US 20150024031A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0024031 A1 Rabinow et al. (43) Pub. Date: Jan. 22, 2015

(54) METHODS AND COMPOSITIONS FOR Publication Classi?cation REDUCING PAIN, INFLAMMATION, AND/OR IMMUNOLOGICAL REACTIONS (51) Int- Cl ASSOCIATED WITH PARENTERALLY A61K 31/445 (200601) ADMINISTERING A PRIMARY A61K 31/426 (200601) THERAPEUTIC AGENT A61K 9/16 (200601) A61K 31/765 (2006.01) (71) ApplicantszBAXTER INTERNATIONAL INC., A61K 38/16 (200601) Deer?eld, IL (US); BAXTER A61K 9/10 (200601) HEALTHCARE SA, Glattpark A61K 31/4418 (200601) (Opifkon) (CH) A61K 31/536 (2006.01) (52) US. Cl. (72) Inventors: Barrett Rabinow, Skokie, IL (Us); Jane CPC ...... A61K 31/445 (2013.01); A61K 31/4418 0_ Werling’ Arlington Heights, IL (Us) (2013.01); A61K31/426 (2013.01); A61K 31/536 (2013.01); A61K 31/765 (2013.01); (73) Assignees: BAXTER INTERNATIONAL INC., A61K 38/16 (201301); fagggglofonon; Deer?eld, IL (US); BAXTER _ _ 12013-01? HEALTHCARE SA Glanpark USPC ...... 424/450, 424/489, 546/335, 514/365, (Op?kon) (CH) ’ 514/230.5; 424/78.37; 514/114; 514/1.1; 424/484 (57) ABSTRACT (21) APPI- N04 14/333,004 Disclosed herein are methods and pharmaceutical composi tions for reducing the pain associated With parenterally _ administering a therapeutic agent. The methods and compo (22) Flled: JUL 16’ 2014 sitions comprise a dispersion comprising microparticles of an analgesic agent in an amount effective to reduce the pain, Related U 5 Application Data in?ammation, and/ or immunological reaction associated ' ' With parenterally administering a primary therapeutic agent, (60) Provisional application No. 61/847,519, ?led on Jul. Wherein the microparticles of the analgesic agent have an 17, 2013. effective particle size of less than 20 micrometers. Patent Application Publication Jan. 22, 2015 Sheet 1 0f 8 US 2015/0024031 A1

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METHODS AND COMPOSITIONS FOR induction of a proliferative cellular response, the production REDUCING PAIN, INFLAMMATION, AND/OR of soluble mediators (including, but not limited to, cytokines, IMMUNOLOGICAL REACTIONS oxygen radicals, enzymes, prostanoids, and vasoactive ASSOCIATED WITH PARENTERALLY amines), or cell surface expression of new or increased num ADMINISTERING A PRIMARY bers of mediators (including, but not limited to, major histo THERAPEUTIC AGENT compatability antigens and cell adhesion molecules). An adverse antigenic response can involve in?ammatory cells FIELD OF THE INVENTION including monocytes, macrophages, T lymphocytes, B lym phocytes, granulocytes (polymorphonuclear leukocytes [0001] This invention is directed to methods and pharma including neutrophils, basophils, and eosinophils), mast ceutical compositions comprising microparticles of an anal cells, dendritic cells, Langerhans cells, and endothelial cells. gesic agent for reducing pain, in?ammation, and/ or immuno Adverse antigenic responses can cause damage to cells and logical reactions associated with parenteral administration of tissues, with severe and even fatal consequences. a primary therapeutic agent. [0006] Many approaches to reduce the potential adverse effects of parenteral administration have been tested. Such BACKGROUND OF THE INVENTION efforts have been largely focused on reducing the concentra [0002] Parenteral dosing of therapeutic agents such as tion of the drug that is in direct contact with body tissues. To drugs, peptides, proteins, vaccines, and the like bypasses the date, efforts have largely focused on reducing the drug con gastrointestinal system and is therefore frequently preferred centration that is in direct contact with body tissues by chang to optimize the absorption, distribution, metabolism, and/or ing the formulation of a pharmaceutical composition. For excretion parameters of the agent. However, it is well known example, with respect to lipid-soluble drugs formulated as that parenteral administration of a therapeutic agent fre emulsions, the ratio of excipient oil to drug has been quently causes pain, in?ammation, and/or immunological increased so as to ‘sequester’ the drug away from the body reactions following exposure of the therapeutic agent to the tissues and encapsulate it within the interior bulk of the emul cells and tissues of the body. sion particle, thereby reducing the concentration of the drug [0003] For example, parenteral administration of a thera on the surface of the emulsion particle and slowing the rate of peutic agent can cause sustained pain at the site of adminis uptake by body tissues in transient contact with the particle tration. For some liquid drug formulations, the pain can be and diminishing any associated reaction (e.g., pain or in?am attributed to the precipitation of the drug at the administration mation) at the site of administration. Other efforts to reduce site (Alvarez-Nunez and Yalkowsky, In! J Pharm, 1999; 185 the potential adverse effects of parenteral administration (1): 45-9). Thus, parenteral administration of relatively con involve optimizing the pH or the osmotic strength of the centrated liquid formulations and particulate drug formula formulation. tions in particular can often be uncomfortable for recipients. [0007] The solubility of some drugs in preferred excipients [0004] Parenteral dosing of a therapeutic agent can also for preparing emulsions such as soybean oil and lecithin is so cause local in?ammation at the site of administration. When poor, however, that relatively toxic excipients such as poly tissues are damaged, for example, by the parenteral adminis ethoxylated caster oil (available from BASF under the Cre tration of a therapeutic agent, cytokines that cause in?amma mophor® and Kolliphor® trade names) are required. For tion are released and can lead to an in?ammatory cascade. example, polyethoxylated caster oil has been used, for In?ammatory cascades are generally considered to include example, to solubilize paclitaxel to facilitate parenteral two phases. The ?rst phase is a cellular response, wherein administration. Generally, such formulations are undesirable white blood cells such as granulocytes, macrophages and because the polyethoxylated caster oil excipient itself fre lymphocytes are recruited to the site of injury, e.g., to clear quently induces an allergic response. Reported symptoms damaged tissues, attacking bacteria, and remove noxious par include tightness in the chest, shortness of breath, and similar ticles. Afterwards, there is a healing phase associated with a reactions consistent with severe anaphylactic responses. rebuilding of tissue and reduction in concentration of white [0008] In addition, it is known that the pH and osmolality of blood cells. The increased ?ow of ?uids, proteins, and cells to pharmaceutical formulations can be controlled to minimize the site of injury during the ?rst phase of the in?ammatory injection site pain. For example, the pH of most pharmaceu cascade results in the symptoms typically associated with tical formulations is held between about 4.2 to 10 in order to in?ammation, including, but not limited to, pain, heat, swell minimize injection site pain. Similarly, the osmolality of most ing, erythema, and leukocyte migration. Left unchecked (as pharmaceutical formulations is generally held between 150 con?rmed, for example, by sustained elevated leukocyte con mosmol/L and 800 mosmol/L to minimize injection site pain. centrations), in?ammation can lead to more serious effects, [0009] Additional alternative dosage forms, including par such as tissue necrosis, endothelial loss, thrombosis, edema, ticle formulations have been proposed. Although antiretrovi hemorrhage, and loss of function. ral drugs such as ritonavir, atazanavir, and efavirenz are typi [0005] Parenteral administration of a therapeutic agent can cally administered orally, nanosuspension formulations also cause a systemic immunological reaction. The systemic thereof have been shown to be long-acting and can elicit immunological reaction can be an adverse response to a for potent antiretroviral and neuroprotective responses in sub eign antigen, such as a hypersensitivity, typically, an allergic jects (Dash et al., AIDS, 2012; 26: 2135-44). However, these reaction. For example, anakinra (Kineret®, Swedish Orphan nanosuspension formulations frequently cause injection site Biovitrum) is a drug used to treat rheumatoid arthritis that can reactions when administered parenterally, e. g., by subcutane cause pain at the site of administration when administered ous or intramuscular injection. Because the performance or parenterally (typically, by injection) and can also trigger an optimal e?icacy of a drug formulated as a nanosuspension allergic reaction, particularly in subjects sensitive to bacterial depends to a large degree on the characteristics of the nano proteins. An adverse antigenic response may include the suspension particle, including its size, shape, zeta potential, US 2015/0024031 A1 Jan. 22, 2015

