Drug composition for treating pain

Abstract

The pharmaceutical composition may comprise a lipophilic oil. The pharmaceutical composition may further comprise an analgesic, anesthetic, anti-inflammatory agent, or a mixture thereof dispersed in the lipophilic oil. The pharmaceutical composition may further comprise a structuring agent, at least a portion of which is insoluble in the lipophilic oil and forms a gel.

Description

[0001] Cross - Reference to Related Applications

[0002] This application claims the benefit of priority of U.S. Provisional Patent Application Serial No. 63 / 267,256, filed on January 28, 2022, entitled "PHARMACEUTICAL COMPOSITIONS FOR TREATING PAIN", the disclosure of which is incorporated herein by reference in its entirety. Background of the Invention

[0003] Local anesthetics are widely used in surgery to anesthetize the surgical site and relieve postoperative pain, but due to their short duration of action, they cannot provide analgesia throughout the period when the patient experiences severe pain. When the anesthesia gradually wears off, opioids are administered to control this pain, most commonly for three or more days until less potent analgesics can control the pain. Summary of the Invention

[0004] The problem that the present disclosure seeks to solve is to provide injectable or implantable compositions that can provide robust pain relief for 2 to 14 days, which are both injectable and viscous enough to be manually implanted into the surgical site and remain at the site of administration long enough to provide a local anesthetic effect. Accordingly, the present disclosure relates to pharmaceutical compositions comprising:

[0005] A lipophilic oil;

[0006] A drug, its salt, or its prodrug (e.g., an analgesic, anesthetic, anti - inflammatory agent, or a mixture thereof) dispersed in the lipophilic oil; and

[0007] A structuring agent, at least a portion of which is insoluble in the lipophilic oil and forms a gel.

[0008] The present disclosure also relates to pharmaceutical compositions comprising:

[0009] Medium - chain triglycerides;

[0010] An anesthetic agent comprising bupivacaine, ropivacaine, or both, present in an amount sufficient to relieve pain in a subject and dispersed in the medium - chain triglycerides; and

[0011] Structuring agents, which include tristearin, distearin, monostearin, behenin, cholesterol, trimyristin, dimyristin, monomyristin, trilaurin, dilaurin, monolaurin, tripalmitin, dipalmitin, monopalmitin, cholesterol, polyglycerol esters of fatty acids, polyglycerol esters of fatty acids, or mixtures thereof.

[0012] The present disclosure relates to a kit, which includes:

[0013] a syringe; and

[0014] The pharmaceutical composition of the present disclosure, which is configured within the syringe.

[0015] The present disclosure also relates to a method for preparing a pharmaceutical composition, the method including:

[0016] a) Mixing a lipophilic oil, an analgesic, and an anesthetic at a temperature above 25°C with stirring to form a first mixture;

[0017] b) Mixing the structuring agent with the first mixture at a temperature above 25°C with stirring and heating to form a second mixture; and

[0018] c) Cooling the second mixture to form the pharmaceutical composition.

[0019] The present disclosure relates to a method for treating a subject with the composition of the present disclosure, which includes administering the composition to a subject in need thereof. Description of the Drawings

[0020] The drawings generally illustrate, by way of example and not limitation, various embodiments of the present disclosure.

[0021] Figure 1 is a graph showing the drug release curves of various oils.

[0022] Figure 2 is a graph showing the drug release curves of various oils.

[0023] Figure 3 is a graph showing the viscosities of various oils.

[0024] Figure 4 is a graph showing the effect of different oil components on viscosity.

[0025] Figure 5 is a graph showing the viscosity curves of various formulations.

[0026] Figure 6 is a graph showing the viscosity of the formulation at body temperature.

[0027] Figures 7A to 7D is a series of graphs showing the storage modulus values of multiple formulations.

[0028] Figure 8A and 8B is a graph showing the peak melting and peak crystallization characteristics of multiple formulations.

[0029] Figure 9A and 9B is a graph showing the rat sciatic nerve block data of multiple formulations.

