Pharmaceutical oil-in-water emulsion for treating pain

Abstract

In some aspects, the techniques described herein relate to a pharmaceutical oil-in-water emulsion, including: a lipophilic oil; a therapeutic agent, salt, or prodrug thereof dispersed in the lipophilic oil; an optional therapeutic agent solubility and release modifying agent; and a surfactant.

Description

PHARMACEUTICAL OIL-IN-WATER EMULSION FOR TREATING PAINCROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application Serial No. 63 / 575,477 entitled “PHARMACEUTICAL OIL- IN-WATER EMULSION FOR TREATING PAIN,” filed April 5, 2024 the disclosure of which is incorporated herein in its entirety by reference.BACKGROUND

[0002] Local anesthetics are widely used in surgery to anesthetize the surgical site and to reduce postoperative pain, but because of their short durations of effect, they are unable to provide analgesia throughout the period when patients experience severe pain. When the anesthetic wears off, opioid medications are given to manage this pain, most often for three or more days, until less potent analgesics are able to control the pain.SUMMARY OF THE DISCLOSURE

[0003] A problem that the instant disclosure seeks to solve is to provide an injectable or implantable emulsion that can provide 1-14 days of robust pain relief that can remain at the administration site long enough to provide a local anesthetic effect.

[0004] In some aspects, the techniques described herein relate to a pharmaceutical oil-in-water emulsion, including: a lipophilic oil; a therapeutic agent, salt, or prodrug thereof dispersed in the lipophilic oil; an optional therapeutic agent solubility and release modifying agent; and a surfactant.BRIEF DESCRIPTION OF THE FIGURES

[0005] The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments of the present disclosure.

[0006] FIG. l is a graph showing the cumulative percent bupivacaine release over time based on theoretical drug loading.

[0007] FIG. 2 shows the maximum solubility of bupivacaine freebase or ropivacaine freebase in castor oil or MCT oil spiked with different levels of ricinoleic acid.

[0008] FIG. 3 shows the maximum solubility of bupivacaine freebase in a castor oil:MCT oil (65:35 weight ratio) spiked with different levels of oleic or ricinoleic acid.

[0009] FIG. 4 shows blood plasma concentration over time following a 7.5 mg / kg (0.56 mL / kg) dose of RBL002 (10% oleic) or RBL004 (no oleic).DETAILED DESCRIPTION OF THE DISCLOSURE

[0010] Reference will now be made in detail to certain aspects of the disclosed subject matter. While the disclosed subject matter will be described in conjunction with the enumerated claims, it will be understood that the exemplified subject matter is not intended to limit the claims to the disclosed subject matter.

[0011] The present disclosure relates to a pharmaceutical oil-in-water emulsion comprising a lipophilic oil component; a therapeutic agent, an optional therapeutic agent solubility and release modifier agent, and a surfactant. These components can form a stable oil-in-water emulsion. The pharmaceutical oil-in- water emulsion can be used in both human and veterinary pain management applications. Possible clinical uses include, but are not limited to, neuraxial, regional and local anesthesia for the treatment of procedural, postoperative, and injury-related pain, local infiltrative anesthesia for myofascial pain (e.g., trigger points), and chronic pain.

[0012] The pharmaceutical oil-in-water emulsions described herein can be used for post-operative pain management as a substitute for drugs used for post-operative pain management that include an opioid. The described pharmaceutical oil-in-water emulsion can be a complete substitution for the drug including an opioid or it can be used in conjunction with a drug including an opioid to reduce the amount of the opioid used in post-operative pain management.

[0013] The emulsion can be applied to a surgical site / wound. Upon closing the surgical site / wound, the emulsion can intercalate within naturalcrevices and smear between compressed tissues. The emulsion can be biodegradable and can, therefore, be naturally resorbed by the body over time.

[0014] The lipophilic oil of the emulsion can be chosen from many suitable oils. For example, the lipophilic oil can include a monoglyceride, diglyceride, triglyceride, sesame oil, soybean oil, castor oil, tributyrin oil, vegetable oil, or a mixture thereof. For example, the lipophilic oil can include a mixture of a medium chain triglyceride oil and castor oil in which either independently ranges from 2 wt% to 98 wt%, 30 wt% to 70 wt%, less than, equal to, or greater than 2 wt%, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or about 98 wt%.

[0015] Sesame oil generally includes 41 wt% linoleic acid, 39 wt% oleic acid, 8 wt% palmitic acid, 5 wt% stearic acid, and trace amounts of other organic acids. Per 100 g, soybean oil has 16 g of saturated fat, 23 g of monounsaturated fat, and 58 g of polyunsaturated fat. The major unsaturated fatty acids in soybean oil triglycerides are 7 to 10 wt% polyunsaturated alpha-linolenic acid, and 51 wt% linoleic acid, and 23 wt% monounsaturated oleic acid. Soybean oil also includes saturated fatty acid such as 4 wt% stearic acid and 10 wt% palmitic acid. Castor oil includes 85 to 95 wt% ricinoleic acid, 2 to 6 wt% oleic acid, 1 to 5 wt% linoleic acid, 0.5 to 1 wt% a-linolenic acid, 0.5 to 1 wt% stearic acid, 0.5 to 1 wt% palmitic acid, 0 to 0.5 wt% dihydroxystearic acid, and 0.2 to 0.5 wt% additional compounds. The tributyrin oil is an ester that is a reaction product of butyric acid and glycerol. The triglyceride can be a medium-chain triglyceride, a short-chain triglyceride, or both. Examples of medium-chain triglycerides include an ester that is a reaction product glycerol with any of a C6-C12 carboxylic acid (e.g., hexanoic acid, octanoic acid, decanoic acid, lauric acid, or a mixture thereof).

[0016] Medium-chain triglycerides can be particularly well suited as the lipophilic oil. Medium-chain triglycerides are shown to accommodate high drug loading and good rates of release. While not intending to be limited to any theory, the benefits of using medium-chain triglycerides in an oil-in-water emulsion are believed to be due to their thin nature and low viscosity, each of which produces more stable and homogenous emulsions (as compared to castor oil, which has good drug solubility but is very viscous).

[0017] A mixture of lipophilic oils can be used. For example, the pharmaceutical oil-in-water emulsion can include a mixture of medium-chain triglycerides and short-chain triglycerides, medium-chain triglycerides and long- chain triglyceride oils, or short-chain triglycerides and long-chain triglycerides. In some examples the solubility of drugs such as bupivacaine can be increased in a mixture of medium-chain triglycerides and short-chain triglycerides at a 90: 10 ratio (medium-chain triglyceride: short-chain triglyceride). As a further example, a mixture of medium-chain triglycerides and castor oil as the lipophilic oil will achieve a higher drug load while reducing viscosity in the overall structure. Triglycerides mentioned herein can include a saturated triglyceride, a monounsaturated triglyceride, or a polyunsaturated triglyceride.

[0018] In a specific example, a mixture of lipophilic oils can include castor oil and medium-chain triglyceride oils are present at a wt:wt ratio ranging from about 25:75 to about 75:25 with respect to each other, about 30:70 to about 70:30, of about 50:50.

[0019] In some examples, high viscosity oils like castor oil may produce unstable emulsions. By using oil blends such as MCT:Castor blends, it is possible to achieve a lower viscosity needed for stable emulsion production while also achieving the solubility / drug loading and extended-release profile necessary to provide a sustained therapeutic dose of a local anesthetic (or other active pharmaceutical ingredient) over multiple days. Additionally, by adding a lipophilic salt, such as oleic acid, bupivacaine drug loading and extended release values can be achieved in emulsions higher and longer than what has been shown in literature. Thus, MCT:Castor Oil blends with the addition of a fatty acid (e.g.„ oleic acid) allow for favorable drug loadings and extended-release profiles from an emulsion, while maintaining stability, and other favorable characteristics.

[0020] The drug can be present in the pharmaceutical oil-in-water emulsion in a therapeutically effective amount. A “therapeutically effective amount” (or “effective amount”) of a compound with respect to use in treatment, refers to an amount of the compound in a preparation which, when administered as part of a desired dosage regimen (to a mammal, such as a human) alleviates a symptom, ameliorates a condition, or slows the onset of disease conditions according to clinically acceptable standards for the disorder or condition to be treated or thecosmetic purpose, e.g., at a reasonable benefit / risk ratio applicable to any medical treatment.

[0021] The term “prophylactic or therapeutic” treatment is art-recognized and includes administration to the patient of one or more compound of the disclosure. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, (e.g., it protects the host against developing the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (e.g., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).

