Post-surgical pain treatment

Abstract

To provide a post-surgical pain treatment.SOLUTION: Disclosed herein are compositions and methods for treating post-surgical pain in a patient in need thereof comprising administering to the patient a therapeutically effective amount of NK-1 receptor antagonist and a pain medication. The NK-1 receptor antagonist has failed to show efficacy in clinical trials of a variety of clinical pain states. The present application demonstrates that the combinational use of NK-1 receptor antagonist and pain medication in a particular manner can reduce post-surgical pain more significantly than the use of the individual active agent alone or other manners of the same combinational use.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present disclosure generally relates to a method for treating postoperative pain. The method includes administering a neurokinin 1 (NK-1) receptor antagonist in combination with an analgesic. The disclosure also relates to a pharmaceutical composition comprising a local anesthetic, an NK-1 receptor antagonist, and a delivery vehicle. [Background technology]

[0002] background Pain is defined by the International Association for the Study of Pain (IASP) as an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage (Classification of Chronic Pain, 2nd ed., Merkskey and Bogduk, eds. (IASP Press, 1994). Effective pain management modalities generally do not involve harmful and / or undesirable It is considered a treatment modality that provides pain relief while minimizing undesirable side effects. The treatment of acute pain, such as postoperative pain following surgery, is an active area of ​​research. Indeed, effective treatment of postoperative pain is now considered an essential component of the overall care of surgical patients.

[0003] Postoperative pain, which may be nociceptive in nature, generally results from inflammation from tissue trauma (e.g., resulting from surgical incision, dissection, or burn) or direct nerve injury (e.g., nerve section, distraction, or compression). Pain relief is of paramount importance to nearly all patients undergoing surgery and to medical professionals treating or caring for patients undergoing or recovering from surgery. One of the most common questions asked by patients prior to surgery is regarding the degree of pain they will experience after surgery (Vadivelu, N., Yale J. of Biology and Medicine 83 (2010), 11-25). Effective analgesia provides the patient with comfort and Ensure early mobilization and improve access to medical facilities (e.g., hospitals, outpatient clinics, etc.). Postoperative pain management is crucial to promote early discharge of patients from hospitals (e.g., assisted living facilities) and speed up recovery periods. Effective treatment of postoperative pain can also reduce the incidence / development of chronic pain syndromes, e.g., neuropathic pain, and / or the development of depression. Additional benefits of effective postoperative pain management include reduced pulmonary and cardiac complications, as well as reduced risk of deep vein thrombosis (Ramsay, M., Proc (Bayl Univ Med Centr) July 2000; 13 (3) :244-247). In contrast, inadequate pain control may increase morbidity or mortality (Sharrock NE et al., Anesth Analg. 1995 Feb;80(2):242-8).

[0004] Although knowledge of the physiology of pain has increased significantly over the past decade, unfortunately, the results in clinical practice have not followed suit. Despite decades of advances in understanding the physiology and psychology of pain, one of the mainstays of pain treatment remains the use of opioids. Opioids are effective analgesics, but they also have many undesirable side effects, such as sedation, respiratory depression, nausea and vomiting, hypotension, bradycardia, and the risk of addiction, to name a few.

[0005] One approach to provide localized, effective, long-acting relief of pain, especially acute pain, such as postoperative pain, is to utilize sustained or extended release systems.Several factors can affect the design of effective drug delivery systems, and certain classes of drugs, such as local anesthetics, are typically considered to be relatively short-lasting and therefore are most often only used for relatively simple or moderate surgeries.There remains a need for methods for postoperative pain treatment that are long-lasting, effective, convenient to administer, and can overcome some of the drawbacks associated with the use of opioids.The methods of the present invention meet these and other needs. NK-1 receptor antagonist is a known class of compounds for the treatment of nausea and vomiting associated with cancer chemotherapy.NK-1 receptor antagonist has failed to show efficacy in clinical trials of various clinical pain conditions.This application demonstrates that the combination of NK-1 receptor antagonist and analgesic in a specific manner can reduce postoperative pain more significantly than the use of each active agent alone or other modes of the same combination. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Classification of Chronic Pain, 2nd ed., Merkskey and Bogduk, IASP Press, 1994 [Non-Patent Document 2] Vadivelu, N., Yale J. of Biology and Medicine vol. 83 (2010), pp. 11-25. [Non-Patent Document 3] Ramsay, M., Proc(Bayl Univ Med Centr) July 2000;13(3):244-247 [Non-Patent Document 4] Sharrock NE et al., Anesth Analg. 1995 February;80(2):242-8 Summary of the Invention [Means for solving the problem]

[0007] The following aspects and embodiments thereof described and illustrated below are meant to be exemplary and illustrative, not limiting in scope.

[0008] In one aspect, a pharmaceutical composition is provided that includes an analgesic agent, an NK-1 receptor antagonist, and a delivery vehicle.

[0009] In one embodiment, a pharmaceutical composition is provided that includes a local anesthetic, an NK-1 receptor antagonist, and a delivery vehicle.

[0010] In one embodiment, a pharmaceutical composition is provided that includes an anti-inflammatory agent, an NK-1 receptor antagonist, and a delivery vehicle.

[0011] In one embodiment, a pharmaceutical composition is provided that includes a nonsteroidal anti-inflammatory drug (NSAID), an NK-1 receptor antagonist, and a delivery vehicle. In one embodiment, a pharmaceutical composition is provided that includes a nonsteroidal anti-inflammatory drug (NSAID), an NK-1 receptor antagonist, a local anesthetic, and a delivery vehicle.

[0012] In one embodiment, a pharmaceutical composition is provided that includes a steroidal anti-inflammatory agent, an NK-1 receptor antagonist, a local anesthetic, and a delivery vehicle.

[0013] In one embodiment, a pharmaceutical composition is provided that includes an analgesic agent, an NK-1 receptor antagonist, and a delivery vehicle.

[0014] In some embodiments, a pharmaceutical composition is provided that includes an NK-1 receptor antagonist, a local anesthetic, and a steroid. In some embodiments, a pharmaceutical composition is provided that includes an NK-1 receptor antagonist, a local anesthetic, and an analgesic.

[0015] In some embodiments, the local anesthetic is a caine-type anesthetic. In some embodiments, the local anesthetic is selected from the group consisting of bupivacaine, ropivacaine, levobupivacaine, dibucaine, mepivacaine, procaine, lidocaine, and tetracaine. In some embodiments, the local anesthetic is bupivacaine or ropivacaine.

[0016] In some embodiments, the local anesthetic is bupivacaine.

[0017] In some embodiments, the local anesthetic is ropivacaine.

[0018] In some embodiments, the NSAID is selected from the group consisting of diflusanil, indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, nabumetone, ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, meloxicam, piroxicam, tenoxicam, droxicam, lornoxicam, isoxicam, celecoxib, rofecoxib, and valdecoxib.

[0019] In some embodiments, the NSAID is meloxicam.

[0020] In some embodiments, the steroidal anti-inflammatory agent is 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clobetasone, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, dexamethasone 21-acetate, dexamethasone 21-phosphate disodium salt, diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene. acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, halopredone acetate, hydrocortamate, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednibal, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and combinations thereof.

[0021] In some embodiments, the analgesic agent is selected from the group consisting of capsinoids, including capsaicin, dihydrocapsaicin, nordihydrocapsaicin, homocapsaicin, homodihydrocapsaicin, and nonivamide, and combinations thereof.

[0022] In some embodiments, the NK-1 receptor antagonist is aprepitant, rolapitant, netupitant, lanepitant, vestipitant, oropyridine. The compound is selected from the group consisting of rubepitant maleate, casopitant, ezlopitant, serlopitant, befetupitant and maropitant, or a pharma- ceutically acceptable salt thereof.

[0023] In some embodiments, the NK-1 receptor antagonist is aprepitant.

[0024] In some embodiments, the composition comprises bupivacaine and aprepitant.

[0025] In some embodiments, the composition comprises a local anesthetic in an amount varying from about 0.1 wt% to 1 wt%, or from about 0.25 wt% to 30 wt%, or from about 0.1 wt% to 10 wt%, or from about 1 wt% to 5 wt%, or from about 0.25 wt% to 3.5 wt%, or from 2 wt% to 5 wt%, or from about 0.5 wt% to 4 wt%, or from about 0.1 wt% to 5 wt% by weight of the composition.

[0026] In some embodiments, the composition comprises an NK-1 receptor antagonist in an amount varying from about 0.001 wt% to 30 wt%, or from about 0.25 wt% to 10 wt%, or from about 0.01 wt% to 10 wt%, or from about 0.1 wt% to 5 wt%, or from about 0.1 wt% to 3.5 wt%, or from 0.1 wt% to 2 wt%, or from about 0.0.1 wt% to 1 wt%, or from about 0.01 wt% to 2 wt% by weight of the composition.

[0027] In some embodiments, the weight ratio of local anesthetic:NK-1 receptor antagonist is in the range of about 100:1 to 1:1, 100:1 to 4:1, 100:1 to 10:1, 75:1 to 1:1, 75:1 to 4:1, 75:1 to 10:1, 50:1 to 1:1, 50:1 to 4:1, 50:1 to 10:1, 25:1 to 1:1, 25:1 to 4:1, 25:1 to 10:1, or 10:1 to 1:1.

[0028] In one embodiment, the composition comprises bupivacaine and aprepitant, wherein the weight ratio of bupivacaine:aprepitant is in the range of about 100:1 to 1:1, 100:1 to 4:1, 100:1 to 10:1, 75:1 to 1:1, 75:1 to 4:1, 75:1 to 10:1, 50:1 to 1:1, 50:1 to 4:1, 50:1 to 10:1, 25:1 to 1:1, 25:1 to 4:1, 25:1 to 10:1, 10:1 to 1:1.

[0029] In some embodiments, the composition comprises ropivacaine and aprepitant.

[0030] In one embodiment, the composition comprises ropivacaine and aprepitant, wherein the weight ratio of ropivacaine:aprepitant is in the range of about 100:1 to 1:1, 100:1 to 4:1, 100:1 to 10:1, 75:1 to 1:1, 75:1 to 4:1, 75:1 to 10:1, 50:1 to 1:1, 50:1 to 4:1, 50:1 to 10:1, 25:1 to 1:1, 25:1 to 4:1, 25:1 to 10:1, 10:1 to 1:1.

[0031] In one embodiment, the composition comprises a caine-type local anesthetic in an amount of about 0.001-10 wt%, 0.25-0.75 wt%, 0.25-2.5 wt%, 0.25-3.5 wt%, 0.25-5 wt%, 1-5 wt%, 1-3.5 wt%, 1-3.0 wt%, 2-3 wt%, 2.1-2.9 wt%, 2.2-2.8 wt%, 2.3-2.7 wt%, 2.4-2.6 wt%, or 2.25-2.75 wt% by weight of the composition.

[0032] In another embodiment, the composition further comprises an NK-1 receptor antagonist, wherein the NK-1 receptor antagonist is present in an amount ranging from about 0.001 wt% to 30 wt%, or from about 0.25 wt% to 10 wt%, or from about 0.01 wt% to 10 wt%, or from about 0.1 wt% to 5 wt%, or from about 0.1 wt% to 3.5 wt%, or from 0.1 wt% to 2 wt%, or from about 0.0.1 wt% to 1 wt%, or from about 0.01 wt% to 2 wt% by weight of the composition.

[0033] In further embodiments, the composition further comprises an NSAID, wherein the ratio of amide type local anesthetic:NSAID is in the range of about 10:1 to 50:1, 15:1 to 50:1, 20:1 to 50:1, 25:1 to 50:1, 15:1 to 45:1, 20:1 to 45:1, 25:1 to 45:1, 30:1 to 45:1, 20:1 to 30:1, 20:1 to 35:1, 20:1 to 40:1, or 30:1 to 35:1. In another embodiment, the ratio of amide type local anesthetic:NSAID is about 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 29:1, 30:1, 31:1, 32:1, 33:1, 34:1, 35:1, 36:1, 37:1, 38:1, 39:1, 40:1, 41:1, 42:1, 43:1, 44:1, 45:1, 46:1, 47:1, 48:1, 49:1, 50:1, 51:1, 52:1, 53:1, 54:1, 55:1, 56:1, 57:1, 58:1, 59:1, 60:1, 61:1, 62:1, 63:1, 64:1, 65:1, 66:1, 67:1, 68:1, 69:1, 70:1, 71:1, 72:1, 73:1, 74:1, 75:1, 76:1, 77:1, 78:1, 79:1, 80:1, 81:1, 82:1, 83:1, 84:1, 85:1, 86:1, 87:1, 88:1, 89:1, 90:1, 91:1 3:1, 34:1, 35:1, 36:1, 37:1, 38:1, 39:1, 40:1, 41:1, 42:1, 43:1, 44:1, 45:1, 46:1, 47:1, 48:1, 49:1, 50:1, 51:1, 52:1, 53:1, 54:1, 55:1, 56:1, 57:1, 58:1, 59:1, or 60:1. In another embodiment, the amide-type local anesthetic is a Cain class anesthetic.

[0034] In one embodiment, the composition comprises bupivacaine and meloxicam, wherein the ratio of bupivacaine:meloxicam is in the range of about 10:1 to 50:1, 15:1 to 50:1, 20:1 to 50:1, 25:1 to 50:1, 15:1 to 45:1, 20:1 to 45:1, 25:1 to 45:1, 30:1 to 45:1, 20:1 to 30:1, 20:1 to 35:1, 20:1 to 40:1, or 30:1 to 35:1. In another embodiment, the ratio of bupivacaine:meloxicam is about 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 29:1, 30:1, 31:1, 32:1, 33:1, 34:1, 35:1, 36:1, 37:1, 38:1, 39:1, 40:1, 41:1, 42:1, 43:1, 44:1, 45:1, 46:1, 47:1, 48:1, 49:1, 50:1, 51:1, 52:1, 53:1, 54:1, 55:1, 56:1, 57:1, 58:1, 59:1, or 60:1.

[0035] In one embodiment, the composition further comprises an NSAID in an amount greater than about 0.01 wt% of the composition, greater than about 0.1 wt%, or greater than about 0.25 wt% of the composition, or between about 0.01-10 wt%, or between about 0.01-7.5 wt%, or between about 0.01-5.0 wt%, or between about 0.01-3.5 wt%.

[0036] In another embodiment, the composition further comprises an NSAID, preferably meloxicam, wherein the NSAID is present in an amount of about 0.005-0.006 wt%, 0.005-0.007 wt%, 0.005-0.008 wt%, 0.005-0.009 wt%, 0.005-1 wt%, 0.005-0.75 wt%, 0.005-0.5 wt%, 0.005-0.25 wt%, 0.0 0.05-0.125wt%, 0.01-1wt%, 0.01-0.75wt%, 0.01-0.5wt%, 0.01-0.25wt%, 0.01-0.125wt%, 0.020-0.100wt%, 0.030-0.100wt%, 0.040-0.100wt%, 0.050-0.090wt%, 0.060-0.080wt%, 0.070-0.080wt%.

[0037] In yet another embodiment, the composition further comprises meloxicam present in an amount greater than 0.001 wt%, less than 1 wt%, less than 0.5 wt%, less than 0.1 wt%, less than 0.08 wt%, less than 0.5 wt%, or less than 0.1 wt% by weight of the composition.

[0038] In one embodiment, the composition is a water-based solution.

[0039] In one embodiment, the composition is injectable.

[0040] In another embodiment, the composition is suitable for administration as an intramuscular injection, transdermal, topical, subcutaneous injection, perineural injection, or into a wound.

[0041] In one embodiment, the delivery vehicle is a sustained release delivery vehicle.

[0042] In one embodiment, the sustained release delivery vehicle is a polymeric composition, a liposomal composition, a microsphere composition, a non-polymeric composition, or an implantable device.

[0043] In one embodiment, the sustained release delivery vehicle is not a microsphere composition.

[0044] In one embodiment, the sustained release delivery vehicle is not a liposomal composition.

[0045] In one embodiment, the sustained release delivery vehicle is not a non-polymeric composition.

[0046] In one embodiment, the sustained release delivery vehicle is not an implantable device.

[0047] In one embodiment, the sustained release delivery vehicle is not a polymeric composition.

[0048] In one embodiment, the delivery vehicle is not a sustained release vehicle. In another embodiment, the delivery vehicle is an immediate release vehicle. In yet another embodiment, at least about 80% of the anesthetic and NK-1 receptor antagonist are released from the delivery vehicle within about 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes or 2 hours. In yet another embodiment, the release of the anesthetic and NK-1 receptor antagonist is determined by in vitro dissolution test at 37°C.

[0049] In one embodiment, the composition has a viscosity of less than 150,000 mPa·s when the viscosity is measured at 25° C. using a viscometer. In another embodiment, the composition has a viscosity of less than 100,000 mPa·s when the viscosity is measured at 25° C. using a viscometer. In one embodiment, the composition has a viscosity of less than 50,000 mPa·s when the viscosity is measured at 25° C. using a viscometer. In yet another embodiment, the composition has a viscosity in the range of about 1,000 mPa·s to 150,000 mPa·s when the viscosity is measured at 25° C. using a viscometer. In some embodiments, the viscometer is a cone and plate viscometer.

[0050] In yet another embodiment, the sustained release delivery vehicle is a liposome selected from the group consisting of small unilamellar vesicles (SUVs), large unilamellar vesicles (LUVs), multilamellar vesicles (MLVs) and multivesicular liposomes (MVLs).

[0051] In one embodiment, the caine-type local anesthetic is entrapped in the aqueous space of the liposome or in the lipid layer of the liposome.

[0052] In one embodiment, the NK-1 receptor antagonist is encapsulated in the aqueous space of the liposome or in the lipid layer of the liposome.

[0053] In yet another embodiment, the sustained release delivery vehicle is a microsphere composed of a bioerodible or biodegradable polymer.

[0054] In one embodiment, the amide-type local anesthetic and the NK-1 receptor antagonist are encapsulated in microspheres.

[0055] In one embodiment, the implantable device is an osmotic pump with a reservoir containing a kine-type local anesthetic and an NK-1 receptor antagonist.

[0056] In one embodiment, the sustained release delivery vehicle is a non-polymeric formulation that includes sucrose isobutyl acetate.

[0057] In one embodiment, the sustained release delivery vehicle is a polymer formulation in the form of a semi-solid polymer formulation comprising a polymer.

[0058] In one embodiment, the polymer is a bioerodible or biodegradable polymer.

[0059] In yet another embodiment, the polymer formulation forms an implant or depot in situ.

[0060] In yet another embodiment, the polymer is selected from the group consisting of polylactide, polyglycolide, poly(lactic-co-glycolic acid) copolymers, polycaprolactone, poly-3-hydroxybutyrate, and polyorthoesters.

[0061] In a further embodiment, the sustained release delivery vehicle is a polymer formulation in the form of a semi-solid polymer formulation comprising a polyorthoester.

[0062] In a further embodiment of any one or more of the preceding embodiments, the composition is a semi-solid or solid composition.

[0063] In one embodiment, the delivery vehicle is a sustained release delivery vehicle. In one embodiment, the sustained release vehicle is a polymer vehicle or polymer formulation.

[0064] In another embodiment, the sustained release polymer vehicle is a solid or semi-solid vehicle that includes a bioerodible or biodegradable polymer.

[0065] In one embodiment, the biodegradable or bioerodible polymer formulation comprises a polymer selected from the group consisting of polylactide, polyglycolide, poly(lactic-co-glycolic acid) copolymer, polycaprolactone, poly-3-hydroxybutyrate, or polyorthoester.

[0066] In one embodiment, the polyorthoester is selected from the polyorthoesters represented by Formulas I, II, III, and IV described herein.

[0067] In certain further embodiments of the foregoing, the polyorthoester is represented by formula I:

[0068] In an alternative embodiment, the sustained release vehicle does not include polylactide, polyglycolide, poly(lactic-co-glycolic acid) copolymer, polycaprolactone, poly-3-hydroxybutyrate, or polyorthoester. In another embodiment, the sustained release vehicle does not include polyorthoester. In yet another embodiment, the sustained release vehicle does not include polyorthoester represented by formula I, II, III, or IV. In yet another embodiment, the sustained release vehicle does not include polyorthoester represented by formula I.

[0069] In yet further embodiments, the composition or delivery vehicle further comprises a solvent. The solvent may be either protic or aprotic in nature. In one embodiment, the composition comprises a polyorthoester and a solvent as a delivery vehicle.

[0070] In another embodiment, the sustained release delivery vehicle is selected from the group consisting of microspheres, microparticles, and homogeneous or heterogeneous matrix depots. In one embodiment, the microsphere, microparticle or depot vehicle is biodegradable or bioerodible.

[0071] In another embodiment, the sustained release delivery vehicle is a liposomal or lipid-based formulation.

[0072] In another embodiment, the sustained release formulation is a polymer-based solid or semi-solid implant, where the local anesthetic and the NK-1 receptor antagonist are dispersed in the polymer-based implant.In one embodiment, the implant is a solid polymer-based vehicle in the form of a suture or staple.

[0073] In certain embodiments, the composition is effective to provide a measurable plasma concentration of the kine-type local anesthetic and / or NK-1 receptor antagonist for a period of up to about 3 days, or up to about 5 days, or up to about 7 days, or up to about 10 days, or for a period of about 1 to about 3 days, about 1 to about 5 days, about 1 to about 7 days, about 3 to about 5 days, about 3 to about 7 days, or about 5 to about 10 days, after administration. In one embodiment, the composition is effective to provide a measurable plasma concentration of the kine-type local anesthetic and / or NK-1 receptor antagonist for a period of about 1 to about 3 days, about 1 to about 5 days, about 1 to about 7 days, about 1 to about 10 days, about 1 to about 12 days, about 1 to about 13 days, or about 1 to about 14 days, after administration. In another embodiment, the plasma concentration of the kine-type local anesthetic and / or NK-1 receptor antagonist is measured by LC / MS / MS (liquid chromatography / tandem mass spectrometry).

[0074] In certain embodiments, the composition is effective to release a significant portion of both the kine-type anesthetic and the NK-1 receptor antagonist from the composition such that about 80% by weight or more of the kine-type anesthetic and / or the NK-1 receptor antagonist is released either in vitro or in vivo over a period of up to about 3 days, or up to about 5 days, or up to about 7 days, or up to about 10 days (e.g., as described in Example 5) after administration or after the initiation of an in vitro drug release experiment, or over a period of about 1 day to about 3 days, about 1 day to about 5 days, about 1 day to about 7 days, or about 5 days to about 10 days, about 2 days to about 5 days, about 3 days to about 5 days, about 4 days to about 5 days, about 2 days to about 4 days, about 3 days to about 4 days, or about 3 days, about 4 days, or about 5 days.

[0075] In one embodiment, the composition is a synergistic composition, where the release of the combination of the kine-type anesthetic and the NK-1 receptor antagonist provides a synergistic level of pain relief that exceeds the level of pain relief provided by the additive effect of adding the kine-type anesthetic and the NK-1 receptor antagonist separately. In another embodiment, the composition provides a longer duration of pain relief than the additive effect of adding the kine-type anesthetic and the NK-1 receptor antagonist separately.

[0076] In one embodiment, the composition is a synergistic composition comprising bupivacaine and aprepitant, wherein the weight ratio of bupivacaine: aprepitant ranges from about 1:100 to 100:1, 20:1 to 1:20, 1:5 to 5:1, 1:1 to 15:1, or 1:1 to 1:15. In yet another embodiment, administration of a synergistic composition comprising bupivacaine and aprepitant to a subject provides a synergistic level of pain relief that exceeds the pain relief provided by the additive effect of administering bupivacaine and aprepitant independently. In another embodiment, the subject is a post-operative patient. In another embodiment, the subject is a patient undergoing surgery. In some embodiments, the subject is a patient scheduled to undergo surgery.

[0077] In one embodiment, the composition is a synergistic composition comprising ropivacaine and aprepitant, wherein the weight ratio of ropivacaine:aprepitant is in the range of about 1:100 to 100:1, 20:1 to 1:20, 1:5 to 5:1, 1:1 to 15:1, or 1:1 to 1:15.

[0078] In yet another embodiment, administering to a subject a synergistic composition comprising ropivacaine and aprepitant provides a synergistic level of pain relief that exceeds the pain relief provided by the additive effect of administering ropivacaine and aprepitant separately. In another embodiment, the subject is a post-operative patient. In another embodiment, the subject is a patient undergoing surgery. In some embodiments, the subject is a patient scheduled to undergo surgery.

[0079] In some embodiments, the delivery vehicle comprises a polar aprotic solvent in which the polyorthoester, the solvent containing the triglyceride viscosity-lowering agent, and the polyorthoester are miscible to form a single phase. The triglyceride viscosity-lowering agent comprises three fatty acid groups each independently containing between 1 and 7 carbon atoms, also referred to herein as "short chain" triglycerides. In another embodiment, the delivery vehicle further comprises a dicarboxylic acid.

[0080] In one embodiment, the triglyceride viscosity-lowering agent is glycerin triacetate (also called triacetin, 1,2,3-triacetoxypropane, or glycerol triacetate).

[0081] In one embodiment, the polar aprotic solvent is an organic solvent that has a solubility of the solvent greater than 25% by weight in water at room temperature.