and surface ligands, and each of the foregoing can exacerbate [0013] In view of the foregoing, there exists a need for injection site reactions, the formulation criteria necessary for compositions and methods capable of reducing the pain, minimizing any adverse affects of parenteral administration in?ammation, and immunological reactions associated with must be carefully balanced against the requirements for opti parenterally administering a therapeutic agent to a subject in mal drug e?icacy. need thereof that preferably does not cause the subject to [0010] Other approaches to addressing pain and in?amma experience pain, induce in?ammation, or compromise the tion at the site of administration have relied on the co-admin e?icacy of the therapeutic agent. istration of a second agent. For example, hyaluronidase has been co-administered with primary therapeutic agents such as SUMMARY OF THE INVENTION bisphosphonates in order to degrade the connective tissue [0014] The invention provides methods of reducing the hyaluronic acid and improve the absorption of the primary pain, in?ammation, and/or immunological reaction associ therapeutic from the site of administration. Unfortunately, an ated with parenterally administering a primary therapeutic unacceptable number of reactions at the site of injection were agent. observed in subject receiving bisphosphonates. [0015] In one embodiment, a method according to the [0011] Local anesthetic agents such as bupivacaine (typi invention comprises parenterally administering to a subject in cally administered by injection or infusion), ropivacaine need thereof a therapeutically effective amount of a disper (typically administered by injection or infusion), and sion comprising microparticles of a primary therapeutic lidocaine (typically administered by injection or topical agent, the dispersion further comprising microparticles of an application) have been used to relieve pain. However, the analgesic agent in an amount effective to reduce the pain, action of such agents is limited and subject to the drug’s in in?ammation, and/ or immunological reaction associated vivo distribution, metabolism, and excretion. Ropivacaine with parenterally administering the primary therapeutic hydrochloride ((S)iN-(2,6-dimethylphenyl)-1-propylpip agent, wherein the microparticles of the primary therapeutic eridine-2-carboxamide) is a local anesthetic drug belonging agent and the microparticles of the analgesic agent have an to the amino amide group which works by blocking nerve effective particle size of less than 20 micrometers. impulses and preventing central (spinal) pain circuits from [0016] In another embodiment, a method according to the developing. The name ropivacaine refers to both the racemate invention comprises parenterally co-administering to a sub and the marketed S-enantiomer Naropin® (AstraZeneca), ject in need thereof a therapeutically effective amount of a which is currently marketed for delivery as an injectable. ?rst dispersion comprising microparticles of a primary thera Ropivacaine formulations and administration are described peutic agent and a second dispersion comprising micropar in EP 151110 B1, EP 239710 B1, and US. Pat. No. 6,620, ticles of an analgesic agent, wherein the second dispersion is 423. Naropin® is currently indicated for surgical anesthesia administered in an amount effective to reduce the pain, via the epidural and intrathecal (spinal) routes of administra in?ammation, and/ or immunological reaction associated tion, major nerve blocks and ?eld block in?ltration. The drug with parenterally administering the primary therapeutic is also indicated for acute pain management via the epidural agent, wherein the microparticles of the primary therapeutic route and also ?eld blocks, intraarticular injection and con agent and the microparticles of the analgesic agent have an tinuous peripheral nerve block. A previous study (Beaussier effective particle size of less than 20 micrometers. et al., Anesthesiology, 2007; 107: 461 -8) showed that continu [0017] In another embodiment, a method according to the ous preperitoneal administration of 0.2% ropivacaine at 10 invention comprises parenterally co-administering to a sub mL per hour for 48 hours after open colorectal resection ject in need thereof a therapeutically effective amount of a reduced morphine consumption, improved pain relief, and primary therapeutic agent and a dispersion comprising micro accelerated postoperative recovery. As a result of that study, particles of an analgesic agent, wherein the dispersion com ropivacaine in?ltration for pain control following various prising microparticles of an analgesic agent is administered in types of surgery has been popularized (e.g., Forastiere et al., an amount effective to reduce the pain, in?ammation, and/ or Brit. J. Anesthesia, 2008; 101: 841-7). Post-operatively, ropi immunological reaction associated with parenterally admin vacaine is administered by continuous infusion or via a pump istering the primary therapeutic agent, wherein the micropar through a catheter running the length of incision for local pain ticles of the analgesic agent have an effective particle size of control. The need for continuous administration of the anal less than 20 micrometers. gesic agent in order to provide long-term relief, however, can [0018] The invention also provides a pharmaceutical com itself be uncomfortable and inconvenient for the recipient. position comprising a dispersion comprising microparticles [0012] The pain, in?ammation, and/or immunological of an analgesic agent in an amount effective to reduce the reactions associated with parenteral administration of a thera pain, in?ammation, and/or immunological reaction associ peutic agent can limit the clinical utility of the therapeutic ated with parenterally administering a primary therapeutic agent, particularly when the primary therapeutic agent is agent, wherein the microparticles of the analgesic agent have administered in particulate form or is known to induce an an effective particle size of less than 20 micrometers. allergic reaction in an unacceptable proportion of recipients. [0019] In another embodiment, a pharmaceutical composi Conventional approaches to modifying pharmaceutical for tion according to the invention comprises a ?brin matrix and mulations of therapeutic agents have had limited success in microparticles of an analgesic agent, said microparticles combating the pain, irritation, and/or immunological reac being dispersed within the ?brin matrix, wherein the micro tions associated with parenteral administration. Additionally, particles of the analgesic agent have an effective particle size administering analgesic agents such as local anesthetics to of less than 20 micrometers. ameliorate the adverse effects of parenterally administering a [0020] In an additional embodiment, the invention provides primary therapeutic agent can be uncomfortable and incon a method of preventing or reducing pain, in?ammation, and/ venient, particularly when continuous administration is indi or immunological reactions in a subject suffering from arthri cated. tis, the method comprising delivering a composition accord US 2015/0024031 A1 Jan. 22, 2015

ing to the invention proximate to a site of arthritis, said strated by the reduction of pain and in?ammation achieved in composition being capable of releasing the analgesic agent in the application Examples. Such a reduction in pain and/or an amount effective for preventing or reducing pain, in?am in?ammation is particularly useful in the context of parenter mation, and/ or immunological reactions at the site of arthritis. ally administered sustained release formulations of a primary [0021] In another embodiment, the invention provides a therapeutic agent and chronically parenterally administered method of preventing or reducing pain, in?ammation, and/or drugs, which are known to cause frequent and persistent pain immunological reactions at a site of surgery or at a wound site and irritation in subjects receiving therapy. in a subject in need thereof, the method comprising delivering [0032] While addressing the pain associated with the a composition according to the invention proximate to the site parenteral administration of a primary therapeutic agent is an of surgery or the wound site, said composition being capable important consideration, resolving pain alone does not of releasing the analgesic agent in an amount effective for always indicate that in?ammation is also mitigated. For some preventing or reducing pain, in?ammation, and/or immuno drugs, there is only a weak correlation between injection site logical reactions at the site of surgery or the wound site. pain and tissue damage (W. Klement, “Pain, irritation and [0022] An analgesic agent according to the invention may tissue damage with injections.” Chapter 2 in Injectable Drug comprise a drug selected from the group consisting of anti Development, eds. P. K. Gupta and G. A. Brazeau. Inter histamines, mast cell stabilizers, corticosteroids, anti-in?am pharm, 1999). Because in?ammation can be severely damag matories, local anesthetics, and combinations thereof. ing, it is particularly useful to control the underlying in?am Examples of preferred analgesic agents include local anes matory reaction that often accompanies parenteral thetic agents such as lidocaine, mepivacaine, prilocalne, pro administration of drugs, rather than solely focus on a single paracaine, etidocaine, bupivacaine, levobupivacaine, ropiv symptom, such as pain. Thus, as shown in the application acaine, dibucaine, articaine, cocaine, procaine, tetracaine, examples, in one preferred embodiment, the methods and articaine, benzocaine, chloroprocaine, etidocaine, pramox compositions of the invention comprising microparticles of ine, dyclorine, benoxinate, butacaine, cyclomethycaine, an analgesic agent surprisingly and bene?cially can be used hexylcaine, piperocaine, procaine, tetracaine, dibucaine, to prevent or mitigate symptoms of in?ammation including, butamben, capsaicin, and combinations thereof. but not limited to, erythema, swelling, leukocyte migration, necrosis, endothelial loss, thrombosis, edema, and hemor BRIEF DESCRIPTION OF THE DRAWINGS rhage in addition to reducing injection site pain. [0023] FIG. 1 shows stability data over 12 weeks for ropi [0033] Furthermore, the aforementioned reduction in pain vacaine formulations l, 3, and 4. FIG. 1A shows the mean and/or in?ammation achieved in the application examples particle size of the ropivacaine suspensions. FIG. 1B shows corroborates that the methods and compositions of the inven the mean particle size of the ropivacaine suspensions and the tion can be used to prevent or reduce immunological reac 99% particle size of suspension 1. tions. Thus, although the invention is largely focused on the [0024] FIG. 2 shows the dissolution pro?le of ropivacaine pain and in?ammation associated with parenteral admini stra as measured by turbidity (N TU) over time (minutes). FIG. 2A tion of a primary therapeutic agent, the applicants note that shows the rate of ropivacaine dissolution for two concentra the observations in the application Examples demonstrating tions of ropivacaine (~0.25 mg/mL and ~0.l6 mg/mL) in that parenterally administering microparticles of analgesic PBS. FIG. 2B shows the rate of ropivacaine dissolution for agent can surprisingly and bene?cially reduce both the pain two concentrations of ropivacaine (~0.25 mg/mL and ~0.38 and in?ammation associated with an insult (such as that mg/mL) in plasma. caused by parenteral administration of a primary therapeutic) [0025] FIG. 3 shows electron micrographs of ropivacaine corroborate and indicate that parenteral administration of microparticles in a ?brin matrix. microparticles of an analgesic agent can also be used to treat [0026] FIG. 4 shows the release of ropivacaine from ?brin an adverse immunological response. Pain, in?ammation, and matrices into human plasma over a period of 8 days in vitro. adverse immunological responses generally are mediated by [0027] FIG. 5 shows the expected ropivacaine daily release the same immune responses. In this respect, it is known that from ?brin matrices into human plasma over a period of 8 parenterally administering a primary therapeutic agent to a days in vivo. subject in need thereof can render the subject susceptible to [0028] FIG. 6 shows the difference in hind limb weight adverse antigenic responses. In particular, the methods bearing for injected (right) and control (left) legs in rats according to the invention can be used to treat immunological treated with celecoxib or ropivacaine in a model of in?am reactions such as those caused by primary therapeutic agents mation. that render the subject susceptible to an adverse antigenic [0029] FIG. 7 shows the difference in foot dragging mea response, for example, proteins and peptides known to induce sured using gait analysis, with a higher gait analysis score adverse antigenic responses in substantial populations, pri indicating an increased tendency to drag the injected leg. mary therapeutics formulated as compositions having a pH [0030] FIG. 8 shows the difference in hind limb weight greater than 10 or having a pH less than 4.2, primary thera bearing (left) and foot-dragging (right) for normal, saline peutics formulated as compositions having an osmolality (control), celecoxib, and ropivacaine treated animals. greater than 800 mosmol/L (including greater than 1 osmol/ L) or having an osmolality less than 150 mosmol/ L (including DETAILED DESCRIPTION OF THE INVENTION less than 100 mo smol/ L), and/ or primary therapeutics formu lated as compositions including relatively toxic excipients [0031] The administration of microparticles of an analgesic such as polyethoxylated caster oil that can induce an allergic agent, particularly a local anesthetic agent such as ropiv response. For example, the primary therapeutic agent may be acaine, can bene?cially reduce pain, in?ammation, and/or a peptide or protein capable of eliciting a hypersensitivity, immunological reactions, such as those associated with i.e., allergic, response. Co-administration of a dispersion parenteral administration of a therapeutic agent, as demon comprising microparticles of an analgesic agent according to US 2015/0024031 Al Jan. 22, 2015