[0022] The exact amount of the drug can vary and is selected depending on the application. As a non-limiting example, the drug can be present in a concentration in a range of from about 0.5% (w / v) to about 40% (w / v), about 1% (w / v) to about 25% (w / v), 2 % (w / v) to about 15 % (w / v) , about 3 % (w / v) to about 10 % (w / v), about 5 % (w / v) to about 8 % (w / v), less than, equal to, or greater than about 0.5 % (w / v), 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 31.5, 32, 32.5, 33, 33.5, 34, 34.5, 35, 35.5, 36, 36.5, 37, 37.5, 38, 38.5, 39, 39.5, or about 40 % (w / v), based on the volume of the lipophilic oil. Whether an amount is therapeutically effective can be a factor of the amount of time that pain is reduced in a subject. For example the pharmaceutical oil-in-water emulsion may be effective to reduce pain in vivo in a subject for a time in a range of from about 24 hours to about 14 days, 48 hours to about 14 days, from about 72 hours to about 96 hours, from about 72 hours to about 80 hours, less than, equal to, or greater than about 24 hours, 25 hours, 26 hours, 27 hours 28 hours, 29 hours 30 hours, 31 hours, 32 hours, 33 hours, 34 hours, 35 hours, 36 hours, 37 hours, 38 hours, 39 hours, 40 hours, 41 hours, 42 hours, 43 hours, 44 hours, 45 hours, 46 hours, 47 hours, 48 hours, 49 hours, 50 hours, 51 hours, 52 hours, 53 hours, 54 hours, 55 hours, 56 hours, 57 hours, 58 hours, 59 hours, 60 hours, 61 hours, 62 hours, 63 hours, 64 hours, 65 hours, 66 hours, 67 hours, 68 hours, 69 hours, 70 hours, 71 hours, 72 hours, 73 hours, 74 hours, 75 hours, 76 hours, 77 hours, 78 hours, 79 hours, 80 hours, 81 hours, 82 hours, 83 hours, 84 hours, 85 hours, 86 hours, 87 hours, 88hours, 89 hours, 90 hours, 91 hours, 92 hours, 93 hours, 94 hours, 95 hours, 96 hours, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or about 14 days. Some pharmaceutical oil-in-water emulsions can be designed to be effective to reduce pain for specified ranges such as 12 hours to 48 hours, 48 hours to 96 hours, 96 hours to 144 hours, 144 hours to 240 hours, or 240 hours to 336 hours. The exact drug release characteristics can be a function of the composition and structure of the pharmaceutical oil-in-water emulsion. For example, a specific blend of lipophilic oils affects drug release characteristics. For example, a specific ion pair (e.g., lipophilic salt) formed with the therapeutic agent can affect the release characteristics.

[0023] The amount of time that that the pharmaceutical oil-in-water emulsion is therapeutically effective can be a result of the release rate of the drug from the lipophilic oil. The drug release from lipophilic oil is controlled by diffusion. Depending on the drugs affinity to the specific lipophilic oil or specific blend of lipophilic oils, the drug will preferentially reside in the lipophilic oil and slowly diffuse into the surrounding aqueous medium in a patient’s body depending on its greater affinity to the lipophilic oil than the aqueous medium.

[0024] The therapeutic agent comprises an analgesic agent, anesthetic agent, or anti-inflammatory agent. In some examples, the anti-inflammatory agent can be an adjuvant.

[0025] As understood herein, an analgesic agent is any member of the group of drugs used to achieve analgesia, relief from pain. They are distinct from anesthetics, which temporarily affect, and in some instances eliminate, sensation. Examples of suitable analgesics can include a nonsteroidal anti-inflammatory drug (NS AID), a COX-2 inhibitor, or a mixture thereof. Non-limiting examples of NS AIDs can include ibuprofen, naproxen, diclofenac, mefenamic acid, indomethacin, cannabidiol, an ion pair thereof, a salt thereof, or a mixture thereof. Non-limiting examples of COX-2 inhibitors can include etoricoxib, meloxicam, celecoxib, an ion pair thereof, a salt thereof, or a mixture thereof.

[0026] As understood herein, an anesthetic agent refers to any agent that produces a local or general loss of sensation, including pain. Anesthetics achieve this effect by acting on the brain or peripheral nervous system to suppress responses to sensory stimulation. The unresponsive state thus induced is knownas anesthesia. General anesthesia involves loss of consciousness, usually for the purpose of relieving the pain of surgery. Local anesthesia involves loss of sensation and / or motor function in one area of the body by the blockage of conduction in nerves.

[0027] While the instant disclosure describes using local anesthetics, it is possible to include a general anesthetic. Suitable examples of local anesthetics include an ester-based anesthetic, an amide-based anesthetic, or a mixture thereof. Non-limiting examples of ester-based anesthetics include procaine, amethocaine, benzocaine, tetracaine, or a mixture thereof. Nonlimiting examples of amide-based anesthetic include lidocaine, prilocaine, bupivacaine, levobupivacaine, ropivacaine, mepivacaine, dibucaine, etidocaine, a salt thereof, or a mixture thereof. The amide-based anesthetics can include the freebase form of the amide-based anesthetic, a hydrochlorinated form of the amide-based anesthetic, or additional salt forms or ion pairs of the amide-based anesthetic including lipophilic salts. A lipophilic salt of the amide-based anesthetic involves pairing the protonated amid-based anesthetic with a lipophilic counterion, which can enhance the solubility of the amide-based anesthetic in the lipophilic oil. This can be beneficial in increasing the loading of the anesthetic agent in the pharmaceutical oil-in-water emulsion. For example, a lipophilic salt or ion pair of the amide-based anesthetic can include a docusate counterion. As an example, the lipophilic salt or ion pair of the amide-based anesthetic can be ropivacaine docusate. As further examples the amide-based local anesthetic is an ion pair, or salt, comprising of bupivacaine butyrate, bupivacaine palmitate, bupivacaine laureate, bupivacaine myristate, bupivacaine stearate, bupivacaine hydroxystearate, bupivacaine oleate, bupivacaine ricinolate, bupivacaine docusate.

[0028] While any of the aforementioned amide-based anesthetics are desirable, ropivacaine can be desirable for use because it includes several known clinical advantages such as good patient safety and good analgesic properties such as sensory selectivity. However, ropivacaine typically exhibits poor solubility in lipophilic oils (including but not limited to medium-chain triglycerides). The relatively poor solubility extends to the freebase and hydrochlorinated forms of ropivacaine. However, it has been unexpectedly shown that ropivacaine docusate exhibits suitable solubility in lipophilic oilssuch as medium-chain triglycerides to allow for a sufficient amount of ropivacaine to be dissolved in the lipophilic oil and to be released at an acceptable rate.

[0029] Suitable examples of anti-inflammatory agents can include aspirin, celecoxib, diclofenac, diflunisal, etodolac, ibuprofen, indomethacin, ketoprofen, ketorolac, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin, or a mixture thereof.

[0030] The pharmaceutical oil-in-water emulsion can include an adjuvant. In the context of drug, an adjuvant refers to drugs with a primary indication other than pain that have analgesic properties. Examples of suitable adjuvants include a barbiturate, an opiate, an anti-inflammatory agent, a cannabinoid, a sympatholytic agent or a mixture thereof. Further examples of suitable adjuvants include corticosteroid, dexamethasone, pethidine, tubocurarine chloride, meloxicam, dexmedetomidine or a mixture thereof.