[0082] In one embodiment, the polar aprotic solvent has a dipole moment greater than about 2 Debye (D).

[0083] In one embodiment, the polar aprotic solvent is a class selected from the group consisting of amides, ethers, ketones, and sulfoxides.

[0084] In another embodiment, the polar aprotic solvent is a sulfoxide selected from the group consisting of dimethyl sulfoxide and decyl methyl sulfoxide.

[0085] In yet another embodiment, the polar aprotic solvent is an amide selected from the group consisting of 2-pyrrolidone, dimethylformamide, N-methyl-2-pyrrolidone, and dimethylacetamide.

[0086] In one embodiment, the polar aprotic solvent is an ether selected from dimethylisosorbide and tetrahydrofuran.

[0087] In one embodiment, the polar aprotic solvent is a ketone selected from the group consisting of acetone and methyl ethyl ketone.

[0088] In one embodiment, the polar aprotic solvent is a lactone selected from the group consisting of ester-caprolactone and butyrolactone.

[0089] In one embodiment, the polar aprotic solvent is propylene carbonate, an ester of an alcohol (4-methyl-1,3-diololan-2-one).

[0090] In one embodiment, the polar aprotic solvent is 1-dodecylazacycloheptan-2-one.

[0091] In one embodiment, the polar aprotic solvent is dimethylsulfoxide (DMSO) or N-methylpyrrolidone (NMP) or dimethylacetamide (DMAC).

[0092] In one embodiment, the polar aprotic solvent is dimethylsulfoxide (DMSO) or N-methylpyrrolidone (NMP).

[0093] In one embodiment, the polar aprotic solvent is dimethylsulfoxide (DMSO).

[0094] In one embodiment, the dicarboxylic acid is maleic acid.

[0095] In one embodiment, the polyorthoester is a polyorthoester represented by the structure shown in Formula I. [ka] In the formula, R * is methyl, ethyl, propyl or butyl, n is the number of repeating units and is an integer ranging from 5 to 400, and A of each partial unit is R 1 or R 3 It is.

[0096] In one embodiment, R * is ethyl.

[0097] In one embodiment, A is R 1 corresponds to R 1 teeth, [ka] p and q are each independently an integer ranging from about 1 to 20; 5 are independently hydrogen or C 1~4 is alkyl, R 6 teeth, [ka] where s is an integer from 0 to 10, t is an integer from 2 to 30, and R 7 is hydrogen or C 1~4 In another embodiment, R7 is C1, C2, C3, or C4 alkyl. In certain embodiments, R 7 is H. In yet another embodiment, R 1 The partial unit is an alpha-hydroxy acid containing partial unit. In another embodiment, p and q are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20. In yet another embodiment, R 5 is independently hydrogen, or C1, C2, C3 or C4 alkyl.

[0098] In one embodiment, A is R 3 corresponds to R 3 teeth, [ka] and x is an integer ranging from 1 to 100. In another embodiment, x is selected from 0, 1, 2, 3, 4, and 5, y is an integer ranging from 2 to 30, and R 8 is hydrogen or C 1~4 In yet another embodiment, R 8is C1, C2, C3 or C4 alkyl. In another embodiment, R 8 is H.

[0099] In one embodiment, the polyorthoester is a polyether ester in which A is R 1 or R 3 and R 1 but, [ka] wherein p and q are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 of any repeat unit, the average number of p or the average number of the sum of p and q (p+q) is between about 1 and 7, x and s are each independently an integer ranging from 0 to 10, and t and y are each independently an integer ranging from 2 to 30. In another embodiment, the sum of p and q is greater than or equal to about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 of any repeat unit, 1 In yet another embodiment, R 5 is H.

[0100] In one embodiment, A is R 1 or R 3 and R 1 teeth, [ka] p and q each independently represent R 1 is an integer ranging from about 1 to 20, about 1 to 15, or about 1 to 10 of any repeating unit, and the average number of p or the average number of p and q (i.e., p+q) is between about 1 and 7. In another embodiment, x and s each independently range from 0 to about 7 or 1 to about 5. In yet another embodiment, t and y each independently range from 2 to 10.

[0101] In one embodiment, R 5 is hydrogen or methyl.

[0102] In one embodiment, s and x are each independently selected from 1, 2, 3, 4, 5, 6, 7, and 8. In another embodiment, s is 2. In yet another embodiment, x is 2.

[0103] In one embodiment, the polyorthoester is 3,9-diethyl-3,9-2,4,8,10-tetraoxaspiro[5.5]undecane-3,9-diyl and A [ka] and A is as previously described.

[0104] In one particular embodiment of the polyorthoester of the delivery system, the polyorthoester has a molecular weight in the range of about 2,500 daltons to 10,000 daltons.

[0105] In one embodiment of the delivery vehicle, the polyorthoester is represented by the structure shown as formula I and is in an amount ranging from about 5 to 95 wt%, 65 to 75 wt%, 60 to 70 wt%, 50 to 70 wt%, 20 to 70 wt%, 50 to 65 wt%, or 55 to 65 wt% by weight of the composition. In another embodiment, the polyorthoester represented by the structure shown as formula I is in an amount of about 40 weight percent, 45 weight percent, 50 weight percent, 55 weight percent, 60 weight percent, 65 weight percent, or 70 weight percent of the composition.

[0106] In one embodiment of the delivery vehicle, the triglyceride viscosity-lowering agent is present in an amount ranging from about 1 wt% to 50 wt%, 1 wt% to 45 wt%, 1 wt% to 40 wt%, 1 wt% to 35 wt%, 1 wt% to 25 wt%, 1 wt% to 20 wt%, 1 wt% to 15 wt%, 1 wt% to 10 wt%, or about 1 wt% to 5 wt% of the composition.

[0107] In one embodiment of the delivery vehicle, the aprotic solvent is present in an amount ranging from about 1 wt% to 50 wt%, 1 wt% to 45 wt%, 1 wt% to 40 wt%, 1 wt% to 35 wt%, 1 wt% to 25 wt%, 1 wt% to 20 wt%, 1 wt% to 15 wt%, 1 wt% to 10 wt%, or about 1 wt% to 5 wt% of the composition.

[0108] In one embodiment of the delivery vehicle, the dicarboxylic acid is present in an amount ranging from about 0.01-0.5 wt%, 0.02-0.4 wt%, 0.03-0.3 wt%, 0.04-0.2 wt%, 0.04-0.15 wt%, 0.05-0.15 wt%, 0.02-0.08 wt%, 0.03-0.07 wt%, 0.04-0.06 wt%, 0.1-0.2 wt%, 0.125-0.175 wt%, or 0.14-0.16 wt% by weight of the composition. In another embodiment of the delivery vehicle, the dicarboxylic acid is about 0.01 wt% to 0.6 wt%, 0.01 wt% to 0.05 wt%, 0.05 wt% to 0.6 wt%, 0.01 wt% to 0.15 wt%, 0.05 wt% to 0.15 wt%, 0.01 wt%, 0.02 wt%, 0.03 wt% by weight of the composition. , 0.04wt%, 0.050wt%, 0.060wt%, 0.070wt%, 0.080wt%, 0.090wt%, 0.100wt%, 0.125wt%, 0.150wt%, 0.175wt%, 0.2wt%, 0.3wt%, 0.4wt%, 0.5wt%, or 0.6wt%.

[0109] In certain embodiments, the composition is administered as a nerve block to treat a painful condition in a patient in need of such treatment.

[0110] In further specific embodiments, the compositions are administered as a nerve block in a patient in need thereof as a prophylactic treatment of a painful condition, such as pre-operative administration for the treatment of post-operative pain.

[0111] In another aspect, a method for treating postoperative pain is provided, comprising administering a therapeutically effective amount of an NK-1 receptor antagonist in combination with an analgesic in a patient in need thereof.Postoperative pain can be neuropathic and / or nociceptive pain.In some embodiments, postoperative pain does not include neuropathic pain.In some embodiments, postoperative pain is nociceptive pain.

[0112] Analgesics refer to active agents for the treatment of pain.Active agents for the treatment of pain are selected from local anesthetics, opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, analgesics, anticonvulsants, serotonin and norepinephrine reuptake inhibitors (SNRIs), acetaminophen, and tricyclic antidepressants.Analgesics can contain more than one active agent.

[0113] In some embodiments, the NK-1 receptor antagonist and the analgesic agent are administered simultaneously, where the NK-1 receptor antagonist and the analgesic agent are contained in a single pharmaceutical composition or in separate / different pharmaceutical compositions.

[0114] In some embodiments, the NK-1 receptor antagonist and the analgesic are administered sequentially, where the NK-1 receptor antagonist is administered first and the analgesic is administered second, or vice versa. Such sequential administration may be close in time or distant in time. In some embodiments, the NK-1 receptor antagonist and the analgesic are both administered pre-operatively. In some embodiments, the NK-1 receptor antagonist and the analgesic are both administered intra-operatively. In some embodiments, the NK-1 receptor antagonist and the analgesic are both administered post-operatively. In some embodiments, one of the NK-1 receptor antagonist and the analgesic is administered pre-operatively and the other is administered post-operatively. In some embodiments, the NK-1 receptor antagonist is administered pre-operatively and the analgesic is administered post-operatively. In some embodiments, the analgesic is administered pre-operatively and the NK-1 receptor antagonist is administered post-operatively. In some embodiments, the NK-1 receptor antagonist is administered pre-operatively and the analgesic is administered intraoperatively. In some embodiments, the analgesic is administered pre-operatively and the NK-1 receptor antagonist is administered intraoperatively.

[0115] In some embodiments, the method for treating postoperative pain comprises administering to a patient in need thereof a therapeutically effective amount of an NK-1 receptor antagonist in combination with an analgesic selected from a local anesthetic, an opioid, an NSAID, an anticonvulsant, an SNRI, acetaminophen, and a tricyclic antidepressant. In some embodiments, the method for treating postoperative pain comprises administering to a patient in need thereof a therapeutically effective amount of an NK-1 receptor antagonist in combination with a local anesthetic. In some embodiments, the method for treating postoperative pain comprises administering to a patient in need thereof a therapeutically effective amount of an NK-1 receptor antagonist in combination with two analgesics selected from a local anesthetic, an opioid, an NSAID, a steroid, an analgesic, an anticonvulsant, an SNRI, acetaminophen, and a tricyclic antidepressant. In some embodiments, the method for treating postoperative pain comprises administering to a patient in need thereof a therapeutically effective amount of an NK-1 receptor antagonist in combination with a local anesthetic and an NSAID. In some embodiments, the method for treating postoperative pain comprises administering to a patient in need thereof a therapeutically effective amount of an NK-1 receptor antagonist in combination with a local anesthetic and a steroid. In some embodiments, the method for treating postoperative pain comprises administering to a patient in need thereof a therapeutically effective amount of an NK-1 receptor antagonist in combination with a local anesthetic and an analgesic. In some embodiments, the method for treating postoperative pain comprises administering to a patient in need thereof a therapeutically effective amount of an NK-1 receptor antagonist in combination with an opioid. In some embodiments, the method for treating postoperative pain comprises administering to a patient in need thereof a therapeutically effective amount of an NK-1 receptor antagonist in combination with acetaminophen. In some embodiments, the method for treating postoperative pain comprises administering to a patient in need thereof a therapeutically effective amount of an NK-1 receptor antagonist in combination with acetaminophen and an opioid.

[0116] In some embodiments, the NK-1 receptor antagonist is administered systemically, where administration may be by enteral administration (absorption of the drug by the digestive tract) or parenteral administration (generally by injection, infusion or implantation). In some embodiments, the NK-1 receptor antagonist is administered locally, for example to a wound site. In some embodiments, the NK-1 receptor antagonist is administered by injection selected from subcutaneous, intramuscular, intravenous, intraperitoneal, intracardiac, intraarticular and intracavernosal injection. In some embodiments, the NK-1 receptor antagonist is administered by intravenous injection. In some embodiments, the NK-1 receptor antagonist is administered by intramuscular injection.

[0117] In some embodiments, the analgesic is administered systemically, where administration can be by enteral administration (absorption of the drug by the digestive tract) or parenteral administration (generally by injection, infusion or implantation). In some embodiments, the analgesic is administered locally, for example to a wound site. In some embodiments, the analgesic is administered by injection selected from subcutaneous, intramuscular, intravenous, intraperitoneal, intracardiac, intraarticular and intracavernous injection. In some embodiments, the analgesic is administered by intravenous injection. In some embodiments, the analgesic is administered by intramuscular injection.

[0118] In some embodiments, the NK-1 receptor antagonist is selected from the group consisting of aprepitant, rolapitant, netupitant, lanepitant, vestipitant, orbepitant maleate, casopitant, ezlopitant, serlopitant, fosaprepitant, befetupitant, and maropitant, or a pharmaceutically acceptable salt thereof.

[0119] In some embodiments, the NK-1 receptor antagonist is aprepitant.

[0120] In some embodiments, the local anesthetic is selected from the group consisting of bupivacaine, ropivacaine, levobupivacaine, dibucaine, mepivacaine, procaine, lidocaine, and tetracaine. In some embodiments, the local anesthetic is bupivacaine or ropivacaine. In some embodiments, the local anesthetic is bupivacaine. In some embodiments, the local anesthetic is ropivacaine.

[0121] In some embodiments, the NSAID is selected from the group consisting of diflusanil, indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, nabumetone, ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, meloxicam, piroxicam, tenoxicam, droxicam, lornoxicam, isoxicam, celecoxib, rofecoxib, and valdecoxib.In certain embodiments, the NSAID is meloxicam.

[0122] In some embodiments, the steroid is 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clobetasone, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, dexamethasone 21-acetate, dexamethasone 21-phosphate disodium salt, diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate. tate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, halopredone acetate, hydrocortamate, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednibal, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and combinations thereof.

[0123] In some embodiments, the analgesic agent is selected from the group consisting of capsinoids, including capsaicin, dihydrocapsaicin, nordihydrocapsaicin, homocapsaicin, homodihydrocapsaicin, and nonivamide, and combinations thereof. In certain embodiments, for example, the following are provided: (Item 1) 1. A method for treating post-operative pain in a patient in need thereof, comprising: The method comprises administering to the patient a therapeutically effective amount of an NK-1 receptor antagonist in combination with an analgesic agent. (Item 2) 2. The method of claim 1, wherein the post-operative pain is not neuropathic. (Item 3) The method according to item 1 or 2, wherein the NK-1 receptor antagonist is selected from aprepitant, rolapitant, netupitant, lanepitant, vestipitant, orbepitant maleate, casopitant, ezlopitant, serlopitant, fosaprepitant, befetupitant and maropitant, and pharmaceutically acceptable salts thereof. (Item 4) The method according to any one of items 1 to 3, wherein the analgesic is selected from local anesthetics, opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), anticonvulsants, serotonin and norepinephrine reuptake inhibitors (SNRIs), acetaminophen, and tricyclic antidepressants. (Item 5) 5. The method according to any one of items 1 to 4, wherein the NK-1 receptor antagonist is aprepitant. (Item 6) 6. The method according to any of items 1 to 5, wherein the analgesic is a local anesthetic and an NSAID. (Item 7) 7. The method according to any of items 4 to 6, wherein the local anesthetic is selected from bupivacaine, levobupivacaine, ropivacaine, etidocaine, lidocaine, mepivacaine, prilocaine, and tetracaine. (Item 8) 8. The method of claim 7, wherein the local anesthetic is bupivacaine or ropivacaine. (Item 9) The method according to any one of items 4 to 8, wherein the NSAID is selected from the group consisting of diflusanil, indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, nabumetone, ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, meloxicam, piroxicam, tenoxicam, droxicam, lornoxicam, isoxicam, celecoxib, rofecoxib, and valdecoxib, for example, meloxicam. (Item 10) 10. The method according to any of items 1 to 9, wherein the NK-1 receptor antagonist and the analgesic are administered during surgery. (Item 11) 10. The method according to any of items 1 to 9, wherein the NK-1 receptor antagonist and the analgesic are administered after surgery. (Item 12) 10. The method according to any of items 1 to 9, comprising administering said NK-1 receptor antagonist post-operatively and said analgesic agent intraoperatively. (Item 13) 10. The method according to any of items 1 to 9, comprising administering said NK-1 receptor antagonist pre-surgery and daily for 1 to 6 days after surgery. (Item 14) 10. The method according to any of items 1 to 9, comprising administering said NK-1 receptor antagonist before surgery and daily for 1 to 6 days after surgery, and administering said analgesic agent during surgery. (Item 15) 10. The method according to any of items 1 to 9, comprising administering the NK-1 receptor antagonist and the NSAID before surgery, and administering the local anesthetic during surgery. (Item 16) The NK-1 receptor antagonist NK-1 receptor antagonists, 11wt / wt%~15wt / wt% emulsion, oil, Co-surfactants, including alcohols; isotonic agent, pH adjusters, and water 16. The method according to any one of items 1 to 15, wherein the compound is administered in the form of an injectable emulsion comprising the compound, and the pH of the emulsion is in the range of about 7.5 to 9.0. (Item 17) 17. The method according to any of items 1 to 14 and 16, wherein the analgesic is administered in the form of a pharmaceutical composition comprising a delivery system, a local anesthetic, and an NSAID. (Item 18) 18. The method of claim 17, wherein the local anesthetic is bupivacaine and the NSAID is meloxicam, and the bupivacaine and meloxicam are present in the composition in a ratio ranging from about 15:1 to 50:1. (Item 19) 16. The method of claim 15, wherein the NK-1 receptor antagonist and the NSAID are administered in the form of a pharmaceutical composition comprising a delivery system, the NK-1 receptor antagonist, and an NSAID. (Item 20) 16. The method of claim 15, wherein the local anesthetic is administered in the form of a pharmaceutical composition comprising a delivery system and the local anesthetic. (Item 21) 16. The method of claim 15, wherein the NK-1 receptor antagonist and the NSAID are administered systemically and the local anesthetic is administered locally. (Item 22) A pharmaceutical composition comprising a kine-type local anesthetic, an NK-1 receptor antagonist, an NSAID, and a delivery vehicle. (Item 23) A pharmaceutical composition comprising a kine-type local anesthetic, an NK-1 receptor antagonist, and a delivery vehicle. (Item 24) A pharmaceutical composition comprising an NSAID, an NK-1 receptor antagonist, and a delivery vehicle. 24. The pharmaceutical composition according to item 22 or 23, wherein the caine-type local anesthetic is selected from bupivacaine, levobupivacaine, ropivacaine, etidocaine, lidocaine, mepivacaine, prilocaine, and tetracaine. (Item 26) The NSAID is diflusanil, indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, nabumetone, ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, meloxicam, piroxicam, tenoxicam, droxicam, lornoxicam, isoxicam, celecoxib, rofecoxib, and valdecanol. 25. The pharmaceutical composition according to item 22 or 24, wherein the coxib is selected from the group consisting of, for example, meloxicam. (Item 27) 27. The pharmaceutical composition according to any of items 22 to 26, wherein the NK-1 receptor antagonist is selected from aprepitant, rolapitant, netupitant, lanepitant, vestipitant, orbepitant maleate, casopitant, ezlopitant, serlopitant, fosaprepitant, befetupitant and maropitant, and pharmaceutically acceptable salts thereof. (Item 28) 28. The pharmaceutical composition according to any of items 22 to 27, wherein the delivery vehicle comprises a polyorthoester of formula (I). (Item 29) 29. The pharmaceutical composition according to any of items 22, 23 and 25 to 28, wherein the weight ratio of the kine-type local anesthetic:NK-1 receptor antagonist is in the range of 1:1 to 60:1. (Item 30) 30. The pharmaceutical composition according to item 29, wherein the weight ratio of the kine-type local anesthetic:NK-1 receptor antagonist is in the range of 1:1 to 5:1. (Item 31) 31. The pharmaceutical composition according to any of items 22 to 30, comprising aprepitant, bupivacaine, meloxicam, and a polyorthoester of formula (I). (Item 32) 32. The pharmaceutical composition according to any of items 22 to 31, further comprising an aprotic solvent. (Item 33) 33. The pharmaceutical composition according to item 32, wherein the aprotic solvent is selected from DMSO, NMP, and DMAC. (Item 34) A method for treating postoperative pain in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition according to any one of items 22 to 33. (Item 35) 35. The method of claim 34, wherein the pharmaceutical composition is administered to a surgical site. [Brief description of the drawings]

[0124] [Figure 1] FIG. 1 is a bar graph of retraction force (gram force) as a function of time (hours) following in vivo administration to animals of compositions comprised of the test compositions as shown below: (i) IV aprepitant at a dose of 6 mg / kg administered once pre-operatively and daily for 5 days post-operatively (Group 1, hatched bars); (ii) IV aprepitant at a dose of 6 mg / kg administered once pre-operatively and daily for 5 days post-operatively with extended release formulations of bupivacaine and meloxicam administered once intraoperatively at 3.4 mL via injection into the wound margin (Group 2, dotted bars); (iii) IV aprepitant at a dose of 6 mg / kg administered once 30 minutes pre-operatively with extended release formulations of bupivacaine and meloxicam administered once intraoperatively at 2.6 mL via injection into the wound margin (Group 3, vertically lined bars).

[0125] [Diagram 2]FIG. 2 is a bar graph of retraction force (gram force) as a function of time (hours) following in vivo administration to animals of compositions comprised of the test compositions as shown: (i) IV aprepitant at a dose of 3.0 mg / kg administered once pre-operatively and daily for 5 days post-operatively with extended release formulations of bupivacaine and meloxicam administered once intraoperatively via injection into the wound margin in 3.4 mL (Group 5, hatched bars); (ii) IV aprepitant at a dose of 6.0 mg / kg administered once pre-operatively and daily for 5 days post-operatively with extended release formulations of bupivacaine administered once intraoperatively via injection into the wound margin in 3.4 mL (Group 3, dotted bars); and (iii) IV aprepitant at a dose of 6.0 mg / kg administered once pre-operatively and daily for 5 days post-operatively with extended release formulations of meloxicam administered once intraoperatively via injection into the wound margin in 3.4 mL (Group 4, vertically lined bars).

[0126] [Diagram 3]FIG. 3 is a bar graph of retraction force (gram force) as a function of time (hours) following in vivo administration to animals of compositions comprised of the test compositions as shown: (i) IV aprepitant at a dose of 1.5 mg / kg administered once pre-operatively and daily for 5 days post-operatively and extended release formulations of bupivacaine and meloxicam administered once intraoperatively in 3.4 mL by injection into the wound margin (Group 6, solid bars); (ii) IV aprepitant at a dose of 6.0 mg / kg administered once pre-operatively and 2 and 3 days post-operatively and extended release formulations of bupivacaine and meloxicam administered once intraoperatively in 3.4 mL by injection into the wound margin (Group 7, shaded bars). ), (iii) IV aprepitant at a dose of 6.0 mg / kg given once preoperatively and 3, 4, and 5 days after surgery with an extended release formulation of bupivacaine and meloxicam given once intraoperatively by injection into the wound edge in 3.4 mL (Group 8, striped bars), and (iv) oral suspension of meloxicam given once preoperatively at a dose of 0.5 mg / kg with IV aprepitant given once preoperatively and daily for 5 days after surgery with an extended release formulation of bupivacaine given once intraoperatively by injection into the wound edge in 3.4 mL (Group 9, dotted bars).

[0127] [Figure 4]FIG. 4 is a bar graph of retraction force (gram force) as a function of time (hours) following in vivo administration to animals of compositions comprised of test compositions as shown: (i) IV aprepitant at a dose of 6.0 mg / kg administered once pre-operatively and daily for 5 days post-operatively with an extended release formulation of bupivacaine and meloxicam administered once intraoperatively by injection into the wound margin in 3.4 mL (Group 2, dotted bar); (ii) IV aprepitant at a dose of 3.0 mg / kg administered once pre-operatively and daily for 5 days post-operatively with 3.4 mL administered once intraoperatively by injection into the wound margin in 3.0 mL. (iii) IV aprepitant given once preoperatively and daily for 5 days postoperatively at a dose of 1.5 mg / kg and extended release bupivacaine and meloxicam given once intraoperatively at 3.4 mL via injection into the wound margin (Group 6, horizontal bars), and (iv) extended release bupivacaine and meloxicam given once intraoperatively at 3.4 mL via injection into the wound margin (medical history data, solid bars).

[0128] [Diagram 5] FIG. 5 is a bar graph of retraction force (gram force) as a function of time (hours and days) following in vivo administration to animals of compositions comprised of the test compositions as shown below: (i) extended release formulations of bupivacaine, meloxicam, and aprepitant (high concentration) dosed once at 3.4 mL by injection into the wound edge during surgery (Group 10, hatched bars), (ii) extended release formulations of bupivacaine, meloxicam, and aprepitant dosed once at 3.4 mL by injection into the wound edge during surgery (Group 11, dotted bars), and (iii) extended release formulations of bupivacaine and meloxicam dosed once at 3.4 mL by injection into the wound edge during surgery (clinical history data, solid bars).