the invention can advantageously decrease the adverse anti tion associated with parenterally administering a therapeuti genic response and other immunological reactions associated cally effective amount of a primary therapeutic agent, with parenteral administration of the primary therapeutic wherein the microparticles of the analgesic agent have an agent. effective particle size of less than 20 micrometers. In one [0034] In one aspect, the primary therapeutic agent and aspect, the pharmaceutical composition further comprises a microparticles of an analgesic agent may be administered in therapeutically effective amount of microparticles of a pri sustained release formulations with similar release pro?les, mary therapeutic agent, wherein the microparticles of the such that the duration of action of both the primary therapeu primary therapeutic agent have an effective particle size of tic agent and the analgesic agent are substantially the same. In less than 20 micrometers. another aspect, the release of microparticles of an analgesic [0039] In another embodiment, a pharmaceutical composi agent from a sustained release formulation can occur for a tion according to the invention comprises a ?brin matrix and length of time greater than the period in which the primary microparticles of an analgesic agent, said microparticles therapeutic agent is released, thus providing extended relief being dispersed within the ?brin matrix, wherein the micro from pain, irritation, and/or immunological reaction associ particles of the analgesic agent have an effective particle size ated with parenteral administration of the primary therapeutic of less than 20 micrometers. In one aspect, the pharmaceuti agent. cal composition is formed by mixing the microparticles of the [0035] The reduction in the adverse and potentially danger analgesic agent with ?brino gen and then adding thrombin to ous effects of parenteral administration achieved using the the mixture to form a ?brin matrix containing dispersed invention minimizes the drawbacks of a parenterally admin microparticles. An example of a commercially available istered therapeutic agent and allows for the development of ?brin matrix composition is Tisseel® (Baxter International, formulations focused on maximizing ef?cacy, thereby Inc.). increasing the overall utility of the therapeutic agent. Further, [0040] In another embodiment, a method of preventing or because of the aforementioned reduction in adverse and reducing pain, in?ammation, and/or immunological reac potentially dangerous effects, the methods according to the tions in a subject suffering from arthritis according to the invention advantageously facilitate parenteral administration invention comprises delivering a pharmaceutical composi of particulate formulations of primary therapeutic agents. In tion comprising a ?brin matrix and microparticles of an anal one embodiment, a method according to the invention com gesic agent, optionally further comprising microparticles of a prises parenterally administering to a subject in need thereof primary therapeutic agent, proximate to a site of arthritis, said a therapeutically effective amount of a dispersion comprising composition being capable of releasing the analgesic agent microparticles of a primary therapeutic agent, the dispersion and/or primary therapeutic agent in an amount effective for further comprising microparticles of an analgesic agent in an preventing or reducing pain, in?ammation, and/or immuno amount effective to reduce the pain, in?ammation, and/or logical reactions at the site of arthritis. In one aspect, the immunological reaction associated with parenterally admin pharmaceutical composition is delivered directly to a site of istering the primary therapeutic agent, wherein the micropar arthritis, i.e., a joint, e.g., of the hand, wrist, elbow, jaw, neck, ticles of the primary therapeutic agent and the microparticles foot, shoulder, spine, ankle, hip, and/or knee. In another of the analgesic agent have an effective particle size of less aspect, the pharmaceutical composition is delivered to the than 20 micrometers. tissue and/or interstitial space surrounding or near the site of [0036] In another embodiment, a method according to the arthritis. invention comprises parenterally co-administering to a sub [0041] In a further embodiment, a method of preventing or ject in need thereof a therapeutically effective amount of a reducing pain, in?ammation, and/or immunological reac ?rst dispersion comprising microparticles of a primary thera tions at a site of surgery or at a wound site in a subject in need peutic agent and a second dispersion comprising micropar thereof according to the invention comprises delivering a ticles of an analgesic agent, wherein the second dispersion is pharmaceutical composition comprising a ?brin matrix and administered in an amount effective to reduce the pain, microparticles of an analgesic agent, optionally further com in?ammation, and/ or immunological reaction associated prising microparticles of a primary therapeutic agent, proxi with parenterally administering the primary therapeutic mate to the site of surgery or the wound site, said composition agent, wherein the microparticles of the primary therapeutic being capable of releasing the analgesic agent and/ or primary agent and the microparticles of the analgesic agent have an therapeutic agent in an amount effective for preventing or effective particle size of less than 20 micrometers. reducing pain, in?ammation, and/or immunological reac [0037] In another embodiment, a method according to the tions at the site of surgery or the wound site. In one aspect, the invention comprises parenterally co-administering to a sub pharmaceutical composition is delivered directly to a site of ject in need thereof a therapeutically effective amount of the surgery or at a wound site, e.g., at an incision, abrasion, primary therapeutic agent and a dispersion comprising micro contusion, laceration, and/ or puncture. In another aspect, the particles of an analgesic agent, wherein the dispersion com pharmaceutical composition is delivered to the tissue and/or prising microparticles of an analgesic agent is administered in interstitial space surrounding or near said site of surgery or an amount effective to reduce the pain, in?ammation, and/or wound site. In various aspects of the foregoing embodiments, immunological reaction associated with parenterally admin the analgesic agent may comprise ropivacaine. The ropiv istering the primary therapeutic agent, wherein the micropar acaine may be substantially free of the (R)-isomer of ropiv ticles of the analgesic agent have an effective particle size of acaine. In another aspect, the pharmaceutical composition less than 20 micrometers. according to this embodiment of the invention further com [0038] In one embodiment, a pharmaceutical composition prises microparticles of a primary therapeutic agent, said according to the invention comprises a dispersion comprising microparticles of the primary therapeutic agent being dis microparticles of an analgesic agent in an amount effective to persed within the ?brin matrix, wherein the microparticles of reduce the pain, in?ammation, and/or immunological reac the primary therapeutic agent have an effective particle size of US 2015/0024031 A1 Jan. 22, 2015