[0031] If the adjuvant includes a cannabinoid, a suitable cannabinoid can be cannabidiol (CBD). However it is possible that other cannabinoids can include cannabigerolic acid (CBGA), cannabigerolic acid monomethylether (CBGAM), cannabigerol (CBG), cannabigerol monomethylether (CBGM), cannabigerovarinic acid (CBGVA), cannabigerovarin (CBGV), cannabichromenic acid (CBCA), cannabichromene (CBC), cannabichromevarinic acid (CBCVA), cannabichromevarin (CBCV), cannabidiolic acid (CBD A), cannabidiol monomethylether (CBDM), cannabidiol-C4 (CBD-C4), cannabidivarinic acid (CBDVA), cannabidivarin (CBDV), cannabidiorcol (CBD-C1), tetrahydrocannabinolic acid A (THCA-A), tetrahydrocannabinolic acid B (THCA-B), tetrahydrocannabinolic acid (THCA), tetrahydrocannabinol (THC), tetrahydrocannabinolic acid C4 (THCA-C4), tetrahydrocannbinol C4 (THC-C4), tetrahydrocannabivarinic acid (THCVA), tetrahydrocannabivarin (THCV), tetrahydrocannabiorcolic acid (THCA-C1), tetrahydrocannabiorcol (THC-C1), A7-cis-iso-tetrahydrocannabivarin, A8- tetrahydrocannabinolic acid (A8-THCA), cannabivarinodiolic (CBNDVA), cannabivarinodiol (CBNDV), A8-tetrahydrocannabinol (A8-THC), A9- tetrahydrocannabinol (A9-THC), cannabicyclolic acid (CBLA), cannabicyclol (CBL), cannabicyclovarin (CBLV), cannabielsoic acid A (CBEA-A), cannabielsoic acid B (CBEA-B), cannabielsoin (CBE), cannabivarinselsoin(CBEV), cannabivarinselsoinic acid (CBEVA), cannabielsoic acid (CBEA), cannabielvarinsoin (CBLV), cannabielvarinsoinic acid (CBLVA), cannabinolic acid (CBNA), cannabinol (CBN), cannabivarinic acid (CBNVA), cannabinol methylether (CBNM), cannabinol-C4 (CBN-C4), cannabivarin (CBV), cannabino-C2 (CBN-C2), cannabiorcol (CBN-C1), cannabinodiol (CBND), cannabinodiolic acid (CBND A), cannabinodivarin (CBDV), cannabitriol (CBT), 10-ethoxy-9-hydroxy-A8a-tetrahydrocannabinol, 8,9-dihydroxy-A6a(10a)- tetrahydrocannabinol (8,9-Di-OH-CBT-C5), cannabitriolvarin (CBTV), ethoxy- cannabitriolvarin (CBTVE), dehydrocannabifuran (DCBF), cannbifuran (CBF), cannabichromanon (CBCN), cannabicitran (CBT), 10-oxo-A6a(10a)- tetrahydrocannabinol (OTHC), A9-cis-tetrahydrocannabinol (cis-THC), cannabiripsol (CBR), 3,4,5,6-tetrahydro-7-hydroxy-alpha-alpha-2-trimethyl-9-n- propyl-2,6-methano-2H-l-benzoxocin-5-methanol (OH-iso-HHCV), trihydroxy - delta-9-tetrahydrocannabinol (triOH-THC), yangonin, epigallocatechin gallate, dodeca-2E,4E,8Z,10Z-tetraenoic acid isobutylamide, and dodeca-2E,4E-dienoic acid isobutyl ami de, a mixture thereof, or a mixture of any of the foregoing with cannabidiol.

[0032] Including the adjuvant can provide a synergistic effect in that the amount of the drug that needs to be added to be considered a therapeutically effective amount can be decreased, relative to a comparative pharmaceutical oil- in-water emulsion differing only by being free of the adjuvant.

[0033] When present, the therapeutic agent solubility and release modifying agent can include butyric acid, capric acid, caprylic acid, arachidic acid, behenic acid, palmitic acid, lauric acid, myristic acid, stearic acid, linoleic acid, arachidonic acid, hydroxystearic acid, oleic acid, ricinoleic acid, docusate, an anion thereof, or a mixture thereof. The therapeutic agent solubility and release modifying agent may be present in a range of from about 0.2 % (w / v) to about 15 % (w / v) of the pharmaceutical oil-in-water emulsion, about 0.5 % (w / v) to about 10 % (w / v), less than, equal to, or greater than about 0.2 % (w / v), 0.5, 1,1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12,12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, or about 25 % (w / v).

[0034] The surfactant can include a lecithin, egg yolk lecithin, soy bean lecithin, phospholipid, PEGylated hydrogenated castor oil, poloxamer, sodiumlauryl sulfate (SLS), sodium laureth sulfate (SLES), cocamidopropyl betaine, sorbitan oleate, polysorbate 20, polysorbate 60, polysorbate 80, sodium dodecylbenzenesulfonate, alkyl polyglucosides (APGs), sodium lauryl ether sulfate (SLES), cetyl alcohol, lauryl glucoside, ammonium lauryl sulfate (ALS), dioctyl sodium sulfosuccinate (DOSS), alkyl carboxylate, sorbitan fatty acid esters, sodium coco-sulfate, sodium stearoyl lactylate, glyceryl stearate, and caprylyl / capryl glucoside, or a mixture thereof. The surfactant can be present in a concentration in a range of from about 0.25 % (w / v) to about 25 % (w / v) of the pharmaceutical oil-in-water emulsion, about 1% (w / v) to about 5% (w / v), less than, equal to, or greater than about 0.25 %, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or about 25% (w / v).

[0035] An average particle size of the pharmaceutical oil-in-water emulsion ranges from about 100 nm to about 10 pm, about 200 nm to about 1000 nm, less than equal to or greater than about 100 nm, 200 nm, 10 pm, 100 pm, 200 pm, 300 pm, 400 pm, 500 pm, 600 pm, 700 pm, 800 pm, 900 pm, or about 1000 pm.

[0036] Pharmaceutical oil-in-water emulsions contain an effective amount of a compound as described herein and optionally one or more other therapeutic agents included in a pharmaceutically acceptable carrier. The term “pharmaceutically acceptable carrier” means one or more compatible solid or liquid fillers, diluents or encapsulating substances which are suitable for administration to a human or other vertebrate animal. The term “carrier” denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application. The components of the pharmaceutical oil-in-water emulsions also can be commingled with the compounds, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficiency.

[0037] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ or portion of the body to another organ or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the composition, not injurious to the patient, and substantiallynon-pyrogenic. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, castor oil, medium chain triglyceride oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer’s solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical oil-in-water emulsions. Pharmaceutical oil-in-water emulsions of the present disclosure are non-pyrogenic, i.e., do not induce significant temperature elevations when administered to a patient.

[0038] The pharmaceutical oil-in-water emulsion can be packaged in any suitable manner. For example, the pharmaceutical oil-in-water emulsion can be packaged in ajar, vessel, or the like such that the pharmaceutical oil-in-water emulsion can be accessed and manually applied at a desired location.Alternatively, the pharmaceutical oil-in-water emulsion can be disposed within a dispensing chamber of a syringe. The syringe can have a needle having a size in a range of from about 14 to about 31 gauge, about 21 to about 25 gauge, less than, equal to, or greater than about 14 gauge, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 31 gauge. Alternatively, the pharmaceutical oil-in- water emulsion can be disposed from the syringe without a needle (e.g., through a cone applicator).

[0039] The pharmaceutical oil-in-water emulsion can be manufactured by pre-homogenizing a mixture comprising the lipophilic oil, surfactant, therapeutic agent, and optional therapeutic agent solubility and release modifying agent. Pre-homogenization is accomplished through high-speed homogenization or sonification. The method further includes homogenizing the pre-homogenized mixture to form the pharmaceutical oil-in-water emulsion. Homogenization can be accomplished with a high-pressure homogenizer. If needed the method can further include adjusting at least one of a pH, tonicity,and salinity of the pre-homogenized mixture, homogenized mixture, or both. The tonicity can be adjusted with sodium chloride, glycerol, sorbitol, xylitol, mannitol, glucose, trehalose, maltose, sucrose, raffinose, lactose, dextran, polyethylene glycol, or propylene glycol. The sodium chloride can be added in a range of from about 0.5 wt% to about 6 wt% of the pharmaceutical oil-in-water emulsion, about 1 wt% to about 2 wt%, less than, equal to, or greater than about 0.5 wt%, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, or about 6 wt% of the pharmaceutical oil-in-water emulsion. Glycerol can be added in a range of from about 0.5 wt% to about 3.5 wt% of the pharmaceutical oil-in-water emulsion, about 1 wt% to about 2.25 wt%, less than, equal to, or greater than about 0.5 wt%, 1, 1.5, 2, 2.5, 3, or about 3.5 wt%. The pH can be adjusted using sodium hydroxide.

[0040] The final step in manufacturing the emulsion includes sterilizing the pharmaceutical oil-in-water emulsion. Sterilization includes use of an autoclave, a filter, gamma irradiation, x-ray irradiation, e-beam irradiation, or a combination thereof.

[0041] In operation, the pharmaceutical oil-in-water emulsion can be administered to a subject. The pharmaceutical oil-in-water emulsion can be administered at or proximate to an injury or wound or treatment site. An example of an injury or wound can include a surgical site. The pharmaceutical oil-in-water emulsion can be administered proximal to an injury or wound. For example, the pharmaceutical oil-in-water emulsion can be administered to a particular location to block a nerve(s) and therefore block pain from the distal injury or wound. In the context of a surgery, the pharmaceutical oil-in-water emulsion can be applied before a surgery, during the course of surgery (e.g., any time before the incision is closed) or after surgery (e.g., after the incision is closed).