[0129] [Figure 6]FIG. 6 is a bar graph of retraction force (gram force) as a function of time (hours and days) following in vivo administration to animals of compositions comprised of the test compositions as indicated: (i) an extended release formulation of bupivacaine, meloxicam, and aprepitant administered once at 3.4 mL intraoperatively by injection at the wound edge (Group 12, solid bars); (ii) an extended release formulation of bupivacaine and aprepitant administered once at 3.4 mL intraoperatively by injection at the wound edge (Group 13, cross-lined bars); (iii) an extended release formulation of bupivacaine and aprepitant administered once at 3.4 mL intraoperatively by injection at the wound edge (Group 14, cross-lined bars); bupivacaine, low-concentration meloxicam, and extended-release aprepitant administered intraoperatively in a single dose of 3.4 mL (group 14, medical history data, checkered bars); (iv) extended-release aprepitant administered intraoperatively in a single dose of 3.4 mL via wound edge injection (group 15, hatched bars); and (v) extended-release meloxicam and aprepitant administered intraoperatively in a single dose of 3.4 mL via wound edge injection (group 16, dotted bars). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0130] Detailed Description Various aspects will now be described more fully hereinafter. Such aspects may be embodied in many different forms, and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey its scope to those skilled in the art.

[0131] I. Definition As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to a "polymer" includes a single polymer, as well as two or more of the same or different polymers, a reference to an "additive" includes a single additive, as well as two or more of the same or different additives, and so forth.

[0132] When a range of values ​​is provided, each intervening value between the upper and lower limits of the range, and any other values ​​stated or intervening in the stated range, are intended to be encompassed by the present disclosure.For example, when a range of 1 μm to 8 μm is stated, 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, and 7 μm, as well as ranges of values ​​higher than or equal to 1 μm, and ranges of values ​​lower than or equal to 8 μm are also intended to be expressly disclosed.As used herein, the term "about" refers to ±5%, ±10%, or ±20% of the modified value.

[0133] The term "emulsion" or "emulsion formulation" refers to a colloidal dispersion of two immiscible liquids in the form of droplets whose diameters are generally between 10 nanometers and 100 microns. If the continuous phase is an aqueous solution, the emulsion is designated by the symbol O / W (oil-in-water) and if the continuous phase is an oil, W / O (water-in-oil). Other examples of emulsions, such as O / W / O (oil-in-water-in-oil), include oil droplets contained within aqueous droplets dispersed in a continuous oil phase.

[0134] A "physically stable" emulsion is one that meets the USP universal limits for a specified storage period at 5°C or room temperature, including (1) a mean droplet size not exceeding 500 nm or 0.5 μm, and (2) a population of large diameter fat globules, expressed as a volume-weighted percentage of fat greater than 5 μm (PFAT5), not exceeding 0.05%. <729> In addition, a physically stable emulsion will have no visible NK-1 receptor antagonist crystals upon storage at 5° C. or at room temperature for the specified period of time. Crystals are considered visible when viewed under 4X to 10X magnification. An emulsion will meet the criteria set forth in the USP <729> and NK-1 receptor antagonist crystals are not visible upon storage at 5° C. or at room temperature for a period equal to or at least 1 week, 2 weeks, 4 weeks, 1 month, 2 months, 6 months, 1 year or 2 years.

[0135] A "chemically stable" emulsion of the present disclosure is one in which the concentration of the active component (i.e., the drug being delivered) does not change by more than about 20% for at least one month under appropriate storage conditions. In certain embodiments, the concentration of the NK-1 receptor antagonist in an emulsion of the present disclosure does not change by more than about 5%, 10%, 15%, or 20% for at least 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, or 24 months under appropriate storage conditions.

[0136] In one example, the stable emulsion composition of the present disclosure is stable over a wide range of temperatures, for example, from -20° C. to 40° C. The composition of the present disclosure may be stored at about 5° C. to about 25° C.

[0137] "Emulsifier" refers to a compound that prevents separation of an injectable emulsion into separate oil and water phases. Emulsifiers useful in the present disclosure are generally: (1) compatible with the other components of the stable emulsions of the present disclosure; (2) do not interfere with the stability or efficacy of the drug contained in the emulsion; (3) are stable and do not degrade in the preparation; and (4) are non-toxic.

[0138] Suitable emulsifiers include, but are not limited to, propylene glycol mono- and di-fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, polyoxyethylene-polyoxypropylene copolymers and block copolymers, salts of fatty alcohol sulfates, sorbitan fatty acid esters, esters of polyethylene-glycol glycerol ethers, oil and wax based emulsifiers, glycerol monostearate, glycerol sorbitan fatty acid esters and phospholipids.

[0139] "Phospholipid" refers to a triester of glycerol in which a secondary alcohol and one primary alcohol are esterified with a fatty acid and the other primary alcohol is esterified with a phosphate group. Exemplary phospholipids useful in the present invention include, but are not limited to, phosphatidylcholines, lecithins (a mixture of choline esters of phosphorylated diacylglycerides), phosphatidylethanolamines, phosphatidylglycerols, and phosphatidic acids, having from about 4 to about 22 carbon atoms, more commonly from about 10 to about 18 carbon atoms, and varying degrees of saturation. Phospholipids can have any combination of fatty acids as their fatty acyl side chains, for example, phospholipids can have saturated fatty acids such as decanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid, icosanoic acid (C20 saturated fatty acids); sodium behenate, or unsaturated fatty acids such as myristoleic acid, palmitoleic acid, oleic acid, sodium linoleate, alpha linolenic acid, sodium arachidonate, eicosapentanoic acid, and the like. The two fatty acyl residues on the lipid may be the same, or they may be different fatty acids.The phospholipid component of the drug delivery composition may be either a single phospholipid or a mixture of several phospholipids.The phospholipid should be acceptable for the selected administration route.

[0140] In one aspect, the phospholipid used as emulsifier in the present invention is naturally occurring phospholipid from natural origin.For example, naturally occurring lecithin is a mixture of diglycerides of stearic acid, palmitic acid and oleic acid linked to the choline ester of phosphoric acid, commonly called phosphatidylcholine, and can be obtained from various sources such as egg and soybean.Soybean lecithin and egg lecithin (including the hydrogenated versions of these compounds) have been characterized in various compositions and are generally recognized as safe, have combined emulsifying and solubilizing properties, and tend to decompose into harmless substances more quickly than most synthetic surfactants.

[0141] The term "lecithin" includes a complex mixture of acetone-insoluble phosphatides, of which phosphatidylcholine is a key component. The term lecithin is also used as a synonym for phosphatidylcholine. Useful lecithins include, but are not limited to, lecithins derived from egg yolk, egg, soybean, and corn. In some embodiments, the emulsifier is a lecithin, such as lecithin derived from egg yolk. The terms egg lecithin and lecithin derived from egg yolk are used interchangeably throughout. The compositions described herein preferably include lecithin as an emulsifier.

[0142] The amount of phospholipid in the emulsions of the present disclosure by weight can be in the range of about 10 wt / wt% to about 20 wt / wt%, 11 wt / wt% to 19 wt / wt%, 11 wt / wt% to 15 wt / wt%, 12 wt / wt% to 13 wt / wt%, 13 wt / wt% to 14 wt / wt%, 13 wt / wt% to 20 wt / wt%, or 12 wt / wt% to 18 wt / wt%. In certain embodiments, the phospholipid in the emulsion is at a concentration by weight of about 11 wt / wt%, 12 wt / wt%, 12.5 wt / wt%, 13 wt / wt%, 13.5 wt / wt%, 14 wt / wt%, 14.5 wt / wt%, or 15 wt / wt%.

[0143] "Oil" refers to an organic liquid of mineral, vegetable, animal, essential or synthetic origin that contains, for example, aliphatic or wax-based hydrocarbons, aromatic hydrocarbons, or mixed aliphatic and aromatic hydrocarbons.

[0144] The term "buffer" or "buffering" as used herein refers to a solution containing both a weak acid and its conjugate base, whose pH changes only slightly upon addition of acid or base. As used herein, the phrase "buffering agent" refers to a species whose inclusion in a solution provides a buffered solution. Buffers are well known in the art and are readily available. Buffers for use with the methods and compositions described herein include, but are not limited to, phosphate, citrate, Tris, carbonate, succinate, maleate, borate, MES, Bis-Tris, ADA, aces, PIPES, MOPSO, Bis-Tri Propane, BES, MOPS, TES, HEPES, DIPSO, MOBS, TAPSO, Trizma, HEPPSO, POPSO, TEA, EPPS, Tricine, Gly-Gly, Bicine, GEPBS, TAPS, AMPD, TABS, AMPSO, CHES, CAPSO, AMP, CAPS, and CABS.

[0145] The term "therapeutic agent" describes any natural or synthetic compound that has biological activity. A "therapeutically effective amount" means the amount that, when administered to an animal or subject for treating or preventing a disorder, condition, or disease, is sufficient to effect treatment for that disorder, condition, or disease.

[0146] The term "substantially" with respect to a particular feature or entity means to a large extent or nearly completely (i.e., to an extent of 85% or greater) with respect to the feature or entity.

[0147] "Bioerodible," "bioerodible," and "biodegradable" are used interchangeably herein and refer to the degradation, disintegration, or digestion of a polymer by the action of living organisms, most notably the action of the biological environment, including physiological pH and temperature. As an example, the primary mechanism for the bioerosion of polyorthoesters is hydrolysis of the inter- and intra-unit linkages of the polyorthoesters.

[0148] "Polymers susceptible to hydrolysis", such as polyorthoesters, refer to polymers that can be decomposed, disassembled or digested by reacting with water molecules. Such polymers contain hydrolyzable groups in the polymer. Examples of polymers susceptible to hydrolysis include, but are not limited to, the polymers described herein, as well as those described in U.S. Patent Nos. 4,079,038, 4,093,709, 4,131,648, 4,138,344, 4,180,646, 4,304,767, 4,957,998, 4,946,931, 5,968,543, 6,613,335 and 8,252,304, and U.S. Patent Application No. 2007 / 0265329, which are incorporated by reference in their entirety.

[0149] "Molecular weight" in the context of polymers such as polyorthoesters refers to the nominal average molecular weight of the polymer, typically determined by molecular sieve chromatography, light scattering techniques, or velocity. Molecular weight can be expressed as either number average molecular weight or weight average molecular weight. Unless otherwise specified, any reference to molecular weight herein refers to weight average molecular weight. Both number average and weight average molecular weight determinations can be measured using gel permeation chromatography or other liquid chromatography techniques. Other methods for measuring molecular weight values ​​can also be used, such as measuring colligative properties (e.g., freezing point depression, boiling point elevation, or osmotic pressure) to determine number average molecular weight, or using light scattering techniques, ultracentrifugation, or viscometry to determine weight average molecular weight. The polymers of the present invention are typically polydisperse (i.e., the number average molecular weight and the weight average molecular weight of the polymer are not equal) and have low polydispersity values, such as less than about 3.0, less than about 2.75, less than about 2.25, less than about 1.5, and less than about 1.03.

[0150] "Semi-solid" refers to the mechanical-physical state of a material that is flowable under moderate stress. Semi-solid materials generally have a viscosity between about 1,000 and 3,000,000 cps (mPa·s) at 37°C, particularly between about 1,000 and 50,000 cps (mPa·s) at 37°C. Viscosity may be measured using a Brookfield Viscometer DV-II Pro with a CPA-44PSYZ cup and measured at 37°C. Viscosity measurements of formulations below 8,000 cps (mPa·s) may be measured using a CPA-40Z spindle and the system may be verified using the Brookfield Viscosity Standard 1,000 cps silicone oil. Viscosity measurements of formulations above 8,000 cps (mPa·s) may be evaluated using a CPA-52Z spindle and standardized using the Brookfield Viscosity Standard 30,000 cps silicone oil.

[0151] "Active agent" or "active ingredient" refers to any compound or mixture of compounds that produces a beneficial or useful result. Active agents are distinguishable from components such as vehicles, carriers, excipients, lubricants, binders and other formulation aids, as well as components that are encapsulated or otherwise protected. Examples of active agents are pharmaceutical, agricultural or cosmetic agents.

[0152] A "small molecule" is a molecule, typically a drug, having a molecular weight below about 900 daltons.

[0153] A "local anesthetic" is a drug that produces reversible local anesthesia, generally to induce the absence of pain sensation.

[0154] "Caine" type drugs, as used herein, refer to basic amino-type local anesthetics such as bupivacaine, levobupivacaine, ropivacaine, etidocaine, lidocaine, mepivacaine, prilocaine, tetracaine, and the like.

[0155] "Pharmaceutically acceptable salt" refers to a salt form of a drug having at least one group suitable for the formation of a salt that does not cause significant adverse toxicological effects to the patient. Pharmaceutically acceptable salts include salts prepared by reaction with inorganic acids, organic acids, basic amino acids, or acidic amino acids, depending on the nature of the functional group(s) in the drug. Suitable pharmaceutically acceptable salts include acid addition salts that can be formed, for example, by mixing a solution of a basic drug with a solution of an acid capable of forming a pharmaceutically acceptable salt form of the basic drug, such as hydrochloric acid, iodic acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, sulfuric acid, and the like. Typical anions for basic drugs include chloride, sulfate, bromide, mesylate, maleate, citrate, and phosphate when they are in protonated form. Suitable pharma- ceutically acceptable salt forms are found, for example, in Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zuerich:Wiley-VCH / VHCA, 2002; PH Stahl and CG Wermuth, eds.

[0156] An "organic acid" is an organic molecule having at least one carboxylic acid group, generally with a molecular weight of less than about 300 Daltons. An organic acid can have two or more carboxylic acid groups, e.g., two, three, or four carboxylic acid groups. An organic acid can be aliphatic or aromatic and can optionally contain additional non-basic substituents, such as hydroxyl, ester, halo, etc. An aliphatic organic acid can also contain one or more unsaturated elements, e.g., double or triple bonds. Exemplary organic acids include ethanoic acid, propanoic acid, butanoic acid, pentanoic acid, benzoic acid, acetylsalicylic acid, citric acid, fumaric acid, maleic acid, salicylic acid, succinic acid, oxalic acid, malonic acid, glutaric acid, adipic acid, pimelic acid, and the like.

[0157] Molar percentage (also referred to as mol%) of an organic acid, as used herein, is relative to the molar amount of the corresponding amino-containing drug. As an example, a composition containing 100 mmol of an amino-containing drug, such as ropivacaine, and 10 mmol of an organic acid contains 10 mole percent of the organic acid.

[0158] "Compatible with polyorthoesters" refers to the property of an additive or additive substance, in one particular aspect of the properties of a polyorthoester, that when mixed with the polyorthoester, forms a single phase and does not cause any physical or chemical changes to the polyorthoester.

[0159] "Therapeutically effective amount" means the amount that, when administered to an animal for treating a disease, is sufficient to effect treatment for the disease.

[0160] "Treating" or "treatment" of a disease includes preventing the disease from occurring in an animal that may be susceptible to the disease but that has not experienced or shown symptoms of the disease (prophylactic treatment), inhibiting the disease (slowing or arresting its onset), causing relief from the symptoms or side effects of the disease (including palliative treatment), and relieving the disease (causing regression of the disease).

[0161] "Optionally" or "as needed" means that the situation described below may or may not occur, and thus the description includes cases where the situation occurs and cases where it does not occur.

[0162] The term "substantially" with respect to a particular feature or entity means to a significant degree or nearly complete (i.e., to a degree of 85% or greater) with respect to that feature or entity.

[0163] The term "about," particularly in relation to a given amount, is meant to encompass a deviation of plus or minus 5 percent.

[0164] II. Pharmaceutical Compositions Comprising an Analgesic and an NK-1 Receptor Antagonist In one embodiment, a composition is provided that includes a local anesthetic, an NK-1 receptor antagonist, and a delivery vehicle. In another embodiment, a composition is provided that includes a local anesthetic, an NK-1 receptor antagonist, an NSAID, and a delivery vehicle. In another embodiment, a composition is provided that includes an NK-1 receptor antagonist, an NSAID, and a delivery vehicle.

[0165] A. Local anesthetics The composition includes a caine-type local anesthetic. Local anesthetics belonging to this class include bupivacaine, levobupivacaine, dibucaine, mepivacaine, procaine, lidocaine, tetracaine, ropivacaine, etc. These compounds are alkali-amides with pKb values ​​ranging from 5.8 to 6.4. That is, the drugs contain a protonatable tertiary amine functional group. For example, the pKa values ​​of ropivacaine, lidocaine, and bupivacaine are 8.1, 7.7, and 8.1, respectively. The amide-type drugs are provided in the composition either in their neutral, basic form, or as their corresponding acid addition salts, or as a mixture of both forms.

[0166] In one embodiment, the caine-type local anesthetic is added to the composition in its free base form. The caine-type anesthetic can be provided as a racemic mixture, i.e., containing equal amounts of R and S enantiomers, or as a single enantiomer, or as an unequal mixture of enantiomers, with one enantiomer being present in excess.

[0167] In one particular embodiment, the composition comprises bupivacaine as the local anesthetic, hi a further embodiment, the composition comprises ropivacaine as the active agent.

[0168] In yet one or more further embodiments, the composition comprises any one or more of the foregoing caine-type local anesthetics, such as, for example, levobupivacaine, dibucaine, mepivacaine, procaine, lidocaine, tetracaine, etc. In yet another embodiment, the amide-type local anesthetic is selected from the group consisting of bupivacaine, ropivacaine, levobupivacaine, dibucaine, mepivacaine, procaine, lidocaine, and tetracaine.

[0169] The compositions may also include one or more additional active agents in addition to the kine-type local anesthetic and NK-1 receptor antagonist (described below).

[0170] The caine-type local anesthetic is dissolved or dispersed in a composition as provided herein. The concentration of the caine-type local anesthetic in the composition is about 0.1 wt% to 1 wt%, 0.1 wt% to 10 wt%, 0.25 wt% to 0.75 wt%, 0.25 wt% to 2.5 wt%, 0.25 wt% to 3.5 wt%, 0.25 wt% to 5 wt%, 1.5 wt% to 5 wt%, 1.5 wt% to 3.5 wt%, 1.5 wt% to 3.0 wt%, 2 wt% to 3 wt%, 2.1 wt% to 2.9 wt%, 2.2 wt% to 2.8 wt%, 2.3 wt% to 2.7 wt%, 2.4 wt% to 2.6 wt%, 2.25 wt% to 2.75 wt%, 1 wt% to 30 wt%, Can vary from 1wt%~10wt%, 10wt%~20wt%, 1wt%~5wt%, 2wt%~5wt%, 2wt%~4wt%, 2wt%~3wt%, 10wt%~15wt%, or 15wt%~20wt%, and can be about 0.25wt%, 0.5wt%, 0.751wt%, 1.1wt%, 1.2wt%, 1.3wt%, 1.4wt%, 1.5wt%, 1.6wt%, 1.7wt%, 1.8wt%, 1.9wt%, 2wt%, 2.1wt%, 2.2w%, 2.3w%, 2.4w%, 2.5w%, 2.6w%, 2.7wt %, 2.8wt%, 2.9wt%, 3wt%, 3.1wt%, 3.2wt%, 3.3wt%, 3.4wt%, 3.5wt%, 3.6 wt%, 3.7wt%, 3.8wt%, 3.9wt%, 4wt%, 4.1wt%, 4.2wt%, 4.3wt%, 4.4wt%, 4. 5wt%, 4.6wt%, 4.7wt%, 4.8wt%, 4.9wt%, 5wt%, 5wt%, 5.1wt%, 5.2wt%, 5.3 wt%, 5.4wt%, 5.5wt%, 5.6wt%, 5.7wt%, 5.8wt%, 5.9wt%, 6wt%, 6.1wt%, 6. 2wt%, 6.3wt%, 6.4wt%, 6.5wt%, 6.6wt%, 6.7wt%, 6.8wt%, 6.9wt%, 7wt%, 7.1wt%, 7.2wt%, 7.3wt%, 7.4wt%, 7.5wt%, 7.6wt%, 7.7wt%, 7.8wt%, 7.9w t%, 8wt%, 8.1wt%, 8.2wt%, 8.3wt%, 8.4wt%, 8.5wt%, 8.6wt%, 8.7wt%, 8.8 wt%, 8.9wt%, 9wt%, 9.1wt%, 9.2wt%, 9.3wt%, 9.4wt%, 9.5wt%, 9.6wt%, 9.7wt%, 9.8wt%, 9.9wt%, 10wt%, 11wt%, 11.1wt%, 11.2wt%, 11.3wt%, 11.4wt%, 11.5wt%, 11.6wt%, 11.7wt%, 11.8wt%, 11.9w t%, 12wt%, 12.1wt%, 12.2wt%, 12.3wt%, 12.4wt%, 12.5wt%, 12.6wt%, 12.7wt%, 12.8wt%, 12.9wt%, 13wt%, 13.1wt%, 13.2wt %, 13.3wt%, 13.4wt%, 13.5wt%, 13.6wt%, 13.7wt%, 13.8wt%, 13.9wt%, 14wt%, 14.1wt%, 14.2wt%, 14.3wt%, 14.4wt%, 14.5w t%, 14.6wt%, 14.7wt%, 14.8wt%, 14.9wt%, 15wt%, 15wt%, 15.1wt%, 15.2wt%, 15.3wt%, 15.4wt%, 5.5wt%, 15.6wt%, 15.7wt% , 15.8wt%, 15.9wt%, 16wt%, 16.1wt%, 16.2wt%, 16.3wt%, 16.4wt%, 16.5wt%, 16.6wt%, 16.7wt%, 16.8wt%, 16.9wt%, 17wt% , 17.1wt%, 17.2wt%, 17.3wt%, 17.4wt%, 17.5wt%, 17.6wt%, 17.7wt%, 17.8wt%, 17.9wt%, 18wt%, 18.1wt%, 18.2wt%, 18.3wt %, 18.4wt%, 18.5wt%, 18.6wt%, 18.7wt%, 18.8wt%, 18.9wt%, 19wt%, 19.1wt%, 19.2wt%, 19.3wt%, 19.4wt%, 19.5wt%, 19.6wt%, 19.7wt%, 19.8wt%, 19.9wt%, 20wt%, 21wt%, 22wt%, 23wt%, 24wt%, 25wt%, 26wt%, 27wt%, 28wt%, 29wt% and 30wt%.

[0171] In one embodiment, the caine-type local anesthetic is present in the composition at between about 0.01 wt% and about 7.5 wt%. In another embodiment, the caine-type local anesthetic is present in the composition at between about 0.1 wt% and about 7.5 wt%, or between about 0.1 wt% and about 5.5 wt%, or between about 0.25 wt% and about 5.2 wt%, or between about 0.25 wt% and about 5.0 wt%.

[0172] B. NK-1 Receptor Antagonists and NSAIDs Suitable NK-1 receptor antagonists for use in the pharmaceutical compositions described herein include RP67580 ((3aR,7aR)-octahydro-2-[1-imino-2-(2-methoxyphenyl)ethyl]-7,7-diphenyl-4H-isoindole)), WIN51078 (17-β-hydroxy-17-α-ethynyl-5-α-androstano[3,2-b]pyrimido[1,2-a]benzimidazole), 1-733,060 ((2S,3S)-3-[[3,5-bis(trisfluoromethyl)phenyl]methoxy]-2-phenylpiperidine hydrochloride), 1-703,606 (cis-2-(diphenylmethel)-N-([2-iodo (R)-1-[2-[3-(3,4-dichlorophenyl)-1-(3,4,5-trimethoxybenzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenylpiperidine-4-carboxamide hydrochloride), serlopitant, maropitant, antagonist D, aprepitant, fosaprepitant, R116301, CGP49823, CP-96345, CP-99994, GR-203040, MDL-103392, l-760735, SDZ-NKT-343, nolpitanitium (SR-140333), AV608, rolapitant , SCH900978, AV608, GSK424887 (GlaxoSmithKline), GSK206136 (GlaxoSmithKline), GR-205171, CP-99994, TAK637 ((S)-7-(3,5-bis-trifluoromethyl-benzyl)-9-methyl-5-p-tolyl-8,9,10,11-tetrahydro-7H-1,7,11a-triaza-cycloocta[b]naphthalene-6,12-dione), LY303870 ([(R)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4-(piperidin-1-yl)piperidin-1-yl)acetyl)amino]propane]), LY68 6017 ((2-chloro-phenyl)-{2-[5-pyridin-4-yl-1-(3,5-bistrifluoromethyl-benzyl)-1H-[1,2,3]triazol-4-yl]-pyridin-3-yl}-methanone), E-6006, casopitant / GW679769 ((2R,4S)-4-(4-acetylpiperazin-1-yl)-N-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]-2-(4-fluoro-2-methylphenyl)-N-methylpiperidine-1-carboxamide), vestipitant, orbepitant and orbepitant maleate, befetupitant, netupitant, ezlopitant, CP-122721, MPC-4505 (Myriad Genetics, Inc.), CP-122721 (Pfizer, Inc.), CJ-12,255 (Pfizer, Inc.), SRR240600 (Sanofi-Aventis), or TA-5538 (Tanabe Seiyaku Co.) (including all pharma- ceutical acceptable salts thereof).

