not start from zero. Based on this first concentration minimum, the curve passes the second maximum, which is higher than the first maximum after the second dose is administered, and the second minimum, which is higher than the first minimum. Decrease to the value. Thus, the blood plasma curve is gradually increased until it reaches and stabilizes at a point where the absorption and elimination are balanced due to the repeated accumulation of repeated doses and the concomitant active agent. This state (where absorption and excretion are in equilibrium and the concentration constantly fluctuates between a defined minimum and a defined maximum) is called steady state.

Ingredient Active Agents The one or more further ingredients may comprise one or more active agents. For example, the active agent can be any compound having opioid receptor agonist activity as discussed herein.

  The active agent may be one or more non-opioid analgesic compound (s), or one or more non-opioid analgesic compound (s) and one or more compound (s) having opioid receptor agonist activity or pharmaceutical And mixtures of these with acceptable salts, esters or prodrugs thereof. Non-opioid analgesic compounds may act to relieve pain by other mechanisms not associated with binding to the opioid receptor. For example, the non-opioid analgesic compound may be a non-steroidal anti-inflammatory compound (NSAID), examples of which include piroxicam, lomoxicam, tenoxicam, salicylic acid (aspirin), and other salicylates such as diflunisal; 2 -Aryl propionic acids (e.g. ibuprofen, carprofen, fenbufen, fenoprofen, flurbiprofen (flubiprofen), ketoprofen, ketorolac, loxoprofen, naproxen, oxaprozin, tiaprofenic acid and suprofen); n-aryl anthranilic acids (e.g. mefenam) Aryl acids (for example, diclofenac, aceclofenac, Semetashin, etodolac, indomethacin (Idomethacin), sulindac and tolmetin), and the like; although, or mixtures thereof may include, but are not limited to.

  The non-opioid analgesic compound may be a COX-1 inhibitor compound or a COX-2 inhibitor compound (Celecoxib (Celebrex®), etoricoxib (etoricoxib), lumiracoxib (lumiracoxib), parecoxib (parecoxib), rofecoxib, valdecoxib or a mixture thereof) (Including but not limited to). The non-opioid analgesic may also be a calcium channel binding substance such as gabapentin or pregabalin or a derivative, analogue or prodrug thereof or a mixture thereof.

  In certain embodiments, the non-analgesic compound is a prodrug of gabapentin having the chemical name 1-[[[[1- (2-methyl-l-oxopropoxy) ethoxy] carbonyl] amino] methyl] cyclohexaneacetic acid. One gabapentin enacarbyl (SolziraTM). The structures of gabapentin, pregabalin and gabapentin enacarbyl are shown below:

  The active agent may further comprise one or more hybrid opioid compound (s), or one or more hybrid opioid compound (s) and one or more compound (s) having opioid receptor agonist activity, or pharmaceutically It may be a mixture with an acceptable salt, ester or prodrug thereof. A hybrid opioid compound is a compound formed by covalently linking two or more opioid compounds together using a linker component. The linker component may be stable or may be hydrolyzed under physiological conditions to provide the parent opioid compound. Hybrid opioid compounds are described in US Provisional Patent Application No. 61 / 153,537 to Holaday et al., Filed February 18, 2009. Hybrid opioid compounds are also described in International Patent Application Publication No. WO 2006/073396 to Portoghese et al.

  The hybrid opioid compounds may comprise two or more compounds having opioid receptor agonist activity linked by a covalent linker component. The hybrid opioid compounds may also include compounds having opioid receptor agonist activity linked to a non-opioid active agent (including but not limited to non-opioid analgesic compounds as described above). In some embodiments, the non-opioid active agent is gabapentin, pregabalin or gabapentin enacarbyl.

  The hybrid opioid compounds may comprise two or more opiate compounds linked together by a covalent linker. These opiate compounds may include, but are not limited to, the opiate compounds described above.

  The active compound may be attached to the linker component by various chemical bonds, preferably at positions on the active agent that do not impair the biological activity of the active agent. Typically, the active agent can be attached to the linker by a reactive group on the active compound or at a position that can be activated to react with the linker component.

Preparation of Ingredients In order to obtain the ingredients of the pharmaceutical composition described herein, combinations of excipients are used at appropriate concentrations to provide the properties and desired pharmacokinetics. The excipients used in the pharmaceutical compositions described herein are commercially available and are listed in either USP or NF. The excipients that contribute to the function and purpose of each active intermediate component and its final component are selected. One skilled in the art recognizes that the concentration of these excipients used may be increased or decreased, as desired to increase or decrease specific properties in the final opioid formulation. . The coating materials used herein are also commercially available and listed in USP or NF, which is incorporated herein by reference.

  The techniques used to make sustained release tablets of the compound opioid described herein are a combination of known pharmaceutical manufacturing processes. Unit processes for the preparation of active intermediates have been used in some commercially available products and are therefore extensible. Two important aspects in the preparation of sustained release tablets of the above compound opioids reside in the manufacture and performance of different types of controlled release slow release pellets. In the example of dual opioid oxycodone / morphine compound products, the production and performance of oxycodone pellets with controlled release release and morphine pellets with controlled release release are equally important. These pellets should provide the same performance as free flowing non-tablet pellets after tablet compression. This important feature is best achieved by appropriately plasticizing the coating network to avoid cracking and brittle fracture of the coating under tableting during tablet compression.

  The material added to the compound (s) for the immediate release component is microcrystalline cellulose, corn (com) starch, pregelatinized starch, potato starch, rice starch, carboxymethyl sodium starch, hydroxypropyl cellulose, hydroxypropyl Methyl cellulose, hydroxyethyl cellulose, ethyl-cellulose, chitosan, hydroxychitosan, hydroxymethylated chitosan, crosslinked chitosan, crosslinked hydroxymethylchitosan, maltodextrin, mannitol, sorbitol, dextrose, maltose, fructose, glucose, levulose, sucrose, polyvinylpyrrolidone (PVP ), Acrylic acid derivatives (Carbopol, Eudragit etc.), polyethylene glycol (eg small molecule It may be high molecular weight PEG having a PEG (PEG2000~10000) and molecular weight of greater than 20,000 daltons (Polyox)), but is not limited thereto. It may also be useful to have these materials present in the range of 1.0-60% (W / W).

  In addition, it may be useful to have other components in the system to aid in the dissolution of the drug, or the degradation of the component after ingestion or administration. These components include surfactants such as sodium lauryl sulfate, sodium monoglycerate, sorbitan monooleate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, glyceryl monostearate, glyceryl monooleate, glyceryl It may be a monobutylate, one of non-ionic surfactants (eg, pluronic surfactants), or any other material having surface active properties, or any combination of the above. These materials may be present in a proportion of 0.05 to 15% (W / W).

  The material in the controlled release component is the same as the material in the immediate release component (except that the additional polymer is incorporated into the component) or the coating covering the pellets or granules. Types of materials useful for this purpose include ethylcellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, carboxymethylcellulose, methylcellulose, nitrocellulose, Eudragit R and Eudragit RL, Carbopol, or molecular weights greater than 8,000 Daltons Although it may be polyethylene glycol which it has, it is not limited thereto. These materials may be present at a concentration of 4-20% (W / W).

