WO2021051080A1 - Opioid independent surgical anesthetic - Google Patents

Abstract

An opioid independent surgical anesthetic composition includes an injectable dosage form of a hydrogel that has a plurality of solid lipid matrix particles entrapped therein. The plurality of solid lipid matrix particles includes a lipophilic local anesthetic drug and a saturated triglyceride. Methods for creating a long-acting local anesthetic product can include creating a bulk solid of a lipid matrix product by heating a lipid solvent above its melting point, dissolving a lipophilic local anesthetic drug therein, and reducing a temperature of the resultant drug-lipid solution to below the melting point of the lipid solvent. The methods can further include crushing the bulk solid of the lipid matrix product to form solid lipid matrix particles and entrapping the solid lipid matrix particles within a hydrogel.

Description

OPIOID INDEPENDENT SURGICAL ANESTHETIC

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH [0001] The invention was made with government support under grant no. 1946204 awarded by the National Science Foundation. The government has certain rights in the invention.

CROSS-REFERENCE TO RELATED APPLICATIONS [0002] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63/014,788, filed April 24, 2020 and entitled “HYALURONIC ACID HYDROGEL ANESTHETIC DRUG DELIVERY SYSTEM” and to U.S. Provisional Patent Application No. 62/900,369, filed September 13, 2019 and entitled “HYALURONIC ACID HYDROGEL ANASTHETIC DRUG DELIVERY SYSTEM.” Each of the foregoing are incorporated herein by reference in in their entirety.

BACKGROUND Technical Field

[0003] The present application relates to anesthetic compositions and methods for creating the same. More particularly, the present application relates to long-acting, opioid independent anesthetics that may be used to manage postoperative pain. Relevant Technology

[0004] Medical practitioners often employ surgical techniques to treat injuries and disorders. Surgical techniques often involve manipulating or structurally altering a patient’s body by — or through — an incision. Even after closing a surgical incision (e.g., with a suture), patients may be subject to postoperative pain at the surgical site, such as acute pain immediately following the surgical operation and/or lingering pain as the surgical site heals.

[0005] Many postoperative pain treatment regimens involve the use of opioids as a centrally-acting analgesic to mitigate the pain. For example, members of a surgery or recovery team may administer an initial dose or doses of opioids to a patient after a surgical procedure, and the patient may be prescribed additional doses of opioids for self administration to maintain analgesia as the effects of the initial dose(s) wear off. The freedom to self-medicate opioids leads some patients to over-medicate or otherwise abuse the use of their prescribed drugs, often leading to opioid addiction or even an overdose. The risks and dangers of opioid addiction and overdosing have gained significant attention in recent years, particularly due to the pervasiveness of opioid addiction within the U.S. and many other countries around the globe.

[0006] In some instances, rather than administering an initial opioid dose, medical practitioners administer a local anesthetic to a surgical site in an effort to treat postoperative pain. However, conventional local anesthetics often only provide analgesia at the surgical site for a few hours following administration. It is time consuming and impractical to administer iterative doses of local anesthetic, and because many local anesthetics are delivered via injection, there is an inherent additional risk of infection. These obstacles and the ease by which centrally acting opioid medications can be administered orally ( e.g as a pill or capsule) contribute to the continued prescription of opioids to treat postoperative pain — despite the personal and social harms clearly linked with their widespread use.

[0007] Alternative pain management strategies are needed to reduce the dependence on opioids for treating postoperative pain. For example, new or alternative local anesthetics are needed that can temporally extend the analgesic effect at a surgical site following administration. However, there is a dearth in the market for such products, and existing products that purport to provide long-acting local analgesia suffer from a number of shortcomings, such as a failure to perform as reported, high cost, complicated drug delivery procedures, and unfavorable drug release profiles.

[0008] Accordingly, there are a number of problems and disadvantages with existing postoperative pain management regimens and opioid independent surgical anesthetics that can be addressed.

BRIEF SUMMARY [0009] Various embodiments disclosed herein are related to systems, methods, components, apparatuses, and kits associated with opioid independent surgical anesthetics. Such embodiments may beneficially improve postoperative pain management and may mitigate the need for centrally-acting opioid medication after a surgical procedure by, for example, facilitating long-acting, local analgesia at a surgical site. [0010] A first aspect provides an opioid independent surgical anesthetic composition.

The opioid independent surgical anesthetic composition includes an injectable dosage form of a hydrogel that has a plurality of solid lipid matrix particles entrapped therein. The plurality of solid lipid matrix particles includes a lipophilic local anesthetic drug and a saturated triglyceride. In some instances, the opioid independent anesthetic composition is provided as part of a kit within a ready -to-use, pre-filled syringe.

[0011] In some embodiments, the hydrogel is a crosslinked hyaluronic acid hydrogel. Furthermore, in some instances, the lipophilic local anesthetic drug is (or includes) bupivacaine and the saturated triglyceride is (or includes) tristearin. In one aspect, the plurality of solid lipid matrix particles substantially include triglycerides forming a b- phase crystalline state. The solid lipid matrix may additionally, or alternatively, have a melting point greater than about 45° C, preferably greater than about 70° C, and/or each of the plurality of solid lipid matrix particles has a longest dimension of about 200 pm or less.

[0012] In another aspect, an opioid independent surgical anesthetic composition includes a ready -to-use injectable dosage form of a cross-linked hyaluronic acid hydrogel having lipid emulsion droplets containing bupivacaine entrained therein. The opioid independent surgical anesthetic composition is configured to release bupivacaine in a biphasic manner when administered at a surgical site. The biphasic release may include a burst phase and a sustained release phase, improving postoperative pain management in an opioid independent fashion. In some embodiments, for example, between 30% - 70% of the bupivacaine is cumulatively released from the hydrogel during the burst phase (e.g., the burst phase may be between 8 - 24 hours post administration), and between 70% - 99% of the bupivacaine is cumulatively released from the hydrogel by 72 hours post administration.