[0030] Figure 10 is a graph showing the efficacy data of multiple formulations in a porcine incisional wound model.

[0031] Figure 11 is a graph showing the solubility of bupivacaine in multiple blends of MCT oil and castor oil.

[0032] Figure 12 is a graph showing the solubility of bupivacaine and multiple lipophilic salts of bupivacaine in MCT oil.

[0033] Figure 13 is a graph showing the release characteristics of bupivacaine and multiple lipophilic salts of bupivacaine in MCT oil. Detailed Description

[0034] Reference will now be made in detail to certain aspects of the disclosed subject matter. While the disclosed subject matter will be described in connection with the enumerated claims, it will be understood that the illustrated subject matter is not intended to limit the claims to the disclosed subject matter.

[0035] The present disclosure relates to a pharmaceutical composition comprising: a lipophilic oil component; a therapeutic agent or a mixture thereof dispersed in the lipophilic oil component; and a structuring agent, at least a portion of which is insoluble in the lipophilic oil. These components can form a semi-solid oleogel composed of a drug-loaded lipophilic oil, which is entrapped in a supramolecular network of self-assembled structures (such as molecular aggregates, crystals, etc.). The pharmaceutical composition can be used for both human and veterinary pain management applications. Possible clinical uses include, but are not limited to, axonal, regional, and local anesthesia for treating surgical, postoperative, and injury-related pain, and local infiltration anesthesia for myofascial pain (e.g., trigger points) and chronic pain.

[0036] The pharmaceutical composition described herein can be used for postoperative pain management as an alternative to a medicament for postoperative pain management that includes an opioid. The pharmaceutical composition can completely replace a medicament that includes an opioid, or it can be used in combination with a medicament that includes an opioid to reduce the amount of opioid used in postoperative pain management.

[0037] The composition can take the form of an injectable semi-solid gel, paste, or an implantable solid. In the form of a semi-solid gel or paste, the composition can be applied to the surgical site / wound, and due to its viscosity, the gel remains where it was initially applied. After closing the surgical site / wound, the semi-solid gel can be embedded within natural crevices and spread between compressed tissue. The self-assembled supramolecular network generated by the structurant prevents the drug-oil phase from migrating away from the site of administration, which is beneficial for safer and more effective local treatment. The structurant network also protects the drug-loaded oil from the surrounding in vivo environment (e.g., the surrounding aqueous in vivo environment), which enables drugs based on long-term diffusion to be released from the oil into the aqueous environment. The composition can be biodegradable and can thus be naturally absorbed by the body over time.

[0038] Depending on the concentration and unique properties of the structurant, the composition can be adjusted to have a variety of mechanical properties. The adjustment of the mechanical properties is related to the generation of a long-acting local anesthetic drug, which represents an improvement over many currently clinically available techniques. If the mechanical properties are too robust, the composition may not be injectable through a small-bore needle (e.g., >23G), which only allows it to be manually implanted into the surgical wound cavity. For some long-acting local anesthetic products for postoperative pain, it is necessary to optimize the mechanical properties so that it can be injected through an acceptable needle size (18 to 25G), but maintain sufficient viscosity to remain at the implantation site.

[0039] Structuring agents can be used to provide sufficient structure and mechanical properties to a composition. For example, if a therapeutic agent or drug (e.g., an analgesic, anesthetic, anti-inflammatory agent, or a mixture thereof) is simply loaded into a common lipophilic oil carrier (e.g., medium-chain triglycerides), the resulting solution will be a thin and flowable liquid, such as an aqueous solution. Thus, if the solution (lacking a structuring agent) is injected or directly implanted into a surgical wound cavity, the solution can migrate and be eliminated from the site of administration, thereby reducing its effectiveness in controlling pain at the target site. Additionally, the rapid elimination of the drug increases the risk of systemic toxicity (e.g., cardiotoxicity or neurotoxicity), which can be life-threatening. Thus, as an example, a favorable long-acting local anesthetic composition should be both injectable and sufficiently viscous to be manually implanted into the surgical site. Some currently clinically available options include solid implantable techniques that can only be implanted into the surgical site, which significantly limits their clinical use. Injectable compositions can be used as extended-duration nerve blocks for regional anesthesia, a technique that has become widespread due to non-opioid management of postoperative pain; however, current injectable options only last less than 24 hours. Thus, the problem that the present disclosure seeks to solve is to provide a safe injectable or implantable composition that can provide robust pain relief (e.g., analgesia) for 2 to 14 days, the composition being both injectable and sufficiently viscous to be manually implanted into the surgical site, while also being able to retain at its implantation site an amount of time sufficient to provide local analgesia.