  In certain embodiments, the component may have a pH sensitive release retardation profile or a non-pH sensitive release retardation profile. The material of the pH sensitive release delay component may be the same as the material of the immediate release component above (except that the additional polymer is incorporated into the component) or the same as the coating covering the pellet or granules. Types of materials useful for this purpose may be, but are not limited to, pthalate cellulose, Eudragit L and other phthalates of cellulose derivatives. These materials may be present at a concentration of 4-20% (W / W).

  The material of the pH sensitive release delay component may be the same as the material of the immediate release component above (except that the additional polymer is incorporated into the component) or the same as the coating covering the pellet or granules. Types of materials useful for this purpose include polyethylene glycol (PEG) (Carbowax, Polyox), waxes (eg, white wax or beeswax), paraffins, acrylic acid derivatives (Eudragit) having molecular weights greater than 4,000 daltons ), Propylene glycol and ethyl cellulose, but is not limited thereto. Typically, these materials may be present in the range of 0.5 to 25% (W / W) of this component.

Pharmaceutical Formulations The present pharmaceutical formulations may comprise one or more components having one or more release profiles. Each of the above components may comprise the same compound (s) and may comprise different compound (s) or mixtures thereof (e.g., within the same formulation, several components have the same compound, Components have different compounds). Additionally, the components may include active agents as described herein.

  For example, the formulation may comprise at least one component, which one component has a controlled release profile.

  The formulation may comprise at least two components (first and second components), each component having a different release profile. For example, the second of the at least two components starts releasing the compound (s) contained therein after at least one hour of the first component The onset usually occurs 6 hours or less after the onset of release of the compound (s) from the first component above).

The formulation may also comprise at least three components (first, second and third components). The first component may be an immediate release component, wherein the onset of release of the compound (s) therefrom is not substantially delayed after administration of the formulation. The second and third components are controlled release components and release of the compound (s) may be delayed. The controlled release component may be a pH sensitive or non pH sensitive delayed component, depending on the type of formulation. The compound (s) released from the release delaying component may be delayed until after the onset of the compound (s) release from the immediate release component. For example, the compound (s) released from the second component may be at a time after the point at which the compound (s) released from the immediate release component may achieve C _max in serum. _max can be achieved. The compound (s) released from the third component may achieve _Cmax in serum after _Cmax of the compound (s) released from the second component.

In certain embodiments, the immediate release component can provide a C _max for the compound (s) released therefrom within about 0.5 to about 2 hours, and the second component is The C _max for the compound (s) released therefrom in about 4 hours or less can result. In general, the C _max for such second component may be achieved after 2 hours after administration of the formulation; however, to obtain a formulation with the desired pharmacokinetic profile herein It is also possible to achieve C _max in a shorter period of time by adjusting the concentrations of excipients and / or coatings described.

In certain embodiments, release of the compound (s) from the third component can be initiated after initiation of release of the compound (s) from both the first and second components. In some embodiments, C _max for the compound (s) released from the third component may be achieved within 8 hours.

The formulation may also comprise at least four components (first, second, third and fourth components) (each of the at least four components having a different release profile). For example, the compound (s) released from each of the at least four different components may achieve C _max at different times.

  The formulation may also comprise at least five components (first, second, third, fourth and fifth components). The first component may be an immediate release component of the first compound or set of first compounds, and the second and third components may be controlled release of the first compound or set of first compounds. It may be an ingredient. The fourth and fifth components may be controlled release components of the second compound or the second set of compounds. By way of example, in certain embodiments, the first compound may be oxycodone and the second compound may be morphine.

In certain embodiments, the formulation may be present in the form of a capsule comprising the ingredients present in the form of a separate tablet or pellet. Thus, for example, the immediate release component may be present in the form of a tablet or pellet, and the controlled release component may be present in the form of another tablet or pellet (each of which comprises the compound (s) contained therein results in the release delay of the variable)), C _max of the pellet or compound released from each tablet containing the pellet (s), reached at different times, C _max of the formulation, achieved in less than 12 hours Be done.

In certain embodiments, the pharmaceutical formulation itself has a controlled release profile. For example, the C _max for all of the compound (s) released from the formulation is about 20 hours, about 17 hours, about 15 hours, about 12 hours, about 11 hours after administration of the formulation After about 8 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours or about 1 hour. In some embodiments, C _max may be achieved less than 2, 1 or 0.5 hours after administration of the formulation. In other embodiments, C _max is greater than 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours of administration of the above components It can be achieved later.

This formulation is about 1 to about 25 hours after repeated administration or after a single dose, or about 20 hours, about 17 hours, about 15 hours, about 12 hours, about 11 hours, about 8 hours, about 6 hours after administration. It may have a _Tmax of about 5 hours, about 4 hours, about 3 hours, about 2 hours or about 1 hour.

In certain embodiments, T _max may be about 4.5 to about 8 hours or about 5 to about 6 hours or about 6 hours after repeated dosing. In some embodiments, the repeated administration is under steady state conditions.

The formulation may comprise about 1 mg to about 100 mg of the compound (s) or may comprise about 2 mg to about 80 mg of the compound (s). When the formulation comprises about 2 mg, the controlled release component may provide an average _Cmax of about 1 to about 3 ng / mL or about 2 ng / mL after repeated dosing. The above AUC ₂₄ after a single dose is about 14.7 ng · hr / mL to about 23.0 ng · hr / mL or about 15.8 ng · hr / mL to about 21.0 ng · hr / mL or about 17.1 ng Hr / mL to about 19.7 ng hr / mL.

When the formulation comprises about 5 mg, the controlled release component may provide an average _Cmax of about 3 to about 7 ng / mL or about 5 ng / mL after repeated dosing. AUC ₂₄ after a single dose is about 40.2 ng · hr / mL to about 62.8 ng · hr / mL or about 43.2 ng · hr / mL to about 57.2 ng · hr / mL or about 46.7 ng · hr / mL to about 53.7 ng · hr / mL.

When the formulation comprises about 10 mg, the controlled release component may provide an average C _max of about 5 to about 15 ng / mL or about 10 ng / mL after repeated dosing. The above AUC ₂₄ after a single dose is about 80.5 ng · hr / mL to about 125.9 ng · hr / mL or about 86.6 ng · hr / mL to about 114.8 ng · hr / mL or about 93.7 ng Hr / mL to about 107.7 ng hr / mL.

When the formulation comprises about 20 mg, the controlled release component may provide an average C _max of about 10 to about 30 ng / mL or about 20 ng / mL after repeated dosing. The above AUC ₂₄ after a single dose is about 166.0 ng · hr / mL to about 259.3 ng · hr / mL or about 178.5 ng · hr / mL to about 236.6 ng · hr / mL or about 193.0 ng Hr / mL to about 222.0 ng hr / mL.