less than 20 micrometers. In various aspects, the micropar [0050] As used herein, the terms “parenteral” and ticles of the analgesic agent and/or primary therapeutic dis “parenterally” refer to the administration of an agent via any persed within the ?brin matrix have an effective particle size route other than oral administration. For example, parenteral of less than 20 micrometers, less than 15 micrometers, less administration may comprise injection, infusion, implanta than 10 micrometers, less than 5 micrometers, or less than 3 tion or any other mode of delivery other than ingestion to any micrometers. In one aspect, the microparticles of the analge site in or on the body ofa subject. sic agent and/ or the microparticles of the primary therapeutic [0051] As used herein, a “primary therapeutic agent” is an agent are released from the ?brin matrix over a course of at agent administered to a subject in need thereof that is capable least one day, at least two days, at least three days, at least four of preventing, reducing, treating, and/or ameliorating the days, at least ?ve days, at least six days, at least one week, or symptoms, pathology, and/or progression of a condition or more. disease affecting the subject. [0042] The following de?nitions may be useful in aiding the skilled practitioner in understanding the invention: [0052] As used herein, “proximate” refers to a location at, adjacent to, or near a reference site. For example, delivery of [0043] As used herein, an “adverse antigenic response” is an undesired immunological reaction triggered by an antigen. a pharmaceutical composition proximate to a site of arthritis, Adverse antigenic responses include four types of hypersen site of surgery, or a wound site refers to delivery of the sitivity reactions: 1) immediate, mediated primarily by IgE in composition directly to said site, as well as delivery of the response to antigens; 2) cytotoxic, mediated primarily by IgM composition to tissue and/or interstitial space contacting, sur or IgG and complement; 3) immune complex, mediated pri rounding, or near to said site. marily by IgG and complement; and 4) delayed-type, medi [0053] As used herein, a “subject” is a non-plant, non ated primarily by T-cells. protist living being. In one aspect, the subject is an animal. In [0044] As used herein, an “analgesic agent” is a drug particular aspects, the animal is a mammal. In more particular administered to a subject to prevent or relieve pain. aspects, the mammal is a human. In other aspects, the mam [0045] As used herein, a “depot” is an injected or implanted mal is non-human, such as a rodent, cat, dog, horse, or cow. As pharmaceutical formulation containing a reservoir of thera used herein, a “subject in need thereof” is a subject suffering peutic agent and/or an analgesic agent that releases a thera from a condition or disease who would bene?t from the peutically effective amount of the agent over an extended administration of a primary therapeutic agent and/or analge period of time, e.g., days or weeks. sic agent. [0046] As used herein, a “dispersion” is a mixture having at [0054] As used herein, the term “composition comprising least one dispersed or discontinuous phase present in a solid, the (S)-isomer” refers to a composition of a drug having a semi-solid or non-solid continuous phase. Representative single stereocenter or a pharmaceutically acceptable salt examples of dispersions in accordance with the disclosure thereof which is substantially free of the (R)-isomer of the include, but are not limited to, solid-in-solid, solid-in-liquid, drug or a pharmaceutically acceptable salt thereof. The term solid in gas (including solid in liquid in gas) compositions. A “substantially free of the (R)-isomer” refers to a composition dispersion can be substantially homogenous or non-homog containing less than 10% by weight, less than 5% by weight, enous. A suspension is a particular dispersion in which the less than 3% by weight, less than 2% by weight, less than 1% discontinuous solid phase, e.g., microparticles, can remain by weight, and/or less than 0.5% by weight of the (R)-isomer stably suspended, i.e., substantially free of aggregation, in the of the drug based on the total amount of drug in the compo continuous phase for any extended period of time, e.g., days sition. The total (R)-isomer and (S)-isomer content can be or weeks. determined using a standard HPLC column or other analyti [0047] As used herein, a “microparticle” is a solid or semi cal methods known in the art. solid particle having an effective particle size less than 20 [0055] As used herein, the term “sustained release” refers micrometers as measured by, for example, dynamic light to the release of a primary therapeutic agent and/ or an anal scattering methods such as photocorrelation spectroscopy, gesic agent from a formulation in a way that deviates from laser diffraction, low-angle laser light scattering (LALLS), immediate release, i.e., less than 50% of the agent is released medium-angle laser light scattering (MALLS), light obscu in the ?rst 30 minutes, the ?rst 90 minutes, the ?rst 24 hours, ration methods such as the Coulter method, rheology, or and/or the ?rst seven days following administration. Thus, light/election microscopy. Microparticles can be amorphous, sustained release includes release of an agent from a formu semicrystalline, crystalline, or a combination thereof as lation for an extended period of time, e.g., hours, days, and/or determined by suitable analytical methods such as differen weeks. In one exemplary embodiment, sustained release tial scanning calorimetry (DSC) or X-ray diffraction. refers to a formulation which releases 100% of the analgesic [0048] As used herein, an “immunological reaction” refers agent in 24 hours, 36 hours, 48 hours, or 60 hours, which to a physiological response to parenteral administration of a formulation provides a persistent therapeutic effect for 3-10 primary therapeutic agent that is mediated by a body’s days, for example 7 days, after release is complete. In another immune system. Immunological reactions include autoim exemplary embodiment, sustained release refers to a formu mune disorders, and hypersensitivity reactions. lation which releases 100% of the primary therapeutic agent [0049] As used herein, a “matrix” is a three-dimensional and/or the analgesic agent over 30 days or 1 month time. Such composition formed from a material, typically a network of sustained release formulations are particularly preferred by synthetic and/ or naturally-occurring polymers, capable of both clinicians and recipients in that administration of the containing and releasing a primary therapeutic agent and/or primary therapeutic and/or the analgesic agents does not have an analgesic agent over an extended period of time, e.g., days to be accomplished as regularly. Most preferably, the sus or weeks. A “?brin matrix” refers to a three-dimensional tained release period of the primary therapeutic agent and the composition comprising ?brin, a protein which can be analgesic agent is substantially the same, e.g., differing only obtained as the reaction product of ?brinogen and thrombin. by 2-3 days or less. US 2015/0024031 A1 Jan. 22, 2015

[0056] The terms “therapeutically effective amount,” pension to form a particle dispersion which is physically “effective amount,” and “amount effective” are used synony more stable than the presuspension. Energy is added by mously and refer to the amount of a primary therapeutic agent mechanical grinding, e. g., pearl milling, ball milling, hammer and/or analgesic agent necessary to achieve a desired thera milling, ?uid energy milling, jet milling, or wet milling. The peutic result in a subject. For example, in certain aspects of presuspension may be further subjected to high shear condi the invention, a therapeutically effective amount of a primary tions including cavitation, shearing, or impact forces utilizing therapeutic agent would be the amount necessary to reduce a micro?uidizer. Energy can also be added to the presuspen and/ or ameliorate the symptoms associated with a disease or sion using a homogenizer such as a piston gap homogenizer disorder. An effective amount of an analgesic agent can be the or counter current ?ow homogenizer. The addition of energy amount necessary to prevent or reduce pain, in?ammation, can also be accomplished using sonication techniques carried and/or immunological reactions associated with parenteral out using any suitable sonication device. Typically, the soni administration of a therapeutic agent. Alternatively, an effec cation device has a sonication horn or probe that can be tive amount of an analgesic agent can be the amount neces inserted into the presuspension to emit sonic energy into the sary to prevent or reduce pain, in?ammation, and/or immu solution. Examples of such techniques are disclosed in Us. nological reactions associated with arthritis, a wound site, a Pat. Nos. 5,145,684 and 5,091,188. site of surgery, or a site of pain. Of course, one of ordinary [0059] Microprecipitation methods generally involve dis skill in the art understands that the “therapeutically effective solving an organic compound in a water-miscible ?rst organic amount,” “effective amount,” and “amount effective” of a solvent to create a ?rst solution and then mixing the ?rst primary therapeutic agent and/or an analgesic agent will solution with a second solvent or water to precipitate the depend upon the therapeutic context and objectives. Addi organic compound to create a presuspension. Energy can then tionally, therapeutically effective amounts of the primary be added to the presuspension as discussed above to form therapeutic agent and the analgesic agent administered are microparticles. For example, a tandem microprecipitation based on subject parameters such as the weight and condition homogenization method can be used to obtain a microparticle of the subject and can be easily determined by the skilled dispersion. Optionally, the ?rst organic solvent is removed practitioner using known dosing protocol information which from the mixture by any suitable means such as centrifugation can be adjusted as needed in view of ascertainable formula or ?ltration methods. One or more optional surfactants set tion variables such as water solubility, particle size, and total forth below can be added to the ?rst organic solvent, to the amount of drug in a given dose. See, for example, Turco, second aqueous solution, or to both the ?rst organic solvent “Sterile Dosage Forms” 4th Ed., Lea & Febiger, 1994. Further and the second aqueous solution. Examples of microprecipi considerations relating to determining an appropriate “thera tation processes are disclosed in Us. Pat. Nos. 5,780,062, peutically effective amount” are known to the skilled clini 6,607,784, 6,869,617, 6,884,436, and 7,037,528. cian and described, in part, below. [0060] Emulsion precipitation methods generally involve [0057] The methods and pharmaceutical compositions providing a multiphase system having an organic phase con according to the invention comprise a dispersion comprising taining a pharmaceutically active compound and an aqueous microparticles of an analgesic agent and may further include phase, the organic phase having the pharmaceutically active a dispersion comprising microparticles of a primary thera compound therein, and sonicating the system to evaporate a peutic agent. In one aspect, the microparticles of the primary portion of the organic phase to cause precipitation of the therapeutic agent and/or the microparticles of the analgesic compound in the aqueous phase to form a dispersion of agent have an effective particle size greater than 100 nanom microparticles. The microparticle dispersion can optionally eters and less than 20 micrometers. For example, the effective be lyophilized. The step of providing a multiphase system particle size may be greater than 100 nanometers and less than includes (1) mixing a water-immiscible solvent with a phar 1 5 micrometers, the effective particle size may be greater than maceutically active compound to de?ne an organic solution; 100 nanometers and less than 10 micrometers, the effective (2) preparing an aqueous-based solution with one or more particle size may be greater than 100 nanometers and less than surface active compounds; and (3) mixing the organic solu 5 micrometers, the effective particle size may be greater than tion with the aqueous solution to form the multiphase system. 100 nanometers and less than 1 micrometer, the effective The organic and aqueous phases can be mixed using homog particle size may be greater than 100 nanometers and less than enizers, colloidal mills, high speed stirring equipment, extru 400 nanometers, the effective particle size may be greater sion equipment, manual agitation or shaking equipment, a than 100 nanometers and less than 200 nanometers, and/ or the micro?uidizer, or other equipment or techniques for provid effective particle size may be greater than 100 nanometers ing high shear conditions. The crude emulsion will have oil and less than 150 nanometers. As a result, the term “nanopar droplets in water that are approximately less than one ticle” is encompassed by the term “microparticle” as de?ned micrometer in diameter. The crude emulsion can be sonicated herein. The processes for preparing the microparticles used in to de?ne a microemulsion and eventually to provide a disper the present invention can be accomplished through numerous sion of microparticles. Examples of emulsion precipitation techniques known in the art. A representative, but non-limit methods are disclosed in Us. Patent Pub. No. 2005/0037083 ing discussion of techniques for preparing microparticles fol and Us. Pat. No. 6,835,396. lows. [0061] Solvent-antisolvent precipitation methods gener [0058] Energy addition methods generally involve adding a ally involve a dispersion created by (1) preparing a liquid pharmaceutically active compound in bulk form to a suitable phase of an active substance in a solvent or a mixture of vehicle such as water or aqueous solution. The vehicle typi solvents which may contain one or more surfactants; (2) cally contains one or more of the surfactants set forth below or preparing a second liquid phase of a non-solvent or a mixture any other liquid in which the pharmaceutical compound is not of non-solvents miscible with the preparation from (1); (3) appreciably soluble, to form a ?rst suspension that can be adding together the solutions of (1) and (2) with stirring; and referred to as a presuspension. Energy is added to the presus (4) removing unwanted solvents to produce a dispersion of US 2015/0024031 A1 Jan. 22, 2015