[0013] In another aspect, a method for creating an opioid independent surgical anesthetic composition includes (i) creating a bulk solid of a lipid matrix product by heating a lipid solvent above a melting point of the lipid solvent, dissolving a lipophilic local anesthetic drug into the lipid solvent to form a drug-lipid solution, and reducing a temperature of the drug-lipid solution to below the melting point of the lipid solvent; (ii) forming solid lipid matrix particles by crushing the bulk solid of the lipid matrix product; and (iii) entrapping a plurality of size-selected solid lipid matrix particles within a hydrogel.

[0014] In some embodiments, creating the bulk solid of the lipid matrix product also includes performing a heat annealing process when reducing the temperature of the drug- lipid solution to below the melting point of the lipid solvent. The heat annealing process can include, for example, maintaining a temperature of the drug-lipid solution at approximately 8° C - 12° C below the melting point of the lipid solvent for a period of time.

[0015] Furthermore, in some embodiments, the lipophilic local anesthetic drug includes bupivacaine, the lipid solvent includes a saturated triglyceride, and the hydrogel includes a cross-linked hyaluronic acid hydrogel. Additionally, or alternatively, each of the plurality of size-selected solid lipid matrix particles has a longest dimension less than about 200 pm.

BRIEF DESCRIPTION OF THE DRAWINGS [0016] In order to describe the manner in which the above recited and other advantages and features of the disclosure can be obtained, a more particular description of the disclosure briefly described above will be rendered by reference to specific embodiments thereof, which are illustrated in the appended drawings. It is appreciated that these drawings depict only typical embodiments of the disclosure and are not therefore to be considered to be limiting of its scope. The disclosure will be described and explained with additional specificity and detail through the use of the accompanying drawings in which: [0017] FIG. 1 illustrates a schematic representation of an opioid independent surgical anesthetic composition that includes solid lipid matrix particles entrapped within a hydrogel and a schematic representation of a procedure for manufacturing the opioid independent surgical anesthetic composition, in accordance with one or more embodiments of the present disclosure;

[0018] FIGs. 2A and 2B illustrate an example of applying an opioid independent surgical anesthetic composition to a surgical site, in accordance with one or more embodiments of the present disclosure;

[0019] FIG. 3 illustrates an example flow diagram depicting acts associated with creating an opioid independent surgical anesthetic composition, in accordance with one or more embodiments of the present disclosure;

[0020] FIG. 4 illustrates a schematic representation of an alternative embodiment of an opioid independent surgical anesthetic composition that includes a hydrogel that entraps lipid emulsion droplets containing bupivacaine entrained therein and a schematic representation of a procedure for manufacturing the opioid independent surgical anesthetic composition, in accordance with one or more embodiments of the present disclosure; [0021] FIG. 5 illustrates a graph of in vitro data of cumulative bupivacaine release over time from various lipid-HA (hyaluronic acid) gel formulations (i.e., opioid independent surgical anesthetic compositions that include hyaluronic acid hydrogels that have lipid emulsion droplets containing bupivacaine entrained therein, such as the opioid independent surgical anesthetic composition of FIG. 4, which can also be referred to herein as lipid emulsion hyaluronic acid local anesthetic (HALA) or hyaluronic acid bupivacaine- loaded emulsion (HA-BLE) composite gel);

[0022] FIGs. 6A and 6B illustrate graphs of in vivo data of paw withdrawal latency and contralateral-ipsilateral latency for rodents treated with a lipid emulsion HALA; [0023] FIG. 7 illustrates a graph of in vivo data showing the maximum possible effect (MPE %) of anesthetic in a thermal nociceptive assay for bupivacaine-loaded emulsions (BLE) and HA-BLE compared to controls of bupivacaine HCL and liposomal bupivacaine;

[0024] FIG. 8 illustrates a graph of cumulative bupivacaine release over time from various HA hydrogel formulations that include bupivacaine-loaded lipid matrix particles (i.e., opioid independent surgical anesthetic compositions that include solid lipid matrix particles entrapped within a hyaluronic acid hydrogel, such as the opioid independent surgical anesthetic composition of FIG. 1); and

[0025] FIG. 9 illustrates a graph of differential scanning calorimetry data of heat annealed bupivacaine-loaded lipid matrix particles and non-annealed bupivacaine-loaded lipid matrix particles, in accordance with one or more embodiments of the present disclosure.

DETAILED DESCRIPTION

[0026] As used in the specification, a word appearing in the singular encompasses its plural counterpart, and a word appearing in the plural encompasses its singular counterpart, unless implicitly or explicitly understood or stated otherwise. Furthermore, it is understood that for any given component or embodiment described herein, any of the possible candidates or alternatives listed for that component may generally be used individually or in combination with one another, unless implicitly or explicitly understood or stated otherwise. Additionally, it will be understood that any list of such candidates or alternatives is merely illustrative, not limiting, unless implicitly or explicitly understood or stated otherwise. In addition, unless otherwise indicated, numbers expressing quantities, constituents, distances, or other measurements used in the specification and claims are to be understood as being modified by the term “about.” [0027] Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the subject matter presented herein. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the subject matter presented herein are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical values, however, inherently contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

Exemplary Opioid Independent Surgical Anesthetics

[0028] As indicated above, alternative pain management strategies are needed to reduce the dependence on opioids for treating postoperative pain. However, existing products that purport to provide long-acting local anesthetic effects are deficient in many respects. For example, one purported extended-release local anesthetic preparation — Exparel^® (Pacira, Parsippany, NJ) — is a liposomal bupivacaine suspension. Although Exparel^® has shown some promise in reducing the quantity of opioids required for maintaining analgesia after surgery, there have been concerns about its true efficacy and duration of effect in reducing post-operative pain (e.g., as demonstrated by independent clinical trials). Exparel^® is also cumbersome to use, requiring the administering physician to repeatedly jab the patient with a needle to deliver subcutaneous injections of the liposomal bupivacaine suspension around the periphery of the wound (or surgical site). This process is also time consuming, taking the physician approximately 10 minutes in the operating room to administer all of the requisite injections.