When the formulation comprises about 40 mg, the controlled release component may provide an average _Cmax of about 25 to about 55 ng / mL or about 40 ng / mL after repeated dosing. The above AUC ₂₄ after a single dose is about 338.5 ng · hr / mL to about 528.9 ng · hr / mL or about 363.9 ng · hr / mL to about 482.3 ng · hr / mL or about 393.5 ng Hr / mL to about 452.7 ng hr / mL.

When the formulation comprises about 80 mg, the controlled release component may provide an average C _max of about 50 to about 110 ng / mL or about 80 ng / mL after repeated dosing. The above AUC ₂₄ after a single dose is about 868.4 ng · hr / mL to about 1356.9 ng · hr / mL or about 933.5 ng · hr / mL to about 1237.5 ng · hr / mL or about 1009.5 ng Hr / mL to about 1161.5 ng hr / mL.

In certain embodiments, C _min can occur within about 12 to about 18 hours following component administration during steady state conditions. In some embodiments, C _min is about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours after administration of the formulation. , After about 19 hours or after about 20 hours. In some embodiments, C _min is less than about 10 hours, less than about 9 hours, less than about 8 hours, less than about 7 hours, less than about 6 hours, less than about 5 hours, or about 4 hours after administration of the formulation. It can occur below. In some embodiments, C _min is about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 14 hours after administration of the formulation. It may occur later or more than about 20 hours. In certain embodiments, the C _min produced about 12 hours after administration is about 1 hour, about 2 hours, about 3 hours or about 4 hours after administration of a formulation that has not yet been absorbed into the bloodstream. It may occur by time later.

In certain embodiments, the formulation is about 10 to about 25 hours after repeated administration, or about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours after administration. , _May have a T _min of about 19 hours or about 20 hours.

In certain embodiments, the formulation may have a T _min of about 13 to about 16 hours after repeated dosing or about 14 hours after repeated dosing.

In some embodiments, the formulation can provide an average C _min of about 0.5 to about 40 ng / mL or about 4 to about 15 ng / mL after repeated dosing.

  The dissolution of this formulation releases about 0 to about 20% of the above compound (s) or a salt thereof after 2 hours, when measured at 50 rpm in water at 37 ° C. in a USP type I device, or 4 Release about 15 to about 60% of the compound (s) or a salt thereof after time, or release about 25 to about 80% of the compound (s) or a salt thereof after 6 hours, or 8 Release about 35 to about 85% of the compound (s) or a salt thereof after time, or release about 45 to about 95% of the compound (s) or a salt thereof after 10 hours, or 12 After time, about 60 to about 100% of the above compound (s) or a salt thereof is released.

  When disclosed herein that the formulation initiates release after another component, such terms are designed and intended such that the formulation provides such a later initiated release. It should be understood to mean. However, despite such design and intent, it is known in the art that some "leakage" of the compound (s) can occur. Such "leakage" is not "release" as used herein.

  In certain embodiments, the pharmaceutical formulation comprises one or more components comprising two opioid compounds in a weight ratio of 2: 1, 2: 2, 2: 3, 2: 5, 3: 1, or 3: 4. May be included. In certain embodiments, the components may include morphine and oxycodone in a weight ratio of about 3: 2.

As an example, the pharmaceutical formulation may comprise a controlled release component comprising a mixture of morphine and oxycodone and an immediate release component comprising oxycodone. In some embodiments, the T _max of oxycodone in the immediate release component may be about 10 minutes to about 1 hour after ingestion. In another embodiment, the T _max is about 10 minutes to about 30 minutes or 45 minutes. The controlled release component may be released at a slower rate and over a longer period of time. For example, in some embodiments, the controlled release component may release an effective amount of a mixture of morphine and oxycodone for 12 hours. In other embodiments, the controlled release component may release effective amounts of morphine and oxycodone for four hours or for eight hours. In still other embodiments, the controlled release component may release an effective amount of morphine and oxycodone for 15, 15, 18, or 30 hours.

  In some embodiments, active agents that are released more slowly may be released in pulses from the pharmaceutical formulations, and pulses of the compounds are released at intervals after ingestion of the formulations. For example, in certain embodiments, the controlled release component releases the first pulse of the more slowly released active agent about 0.5 to 1 hour after ingestion and then about 4 hours after ingestion. And about 8 hours after ingestion and release of a third pulse of drug.

Preparation of Formulations In one embodiment, the pharmaceutical composition is tablets and capsules for oral administration. These tablets or capsules may contain conventional excipients, such as binding agents, fillers, lubricants, disintegrants or wetting agents. In one embodiment, the tablet or capsule is coated according to methods well known in the art.

  Granules that best serve this purpose are highly deformable during compression so that any leakage prior to the specified release time from the coated pellets is minimized as much as possible. In one embodiment, it may be desirable to have a brief delay or delay at the first burst, or have an oxycodone release in the immediate release bolus portion of the formulation. In some embodiments, the tablet is less than about 500 mg, less than about 450 mg, less than about 400 mg, less than about 350 mg, less than about 300 mg, less than about 250 mg, less than about 200 mg, less than about 150 mg, less than about 100 mg, less than about 50 mg , Less than about 25 mg or less than about 10 mg, and its drug load is about 20%, about 15%, about 10%, about 5% (w / w) or less of the formulation is there. In one embodiment, the goal is to have a tablet size that is as effective as possible, while providing good uniformity and integrity of the pellets in the tablet.

  The disintegrant used in the tablet of the present invention is not particularly limited as long as it is a disintegrant used for pharmaceutical preparations. Examples include crospovidone, crystalline cellulose, hydroxypropyl cellulose with low substitution, croscarmellose sodium, carmellose calcium, sodium carboxy starch, sodium carboxymethyl starch, potato starch, wheat starch, corn starch, rice starch, parts Pregelatinized starch and hydroxypropyl starch may be mentioned. One or two or more of these may be used. Crospovidone is particularly preferred. The type of disintegrant used to coat the granules according to the invention may be the same as or different from that used inside the granules.

  Examples of pharmaceutically acceptable additives used in the tablet of the present invention include excipients, lubricants, pH adjusters, flavor masking agents, sweeteners, acidulants, cooling agents, foaming agents, Preservatives, fluidizers, antioxidants, colorants, stabilizers, surfactants, buffers, perfumes, binders and drug solubilizers may be mentioned. One skilled in the art can immediately list specific examples of these additives.

  These additives, inside the granules, outside the disintegrant coated granules, in the coating of the disintegrant, and all of these, as long as they do not damage the benefits of the present invention. It can be properly formulated.