[0042] If the emulsion is used for local treatment it can be locally infiltrated or locally instilled into the subject’s tissue to generate a local, field, or regional block, or the pharmaceutical oil-in-water emulsion can be a nerve block composition or a fascial plane block composition. The nerve block composition or fascial plane block composition comprises an axillary block, supraclavicular block, infraclavicular block, interscalene block, radial nerve block, median nerve block, ulnar nerve block, femoral nerve block, sciatic nerve block, poplitealblock, ankle block, saphenous nerve block, obturator nerve block, intercostal nerve block, ilioinguinal / iliohypogastric nerve block, genitofemoral nerve block, occipital nerve block, supraorbital nerve block, infraorbital nerve block, transversus abdominis plane (tap) block, quadratus lumborum (ql) block, erector spinae plane (esp) block, pectoral nerves (pecs) block, serratus anterior plane block, fascia iliaca block, rectus sheath block, upper extremity, suprascapular nerve block, axillary nerve block, musculocutaneous nerve block, lower extremity, lateral femoral cutaneous nerve block, tibial nerve block, deep peroneal nerve block, sural nerve block, trunk paravertebral block, pudendal nerve block, GON block (greater occipital nerve), LON block (lesser occipital nerve), or a combination thereof.

[0043] As used herein, the term “kit” refers to a product (e.g. medicament, kit-of-parts) comprising one package or one or more separate packages of:(i). A pharmaceutical oil-in-water emulsion containing an active pharmaceutical ingredient and at least one further active pharmaceutical ingredient and optionally a medical device. The at least one further active pharmaceutical ingredient may be present in said pharmaceutical oil-in- water emulsion, i.e. the kit may comprise one or more packages, wherein each package comprises one pharmaceutical oil-in-water emulsion which comprises two or more active pharmaceutical ingredients. The further active pharmaceutical ingredient may also be present in a further pharmaceutical oil-in-water emulsion, i.e. the kit may comprise separate packages of two or more pharmaceutical oil-in-water emulsions, wherein each pharmaceutical oil-in-water emulsion contains one active pharmaceutical ingredient.Or(ii). A pharmaceutical oil-in-water emulsion containing an active pharmaceutical ingredient and medical device.

[0044] A kit may comprise one package only or may comprise one or more separate packages. For example, the kit may be a product (e.g. medicament) containing two or more vials each containing a defined pharmaceutical oil-in-water emulsion, wherein each pharmaceutical oil-in-water emulsion contains at least one active pharmaceutical ingredient. For example,the kit may comprise (i.) a vial containing a defined pharmaceutical oil-in-water emulsion and (ii). further a tablet, capsule, powder or any other oral dosage form which contains at least one further active pharmaceutical ingredient. The kit may further comprise a package leaflet with instructions for how to administer the pharmaceutical oil-in-water emulsion and the at least one further active pharmaceutical ingredient.

[0045] As used herein, the term “medical device” means any instrument, apparatus, implant, in vitro reagent or similar or related article that is used to diagnose, prevent, or treat a disease of other condition, and does not achieve its purpose through pharmacological action within or on the body.

[0046] As used herein, a medical device may be a syringe, an injection system, an infusion system, or a pump. As used herein, a medical device may be mechanically or electromechanically driven.

[0047] The ingredients in the pharmaceutical oil-in-water emulsion can be defined as being Generally Recognized as Safe (“GRAS”). A full list of GRAS ingredients can be found in the GRAS Substances (SCOGS) Database maintained by the United States Food and Drug Administration. About 50% to about 100% of the ingredients in the pharmaceutical oil-in-water emulsion can be classified as being GRAS ingredients, about 75% to about 100%, about 90% to about 100%, less than, equal to, or greater than about 50%, 55, 60, 65, 70, 75, 80, 85, 90, 95, or about 100% of the ingredients in the pharmaceutical oil-in- water emulsion can be classified as being GRAS ingredients.Examples

[0048] Various aspects of the present disclosure can be better understood by reference to the following Examples which are offered by way of illustration. The present disclosure is not limited to the Examples given herein.Example 1 : Emulsion Manufacturing

[0049] Bupivacaine, castor oil, MCT oil, oleic acid (if used), and PEG- 35 castor oil were added to a beaker and heated under stirring to dissolve all bupivacaine. Once all the Active pharmaceutical ingredient (API), bupivacaine in this example, had dissolved, the beaker was moved to a 40C water bath. Water was measured in a separate vessel and heated to 40C. A coarse emulsion was created by slowly adding the oil / drug mixture to water under high shearing(20,000 rpm) for 30 seconds. The resulting emulsion was then processed through a high-pressure homogenizer at 25 kPSI, three times.

[0050] After fabrication the emulsion solutions pH was adjusted to approximately 8 and formulations were sealed in glass vials and then autoclaved.Example 2: In Vitro Release

[0051] 0.5 mL of emulsion of Example 1 is added to a SnakeSkin dialysis bag (lOkDa MWCO) along with 4 mL of IX phosphate-buffered saline (PBS, pH 6.5). The ends of the dialysis bag are secured with string and then placed in a metal sinker cage. Dissolution was conducted in a USP apparatus (type 2) with a 500 mL sink of PBS (pH 6.5) maintained at 37C and 50 rpm paddle speed. At predetermined time points, 1 mL of PBS was collected from the sink and was not replaced. Samples were analyzed via HPLC.

[0052] FIG. l is a graph showing the cumulative percent bupivacaine release over time based on theoretical drug loading. Emulsions formulations are RBL002 (10% oleic) and RBL004 (no oleic). Each data point has n=2. Error bars denote standard error mean.Example 3: Solubility Testing

[0053] Approximately 10 mL of oil was added to a 15 mL conical tube with an excess of Bupivacaine freebase or Ropivacaine freebase. Tubes were vortexed to mix, and then placed on a nutating shaker at room temperature. Each day the tubes were assessed. If all the API had been dissolved, more was added.

[0054] After 3 days of mixing, samples were vortexed to separate undissolved API. Then dissolved API was extracted from the supernatant using Hexane and analyzed via HPLC.

[0055] FIG. 2 shows the maximum solubility of bupivacaine freebase or ropivacaine freebase in castor oil or MCT oil spiked with different levels of ricinoleic acid. Each data point has n=2. Error bars denote standard error mean.

[0056] FIG. 3 shows the maximum solubility of bupivacaine freebase in a castor oil:MCT oil (65:35 weight ratio) spiked with different levels of oleic or ricinoleic acid. Error bars denote standard error mean between triplicate HPLC injections (same sample prep).Example 4: In Vivo Rat Study

[0057] Rats received treatment as a single perineural injection at the sciatic nerve under mild anesthesia. At predetermined time points, blood was collected via retro-orbital plexus under mild anesthesia. Blood samples were analyzed via HPLC.

[0058] FIG. 4 shows blood plasma concentration over time following a 7.5 mg / kg (0.56 mL / kg) dose of RBL002 (10% oleic) or RBL004 (no oleic). Each data point has n=3. Error bars denote standard error mean.Rat Study Formulations (w / v of final solution)PEG-35,, ■ • „ . Castor MCT Oleic _Formulation Bupivacaine , Castor Glycerol WaterHOil Oil AcidJOilRBL001 1.33% 15.11% 8.14% 1.75% 1.50% 2.25% 69.52%RBL0021.33% 9.75% 5.25% 10.00% 1.50% 2.25% 69.52%(High Oleic)RBL0041.33% 16.25% 8.75% 0.00% 1.50% 2.25% 69.52%(No Oleic)

[0059] The Examples established that a ratio of CastorMCT 65:35 was favorable for stable emulsion production with the highest drug loading and release duration. Additionally, oleic acid or ricinoleic acid were needed to increase drug loading and release further. We found that adding the fatty acid at molar ratios greater than 1 :2 bupivacaine: fatty acid were ideal. The solubility and release increases with further addition of fatty acid, so the system is tunable.

[0060] The Examples show that favorable formulations may have a total lipid content (castor, MCT, fatty acid, and surfactant) of 10-30% and 0.5-3% bupivacaine, depending on the final. Further formulations may include 15%- 25% total lipid content and 1-2% bupivacaine.

[0061] The terms and expressions that have been employed are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shownand described or portions thereof, but it is recognized that various modifications are possible within the scope of the aspects of the present disclosure. Thus, it should be understood that although the present disclosure has been specifically disclosed by specific aspects and optional features, modification and variation of the concepts herein disclosed may be resorted to by those of ordinary skill in the art, and that such modifications and variations are considered to be within the scope of aspects of the present disclosure.Exemplary Aspects.