[0029] Additionally, Exparel^® typically fails to provide a burst effect of drug release following injection, making Exparel^® unsuitable for managing acute pain at a surgical site immediately following a surgical procedure. To address this issue, Pacira, the manufacturer of Exparel^® recommends mixing the liposomal bupivacaine with standard bupivacaine (e.g., bupivacaine HC1) prior to infiltration, or separately injecting standard bupivacaine at the surgical site (e.g., with a separate syringe) in conjunction with Exparel^®. Using Exparel^® in conjunction with standard bupivacaine further adds to the complexity, time, and/or cost associated with implementing Exparel^® for postoperative pain management and underscores its inability to provide sufficient analgesia at the injection site without additional anesthetics.

[0030] These concerns, coupled with the high cost of Exparel^®, have led to significant concerns about the cost utility and efficacy of Exparel^®.

[0031] As noted above, Exparel^® comprises liposomal bupivacaine. Liposomes may experience accelerated release of their contents in vivo due to disruptive serum protein adsorption to the lipid bilayer and by retardation of electrostatic potential by salts/ions in the physiologic milieu. Such reactions to in vivo conditions may be a cause of the failure of liposomal bupivacaine to satisfy the needs of medical practitioners for a long-acting local anesthetic. Other attempts to create lipid micro/nano-particle bupivacaine sustained release systems have failed due to instability, poor drug loading, and/or rapid drug expulsion during storage. For example, unstable a-phase lipid polymorphs may spontaneously transition to the thermodynamically favored b-phase and expel loaded drugs during the phase transition.

[0032] Accordingly, there exists a long-felt need for an improved opioid independent, long-acting local anesthetic formulation that provides, for example, prolonged analgesia following administration (e.g., 48 hours or longer, such as 72 hours or longer), that can be administered in a simple, non-time-consuming manner (e.g., as a ready -to-use composition that is pre-filled — and deliverable through — a conventional syringe), and that demonstrates an initial burst release of anesthetic followed by localized, sustained release of anesthetic to address both the acute and lingering postoperative pain — all preferably at an affordable price.

[0033] Various embodiments disclosed herein are related to systems, methods, components, apparatuses, and kits associated with opioid independent surgical anesthetics. In one example embodiment, an opioid independent surgical anesthetic composition includes an injectable dosage form of a hydrogel that has a plurality of solid lipid matrix particles entrapped therein. The plurality of solid lipid matrix particles includes a lipophilic local anesthetic drug and a saturated triglyceride. In another example embodiment, an opioid independent surgical anesthetic composition includes a ready -to-use injectable dosage form of a cross-linked hyaluronic acid hydrogel having lipid emulsion droplets containing bupivacaine entrained therein.

[0034] Those skilled in the art will recognize, in view of the present disclosure, that at least some of the disclosed embodiments may address various shortcomings and/or problems associated with conventional techniques and products for managing postoperative pain.

[0035] For example, at least some anesthetic compositions of the present disclosure utilize a hydrogel, such as a hyaluronic acid hydrogel, as a carrier to facilitate drug delivery (at least some anesthetic compositions of the present disclosure may be generalized as hyaluronic acid local anesthetics (HALAs), such as a lipid emulsion HALA or a lipid matrix particle HALA). Although hyaluronic acid hydrogels exhibit a gel-like consistency, hyaluronic acid hydrogels also exhibit shear-thinning mechanical properties, enabling a HALA to be injected through a small-gauged needle (e.g., 18 G-25 G) similar to standard local anesthetics prepared as an aqueous solution (or other liquid form). Unlike plain bupivacaine, which has the consistency of water, a HALA reforms into a stable gel following injection through a syringe. This allows a HALA to be applied topically, avoiding complicated and/or repetitive subcutaneous injection procedures. For example, at the end of a surgical procedure, medical practitioners may easily apply a HALA within the wound and suture the wound closed over the HALA, disposing local anesthetic directly at the source of the pain. The drug then elutes from the carrier hyaluronic acid hydrogel to provide a local analgesic effect safely and reliably. It should be appreciated that the gel like consistency of the hydrogel advantageously allows it to conform to the wound bed as the surgical site is closed. This acts to provide anesthetic across the surface area of the wound and more efficiently direct its analgesic effects to the disrupted tissue where the pain and inflammation is more intense/originating.

[0036] In addition, at least some HALAs of the present disclosure are configured to provide a high-rate burst drug release upon administration to a surgical site followed by a low-rate prolonged drug release. In this regard, a HALA of the present disclosure may address both acute pain that immediately follows a surgical procedure as well as lingering pain experienced as a surgical site heals. Accordingly, at least some HALAs of the present disclosure provide medical practitioners with a single product that manages both acute postoperative pain and lingering postoperative pain (e.g., in contrast with existing products that require complicated admixing procedures prior to drug administration or contemporaneous administration of multiple drug products).

[0037] In some instances, a HALA implements bupivacaine as an anesthetic agent, which is known to be cardiotoxic. Notwithstanding the cardiotoxic properties of bupivacaine, the controlled release characteristics of the HALAs of the present disclosure may enable HALAs to include a high concentration of bupivacaine relative to conventional products (e.g., 1.5% or greater w/v bupivacaine compared to 0.5% w/v for bupivacaine HCL and 1.33% w/v Exparel^®) while still safely providing superior analgesic effects without risk of cardiotoxicity.