microparticles. Unlike the methods described above, a ?nal coagulants, anti-depressants, anti-epileptics, anti-?brotic step of adding energy to the suspension to form the dispersion agents, anti-infective agents (e.g., anti-fungals, antibiotics, is not necessary. Examples of solvent-antisolvent precipita and anti-viral agents including anti-retroviral agents such as tion techniques are disclosed in Us. Pat. Nos. 5,118,528 and protease inhibitors, nucleoside reverse transcriptase inhibi 5,100,591 . tors, non-nucleoside reverse transcriptase inhibitors, entry [0062] Other methods for producing dispersions compris inhibitors Which are also called fusion inhibitors, and inte ing microparticles that may be used in accordance With the grase inhibitors), antihistamines, anti-muscarinic agents, invention include, but are not limited to, phase inversion anti-mycobacterial agents, anti-neoplastic agents, anti-proto precipitation, pH shift precipitation, infusion precipitation, zoal agents, anxiolytics, beta-adrenoceptor blocking agents, temperature shift precipitation, solvent evaporation precipi cough suppressants, dopaminergics, hemostatics, hemato tation, reaction precipitation, compressed ?uid precipitation, logical agents, hypnotics, immunological agents, muscarin spraying onto cryogenic ?uids, and protein microsphere pre ics, parasympathomimetics, peptides, proteins, prostaglan cipitation. dins, radio-pharmaceuticals, stimulants, sympathomimetics, [0063] Microparticle dispersions can be formed using one vitamins, xanthines, vaccines, growth factors, hormones, or more surfactants. Suitable surfactants may be anionic, antiprion agents, diagnostic agents, and combinations cationic, ZWitterionic and/or nonionic surfactants. Examples thereof. A description of classes of therapeutic agents and a of surfactants include, but are not limited to, alkyl sulfonates, listing of species Within each class can be found in Martin alkyl phosphates, alkyl phosphonates, potassium laurate, tri dale, The Extra Pharmacopoeia, 31st Edition, The Pharma ethanolamine stearate, sodium lauryl sulfate, sodium dode ceutical Press, London, 1996. The listed therapeutic agents cylsulfate, alkyl polyoxyethylene sulfates, sodium alginate, are commercially available and/or can be prepared by known dioctyl sodium sulfosuccinate, phosphatidyl glycerol, phos techniques. In one aspect, a primary therapeutic agent accord phatidyl inosine, phosphatidylinositol, diphosphatidylglyc ing to the invention is selected from the group consisting of erol, phosphatidylserine, phosphatidic acid and their salts, peptides, proteins, antibodies, anti-retroviral drugs, psycho sodium carboxymethylcellulose, cholic acid and other bile therapeutic agents, bisphosphonates, and combinations acids, phosphatidylcholine, phosphatidylethanolamine, dia thereof. In one aspect, the primary therapeutic agent and the cyl-glycero-phosphoethanolamine, dimyristoyl-glycero analgesic agent are different both structurally and function phosphoethanolamine (DMPE), dipalmitoyl-glycero-phos ally, i.e., the primary therapeutic agent and the analgesic phoethanolamine (DPPE), distearoyl-glycero agent not only comprise different compounds but are also phosphoethanolamine (DSPE), distearoyl-phosphatidyl members of different therapeutic classes. Accordingly, in a ethanolamine-methyl-polyethyleneglycol conjugate (mPEG preferred aspect, the primary therapeutic is not a drug DSPE), dioleolyl-glycero-phosphoethanolamine (DOPE), selected from the group consisting of antihistamines, mast polyethylene glycol (PEG), benzalkonium chloride, cetyltri cell stabilizers, corticosteroids, anti-in?ammatories, local methylammonium bromide, chitosans, lauryldimethylbenzy anesthetics, and combinations thereof, i.e., the primary thera lammonium chloride, acyl camitine hydrochlorides, dimeth peutic is not an analgesic agent according to the invention. yldioctadecylammomium bromide (DDAB), [0065] Exemplary primary therapeutic agents that may dioleoyltrimethylammonium propane (DOTAP), N-[1-(2,3 cause irritation When administered parenterally include, but dioleyloxy)propyl]-N,N,N-trimethylammonium (DOTMA), are not limited to, abciximab, abobotulinumtoxina, adali dimyristoyltrimethylammonium propane (DMTAP), dim mumab, aminocaproic acid, anakinra, anti-inhibitor coagu ethylaminoethanecarbamoyl cholesterol (DC-Chol), 1,2-dia lant complex, anti-hemophilic factor, aprepitant, arformot cylglycero-3-(O-alkyl)phosphocholine, O-alkylphosphati erol tartrate, bisphosphonates, bortezomib, botulinum toxin dylcholine, alkyl pyridinium halides, long-chain alkyl types A and B, calcitriol, certolizumab pegol, chlorampheni amines, n-octylamine and oleylamine glyceryl esters, poly col palmitate, chloramphenicol sodium succinate, choriogo oxyethylene fatty alcohol ethers, polyoxyethylene sorbitan nadotropin alfa, chorionic gonadotrophin, cilastatin, coagu fatty acid esters (polysorbates), polyoxyethylene fatty acid lation Factor VIIa, dalteparin sodium, darbepoetin alfa, esters, sorbitan esters, glycerol monostearate, polyethylene decitabine, dexrazoxane hydrochloride, digoxin, follitropin glycols, polypropylene glycols, cetyl alcohol, cetostearyl alpha, follitropin beta, fosphenyloin, fulvestrant, enoxaparin alcohol, stearyl alcohol, aryl alkyl polyether alcohols, poly sodium, epopostenol sodium, ertapenem, esmolol, estrogens, oxyethylene-polyoxypropylene copolymers (poloxamers), etonogestrel, glatiramer acetate, human immune globulin poloxamines, methylcellulose, hydroxymethylcellulose, intravenous, ibandronate, imipenem, interferon alfa-2b, hydroxypropylcellulose, hydroxypropylmethylcellulose, interferon beta-1b, insulin glargine, interferon gamma-1B, noncrystalline cellulose, polysaccharides including starch lacosamide, maraviroc, mitomycin, onabotulinumtoxina, and starch derivatives such as hydroxyethylstarch (HES), octreotide, arsenic trioxide, olanzapine, ondansetron, polyvinyl alcohol, and polyvinylpyrrolidone. peginterferon alfa-2b, phenyloin, piperacillin, rocuronium [0064] In one aspect, a primary therapeutic agent according bromide, sodium hyaluronate, tazobactam, teriparatide, tige to the invention comprises a drug, diagnostic agent, or vac cycline, risperidone, Ziprasidone hydrochloride, Ziprasidone cine associated With pain on injection. The primary therapeu mesylate, zoledronic acid, aZithromycin, bivalirudin, busul tic agent can be selected from a variety of known pharmaceu fan, carboprost tromethamine, cytarabine, danaparoid, tical compounds including, but not limited to: analeptics, dimercaprol, divalproex, doxorubicin, ferric gluconate, fos anti-cancer agents, antibodies, adrenergic agents, adrenergic carnet, furosemide, gadobenate dimeglumine, gadobutrol, blocking agents, adrenolytics, adrenomimetics, anti-cholin gadofosveset, gadoteridol, hydroxocobalamin, incobotuli ergic agents, anti-cholinesterases, anticonvulsants, alkylating numtoxin A, interferon alfacon-1, interferon beta-1a, iopro agents, alkaloids, allosteric inhibitors, anorexiants, antacids, mide, ioversol, laronidase, leuprolide, meropenem, mesna, anti-diarrheals, antidotes, anti-folics, anti-pyretics, anti-rheu naltrexone, nicardipine, ribavirin phentolamine, rimabotuli matic agents, psychotherapeutic agents, anti-helmintics, anti numtoxin B, somatropin, thiotepa, treprostinil, triptorelin, US 2015/0024031 A1 Jan. 22, 2015