[0173] In some embodiments, the NK-1 receptor antagonist is selected from aprepitant, rolapitant, netupitant, lanepitant, vestipitant, orbepitant maleate, casopitant, ezlopitant, serlopitant, befetupitant and maropitant, or a pharmaceutically acceptable salt thereof. In one embodiment, the NK-1 receptor antagonist is aprepitant.

[0174] The NK-1 receptor antagonist is dissolved or dispersed in the composition, as provided herein. The concentration of the NK-1 receptor antagonist in the composition is about 0.01 wt% to 1 wt%, 0.01 wt% to 5 wt%, 0.01 wt% to 10 wt%, 0.1 wt% to 1 wt%, 0.1 wt% to 2.5 wt%, 0.1 wt% to 5 wt%, 0.2 wt% to 1 wt%, 0.2 wt% to 2 wt%, 0.2 wt% to 3.5 wt%, 0.2 wt% to 5 wt%, 2.1 wt% to 2.9 wt%, 2.2 wt% to 2.8 wt%, 2.3 wt% to 2.7 wt%, 2.4 wt% to 2.6 wt%, 2.25 wt% to 2.75 wt%, 1 wt% to 30 wt%, It can vary from 1wt%~10wt%, 10wt%~20wt%, 1wt%~5wt%, 2wt%~5wt%, 2wt%~4wt%, 2wt%~3wt%, 10wt%~15wt%, or 15wt%~20wt%, and can be about 0.01wt%, 0.02wt%, 0.03wt%, 0.04wt%, 0.05wt%, 0.06wt%, 0.07wt%, 0.08wt%, 0.09wt%, 0.1wt%, 0.1wt%0.2wt%, 0.3wt%, 0.4wt%, 0.5w%, 0.6w%, 0.7w%, 0.8w%, 0.9 wt%, 1wt%, 1.1wt%, 1.2wt%, 1.3wt%, 1.4wt%, 1.5wt%, 1.6wt%, 1.7wt%, 1 .8wt%, 1.9wt%, 2wt%, 2.1wt%, 2.2wt%, 2.3wt%, 2.4wt%, 2.5wt%, 2.6wt% , 2.7wt%, 2.8wt%, 2.9wt%, 3wt%, 3.1wt%, 3.2wt%, 3.3wt%, 3.4wt%, 3.5w t%, 3.6wt%, 3.7wt%, 3.8wt%, 3.9wt%, 4wt%, 4.1wt%, 4.2wt%, 4.3wt%, 4.4 wt%, 4.5wt%, 4.6wt%, 4.7wt%, 4.8wt%, 4.9wt%, 5wt%, 5.1wt%, 5.2wt%, 5 .3wt%, 5.4wt%, 5.5wt%, 5.6wt%, 5.7wt%, 5.8wt%, 5.9wt%, 6wt%, 6.1wt%, 6.2wt%, 6.3wt%, 6.4wt%, 6.5wt%, 6.6wt%, 6.7wt%, 6.8wt%, 6.9wt%, 7wt %, 7.1wt%, 7.2wt%, 7.3wt%, 7.4wt%, 7.5wt%, 7.6wt%, 7.7wt%, 7.8wt%, 7.It may be 9wt%, 8wt%, 8.1wt%, 8.2wt%, 8.3wt%, 8.4wt%, 8.5wt%, 8.6wt%, 8.7wt%, 8.8wt%, 8.9wt%, 9wt%, 9.1wt%, 9.2wt%, 9.3wt%, 9.4wt%, 9.5wt%, 9.6wt%, 9.7wt%, 9.8wt%, 9.9wt%, or 10wt%.

[0175] In one embodiment, the NK-1 receptor antagonist is present in the composition in an amount of greater than 0.001 percent, less than 5 wt%, less than 2.5 wt%, less than 1 wt%, less than 0.5 wt%, or less than 0.3 wt%.

[0176] In one embodiment, the composition comprises a kine-type local anesthetic and an NK-1 receptor antagonist, wherein the weight ratio of local anesthetic:NK-1 receptor antagonist is about 100:1 to 1:1, 100:1 to 2.5:1, 100:1 to 7.5:1, 100:1 to 10:1, 100:1 to 1:100, 75:1 to 1:1, 75:1 to 2.5:1, 75:1 to 7.5:1, 75:1 to 10: 1, 75:1 to 1:75, 50:1 to 1:1, 50:1 to 2.5:1, 50:1 to 7.5:1, 50:1 to 10:1, 50:1 to 1:50, 25:1 to 1:1, 25:1 to 2.5:1, 25:1 to 7.5:1, 25:1 to 10:1, 25:1 to 1:25, 10:1 to 1:1, 10:1 to 2.5:1, 10:1 to 7.5:1, 10:1 to 10:1, 10:1 to 1:10. In certain embodiments, the caine-type local anesthetic is bupivacaine and the NK-1 receptor antagonist is aprepitant. In alternative certain embodiments, the amide-type local anesthetic is ropivacaine and the NK-1 receptor antagonist is aprepitant.

[0177] The NSAID is selected from the group consisting of diflusanil, indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, nabumetone, ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, meloxicam, piroxicam, tenoxicam, droxicam, lornoxicam, isoxicam, celecoxib, rofecoxib, and valdecoxib. In some embodiments, the NSAID is meloxicam.

[0178] The concentration of the NSAID in the composition can vary from about 0.01 wt% to 10 wt%, 0.01 wt% to 5 wt%, 0.01 wt% to 3 wt%, 0.01 wt% to 1 wt%, 0.10 wt% to 10 wt%, 0.1 wt% to 5 wt%, 0.1 wt% to 3 wt%, 0.1 wt% to 1 wt%, 0.01 wt%, 0.011 wt%, 0.012 wt%, 0.013 wt%, 0.014 wt%, 0.015 wt%, 0.016 wt%, 0.017 wt%, 0.018 wt%, 0.019 wt%, 0.02 wt%, 0.021 wt%, 0.022 wt%, 0.023 wt%, 0.024 wt%, 0.025 wt%, 0.026 wt%, 0.027 wt%, 0.028 wt%, 0.029 wt%, 0.030 wt%, 0.031 wt%, 0.032 wt%, 0.033 wt%, 0.034 wt%, 0.035 wt%, 0.036 wt%, 0.037 wt%, 0.038 wt%, 0.039 wt%, 0.040 wt%, 0.041 wt%, 0.042 wt%, 0.043 wt%, 0.044 wt%, 0.045 wt%, 0.046 wt%, 0.047 wt%, 0.048 wt%, 0.049 wt%, 0.050 wt%, 0.051 wt%, 0.052 wt%, t%, 0.024wt%, 0.025wt%, 0.026wt%, 0.027wt%, 0.028wt%, 0.029wt%, 0.030 wt%, 0.031wt%, 0.032wt%, 0.033wt%, 0.034wt%, 0.035wt%, 0.036wt%, 0.03 7wt%, 0.038wt%, 0.039wt%, 0.040wt%, 0.041wt%, 0.042wt%, 0.043wt%, 0.0 44wt%, 0.045wt%, 0.046wt%, 0.047wt%, 0.048wt%, 0.049wt%, 0.05wt%, 0.05 1wt%, 0.052wt%, 0.053wt%, 0.054wt%, 0.055wt%, 0.056wt%, 0.057wt%, 0.0 58wt%, 0.059wt%, 0.06wt%, 0.061wt%, 0.062wt%, 0.063wt%, 0.064wt%, 0.0 65wt%, 0.066wt%, 0.067wt%, 0.068wt%, 0.069wt%, 0.07wt%, 0.071wt%, 0.0 72wt%, 0.073wt%, 0.074wt%, 0.075wt%, 0.076wt%, 0.077wt%, 0.078wt%, 0.0 79wt%, 0.08wt%, 0.081wt%, 0.082wt%, 0.083wt%, 0.084wt%, 0.085wt%, 0.0 86wt%, 0.087wt%, 0.088wt%, 0.089wt%, 0.09wt%, 0.091wt%, 0.092wt%, 0.0 93wt%, 0.094wt%, 0.095wt%, 0.096wt%, 0.097wt%, 0.098wt%, 0.099wt%, 0. 1wt%, 0.11wt%, 0.12wt%, 0.13wt%, 0.14wt%, 0.15wt%, 0.16wt%, 0.17wt%, 0.<h2 style=";text-align:left;direction:ltr">18wt%, 0.19wt%, 0.2wt%, 0.21wt%, 0.22wt%, 0.23wt%, 0.24wt%, 0.25wt%, 0.26wt%, 0.27wt%, 0.28wt%, 0.29wt%, 0.30wt%, 0.31wt%, 0.32wt%, 0.33wt% 0.34wt%、0.35wt%、0.36wt%、0.37wt%、0.38wt%、0.39wt%、0.40wt%、0.41wt %、0.42wt%、0.43wt%、0.44wt%、0.45wt%、0.46wt%、0.47wt%、0.48wt%、0.49w t%、0.5wt%、0.5.1wt%、0.52wt%、0.53wt%、0.54wt%、0.55wt%、0.56wt%、0.5 7wt%、0.58wt%、0.59wt%、0.6wt%、0.61wt%、0.62wt%、0.63wt%、0.64wt%、0.6 5wt%, 0.66wt%, 0.67wt%, 0.68wt%, 0.69wt%, 0.7wt%, 0.71wt%, 0.72wt%, 0.73wt%, 0.74wt%, 0.75wt%, 0.76wt%, 0.77wt%, 0.78wt%, 0.79wt%, 0.8wt%, 0. 81wt%, 0.82wt%, 0.83wt%, 0.84wt%, 0.85wt%, 0.86wt%, 0.87wt%, 0.88wt%, 0.89wt%, 0.9wt%, 0.91wt%, 0.92wt%, 0.93wt%, 0.94wt%, 0.95wt%, 0.96wt% 0.97wt%、0.98wt%、0.99wt%、1.0wt%、1.01wt%、1.02wt%、1.03wt%、1.04wt% 、1.05wt%、1.06wt%、1.07wt%、1.08wt%、1.09wt%、1.1wt%、1.11wt%、1.12wt% 、1.13wt%、1.14wt%、1.15wt%、1.16wt%、1.17wt%、1.18wt%、1.19wt%、1.2wt %、1.21wt%、1.22wt%、1.23wt%、1.24wt%、1.25wt%、1.26wt%、1.27wt%、1.28w t%、1.29wt%、1.30wt%、1.31wt%、1.32wt%、1.33wt%、1.34wt%、1.35wt%、1.3 6wt%、1.37wt%、1.38wt%、1.39wt%、1.40wt%、1.41wt%、1.42wt%、1.43wt%、1.<h2 style=";text-align:left;direction:ltr">44wt%、1.45wt%、1.46wt%、1.47wt%、1.48wt%、1.49wt%、1.5wt%、1.5.1wt%、 1.52wt%、1.53wt%、1.54wt%、1.55wt%、1.56wt%、1.57wt%、1.58wt%、1.59wt %, 1.6wt%, 1.61wt%, 1.62wt%, 1.63wt%, 1.64wt%, 1.65wt%, 1.66wt%, 1.67wt%, 1.68wt%, 1.69wt%, 1.7wt%, 1.71wt%, 1.72wt%, 1.73wt%, 1.74wt%, 1.75 wt%、1.76wt%、1.77wt%、1.78wt%、1.79wt%、1.8wt%、1.81wt%、1.82wt%、1.8 3wt%、1.84wt%、1.85wt%、1.86wt%、1.87wt%、1.88wt%、1.89wt%、1.9wt%、1. 91wt%, 1.92wt%, 1.93wt%, 1.94wt%, 1.95wt%, 1.96wt%, 1.97wt%, 1.98wt%, 1.99wt%, 2.00wt%, 2.01wt%, 2.02wt%, 2.03wt%, 2.04wt%, 2.05wt%, 2.06wt% 、2.07wt%、2.08wt%、2.09wt%、2.1wt%、2.11wt%、2.12wt%、2.13wt%、2.14wt %、2.15wt%、2.16wt%、2.17wt%、2.18wt%、2.19wt%、2.20wt%、2.21wt%、2.22 wt%、2.23wt%、2.24wt%、2.25wt%、2.26wt%、2.27wt%、2.28wt%、2.29wt%、2. 30wt%、2.31wt%、2.32wt%、2.33wt%、2.34wt%、2.35wt%、2.36wt%、2.37wt%、 2.38wt%、2.39wt%、2.40wt%、2.41wt%、2.42wt%、2.43wt%、2.44wt%、2.45wt %、2.46wt%、2.47wt%、2.48wt%、2.49wt%、2.5wt%、2.5.1wt%、2.52wt%、2.53 wt%、2.54wt%、2.55wt%、2.56wt%、2.57wt%、2.58wt%、2.59wt%、2.6wt%、2.6 1wt%、2.62wt%、2.63wt%、2.64wt%、2.65wt%、2.66wt%、2.67wt%、2.68wt%、2.<h2 style=";text-align:left;direction:ltr">69wt%, 2.7wt%, 2.71wt%, 2.72wt%, 2.73wt%, 2.74wt%, 2.75wt%, 2.76wt%, 2.77wt%, 2.78wt%, 2.79wt%, 2.8wt%, 2.81wt%, 2.82wt%, 2.83wt%, 2.84wt% 2.85wt%, 2.86wt%, 2.87wt%, 2.88wt%, 2.89wt%, 2.9wt%, 2.91wt%, 2.92wt%, 2.93wt%, 2.94wt%, 2.95wt%, 2.96wt%, 2.97wt%, 2.98wt%, 2.99wt%, 3.0wt% 、3.01wt%、3.02wt%、3.03wt%、3.04wt%、3.05wt%、3.06wt%、3.07wt%、3.08w t%、3.09wt%、3.1wt%、3.11wt%、3.12wt%、3.13wt%、3.14wt%、3.15wt%、3.16w t%、3.17wt%、3.18wt%、3.19wt%、3.20wt%、3.21wt%、3.22wt%、3.23wt%、3.2 4wt%、3.25wt%、3.26wt%、3.27wt%、3.28wt%、3.29wt%、3.30wt%、3.31wt%、3. 32wt%, 3.33wt%, 3.34wt%, 3.35wt%, 3.36wt%, 3.37wt%, 3.38wt%, 3.39wt%, 3.40wt%, 3.41wt%, 3.42wt%, 3.43wt%, 3.44wt%, 3.45wt%, 3.46wt%, 3.47wt% 、3.48wt%、3.49wt%、3.5wt%、3.5.1wt%、3.52wt%、3.53wt%、3.54wt%、3.55w t%、3.56wt%、3.57wt%、3.58wt%、3.59wt%、3.6wt%、3.61wt%、3.62wt%、3.63w t%、3.64wt%、3.65wt%、3.66wt%、3.67wt%、3.68wt%、3.69wt%、3.7wt%、3.71 wt%、3.72wt%、3.73wt%、3.74wt%、3.75wt%、3.76wt%、3.77wt%、3.78wt%、3.7 9wt%, 3.8wt%, 3.81wt%, 3.82wt%, 3.83wt%, 3.84wt%, 3.85wt%, 3.86wt%, 3.87wt%, 3.88wt%, 3.89wt%, 3.9wt%, 3.91wt%, 3.92wt%, 3.93wt%, 3.94wt%, 3.95wt%, 3.96wt%, 3.97wt%, 3.98wt%, 3.99wt%, 4.0wt%, 4.25wt%, 4.5wt%, 4.75wt%, 5.0wt%, 5.25wt%, 5.5wt%, 5.75wt%, 6.0wt%, 6.25wt%, 6.5wt%, 6.75wt%, 7.0wt%, 7.25wt%, 7.5wt%, 7.75wt%, 8.0wt%, 8.25wt%, 8.5wt%, 8.75wt%, 9.0wt%, 9.25wt%, 9.5wt%, 9.75wt%, or 10.0wt%.

[0179] C. Delivery Vehicles The composition further comprises a delivery vehicle. In one embodiment, the delivery vehicle is a sustained release vehicle, and exemplary vehicles include polymeric formulations, liposomes, microspheres, implantable devices, or non-polymeric formulations. Examples of these vehicles are described herein.

[0180] 1. Liposomes Liposomes are vesicles composed of lipids arranged in a spherical bilayer. Liposomes are usually classified as small unilamellar vesicles (SUVs), large unilamellar vesicles (LUVs), multilamellar vesicles (MLVs) or multivesicular liposomes (MVLs). By definition, SUVs and LUVs have only one bilayer, whereas MLVs contain multiple concentric bilayers (see, e.g., Stryer, Biochemistry, 2nd ed., WH Freeman & Co., p. 213 (1981)). MVLs were first reported by Kim et al. (Biochim, Biophys. Acta, 728:339-348, 1983) and contain multiple non-concentric aqueous chambers per particle (see U.S. Pat. Nos. 6,132,766 and 8,182,835, which are incorporated by reference in their entireties).

[0181] Liposomes suitable for use in the composition of the present invention include liposomes that are mainly composed of vesicle-forming lipids.Vesicle-forming lipids can spontaneously form bilayer vesicles in water, as exemplified by phospholipids.Liposomes can also include other lipids incorporated in lipid bilayers, such as cholesterol, with hydrophobic parts in contact with the interior, hydrophobic regions of the bilayer membrane, and head parts that are oriented toward the outer polar surface of the bilayer membrane.

[0182] Vesicle-forming lipids can have two hydrocarbon chains, typically acyl chains, and either polar or non-polar heads. There are a variety of vesicle-forming synthetic lipids and vesicle-forming naturally occurring lipids, including phospholipids such as phosphatidylcholine, phosphatidylethanolamine, phosphatidic acid, phosphatidylinositol, and sphingomyelin, whose two hydrocarbon chains are typically between about 14 and 22 carbon atoms in length and have various degrees of unsaturation. The aforementioned lipids and phospholipids, whose acyl chains have various degrees of saturation, can be obtained commercially or prepared according to published methods. Other suitable lipids include glycolipids and sterols, such as cholesterol.

[0183] In one embodiment, the lipids forming the vesicles are selected to achieve a specified degree of fluidity or rigidity, to control the stability of the liposomes in serum, and to control the release rate of the drug encapsulated in the liposomes. Liposomes can be prepared by a variety of techniques (e.g., Szoka, F., Jr. et al., Ann. Rev. Biophys. Bioeng. 9:467 (1999)). (See U.S. Pat. No. 5,631,018, 1980). It will be understood that lipid-based delivery vehicles other than liposomes, such as micelles and emulsions, are also contemplated.

[0184] In one embodiment, the amide-type local anesthetic and the enolic acid NSAID are encapsulated in the aqueous space of the liposome or in the lipid layer of the liposome.

[0185] 2. Microspheres / Microparticles / Microcapsules In another embodiment, the delivery vehicle is a microsphere, microparticle or microcapsule. Microspheres in the form of a spherical polymer matrix with interconnected pores in which the active agent is incorporated are described, for example, in U.S. Pat. No. 4,818,542. The microparticles composed of one or more polymers in which the active agent is incorporated or associated can be made of biodegradable or non-biodegradable polymers, such as poly(vinylpyrrolidone) and poly(acrylamide), suitable for in vivo use. The microspheres or microparticles can be administered as part of a formulation that forms a depot in situ or as part of an implant. The active agent is released in a controlled manner from the microspheres or microparticles to provide the desired therapeutic efficacy. In one embodiment, the sustained release delivery vehicle is a microsphere composed of a biodegradable or biodegradable polymer. In another embodiment, the amide-type local anesthetic and the enolic acid NSAID are encapsulated in the microspheres.

[0186] 3. Embedded Devices Implantable devices having reservoirs that contain and controllably release active agents are known in the medical field.In one embodiment, osmotic, mechanical, or electromechanical devices are provided for implanting and sustained release of active agents.Examples of implantable devices are described in U.S. Patent Nos. 7,655,254, 8,603,051 and 8,603,076, and U.S. Patent Application Publication No. 2003 / 0032947.

[0187] 4. Non-polymeric formulations The delivery vehicle can also take the form of a pharma- ceutically acceptable non-polymeric carrier. For example, the non-polymeric formulation can include sucrose isobutyl acetate as a pharma- ceutically acceptable non-polymeric carrier, and an optional solvent, such as benzyl alcohol. The non-polymeric formulation can be liquid. The liquid non-polymeric formulation provides sustained local anesthesia to the subject for a period of about 24-36 hours, 36-48 hours, 48-60 hours, 60-72 hours, 3-4 days, or 3-5 days after administration. In one embodiment, the delivery vehicle is composed of between about 50-80 wt% sucrose isobutyl acetate and between about 5-25 wt% benzyl alcohol, or between 55-75 wt% sucrose isobutyl acetate and between about 15-25 wt% benzyl alcohol, with the remainder to 100 wt% being the active agent. Exemplary non-polymeric formulations of this type are described in EP 1809329, which is incorporated herein by reference in its entirety.

[0188] In some embodiments, the liquid non-polymeric carrier is a liquid carrier material having a viscosity of less than about 50,000 mPa·s at 37° C., as measured using a viscometer. Alternatively, the carrier has a viscosity of less than about 10,000 mPa·s, as measured using a viscometer at 37° C. In another embodiment, the liquid non-polymeric carrier is a liquid carrier material having a viscosity of less than about 5,000 mPa·s at 37° C. In yet another embodiment, the liquid non-polymeric carrier is a liquid carrier material having a viscosity of less than about 2,500 mPa·s at 37° C.

[0189] In another embodiment, the non-polymeric formulation is an aqueous solution.

[0190] 5. Polymer Formulations Exemplary polymer formulations as sustained release delivery vehicles include those comprised of biodegradable or biodegradable polymers. When comprised of biodegradable or biodegradable polymers, the vehicle may be a solid or semi-solid vehicle. Biodegradable and / or biodegradable polymers are known in the art, including, but not limited to, polylactides, polyglycolides, poly(lactic-co-glycolic acid) copolymers, polycaprolactones, poly-3-hydroxybutyrates, and polyorthoesters. Semi-solid polymers exist in either a glassy state or a viscous liquid state. Semi-solid polymers typically exhibit a glass transition temperature (Tg) below room temperature. Below the Tg, the semi-solid polymers can be considered to exist in a glassy state, and above the Tg, the polyorthoesters can be considered to exist in a liquid state. Semi-solid polyorthoester polymers are not thermoplastic polymers.

[0191] In one embodiment, the biodegradable or biodegradable polymer is selected to provide a certain degradation or erosion rate to achieve the desired release rate of the enolic acid type NSAID and the amide or anilide type anesthetic. The delivery vehicle and the active agent can be formulated to provide a semi-solid or solid composition. For example, in one embodiment, a semi-solid delivery vehicle composed of a polyorthoester is provided, some examples of which are described herein. In another embodiment, the delivery polymer vehicle forms an implant or depot in situ.

[0192] In another embodiment, a solid delivery vehicle composed of a biodegradable or bioerodible polymer is provided, where the solid vehicle is in the form of a rod or disk. The rods and disks are suitable for implantation into a patient, and the biodegradable or bioerodible polymers in which the active agent is incorporated can be formulated to tailor the release of the active agent. For example, the rods or disks can be formulated from different polymers with different biodegradation rates, or different molecular weight polymers can be used, and additional substances or additives can be added to the active agent-polymer matrix to tailor the drug release rate. The rods or disks can also comprise materials commonly used and / or usable in sutures, including the biodegradable polymers mentioned above, as well as polyglactin and copolymers of glycolide and trimethylene carbonate (TMC) (polyglyconates).

[0193] In one embodiment, the delivery vehicle is composed of a polyorthoester.

[0194] The polyorthoesters useful in the compositions provided herein are generally composed of alternating residues resulting from the reaction of diketene acetals and diols, where each adjacent pair of residues derived from diketene acetals is separated by the residue of the reacted diol. The polyorthoesters can include α-hydroxy acid-containing moieties, i.e., moieties derived from α-hydroxy acids or their cyclic diesters, such as glycolide, lactide, or combinations thereof, i.e., poly(lactide-co-glycolide) containing any ratio of lactide to glycolide, e.g., 75:25, 65:35, 50:50, etc. Such moieties are also referred to as latent acid moieties, and these latent acid moieties, as used herein, also fall under the more general "diol" classification due to their terminal hydroxyl groups. The polyorthoesters can be prepared, for example, as described in U.S. Pat. Nos. 4,549,010 and 5,968,543. Exemplary polyorthoesters suitable for use in the compositions provided herein are described in U.S. Pat. No. 8,252,304.

[0195] α-Hydroxy acid-containing subunit R 1 The molar percentage of is generally in the range of 0 to 20 mol % of the total diol constituents (R 1 and R 3(provided below). In one or more embodiments, the molar percentage of alpha-hydroxy acid containing moieties in the polyorthoester formulation is at least about 0.01 molar percent. Exemplary percentages of alpha-hydroxy acid containing moieties in the polymer are from about 0 to about 50 molar percent, or from about 0 to about 25 molar percent, or from about 0.05 to about 30 molar percent, or from about 0.1 to about 25 molar percent. For example, in one embodiment, the percentage of alpha-hydroxy acid containing moieties in the polymer is from about 0 to about 50 molar percent. In another embodiment, the percentage of alpha-hydroxy acid containing moieties in the polymer is from about 0 to about 30 molar percent. In yet another particular embodiment, the percentage of alpha-hydroxy acid containing moieties in the polymer is from about 0.05 to about 25 molar percent. In yet another embodiment, the percentage of alpha-hydroxy acid containing moieties in the polymer is about 0.1 to about 25 mole percent, about 0.1 to about 50 mole percent, about 10 to about 40 mole percent, about 5 to about 25 mole percent, about 10 to about 25 mole percent, or about 15 to about 25 mole percent. By way of example, the percentage of alpha-hydroxy acid containing moieties can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 24, 26, 27, 28, 29, or 30 mole percent, including any and all ranges formed by the combination of any one of the lower and any higher mole percentage values ​​therebetween. In one embodiment, the percentage of alpha-hydroxy acid containing moieties is less than 40 mole percent or less than 30 mole percent.