[0038] The manufacturing protocol and materials for creating at least some of the HALAs of the present disclosure are simple and/or inexpensive, particularly when compared with the manufacturing protocol and materials for creating existing products that attempt to provide long-acting local anesthetic effects. In addition, HALA products of the present disclosure may be provided to medical practitioners in a shelf-stable and ready- to-use, pre-filled syringe (e.g., 5cc or 10 cc) that is operable to manage both immediate postoperative pain (via an initial burst drug release) and lingering postoperative pain (via a subsequent sustained drug release) with a single application. It should be appreciated that the disclosed HALA products are beneficially shelf-stable, allowing for extended storage periods without loss of desired therapeutic effect. Accordingly, a HALA of the present disclosure may allow medical practitioners to avoid complicated admixing procedures, multiple injection procedures, contemporaneous administration of multiple anesthetic drugs (e.g., Exparel^® and bupivacaine HCL), and/or other drawbacks associated with existing local anesthetics that attempt to provide long-acting effects.

[0039] In some embodiments, lipid matrix particle HALAs implement solid lipid matrix particles formed under controlled heating/cooling conditions that allow for heat annealing of the lipid melt used to form the solid lipid matrix particles. Heat annealing may advantageously remove unstable polymorphs from the lipid melt in preparation for pulverization to form the solid lipid matrix particles for entrapment within a hyaluronic acid hydrogel. In some instances, the removal of unstable polymorphs contributes to the stable and predictable diffusion-controlled drug release from lipid matrix particle HALAs. [0040] Because the HALAs of the present disclosure may facilitate extended local control of pain at a surgical site, the HALAs of the present disclosure may provide a postoperative pain management alternative that mitigates or avoids the use of centrally- acting opioids for pain management (particularly self-administered opioids). In this regard, the HALAs of the present disclosure may help patients to avoid any potential opioid dependency, overdose, and/or addiction by allowing medical practitioners to treat a surgical site with an opioid-independent, effective, safe, and long-acting local anesthetic. [0041] Although the present disclosure focuses in some respects on topical applications of HALAs within human patients, those skilled in the art will recognize, in view of the present disclosure, that these implementations are provided as examples only and are in no way limiting of the present disclosure. For example, a user may inject a HALA subcutaneously as a nerve blocking agent and/or on an animal subject in accordance with implementations of the present disclosure.

[0042] Furthermore, although the present disclosure focuses, in some respects, on HALAs that implement bupivacaine as an anesthetic agent, a HALA may implement additional or alternative anesthetic agents, such as lidocaine or other amide based local anesthetics such as articaine, cinchocaine/dibucaine, etidocaine, levobupivacaine, lignocaine, mepivacaine, prilocaine, ropivacaine, trimecaine, and/or others.

[0043] Having just described some of the various high-level features and benefits of the disclosed embodiments, attention will now be directed to FIGs. 1 through 9. These figures illustrate various conceptual representations, components, systems, methods, and supporting illustrations related to the disclosed embodiments.

[0044] FIG. 1 illustrates a schematic representation of an opioid independent surgical anesthetic composition (i.e., lipid matrix particle HALA 100). FIG. 1 illustrates that the lipid matrix particle HALA 100 includes solid lipid matrix particles 105 entrapped within a hydrogel 110. As indicated hereinabove, in at least some embodiments, the hydrogel 110 comprises a crosslinked hyaluronic acid hydrogel formed from hyaluronic acid 115. Hyaluronic acid 115 is a naturally occurring component of extracellular matrix and has demonstrated safety (e.g., a very low risk of side-effects).

[0045] In the example depicted in FIG. 1, the hydrogel 110 is formed from thiol- modified chains of hyaluronic acid 115 that are crosslinked by thiol -reactive poly(ethylene glycol) diacrylate (PEGDA) 120 crosslinkers. The crosslinking restricts movement of the chains of hyaluronic acid 115 and forming a network structure that gives the hydrogel 110 its gel-like mechanical properties.

[0046] As noted above, FIG. 1 also illustrates that the hydrogel 110 entraps solid lipid matrix particles 105 that are infused with a local anesthetic agent (e.g., bupivacaine 125 shown in FIG. 1 infused throughout solid lipid matrix particles 105 of the lipid matrix particle HALA 100). As will be described hereinafter, preliminary results indicate that the hydrogel 110 may shield at least some of the bupivacaine-loaded solid lipid matrix particles 105 from harsh in vivo conditions, thereby facilitating a controlled, prolonged release of bupivacaine 125 from the lipid matrix particle HALA 100 into a surgical or injection site.

[0047] FIG. 1 illustrates a schematic representation of a procedure for manufacturing the solid lipid matrix particles 105 for creating a lipid matrix particle HALA 100. FIG. 1 shows that the solid lipid matrix particles 105 may, in some implementations, be formed from a combination of a saturated triglyceride 130 and a lipophilic local anesthetic drug (e.g., bupivacaine 125 illustrated in FIG. 1 above the saturated triglyceride 130). For example, the saturated triglyceride 130 may be heated (e.g., via hotplate 135 or other heating device) to a temperature above its melting point, forming a triglyceride lipid melt. Freebase bupivacaine 125 may be dissolved into the triglyceride lipid melt (indicated in FIG. 1 by arrow 140), forming a bupivacaine-lipid solution.