[0040] The lipophilic oil of the composition can be selected from many suitable oils. For example, the lipophilic oil can include monoglycerides, diglycerides, triglycerides, sesame oil, soybean oil, castor oil, tributyrin oil, vegetable oil, or a mixture thereof. For example, the lipophilic oil can include a mixture of medium-chain triglyceride oil and castor oil, each independently being 5 wt% to 98 wt%, 30 wt% to 70 wt%, less than, equal to, or greater than 5 wt%, 10 wt%, 15 wt%, 20 wt%, 25 wt%, 30 wt%, 35 wt%, 40 wt%, 45 wt%, 50 wt%, 55 wt%, 60 wt%, 65 wt%, 70 wt%, 75 wt%, 80 wt%, 85 wt%, 90 wt%, or about 98 wt%. Sesame oil typically includes 41 wt% linoleic acid, 39 wt% oleic acid, 8 wt% palmitic acid, 5 wt% stearic acid, and trace amounts of other organic acids. Every 100 g of soybean oil has 16 g of saturated fat, 23 g of monounsaturated fat, and 58 g of polyunsaturated fat. The main unsaturated fatty acids in soybean oil triglycerides are 7 wt% to 10 wt% polyunsaturated α-linolenic acid, 51 wt% linoleic acid, and 23 wt% monounsaturated oleic acid. Soybean oil also includes saturated fatty acids, such as 4 wt% stearic acid and 10 wt% palmitic acid. Castor oil includes 85 wt% to 95 wt% ricinoleic acid, 2 wt% to 6 wt% oleic acid, 1 wt% to 5 wt% linoleic acid, 0.5 wt% to 1 wt% α-linolenic acid, 0.5 wt% to 1% stearic acid, 0.5 wt% to 1 wt% palmitic acid, 0 wt% to 0.5 wt% of dihydroxystearic acid, and 0.2 wt% to 0.5 wt% of additional compounds. Tributyrin oil is an ester that is a reaction product of butyric acid and glycerol. The triglycerides can be medium-chain triglycerides, short-chain triglycerides, or both. Some examples of medium-chain triglycerides include esters that are reaction products of glycerol and any one of C6-C12 carboxylic acids (e.g., caproic acid, caprylic acid, capric acid, lauric acid, or a mixture thereof).

[0041] Medium-chain triglycerides can be particularly suitable as the lipophilic oil. While not intended to be limited by any theory, the benefits of using medium-chain triglycerides are thought to be due to their thin nature and low viscosity, each of which makes them injectable (compared to castor oil, which has good drug solubility but is very viscous). Additionally, medium-chain triglycerides are shown to provide a high drug load and a good release rate. Thus, medium-chain triglycerides are beneficial because they exhibit a viscosity that makes them injectable, are structured into supramolecular gels using structuring agents, are loaded with a sufficient amount of drug, and exhibit a good drug release profile.

[0042] Mixtures of lipophilic oils can be used. For example, the pharmaceutical composition can include a mixture of the following: 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 instances, the solubility of a drug (e.g., ropivacaine) can be increased in a mixture of medium-chain triglycerides and short-chain triglycerides at 90:10 (medium-chain triglycerides: short-chain triglycerides). As another example, a mixture of medium-chain triglycerides and castor oil as a lipophilic oil will achieve a higher drug load while reducing the viscosity in the overall structure.