[0196] More specifically, the poly(ortho esters) for use in the compositions and delivery systems provided herein are described by the formula: [ka] In the formula, R * is C 1~4alkyl (e.g., C1, C2, C3 or C4 alkyl), n is an integer ranging from 5 to 400, and A in each subunit is R 1 or R 3 That is, any monomer unit of the polymer of formula I [ka] In the above, A is R 1 or R 3 It can be either of the following.

[0197] In certain embodiments, R * is ethyl (i.e., C alkyl). * is ethyl) is a diol provided herein and a moiety of the structure [ka] This corresponds to the partial unit obtained from the reaction of 3,9-di(ethylidene)-2,4,8,10-tetraoxaspiro[5.5]undecane (DETOSU), a diketene acetal having the formula:

[0198] With reference to formula I, as previously described, A is R 1 It can be equivalent to R 1 teeth, [ka] and p and q are each independently an integer ranging from about 1 to 20 (e.g., each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20), and each R 5 are independently hydrogen or C 1~4 alkyl (e.g., H, or C1, C2, C3 or C4 alkyl), R 6 teeth, [ka] where s is an integer from 0 to 10 (e.g., selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10), t is an integer from 2 to 30, and R 7 is hydrogen or C 1~4 is alkyl (e.g., H, or C1, C2, C3, or C4 alkyl). In one or more particular embodiments, R 7 is H. 1 The subunits are alpha-hydroxy acid containing subunits, ie subunits derived from alpha-hydroxy acids or cyclic diesters thereof.

[0199] With reference to formula I, A can also be R 3 It can be equivalent to R 3 teeth, [ka] where x is an integer ranging from 1 to 100, and in certain specific cases is selected from 1, 2, 3, 4, and 5; y is an integer ranging from 2 to 30; R 8 is hydrogen or C 1~4 It is alkyl (C1, C2, C3 or C4 alkyl).

[0200] In certain embodiments, R 8 is H.

[0201] In some embodiments, the poly(ortho ester) is a poly(ortho ester) in which A is R 1 or R 3 and R 1 but, [ka] p and q are each independently an integer ranging from about 1 to 20; R 1is present in the poly(ortho ester) polymer, the average number of p or the average number of p and q together (p+q) is between about 1 and 7 (e.g., 1, 2, 3, 4, 5, 6, 7), x and s are each independently an integer in the range of 0 to 10, and t and y are each independently an integer in the range of 2 to 30. 5 is H.

[0202] Further particular poly(ortho esters) are those in which A is R 1 or R 3 and R 1 but, [ka] wherein p and q are each independently an integer varying between about 1 and 20, or between about 1 and 15, or between about 1 and 10; R 1 is present in the poly(orthoester) polymer, the average number of p or the average number of p and q (i.e., p+q) is between about 1 and 7. Additionally, the specific ranges for x and s (see specific embodiments above, or see any polyorthoester provided herein) are each independently a range that is an integer ranging from 0 to 7 or 1 to 5. Similarly, the specific ranges for t and y are each independently a range that varies from 2 to 10.

[0203] Certain polyorthoesters are R 5 is hydrogen or methyl.

[0204] In certain specific embodiments, s and x are each independently selected from 1, 2, 3, 4, 5, 6, 7, and 8. In some particular embodiments, s is 2. In some other particular embodiments, x is 2.

[0205] An exemplary polyorthoester is 3,9-diethyl-3,9-2,4,8,10-tetraoxaspiro[5.5]undecane-3,9-diyl, [ka] wherein A is as defined above.

[0206] Polyorthoesters such as those described herein include an exemplary diketene acetal, 3,9-di(ethylidene)-2,4,8,10-tetraoxaspiro[5.5]undecane (DETOSU). [ka] with one or more diols as described above, e.g., HO-R 1 -OH or HO-R 3 -OH. Exemplary diols include oligoethylene glycols, such as triethylene glycol (TEG), oligoethylene glycols modified at one or both ends with α-hydroxy acids, such as oligoethylene glycol diglycolide or oligoethylene glycol dilactide, organic diols having a hydrocarbyl core of 2 to 30 carbon atoms, such as 1,6-hexanediol, 1,10-decanediol, cis / trans 1,4-cyclohexanedimethanol, para-menthane-3,8-diol, 1,4-butanediol, 1,5-pentanediol, 1,7-heptanediol, 1,8-octanediol, 1,10-decanediol, 1,12-dodecanediol, and cyclic equivalents thereof (the hydroxyl groups can be in any two positions within the cycloalkyl or alkylene ring). The organic diols can have 2 to 20 carbon atoms. The organic diols may be linear, branched or cyclic and may be saturated or unsaturated. Generally, the unsaturated diols have from 1 to 3 elements of unsaturation. A particular poly(ortho ester) contains a total of about 10 to 50 mole percent of moieties derived from one or more organic diols having a hydrocarbyl core.

[0207] H.O.R. 1 Diols such as —OH may be prepared as described in U.S. Pat. No. 5,968,543 and Heller et al., J. Polymer Sci., Polymer Letters, ed., vol. 18:293-297 (1980). For example, diols of the formula HO-R 1 -OH diols have the formula HO-R 3 It can be prepared by reacting a diol of -OH with between 0.5 and 10 molar equivalents of a cyclic diester of an α-hydroxy acid, such as lactide or glycolide, and allowing the reaction to proceed at 100-200° C. for about 12 hours to about 48 hours. Suitable solvents for the reaction include organic solvents such as dimethylacetamide, dimethylsulfoxide, dimethylformamide, acetonitrile, pyrrolidone, tetrahydrofuran, and methyl butyl ether. Although the diol product is generally referred to herein as a separate, simplified entity, e.g., TEG diglycolide (and the diol reaction product, e.g., TEG diglycolide), those skilled in the art will understand that the diol is actually a complex mixture resulting from the reaction due to the reactive nature of the reactants, e.g., ring opening of glycolide, and thus the term TEG diglycolide (or any other term referring to a similar product) generally refers to the average or overall properties of the product.

[0208] A particular polyorthoester is prepared by reacting 3,9-di(ethylidene)-2,4,8,10-tetraoxaspiro[5.5]undecane (DETOSU) with one or more reactive diols. Generally, the polyorthoester is prepared by reacting DETOSU with two or more reactive diols under anhydrous conditions. A particular polyorthoester is prepared by reacting DETOSU with triethylene glycol and triethylene glycol diglycolide as described in U.S. Pat. No. 8,252,305. A particular polyorthoester prepared from DETOSU-triethylene glycol-triethylene glycol diglycolide has a molar ratio of the components of 90:80:20, although the relative ratios of the components may vary appropriately as described above.

[0209] The polyorthoesters formed by the reaction of DETOSU with TEG and TEG diglycolide can generally be described as having the following moieties, where R 1 corresponds to the diolate moiety derived from triethylene glycol diglycolide (formed by reaction of glycolide with TEG), and R 3 corresponds to the diolate moiety derived from triethylene glycol, and A corresponds to R 1 and R 1 teeth, [ka] and R 5 is H and R 6 teeth, [ka] and the constituents of the resulting polyorthoester are [ka] where the sum of p and q is 2 on average, s is 2, and A is R 3 If so, then R 3 teeth, [ka] and x is 2, and the resulting polyorthoester moieties or components are [ka] Corresponding structures can be readily envisioned for polyorthoesters prepared from the various α-hydroxy acid containing moieties described herein and additional diols.

[0210] Exemplary polyorthoesters have a weight average molecular weight of from about 1000 Da to about 200,000 Da, for example, from about 2,500 Da to about 100,000 Da, or from about 3,500 Da to about 20,000 Da, or from about 4,000 Da to about 10,000 Da, or from about 5,000 Da to about 8,000 Da. Exemplary molecular weights (Da) are 2500, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000, 9500, 10,000, 20,000, 30,000, 40,000, 50,000, 60,000, 70,000, 80,000, 90,000, 100,000, 120,000, 150,000, 175,000 and 200,000, and ranges therebetween, including ranges formed by combining any one of the lower molecular weights as set forth above with any one of the higher molecular weights as provided above for that selected lower molecular weight.

[0211] In one particular embodiment of the polyorthoester of the delivery system, the polyorthoester has a molecular weight in the range of about 2,500 daltons to 10,000 daltons.

[0212] In one embodiment, the poly(orthoesters) described in this section are semi-solid at both room temperature and above room temperature. 3 Polyorthoester (R 3 teeth, [ka] (wherein x is 2) is a semi-solid polymer at both room temperature and above room temperature. Semi-solid polymers exist in either a glassy state or a viscous liquid state. Semi-solid polymers typically exhibit a glass transition temperature (Tg) below room temperature. Below the Tg, the semi-solid polymer can be considered to exist in a glassy state, and above the Tg, the polyorthoester can be considered to exist in a liquid state. Semi-solid polyorthoester polymers are not thermoplastic polymers.

[0213] In general, polyorthoesters according to any one of the following formulas, Formula I, Formula II, Formula III, or Formula IV, are suitable for use in the compositions and / or delivery vehicles provided herein. [ka] With reference to Formulas I-IV: R is a bond, -(CH2) a - or -(CH2) b -O-(CH2) c wherein a is an integer from 1 to 12 (e.g., selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12), and b and c are independently integers from 1 to 5 (e.g., selected from 1, 2, 3, 4, and 5); R * is C 1~4 is alkyl, R o , R'' and R''' are each independently H or C 1~4 is alkyl, n is an integer of at least 5; A is a diol.

[0214] For example, the compositions and delivery vehicles described herein can be comprised of polyorthoesters of Formula I, Formula II, Formula III, or Formula IV, where: R is a bond, -(CH2) a - or -(CH2) b -O-(CH2)c a is an integer from 1 to 12, and b and c are independently integers from 1 to 5; R * is C 1~4 is alkyl, R o , R'' and R''' are each independently H or C 1~4 is alkyl, n is an integer of at least 5; A is R 1 , R 2 , R 3 , or R 4 and R 1 is an α-hydroxy acid containing moiety, as described in the preceding paragraph; R 5 is hydrogen or C 1~4 alkyl (e.g., methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl); R 6 teeth, [ka] is selected from the group consisting of s is an integer ranging from 0 to 10; t is an integer ranging from 2 to 30; R 7 is hydrogen or C 1~4 is alkyl, R 2 teeth, [ka] and R 3 teeth, [ka] and x is an integer ranging from 0 to 200; y is an integer ranging from 2 to 30; R 8 is hydrogen or C 1~4 is alkyl, R 9 and R 10 are independently 1~12 is alkylene, R 11 is hydrogen or C 1~6 is alkyl, R 12 is C 1~6 alkyl, or R 11 and R 12 Let's get together and 3~10 It becomes alkylene, R 4 is the residue of a diol containing at least one functional group independently selected from amide, imide, urea, and urethane (carbmate) groups.

[0215] In certain cases, the polyorthoester may be one in which A is R 1 , R 3 , or R 4 A polyorthoester according to any one of formulas I-IV, wherein: R 3 teeth, [ka] is selected from x is an integer from 0 to 100; y is an integer from 2 to 30; R 8 is hydrogen or C 1~4 is alkyl, R 9 and R 10 are independently 1~12 is alkylene, R 11 is hydrogen or C 1~6 is alkyl, R 12 is C 1~6 alkyl, or R 11 and R 12 Let's get together and 3~10 It becomes alkylene, R 4is the residue of a diol containing at least one functional group independently selected from amide, imide, urea, and urethane groups; R 5 is hydrogen or C 1~4 It is an alkyl.

[0216] In one particular embodiment of the polyorthoester, 1 The fraction of A units having the formula: is between 0 and 20 mole percent.

[0217] An exemplary polyorthoester is described by Formula I, II, III or IV, where: All of these units are R 2 does not have A equal to R 3 teeth, [ka] and x is an integer from 1 to 100; y is an integer from 2 to 30; R 6 teeth, [ka] and s is an integer from 1 to 10; t is an integer from 2 to 30; R 5 , R 7 , and R 8 is independently hydrogen or methyl.

[0218] Further representative polyorthoesters of formula I, II, III or IV include R 3 and R 6 are both -(CH2-CH2-O)2-(CH2-CH2)-, and R 5 is methyl and p and q are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0219] In another embodiment of the polyorthoester of formula I, II, III or IV, R 3 and R 6 are both -(CH2-CH2-O)9-(CH2-CH2)-, and R 5 is methyl and p or the sum of p and q is on average 2.

[0220] In another variation, the polyorthoester has formula I, II, III or IV, where R is -(CH) b -O-(CH2) c b and c are both 2; R * is a C2 alkyl.

[0221] Further representative polyorthoesters of formula I, II, III or IV include R 5 is hydrogen or methyl, and R 6 but, [ka] and s is an integer from 1 to 10, or in some embodiments, s is selected from 1, 2, 3, or 4, and t is an integer from 2 to 30, particularly selected from 2, 3, 4, 5, 6, 7, 8, 9, and 10; and R 7 is hydrogen or methyl, and R 3 but, [ka] where x is an integer from 1 to 10, or in some embodiments selected from 1, 2, 3, or 4, y is an integer from 2 to 30, particularly selected from 2, 3, 4, 5, 6, 7, 8, 9, and 10, and R 8 is hydrogen or methyl, and R 4 is selected from the residue of an aliphatic diol having 2 to 20 carbon atoms (e.g., selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 carbon atoms), and in some embodiments, R 4A is a polyorthoester having 2 to 10 carbon atoms interrupted by one or two amide, imide, urea, or urethane groups. In some cases, A in the polyorthoester is R 1 The proportion of moieties that are R is about 0.01 to 50 mole percent. 1 The proportion of moieties in the polyorthoester where A is R is about 0 to about 30 mole percent, or about 0.1 to 25 mole percent. As an exemplary molar percentage, 1 In one embodiment, the mole percent is 20. Additionally, in one or more embodiments, A is R 2 the proportion of the subunits that are less than about 20 percent, less than about 10 percent, or less than about 5 percent, and A is R 4 The percentage of the portion units that are is less than 20 percent, less than about 10 percent, or less than 5 percent.

[0222] In certain embodiments, the polyorthoester shown in Formula I, Formula II, Formula III, and Formula IV is one of alternating residues of a diketene acetal and a diol, with each adjacent pair of diketene acetal residues separated by the residue of one polyol, such as a diol.

[0223] Methods for making polyorthoesters are well known in the art and are described, for example, in US Pat. Nos. 6,613,355 and 8,252,304.

[0224] 6. Solvents and additives as required The composition may further comprise one or more pharma- ceutically acceptable excipients, some examples of which are described herein.

[0225] In embodiments where the delivery vehicle is a polymer formulation, particularly where the polymer is a polyorthoester, the delivery vehicle can optionally include an organic acid, such as those described in co-owned U.S. Patent Application No. 61 / 982,300, filed April 21, 2014, which is incorporated herein by reference in its entirety. The organic acid facilitates the release of the active agent, such as a caine-type local anesthetic, from the vehicle or composition, particularly during the initial phase of delivery (e.g., days 1-3 after administration). Generally, the organic acid is a carboxylic acid. The most suitable acids are organic acids having a molecular weight of less than about 300 daltons. Representative organic acids include, for example, fumaric or maleic acid, ethanoic acid, propanoic acid, butanoic acid, pentanoic acid, hexanoic acid, heptanoic acid, benzoic acid, salicylic acid and acetylsalicylic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, and the like.

[0226] The delivery vehicle can include about 0.01 wt% to 0.6 wt% or about 0.01 wt% to 0.2 wt% of the dicarboxylic acid. The amount of organic acid additive included in the vehicle will depend, at least in part, on the identity of the particular active agent, the amount of active agent contained in the vehicle, the particular polyorthoester, its amount, and the desired delivery profile.

[0227] For a given organic acid, vehicles containing greater amounts of organic acid exhibit a more rapid release rate, which release is typically most pronounced during the first 1-3 days after administration, and precludes crystallization of the active agent from homogeneous compositions.

[0228] In another embodiment, the delivery vehicle in the form of a semi-solid polyorthoester polymer formulation may also contain one or more liquid additives. The additives may be liquid additives compatible with the pharma- ceutically acceptable polyorthoester. Such additives are liquid at room temperature and readily miscible with the polyorthoester. Exemplary liquid additives compatible with the polyorthoester include both protic and aprotic solvents. Protic liquid additives include polyethylene glycols having a molecular weight between about 200 Da and 4,000 Da, or polyethylene glycol derivatives or copolymers having a molecular weight between about 200 Da and 4,000 Da, such as end-capped PEGs, such as monomethoxypolyethylene glycols, or mono-, di-, or triglycerides of C2-C19 aliphatic carboxylic acids or mixtures of such acids, as well as alkoxylated tetrahydrofurfuryl alcohols. Further suitable liquid additives include C1-C4 alkyl ethers of alkoxylated tetrahydrofurfuryl alcohols, and C2-C19 aliphatic carboxylic acid esters, and the like. A particular additive for the semi-solid vehicle is monomethoxy-PEG having a molecular weight selected from 400, 450, 500, 550, 600 and 650 Da.

[0229] Further liquid additives include aprotic solvents. Suitable aprotic solvents for use, as well as exemplary polyorthoester vehicles containing aprotic solvents, are described in U.S. Patent Application Publication No. 2014 / 0275046, the entire contents of which are incorporated herein by reference. Examples of biocompatible hydrophilic aprotic organic solvents include, for example, amides, such as N-methyl-2-pyrrolidone (NMP), 2-pyrrolidone, N-ethyl-2-pyrrolidone, N-cyclohexyl-2-pyrrolidone, dimethyl ether, and the like. esters of monobasic acids, such as methyl lactate, ethyl lactate, and methyl acetate; sulfoxides, such as dimethyl sulfoxide and decyl methyl sulfoxide; lactones, such as e-caprolactone and butyrolactone; ketones, such as acetone and methyl ethyl ketone; and ethers, such as dimethyl isosorbide and tetrahydrofuran.

[0230] An exemplary semi-solid composition includes a polyorthoester, a liquid additive such as NMP or DMSO, a caine type local anesthetic such as bupivacaine or ropivacaine, and an NK-1 receptor antagonist such as aprepitant, and optionally an organic acid additive such as maleic acid. The relative concentrations of the components of the semi-solid composition will vary depending on the amount of caine local anesthetic(s), NK-1 receptor antagonist, polyorthoester, polyorthoester compatible liquid additive, and organic acid additive, if present. The weight percent of the polyorthoester compatible liquid additive may range from about 10 to 50 weight percent, or about 10 to 40 weight percent, or 10 to 30 weight percent, or 10 to 25 weight percent, or 1 to 20 weight percent, or 5 to 15 weight percent, or 5 to 10 weight percent. Exemplary amounts of liquid additive compatible with the polyorthoester are about 5, 6, 7, 8, 9, 10, 12, 15, 20, 25, 30, 35, 40, 45 or 50 weight percent.

[0231] In another embodiment, the compositions described herein, particularly semi-solid compositions comprising a liquid additive such as a polyorthoester, NMP or DMSO, a caine-type local anesthetic such as bupivacaine or ropivacaine, and an NK-1 receptor antagonist such as aprepitant, and optionally an organic acid additive, further comprise a viscosity-reducing triglyceride solvent such as those disclosed in the present application.

[0232] A delivery vehicle in the form of a semi-solid polymer formulation can be prepared by mixing or blending the active agent, the polymer, e.g., polyorthoester, optionally a liquid additive compatible with the polymer / polyorthoester, and any other further additive substances or additives as desired. Mixing or blending can be carried out by any suitable method, generally at a temperature below about 50° C., e.g., at room temperature, although in certain cases, depending on the nature of the materials, mixing or blending can be carried out at higher temperatures, e.g., about 25-100° C. Mixing or blending is generally carried out in the absence of additional solvents to obtain a homogeneous, flowable, non-viscous vehicle at room temperature.

[0233] The polymer-compatible liquid additive is typically added to the composition in an amount ranging from about 5 weight percent to about 70 weight percent based on the total weight of the composition. The liquid additive may be present in the composition in an amount ranging from about 5 weight percent to about 50 weight percent. In other embodiments, the liquid additive is present in the composition in an amount ranging from about 5 to 10 wt%, 5 to 15 wt%, 10 to 60 wt%, 15 to 60 wt%, 15 to 50 wt%, 20 to 60 wt%, 25 to 50 wt%, 30 to 70 wt%, 30 to 60 wt%, 30 to 50 wt%, 35 to 70 wt%, 35 to 60 wt%, or 35 to 50 wt%.

[0234] The release rate of the active agent (e.g., drug) can be controlled by adjusting the composition and amount of the polymer and / or by the selection and amount of additional substances / additives, if necessary. The chemical structure of the polymer (i.e., the type of monomer used, or the ratio of monomers for copolymers or terpolymers, the end groups on the polymer chain, and the molecular weight of the polymer) determines the hydrophilicity or lipophilicity of the polymeric material and contributes to the degradation time of the polymer depot. More hydrophilic polymers (e.g., polyorthoesters in which the diol monomers are hydrophilic, such as triethylene glycol, tetraethylene glycol, or polyethylene glycol) are used for applications requiring a more rapid release rate and a shorter release period. The composition comprises an effective amount of delivery vehicle and active agent to produce the desired therapeutic effect over the release period.

[0235] In this application, the singular form is used to describe polyorthoester and other composition components, but it is understood that more than one polyorthoester and / or more than one kine-type local anesthetic or NK-1 receptor antagonist selected from the above group can be used in the delivery system.In some embodiments of the compositions described herein, the composition further comprises one or more additional additives.In one embodiment, the specific additive does not affect the release of the active agent from the composition.

[0236] It will be understood that, although not required, other pharma- ceutically acceptable inactive agents, such as colorants and preservatives, can also be incorporated into the composition.

[0237] 7. Aqueous Compositions Comprising Kine and NK-1 Receptor Antagonists As described herein, it has been discovered that administering a combination of a kine-type local anesthetic and an NK-1 receptor antagonist provides a surprisingly effective level and duration of pain relief in subjects.Based on this disclosure and the guidance provided herein, those skilled in the art will understand that the combination of a kine-type local anesthetic and an NK-1 receptor antagonist is also more effective than an equivalent amount of a kine-type local anesthetic or an NK-1 receptor antagonist administered alone.Therefore, an aqueous solution comprising a kine-type local anesthetic and an NK-1 receptor antagonist is also disclosed.In a particular embodiment, the NK-1 receptor antagonist in the aqueous composition is aprepitant.In a more particular embodiment, the aqueous composition comprises aprepitant and bupivacaine.

[0238] Cain-type local anesthetics suitable for aqueous combination are commercially available as injectable solutions, including, but not limited to, lidocaine, mepivacaine, bupivacaine, and etidocaine.Pharmaceutically acceptable solutions of NK-1 receptor antagonists, such as aprepitant, are disclosed, for example, in US Patent Application Publication No. 15 / 012,532 and US Patent No. 9,561,229.Thus, for example, a pharma-ceutically acceptable solution of aprepitant can be mixed with a solution of cain-type local anesthetic before administration to a subject.For example, mixing can be performed less than 1 hour before administration, or 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours before administration. The mixture of cainyl local anesthetic and NK-1 receptor antagonist provides more effective pain relief than the same amount of cainyl local anesthetic or NK-1 receptor antagonist alone.The higher effectiveness of this combination formulation to provide pain relief can be measured, for example, by using von Frey assay, where subject's pain tolerance is higher when administering the combination of meloxicam and amide type local anesthetic than when administering either active agent alone.

[0239] Thus, in one embodiment, an aqueous pharmaceutical composition is contemplated that includes a therapeutically effective amount of aprepitant and a therapeutically effective amount of a caine-type local anesthetic. In one embodiment, administration of the composition to a subject provides pain relief to the subject for a period of about 4 days to about 6 days following administration.

[0240] In another embodiment, an aqueous solution comprising a therapeutically effective amount of aprepitant is provided, wherein the solution is suitable for addition to a pharmaceutical solution comprising a therapeutically effective amount of a caine-type local anesthetic to form a mixed solution suitable for administration to a subject in need thereof. In one embodiment, administration of the mixed solution to a subject provides pain relief to the subject for a period of about 4 hours to about 12 hours, or for a period of about 4 to 24 hours, or 2 to 4 hours, or 2 to 6 hours, or 3 to 5 hours following administration.

[0241] In one embodiment, the mixed solution is for use in a method for treating a subject with pain, the method comprising: mixing a pharmaceutical solution of aprepitant with a pharmaceutical solution of a caine-type local anesthetic to prepare a mixed solution; and administering the mixed solution to the subject within 24 hours of preparing the mixed solution. The method may also comprise prophylactically treating the subject with pain.