[0048] The bupivacaine-lipid solution may then be cooled to form a bupivacaine- loaded lipid matrix bulk solid 145 (indicated in FIG. 1 by arrow 150). In some instances, cooling the bupivacaine-lipid solution involves performing a heat annealing process. For example, a heat annealing process may include maintaining a temperature that is between about 5° C - 20° C below the melting point of the saturated triglyceride 130, preferably approximately 10° C below the melting point of the saturated triglyceride 130, for an extended period of time (e.g., longer than 30 minutes, preferably longer than about an hour, more preferably approximately 2 hours) as the bupivacaine-lipid solution solidifies to form the bupivacaine-loaded lipid matrix bulk solid 145.

[0049] Triglycerides are known to crystalize into three phases upon solidification from melt. Triglycerides may solidify into an unstable a-phase crystalline state, an intermediary b'-phase crystalline state, and a stable b-phase crystalline state. Omitting or avoiding unstable a-phase and b'-phase crystalline structures from the bupivacaine-loaded lipid matrix bulk solid 145 may increase thermodynamic stability of solid lipid matrix particles 105 formed from the bupivacaine-loaded lipid matrix bulk solid 145 (e.g., which may possibly increase shelf life stability) and may contribute to the predictable diffusion- controlled drug release from the lipid matrix particle HALA 100 (see FIG. 8).

[0050] Preliminary results indicate that performing the heat annealing process described herein may remove substantially all unstable a-phase and b'-phase crystalline structures from a bupivacaine-loaded lipid matrix bulk solid 145, providing a bupivacaine- loaded lipid matrix bulk solid 145 that substantially comprises forming a b-phase crystalline state. By way of example, attention is briefly directed to FIG. 9, which illustrates a graph of differential scanning calorimetry data of non-annealed bupivacaine- loaded lipid matrix particles (curve 910) and heat annealed bupivacaine-loaded lipid matrix particles (curve 920). As is evident from curve 910 of FIG. 9, the heat flow necessary to increase the temperature of the non-annealed bupivacaine-loaded lipid matrix particles includes significant fluctuations between about 50° C - 70° C, which indicates the presence of unstable a-phase triglyceride crystalline structures in non-annealed bupivacaine-loaded lipid matrix particles. In contrast, as is evident from curve 920 of FIG. 9, such fluctuations do not appear between about 50° C - 70° C for heat annealed bupivacaine-loaded lipid matrix particles, indicating that unstable a-phase triglyceride crystalline structures are not present in heat annealed bupivacaine-loaded lipid matrix particles.

[0051] The bupivacaine-loaded lipid matrix bulk solid 145 may be pulverized or crushed (e.g., with a mortar and pestle or functional equivalent) to form solid lipid matrix particles 105 in powder form (indicated in FIG. 1 by arrow 155). The solid lipid matrix particles 105 may be admixed with components for forming the hydrogel 110 (e.g., hyaluronic acid 115, PEGDA 120; admixing indicated in FIG. 1 by arrows 160, 165, and 170). In some instances, the admixed solid lipid matrix particles 105, hyaluronic acid 115, and PEGDA 120 are disposed within a syringe 175 where crosslinking may complete to form a lipid matrix particle FLALA 100 that is ready for immediate use by a medical practitioner in a manner that avoids bedside admixing or other complicated procedures or that can be stored for later use.

[0052] Furthermore, in some instances, the solid lipid matrix particles 105 that are size selected prior to admixing with the components for forming the hydrogel 110 (e.g., including only solid lipid matrix particles that have a longest dimension of between about 25 pm - 500 pm, preferably between about 50 pm - 300 pm, more preferably about 200 pm or less). For example, the solid lipid matrix particles 105 formed by pulverizing the bupivacaine-loaded lipid matrix bulk solid 145 (indicated by arrow 155) may be sieved to isolate solid lipid matrix particles of different size ranges, such as 25 pm or smaller, between 25 pm and 50 pm, between 100 pm and 125 pm, etc. (e.g., using ASTM (American Society for Testing and Materials) standardized sieves with pore sizes of 25, 50, 100, and 125 pm). In some instances, drug release characteristics of a lipid matrix particle FLALA 100 may be tuned/customized based on size selection of the solid lipid matrix particles 105 used to form the lipid matrix particle FLALA 100. [0053] Drug release characteristics of a lipid matrix particle HALA 100 may be customized by modifying various components, such as lipid matrix particle size (as indicated above), triglyceride fatty acid chain length, blends of triglycerides with different fatty acid chains and/or lengths, crystallization morphology (e.g., tunable by modifying heat annealing or refraining from performing heat annealing), drug loading concentration, type and/or degree and/or mass ratio of crosslinking, and/or others. In one example, a lipid matrix particle HALA 100 includes thiolated-hyaluronic acid at 1.25% w/v crosslinked by PEGDA at 0.833% w/v, where the bupivacaine concentration is 2% w/v. Other configurations are within the scope of this disclosure.

[0054] In some instances, the triglyceride 130 used to form the solid lipid matrix particles 105 of FIG. 1 comprises a saturated triglyceride with a melting point above room temperature (e.g., a melting point greater than about 45° C, such as about 70° C or greater), such as trilaurin, trimyristin, tripalmitin, tristearin, and/or others.

[0055] Although the discussion of FIG. 1 focuses, in at least some respects, on lipid matrix particle HALAs 100 formed with hyaluronic acid hydrogels that are crosslinked by PEGDA, other types of hydrogels and/or crosslinkers are within the scope of this disclosure. For example, a hydrogel can be crosslinked without the presence of PEGDA where the thiol-modified hyaluronan crosslinks with itself via oxidative disulfide bond formation to form hydrogels. Furthermore, as noted above, other lipophilic local anesthetic drugs aside from bupivacaine are within the scope of this disclosure.

[0056] FIGs. 2A and 2B illustrate an example of applying an opioid independent surgical anesthetic composition to a surgical site 200 (e.g., on an appendage of a human or animal subject). In particular, FIG. 2 A illustrates the syringe 175 from FIG. 1 loaded with lipid matrix particle HALA 100, where the syringe 175 is being used to topically apply the lipid matrix particle HALA 100 over the surgical site 200.