[0062] The following exemplary aspects are provided, the numbering of which is not to be construed as designating levels of importance:

[0063] Aspect 1 provides a pharmaceutical oil-in-water emulsion, comprising: a lipophilic oil; a therapeutic agent, salt, or prodrug thereof dispersed in the lipophilic oil; an optional therapeutic agent solubility and release modifying agent; and a surfactant.

[0064] Aspect 2 provides the pharmaceutical oil-in-water emulsion of Aspect 1, wherein the lipophilic oil is in a range of from about 2% (w / v) to about 40 % (w / v) of the pharmaceutical oil-in-water emulsion.

[0065] Aspect 3 provides the pharmaceutical oil-in-water emulsion of Aspect 1, wherein the lipophilic oil is in a range of from about 10% (w / v) to about 25% (w / v) of the pharmaceutical oil-in-water emulsion.

[0066] Aspect 4 provides the pharmaceutical oil-in-water emulsion of Aspect 1, wherein the lipophilic oil is in a range of from about 15% (w / v) to about 20 % (w / v) of the pharmaceutical oil-in-water emulsion.

[0067] Aspect 5 provides the pharmaceutical oil-in-water emulsion of Aspect 1, wherei n therapeutic agent solubility and release modifying agent is present.

[0068] Aspect 6 provides the pharmaceutical oil-in-water emulsion of Aspect 3, wherein the lipophilic oil comprises a monoglyceride, diglyceride, triglyceride, medium-chain triglyceride oil, sesame oil, soybean oil, castor oil, vegetable oil, tributyrin oil, or a mixture thereof

[0069] Aspect 7 provides the pharmaceutical oil-in-water emulsion of Aspect 6, wherein the lipophilic oil comprises a mixture of castor oil and medium-chain triglyceride

[0070] Aspect 8 provides the pharmaceutical oil-in-water emulsion of Aspect 7, wherein the castor oil and medium-chain triglyceride oils are present at a wt:wt ratio ranging from about 25:75 to about 75:25 with respect to each other.

[0071] Aspect 9 provides the pharmaceutical oil-in-water emulsion of Aspect 8, wherein the castor oil and medium-chain triglyceride oils are present at a wt:wt ratio of about 50:50 with respect to each other.

[0072] Aspect 10 provides the pharmaceutical oil-in-water emulsion of Aspect 6, wherein the triglyceride is a saturated triglyceride, a monounsaturated triglyceride, or a polyunsaturated triglyceride.

[0073] Aspect 11 provides the pharmaceutical oil-in-water emulsion of Aspect 6, wherein the triglyceride comprises a medium-chain triglyceride, a short-chain triglyceride, long-chain triglyceride, or a mixture thereof.

[0074] Aspect 12 provides the pharmaceutical oil-in-water emulsion of Aspect 6, wherein the triglyceride comprises the medium-chain triglyceride.

[0075] Aspect 13 provides the pharmaceutical oil-in-water emulsion of Aspect 12, wherein the medium-chain triglyceride comprises a glyceride of a C6-C12 carboxylic acid, or a mixture thereof.

[0076] Aspect 14 provides the pharmaceutical oil-in-water emulsion of any of Aspects 1-13, wherein the therapeutic agent solubility and release modifying agent comprises butyric acid, capric acid, caprylic acid, arachidic acid, behenic acid, palmitic acid, lauric acid, myristic acid, stearic acid, linoleic acid, arachidonic acid, hydroxystearic acid, oleic acid, ricinoleic acid, docusate, an anion thereof, or a mixture thereof.

[0077] Aspect 15 provides the pharmaceutical oil-in-water emulsion of any of Aspects 1-14, wherein the therapeutic agent solubility and release modifying agent, comprises oleic acid, ricinoleic acid, an anion thereof, or a mixture thereof.

[0078] Aspect 16 provides the pharmaceutical oil-in-water emulsion of Aspect 14, wherein the therapeutic agent solubility and release modifying agentis in a range of from about 0.2 % (w / v) to about 15 % (w / v) of the pharmaceutical oil-in-water emulsion.

[0079] Aspect 17 provides the pharmaceutical oil-in-water emulsion of Aspect 14, wherein the therapeutic agent solubility and release modifying agent is in a range of from about 0.5 % (w / v) to about 10 % (w / v) of the pharmaceutical oil-in-water emulsion.

[0080] Aspect 18 provides the pharmaceutical oil-in-water emulsion of Aspect 1, wherein the surfactant comprises a lecithin, egg yolk lecithin, soy bean lecithin, phospholipid, PEGylated hydrogenated castor oil, poloxamer, sodium lauryl sulfate (SLS), sodium laureth sulfate (SLES), cocamidopropyl betaine, sorbitan oleate, polysorbate 20, polysorbate 60, polysorbate 80, sodium dodecylbenzenesulfonate, alkyl polyglucosides (APGs), sodium lauryl ether sulfate (SLES), cetyl alcohol, lauryl glucoside, ammonium lauryl sulfate (ALS), dioctyl sodium sulfosuccinate (DOSS), alkyl carboxylate, sorbitan fatty acid esters, sodium coco-sulfate, sodium stearoyl lactylate, glyceryl stearate, and caprylyl / capryl glucoside, or a mixture thereof.

[0081] Aspect 19 provides the pharmaceutical oil-in-water emulsion of Aspect 1, wherein the surfactant comprises egg yolk lecithin.

[0082] Aspect 20 provides the pharmaceutical oil-in-water emulsion of Aspect 1, wherein the surfactant is present in a concentration in a range of from about 0.25 % (w / v) to about 25 % (w / v) of the pharmaceutical oil-in-water emulsion.

[0083] Aspect 21 provides the pharmaceutical oil-in-water emulsion of Aspect 20, wherein the surfactant is present in a concentration in a range of from about 1% (w / v) to about 5% (w / v) of the pharmaceutical oil-in-water emulsion.

[0084] Aspect 22 provides the pharmaceutical oil-in-water emulsion of Aspect 1, wherein the therapeutic agent comprises an analgesic agent, anesthetic agent, anti-inflammatory agent, a sympatholytic agent, an anxiolytic agent, a cannabinoid, or a mixture thereof dispersed in the lipophilic oil.

[0085] Aspect 23 provides the pharmaceutical oil-in-water emulsion of Aspect 22, wherein the analgesic agent, anesthetic agent, or both present in amount sufficient to reduce pain in a subject.

[0086] Aspect 24 provides the pharmaceutical oil-in-water emulsion of Aspect 23, wherein the pharmaceutical oil-in-water emulsion comprises the analgesic agent.

[0087] Aspect 25 provides the pharmaceutical oil-in-water emulsion of Aspect 24, wherein the analgesic agent comprises a nonsteroidal antiinflammatory drug, a COX-2 inhibitor, or a mixture thereof.

[0088] Aspect 26 provides the pharmaceutical oil-in-water emulsion of Aspect 25, wherein the nonsteroidal anti-inflammatory drug comprises ibuprofen, naproxen, diclofenac, mefenamic acid, indomethacin, cannabidiol, an ion pair thereof, a salt thereof, or a mixture thereof.

[0089] Aspect 27 provides the pharmaceutical oil-in-water emulsion of Aspect 25, wherein the COX-2 inhibitor comprises etoricoxib, meloxicam, celecoxib, an ion pair thereof, a salt thereof, or a mixture thereof.

[0090] Aspect 28 provides the pharmaceutical oil-in-water emulsion of Aspect 1, wherein the pharmaceutical oil-in-water emulsion comprises an anesthetic agent and the anesthetic agent is a local anesthetic.

[0091] Aspect 29 provides the pharmaceutical oil-in-water emulsion of Aspect 28, wherein the anesthetic agent comprises an ester-based local anesthetic, an amide-based local anesthetic, or a prodrug, or ion pair thereof, or salt thereof, or a mixture thereof.

[0092] Aspect 30 provides the pharmaceutical oil-in-water emulsion of Aspect 29, wherein the ester-based local anesthetic comprises procaine, amethocaine, benzocaine, tetracaine, or a prodrug, or ion pair thereof, or salt thereof, or a mixture thereof.

[0093] Aspect 31 provides the pharmaceutical oil-in-water emulsion of Aspect 30, wherein the local amide-based anesthetic comprises lidocaine, prilocaine, bupivacaine, levobupivacaine, ropivacaine, mepivacaine, dibucaine, etidocaine, articaine, a prodrug, or ion pair thereof, or salt thereof, or a mixture thereof.

[0094] Aspect 32 provides the pharmaceutical oil-in-water emulsion of Aspect 31, wherein the amide-based anesthetic comprises bupivacaine, ropivacaine, a salt thereof, ion pair thereof, or a mixture thereof.