[0043] A structurant (also known as an organic structurant, oil structurant, or supramolecular structurant) imparts structure to the lipophilic oil. For example, the structurant helps to form a gel. An example of a gel type is a supramolecular gel, which is a complex of molecules held together by non-covalent interactions (such as hydrogen bonds, π-π interactions, anion-π interactions, cation-π interactions, and van der Waals forces). The process by which the supramolecular assembly forms is called molecular self-assembly. Molecular self-assembly refers to the process in which molecules adopt a defined arrangement without guidance or management from an external source.

[0044] Based on the volume of the lipophilic oil, the structurant is present in the pharmaceutical composition at the following concentrations: from about 0.1% (w / v) to about 25% (w / v), from about 5% (w / v) to about 25% (w / v), from about 10% (w / v) to about 15% (w / v), from about 5% (w / v) to 10% (w / v), from about 5% (w / v) to 15% (w / v), from about 10% (w / v) to 20% (w / v), less than, equal to, or greater than about 0.1% (w / v), 0.5, 1, 1.5, 2, 25, 3, 35, 4, 45, 5, 55, 6, 65, 7, 75, 8, 85, 9, 95, 10, 105, 11, 115, 12, 125, 13, 13.5, 14, 145, 15, 155, 16, 165, 17, 17.5, 18, 185, 19, 19.5, 20, 20.5, 21, 215, 22, 225, 23, 235, 24, 245, or about 25% (w / v). The structurant or mixture of structurants used can depend on several factors, such as the melting point of the structurant. For example, the melting point of the structurant can be from about 40 °C to about 100 °C, from about 50 °C to about 85 °C, from about 45 °C to about 60 °C, from about 50 °C to about 70 °C, less than, equal to, or greater than about 40 °C, 45 °C, 50 °C, 55 °C, 60 °C, 65 °C, 70 °C, 75 °C, 80 °C, 85 °C, 90 °C, 95 °C, or 100 °C.

[0045] Some examples of suitable structuring agents include monoglycerides, diglycerides, triglycerides, polyglycerol esters of fatty acids, or mixtures thereof. The polyglycerol used herein can be diglycerol or triglycerol and can be fully or partially esterified with saturated or unsaturated fatty acid moieties. The fatty acids can include caprylic acid (C8), capric acid (C10), lauric acid (C12), myristic acid (C14), palmitic acid (C16), stearic acid (C18), arachidonic acid (C20), behenic acid (C22), or mixtures thereof. Some more specific examples of suitable structuring agents include glyceryl tristearate, glyceryl distearate, glyceryl monostearate, glyceryl dibehenate, cholesterol, glyceryl trimyristate, glyceryl dimyristate, glyceryl monomyristate, glyceryl trilaurate, glyceryl dilaurate, glyceryl monolaurate, glyceryl tripalmitate, glyceryl dipalmitate, glyceryl monopalmitate, diglycerol esterified with stearic acid, cholesterol, or mixtures thereof.

[0046] At least a portion of the structuring agent phase separates in the lipophilic oil. Thus, for example, a portion of the structuring agent can be partially dissolved in the lipophilic oil (first phase), while a second portion is insoluble in the lipophilic oil (second phase). The phase separation of the structuring agent enables the structuring agent to contribute to the formation of a supramolecular gel of the pharmaceutical composition in the lipophilic oil. If the structuring agent is too soluble in the lipophilic oil, it will dissolve in the lipophilic oil and will not form a supramolecular gel. If the structuring agent is too insoluble, it will not interact with the lipophilic oil and the pharmaceutical composition will be in the form of a heterogeneous and unstable gel with the structuring agent precipitating out.