[0057] As noted hereinabove, although hyaluronic acid hydrogels exhibit a gel-like consistency (similar to hair gel), hyaluronic acid hydrogels also exhibit shear-thinning mechanical properties, enabling the lipid matrix particle HALA 100 to be injectable through the needle of the syringe 175 (e.g., 18 G-25 G). After passing through the needle of the syringe 175, the lipid matrix particle HALA 100 reforms into a stable gel. Because of its viscosity, in some instances, the lipid matrix particle HALA 100 gel remains where initially applied over the surgical site 200. [0058] FIG. 2B illustrates the surgical site 200 of FIG. 2 A, where the surgical site 200 has been closed (e.g., via suture 205). Upon closing the surgical site/wound, the lipid matrix particle HALA 100 intercalates within natural crevices of the surgical site 200 and smears between compressed tissues. The hydrogel of the lipid matrix particle HALA 100 serves to physically sequester the bupivacaine-loaded lipid matrix particles, temporarily shielding them from surrounding in vivo environment. The hydrogel serves to conceal the lipid matrix particles from the immediate in vivo environment and slows the degradation and removal of the bupivacaine drug load from the lipid matrix particle HALA 100 into the surgical wound region, therefore allowing the natural prolonged release of the bupivacaine. The formulation will be naturally absorbed by the body over time.

[0059] Accordingly, a lipid matrix particle HALA 100 of the present disclosure may be applied in a simple manner (e.g., topical application, as shown in FIG. 2A), avoiding complicated and/or repetitive injection and/or admixing procedures (sometimes involving multiple syringes for treating both immediate postoperative pain and lingering postoperative pain) associated with conventional products that attempt to provide long- acting local anesthetic effects.

[0060] Some embodiments of the present disclosure can also be described in terms of acts (e.g., acts of a method) for accomplishing a particular result. Along these lines, FIG. 3 illustrates an example flow diagram 300 depicting acts associated with creating an opioid independent surgical anesthetic composition (e.g., a lipid matrix particle HALA 100). Although the acts shown in flow diagram 300 may be illustrated and/or discussed in a certain order, no particular ordering is required unless specifically stated or required because an act is dependent on another act being completed prior to the act being performed.

[0061] In some instances, the acts of the flow diagrams are described below with reference to the systems, components, structures, and/or elements of FIG. 1. For instance, at least some reference numerals included parenthetically hereinbelow refer, by way of illustrative example, to systems, components, structures, and/or elements described hereinabove with reference to FIG. 1.

[0062] Act 305 of flow diagram 300 includes creating a bulk solid of a lipid matrix product (145). Creating a bulk solid of a lipid matrix product can itself include various sub-acts. For example, act 305 A includes heating a lipid solvent above a melting point of the lipid solvent. In some instances, the lipid solvent includes a saturated triglyceride (130), such as tristearin with a melting point of approximately 72.5° C. Act 305B includes dissolving a lipophilic local anesthetic drug into the lipid solvent to form a drug-lipid solution. In some implementations, the lipophilic local anesthetic drug comprises freebase bupivacaine (125) or another amide based local anesthetic.

[0063] Act 305C includes reducing a temperature of the drug-lipid solution to below the melting point of the lipid solvent, thereby forming the bulk solid of the lipid matrix product. In some instances, reducing the temperature of the drug-lipid solution includes performing a heat annealing process when reducing the temperature of the drug-lipid solution to below the melting point of the lipid solvent. The heat annealing process may include maintaining a temperature of the drug-lipid solution as it forms the bulk solid at approximately 8° C - 12° C below the melting point of the lipid solvent for a period of time (e.g., one hour or longer, such as 2 hours). For example, where the lipid solvent comprises tri stearin, a heat annealing process may include maintaining a temperature of the drug-lipid solution at 62° C for a time period of 2 hours.

[0064] Act 310 of flow diagram 300 includes forming solid lipid matrix particles (105). In some instances, forming the solid lipid matrix particles (105) includes crushing or pulverizing the bulk solid of the lipid matrix product (145) (e.g., with a mortar and pestle or device of similar functionality). In some instances, the solid lipid matrix particles (105) may be sieved to isolate the solid lipid matrix particles (105) into different size ranges.

[0065] Act 315 of flow diagram 300 includes entrapping a plurality of size-selected solid lipid matrix particles (105) within a hydrogel (110). In some embodiments, as described above, the size-selected solid lipid matrix particles (105) have a longest dimension that is between about 25 pm - 500 pm, preferably between about 50 pm - 300 pm, more preferably about 200 pm or less (e.g., 25 pm or smaller, between 25 pm and 50 pm, between 100 pm and 125 pm, etc.). The hydrogel (110) may comprise a cross-linked hyaluronic acid hydrogel.

[0066] Act 320 of flow diagram 300 includes loading the composite gel system (lipid matrix particle HALA 100) into a sealed syringe (175). In some instances, the lipid matrix particle HALA 100 finishes crosslinking within the syringe (175). The shear-thinning properties of the composite gel system may facilitate injectability of the composite gel system through the syringe (175), provide a convenient and simple mechanism for delivery of the composite gel system to a treatment site. [0067] FIG. 4 illustrates a schematic representation of an alternative embodiment of an opioid independent surgical anesthetic composition (i.e., lipid emulsion HALA 400). FIG. 4 illustrates that the lipid emulsion HALA 400 includes a hydrogel 405 that entraps lipid emulsion droplets 410 containing bupivacaine 415 entrained therein. Similar to the hydrogel 110 described hereinabove with reference to FIG. 1, the hydrogel 405 of the lipid emulsion HALA 400 may comprise thiol-modified hyaluronic acid 420 and thiol -reactive PEGDA 425. The hydrogel 405 may shield at least some of the lipid emulsion droplets 410 that contain bupivacaine 415 entrained therein from harsh in vivo conditions, thereby facilitating a controlled, prolonged release of bupivacaine 415 from the lipid emulsion HALA 400 into a surgical or injection site.