  Any lubricant used for pharmaceutical preparations may be used without limitation. Examples of lubricants used in the tablet of the present invention include light anhydrous silicic acid, magnesium stearate, stearic acid, calcium stearate, aluminum stearate, aluminum monostearate, sucrose fatty acid ester, polyethylene glycol, stearyl fumaric acid Sodium, stearyl alcohol, talc, titanium oxide, hydrous silicon dioxide, magnesium silicate, synthetic aluminum silicate, calcium hydrogen phosphate, hydrogenated castor oil, hydrogenated rapeseed oil, carnauba wax, beeswax, microcrystalline wax and sodium lauryl sulfate obtain. One or two or more of these lubricants may be used. Among these, it is preferable to use one or more selected from light anhydrous silicic acid and magnesium stearate. In particular, a combination of anhydrous silicic acid contained inside the granules and magnesium stearate contained outside the granules is preferred.

  When the formulation is present in the form of a tablet, the shape of the tablet is not particularly limited as long as it can be produced without difficulty using conventional or somewhat modified production equipment. The disk shape, a general concept for tablets, may be mentioned as a representative example. The overall size is not particularly limited. For example, the shorter diameter (diameter in the case of a disc tablet) is suitably in the range of 6 to 20 mm, preferably 8 to 12 mm. The thickness is also not particularly limited, but appropriately 1 to 10 mm, preferably 2 to 8 mm.

  In some embodiments, it may be desirable for the first slight delay to be achieved by adding to the tablet a release retarding coating that will also act as a flavor masking agent. If desired, the coating may be white or colored or transparent or opaque. If desired, an identification NDC code (within the United States) or similar identification code may also be printed on the tablet.

  The compounds used in the tablets of the present invention may be coated with film coatings, excipients, binders, lubricants etc depending on their properties and plasticizers may be added.

Anti-Abuse Properties In another aspect of the present invention, the pharmaceutical compositions described herein are for making compositions that may be used for non-medical purposes or as drugs of abuse. It has properties that are useful in deterring their use.

  Intentional or unintended tampering from a sustained release formulation rapidly delivers large doses (as a result of conversion of sustained release product to immediate release form), and can And may result in life-threatening side effects, including respiratory depression and failure, sedation, cardiovascular collapse, coma and death.

  Consumers and recreational drug users usually use sustained release opioids by various routes of administration. Commonly used methods include (a) parenteral (e.g. intravenous injection), (b) intranasal (e.g. nasally inhaled) and (c) temporary of intact or crushed tablets or capsules Or repeated oral intake.

  One mode of abuse is to first mix the tablets or capsules with a suitable solvent (eg, water or alcohol), and then filter and / or use the opioid component from the mixture for intravenous injection. It involves the extraction of opioids from the components by extraction. Another mode of abuse of sustained release opioids is to dissolve the drug in water, alcohol or another "recreational solvent" to promote its release, in order to obtain the effect of producing high peak concentrations and maximum euphoria And taking its contents orally.

  The term "tamper" alters the physical properties of the component (eg, if the opioid is present in a sustained release form, it is modified to release it for immediate release, or the opioid agonist is not Means any manipulation by mechanical, thermal and / or chemical means that changes to make it available for appropriate use (eg, administration by an alternative route, eg, parenterally) . The tampering may be, for example, by grinding, shearing, grinding, mechanical extraction, solvent extraction, solvent immersion, burning, heating, or any combination thereof.

  The terms "abuse", "opioid agonist abuse" or "opioid abuse" in the context of the present invention refer to the opioid agonist alone or when it refers to the action of the opioid agonist in causing the above. Intermittent use, distraction use and long-term use in combination with other drugs, including: (i) use in amounts not in accordance with standard medical practice or by the method and route of administration; (ii B) use outside the scope of specific instructions for use provided by qualified medical professionals; (iii) use outside the supervision of qualified medical professionals; (iv) provided by legal suppliers of drugs Use outside the scope of the approved instructions for proper use; (v) as a specifically approved ingredient for medical use as a pharmaceutical preparation There is no use; (vi) there is a strong desire and effort to obtain it; (vii) use with evidence of forced use; (viii) operation of the medical system (history, severity of symptoms, disease) Use by acquisition due to the severity of the patient's identity, misstatement of the patient's identity, including doctor shopping, prescription forgery); (ix) use that has lost control over use; (x) use that disregards harm; (xi) Use by obtaining from a non-medical source; (xii) sale to a non-medical supply chain by an individual or use by another person via a cross-flow; (xiii) a medically unapproved or unintended mood Use for the purpose of changing.

  The terms "abuse resistant", "abuse deterrence" and "restrain abuse" are used interchangeably in the context of the present invention and they are: (i) intentional, unintentional or accidental of the components described above Resist physical manipulation or tampering (eg mechanical, thermal and chemical means and / or filtration, grinding, shearing, grinding, chewing, dissolving, melting, needle aspiration, inhalation, aeration, extraction) , Deter them, prevent, reduce, delay and / or fail; (ii) outside the scope of specific instructions for use provided by qualified medical professionals, of qualified medical professionals Intentional, unintentional or accidental use or misuse of the above components outside the supervision and outside the scope of the licensed directions for proper use provided by legal manufacturers of the above drugs (eg high Resist intravenous, intranasal use, use by inhalation and oral intake) to obtain peak concentrations, arrest, prevent, reduce, delay, and / or fail them; (iii) the invention Resist intentional, unintentional or accidental conversion of sustained release components of the drug into a more immediate release form, arrest, prevent, reduce, delay, and / or fail them; (Iv) deters the intentional and iatrogenic increase of the physical and mental effects required by recreational drug users, addicts, and patients with addiction disorders and with pain, deterring them, Prevent, reduce, delay, and / or fail; (v) resist attempts to improperly administer the above components to third parties (eg, in beverages), deter them, prevent To reduce, retard, delay and / or fail; (vi) resist attempts to obtain such components by the operation of the medical system and from non-medical sources, deter them, prevent, reduce, Delaying and / or failing; (vii) resisting the sale or cross flow of the above components to the non-medical supply chain and for the purpose of changing the medically unapproved or unintended mood, Inhibit, prevent, reduce, delay and / or fail; (viii) alter the physical, pharmaceutical, pharmacological and / or medical properties of the above components separately from what the manufacturer intended Resist intentional, unintentional or accidental attempts to cause, deter them, prevent, reduce, delay them And pharmaceutical compositions and methods that cause and / or fail.

  When the components of the pharmaceutical preparation are tampered with, the pharmaceutical preparation reduces the amount of opioid agonist released in an immediate release form, thereby enhancing the euphoric and pleasure effects of the opioid agonist of the component. , Enhancing, rewarding, mood-altering and toxic effects are reduced.

  In certain embodiments, if tampered with, it is not suitable for use due to the use of certain excipients (eg, povidone (Kollidon 30) or polyoxyl 35 castor oil (Cremophor ELTM) or sodium lauryl sulfate) A gelatinous mass is produced. When an aqueous solvent or aqueous alcohol solvent is added, the powdered excipient and drug mixture becomes a gelatinous mass that will be a problem for easy extraction of the opioid. Cremophor mixed with methacrylic acid polymer and cellulose polymer is an example of typical components that cause this feature of the invention.

  Another method of producing abuse-resistant opioid compositions is provided in US Published Patent Application US20090082466, the teaching of which is incorporated herein by reference in its entirety.