[0095] Aspect 33 provides the pharmaceutical oil-in-water emulsion of Aspect 32, wherein the amide-based local anesthetic is an ion pair, or salt,comprising of bupivacaine butyrate, bupivacaine palmitate, bupivacaine laureate, bupivacaine myristate, bupivacaine stearate, bupivacaine hydroxystearate, bupivacaine oleate, bupivacaine ricinolate, bupivacaine docusate.

[0096] Aspect 34 provides the pharmaceutical oil-in-water emulsion of Aspect 22, wherein the pharmaceutical oil-in-water emulsion comprises a mixture of the analgesic agent, the anesthetic agent, and the anti-inflammatory agent.

[0097] Aspect 35 provides the pharmaceutical oil-in-water emulsion of Aspect 22, wherein the pharmaceutical oil-in-water emulsion comprises a mixture of the analgesic agent and the anesthetic agent.

[0098] Aspect 36 provides the pharmaceutical oil-in-water emulsion of Aspect 22, wherein the analgesic agent, anesthetic agent, or both are present in a concentration in a range of from about 0.1 % (w / v) to about 30% (w / v) based on a volume of the lipophilic oil.

[0099] Aspect 37 provides the pharmaceutical oil-in-water emulsion of Aspect 22, wherein the analgesic agent, anesthetic agent, or both are present in a concentration in a range of from about 5 % (w / v) to about 15% (w / v) based on a volume of the lipophilic oil.

[0100] Aspect 38 provides the pharmaceutical oil-in-water emulsion of Aspect 35, wherein the analgesic agent, anesthetic agent, or both present in a concentration in a range of from about 0.5 % (w / v) to about 6 % (w / v) of the pharmaceutical oil-in-water emulsion.

[0101] Aspect 39 provides the pharmaceutical oil-in-water emulsion of Aspect 35, wherein the analgesic agent, anesthetic agent, or both present in a concentration in a range of from about 0.7 % (w / v) to about 2.5 % (w / v) of the pharmaceutical oil-in-water emulsion.

[0102] Aspect 40 provides the pharmaceutical oil-in-water emulsion of Aspect 22, wherein the anti-inflammatory agent comprises aspirin, celecoxib, diclofenac, diflunisal, etodolac, ibuprofen, indomethacin, ketoprofen, ketorolac, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin, cannabidiol, a salt thereof, an ion pair thereof, or a mixture thereof.

[0103] Aspect 41 provides the pharmaceutical oil-in-water emulsion of Aspect 22, further comprising an adjuvant.

[0104] Aspect 42 provides the pharmaceutical oil-in-water emulsion of Aspect 41, wherein the adjuvant comprises a nonsteroidal anti-inflammatory drug, corticosteroid, alpha-2-agonist, pethidine, barbiturate, opiate, tubocurarine chloride, a cannabinoid, meloxicam a salt thereof, or ion pair thereof, or a mixture thereof.

[0105] Aspect 43 provides the pharmaceutical oil-in-water emulsion of Aspect 42, wherein the cannabinoid is cannabidiol (CBD).

[0106] Aspect 44 provides the pharmaceutical oil-in-water emulsion of Aspect 43, wherein the pharmaceutical oil-in-water emulsion is effective at relieving pain in a subject using a smaller concentration of the analgesic agent, anesthetic agent, an anti-inflammatory agent, or mixture thereof and / or has a longer pain relieving effect, compared to a corresponding pharmaceutical oil-in- water emulsion that is free of the adjuvant.

[0107] Aspect 45 provides the pharmaceutical oil-in-water emulsion of Aspect 1, wherein the pharmaceutical oil-in-water emulsion is effective to reduce pain in a subject for a time in a range of from about 12 hours to about 14 days.

[0108] Aspect 46 provides the pharmaceutical oil-in-water emulsion of Aspect 1, wherein the pharmaceutical oil-in-water emulsion is effective to reduce pain in a subject for a time in a range of from about 24 hours to about 96 hours.

[0109] Aspect 47 provides the pharmaceutical oil-in-water emulsion of Aspect 1, wherein the pharmaceutical oil-in-water emulsion is effective to reduce pain in a subject for a time in a range of from about 96 hours to about 168 hours.

[0110] Aspect 48 provides the pharmaceutical oil-in-water emulsion of Aspect 1, wherein the pharmaceutical oil-in-water emulsion is effective to reduce pain in a subject for a time in a range of from about 168 hours to about 336 hours.

[0111] Aspect 49 provides the pharmaceutical oil-in-water emulsion of Aspect 1, wherein an average particle size of the pharmaceutical oil-in-water emulsion ranges from about 100 nm to about 10 pm.

[0112] Aspect 50 provides the pharmaceutical oil-in-water emulsion of Aspect 1, wherein an average particle size of the pharmaceutical oil-in-water emulsion ranges from about 200 nm to about 1000 pm.

[0113] Aspect 51 provides a method of manufacturing the pharmaceutical oil-in-water emulsion of Aspect 1, the method comprising: pre-homogenizing a mixture comprising the lipophilic oil, surfactant, and therapeutic agent, homogenizing the pre-homogenized mixture to form the pharmaceutical oil-in-water emulsion.

[0114] Aspect 52 provides the method of Aspect 51, wherei n prehomogenization is accomplished through high-speed homogenization or sonification.

[0115] Aspect 53 provides the method of Aspect 51, wherei n the prehomogenized mixture is homogenized with a high-pressure homogenizer.

[0116] Aspect 54 provides the method of Aspect 51, further comprising adjusting at least one of a pH, tonicity, and salinity of the pre-homogenized mixture, homogenized mixture, or both.

[0117] Aspect 55 provides the method of Aspect 54 wherein the tonicity is adjusted with sodium chloride, glycerol, sorbitol, xylitol, mannitol, glucose, trehalose, maltose, sucrose, raffinose, lactose, dextran, polyethylene glycol, or propylene glycol.

[0118] Aspect 56 provides the method of Aspect 55, wherein the sodium chloride is added in a range of from about 0.5 wt% to about 2 wt% of the pharmaceutical oil-in-water emulsion.

[0119] Aspect 57 provides the method of Aspect 56 wherein the sodium chloride is added in a range of from about 1 wt% to about 6 wt% of the pharmaceutical oil-in-water emulsion.

[0120] Aspect 58 provides the method of Aspect 55 wherein the glycerol is added in a range of from about 0.5 wt% to about 3.5 wt% of the pharmaceutical oil-in-water emulsion.

[0121] Aspect 59 provides the method of Aspect 58 wherein the glycerol is added in a range of from about 1 wt% to about 2.25 wt% of the pharmaceutical oil-in-water emulsion.

[0122] Aspect 60 provides the method of Aspect 54, wherein the pH is adjusted using sodium hydroxide.

[0123] Aspect 61 provides the method of Aspect 51 further comprising sterilizing the pharmaceutical oil-in-water emulsion.

[0124] Aspect 62 provides the method of Aspect 61, wherein sterilizing the pharmaceutical oil-in-water emulsion comprises the use of an autoclave, a filter, gamma irradiation, x-ray irradiation, e-beam irradiation, or a combination thereof.

[0125] Aspect 63 provides a method of treating pain in a subject comprising in need thereof, with the pharmaceutical oil-in-water emulsion of Aspect 1, comprising administering the pharmaceutical oil-in-water emulsion to the subject via injecting the pharmaceutical oil-in-water emulsion through a syringe, through a needle having a size of about 14-31 gauge.

[0126] Aspect 64 provides the method of Aspect 63, wheri n the pharmaceutical oil-in-water emulsion is locally infiltrated or locally instilled into the subject’s tissue to generate a local, field, or regional block, or the pharmaceutical oil-in-water emulsion is a nerve block composition or a fascial plane block composition

[0127] Aspect 65 provides the method of Aspect 64, wherei n the nerve block composition or fascial plane block composition comprises an axillary block, supraclavicular block, infraclavicular block, interscalene block, radial nerve block, median nerve block, ulnar nerve block, femoral nerve block, sciatic nerve block, popliteal block, ankle block, saphenous nerve block, obturator nerve block, intercostal nerve block, ilioinguinal / iliohypogastric nerve block, genitofemoral nerve block, occipital nerve block, supraorbital nerve block, infraorbital nerve block, transversus abdominis plane (tap) block, quadratus lumborum (ql) block, erector spinae plane (esp) block, pectoral nerves (pecs) block, serratus anterior plane block, fascia iliaca block, rectus sheath block, upper extremity, suprascapular nerve block, axillary nerve block, musculocutaneous nerve block, lower extremity, lateral femoral cutaneous nerve block, tibial nerve block, deep peroneal nerve block, sural nerve block, trunk paravertebral block, pudendal nerve block, GON block (greater occipital nerve), LON block (lesser occipital nerve), or a combination thereof.