[0047] Supramolecular gels can themselves be characterized as semi-solid compositions (or referred to as quasi-solids or semi-liquids). While in some respects similar to solids (e.g., having the ability to support their own weight and maintain their shape), semi-solid compositions also share some liquid properties (e.g., the shape conforms to something applying pressure to it and is able to flow under pressure). Selecting a suitable structurant also affects the viscosity of the pharmaceutical composition. A suitable viscosity enables the pharmaceutical composition to remain substantially in the desired location within the body. An example of a suitable viscosity at 37 °C is from about 1,000 cP to about 1,000,000 cP, from about 100,000 cP to about 1,000,000 cP, from about 5,000 cP to about 200,000 cP, from about 10,000 cP to about 100,000 cP, from about 50,000 cP to about 150,000 cP, from about 10,000 cP to about 500,000 cP, 20,000 cP to about 90,000 cP, less than, equal to, or greater than about 10,000, 15,000, 20,000, 25,000, 30,000, 35,000, 40,000, 45,000, 50,000, 55,000, 60,000, 65,000, 70,000, 80,000, 85,000, 90,000, 95,000, 100,00, 105,000, 110,000, 115,000, 120,000, 125,000, 130,000, 135,000, 140,000, 145,000, 150,000, 155,000, 160,000, 165,000, 170,000, 175,000, 180,000, 185,000, 190,000, 195,000, 200,000, 205,000, 210,000, 215,000, 220,000, 225,000, 230,000, 235,000, 240,000, 245,000, 250,000, 255,000, 260,000, 265,000, 270,000, 275,000, 280,000, 285,000, 290,000, 295,000, 300,000, 305,000, 310,000, 315,000, 320,000, 325,000, 330,000, 335,000, 340,000, 345,000, 350,000, 355,000, 360,000, 365,000, 370,000, 375,000, 380,000, 385,000, 390,000, 395,000, 400,000, 405,000, 410,000, 415,000, 420,000, 425,000, 430,000, 435,000, 440,000,445,000,450,000,455,000,460,000,465,000,470,000,475,000,480,000,485,000,490,000,495,000,500,000,600,00,605,000,610,000,615,000,620,000,625,000.630,000,635,000,640,000,645,000,650,000,655,000,660,000,665,000,670,000,675,000,680,000,685,000,690,000,695,000,700,000,705,000,710,000,715,000,720,000,725,000,730,000,735,000,740,000,745,000,750,000,755,000,760,000,765,000,770,000,775,000,780,000,785,000,790,000,795,000,800,000,805,000,810,000,815,000,820,000,825,000,830,000,835,000,840,000,845,000,850,000,855,000,860,000,865,000,870,000,875,000,980,000,985,000,990,000,995,000,1,000,000 cP.,

[0048] If the viscosity is too low, the pharmaceutical composition will disperse beyond the desired location. Additionally, if the viscosity is too low, it can result in uncontrolled drug release. Conversely, if the viscosity is too high, it may not be possible to inject the pharmaceutical composition to the desired location. This may make manual application (e.g., by hand or using an instrument to apply or spread the composition to the site) the only viable option. However, if the viscosity is too high, even manual application may be impractical. The viscosity required to maintain material retention at the application site is often too high to be injectable through clinically relevant needle sizes (18G to 25G needles). A specific disadvantage of not being able to inject through these needles is that such solutions cannot be used as nerve blocks. To overcome this, the disclosed pharmaceutical compositions are engineered to be shear-thinning, which is defined as the ability of a material to decrease in viscosity as shear increases. Such compositions can be pre-loaded into a syringe, extruded after shear is applied, and regain their viscosity after the mechanical load stops, a process known as self-healing. This self-healing behavior allows for improved application and material retention, thus enhancing the usefulness and efficacy of the pharmaceutical product, while also exhibiting the extended drug release characteristics described herein. As an example, when sheared in a scan range of 0.01 hz to 200 hz, the viscosity at 37 °C can be as low as about 10 cP to about 10,000 cP, about 20 cP to about 5,000 cP, about 20 cP to about 500 cP, less than, equal to, or greater than about 10 cP,

[0049] 100, 200, 300, 400, 500, 600, 700, 800, 900, 1,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000 or about 10,000 cP. Unless otherwise stated, all viscosity values described herein are obtained at 37 °C using a HAAKE Mars 60 rheometer obtained from Thermo-Fisher Scientific, Waltman MA.