[0068] FIG. 4 also illustrates a schematic representation of a procedure for manufacturing the lipid emulsion HALA 400. As depicted in FIG. 4, freebase bupivacaine 415 may be mixed with a lipid emulsion 410, indicated in FIG. 4 by arrows 430 and 435. In one example, the lipid emulsion 410 may comprise Intralipid^® 20%, an FDA approved parenteral nutrition lipid emulsion that includes 20% soybean oil, 1.2% egg yolk phospholipids, and 2.25% glycerin. The mixture may be homogenized using a homogenizer (e.g., using high-speed homogenization, high-pressure homogenization, sonication, microfluidic homogenization, and/or other techniques), resulting in a bupivacaine-loaded emulsion 440 that comprises lipid emulsion droplets 410 that contain bupivacaine 415 loaded therein.

[0069] The bupivacaine-loaded emulsion 440 may then be mixed with components for forming the hydrogel 405 (e.g., hyaluronic acid 420, PEGDA 425; mixing indicated in FIG. 4 by arrows 445, 450, and 455). Similar to the lipid matrix particle HALA 100 described hereinabove with reference to FIG. 1, the mixed bupivacaine-loaded emulsion 440, hyaluronic acid 420, and PEGDA 425 may be disposed within a syringe 475, providing a lipid emulsion HALA 400 that is ready for immediate use by a medical practitioner in a manner that avoids bedside admixing or other complicated procedures. [0070] The lipid emulsion HALA 400 may be administered to a treatment site in a manner that is similar to those described hereinabove for the lipid matrix particle HALA 100 (e.g., see FIGs. 2A and 2B). Furthermore, drug release characteristics of a lipid emulsion HALA 400 may be customized by modifying various components, such as homogenization parameters (e.g., pressure, cycles, phospholipid content, etc.), % amount of lipids used, drug load concentration, type and/or degree and/or mass ratio of crosslinking, and/or others.

EXAMPLES

[0071] The following examples as set forth herein are intended for illustrative purposes only and are not intended to limit the scope of the disclosure in any way. Rather, the examples are intended to demonstrate one or more aspects and/or advantages of the opioid independent surgical anesthetics disclosed herein.

Example 1 [0072] FIG. 5 illustrates a graph of in vitro data of cumulative bupivacaine release over time from various lipid-HA (hyaluronic acid) gel formulations. Some of the lipid-HA gel formulations represented in FIG. 5 correspond to the lipid emulsion FLALA formulations described hereinabove with reference to FIG. 4. FIG. 5 includes data for a 0% lipid HA gel formulation, a 2% lipid emulsion HALA, and a 4% lipid emulsion HALA. [0073] As is evident from FIG. 5, the illustrated lipid emulsion HALA formulations are configured to release bupivacaine in a biphasic manner (i.e., an initial high release rate burst phase followed by a low release rate sustained release phase). For example, the various HALA formulations represented in FIG. 5 released a significant portion of bupivacaine (e.g., to achieve a cumulative release % within a range of about 30% - 70%) during an initial burst phase within a range of about 8 - 24 hours post administration. Following the burst phase, the various HALA formulations released additional bupivacaine following the initial burst phase (e.g., to achieve a cumulative release % within a range of about 70% - 99%) during a sustained release phase (e.g., between the burst phase and about 72 hours or more post administration). [0074] A comparison of the cumulative release profiles of the various HALA formulations represented in FIG. 5 indicates that drug release from a HALA is modifiable based on the amount of lipids used in the HALA formulation. For example, the 4% lipid formulation of FIG. 5 achieved drug release at a lower rate during the burst phase than the 2% or 0% lipid formulations. [0075] The results illustrated in FIG. 5 underscore the tunability of temporal anesthetic release in burst and sustained release phases, which enable the lipid emulsion HALA formulations of the present disclosure to address both acute postoperative pain (e.g., via initial burst drug release) as well as lingering pain experienced as a surgical site heals (e.g., via sustained drug release following the burst release).

Example 2

[0076] FIGs. 6A and 6B illustrate graphs of in vivo data of paw withdrawal latency and contra-ipsi latency for rodents treated with a lipid emulsion HALA. The data represented in the graphs of FIGs. 6A and 6B were obtained according to the Hargreaves Assay, which is a standardized rodent thermal nociception assay that assesses a rodent’s paw withdrawal latency after application of a thermal stimulus. Bupivacaine HCL and Exparel^® were delivered via injections into tissue adjacent to the sciatic nerve. Lipid emulsion HALA gel was administered via infiltration into the sciatic nerve cavity. Paw withdrawal latency was measured after application of a thermal stimulus to the injured paw. As is evident from FIG. 6A, the lipid emulsion HALA group had generally higher paw withdrawal latencies than both the bupivacaine HCL and Exparel^®, indicating greater anesthetic effect from the lipid emulsion HALA group. Furthermore, FIG. 6B illustrates contralateral-ipsilateral latencies measured for rodents treated with bupivacaine HCL, Exparel^®, and lipid emulsion HALA, as described above. As is evident from FIG. 6B, the lipid emulsion HALA group had generally lower paw contralateral-ipsilateral latencies than both the bupivacaine HCL and Exparel^®, indicating greater anesthetic effect from the lipid emulsion HALA group.