[0128] Throughout this document, values expressed in a range format should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, a range of “about 0.1% to about 5%” or “about 0.1% to 5%” should be interpreted to include not just about 0.1% to about 5%, but also the individual values (e.g., 1%, 2%, 3%, and 4%) and the sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range. The statement “about X to Y” has the same meaning as “about X to about Y,” unless indicated otherwise. Likewise, the statement “about X, Y, or about Z” has the same meaning as “about X, about Y, or about Z,” unless indicated otherwise.

[0129] In this document, the terms “a,” “an,” or “the” are used to include one or more than one unless the context clearly dictates otherwise. The term “or” is used to refer to a nonexclusive “or” unless otherwise indicated. The statement “at least one of A and B” or “at least one of A or B” has the same meaning as “A, B, or A and B.” In addition, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. Any use of section headings is intended to aid reading of the document and is not to be interpreted as limiting; information that is relevant to a section heading may occur within or outside of that particular section.

[0130] In the methods described herein, the acts can be carried out in any order without departing from the principles of the disclosure, except when a temporal or operational sequence is explicitly recited. Furthermore, specified acts can be carried out concurrently unless explicit claim language recites that they be carried out separately. For example, a claimed act of doing X and a claimed act of doing Y can be conducted simultaneously within a single operation, and the resulting process will fall within the literal scope of the claimed process.

[0131] The term “about” as used herein can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range, and includes the exact stated value or range. The term “substantially” as used herein refers to a majority of, ormostly, as in at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%. The term “substantially free of’ as used herein can mean having none or having a trivial amount of, such that the amount of material present does not affect the material properties of the composition including the material, such that about 0 wt% to about 5 wt% of the composition is the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than or equal to about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less, or about 0 wt%.

Claims

CLAIMSWhat is claimed is:

1. A pharmaceutical oil-in-water emulsion, comprising: a lipophilic oil; a therapeutic agent, salt, or prodrug thereof dispersed in the lipophilic oil; an optional therapeutic agent solubility and release modifying agent; and a surfactant.

2. The pharmaceutical oil-in-water emulsion of claim 1, wherein the lipophilic oil is in a range of from about 2% (w / v) to about 40 % (w / v) of the pharmaceutical oil-in-water emulsion.

3. The pharmaceutical oil-in-water emulsion of claim 1, wherein the lipophilic oil is in a range of from about 10% (w / v) to about 25% (w / v) of the pharmaceutical oil-in-water emulsion.

4. The pharmaceutical oil-in-water emulsion of claim 1, wherein the lipophilic oil is in a range of from about 15% (w / v) to about 25 % (w / v) of the pharmaceutical oil-in-water emulsion.

5. The pharmaceutical oil-in-water emulsion of claim 1, wherein therapeutic agent solubility and release modifying agent is present.

6. The pharmaceutical oil-in-water emulsion of claim 3, wherein the lipophilic oil comprises a monoglyceride, diglyceride, triglyceride, medium-chain triglyceride oil, sesame oil, soybean oil, castor oil, vegetable oil, tributyrin oil, or a mixture thereof.

7. The pharmaceutical oil-in-water emulsion of claim 6, wherein the lipophilic oil comprises a mixture of castor oil and medium-chain triglyceride8. The pharmaceutical oil-in-water emulsion of claim 7, wherein the castor oil and medium-chain triglyceride oils are present at a wt:wt ratio ranging from about 25:75 to about 75:25 with respect to each other.

9. The pharmaceutical oil-in-water emulsion of claim 8, wherein the castor oil and medium-chain triglyceride oils are present at a wt:wt ratio of about 50:50 with respect to each other.

10. The pharmaceutical oil-in-water emulsion of claim 6, wherein the triglyceride is a saturated triglyceride, a monounsaturated triglyceride, or a polyunsaturated triglyceride.

11. The pharmaceutical oil-in-water emulsion of claim 6, wherein the triglyceride comprises a medium-chain triglyceride, a short-chain triglyceride, long-chain triglyceride, or a mixture thereof.

12. The pharmaceutical oil-in-water emulsion of claim 6, wherein the triglyceride comprises the medium-chain triglyceride.

13. The pharmaceutical oil-in-water emulsion of claim 12, wherein the medium-chain triglyceride comprises a glyceride of a C6-C12 carboxylic acid, or a mixture thereof.

14. The pharmaceutical oil-in-water emulsion of any of claims 1-13, wherein the therapeutic agent solubility and release modifying agent comprises butyric acid, capric acid, caprylic acid, arachidic acid, behenic acid, palmitic acid, lauric acid, myristic acid, stearic acid, linoleic acid, arachidonic acid, hydroxystearic acid, oleic acid, ricinoleic acid, docusate, an anion thereof, or a mixture thereof.

15. The pharmaceutical oil-in-water emulsion of any of claims 1-14, wherein the therapeutic agent solubility and release modifying agent, comprises oleic acid, ricinoleic acid, an anion thereof, or a mixture thereof.

16. The pharmaceutical oil-in-water emulsion of claim 14, wherein the therapeutic agent solubility and release modifying agent is in a range of from about 0.2 % (w / v) to about 25 % (w / v) of the pharmaceutical oil-in-water emulsion.

17. The pharmaceutical oil-in-water emulsion of claim 14, wherein the therapeutic agent solubility and release modifying agent is in a range of from about 0.5 % (w / v) to about 15 % (w / v) of the pharmaceutical oil-in-water emulsion.

18. The pharmaceutical oil-in-water emulsion of claim 1, wherein the surfactant comprises a lecithin, egg yolk lecithin, soy bean lecithin, phospholipid, PEGylated hydrogenated castor oil, poloxamer, sodium lauryl sulfate (SLS), sodium laureth sulfate (SLES), cocamidopropyl betaine, sorbitan oleate, polysorbate 20, polysorbate 60, polysorbate 80, sodium dodecylbenzenesulfonate, alkyl polyglucosides (APGs), sodium lauryl ether sulfate (SLES), cetyl alcohol, lauryl glucoside, ammonium lauryl sulfate (ALS), dioctyl sodium sulfosuccinate (DOSS), alkyl carboxylate, sorbitan fatty acid esters, sodium coco-sulfate, sodium stearoyl lactylate, glyceryl stearate, and caprylyl / capryl glucoside, or a mixture thereof.

19. The pharmaceutical oil-in-water emulsion of claim 1, wherein the surfactant comprises egg yolk lecithin, PEGylated hydrogenated castor oil, or a mixture thereof.

20. The pharmaceutical oil-in-water emulsion of claim 1, wherein the surfactant is present in a concentration in a range of from about 0.25 % (w / v) to about 25 % (w / v) of the pharmaceutical oil-in-water emulsion.

21. The pharmaceutical oil-in-water emulsion of claim 20, wherein the surfactant is present in a concentration in a range of from about 1% (w / v) to about 5% (w / v) of the pharmaceutical oil-in-water emulsion.

22. The pharmaceutical oil-in-water emulsion of claim 1, wherein the therapeutic agent comprises an analgesic agent, anesthetic agent, antiinflammatory agent, a sympatholytic agent, an anxiolytic agent, a cannabinoid, or a mixture thereof dispersed in the lipophilic oil.

23. The pharmaceutical oil-in-water emulsion of claim 22, wherein the analgesic agent, anesthetic agent, or both present in amount sufficient to reduce pain in a subject.

24. The pharmaceutical oil-in-water emulsion of claim 23, wherein the pharmaceutical oil-in-water emulsion comprises the analgesic agent.

25. The pharmaceutical oil-in-water emulsion of claim 24, wherein the analgesic agent comprises, a nonsteroidal anti-inflammatory drug, a COX-2 inhibitor, or a mixture thereof.

26. The pharmaceutical oil-in-water emulsion of claim 25, wherein the nonsteroidal anti-inflammatory drug comprises ibuprofen, naproxen, diclofenac, mefenamic acid, indomethacin, cannabidiol, an ion pair thereof, a salt thereof, or a mixture thereof.

27. The pharmaceutical oil-in-water emulsion of claim 25, wherein the COX- 2 inhibitor comprises etoricoxib, meloxicam, celecoxib, an ion pair thereof, a salt thereof, or a mixture thereof.

28. The pharmaceutical oil-in-water emulsion of claim 1, wherein the pharmaceutical oil-in-water emulsion comprises an anesthetic agent and the anesthetic agent is a local anesthetic.

29. The pharmaceutical oil-in-water emulsion of claim 28, wherein the anesthetic agent comprises an ester-based local anesthetic, an amide-based local anesthetic, or a prodrug, or ion pair thereof, or salt thereof, or a mixture thereof.