[0050] The drug can be present in the pharmaceutical composition in a therapeutically effective amount. For use in therapy, a "therapeutically effective amount" (or "effective amount") of a compound refers to the amount of the compound in a formulation that, when administered as part of a desired dosage regimen (administered to a mammal, e.g., a human), alleviates symptoms, improves the condition, or slows the onset of a disease condition according to clinically acceptable criteria applicable to the disorder or condition to be treated or for cosmetic purposes (e.g., with a reasonable benefit / risk ratio applicable to any medical treatment).

[0051] The term "prophylactic or therapeutic" treatment is well recognized in the art and includes administering to a patient one or more compounds of the present disclosure. If it is administered prior to the clinical manifestation of an undesired condition (e.g., a disease or other undesired state of a host animal), the treatment is prophylactic (i.e., it protects the host from developing the undesired condition), while if it is administered after the manifestation of the undesired condition, the treatment is therapeutic (i.e., it is intended to reduce, mitigate an existing undesired condition or its side effects or to stabilize an existing undesired condition or its side effects).

[0052] The exact amount of the drug can vary and is selected according to the application. As a non-limiting example, based on the volume of the lipophilic oil, the drug can be present at the following concentrations: 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 the amount is therapeutically effective can be a factor in the amount of time pain is alleviated in the subject. For example, the pharmaceutical composition can be effective in alleviating in vivo pain in the subject for the following times: about 24 hours to about 14 days, 48 hours to about 14 days, about 72 hours to about 96 hours, 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, 88 hours, 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 compositions can be designed to effectively relieve pain for a specific range, 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 structure of the pharmaceutical composition. For example, a specific blend of lipophilic oils affects the drug release characteristics. For example, a specific ion pair formed by a therapeutic agent (e.g., a lipophilic salt) can affect the release characteristics.

[0053] The amount of time for which the pharmaceutical composition is therapeutically effective can be the result of the rate of drug release from the lipophilic oil. The release of the drug from the lipophilic oil is controlled by diffusion. Depending on the affinity of the drug for a specific lipophilic oil or a specific blend of lipophilic oils, the drug will preferentially reside in the lipophilic oil and slowly diffuse into the surrounding aqueous medium in the patient's body, depending on its greater affinity for the lipophilic oil than for the aqueous medium. The drug release rate also depends on the interfacial area between the oil-based carrier and the surrounding aqueous in vivo environment. The above interfacial area can be controlled by a supramolecular gel provided by a structuring agent. In the absence of any structure, the pharmaceutical composition can flow and diffuse freely in the body, which significantly increases its interfacial surface area and thus significantly accelerates its drug release rate. However, if the lipophilic oil forms a viscous semi-solid through its supramolecular gel, it will have a significantly reduced diffusion ability and an increased interfacial area, thus reducing the rate of drug release and prolonging the action of local controlled non-opioid pain management (if the drug is used as an analgesic or anesthetic).