Example 3

[0077] FIG. 7 illustrates a graph of in vivo data showing the maximum possible effect (MPE) % of anesthetic in a thermal nociceptive assay for bupivacaine-loaded emulsions (BLE) (without a hyaluronic acid hydrogel carrier) and HA-BLE (corresponding to lipid emulsion HALA, described hereinabove) compared to controls of bupivacaine HCL and liposomal bupivacaine. A rat sciatic nerve block model and thermal nociceptive assay was used to compare the anesthetic effect of the compositions described above. As is evident from FIG. 7, HA-BLE produced a significantly greater anesthetic effect and duration compared to Exparel® (liposomal bupivacaine) and 0.25% bupivacaine HCL, alone. Example 4

[0078] FIG. 8 illustrates a graph of cumulative bupivacaine release over time from various HA hydrogel formulations that include bupivacaine-loaded lipid matrix particles (i.e., lipid matrix particle HALA, as described hereinabove with reference to FIGs. 1 - 3). In particular, FIG. 8 illustrates bupivacaine release profiles for a lipid matrix particle HALA formed with trilaurin and for a lipid matrix particle HALA formed with tristearin (having a longer triglyceride chain than trilaurin).

[0079] Similar to the lipid emulsion HALA formulations represented in FIG. 5, the lipid matrix particle HALA compositions represented in FIG. 8 demonstrate controlled release of bupivacaine, in particular in an initial burst phase and a subsequent sustained release phase. The sustained release phases for the lipid matrix particle HALA compositions of FIG. 8 appear to extend for longer periods of time than the sustained release phases of the lipid emulsion HALA compositions of FIG. 5, indicating that lipid matrix particle HALA compositions show promise for effectuating long-acting anesthetic effects to combat postoperative pain.

[0080] Furthermore, as is evident from FIG. 8, the lipid matrix particle HALA formed with tristearin appears to have a significantly slower drug release profile than the lipid matrix particle HALA formed with trilaurin, indicating that the triglyceride chain length selected to form solid lipid matrix particles may influence the drug release characteristics of the lipid matrix particle HALAs.

[0081] Accordingly, at least some HALAs of the present disclosure are configured to provide a high-rate burst drug release upon administration to a surgical site followed by a low-rate prolonged drug release. In this regard, a HALA of the present disclosure may address both acute pain that immediately follows a surgical procedure as well as lingering pain experienced as a surgical site heals and have the potential to reduce or eliminate dependence on systemic opioids as a method for postoperative pain management.

[0082] It is to be understood that features described with regard to the various embodiments herein may be mixed and matched in any desired combination. In addition, the concepts disclosed or envisioned herein may be embodied in other specific forms. The described embodiments are to be considered in all respects only as illustrative and not restrictive. The scope is, therefore, indicated by the appended claims rather than by the foregoing description. All changes which come within the meaning and range of equivalency of the claims are to be embraced within their scope.

Claims

CLAIMS What is claimed is:

1. An opioid independent surgical anesthetic composition, comprising an injectable dosage form of a hydrogel having a plurality of solid lipid matrix particles entrapped therein, the plurality of solid lipid matrix particles comprising a lipophilic local anesthetic drug and a saturated triglyceride.

2. The composition of claim 1, wherein the hydrogel comprises a crosslinked hyaluronic acid hydrogel.

3. The composition of claim 1 or claim 2, wherein the lipophilic local anesthetic drug comprises bupivacaine.

4. The composition of any one of claims 1 - 3, wherein the plurality of solid lipid matrix particles substantially comprises triglycerides forming a b-phase crystalline state.

5. The composition of any one of claims 1 -4, wherein the solid lipid matrix particles have a melting point greater than about 45° C, preferably greater than about 70° C.

6. The composition of any one of claims 1 - 5, wherein the saturated triglyceride comprises tristearin.

7. The composition of any one of claims 1 - 4, wherein each of the plurality of solid lipid matrix particles has a longest dimension of about 200 pm or less.

8. An opioid independent surgical anesthetic composition, consisting essentially of a ready -to-use injectable dosage form of a cross-linked hyaluronic acid hydrogel having a lipid emulsion containing bupivacaine entrained therein.

9. The composition of any one of claims 1 - 8, configured to release bupivacaine in a biphasic manner when administered at a surgical site, the biphasic release comprising a burst phase and a sustained release phase.

10. The composition of claim 9, wherein between 30% - 70% of the bupivacaine is cumulatively released from the hydrogel during the burst phase between 8 - 24 hours post administration.

11. The composition of any one of claims 8 - 10, wherein between 70% - 99% of the bupivacaine is cumulatively released from the hydrogel by 72 hours post administration.

12. A kit comprising the opioid independent anesthetic composition of any one of claims 1 - 11 within a ready -to-use, pre-filled syringe.

13. A method for creating a long-acting local anesthetic product, comprising: creating a bulk solid of a lipid matrix product by: heating a lipid solvent above a melting point of the lipid solvent; dissolving a lipophilic local anesthetic drug into the lipid solvent to form a drug-lipid solution; and reducing a temperature of the drug-lipid solution to below the melting point of the lipid solvent; forming solid lipid matrix particles by crushing the bulk solid of the lipid matrix product; and entrapping a plurality of the solid lipid matrix particles within a hydrogel.

14. The method of claim 13, wherein creating the bulk solid of the lipid matrix product further comprises performing a heat annealing process when reducing the temperature of the drug-lipid solution to below the melting point of the lipid solvent, wherein the heat annealing process comprises maintaining a temperature of the drug-lipid solution at approximately 8° C - 12° C below the melting point of the lipid solvent for approximately one hour or longer.

15. The method of claim 14, wherein the lipophilic local anesthetic drug comprises bupivacaine, wherein the lipid solvent comprises a saturated triglyceride, and wherein the hydrogel comprises a cross-linked hyaluronic acid hydrogel.