valproic acid, valproic acid derivatives, varicella-zoster agent’s duration of action, compared to a liquid formulation, immunoglobulin, vinorelbine, cytarabine, alefacept, bivaliru and allow for increased drug loading, e.g., in weight per unit din, edetate calcium disodium, epirubicin hydrochloride, ?u volume of tissue, which can also extend the active period of mazenil, idarubicin hydrochloride, lansoprazole, mitox the compound. In one aspect, the analgesic agent comprises a antrone hydrochloride, paromomycin sulfate, polymyxin B drug selected from the group consisting of antihistamines, sulfate, pralidoxime chloride, progesterone, alpha-1-protein mast cell stabilizers, corticosteroids, anti-in?ammatories ase inhibitor, dipyridamole, epirubicin hydrochloride, epo including but not limited to Substance P inhibitors and IL-18 prostenol sodium, valproate sodium, tobramycin, cefotetan, inhibitors, local anesthetics, and combinations thereof. In desmopressin, doxycycline, atropine, atropine sulfate dimen certain aspects, the invention includes amino amide anesthet hydrinate, edetate calcium disodium, penicillin G, promet ics, amino ester anesthetics, amino amide derivatives, and hazine hydrochloride, spectinomycin hydrochloride, ami their salts, hydrates, and prodrugs. Examples of suitable anal noglycosides, aminopenicillins, ampicillin sodium, gesic agents include, but are not limited to, local anesthetic sulbactam sodium, cardiac glycosides, ceftazidime, labetalol agents such as lidocaine, mepivacaine, prilocalne, etidocaine, hydrochloride, methocarbamol, pralidoxime chloride, spec bupivacaine, levobupivacaine, ropivacaine, dibucaine, artic tinomycin hydrochloride, terbutaline sulfate, amidotrizoic aine, cocaine, procaine, mepivacaine, prilocalne, articaine, acid, bleomycin sulfate, carbenicillin sodium, cefalotin benzocaine, chloroprocaine, etidocaine, tetracaine, sodium, clarithromycin, clodronate, clodronic acid, dacarba dibucaine, butamben, capsaicin, their salts, hydrates, pro zine, epoetin alfa, epoetin beta, epoetin delta, epoetin gamma, drugs, and combinations thereof. epoetin omega, epoetin theta, epoetin zeta, meglumine ami [0068] In one aspect, the analgesic agent is an inhibitor of dotrizoate, oxamniquine, sermorelin acetate, sodium amidot the proin?ammatory agents Substance P and/or Interleukin rizoate, somatorelin, sumatriptan, sumatriptan succinate, 18 (IL-18). Substance P is a neuropeptide that orchestrates the vesnarinone, tobramycin, thymostimulin, thymopentin, in?ammatory response by eliciting ingress of in?ammatory teceleukin, pidotimod, oprelvekin, interleukins, simvastatin, white cells into the tissue area. IL-18 is a cytokine that tri?usal, denileukin diftitox, celmoleukin, aldesleukin, trivax, induces natural killer and T cells to release interferon. The nadolol, INGAP, ilodecakin, denenicokin, darleukin, losar inhibition of Substance P and/or IL-18 can be measured, for tan, oncostatin M, and combinations thereof. Exemplary vac example, by analyzing tissue samples to determine the con cines associated with injection site pain include, but are not centrations of the agents and downstream cytokines. Inhibit limited to, vaccines against diphtheria, in?uenza, Haemophi ing mediators of the in?ammatory cascade such as Substance lus in?uenzae type B, Hepatitis A, Hepatitis B, human papil P and IL-18 reduces in?ammation and its symptoms, result lomavirus, measles, meningitis, mumps, pertussis, polio, ing in more effective and prolonged pain relief. Ropivacaine, rabies, rubella, tetanus, and combinations thereof. lepobupivacaine, and lidocaine can all act as inhibitors of [0066] In one aspect, the primary therapeutic agent com Substance P (Dias et al., Anaesthesia, 2008; 63(2):151-5). prises an anti-retroviral drug, for example, an anti-HIV drug. Other examples of inhibitors of Substance P and/or IL-18 In one aspect, the primary therapeutic agent may comprise a include, but are not limited to ustekinumab, tocilizumab, drug selected from the group consisting of protease inhibi sareito, tacrolimus, rilonacept, iguratimod, hydrocortisone, tors, nucleoside reverse transcriptase inhibitors, non-nucleo diacerein, aceclofenac, daclizumab, canakinumab, basilix side reverse transcriptase inhibitors, entry inhibitors which imab, actarit, sirukumab, secukinumab, sarilumab, resli are also called fusion inhibitors, integrase inhibitors, and zumab, reparixin, MK-3222 (Merck), mepolizumab, MABpl combinations thereof. Examples of protease inhibitors C(Biotech), lebrikizumab, ixekizumab, inolimomab, gevoki include, but are not limited to, fosamprenavir, indinavir, zumab, brodalumab, briakinumab, tralokinumab, iltuximab, ritonavir, saquinavir, nel?navir, atazanavir and combinations olokizumab, NN-8226 (Novo Nordisk), lisofylline, gusel thereof, such as a combination of ritonavir and atazanavir. kumab, GSK-1070806 (GlaxoSmithKline), givinostat, dupi Examples of nucleoside reverse transcriptase inhibitors lumab, dersalazine sodium, clazakizumab, benralizumab, include, but are not limited to, abacavir, zidovudine, ASM-8 (Pharmaxis), anrukinzumab, AN-2898 and AN-2728 didanosine, stavudine, zalcitabine, lamivudine and combina (Anacor), AMG-139 and AMG-108 (Amgen), ALX-0061 tions thereof. Examples of non-nucleoside reverse tran (Ablynx),AC-201 (TWi Biotechnology), TT-301 and TT 302 scriptase inhibitors include, but are not limited to, efavirenz, (Transition Therapeutics), SA-237 (Chugai), NI-1401 and nevirapine, delaviradine (mesylate), and combinations NI-1201 (N ovimmune), MEDI-5117 (AstraZeneca), HMPL thereof. Examples of fusion inhibitors include, but are not 011 (Hutchison MediPharma), EBI-005 (Eleven Biothera limited to, maraviroc and enfuvirtide. Examples of integrase peutics), BMS-981164 (Bristol-Myers Squibb), BI-655066 inhibitors include, but are not limited to, dolutegravir and (Boehringer Ingelheim), ABT-981 and ABT-122 (Abbott), S/GSK1265744 (ViiV Healthcare). Exemplary combinations XT-101 (Xalud Therapeutics), SM-401 (SuppreMol), ral?na of anti-retroviral drugs include, but are not limited to, mide, PRS-060 (Pieris), in?ammasome modulators, IL-6 ritonavir/atazanavir/efavirenz, lamivudine/zidovudine, lami inhibitors, IL-6 antagonists, IL-15 antagonist, IL-12/23 vudine/abacavir, abacavir/lamivudine/zidovudine, and inhibitors, HuMax-IL8 (Cormorant), E-36041 (Ensemble dolutegravir/lamivudine/abacavir. Typical combinations Therapeutics), DRM-02 (Derrnira), ARGX-109 (arGEN-X), include two nucleoside reverse transcriptase inhibitors plus and combinations thereof. Further still, suitable inhibitors of one protease inhibitor or two nucleo side reverse transcriptase Substance P and/or IL-18 can be identi?ed using the assay inhibitors plus one non-nucleoside reverse transcriptase described in the application examples. inhibitors. [0069] In one aspect, the primary therapeutic agent and/or [0067] An analgesic agent according to the invention may the analgesic agent, most typically the analgesic agent, is a comprise any analgesic agent known in the art. A dispersion poorly water-soluble compound, i.e., the solubility of the comprising microparticles of an analgesic agent according to compound in water is less than about 10 mg/mL, and prefer the invention can advantageously prolong the analgesic ably less than about 1 mg/mL, for example, less than 0.5 US 2015/0024031 A1 Jan. 22, 2015