[0242] In one embodiment, a composition is provided that includes aprepitant, bupivacaine or ropivacaine, meloxicam, and a polyorthoester. In some embodiments, the polyorthoester is of any of formulas I-IV. In some embodiments, the composition further includes at least one selected from an aprotic solvent, an organic acid, and a viscosity reducing agent. In some embodiments, the composition includes aprepitant, bupivacaine, meloxicam, maleic acid, DMSO or NMP, triacetin, and a polyorthoester.

[0243] III. Methods of Treating Post-Surgical Pain The present disclosure is also directed to a method of treating post-operative pain in a patient in need thereof, comprising administering to the patient in need thereof an NK-1 receptor antagonist in combination with an analgesic agent.

[0244] In some embodiments, the NK-1 receptor and the analgesic are administered simultaneously, where the NK-1 receptor antagonist is administered in a pharmaceutical composition that also includes the analgesic and a pharma- ceutical acceptable excipient. In some embodiments, the NK-1 receptor and the analgesic are administered simultaneously, where the NK-1 receptor antagonist is administered in a pharmaceutical composition that is separate from the composition that includes the analgesic.

[0245] In some embodiments, the NK-1 receptor antagonist and the analgesic agent are administered sequentially, wherein the NK-1 receptor antagonist and the analgesic agent are present in separate pharmaceutical compositions comprising a delivery vehicle, each of which may further comprise a pharma- ceutically acceptable excipient.

[0246] In some embodiments, the NK-1 receptor antagonist is administered to a patient in need thereof pre-operatively and the analgesic is administered intraoperatively. In some embodiments, the analgesic is administered to a patient in need thereof pre-operatively and the NK-1 receptor antagonist is administered intraoperatively. In some embodiments, the NK-1 receptor antagonist and the analgesic are both administered to a patient in need thereof post-operatively. In some embodiments, the NK-1 receptor antagonist and the analgesic are both administered pre-operatively.

[0247] In some embodiments, the methods disclosed herein include administering to a patient in need of postoperative pain treatment an NK-1 receptor antagonist in combination with an analgesic selected from a local anesthetic, an opioid, an NSAID, an anticonvulsant, a serotonin and norepinephrine reuptake inhibitor (SNRI), an acetaminophen, and a tricyclic antidepressant.In some embodiments, the methods disclosed herein include administering to a patient in need of postoperative pain treatment an NK-1 receptor antagonist in combination with a local anesthetic.

[0248] In some embodiments, the method disclosed herein comprises administering to a patient in need of postoperative pain treatment an NK-1 receptor antagonist in combination with two analgesics selected from a local anesthetic, an opioid, an NSAID, an anticonvulsant, a serotonin and norepinephrine reuptake inhibitor (SNRI), acetaminophen, and a tricyclic antidepressant.In some embodiments, the method disclosed herein comprises administering to a patient in need of postoperative pain treatment an NK-1 receptor antagonist in combination with acetaminophen and an opioid.In some embodiments, the method disclosed herein comprises administering to a patient in need of postoperative pain treatment an NK-1 receptor antagonist in combination with a local anesthetic and an NSAID.

[0249] In some embodiments, the method further comprises administration of an NK-1 receptor antagonist daily for 1, 2, 3, 4, 5, or 6 days following surgery.

[0250] In some embodiments, the methods disclosed herein include administering to a patient in need of postoperative pain treatment: (1) an NK-1 receptor antagonist preoperatively (e.g., once) and daily for 1-6 days after surgery; and (2) a local anesthetic during surgery. In some embodiments, the NK-1 receptor antagonist is aprepitant. In some embodiments, the analgesic includes both a local anesthetic, such as bupivacaine or ropivacaine, and an NSAID, such as meloxicam.

[0251] In some embodiments, the methods disclosed herein include administering to a patient in need of postoperative pain treatment: (1) an NK-1 receptor antagonist and an NSAID preoperatively (e.g., once) and once daily for 1-6 days after surgery, and (2) a local anesthetic during surgery. In some embodiments, the NK-1 receptor antagonist is aprepitant. In some embodiments, the NSAID is meloxicam. In some embodiments, the local anesthetic is bupivacaine or ropivacaine.

[0252] In some embodiments, the administration of the NK-1 receptor antagonist is by systemic administration, such as intravenous administration or oral administration. In some embodiments, the administration of the NK-1 receptor antagonist is by local administration, such as topical administration.

[0253] In some embodiments, the administration of the analgesic agent is by systemic administration, such as oral or intravenous administration. In some embodiments, the administration of the analgesic agent is by local administration, such as topical administration.

[0254] In some embodiments, the administration of the composition comprising the NK-1 receptor antagonist and the analgesic is by systemic administration, such as oral or intravenous administration of the composition. In some embodiments, the administration of the composition is by local administration, such as topical administration of the composition.

[0255] A. NK-1 receptor antagonist Suitable NK-1 receptor antagonists for use in the method include RP67580 ((3aR,7aR)-octahydro-2-[1-imino-2-(2-methoxyphenyl)ethyl]-7,7-diphenyl-4H-isoindole)), WIN51078 (17-β-hydroxy-17-α-ethynyl-5-α-androstano[3,2-b]pyrimido[1,2-a]benzimidazole), 1-733,060 ((2S,3S)-3-[[3,5-bis(trisfluoromethyl)phenyl]methoxy]-2-phenylpiperidine hydrochloride), 1-703,606 (cis-2-(diphenylmethyl)-N-([2-iodophenyl]methyl)-1-azabicyclo(2.2.2) Octan-3-amine), MDL105,212 ((R)-1-[2-[3-(3,4-dichlorophenyl)-1-(3,4,5-trimethoxybenzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenylpiperidine-4-carboxamide hydrochloride), serlopitant, maropitant, antagonist D, aprepitant, fosaprepitant, R116301, CGP49823, CP-96345, CP-99994, GR-203040, MDL-103392, l-76073 5, SDZ-NKT-343, norpitanitinium (SR-140333), AV608, rolapitant, SCH900978, AV608, GSK424887 (GlaxoSmithKline), GSK206136 (GlaxoSmithKline), GR-205171, CP-99994, TAK637 ((S)-7-(3,5-bis-trifluoromethyl-benzyl)-9-methyl-5-p-tolyl-8,9,10,11-tetrahydro-7H-1,7,11a-triaza-cyclo octa[b]naphthalene-6,12-dione), LY303870 ([(R)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4-(piperidin-1-yl)piperidin-1-yl)acetyl)amino]propane]), LY686017 ((2-chloro-phenyl)-{2-[5-pyridin-4-yl-1-(3,5-bistrifluoromethyl-benzyl)-1H-[1,2,3]triazol-4-yl]-pyridine-3- yl}-methanone), E-6006, casopitant / GW679769 ((2R,4S)-4-(4-acetylpiperazin-1-yl)-N-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]-2-(4-fluoro-2-methylphenyl)-N-methylpiperidine-1-carboxamide), vestipitant, orbepitant and orbepitant maleate, befetupitant, netupitant, ezlopitant, CP-122721, MPC-4505 (Myriad Genetics, Inc.), CP-122721 (Pfizer, Inc.), CJ-12,255 (Pfizer, Inc.), SRR240600 (Sanofi-Aventis), or TA-5538 (Tanabe Seiyaku Co.) (including all pharma- ceutically acceptable salts thereof).

[0256] B. Analgesics The analgesic used in the method for treating postoperative pain as disclosed herein refers to an active agent for treating pain.The active agent is selected from local anesthetics, opioids, NSAIDs, anticonvulsants, serotonin and norepinephrine reuptake inhibitors (SNRIs), acetaminophen, and tricyclic antidepressants.

[0257] The local anesthetic may be of the "caine" class, including, for example, benzocaine, chloroprocaine, cocaine, cyclomethycaine, dimethocaine, piperocaine, propoxycaine, procaine, proparacaine, tetracaine, articaine, bupivacaine, dibucaine, levobupivacaine, lidocaine, mepivacaine, prolocaine, ropivacaine, and trimecaine. In some embodiments, the local anesthetic is selected from bupivacaine, ropivacaine, levobupivacaine, dibucaine, mepivacaine, procaine, lidocaine, and tetracaine. Other local anesthetics include, for example, saxitoxin, neosaxitoxin, tetrodotoxin, menthol, eugenol, and spilanthol. In the methods disclosed herein, the local anesthetic may be administered in the form of a pharmaceutical composition and / or dosage regimen approved by the FDA.

[0258] Opioids are a type of narcotic painkiller. Opioids work by binding to opioid receptors in the brain, spinal cord and other areas of the body, reducing pain messages to the brain and pain sensations. Opioid painkillers include, for example, buprenorphine, butorphanol, dextromoramide, dezocine, dextropropoxyphene, diamorphine, fentanyl, alfentanil, sufentanil, hydrocodone, hydromorphone, ketobemidone, levomethadyl, mepiridine, methadone, morphine, nalbuphine, opium, oxycodone, papaveretum, pentazocine, pethidine, phenoperidine, piritramide, dextropropoxyphene, remifentanil, tilidine, tramadol, codeine, dihydrocodeine, meptazinol, dezocine, eptazocine, and flupirtine. In the methods disclosed herein, the opioid may be administered in the form of a pharmaceutical composition and / or dosage regimen that is FDA approved.

[0259] NSAIDs function by inhibiting the activity of cyclooxygenase.NSAIDs can be classified into, for example, salicylates, propionic acid derivatives, acetic acid derivatives, enolic acid derivatives, anthranilic acid derivatives, selective cox-2 inhibitors, sulfonanilides, and others, such as clonixin, licofelone, and H-harpagide.Exemplary NSAIDs include ketoprofen, diclofenac, diflusanil, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, tolmetin, piroxicam, celecoxib, meloxicam, nabumetone, naproxen, oxaprozin, rofecoxib, sulindac, valdecoxib, aspirin, and acetaminophen.In some embodiments, the NSAID is selected from coxib derivatives, including, for example, celecoxib, rofecoxib, and valdecoxib. In some embodiments, the NSAID is selected from enolic acid derivatives, including, for example, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam, and phenylbutazone. In some embodiments, the NSAID is ibuprofen. In the methods disclosed herein, the NSAID can be administered in the form of a pharmaceutical composition and / or dosage regimen approved by the FDA. For example, the NSAID can be administered as Caldolor®, an intravenous injection form of ibuprofen. In addition, for example, the NSAID is administered as Voltaren® gel, a topical gel form of diclofenac.

[0260] Anticonvulsants such as phenobarbital, clonazepam, valproic acid, topiramate, gabapentin, pregabalin and tiagabine may have antihyperalgesic and antinociceptive activity.In the methods disclosed herein, anticonvulsants may be administered in the form of pharmaceutical compositions and / or dosage regimens approved by the FDA.For example, gabapentin may be administered as Gralise®, a tablet form of gabapentin, and pregabalin may be administered as Lyrica®, a capsule or oral solution form of pregabalin.

[0261] SNRIs are a class of drugs that are effective in treating depression. SNRIs are also used to treat conditions such as long-term pain (Tom, in the literature, states that SNRIs are used to treat neuralgia). SNRIs approved by the FDA for treating depression include desvenlafaxine, duloxetine, levomilnacipran, and venlafaxine. In the methods disclosed herein, the SNRI can be administered in the form of a pharmaceutical composition and / or dosage regimen approved by the FDA. For example, duloxetine can be administered as Cymbalta®, which is a capsule form of duloxetine.

[0262] Tricyclic antidepressants have also been found to be effective in treating pain.Tricyclic antidepressants include amitriptyline, imipramine, clomipramine, doxepin, nortriptyline and desipramine.In the methods disclosed herein, tricyclic antidepressants can be administered in the form of pharmaceutical compositions and / or dosage regimens approved by FDA.

[0263] Acetaminophen is used in pain management, for example for post-operative pain relief, both for mild to moderate pain and for moderate to severe pain. In the methods disclosed herein, acetaminophen can be administered as Ofirmev®, an injectable form of acetaminophen approved by the FDA.

[0264] In the method disclosed herein, NK-1 receptor antagonist is administered in the form of a pharmaceutical composition that further comprises pharma- ceutical acceptable additives.In some embodiments, NK-1 receptor antagonist is administered in a pharmaceutical composition that also comprises an analgesic.In some embodiments, NK-1 receptor antagonist is administered in a pharmaceutical composition that also comprises a kine-type local anesthetic as disclosed above.

[0265] C. NK-1 Receptor Antagonist and Analgesic Agent Administered in Separate Compositions In some embodiments, the NK-1 receptor antagonist is administered in a pharmaceutical composition that is separate from the pharmaceutical composition that includes the analgesic, i.e., the pharmaceutical composition that includes the NK-1 receptor antagonist does not include the analgesic. In these embodiments, the pharmaceutical composition that includes the NK-1 receptor antagonist may be an oil-in-water emulsion as described in U.S. Patent Application Publication No. 15 / 012,532, the entire contents of which are incorporated herein by reference.

[0266] 1. Pharmaceutical composition comprising an NK-1 receptor antagonist without an analgesic In some embodiments, the NK-1 receptor antagonist is administered in the form of a pharmaceutical composition that is an oil-in-water emulsion comprising the NK-1 receptor antagonist, an emulsifier, an oil, a co-surfactant, a tonicity agent, a pH adjusting agent, and water.

[0267] The emulsion is intended for intravenous injection and can remain physically and chemically stable for the shelf life of the formulation.

[0268] In some embodiments, the oil is selected from the group consisting of coconut oil, olive oil, soybean oil, safflower oil, triglycerides, octyl and decyl glycerates, ethyl oleate, glyceryl linoleate, ethyl linoleate, glyceryl oleate, cholesteryl oleate / linoleate, or mixtures thereof. In other embodiments, the oil is hydrolyzed. In yet other embodiments, the oil is structurally modified.

[0269] In some embodiments, the emulsifier comprises a phospholipid, hi another embodiment, the emulsifier is selected from the group consisting of egg phospholipids, soybean phospholipids, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, phosphatidic acid, mixed chain phospholipids, lysophospholipids, hydrogenated phospholipids, partially hydrogenated phospholipids, and mixtures thereof.

[0270] In some embodiments, the co-surfactant comprises an alcohol, hi other embodiments, the co-surfactant is ethanol.

[0271] In some embodiments, the pH adjusting agent comprises an oleate or a pharma- ceutically acceptable salt thereof. In other embodiments, the oleate is sodium oleate, potassium oleate, or ammonium oleate. In yet other embodiments, the pH adjusting agent is sodium oleate or a pharma- ceutically acceptable salt thereof.

[0272] In some embodiments, the pH adjusting agent comprises a buffer. In other embodiments, the buffer is selected from the group consisting of phosphate buffer, citrate buffer, Tris buffer, carbonate buffer, succinate buffer, maleate buffer and borate buffer. In yet other embodiments, the buffer is selected from the group consisting of phosphate buffered saline (PBS), modified PBS (PBS-mod) and citrate buffer.

[0273] In some embodiments, the pH adjusting agent comprises an oleate salt and a buffer, hi other embodiments, the oleate salt is sodium oleate and the buffer is a Tris buffer.

[0274] In some embodiments, the pH adjuster is selected from the group consisting of sodium hydroxide, potassium hydroxide, magnesium hydroxide, sodium carbonate, Tris, sodium linoleate, sodium oleate, potassium oleate, ammonium oleate, potassium carbonate, potassium linoleate, and mixtures thereof.

[0275] In some embodiments, the composition comprises about 5 wt / wt% (weight / weight%) to 15 wt / wt%, 5 wt / wt% to 10 wt / wt%, 7 wt / wt% to 10 wt / wt%, 8 wt / wt% to 9 wt / wt%, or 9 wt / wt% to 10 wt / wt% oil. In another embodiment, the composition comprises about 8 wt / wt%, 8.5 wt / wt%, 9 wt / wt%, 9.5 wt / wt%, 10 wt / wt%, or 10.5 wt / wt% oil. In yet another embodiment, the oil is soybean oil.

[0276] In some embodiments, the composition comprises about 10 wt / wt% to 20 wt / wt%, 12 wt / wt% to 17 wt / wt%, 13 wt / wt% to 16 wt / wt%, 13 wt / wt% to 15 wt / wt%, 14 wt / wt% to 15 wt / wt%, or 13 wt / wt% to 14 wt / wt% of an emulsifier. In other embodiments, the composition comprises about 13 wt / wt%, 13.5 wt / wt%, 14 wt / wt%, 14.5 wt / wt%, 15 wt / wt%, 16 wt / wt%, 17 wt / wt%, 18 wt / wt%, 19 wt / wt%, or 20 wt / wt% of an emulsifier. In yet other embodiments, the emulsifier is lecithin. In another embodiment, the lecithin is egg yolk lecithin.

[0277] In some embodiments, the composition comprises about 0.05 wt / wt% to 1.5 wt / wt%, 0.1 wt / wt% to 1.0 wt / wt%, 0.2 wt / wt% to 0.8 wt / wt%, 0.3 wt / wt% to 0.7 wt / wt%, 0.4 wt / wt% to 0.6 wt / wt%, or 0.4 wt / wt% to 0.5 wt / wt% of oleate or a salt thereof. In other embodiments, the composition comprises about 0.05 wt / wt%, 0.1 wt / wt%, 0.2 wt / wt%, 0.3 wt / wt%, 0.4 wt / wt%, 0.45 wt / wt%, 0.5 wt / wt%, 0.6 wt / wt%, 0.7 wt / wt%, 0.8 wt / wt%, 0.9 wt / wt%, 1.0 wt / wt%, or 1.5 wt / wt% of oleate or a salt thereof. In yet other embodiments, the oleate is sodium oleate. In yet another embodiment, the oleate or sodium oleate is a pH adjusting agent.

[0278] In some embodiments, the composition is about 20wt / wt% to 50wt / wt%, 30wt / wt% to 50wt / wt%, 35wt / wt% to 45wt / wt%, 30wt / wt% to 45wt / wt%, 37wt / wt% wt%~42wt / wt%, 38wt / wt%~40wt / wt%, 30wt / wt%, 31wt / wt%, 32wt / wt%, 33wt / wt%, 34wt / wt%, 35wt / wt%, 36wt / wt% , 37 wt / wt%, 38 wt / wt%, 39 wt / wt%, 40 wt / wt%, 41 wt / wt%, 42 wt / wt%, 43 wt / wt%, 44 wt / wt%, 45 wt / wt%, 46 wt / wt%, 47 wt / wt%, 48 wt / wt%, 49 wt / wt%, 50 wt / wt% of oil expressed as a percentage by weight of oil per sum of the weights of oil, emulsifier and oleate in a unit of composition. In other embodiments, the oil is soybean oil.

[0279] In some embodiments, the composition is about 20wt / wt% to 50wt / wt%, 30wt / wt% to 50wt / wt%, 35wt / wt% to 45wt / wt%, 30wt / wt% to 45wt / wt%, 37w t / wt%~42wt / wt%, 38wt / wt%~40wt / wt%, 30wt / wt%, 31wt / wt%, 32wt / wt%, 33wt / wt%, 34wt / wt%, 35wt / wt%, 36wt In another embodiment, the oil is soybean oil, 37wt / wt%, 38wt / wt%, 39wt / wt%, 40wt / wt%, 41wt / wt%, 42wt / wt%, 43wt / wt%, 44wt / wt%, 45wt / wt%, 46wt / wt%, 47wt / wt%, 48wt / wt%, 49wt / wt%, 50wt / wt% of the oil expressed as a percentage by weight of oil per the sum of the weights of oil and emulsifier in a unit of composition. In another embodiment, the oil is soybean oil.

[0280] In some embodiments, the composition is about 40 wt / wt% to 80 wt / wt%, 50 wt / wt% to 70 wt / wt%, 55 wt / wt% to 65 wt / wt%, 57 wt / wt% to 63 wt / wt%, 58 to 60 wt / wt%, 35 wt / wt% to 40 wt / wt%, 30 wt / wt% to 40 wt / wt%, 50 wt / wt%, 51 wt / wt%, 52 wt / wt%, 53 wt / wt%, 54 wt / wt%, 55 wt / wt%, 56 wt / wt%, The emulsifier may comprise 57wt / wt%, 58wt / wt%, 59wt / wt%, 60wt / wt%, 61wt / wt%, 62wt / wt%, 63wt / wt%, 64wt / wt%, 65wt / wt%, 66wt / wt%, 67wt / wt%, 68wt / wt%, 69wt / wt%, 70wt / wt% of the emulsifier expressed as a percentage of the weight of the emulsifier per the sum of the weights of the oil, emulsifier and oleate in a unit of the composition. In another embodiment, the emulsifier is lecithin. In yet another embodiment, the lecithin is egg yolk lecithin.

[0281] In some embodiments, the composition is about 40 wt / wt% to 80 wt / wt%, 50 wt / wt% to 70 wt / wt%, 55 wt / wt% to 65 wt / wt%, 57 wt / wt% to 63 wt / wt%, 58 to 60 wt / wt%, 35 wt / wt% to 40 wt / wt%, 30 wt / wt% to 40 wt / wt%, 50 wt / wt%, 51 wt / wt%, 52 wt / wt%, 53 wt / wt%, 54 wt / wt%, 55 wt / wt%, The emulsifier is expressed as a percentage of the weight of emulsifier per the sum of the weights of oil and emulsifier in a unit of composition of 56wt / wt%, 57wt / wt%, 58wt / wt%, 59wt / wt%, 60wt / wt%, 61wt / wt%, 62wt / wt%, 63wt / wt%, 64wt / wt%, 65wt / wt%, 66wt / wt%, 67wt / wt%, 68wt / wt%, 69wt / wt%, 70wt / wt%. In another embodiment, the emulsifier is lecithin. In yet another embodiment, the lecithin is egg yolk lecithin.

[0282] In some embodiments, the ratio of oil to NK-1 receptor antagonist (wt%:wt%) in the composition is in the range of about 5:1 to 20:1, 5:1 to 15:1, 5:1 to 10:1, 11:1 to 20:1, 11:1 to 15:1, 12:1 to 16:1, 12:1 to 14:1, 11:1 to 15:1, 12:1 to 14:1, 12.5:1 to 13.5:1, 13:1 to 14:1, or 12:1 to 15:1. In other embodiments, the ratio of oil to NK-1 receptor antagonist (wt%:wt%) in the composition is about 11:1 to 20:1, 11:1 to 15:1, 12:1 to 16:1, 12:1 to 14:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 11.5:1, 12:1, 12.5:1, 13:1, 13.5:1, 14:1, 14.5:1, or 15:1, 15.5:1, 16:1.

[0283] In some embodiments, the ratio of emulsifier to NK-1 receptor antagonist in the composition (wt%:wt%) ranges from about 10:1 to 30:1, 10:1 to 20:1, 15:1 to 30:1, 20:1 to 25:1, 18:1 to 22:1, 19:1 to 20:1, or 10:1 to 30:1. In other embodiments, the ratio of emulsifier to NK-1 receptor antagonist in the composition (wt%:wt%) ranges from about 10:1, 11:1, 13:1, 14:1, 15:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, or 30:1.

[0284] In some embodiments, the ratio (wt%:wt%) of (emulsifier+oil) to NK-1 receptor antagonist in the composition ranges from about 20:1 to 40:1, 25:1 to 35:1, 30:1 to 35:1, or 32:1 to 34:1. In other embodiments, the ratio (wt%:wt%) of (emulsifier+oil) to NK-1 receptor antagonist in the composition is about 25:1, 26:1, 27:1, 28:1, 29:1, 30:1, 31:1, 32:1, 33:1, 34:1, 35:1, 36:1, 37:1, 38:1, or 40:1.

[0285] In some embodiments, the ratio of emulsifier to oil (wt%:wt%) in the composition ranges from about 0.5:1 to 4:1, 1:1 to 2:1, 1.25:1 to 1.75:1, or 1.4:1 to 1.6:1. In other embodiments, the ratio of emulsifier to oil (wt%:wt%) in the composition is about 0.5:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2:1, 1.05:1, 1.15:1, 1.25:1, 1.35:1, 1.45:1, 1.55:1, 1.65:1, 1.75:1, 1.85:1, or 1.95:1.

[0286] In some embodiments, a therapeutic dose of the pharmaceutical composition comprises about 1-4g, 1.5-3g, 1.8-2.8g, 2.3-2.8g, 1.8-2.3g, 1g, 1.1g, 1.2g, 1.3g, 1.4g, 1.5g, 1.6g, 1.7g, 1.8g, 1.9g, 2g, 2.1g, 2.2g, 2.3g, 2.4g, 2.5g, 2.6g, 2.7g, 2.8g, 2.9g, 3g, 3.1g, 3.2g, 3.3g, 3.4g, 3.5g, 3.6g, 3.7g, 3.8g, 3.9g, 4g of emulsifier. In other embodiments, the emulsifier is lecithin. In yet other embodiments, the emulsifier is egg yolk lecithin.