Administration of Formulation One aspect of the present invention is a method for treating pain comprising administering a formulation as described herein.

  The preparation may be administered, for example, by any of the following administration routes: sublingual, buccal, transmucosal, transdermal, parenteral, oral and the like. In certain embodiments, the formulations may be prepared in a manner suitable for oral administration. Thus, for example, for oral administration, each of the above components may be used as pellets, granules, powders, liquids or particles, which are then formed into a single pharmaceutical product, eg a capsule Or embedded in a tablet or suspended in a liquid for oral administration. As used herein, the term "formulation" also refers to a single pharmaceutical product comprising at least one component.

  In certain embodiments, the formulations are for oral administration and may be present in the form of tablets or capsules or in the form of multiple unit components. The formulations may be adapted for oral administration 1 to 6 times daily, usually 1 to 4 times daily (e.g. 1 to 3 times) daily, twice daily or once daily. In the context of the present invention, the term "once daily" requires that the above pharmaceutical composition be administered only once daily to obtain an effective therapeutic amount of the compound to provide a suitable therapeutic response. Is intended to mean.

  The final dose of the compound (s) provided by administration of the present formulation is about 100 mg, about 95 mg, about 90 mg, about 85 mg, about 80 mg, about 75 mg, about 70 mg, about 65 mg, about 60 mg, about 55 mg, by weight About 50 mg, about 45 mg, about 35 mg, about 30 mg, about 25 mg, about 20 mg, about 15 mg, about 12 mg, about 10 mg, about 8 mg, about 5 mg, about 4 mg, about 3 mg, about 2 mg or about 1 mg .

  The dosage of the opioid compound depends on the specific substance, the age of the human or animal treated with the composition and the like, the condition of body weight, and the like. All such factors are well known to those skilled in the art.

  The invention will be more readily understood by reference to the following examples, which are provided for the purpose of illustration and are not intended to limit the invention.

Example 1: Opioid Component The components for use in pharmaceutical formulations were developed as shown in Tables 1-8.

Example 2: Pharmacokinetic profile of opioid formulations An oxycodone formulation is provided having the following pharmacokinetic profile: The above pharmacokinetic profile is achieved by adjusting the concentration of the excipients using the method described in the charts shown in FIGS. This 8 mg oxycodone formulation has a C _{max of} 8 hours and a C _min of 14 hours.

B. An oxycodone formulation is provided having the following pharmacokinetic profile: The above pharmacokinetic profile is achieved by adjusting the concentrations of opioid compound and excipient using the methods described in the charts shown in FIGS. This 8 mg oxycodone formulation has a C _{max of} 6 hours and a C _min of 16 hours.

C. Dual opioid oxycodone / morphine formulations are provided having the following pharmacokinetic profiles: The above pharmacokinetic profile is achieved by adjusting the concentrations of opioid compound and excipient using the methods described in the charts shown in FIGS. The morphine formulation of oxycodone / 4 mg of 8mg for both opioids for _{C max} and both opioid that 6-20 hours with a _{C min} of 15 to 26 hours.

D. Dual opioid oxycodone / morphine formulations are provided having the following pharmacokinetic profiles: The above pharmacokinetic profile is achieved by adjusting the concentrations of opioid compound and excipient using the methods described in the charts shown in FIGS. The 18 mg morphine / 12 mg oxycodone formulation has a C _{max of} 6 hours and a C _min of 16 hours.

Example 3 Preparation of Sustained Release Intermediate Pellet Formulations Sustained release intermediate pellet formulations A and B having compositions as shown in Tables 9 and 10 were prepared.

  The manufacturing process for mixing the present formulation is illustrated in the flow diagram of FIG. To prepare this formulation, oxycodone hydrochloride, microcrystalline cellulose and povidone (Kollidon 30) were manually sifted individually through a # 20 mesh screen into a collection vessel. The screened mixture was transferred to the high shear granulator granulating bowl and dry mixed for 3 minutes.

  A granulating solution containing purified water mixed with polyoxyl 35 castor oil was sprayed at a constant rate into the granulating bowl while mixing on a low speed impeller or low speed chopper setting. The resulting granulation mixture was constantly evaluated visually and, if necessary, additional purified water was sprayed onto the mass.

  The granulation mixture was then subjected to an extrusion-spheronization process using an extruder and a plate spheronizer. The wet mass was uniformly extruded through a 0.8 mm sieve into a marmurizing bowl (where the extrudate was in the form of pellets of the appropriate size).

  The pellets were dried using a Fluid Bed Dryer Granulator to a test target of loss on drying (LOD) of ≦ 3%. The dried pellets were passed through a # 20 and # 40 mesh sized stainless steel screen to obtain a preferred fraction and backed by dual polyethylene for retention and storage of the pellet spray coating Sieved in a fiber drum.

  The pellets were then subjected to spray coating using a fluid bed dryer. In a stainless steel container, the coating ingredients were mixed with the isopropyl alcohol / water solution using a pneumatic propeller mixer for at least 1 hour until a clear solution was obtained. The enteric coating solution was prepared by mixing the enteric coating components using a pneumatic mixer in a separate stainless steel container for at least 1 hour until a clear solution was obtained. The polymer coating solution was sprayed onto the pellets while continuously monitoring the spray conditions. The finished pellets were discharged onto a double polyethylene lined fiber drum to retain and store the work-in-process for lubrication.

  The lubricated pellets are sieved through a # 18 and # 40 mesh sized stainless steel sieve to obtain the desired fraction and drained onto a double polyethylene backed fiber drum to retain storage And blend the tablets.

Example 4: Pharmacokinetic testing of formulations A and B Methods Formulation A or B as described in Example 3 or by performing a single dose, 3 period, 3 series, 3 treatment crossover test The pharmacokinetic profiles of oxycodone in human subjects orally administered with the reference formulation (OxyContin® 20 mg (oxycodone CR) coadministered with MS Contin® 30 mg (morphine CR)) were compared.

  Each subject participates in a series of three periods, where each period includes (i) pre-administration screening and registration procedures (check-in), (ii) administration of the above formulation, and (iii) administration Later sample collection and follow up were included. The subjects received different formulations in each period and were randomly divided to determine the order in which they were administered.

  Pre-dose screening and registration procedures include physical examination and recording of the subject's vital signs. The opioid antagonist naltrexone (50 mg) was administered 0.5 hours prior to dosing. After 10 minutes and 0.5 hours, 1 hour, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 5.5 hours, 6 hours and 6.5 hours of the above drug administration. Blood samples were collected after 7 hours, 8 hours, 10 hours, 12 hours, 14 hours, 18 hours, 21 hours, 24 hours, 48 hours and 72 hours.