mg/mL. These poorly water-soluble compounds are particu of the analgesic agent can be delivered via injection, for larly suitable for aqueous suspension preparations since there example, by intraarticular, intracerebral (intraparenchymal), are limited alternatives for formulating these compounds in intracerebroventricular, intracerebrospinal, intracranial, an aqueous medium. Surfactants can adsorb to the surface of intramuscular, intradermal, intraperitoneal, subcutaneous, particles comprising such poorly water soluble active agents intraocular, intraportal, intranasal, or intralesional routes. to form a substantially uniform coating thereon. For example, Typically, the administration of the primary therapeutic agent the hydrophobic tail moieties of surfactants can associate and/or the microparticles of the analgesic agent is via intraar with hydrophobic regions on the particle surface. In addition, ticular injection, intradermal injection, subcutaneous injec electrostatic interactions between the surfactant and nega tions, and/ or intramuscular injection. tively charged regions on the particle surface can stabilize the [0074] In addition, the primary therapeutic agent and the coating comprising the surfactant. Such surfactant coatings microparticles of the analgesic agent can be introduced for can advantageously increase the stability of a dispersion such treatment into a mammal by parenteral modes including, but that particle aggregation is substantially reduced. not limited to, intratumor, topical, subconjunctival, intrablad [0070] Alternatively, the primary therapeutic agent and/or der, intravaginal, epidural, intracostal, inhalation, transder analgesic agent can be a water-soluble compound. To form mal, transserosal, intrabuccal, dissolution in the mouth or aqueous suspensions of water-soluble compounds the water other body cavities, instillation to the airway, insuf?ation soluble active compounds can be entrapped in a solid carrier through the airway, injection into vessels, tumors, organ and matrix (for example, polylactate-polyglycolate copolymer, the like, and injection or deposition into cavities in the body of albumin, or starch) or encapsulated in a surrounding vesicle a mammal. In a particular aspect, the primary therapeutic that is substantially impermeable to the active agent. An agent and/or the microparticles of the analgesic agent are encapsulating vesicle can be a polymeric coating such as delivered surgically, e.g., by implantation. In a further aspect, polyacrylate. Further, the microparticles containing these the primary therapeutic and/ or the microparticles of the anal water soluble compounds can be modi?ed to improve chemi gesic agent are delivered in a spray. A spray containing micro cal stability and control the pharrnacokinetic properties of the particles of the analgesic agent can advantageously be admin compounds, for example, by controlling the release of the istered transdermally in the site of surgery (e.g., caused by compounds from the microparticles. Examples of water implantation of a depot or other sustained release formulation soluble compounds include, but are not limited to, simple of the primary therapeutic agent) or injury (e.g., caused by organic compounds, proteins, peptides, nucleotides, and car injection of the primary therapeutic agent). bohydrates. [0075] Delivery of the primary therapeutic agent and/ or the [0071] In one aspect, the analgesic agent comprises the microparticles of the analgesic agent can be administered to (S)-isomer of ropivacaine and/or bupivacaine and/or their any site in the body. In certain aspects, the site of administra salts and/ or prodrugs. In one embodiment, the analgesic agent tion is in the nerves, liver, kidney, heart, lung, eye, gas comprising the (S)-isomer of ropivacaine and/or bupivacaine trointestinal tract, skin, and/ or brain. In one aspect, the site of and/or their salts and/or prodrugs is substantially free of the administration is any site of the body in need of pain preven (R)-isomer form. For example, the analgesic agent compris tion or pain relief. ing the (S)-isomer of ropivacaine and/or bupivacaine contains [0076] The primary therapeutic agent and the micropar the (R)-isomer of ropivacaine and/or bupivacaine in an ticles of the analgesic agent may be delivered into a subject amount less than 10% by weight, less than 5% by weight, less using a variety of different means. In one aspect, direct injec than 3% by weight, less than 2% by weight, less than 1% by tion by needle and syringe can be used. In certain aspects, weight, and/or less than 0.5% by weight of the drug or a direct injection includes mixing microparticles of the primary pharmaceutically acceptable salt thereof. In a particular therapeutic agent and the analgesic agent in the syringe aspect, the analgesic agent comprises ropivacaine, a ropiv immediately prior to administration or injection in a subject. acaine salt, a ropivacaine prodrug, a ropivacaine analog, a In other aspects, the invention includes the use of a mixing ropivacaine derivative, or a combination thereof. chamber between the syringe and needle to facilitate mixing. [0072] The primary therapeutic agent and the analgesic In some aspects, the primary therapeutic agent and micropar agent according to the invention may be administered simul ticles of the analgesic agent are administered by bolus inj ec taneously. In one aspect, the primary therapeutic agent and tion or by implantation device. In certain aspects, a bolus analgesic agent are administered concurrently in a single injection is given by intravenous infusion or by direct inj ec dispersion or pharmaceutical composition containing both tion, using a syringe. This mode of administration may be the primary therapeutic agent and the microparticles of the desirable in surgical patients, if appropriate, such as patients analgesic agent. Alternatively, the primary therapeutic agent having cardiac surgery, e.g., coronary artery bypass graft may be administered separately; for example, the primary surgery and/ or valve replacement surgery. However, infusion therapeutic agent may be administered before the analgesic and other continuous administration methods are generally agent or the analgesic agent may be administered before the disfavored because of the inconvenience and discomfort that primary therapeutic agent. the subject often experiences during administration. Thus, in [0073] The primary therapeutic agent may be parenterally one aspect, neither the primary therapeutic agent nor the administered according to the invention in a number of for analgesic agent is administered by a continuous administra mulations, such as microparticle dispersions, solutions, tion method. In other aspects, a single injection is given emulsions, liposomes, implants, and combinations thereof. In intramuscularly or subcutaneously. Shorter or longer time aspects of the invention, the primary therapeutic agent and the periods of administration can be used, as determined to be microparticles of the analgesic agent can be parenterally appropriate by one of skill in this art. administered to a subject through varied routes, most fre [0077] Alternatively or additionally, the primary therapeu quently by injection, infusion, or implantation. In some tic agent and the microparticles of the analgesic agent are aspects, the primary therapeutic agent and the microparticles administered locally via implantation of a membrane, US 2015/0024031 A1 Jan. 22, 2015