30. The pharmaceutical oil-in-water emulsion of claim 29, wherein the ester- based local anesthetic comprises procaine, amethocaine, benzocaine, tetracaine, or a prodrug, or ion pair thereof, or salt thereof, or a mixture thereof.

31. The pharmaceutical oil-in-water emulsion of claim 30, wherein the local amide-based anesthetic comprises lidocaine, prilocaine, bupivacaine, levobupivacaine, ropivacaine, mepivacaine, dibucaine, etidocaine, articaine, a prodrug, or ion pair thereof, or salt thereof, or a mixture thereof.

32. The pharmaceutical oil-in-water emulsion of claim 31, wherein the amide-based anesthetic comprises bupivacaine, ropivacaine, a salt thereof, ion pair thereof, or a mixture thereof.

33. The pharmaceutical oil-in-water emulsion of claim 32, wherein the amide-based local anesthetic is an ion pair, or salt, comprising of bupivacaine butyrate, bupivacaine palmitate, bupivacaine laureate, bupivacaine myristate, bupivacaine stearate, bupivacaine hydroxystearate, bupivacaine oleate, bupivacaine ricinolate, bupivacaine docusate.

34. The pharmaceutical oil-in-water emulsion of claim 22, wherein the pharmaceutical oil-in-water emulsion comprises a mixture of the analgesic agent, the anesthetic agent, and the anti-inflammatory agent.

35. The pharmaceutical oil-in-water emulsion of claim 22, wherein the pharmaceutical oil-in-water emulsion comprises a mixture of the analgesic agent and the anesthetic agent.

36. The pharmaceutical oil-in-water emulsion of claim 22, wherein the analgesic agent, anesthetic agent, or both are present in a concentration in a range of from about 0.1 % (w / v) to about 30% (w / v) based on a volume of the lipophilic oil.

37. The pharmaceutical oil-in-water emulsion of claim 22, wherein the analgesic agent, anesthetic agent, or both are present in a concentration in a range of from about 5 % (w / v) to about 15% (w / v) based on a volume of the lipophilic oil.

38. The pharmaceutical oil-in-water emulsion of claim 35, wherein the analgesic agent, anesthetic agent, or both present in a concentration in a range of from about 0.5 % (w / v) to about 6 % (w / v) of the pharmaceutical oil-in-water emulsion.

39. The pharmaceutical oil-in-water emulsion of claim 35, wherein the analgesic agent, anesthetic agent, or both present in a concentration in a range of from about 0.7 % (w / v) to about 2.5 % (w / v) of the pharmaceutical oil-in-water emulsion.

40. The pharmaceutical oil-in-water emulsion of claim 22, wherein the antiinflammatory agent comprises aspirin, celecoxib, diclofenac, diflunisal, etodolac, ibuprofen, indomethacin, ketoprofen, ketorolac, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin, cannabidiol, a salt thereof, an ion pair thereof, or a mixture thereof.

41. The pharmaceutical oil-in-water emulsion of claim 22, further comprising an adjuvant.

42. The pharmaceutical oil-in-water emulsion of claim 41, wherein the adjuvant comprises a nonsteroidal anti-inflammatory drug, corticosteroid, alpha- 2-agonist, pethidine, barbiturate, opiate, tubocurarine chloride, a cannabinoid, meloxicam a salt thereof, or ion pair thereof, or a mixture thereof.

43. The pharmaceutical oil-in-water emulsion of claim 42, wherein the cannabinoid is cannabidiol (CBD).

44. The pharmaceutical oil-in-water emulsion of claim 43, wherein the pharmaceutical oil-in-water emulsion is effective at relieving pain in a subject using a smaller concentration of the analgesic agent, anesthetic agent, an antiinflammatory agent, or mixture thereof and / or has a longer pain relieving effect, compared to a corresponding pharmaceutical oil-in-water emulsion that is free of the adjuvant.

45. The pharmaceutical oil-in-water emulsion of claim 1, wherein the pharmaceutical oil-in-water emulsion is effective to reduce pain in a subject for a time in a range of from about 12 hours to about 14 days.

46. The pharmaceutical oil-in-water emulsion of claim 1, wherein the pharmaceutical oil-in-water emulsion is effective to reduce pain in a subject for a time in a range of from about 24 hours to about 96 hours.

47. The pharmaceutical oil-in-water emulsion of claim 1, wherein the pharmaceutical oil-in-water emulsion is effective to reduce pain in a subject for a time in a range of from about 96 hours to about 168 hours.

48. The pharmaceutical oil-in-water emulsion of claim 1, wherein the pharmaceutical oil-in-water emulsion is effective to reduce pain in a subject for a time in a range of from about 168 hours to about 336 hours.

49. The pharmaceutical oil-in-water emulsion of claim 1, wherein an average particle size of the pharmaceutical oil-in-water emulsion ranges from about 100 nm to about 10 pm.

50. The pharmaceutical oil-in-water emulsion of claim 1, wherein an average particle size of the pharmaceutical oil-in-water emulsion ranges from about100 nm to about 1000 nm.

51. A method of manufacturing the pharmaceutical oil-in-water emulsion of claim 1, the method comprising: pre-homogenizing a mixture comprising the lipophilic oil, surfactant, and therapeutic agent, homogenizing the pre-homogenized mixture to form the pharmaceutical oil-in-water emulsion.

52. The method of claim 51, wherein pre-homogenization is accomplished through high-speed homogenization or sonification.

53. The method of claim 51, wherein the pre-homogenized mixture is homogenized with a high-pressure homogenizer.

54. The method of claim 51, further comprising adjusting at least one of a pH, tonicity, and salinity of the pre-homogenized mixture, homogenized mixture, or both.

55. The method of claim 54 wherein the tonicity is adjusted with sodium chloride, glycerol, sorbitol, xylitol, mannitol, glucose, trehalose, maltose, sucrose, raffinose, lactose, dextran, polyethylene glycol, or propylene glycol.

56. The method of claim 55, wherein the sodium chloride is added in a range of from about 0.5 wt% to about 2 wt% of the pharmaceutical oil-in-water emulsion.

57. The method of claim 56 wherein the sodium chloride is added in a range of from about 1 wt% to about 6 wt% of the pharmaceutical oil-in-water emulsion.

58. The method of claim 55 wherein the glycerol is added in a range of from about 0.5 wt% to about 3.5 wt% of the pharmaceutical oil-in-water emulsion.

59. The method of claim 58 wherein the glycerol is added in a range of from about 1 wt% to about 2.25 wt% of the pharmaceutical oil-in-water emulsion.

60. The method of claim 54, wherein the pH is adjusted using sodium hydroxide.

61. The method of claim 51 further comprising sterilizing the pharmaceutical oil-in-water emulsion.

62. The method of claim 61, wherein sterilizing the pharmaceutical oil-in- water emulsion comprises the use of an autoclave, a filter, gamma irradiation, x- ray irradiation, e-beam irradiation, or a combination thereof.

63. A method of treating pain in a subject comprising in need thereof, with the pharmaceutical oil-in-water emulsion of claim 1, comprising administering the pharmaceutical oil-in-water emulsion to the subject via injecting the pharmaceutical oil-in-water emulsion through a syringe, through a needle having a size of about 14-31 gauge.

64. The method of claim 63, wherein the pharmaceutical oil-in-water emulsion is locally infiltrated or locally instilled into the subject’s tissue to generate a local, field, or regional block, or the pharmaceutical oil-in-water emulsion is a nerve block composition or a fascial plane block composition.

65. The method of claim 64, wherein the nerve block composition or fascial plane block composition comprises an axillary block, supraclavicular block, infraclavicular block, interscalene block, radial nerve block, median nerve block, ulnar nerve block, femoral nerve block, sciatic nerve block, popliteal block, ankle block, saphenous nerve block, obturator nerve block, intercostal nerve block, ilioinguinal / iliohypogastric nerve block, genitofemoral nerve block, occipital nerve block, supraorbital nerve block, infraorbital nerve block, transversus abdominis plane (tap) block, quadratus lumborum (ql) block, erector spinae plane (esp) block, pectoral nerves (pecs) block, serratus anterior plane block, fascia iliaca block, rectus sheath block, upper extremity, suprascapular nerve block, axillary nerve block, musculocutaneous nerve block, lower extremity, lateral femoral cutaneous nerve block, tibial nerve block, deep peroneal nerve block, sural nerve block, trunk paravertebral block, pudendal nerve block, GON block (greater occipital nerve), LON block (lesser occipital nerve), or a combination thereof.

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