Morphine and oxycodone in plasma of blood samples were measured by liquid chromatography (LC / MS / MS) with tandem mass spectrometry confirmed over the following ranges:
Morphine 0.25 to 100 ng / mL
Oxycodone 50 to 50,000 pg / mL
Results The mean plasma concentrations of oxycodone at the time of sample collection are shown in Figure 13 (up to 72 hours) and Figure 14 (first 24 hours). Formulation A resulted in higher plasma levels of oxycodone during the 5 to 16 hours after treatment, as compared to its reference formulation, but its plasma levels were generally lower thereafter. On the other hand, formulation B resulted in approximately the same or higher plasma levels of oxycodone after 6 hours of treatment as compared to the above reference formulation, which lasted for 48 hours. During this period, the plasma levels of oxycodone produced by formulation B were on average 30% higher than the plasma levels produced by the above reference formulation.

  These data were used to present the plasma profile of oxycodone resulting from administering multiple doses of Formulation B as shown in FIGS. FIG. 15 depicts the plasma profile of the above oxycodone through the administration of four doses of formulation B, showing that with this dosing regimen, plasma levels of oxycodone can be maintained between about 7 and about 20 ng / mL. Be

FIG. 16 shows the plasma profile of the above oxycodone that can be attributed to different dosing strengths, focusing on single doses in a multiple dose regimen after the plasma levels reach steady state; steady state is , Characterized by consistent peaks and troughs in multi-dose plasma profiles. FIG. 16 shows that at steady state C _max reflects the intensity of the dose administered.

  Figures 17 and 18 represent the presentation of the above oxycodone plasma profile for multiple doses of a formulation comprising a combination of immediate release formulation (10%) and formulation B (90%). FIG. 17 demonstrates the plasma profile of the oxycodone by administration of four doses of the combination preparation, wherein with this dosing regimen, plasma levels of oxycodone can be maintained between about 10 and about 19 ng / mL. It shows.

FIG. 18 shows the plasma profile of the oxycodone that can be produced after administration of the combination formulation at different dosing strengths. FIG. 18 focuses on a single dose in the multiple dose regimen after the plasma levels reach steady state, characterized by consistent peaks and troughs in the multiple dose plasma profile. This presentation indicates that at steady state C _max is less than the dose administered.

  A comparison of formulation A relative to the reference formulation for the oxycodone plasma profile and a comparison of formulation B relative to the reference formulation for the oxycodone plasma profile are shown in Tables 11 and 12.

AUC _t formulations A and B is less than AUC _t of the reference formulation, AUC _t formulations A and B were within less and 7%, respectively 14%. Also, the T _max for both formulations A and B are also greater than the T _{max of the} above reference formulation, which was not expected.

Example 5: Immediate Release Composition of Oxycodone Containing Controlled Release Mixture of Oxycodone-morphine Ammonio methacrylate copolymer, hypromellose, lactose, magnesium stereate, polyethylene glycol 400, povidone, sodium hydroxide, sorbic acid, In the art to prepare tablets for oral solid and oral ingredients comprising a core of 5.0 mg oxycodone hydrochloride and 5.0 mg morphine sulfate as active ingredients with stearyl alcohol, talc, titanium dioxide and triacetin, as tablets for tablets It is prepared according to known standard methods. The outer side of the tablet is 10 mg of oxycodone hydrochloride and gelatin, hypromellose, corn starch, polyethylene glycol, polysorbate 80, red iron oxide, silicon dioxide, sodium laurel sulfate, sucrose, titanium dioxide and yellow iron oxide. Coated with a controlled release formulation. The resulting tablets are administered to a patient to reduce pain, which results in effective analgesia without the occurrence of morphine-induced respiratory depression.

Example 6: General procedure for preparing a controlled release formulation The following production outline is provided for the purpose of illustration for the preparation of a controlled release compressed tablet comprising morphine sulfate and oxycodone hydrochloride.

Preparation of pellet core Active drug substance (morphine sulfate and oxycodone hydrochloride), microcrystalline cellulose, USP and povidone K30, NF were separately hand-screened through a # 20 mesh sieve into a collection vessel . The screened mixture was transferred to the granulating bowl of a high shear granulator (e.g., PMA-25 or PMA-65) and dry mixed for 3 minutes.

  A granulating solution consisting of a pre-mixed solution of purified water, USP and polyoxyl 35 castor oil, NF was sprayed at a constant speed into the granulating bowl and mixed at a low speed impeller / low speed chopper setting. The granulation results were continuously assessed visually and, if necessary, additional purified water, USP was sprayed onto the mass. At the end of the granulation period, samples were taken for in-process testing for water content.

  After sampling was complete, the granulation was stopped for an extrusion-spheronization process using a Luwa extruder and plate spheronizer or equivalent. The wet mass was extruded through a 0.8 mm sieve uniformly into a marmalizing bowl (where the extrudate was formed into pellets of the appropriate size).

  Fluidized bed drying of the pellets was performed using GPCG-3, GPCG-5 or equivalent, using suitable process parameters, to a loss on drying (LOD) test target of ≦ 5%. The dried pellets are sieved through a # 20 and # 40 mesh sized stainless steel screen to obtain the desired fraction in a double PE backed fiber drum for storage of work in process Retained and spray coated pellets.

Preparation of controlled release coated beadlets Ammonio methacrylate copolymer and triethyl citrate in a solution of isopropyl alcohol / water in a stainless steel container using a pneumatic propeller mixer for at least 1 hour until a clear solution is obtained Mixed. Talc was then added to the vessel with continuous stirring. Fluid bed spray coating of the core pellets was performed using a GPCG-5 Wurster fitted with a 1.0 mm spray nozzle using suitable process parameters.

Preparation of enteric coated beadlets An enteric coating solution was prepared by mixing the methacrylic acid copolymer and triethyl citrate in a separate container using a pneumatic mixer for at least 1 hour in a stainless steel container . Talc was then added to the vessel with continuous stirring. The polymer coating solution was subsequently sprayed onto the beadlets at a constant rate, with continuous monitoring of the spray conditions. The enteric coated beadlets were discharged into a double polyethylene lined fiber drum to retain and store the work-in-process for lubrication.

Example 7 Dissolution Test for Controlled Release Formulations A dissolution test was designed for use with an automatic dissolution sampling station (eg, Varian VK 8000). If such a device is not available, appropriate adjustments can be made to manually remove the sample.
Device: USP <711> Device 2 (paddle)
Automatic elution sampling station container size / type: about 1000 mL / transparent glass, round bottom container rotational speed: about 50 rpm throughout
Medium and volume: Stage 1 (acid stage) 0-2 hours: 750 mL of acidic elution medium A, 37.0 ± 0.5 ° C. for 2 hours
Stage 2 (buffer stage) 2-11 hours: 1000 mL, 37.0 ± 0.5 ° C., prepared by adding 250 mL of elution medium B and 20 mL of elution medium A to the medium remnant in the vessel from stage 1. . The stage 2 medium should have a pH of about 6.8.
Test temperature: about 37.0 ± 0.5 ° C
Weight: Basket-shaped weight (0.46 ′ ′ × 0.80 ′ ′) 40 mesh, 316-SS wire cloth collection volume: about 10 mL
Profile time points: approximately 1, 2, 3, 4, 6, 9 and 11 hours Medium displacement: no sampling: automatic filter type / size: in-line 10 μm polyethylene full flow filter Example 8: composition of controlled release opioid formulation Example 6 The following formulations were prepared according to the following procedure:

  Various formulations were prepared with various% coating levels (eg, 25%, 35%, 45%, 50% and 55%) of the ammonio methacrylate RS / RL polymer. Figures 19 (a) and 20 (a) provide representative elution profiles for morphine sulfate and oxycodone hydrochloride, respectively.