sponge, or another appropriate material onto/into which the agent and the other containing microparticles of the analgesic dispersion has been absorbed or encapsulated. Where an agent can be used. Alternatively, a single implant can contain implantation device is used, the device, in various aspects, is microparticles of both the primary therapeutic agent and the implanted into any suitable tissue or organ, and delivery of the analgesic agent. primary therapeutic agent and/or the microparticles of the [0082] In a further aspect, the primary therapeutic agent analgesic agent may be via diffusion, sustained release, bolus, and/or the analgesic agent is incorporated in a matrix. For or continuous release. example, the microparticles of the analgesic agent can be [0078] Separate dispersions, one containing microparticles incorporated in a matrix. In one embodiment, the matrix of the primary therapeutic agent and the other containing further comprises microparticles of the primary therapeutic. microparticles of the analgesic agent, can be used. Alterna In another embodiment, separate matrices, one containing the tively, a single dispersion can contain microparticles of both primary therapeutic agent and the other containing micropar the primary therapeutic agent and the analgesic agent. ticles of the analgesic agent, can be used. A matrix may be [0079] In one aspect, the dispersion(s) comprising the pri composed of natural polymers such as ?brinogen or collagen, mary therapeutic agent and/or analgesic agent is a sustained synthetic polymers, or a combination thereof. Suitable syn release formulation. Sustained release formulations known in thetic polymers include, but are not limited to, polymers such the art that are suitable for use with the invention include but as poly(lactide) (PLA), poly(glycolic acid) (PGA), poly(lac are not limited to depot injections, in situ forming implants, tide-co-glycolide) (PLGA), poly(caprolactone), polycarbon polymer matrices, tissue sealants, glues, and combinations ates, polyamides, polyanhydrides, polyamino acids, poly thereof. Other speci?c examples of sustained release formu ortho esters, polyacetals, polycyanoacrylates and degradable lations include, but are not limited to, oil-based solutions, polyurethanes, and non-erodible polymers such as polyacry injectable drug suspensions, liposomes (e.g., DepoFoam® lates, ethylene-vinyl acetate polymers and other acyl substi (Pacira Pharmaceuticals, Inc. Parsippany, N.J.), and polymer tuted cellulose acetates, derivatives and combinations based microspheres. Sustained release formulations can also thereof. be developed by altering microparticle size, using speci?c crystal forms and/or using hydrophobic salts. In one aspect, [0083] In a further aspect, the primary therapeutic agent and/or the analgesic agent is incorporated into a tissue seal the sustained release formulation releases the primary thera ant/glue. For example, the microparticles of the analgesic peutic and the analgesic agent for substantially the same agent can be incorporated into a tissue sealant/glue. In one period of time. In another aspect, the half-life, i.e., the time embodiment, the tissue sealant/ glue further comprises micro needed to release half of the drug initially present in the particles of the primary therapeutic. In another embodiment, formulation, of the formulation containing the analgesic separate tissue sealant/glues, one containing the primary agent is greater than the half-life of the formulation contain therapeutic agent and the other containing microparticles of ing the primary therapeutic agent. In another aspect, the half life of the formulation containing the analgesic agent is less the analgesic agent, can be used. Tissue sealants are a type of surgical tissue adhesive used to control surgical bleeding, than the half-life of the formulation containing the primary speed wound healing, close body organs or cover suture therapeutic agent, but the analgesic agent is still effective for holes, and provide slow-release delivery of medications such reducing the pain, in?ammation, and/or immunologic reac tion associated with parenterally administering the primary as antibiotics to exposed tissues. Tissue sealants may com prise the natural and/or synthetic polymers listed above. therapeutic agent over the residence time of the primary Examples of commercially available tissue sealants include, therapeutic agent even when the analgesic agent is no longer but are not limited to, Tisseel® (Baxter International Inc.), detectable in the blood or even in a tissue of a subject. Poly BioGlue® (CryoLife), and TissuGlu® (Cohera Medical, mers suitable for use in sustained release formulations include, but are not limited to, polylactides (PLA), polygly Inc.). colides (PGA), poly(lactide-co-glycolide) (PLGA), polyca [0084] In other aspects of the invention, additional ways of prolactone (PCL), polyethylene glycol (PEG), polyglycon delivering the composition to a subject will be evident to ate, polypropylene glycol (PPG), polyanhydrides, those skilled in the art, including alternative formulations polyorthoesters, polyhydroxybutyrate (PHB), poly(diox involving sustained release delivery. anone), polyalkylcyanoacrylates, chitosan, and combinations [0085] One skilled in the art will appreciate that the appro thereof. priate therapeutically effective dosage levels for treatment [0080] In another aspect, the primary therapeutic agent will vary depending, in part, upon the tissue site to which the and/or the analgesic agent are administered in the form of a primary therapeutic agent and/or analgesic agent is delivered, depot injection. Separate depot injections, one containing the the indication for which the treatment is being used, the route primary therapeutic agent and the other containing micropar of administration, and the size (body weight, body surface or ticles of the analgesic agent, can be used. Alternatively, a organ size) and condition (age and general health) of the single depot injection can contain both the primary therapeu patient. Accordingly, the clinician may adjust the dosage and tic agent and the analgesic agent. modify the route of administration to obtain the optimal [0081] In another aspect, the primary therapeutic agent therapeutic effect. and/ or the analgesic agent are administered in the form of an in situ forming implant, for example, as described in Kempe [0086] Each publication, patent application, patent, and other reference cited herein is incorporated by reference in its and Mader, J Control Release. 2012; 161(2): 668-79. Examples of in situ forming implants include, but are not entirety to the extent that it is not inconsistent with the present limited to, thermoplastic pastes, in situ cross-linked polymer disclosure. systems, in situ polymer precipitation, thermally induced gel [0087] The following Examples are provided for illustra ling systems, and in situ solidifying organogels. Separate in tion only and are not in any way to limit the scope of the situ forming implants, one containing the primary therapeutic invention. US 2015/0024031 A1 Jan. 22, 2015 11

Example 1 [0091] Formulations #1, #3 and #4 were also prepared at a slightly larger scale (40 mL), with all other conditions as Microparticle Dispersions of an Analgesic Agent described above, and stability testing was performed. The stability data for Formulations #1, #3, and #4 is shown in [0088] Dispersions comprising microparticles of the anal FIGS. 1A and 1B. The mean particle size of the micropar gesic agent ropivacaine were prepared using an energy addi ticles in the dispersions was found to be stable when stored for tion/homogenization procedure. Five ropivacaine formula 12 weeks at 513° C. tions were prepared using ropivacaine hydrochloride as [0092] The solubility of Formulation #1 (i.e., the micro starting material and are described in Table 1 below. particles of Formulation #1) was assessed in both human TABLE 1

Formulation

Component #1 #2 #3 #4 #5 Ropivacaine hydrochloride 1% (w/v) 1% (w/v) 1% (w/v) 1% (w/v) 1% (w/v) Sodium phosphate 0.3118 g/L 0.3118 g/L 0.3118 gL 0.3118 g/L 0.3118 g/L monobasic, monohydrate Sodium phosphate dibasic, 1.0994 g/L 1.0994 g/L 1.0994 gL 1.0994 g/L 1.0994 g/L anhydrous Glycerin 2.25% (w/v) 2.25% (w/v) 2.25% (w/v) 2.25% (w/v) 2.25% (w/v) Poloxalner188 0.5% (w/v) i 0.5% (w/v) i 0.1% (w/v) DSPE—mPEG 2000 0.2% (W/v) i i i i Polysorbate 80 (Tween 80) i i 0.25% (w/v) i i Lipoid E80 i 1.2% i 1.2% (w/v) i

Sodium i i i i 0.1% (w/v) Deoxycholate 1,2—Dimyristoyl—sn—glycero— i i i 0.2% (w/v) i 3—phosphoglycerol, sodium Water Qs Qs Qs Qs Qs Particle Size 2 pm 6 pm 2 pm 3 pm 1.5 pm

[0089] To prepare the ropivacaine free base, 4 grams of plasma and phosphate buffered saline (PBS). Three tubes for ropivacaine HCl was added to 56 mL of water in a beaker. The each media were prepared by transferring 1 mL of either solution in the beaker was stirred and heated at 75° C. to plasma or PBS into microcentrifuge tubes and adding 120 [1L disperse and dissolve the drug. When the solution appeared of the Formulation #1 suspension. The tubes were inverted to visually clear, the heat was removed. Sodium hydroxide mix. All six tubes were visually turbid at the start of the (NaOH, 1N) was added to the solution while stirring to cause experiment. The tubes were then placed on a spinner and precipitation. The addition of NaOH was continued until the incubated at 37° C. for 4 days. When the tubes were removed solution pH was greater than 10. The solution was allowed to from spinner they were still visually turbid. The samples were cool to room temperature and then ?ltered. The ?ltercake was centrifuged to separate remaining solids, and 100 [1L of each dried in a vacuum oven. The resulting material was analyzed supernatant was submitted for ropivacaine quantitation by HPLC. The solubility of Formulation #1 (average of three by differential scanning calorimetry (DSC). The melting replicates) was 0.34 mg/mL in PBS and 0.48 mg/mL in point was found to be approximately 149° C., close to the plasma. published melting point of ropivacaine free base (144° C. to 146° C., Merck Index) and distinctly different from the melt [0093] The dissolution pro?le of Formulation #1 was ing point of ropivacaine hydrochloride (270° C., Merck assessed using a turbidimetric method. Dissolution in both human plasma and PBS was evaluated. Brie?y, 25 mL of Index). either plasma or PBS were added to a turbidimeter vial and [0090] Surfactant solutions were prepared by dissolving all the baseline turbidity of each media was measured using a the formulation components of Formulations #1 to #5 except HACH 2100AN laboratory turbidimeter (Hach Co.). Then, ropivacaine in water. The pH of the solutions was approxi varying amounts of Formulation #1 were added and dispersed mately 7.4 to 7.5. Laboratory scale (20 mL) suspensions were in the media using an overhead stirrer for ?ve seconds to prepared with a target concentration of 10 mg/mL ropiv create ropivacaine concentrations from about 0.16 mg/mL to acaine using an energy addition/homogenization procedure. about 0.38 mg/mL. Nephelometric turbidity unit (NTU) mea Brie?y, ropivacaine free base was added to the surfactant surements were taken at various intervals until the readings solutions and dispersed using a rotor-stator mixer. The result either returned to baseline or did not change signi?cantly. ing dispersions were transferred to a piston-gap homogenizer After the last measurement, each vial was removed and and circulated at static pressure until the suspension tempera inspected visually. Vials containing ropivacaine microdisper ture was less than 10° C. The dispersion was then homog sions in plasma contained clear solution. For PBS, the vial at enized at a target pressure of 20,000:2,000 psi and a target the higher ropivacaine concentration (about 0.25 mg/mL) temperature of less than 10° C. Dispersions were collected was found to be visually turbid, whereas, the vial at the lower after approximately 30 to 60 minutes of homogenization and ropivacaine concentration (about 0.16 mg/mL) contained had a ?nal ropivacaine microparticle size of approximately clear solution. The dissolution pro?les of various concentra 1.5 micrometers (Formulation #5), 2 micrometers (Formula tions of ropivacaine in PBS and plasma are shown in FIG. 2. tion #1), 2 micrometers (Formulation #3), 3 micrometers [0094] From FIG. 2A, the PBS solubility limit for ropiv (Formulation #4), or 6 micrometers (Formulation #2). acaine microparticles apparently lies between 0.16 mg/mL