[0287] In some embodiments, a therapeutic dose of the pharmaceutical composition comprises about 0.5-3 g, 1-2.5 g, 1-2 g, 1-1.5 g, 1.5-2 g, 0.5 g, 0.6 g, 0.7 g, 0.8 g, 0.9 g, 1 g, 1.1 g, 1.2 g, 1.3 g, 1.4 g, 1.5 g, 1.6 g, 1.7 g, 1.8 g, 1.9 g, 2 g, 2.1 g, 2.2 g, 2.3 g, 2.4 g, 2.5 g of oil. In other embodiments, the oil is soybean oil.

[0288] In some embodiments, a therapeutic dose of the pharmaceutical composition comprises about 50-600 mg, 100-600 mg, 100-500 mg, 100-400 mg, 100-300 mg, 100-200 mg, 200-400 mg, 50-250 mg, 75-200 mg, 100-150 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, or 600 mg of an NK-1 receptor antagonist.

[0289] In some embodiments, the composition comprises between about 0 wt / wt% and 10 wt / wt%, between 1 wt / wt% and 9 wt / wt%, between 2 wt / wt% and 6 wt / wt%, between 2 wt / wt% and 4 wt / wt%, or between 2 wt / wt% and 3 wt / wt% of a co-surfactant. In other embodiments, the composition comprises less than 10 wt / wt%, less than 9 wt / wt%, less than 8 wt / wt%, less than 7, less than 6 wt / wt%, less than 5 wt / wt%, less than 4 wt / wt%, less than 3 wt / wt%, less than 2 wt / wt%, or less than 1 wt / wt% of a co-surfactant.

[0290] In some embodiments, the composition comprises between about 0 wt / wt% and 10 wt / wt%, between 1 wt / wt% and 9 wt / wt%, or between 2 wt / wt% and 6 wt / wt% ethanol, in other embodiments, the composition comprises less than 10 wt / wt%, less than 9 wt / wt%, less than 8 wt / wt%, less than 7, less than 6 wt / wt%, less than 5 wt / wt%, less than 4 wt / wt%, less than 3 wt / wt%, less than 2 wt / wt%, or less than 1 wt / wt% ethanol.

[0291] In some embodiments, the emulsion further comprises a penetrant.

[0292] In some embodiments, the emulsion further comprises a buffer.

[0293] In some embodiments, the emulsion comprises a buffer but does not comprise a pH adjusting agent distinct from the buffer, while in other embodiments the buffer functions as both a pH adjusting agent and a buffer.

[0294] In some embodiments, when the emulsion includes a buffer, the emulsion does not contain a tonicity agent.

[0295] In some embodiments, the buffer is selected from the group consisting of phosphate buffer, citrate buffer, Tris buffer, carbonate buffer, succinate buffer, maleate buffer and borate buffer. In other embodiments, the buffer is selected from the group of phosphate buffered saline (PBS), modified PBS (PBS-mod) and citrate buffer.

[0296] In some embodiments, the emulsion is a buffered, substantially isotonic oil-in-water emulsion.

[0297] In some embodiments, the osmotic agent is selected from the group consisting of glycerol, sorbitol, xylitol, mannitol, glucose, trehalose, maltose, sucrose, raffinose, lactose, dextran, polyethylene glycol, or propylene glycol, in other embodiments, the osmotic agent is an inorganic salt, such as sodium chloride, and mixtures thereof.

[0298] In some embodiments, the composition has a pH of about 6-9, 7-9, 7.5-9, 7.5-8.5, 8-9, 6-8, 7-8, or 6, 7, 8, or 9.

[0299] In some embodiments, the composition comprises about 0 wt / wt% to 25 wt / wt%, 2 wt / wt% to 20 wt / wt%, 3 wt / wt% to 15 wt%, or 3 wt / wt% to 8 wt / wt% of a tonicity agent. In other embodiments, the composition comprises about 1 wt / wt%, 2 wt / wt%, 3 wt / wt%, 4 wt / wt%, 5 wt / wt%, 6 wt / wt%, 7 wt / wt%, 8 wt / wt%, 9 wt / wt%, or 10 wt / wt%, 11 wt / wt%, 12 wt / wt%, 13 wt / wt%, 14 wt / wt%, 15 wt / wt%, 16 wt / wt%, 17 wt / wt%, 18 wt / wt%, 19 wt / wt%, or 20 wt / wt%, 21 wt / wt%, 22 wt / wt%, 23 wt / wt%, 24 wt / wt%, 25 wt / wt% of a tonicity agent. In yet other embodiments, the composition does not comprise a tonicity agent.

[0300] In some embodiments, the composition comprises between about 0 wt / wt% and 25 wt / wt%, between 2 wt / wt% and 20 wt / wt%, between 3 wt / wt% and 15 wt / wt%, or between 3 wt / wt% and 8 wt / wt% of a penetrating agent. In other embodiments, the composition comprises about 1 wt / wt%, 2 wt / wt%, 3 wt / wt%, 4 wt / wt%, 5 wt / wt%, 6 wt / wt%, 7 wt / wt%, 8 wt / wt%, 9 wt / wt%, or 10 wt / wt%, 11 wt / wt%, 12 wt / wt%, 13 wt / wt%, 14 wt / wt%, 15 wt / wt%, 16 wt / wt%, 17 wt / wt%, 18 wt / wt%, 19 wt / wt%, or 20 wt / wt%, 21 wt / wt%, 22 wt / wt%, 23 wt / wt%, 24 wt / wt%, 25 wt / wt% of a penetrant. In yet other embodiments, the composition does not comprise a penetrant.

[0301] In some embodiments, the aqueous phase comprises a dose of dexamethasone sodium phosphate of the therapeutic dose of the pharmaceutical composition. In other embodiments, the dose of dexamethasone sodium phosphate is in the range of about 0.5 mg to 30 mg, 0.5 mg to 25 mg, 1 mg to 20 mg, 10 mg to 20 mg, or 3 mg to 16 mg. In yet other embodiments, the dose of dexamethasone sodium phosphate is about 9 mg or 16 mg of the therapeutic dose of the pharmaceutical composition. In those embodiments including a dose of dexamethasone, a therapeutic dose of the pharmaceutical composition comprises about 50-600 mg, 100-600 mg, 100-500 mg, 100-400 mg, 100-300 mg, 100-200 mg, 200-400 mg, 50-250 mg, 75-200 mg, 100-150 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, or 600 mg of the NK-1 receptor antagonist.

[0302] In some embodiments, the emulsion comprises a therapeutic dose of dexamethasone in the pharmaceutical composition. In other embodiments, the dose of dexamethasone is in the range of about 0.5 mg to 30 mg, 0.5 mg to 20 mg, 1 mg to 18 mg, 10 mg to 20 mg, or 3 mg to 16 mg. In other embodiments, the dose of dexamethasone is in the range of about 8 mg or 12 mg of the therapeutic dose of the pharmaceutical composition. In those embodiments including a dose of dexamethasone, a therapeutic dose of the pharmaceutical composition comprises about 50-600 mg, 100-600 mg, 100-500 mg, 100-400 mg, 100-300 mg, 100-200 mg, 200-400 mg, 50-250 mg, 75-200 mg, 100-150 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, or 600 mg of the NK-1 receptor antagonist.

[0303] In some embodiments, the emulsion comprises between about 0.002 wt / wt% and 0.2 wt / wt%, between 0.003 wt / wt% and 0.16 wt / wt%, between 0.02 wt / wt% and 0.1 wt / wt% dexamethasone sodium phosphate.

[0304] In some embodiments, the composition is a stable system that maintains an intensity weighted average particle size of about 50 nm to 1000 nm, 50 nm to 500 nm, 50 nm to 400 nm, 50 nm to 300 nm, 50 nm to 200 nm, or 50 nm to 100 nm as determined by dynamic light scattering (DLS). In another embodiment, the average droplet size is maintained below 500 nm for at least 1 month, 3 months, 6 months, 9 months, 12 months, 2 years, or 3 years at room temperature. In other embodiments, the average droplet size is maintained below 500 nm for at least 1 month, 3 months, 6 months, 9 months, 12 months, 2 years, or 3 years at 5° C.

[0305] In some embodiments, the NK-1 receptor antagonist is aprepitant. In some embodiments, the NK-1 receptor antagonist is selected from aprepitant, rolapitant, netupitant, lanepitant, vestipitant, orbepitant maleate, casopitant, ezlopitant, serlopitant, befetupitant and maropitant, or a pharmaceutically acceptable salt thereof.

[0306] In some embodiments, the NK-1 receptor antagonist is selected from the group consisting of rolapitant, netupitant, casopitant, ezlopitant, vestipitant, serlopitant, maropitant, and orvepitant.

[0307] 2. Pharmaceutical composition containing a local anesthetic without an NK-1 receptor antagonist In the method disclosed herein, the analgesic is administered in the form of a pharmaceutical composition that further comprises pharma- ceutical acceptable additives.In some embodiments, the analgesic is in the form of a pharmaceutical composition that also comprises NK-1 receptor antagonist.For example, the method comprises administering to the surgical site a composition that comprises a local anesthetic, an NSAID, and an NK-1 receptor antagonist in an extended release formulation.

[0308] In some embodiments, the analgesic is a pharmaceutical composition that is separate from the composition that includes the NK-1 receptor antagonist. In some embodiments, the analgesic is a pharmaceutical composition that is separate from the composition that includes the NK-1 receptor antagonist, where the pharmaceutical composition includes a polyorthoester, an organic acid, and an analgesic, such as a local anesthetic that includes an amino group, such as the pharmaceutical compositions disclosed in U.S. Patent Application No. 14 / 691,491, the entirety of which is incorporated herein by reference.

[0309] In some embodiments, the analgesic containing an amino group is a caine-type anesthetic. In some embodiments, the caine-type anesthetic is selected from bupivacaine, ropivacaine, levobupivacaine, dibucaine, mepivacaine, procaine, lidocaine, and tetracaine. In some embodiments, the analgesic is bupivacaine or ropivacaine.

[0310] The concentration of the caine-type anesthetic in the composition can vary from about 1 wt% to 30 wt%, or from about 1 wt% to 10 wt%, or from about 10 wt% to 20 wt%, or from about 2 wt% to 5 wt%, or from about 10 wt% to 15 wt%, or from about 15 wt% to 20 wt%.

[0311] In one or more embodiments related to the foregoing, the caine-type anesthetic is added to the composition in its free base form (ie, not in the form of an ammonium salt).

[0312] In still some further embodiments, the organic acid is a C2-C12 carboxylic acid. In some other embodiments, the organic acid is a C2-C12 dicarboxylic acid. In some other embodiments, the organic acid is a C2-C8 carboxylic acid. In some other embodiments, the organic acid is a C2-C8 dicarboxylic acid.

[0313] In still some further embodiments, the organic acid is selected from the group consisting of oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, fumaric acid, maleic acid, citric acid, acetylsalicylic acid, and salicylic acid.

[0314] In one or more embodiments, the organic acid is included in the formulation in an amount less than equimolar to the caine-type anesthetic, such that the caine-type anesthetic is present as a mixed salt-base, hi certain embodiments, the composition includes about 1 to 95 molar percent of the organic acid relative to the caine-type anesthetic.

[0315] In certain embodiments, the organic acid is a monocarboxylic acid.

[0316] In one or more related embodiments, the composition comprises about 10 to 80 mole percent of a monocarboxylic acid relative to the caine-type anesthetic.

[0317] In one or more further embodiments, the organic acid is a monocarboxylic or dicarboxylic acid.

[0318] In one or more further embodiments, the organic acid is a dicarboxylic acid or a tricarboxylic acid.

[0319] In some further embodiments, the composition comprises about 10-40 mole percent of a dicarboxylic acid relative to the caine-type anesthetic.

[0320] In some embodiments, the organic acid is a C2-C8 aliphatic unsubstituted or substituted saturated straight chain dicarboxylic acid. In certain related embodiments, the dicarboxylic acid is selected from the group consisting of oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, and pimelic acid.

[0321] In still some further embodiments, the organic acid is a C2-C8 aliphatic unsubstituted or substituted dicarboxylic acid containing one or more unsaturated elements (e.g., one or more double or triple bonds). In one or more particular embodiments, the organic acid is either fumaric acid or maleic acid.

[0322] In yet one or more further embodiments, the organic acid is a hydroxy-substituted tricarboxylic acid, a C2-C8 tricarboxylic acid, such as citric acid.

[0323] In yet further embodiments, the organic acid is an aromatic carboxylic acid. In certain embodiments, the organic acid is, for example, a benzoic acid or a substituted benzoic acid having 7 to 14 carbon atoms. Examples include acetylsalicylic acid and salicylic acid.

[0324] In yet one or more other embodiments, the organic acid is maleic acid.

[0325] In some embodiments, the composition is a semi-solid.

[0326] In some embodiments, the polyorthoester is represented by the structure shown as Formula I. [ka] In the formula, R * is methyl, ethyl, propyl or butyl, n is the number of repeating units and is an integer ranging from 5 to 400, and A of each partial unit is R 1 or R 3 It is.

[0327] In some embodiments directed to formula I, R* is ethyl.

[0328] In still some further embodiments directed to formula III, A is R 1 corresponds to R 1 teeth, [ka] and p and q are each independently an integer ranging from about 1 to 20; 5 are independently hydrogen or C 1~4 is alkyl, R 6 teeth, [ka] where s is an integer from 0 to 10, t is an integer from 2 to 30, and R 7 is hydrogen or C 1~4 It is an alkyl.

[0329] In some other embodiments of formula I, R7 is C1, C2, C3, or C4 alkyl. In some particular embodiments, R 7 is H.

[0330] In still yet other embodiments, R 1 The subunits are alpha-hydroxy acid containing subunits.

[0331] In still other embodiments, p and q are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0332] In yet another embodiment, R5 is independently hydrogen or C1, C2, C3, or C4 alkyl.

[0333] In some embodiments, A is R 3 corresponds to R 3 teeth, [ka] and x is an integer ranging from 1 to 100. In another embodiment, x is selected from 0, 1, 2, 3, 4, and 5, y is an integer ranging from 2 to 30, and R 8 is hydrogen or C 1~4 In yet another embodiment, R 8 is C1, C2, C3 or C4 alkyl. In another embodiment, R 8 is H.

[0334] In some embodiments, the polyorthoester is a polyol having A, R 1 or R 3 is a polyorthoester of formula I, formula II, formula III or formula IV, in particular of formula I, R 1 teeth, [ka] and p and q are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 of any repeat unit, the average number of p or the average number of the sum of p and q (p+q) is between about 1 and 7, x and s are each independently an integer ranging from 0 to 10, and t and y are each independently an integer ranging from 2 to 30. In a further embodiment, the sum of p and q is between about 1 and 7, and x and s are each independently an integer ranging from 0 to 10, and t and y are each independently an integer ranging from 2 to 30. 1 In still some further embodiments, R 5 is H.

[0335] In still further embodiments, A is R 1 or R 3 and R 1 teeth, [ka] and p and q each independently represent R 1is an integer ranging from about 1 to 20, about 1 to 15, or about 1 to 10 of any repeating unit, and the average number of p or the average number of p and q (i.e., p+q) is between about 1 and 7. In one or more other embodiments, x and s each independently range from 0 to about 7 or 1 to about 5. In yet another embodiment, t and y each independently range from 2 to 10.

[0336] In one embodiment, R 5 is hydrogen or methyl.

[0337] In one embodiment, s and x are each independently selected from 1, 2, 3, 4, 5, 6, 7, and 8. In certain embodiments, s is 2. In even further embodiments, x is 2.

[0338] In one embodiment, the polyorthoester is 3,9-diethyl-3,9-2,4,8,10-tetraoxaspiro[5.5]undecane-3,9-diyl and A: [ka] and A is as previously described.

[0339] In yet one or more further embodiments, the composition comprising a polyorthoester, an organic acid, and a caine-type anesthetic further comprises a solvent. The solvent may be either protic or aprotic in nature.

[0340] In yet one or more further embodiments, the caine-type anesthetic is solubilized in the composition.

[0341] In some embodiments, the composition comprises a polyorthoester, maleic acid, and a caine-type anesthetic.

[0342] In some embodiments, the analgesic is in the form of a pharmaceutical composition that is separate from the composition comprising the NK-1 receptor antagonist, where the pharmaceutical composition comprises a delivery vehicle and a local anesthetic and an NSAID as the analgesic, such as the pharmaceutical compositions disclosed in U.S. Patent Application No. 15 / 331,767, the entirety of which is incorporated herein by reference.

[0343] In some embodiments, the local anesthetic is a caine type local anesthetic. In some embodiments, the caine type local anesthetic is selected from bupivacaine, ropivacaine, levobupivacaine, dibucaine, mepivacaine, procaine, lidocaine, and tetracaine. In some embodiments, the caine type local anesthetic is bupivacaine or ropivacaine.

[0344] In some embodiments, the ratio of amide local anesthetic:NSAID is in the range of about 10:1 to 50:1, 15:1 to 50:1, 20:1 to 50:1, 25:1 to 50:1, 15:1 to 45:1, 20:1 to 45:1, 25:1 to 45:1, 30:1 to 45:1, 20:1 to 30:1, 20:1 to 35:1, 20:1 to 40:1, or 30:1 to 35:1. In another embodiment, the ratio of amide type local anesthetic:NSAID is about 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 29: 1, 30:1, 31:1, 32:1, 33:1, 34:1, 35:1, 36:1, 37:1, 38:1, 39:1, 40:1, 41:1, 42:1, 43:1, 44:1, 45:1, 46:1, 47:1, 48:1, 49:1, 50:1, 51:1, 52:1, 53:1, 54:1, 55:1, 56:1, 57:1, 58:1, 59:1, or 60:1.

[0345] In some embodiments, the composition comprises bupivacaine and meloxicam, wherein the ratio of bupivacaine:meloxicam is in the range of about 10:1 to 50:1, 15:1 to 50:1, 20:1 to 50:1, 25:1 to 50:1, 15:1 to 45:1, 20:1 to 45:1, 25:1 to 45:1, 30:1 to 45:1, 20:1 to 30:1, 20:1 to 35:1, 20:1 to 40:1, or 30:1 to 35:1. In another embodiment, the ratio of bupivacaine:meloxicam is about 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 29:1, 30:1, 31:1, 32:1, 33:1, 34:1, 35:1, 36:1, 37:1, 38:1, 39:1, 40:1, 41:1, 42:1, 43:1, 44:1, 45:1, 46:1, 47:1, 48:1, 49:1, 50:1, 51:1, 52:1, 53:1, 54:1, 55:1, 56:1, 57:1, 58:1, 59:1, 60:1, 61:1, 62:1, 63:1, 64:1, 65:1, 66:1, 67:1, 68:1, 69:1, 70:1, 71:1, 72:1, 73:1, 74:1, 75:1, 76:1, 77:1, 78:1, 79:1, 80:1, 81:1, 82:1, 83:1, 84:1, 85:1, 86:1, 87:1, 88:1, 89:1, 90:1, 91:1, :1, 34:1, 35:1, 36:1, 37:1, 38:1, 39:1, 40:1, 41:1, 42:1, 43:1, 44:1, 45:1, 46:1, 47:1, 48:1, 49:1, 50:1, 51:1, 52:1, 53:1, 54:1, 55:1, 56:1, 57:1, 58:1, 59:1, or 60:1.

[0346] In some embodiments, the composition comprises ropivacaine and meloxicam.

[0347] In some embodiments, the composition comprises ropivacaine and meloxicam, wherein the ratio of ropivacaine:meloxicam is in the range of about 10:1 to 50:1, 15:1 to 50:1, 20:1 to 50:1, 25:1 to 50:1, 15:1 to 45:1, 20:1 to 45:1, 25:1 to 45:1, 30:1 to 45:1, 20:1 to 30:1, 20:1 to 35:1, 20:1 to 40:1, or 30:1 to 35:1. In another embodiment, the ratio of ropivacaine:meloxicam is about 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 29:1 , 30:1, 31:1, 32:1, 33:1, 34:1, 35:1, 36:1, 37:1, 38:1, 39:1, 40:1, 41:1, 42:1, 43:1, 44:1, 45:1, 46:1, 47:1, 48:1, 49:1, 50:1, 51:1, 52:1, 53:1, 54:1, 55:1, 56:1, 57:1, 58:1, 59:1, or 60:1.

[0348] In some embodiments, the composition comprises a caine-type local anesthetic in an amount of about 0.1-8 wt%, 1-7 wt%, 1-6 wt%, 1-5 wt%, or 1-4 wt%, 1-3 wt%, 1.5-5 wt%, 1.5-3.5 wt%, 1.5-3.0 wt%, 2-3 wt%, 2.1-2.9 wt%, 2.2-2.8 wt%, 2.3-2.7 wt%, 2.4-2.6 wt%, 2.25-2.75, 0.25-0.75 wt%, 0.25-2.5 wt%, 0.25-3.5 wt%, or 0.25-5 wt% by weight of the composition. In another embodiment, the composition further comprises an NSAID, preferably meloxicam, wherein the meloxicam is present in an amount of about 0.005-0.006 wt%, 0.005-0.007 wt%, 0.005-0.008 wt%, 0.005-0.009 wt%, 0.005-1 wt%, 0.005-0.75 wt%, 0.005-0.5 wt%, 0.005-0.25 wt%, 0. It is present in an amount ranging from 0.05-0.125wt%, 0.01-1wt%, 0.01-0.75wt%, 0.01-0.5wt%, 0.01-0.25wt%, 0.01-0.125wt%, 0.020-0.100wt%, 0.030-0.100wt%, 0.040-0.100wt%, 0.050-0.090wt%, 0.060-0.080wt%, 0.070-0.080wt%.

[0349] In some embodiments, the composition is a water-based solution.

[0350] In some embodiments, the composition is injectable.

[0351] In some embodiments, the composition is suitable for administration as an intramuscular injection, transdermal, topical, subcutaneous injection, perineural injection, or into a wound.

[0352] In some embodiments, the delivery vehicle is a sustained release delivery vehicle.

[0353] In some embodiments, the sustained release delivery vehicle is a polymeric composition, a liposomal composition, a microsphere composition, a non-polymeric composition, or an implantable device.

[0354] In some embodiments, the sustained release delivery vehicle is not a microsphere composition.

[0355] In some embodiments, the sustained release delivery vehicle is not a liposomal composition.

[0356] In some embodiments, the sustained release delivery vehicle is not a non-polymeric composition.

[0357] In some embodiments, the sustained release delivery vehicle is not an implantable device.

[0358] In some embodiments, the sustained release delivery vehicle is not a polymeric composition.

[0359] In some embodiments, the delivery vehicle is not a sustained release vehicle. In another embodiment, the delivery vehicle is an immediate release vehicle. In yet another embodiment, at least about 80% of the anesthetic and NSAID are released from the delivery vehicle within about 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes or 2 hours. In yet another embodiment, the release of the anesthetic and NSAID is determined by in vitro dissolution test at 37°C.

[0360] In some embodiments, the composition has a viscosity of less than 10,000 mPa·s when the viscosity is measured using a viscometer at 37° C. In another embodiment, the composition has a viscosity of less than 5,000 mPa·s when the viscosity is measured using a viscometer at 37° C. In yet another embodiment, the composition has a viscosity in the range of about 2500 mPa·s to 10,000 mPa·s when the viscosity is measured using a viscometer at 37° C. In some embodiments, the viscometer is a cone and plate viscometer.

[0361] In yet another embodiment, the sustained release delivery vehicle is a liposome selected from the group consisting of small unilamellar vesicles (SUVs), large unilamellar vesicles (LUVs), multilamellar vesicles (MLVs) and multivesicular liposomes (MVLs).

[0362] In some embodiments, the amide-type local anesthetic is encapsulated in the aqueous space of the liposome or in the lipid layer of the liposome.

[0363] In some embodiments, a nonsteroidal anti-inflammatory drug (NSAID) is encapsulated in the aqueous space of the liposome or in the lipid layer of the liposome.

[0364] In yet another embodiment, the sustained release delivery vehicle is a microsphere composed of a bioerodible or biodegradable polymer.

[0365] In some embodiments, the amide-type local anesthetic and the nonsteroidal anti-inflammatory drug (NSAID) are encapsulated in microspheres.

[0366] In some embodiments, the implantable device is an osmotic pump with a reservoir containing an amide-type local anesthetic and a nonsteroidal anti-inflammatory drug (NSAID).

[0367] In some embodiments, the sustained release delivery vehicle is a non-polymeric formulation including sucrose isobutyl acetate.

[0368] In some embodiments, the sustained release delivery vehicle is a polymer formulation in the form of a semi-solid polymer formulation comprising a polymer, a caine-type local anesthetic and a nonsteroidal anti-inflammatory drug (NSAID).

[0369] In some embodiments, the polymer is a bioerodible or biodegradable polymer.

[0370] In yet another embodiment, the polymer formulation forms an implant or depot in situ.

[0371] In yet another embodiment, the polymer is selected from the group consisting of polylactide, polyglycolide, poly(lactic-co-glycolic acid) copolymers, polycaprolactone, poly-3-hydroxybutyrate, and polyorthoesters.

[0372] In a further embodiment, the sustained release delivery vehicle is a polymer formulation in the form of a semi-solid polymer formulation comprising a polyorthoester, a caine-type local anesthetic and a nonsteroidal anti-inflammatory drug (NSAID).