  Various tablet formulations were prepared with various% enteric coating levels (eg, 10%, 15%, 20%, 25%, 30% and 40%). Figures 21 and 22 provide representative elution profiles for morphine sulfate and oxycodone hydrochloride, respectively.

Example 9 Dissolution test for various% modified release coating levels and enteric coating levels Two lots (about 3 kg) of morphine sulfate / oxycodone (3: 2 weight ratio) core pellet, 90/10 (see Lot 1, Table 13) And an RS / RL polymer ratio of 80/20 (lot 2). Each lot was coated at various coating levels (25%, 35%, 45%, 50% and 55%) and samples were collected during the coating process. Elution tests (Figures 19 and 20) were performed on Lots 1 and 2 at various coating levels.

  In addition, coated pellets (50% RS / RL coating level) obtained from lot 1 are subjected to enteric coating of various% coating levels (10%, 15%, 25%, 30% and 40%) Thus, enteric-coated tablets were obtained and tested for dissolution (FIGS. 21 and 22).

  Enteric coated tablet lots (with 10% and 15% enteric coatings) have different tableting levels by also analyzing for dissolution depending on tablet hardness (low, medium or high) The resistance of the tablets to was determined (Figures 23 and 24).

  The summary of the above dissolution test is provided in Table 15.

  Figures 19 and 20 illustrate the versatility of the controlled release core beadlets at various% coating levels in obtaining the desired dissolution profile. The broad elution profile allows for the determination of specific in vivo pharmacokinetic plasma levels targeting and correlation between in vitro and in vivo.

  Figures 21 and 22 also show the versatility of enteric coated modified release core beadlets at various% enteric coating levels in obtaining the desired elution profile. Again, the broad elution profile allows for the determination of specific in vivo pharmacokinetic plasma level targeting and correlation between in vitro and in vivo.

  Figures 23 and 24 show the effect of tableting force on tablets containing enteric coated beadlets comprising controlled release coated pellets of morphine sulfate and oxycodone hydrochloride. It is generally known that high tableting power can significantly reduce tablet dissolution, particularly when coating polymers known to be brittle (eg, ammonio methacrylate copolymer types A and B) are used There is. Figures 23 and 24 demonstrate that low or high tableting forces do not affect tablet dissolution. This result is unexpected and demonstrates the elasticity of the formulation / coating to tableting forces.

Example 10 Composition of Controlled Release Opioid Formulations Following the procedure of Example 6, the following formulations were prepared:

  25-27 provide representative dissolution profiles of morphine sulfate and oxycodone hydrochloride, respectively, for the formulations provided in Table 16. These figures illustrate the versatility of the controlled release core beadlets at various% coating levels in obtaining the desired elution profile. Enteric coated beadlet formulations are also provided which allow to achieve a wide range of dissolution profiles.

  It will be appreciated that the above relates only to certain disclosed embodiments of the invention, and without departing from the spirit and scope of the invention as set forth in the appended claims. It should be understood that numerous modifications or alterations may be made there.

Claims (45)

A pharmaceutical formulation for treating pain in humans comprising one or more opioid components, wherein:
(A) the one or more opioid components have one or more release profiles;
(B) at least one of the opioid components is a controlled release opioid component, including an opioid, wherein the opioid is oxycodone or a salt thereof;
The pharmaceutical formulation provides a time to maximal plasma concentration of oxycodone or salt thereof (T _max ) of about 4.5 to about 8 hours after repeated administration. The controlled release opioid component further comprises one or more additional opioids selected from the group consisting of morphine, codeine, hydromorphone, hydrocodone, dihydrocodeine, dihydromorphine, oxymorphone, mixtures thereof and salts thereof. The pharmaceutical preparation according to 1. When the formulation contains a total dose of about 2 mg of oxycodone or a salt thereof, the area under the curve of about 14.7 ng · hr / mL to about 23.0 ng · hr / mL from about 0 to about 24 hours after a single dose. _{(AUC 24)} to provide a pharmaceutical formulation according to claim 1. 4. The pharmaceutical formulation of claim 3, formulated for a total dose of oxycodone or a salt thereof different than about 2 mg, and having an AUC ₂₄ proportional to said 2 mg AUC ₂₄ . When the formulation comprises a total dose of about 2 mg of oxycodone or a salt thereof, the mean maximum plasma concentration (C _{max of} oxycodone or a salt thereof of about 1 to about 3 ng / mL after repeated dosing that is during steady state conditions The pharmaceutical preparation according to claim 1, which provides 6. The pharmaceutical formulation of claim 5, formulated for a total dose of oxycodone or a salt thereof different than about 2 mg, and having a C _max proportional to the C _max of 2 mg. When the formulation contains a total dose of about 5 mg of oxycodone or a salt thereof, the area under the curve of about 0 to about 24 hours of about 40.2 ng · hr / mL to about 62.8 ng · hr / mL after a single dose. _{(AUC 24)} to provide a pharmaceutical formulation according to claim 1. 8. The pharmaceutical formulation of claim 7, formulated for a total dose of oxycodone or a salt thereof different than about 5 mg, and having an AUC ₂₄ proportional to said 5 mg AUC ₂₄ . When the formulation comprises a total dose of about 5 mg of oxycodone or a salt thereof, the mean maximum plasma concentration (C _{max of} oxycodone or a salt thereof of about 3 to about 7 ng / mL after repeated dosing that is during steady state conditions The pharmaceutical preparation according to claim 1, which provides 10. The pharmaceutical formulation according to claim 9, formulated for a total dose of oxycodone or a salt thereof different from about 5 mg, and having a _Cmax proportional to the _Cmax of 5 mg. When the formulation comprises a total dose of about 10 mg of oxycodone or a salt thereof, the area under the curve of about 80.5 ng · hr / mL to about 125.9 ng · hr / mL from about 0 to about 24 hours after a single dose. _{(AUC 24)} to provide a pharmaceutical formulation according to claim 1. 12. The pharmaceutical formulation of claim 11, formulated for a total dose of oxycodone or a salt thereof different from about 10 mg, and having an AUC ₂₄ proportional to the AUC ₂₄ of 10 mg. When the formulation comprises a total dose of about 10 mg of oxycodone or a salt thereof, the mean maximum plasma concentration (C _{max of} oxycodone or a salt thereof of about 5 to about 15 ng / mL after repeated dosing that is during steady state conditions The pharmaceutical preparation according to claim 1, which provides The approximately 10mg formulated for oxycodone or a salt thereof with different total doses, and have a _{C max} which is proportional to the _{C max} of the 10mg, pharmaceutical formulation of claim 13. When the formulation contains a total dose of about 20 mg of oxycodone or a salt thereof, the area under the curve of about 0 to about 24 hours of about 166.0 ng · hr / mL to about 259.3 ng · hr / mL after a single dose. _{(AUC 24)} to provide a pharmaceutical formulation according to claim 1. 16. The pharmaceutical formulation according to claim 15, formulated for a total dose of oxycodone or a salt thereof different from about 20 mg, and having an AUC ₂₄ proportional to said AUC ₂₄ of 20 mg. When the formulation comprises a total dose of about 20 mg of oxycodone or a salt thereof, the mean maximum plasma concentration (C _{max of} oxycodone or a salt thereof of about 10 to about 30 ng / mL after repeated dosing that is during steady state conditions The pharmaceutical preparation according to claim 1, which provides The approximately 20mg formulated for oxycodone or a salt thereof with different total doses, and have a _{C max} which is proportional to the _{C max} of the 20mg, pharmaceutical formulation of claim 17. When the formulation comprises a total dose of about 40 mg of oxycodone or a salt thereof, an area under the curve of about 0 to about 24 hours of about 338.5 ng · hr / mL to about 528.9 ng · hr / mL after a single dose. _{(AUC 24)} to provide a pharmaceutical formulation according to claim 1. 20. The pharmaceutical formulation of claim 19, formulated for a total dose of oxycodone or a salt thereof different than about 40 mg, and having an AUC ₂₄ proportional to said 40 mg AUC ₂₄ . When the formulation comprises a total dose of about 40 mg of oxycodone or a salt thereof, the average maximum plasma concentration (C _{max of} oxycodone or a salt thereof of about 25 to about 55 ng / mL after repeated dosing that is during steady state conditions The pharmaceutical preparation according to claim 1, which provides 22. The pharmaceutical formulation of claim 21 formulated for a total dose of oxycodone or a salt thereof different than about 40 mg, and having a _Cmax proportional to the _Cmax of 40 mg. When the formulation comprises a total dose of about 80 mg of oxycodone or a salt thereof, the area under the curve of about 868.4 ng · hr / mL to about 1356.9 ng · hr / mL from about 0 to about 24 hours after a single dose. _{(AUC 24)} to provide a pharmaceutical formulation according to claim 1. _24. The pharmaceutical formulation of claim 23, formulated for a total dose of oxycodone or a salt thereof different than about 80 mg, and having an AUC ₂₄ proportional to said 80 mg AUC ₂₄ . When the formulation comprises a total dose of about 80 mg of oxycodone or a salt thereof, an average peak plasma concentration of oxycodone or a salt thereof of about 50 to about 110 ng / mL after repeated dosing that is during steady state conditions The pharmaceutical formulation of claim 1, which provides (C _max ). 26. The pharmaceutical formulation of claim 25, formulated for a total dose of oxycodone or a salt thereof different than about 80 mg, and having a C _max proportional to said C _max of 80 mg. The pharmaceutical formulation of claim 1 comprising a second controlled release opioid component. 28. The method according to claim 27, wherein said second controlled release opioid component comprises an opioid selected from the group consisting of morphine, codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine, oxymorphone, mixtures thereof and salts thereof. Pharmaceutical formulations. The pharmaceutical formulation of claim 1 comprising an immediate release opioid component. 30. The medicine according to claim 29, wherein said immediate release opioid component comprises an opioid selected from the group consisting of morphine, codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine, oxymorphone, mixtures thereof and salts thereof. Formulation. 31. The pharmaceutical preparation according to claim 30, wherein the opioid in the immediate release opioid component is morphine or a salt thereof. 32. The pharmaceutical preparation according to claim 31, wherein all morphine or a salt thereof and all oxycodone or a salt thereof in the preparation are present in a weight ratio of morphine or a salt thereof to oxycodone or a salt thereof of about 3: 2. A second opioid component and a third opioid component, where:
(A) the second opioid component is an immediate release opioid component, including an opioid having a kappa agonist activity; and (b) the third opioid component is a controlled release opioid component, a mu agonist activity Containing opioids,
The pharmaceutical preparation according to claim 1. 34. The pharmaceutical preparation of claim 33, wherein the opioid having kappa agonist activity is oxycodone or a salt thereof. 34. The pharmaceutical preparation according to claim 33, wherein the opioid having mu agonist activity is morphine or a salt thereof. The pharmaceutical formulation of claim 1, wherein the controlled release opioid component comprises morphine or a salt thereof. 37. The pharmaceutical formulation of claim 36, wherein the controlled release opioid component comprises morphine or a salt thereof and oxycodone or a salt thereof in an amount of about 3: 2 by weight. 2. The method according to claim 1, wherein the dissolution of said formulation releases about 0 to about 20% of said oxycodone or a salt thereof after 2 hours when measured at about 50 rpm in water at about 37 ° C in a USP Type I device. Pharmaceutical formulations. The dissolution of said formulation releases about 15 to about 60% of said oxycodone or salt thereof after 4 hours when measured at about 50 rpm in water at about 37 ° C. in a USP Type I device. Pharmaceutical formulations. The dissolution of said formulation releases about 25 to about 80% of said oxycodone or salt thereof after 6 hours when measured at about 50 rpm in water at about 37 ° C. in a USP Type I device. Pharmaceutical formulations. The dissolution of said formulation releases about 35 to about 85% of said oxycodone or a salt thereof after 8 hours when measured at about 50 rpm in water at about 37 ° C. in a USP Type I device. Pharmaceutical formulations. 2. The method according to claim 1, wherein the dissolution of said formulation releases about 45 to about 95% of said oxycodone or a salt thereof after 10 hours when measured at about 50 rpm in water at about 37 ° C in a USP Type I device. Pharmaceutical formulations. The dissolution of said formulation releases about 60 to about 100% of said oxycodone or salt thereof after 12 hours when measured at about 50 rpm in water at about 37 ° C. in a USP Type I device. Pharmaceutical formulations. A method of controlling the release of one or more compounds having opioid receptor agonist activity for absorption in humans, comprising administering a pharmaceutical formulation comprising one or more components, here:
(A) the one or more opioid components have one or more release profiles;
(B) at least one of the opioid components is a controlled release opioid component, including an opioid, wherein the opioid is oxycodone or a salt thereof;
The method wherein the pharmaceutical formulation provides a maximum plasma concentration time to reach (T _max ) of oxycodone or salt thereof of about 4.5 to about 8 hours after repeated administration. A method of treating pain in a human comprising administering a pharmaceutical formulation comprising one or more components, wherein:
(A) the one or more opioid components have one or more release profiles;
(B) at least one of the opioid components is a controlled release opioid component, including an opioid, wherein the opioid is oxycodone or a salt thereof;
The method wherein the pharmaceutical formulation provides a maximum plasma concentration time to reach (T _max ) of oxycodone or salt thereof of about 4.5 to about 8 hours after repeated administration.