[0373] In some embodiments, the caine-type local anesthetic is selected from the group consisting of bupivacaine, ropivacaine, levobupivacaine, dibucaine, mepivacaine, procaine, lidocaine, and tetracaine, hi another embodiment, the amide-type local anesthetic is selected from bupivacaine and ropivacaine.

[0374] In some embodiments, the amide-type local anesthetic is ropivacaine.

[0375] In some embodiments, the amide-type local anesthetic is bupivacaine.

[0376] In some embodiments of any one or more of the preceding embodiments, the nonsteroidal anti-inflammatory drug (NSAID) is an enolic acid NSAID. Exemplary enolic acid NSAIDs include meloxicam, piroxicam, tenoxicam, droxicam, lornoxicam, and isoxicam.

[0377] In some embodiments, the enolic acid NSAID is meloxicam.

[0378] In some embodiments of any one or more of the preceding embodiments, the composition is a semi-solid or solid composition.

[0379] In some embodiments, the delivery vehicle is a sustained release delivery vehicle. In some embodiments, the sustained release vehicle is a polymer vehicle or polymer formulation.

[0380] In another embodiment, the sustained release polymer vehicle is a solid or semi-solid vehicle that includes a bioerodible or biodegradable polymer.

[0381] In certain embodiments, the biodegradable or bioerodible polymer formulation comprises a polymer selected from the group consisting of polylactide, polyglycolide, poly(lactic-co-glycolic acid) copolymer, polycaprolactone, poly-3-hydroxybutyrate, or polyorthoester.

[0382] In some embodiments, the polyorthoester is selected from the polyorthoesters represented by formula III described herein.

[0383] In alternative embodiments, the sustained release vehicle does not include polylactide, polyglycolide, poly(lactic-co-glycolic acid) copolymer, polycaprolactone, poly-3-hydroxybutyrate, or polyorthoester. In another embodiment, the sustained release vehicle does not include polyorthoester. In yet another embodiment, the sustained release vehicle does not include polyorthoester represented by formula I.

[0384] In yet further embodiments, the composition or delivery vehicle further comprises a solvent. The solvent may be either protic or aprotic in nature. In some embodiments, the composition comprises a polyorthoester and a solvent as a delivery vehicle.

[0385] In another embodiment, the sustained release delivery vehicle is selected from the group consisting of microspheres, microparticles, and homogeneous or heterogeneous matrix depots. In some embodiments, the microspheres, microparticles, or depot vehicles are biodegradable or bioerodible.

[0386] In another embodiment, the sustained release delivery vehicle is a liposomal or lipid-based formulation.

[0387] In another embodiment, the sustained release formulation is a polymer-based solid or semi-solid implant, and the caine-type local anesthetic and the enolic acid NSAID are dispersed in the polymer-based implant. In some embodiments, the implant is a solid polymer-based vehicle in the form of a suture or staple.

[0388] A post-operative model was used to study the pain relief profile provided by the method described herein.The data unexpectedly show that both NK-1 antagonist and analgesic drug can obtain surprisingly enhanced pain relief when administered after surgery.

[0389] The methods disclosed herein include administering to a patient in need of post-operative pain treatment: (1) a composition comprising an NK-1 receptor antagonist disclosed herein prior to surgery and daily thereafter for 1-6 days; and (2) a composition comprising a local anesthetic (e.g., bupivacaine or ropivacaine) and an NSAID (e.g., meloxicam) prior to surgery, during surgery, or at the end of surgery. In some embodiments, the composition comprising an NK-1 receptor antagonist is administered systemically, e.g., orally or by IV. In some embodiments, the composition comprising a local anesthetic and an NSAID is in an extended release form as disclosed herein. In some embodiments, an extended release composition comprising a local anesthetic and an NSAID is administered to the surgical site. In some embodiments, the NK-1 receptor antagonist is aprepitant. In some embodiments, the local anesthetic is bupivacaine. In some embodiments, the NSAID is meloxicam.

[0390] The methods disclosed herein include administering to a patient in need of post-operative pain treatment a composition comprising an NK-1 receptor antagonist, an NSAID, a local anesthetic, and a delivery vehicle as disclosed herein. The administration occurs before surgery, during surgery, or at the end of surgery. The method may further include administering the composition comprising the NK-1 receptor antagonist daily for 1-6 days after surgery. In some embodiments, the composition comprising the NK-1 receptor antagonist, an NSAID, and a local anesthetic is in the form of an extended release composition as disclosed herein. In some embodiments, the extended release composition comprising the NK-1 receptor antagonist, an NSAID, and a local anesthetic is administered to the surgical site. In some embodiments, the NK-1 receptor antagonist is aprepitant. In some embodiments, the local anesthetic is bupivacaine. In some embodiments, the NSAID is meloxicam.

[0391] The methods disclosed herein include administering to a patient in need of post-operative pain treatment: (1) an NK-1 receptor antagonist and an NSAID disclosed herein before surgery and daily thereafter for 1-6 days, orally, IV, subcutaneously, or by other means that results in systemic exposure; and (2) a composition comprising a local anesthetic before surgery, during surgery, or at the end of surgery. In some embodiments, the NK-1 receptor antagonist and the NSAID are provided in a single composition. In some embodiments, the NK-1 receptor antagonist and the NSAID are provided in separate compositions. In some embodiments, the composition comprising a local anesthetic is in an extended release form. In some embodiments, an extended release composition comprising a local anesthetic is administered to the surgical site. In some embodiments, the composition comprising an NK-1 receptor antagonist and an NSAID is in the form of an extended release composition disclosed herein. In some embodiments, the NK-1 receptor antagonist is aprepitant. In some embodiments, the local anesthetic is bupivacaine. In some embodiments, the NSAID is meloxicam.

[0392] Example 1 describes three studies conducted to evaluate the ability to reduce postoperative incision (postoperative or POP) pain in a porcine model system.Using a porcine postoperative (POP) pain model system, in which a 7 cm long skin and fascial incision is made on the left flank of pigs under general anesthesia, NK-1 receptor antagonists are applied to the wound alone or in combination with analgesics (i.e., bupivacaine and meloxicam).The skin incision is then closed using sterile sutures.Postoperative pain is assessed using von Frey methodology, with the results shown in Figure 1.

[0393] 1 is a bar graph of retraction force (gram force) as a function of time after surgery (hours) measured for in vivo administration to pigs of a composition comprised of aprepitant once preoperatively and daily for 5 days postoperatively (Group 1, hatched), or in combination with a once intraoperative administration of a composition comprising bupivacaine and meloxicam (Group 2, dotted), or for in vivo administration to pigs of a composition comprised of aprepitant once preoperatively (Group 3, vertically shaded), combined with a once intraoperative administration of a composition comprising bupivacaine and meloxicam. The efficacy of the use of aprepitant in combination with CAM lasted longer and provided deeper analgesic effects than aprepitant alone.

[0394] Example 2 describes studies conducted to evaluate the analgesic effects of (1) co-administration of aprepitant with a bupivacaine composition, (2) co-administration of aprepitant with a meloxicam composition, and (3) co-administration of a lower dose of aprepitant than that of Example 1 (6.0 mg / kg in Example 1 vs. 3.0 mg / kg in Example 2) with a composition containing both bupivacaine and meloxicam. The studies used the porcine model system described in Example 1. Postoperative pain was assessed using von Frey methodology with the results shown in FIG. 2.

[0395] FIG. 2 shows that (1) co-administration of aprepitant and meloxicam, e.g., 6.0 mg / kg aprepitant by slow IV push 30 minutes before surgery and then daily for 5 days after von Frey fiber assessment, with 4.0 g of an extended release formulation of meloxicam to the edges of the surgical incision prior to suturing, had no analgesic effect (Group 4); (2) co-administration of aprepitant and bupivacaine, e.g., 6.0 mg / kg aprepitant by slow IV push 30 minutes before surgery and then daily for 5 days after von Frey fiber assessment, with 4.0 g of an extended release formulation of bupivacaine to the edges of the surgical incision prior to suturing, only had analgesic activity consistent with bupivacaine alone (Group 3); and (3) co-administration of a low dose of aprepitant with a composition containing both bupivacaine and meloxicam, e.g., 30 minutes before surgery and then daily for 5 days after von Frey fiber assessment, had no analgesic effect (Group 4). Concomitant administration of 3.0 mg / kg aprepitant by slow IV push daily for 5 days following Frey fiber assessment, along with 4.0 g of a composition containing bupivacaine and meloxicam administered to the wound edges prior to suturing, demonstrated sustained good analgesia for the 5 days of treatment (Group 5).

[0396] Example 3 further describes a study conducted to evaluate the analgesic effect of low doses of aprepitant (e.g., 1.5 mg / kg) and less frequent administration of aprepitant. The study used the pig model system described in Example 1. Postoperative pain was assessed using von Frey methodology, with the results shown in Figure 3.

[0397] FIG. 3 is a bar graph of retraction force (gram force) as a function of time (hours) following in vivo administration to animals of compositions comprised of the test compositions as shown: (i) IV aprepitant at a dose of 1.5 mg / kg administered once pre-operatively and daily for 5 days post-operatively and extended release formulations of bupivacaine and meloxicam administered once intraoperatively in 3.4 mL by injection into the wound margin (Group 6, solid bars); (ii) IV aprepitant at a dose of 6.0 mg / kg administered once pre-operatively and 2 and 3 days post-operatively and extended release formulations of bupivacaine and meloxicam administered once intraoperatively in 3.4 mL by injection into the wound margin (Group 7, hatched bars). ), (iii) IV aprepitant at a dose of 6.0 mg / kg administered once preoperatively and 3, 4, and 5 days after surgery with an extended release formulation of bupivacaine and meloxicam administered once intraoperatively via injection into the wound margin in 3.4 mL (Group 8, bar with horizontal stripe), and (iv) oral suspension of meloxicam administered once preoperatively at a dose of 0.5 mg / kg with IV aprepitant administered once preoperatively and once daily for 5 days after surgery with an extended release formulation of bupivacaine administered once intraoperatively via injection into the wound margin in 3.4 mL (Group 9, bar with dotted stripe). When aprepitant was administered at 1.5 mg / kg, good analgesic effects were observed for 3 days of treatment, but were significantly reduced on days 4 and 5. Animals in Group 7 dosed on days 1-3 show enhanced analgesia followed by a somewhat unexpected decrease in analgesia on day 4. Group 8 animals, in which dosing began on day 3, do not show enhanced analgesia. It therefore appears that dosing with CINVANTI should be initiated prior to surgery and administered daily thereafter.

[0398] Example 4 evaluated the effect of bupivacaine, meloxicam and aprepitant formulated into an extended release formulation containing all three active agents for administration into a surgical incision. The study used the porcine model system described in Example 1. Postoperative pain was assessed using von Frey methodology, with the results shown in Figure 5.

[0399] 5 is a bar graph of withdrawal force (gram force) as a function of time (hours) following in vivo administration to animals of two compositions consisting of a combination of bupivacaine, meloxicam, and one formulated with a high concentration of aprepitant and one formulated with a low concentration of aprepitant. Both combination formulations of bupivacaine, meloxicam, and aprepitant administered as a single wound site dose during surgery provided nearly complete analgesia for the duration of the study.

[0400] Figure 4 compares the analgesic effects of aprepitant dosed at 1.5, 3.0, and 6.0 mg / kg based on the data of Examples 1-3. These results show that the dose response for aprepitant at a dose of 3 mg / kg provides enhanced analgesia for the duration of aprepitant dosing, and that 1.5 mg / kg provides enhanced analgesia for the 3 days that a composition containing bupivacaine and meloxicam typically provides analgesia.

[0401] Example 5 evaluated various combinations of bupivacaine, meloxicam, and aprepitant. Meloxicam and aprepitant, aprepitant alone, bupivacaine, low concentrations of meloxicam and aprepitant, and bupivacaine and An extended-release formulation of aprepitant was compared to an extended-release formulation of bupivacaine, meloxicam, and aprepitant. None of the combination formulations tested provided analgesia comparable to the combination of bupivacaine, meloxicam, and aprepitant.

[0402] Figure 6 is a bar graph comparing the analgesic effects of various combinations of bupivacaine, meloxicam and aprepitant as described in Example 5. The combination formulation of bupivacaine, meloxicam and aprepitant (Group 12, solid bars) administered as a single wound site dose during surgery provided excellent analgesia throughout the study period. In contrast, formulations of bupivacaine and aprepitant (Group 13, horizontal bars), bupivacaine, low concentrations of meloxicam and aprepitant (Group 14, checkered bars), aprepitant alone (Group 15, diagonal bars), and meloxicam and aprepitant (Group 16, dotted bars) provided moderate analgesia for the first 24 hours with the bupivacaine-containing formulation, and little analgesia was observed from 24 hours to 114 hours. EXAMPLES

[0403] The following examples are illustrative in nature and are not intended to be limiting.

[0404] Example 1 Comparison of postoperative pain reduction Various methods were evaluated for their ability to reduce postoperative incisional (post-operative or POP) pain in a porcine model system. In this model, a 7 cm long skin and fascial incision was made in the left flank under general anesthesia. Aprepitant and / or bupivacaine and meloxicam were applied to the wound. The skin incision was then closed using sterile sutures. All studies described below evaluated 4 pigs per group.

[0405] Postoperative pain was assessed using von Frey methodology. von Frey filaments (Ugo Basile) were applied to the flank skin surface approximately 0.5 cm proximal to the incision line. Increasing diameters of filaments were applied (thicker fibers with higher gram forces, thinner fibers with lower gram forces) until the animal withdrew from the stimulus. Each filament was applied 3-5 times. If no withdrawal occurred, a thicker filament was applied. The maximum filament force was 60 g. If withdrawal occurred, a thinner filament was applied. By alternating between filament thicknesses, the gram force required to produce a withdrawal response was determined and recorded. The greater the force applied, the more effective the analgesia.

[0406] Several studies have evaluated an emulsion composition containing aprepitant with saline (1:7 dilution) and administered by intravenous infusion at 6mg / kg administered as a slow bolus via an IV catheter in the ear. In one study, eight piglets divided into two groups of four piglets were administered a single dose of aprepitant before surgery, followed by daily dosing for five days thereafter. One group of four did not receive any further study drug, and one group of four received a single dose of an extended release combination of bupivacaine and meloxicam administered to the wound site during surgery. In a second study, four piglets were administered a single dose of aprepitant before surgery, and also received a single dose of an extended release combination of bupivacaine and meloxicam administered to the wound site during surgery.

[0407] Extended release bupivacaine and meloxicam were administered after the incision was made. Each test composition was administered by subcutaneous injection at the lateral edge of the wound. Table 1 summarizes the test groups and compositions. Analgesia was assessed by response in the von Frey test as previously described. The baseline (preoperative) withdrawal score in the von Frey test was 60 g. [Table 1]

[0408] The average von Frey response for animals in each test group is shown in Figure 1, where the withdrawal force (gram force) is shown as a function of time (hours) after in vivo administration to pigs. The test compositions are shown as follows: (i) IV aprepitant at a dose of 6 mg / kg administered once before surgery and daily for 5 days after surgery (Group 1, hatched bar); (ii) IV aprepitant at a dose of 6 mg / kg administered once before surgery and daily for 5 days after surgery and an extended release formulation of bupivacaine and meloxicam administered once intraoperatively by injection into the wound margin (Group 2, dotted bar); (iii) IV aprepitant at a dose of 6 mg / kg administered once 30 minutes before surgery and an extended release formulation of bupivacaine and meloxicam administered once intraoperatively by injection into the wound margin (Group 3, vertically lined bar). The tested compositions are presented in Tables 2 and 3 below. [Table 2] [Table 3]

[0409] For animals treated daily with IV aprepitant, little analgesic response was observed.In contrast, the combined treatment of daily IV aprepitant and a single wound site administration of extended release bupivacaine and meloxicam during surgery resulted in almost complete analgesia during the study period.The group that was administered aprepitant only before surgery and a single wound site administration of extended release bupivacaine and meloxicam during surgery showed very good analgesia on day 1, but at 24 hours and later, analgesia was lower.

[0410] Example 2 Postoperative pain reduction using low doses of aprepitant The analgesic effect of low doses of aprepitant (i.e., less than 6.0 mg / kg) was evaluated following a similar procedure described in Example 1. The analgesic effect of coadministration of aprepitant with an extended release formulation of meloxicam or an extended release formulation of bupivacaine was also evaluated.

[0411] The study groups and compositions are summarized in Table 4. Analgesia was assessed by response in the von Frey test as previously described. The baseline (pre-operative) withdrawal score in the von Frey test was 60 g. [Table 4]

[0412] The aprepitant compositions in Table 4 are the same as the compositions containing aprepitant in Table 2. The bupivacaine + meloxicam compositions in Table 4 are the same compositions containing bupivacaine and meloxicam in Table 3. The bupivacaine and meloxicam compositions in Table 4 are presented in Tables 5 and 6, respectively: [Table 5] [Table 6]

[0413] The average von Frey response for animals in each test group is shown in FIG. 2, where withdrawal force (gram force) is shown as a function of time (hours) after in vivo administration to pigs. The test compositions are shown as follows: (i) IV aprepitant at a dose of 3.0 mg / kg administered once pre-operatively and daily for 5 days after surgery with an extended release formulation of bupivacaine and meloxicam administered once intraoperatively by injection into the wound margin in 3.4 mL (Group 5, hatched bars); (ii) IV aprepitant at a dose of 6.0 mg / kg administered once pre-operatively and daily for 5 days after surgery with an extended release formulation of bupivacaine administered once intraoperatively by injection into the wound margin in 3.4 mL (Group 3, dotted bars); and (iii) IV aprepitant at a dose of 6.0 mg / kg administered once pre-operatively and daily for 5 days after surgery with an extended release formulation of meloxicam administered once intraoperatively by injection into the wound margin in 3.4 mL (Group 4, vertically striped bars).

[0414] Group 4 showed no analgesic activity. Group 3 showed analgesic activity consistent with the bupivacaine composition alone. These results indicate that the analgesic effect of aprepitant was observed only when both bupivacaine and meloxicam were co-administered. Group 5 showed good analgesia for 5 days of treatment, but it decreased significantly on the 6th and 7th days.

[0415] Example 3 Postoperative pain reduction with different aprepitant dosing times Another study following the same experimental procedure described in Example 1 evaluated the potential analgesic effect of low doses of aprepitant evaluated in Examples 1 and 2. To evaluate whether the effect of aprepitant was sustainable after an extended period of dosing, this study also evaluated the effect of a 3-day dosing of aprepitant co-administered with extended release formulations of bupivacaine and meloxicam. Conversely, this study also evaluated the effect of delaying dosing of aprepitant and dosing of extended release formulations of bupivacaine and meloxicam for several days after surgery. Finally, to determine whether the effect of locally delivered meloxicam can be replaced by systemically delivered meloxicam, oral dosing of meloxicam combined with local delivery of extended release formulations of bupivacaine and IV administration of aprepitant was evaluated.

[0416] Group 6 received 1.5 mg / kg aprepitant by slow IV push 30 minutes before surgery and then daily for 5 days after von Frey fiber assessment, and the surgical incision was dosed with 3.4 mL of an extended release formulation of bupivacaine and meloxicam administered to the wound margins followed by suturing.

[0417] Animals in Group 7 were dosed with 6 mg / kg aprepitant by slow IV push 30 minutes prior to surgery and on days 2 and 3 (24 and 48 hours) after von Frey fiber assessment. Animals in Group 8 were dosed with 6 mg / kg aprepitant by slow IV push beginning on day 3 with additional doses on days 4 and 5 (48, 72, and 96 hours) after von Frey fiber assessment. Animals in both groups also received 3.4 mL of an extended release formulation of bupivacaine and meloxicam at the edges of the surgical incision, which were then sutured.

[0418] Animals in Group 9 were dosed with 0.5 mg / kg meloxicam (Loxicom oral suspension) and 6 mg / kg aprepitant by slow IV push 30 minutes prior to surgery and then daily for 5 days after von Frey fiber assessment. Animals in this group also received 3.4 mL of an extended release formulation of bupivacaine at the edges of the surgical incision, which were then sutured.

[0419] The study groups and compositions are summarized in Table 7. Analgesia was assessed by response in the von Frey test as previously described. The baseline (pre-operative) withdrawal score in the von Frey test was 60 g. [Table 7] The aprepitant compositions in Table 7 are the same as the aprepitant-containing compositions in Table 2. The bupivacaine + meloxicam compositions in Table 7 are the same bupivacaine and meloxicam-containing compositions in Table 3. The bupivacaine compositions in Table 7 are the same as the compositions in Table 5.

[0420] The average von Frey response for animals in each test group is shown in Figure 3, where withdrawal force (gram force) is shown as a function of time (hours) after in vivo administration in pigs. Animals in Group 6 (solid bars) showed good analgesia for 3 days of treatment, which decreased significantly on days 4 and 5.

[0421] Comparing the results for Groups 7 (hatched bars) and 8 (hatched bars), focusing on the results on day 2 (48 hour time point), animals in Group 7 dosed on days 1-3 show enhanced analgesia, followed by some unexpected decline in analgesia on day 4. Animals in Group 8, where dosing began on day 3, do not show enhanced analgesia. Thus, it appears that aprepitant dosing is best if initiated preoperatively and should be dosed daily thereafter.

[0422] Group 9 (dotted bars) shows poor analgesia from 24 to 144 hours. These results indicate that meloxicam is optimally effective when administered topically. While systemically administered meloxicam can provide analgesia, high doses (greater than 0.5 mg / kg) may be required.

[0423] The results of this study and the studies in Examples 1 and 2 are presented in Figure 4 for comparison. These results show that the dose response for aprepitant at a dose of 6 mg / kg (Group 2, dotted bars) provides enhanced analgesia for the duration of aprepitant dosing, 3 mg / kg (Group 5, hatched bars), and 1.5 mg / kg (Group 6, horizontal bars) provide enhanced analgesia for the 3 days during which extended release formulations of bupivacaine and meloxicam typically provide analgesia. Clinical history data for the extended release combination of bupivacaine and meloxicam (2.5% w / w and 0.075% w / w, respectively) are shown in solid bars.

[0424] Example 4 Coformulated extended-release bupivacaine, meloxicam and aprepitant A study was conducted to evaluate the efficacy of bupivacaine, meloxicam and aprepitant formulated into an extended release formulation containing all three active agents for administration into a surgical incision. Group 10 animals were dosed with 3.4 mL of an extended release formulation containing bupivacaine, meloxicam and a high concentration of aprepitant. Group 11 animals were dosed with 3.4 mL of an extended release formulation containing bupivacaine, meloxicam and a low concentration of aprepitant.

[0425] Table 8 summarizes the study groups and compositions. Analgesia was assessed by response in the von Frey test as previously described. The baseline (pre-operative) withdrawal score in the von Frey test was 60 g. [Table 8]

[0426] The compositions are presented in Table 9. [Table 9] [Table 10]

[0427] The mean von Frey responses for animals in each test group are shown in Figure 5, where withdrawal force (gram force) is shown as a function of time (hours) after in vivo administration in pigs. In both Groups 10 and 11 animals, the combination formulation of bupivacaine, meloxicam, and high or low concentrations of aprepitant administered as a single wound site dose during surgery provided near complete analgesia for the duration of the study. Clinical history data for the extended release combination of bupivacaine and meloxicam (2.5% w / w and 0.075% w / w, respectively) are shown as solid bars.

[0428] Example 5 Evaluating the contribution of the combination of bupivacaine, meloxicam and aprepitant The test groups and compositions are summarized in Table 11. Analgesia was assessed by response in the von Frey test as previously described. The baseline (pre-operative) withdrawal score in the von Frey test was 60 g. [Table 11]

[0429] The compositions are presented in Tables 12-16. [Table 12] [Table 13] [Table 14] [Table 15] [Table 16]

[0430] The mean von Frey responses for animals in each test group are shown in Figure 6, where withdrawal force (gram force) is shown as a function of time (hours) after in vivo administration in pigs. The combination formulation of bupivacaine, meloxicam, and aprepitant (Group 12, solid bars), administered as a single wound site administration during surgery, provided excellent analgesia for the duration of the study. In contrast, formulations of bupivacaine and aprepitant (Group 13, lined bars), bupivacaine, low concentrations of meloxicam, and aprepitant (Group 14, grid bars), aprepitant alone (Group 15, hatched bars), and meloxicam and aprepitant (Group 16, dotted bars) provided moderate analgesia for the first 24 hours with little analgesia seen from 24 hours to 114 hours relative to the bupivacaine-containing formulation.

[0431] Further embodiments of the present compositions and methods will be apparent from the description, drawings, examples, and claims. As can be understood from the foregoing description, any and all features described herein, and any and all combinations of two or more such features, are included within the scope of the present disclosure, provided that the features included in such combinations are not mutually inconsistent. Moreover, any feature or combination of features may be specifically excluded from any embodiment of the invention. While compositions and methods are described in terms of "comprising," "containing," or "including" various components or steps, compositions or methods may also be described in terms of "comprising," "containing," or "including," various components or steps. The components and compositions may "consist essentially of" or "consist of." The term "consist essentially of" excludes active agents not listed after the term.

Claims

[Claim 1] The invention described in the specification.

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