[0054] Therapeutic agents include analgesics, anesthetics, and anti-inflammatory agents. A variety of lipophilic therapeutic agents in their base form can be covalently or non-covalently modified to increase their lipophilicity and the resulting solubility and drug-loading capacity in a base oil. This is achieved by altering the physicochemical properties of the drug (e.g., melting point, polarity, hydrophobicity, partition coefficient). Using covalent modification, prodrugs of the agent can be synthesized that are significantly more lipophilic and suitable for the disclosed compositions. This can also be achieved using non-covalent modification. For example, hydrophobic ion pairing can be used to ion pair a charged drug molecule with an oppositely charged molecule having a hydrophobic moiety. The resulting complex is more lipophilic and hydrophobic, enabling better encapsulation in lipid-based formulations and more controlled release from lipid-based formulations. Thus, both covalent and non-covalent modulation of the drug can be used to adjust the drug release of natural lipophilic or natural hydrophobic drugs from the system. For different drugs and intended uses, the desired solubility and partition coefficient from the base oil will also be different. For example, a drug with a log P less than 2 can be modified by forming a prodrug that has a log P greater than the recorded log P value (e.g., at least 2). These examples of covalent and non-covalent chemical modifications increase lipophilicity, resulting in a higher affinity for the base oil and thus a slower modified release profile. In one such example, a drug with a log P less than 2 can contain a hydroxyl or amino functional group that can form an ester or amide with a C 12 -C 22 carboxylic acid. The resulting C 12 -C 22 ester or amide can have a recorded log P value (e.g., at least 3). As an alternative or supplement, the drug or prodrug can be modified by ion pairing it with a hydrophobic counterion that can have a recorded log P value. For example, the drug or prodrug can be synthesized as a docusate salt or can be ion-exchanged to form a docusate salt, where docusate is the counterion of the drug. Other such counterions are known in the art and are contemplated herein. Thus, in addition to the analgesics, anesthetics, and anti-inflammatory agents described herein, the pharmaceutical compositions described herein can also be formulated to contain one or more excipients, and the excipient (adjuvant agent) can also be covalently or non-covalently modified. Some examples include but are not limited to sympatholytics (e.g., dexmedetomidine, clonidine), anxiolytics (e.g., midazolam), anti-inflammatory agents (e.g., dexamethasone, NSAID, COX-2 inhibitors), and cannabinoids (e.g., cannabidiol).

[0055] As used herein, the partition coefficient or log P is a measure of the lipophilicity of a drug and is an indication of its ability to cross cell membranes. It is defined as the ratio of the drug distributed between the organic and aqueous layers at equilibrium. The partition coefficient of a drug can be determined by shaking it with equal portions of two immiscible solvents (an organic layer saturated with water and an aqueous drug solution) until equilibrium is reached. The amount of the drug in one of the layers is determined and the value is calculated. The octanol-water partition is the system commonly used for this study. Although the partition coefficient alone may not provide information on absorption, it characterizes the lipophilic-hydrophilic balance of the drug and supports the screening of compounds for their biological properties. In combination with Log P, the melting point of a drug can also be used to screen compounds for their lipid solubility. Molecules with high melting points tend to be less soluble than predicted based on their Log P. Molecules with low melting points tend to be more soluble than predicted based on their Log P.

[0056] As understood herein, an analgesic is any member of the group of drugs used to achieve analgesia (relief from pain). They differ from anesthetics in that they temporarily affect sensation and in some cases abolish it. Some examples of suitable analgesics can include nonsteroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors, or mixtures thereof. Some non-limiting examples of NSAIDs can include ibuprofen, naproxen, diclofenac, mefenamic acid, indomethacin, cannabidiol, its ion pairs, its salts, or mixtures of these. Some non-limiting examples of COX-2 inhibitors can include etoricoxib, meloxicam, celecoxib, its ion pairs, its salts, or mixtures of these.

[0057] As understood herein, an anesthetic refers to any agent that produces a local or general loss of sensation, including pain. Anesthetics achieve this by acting on the brain or the peripheral nervous system to inhibit the response to sensory stimuli. Thus, the induced state of unresponsiveness is called anesthesia. General anesthesia involves a loss of consciousness, usually for the purpose of relieving surgical pain. Local anesthesia involves the loss of sensory and / or motor function in a region of the body through a conduction block in a nerve.

[0058] Although the present disclosure describes the use of local anesthetics, general anesthetics may also be included. Some suitable examples of local anesthetics include ester-based anesthetics, amide-based anesthetics, or mixtures thereof. Some non-limiting examples of ester-based anesthetics include procaine, amethocaine, benzocaine, tetracaine, or mixtures thereof. Some non-limiting examples of amide-based anesthetics include lidocaine, prilocaine, bupivacaine, levobupivacaine, ropivacaine, mepivacaine, dibucaine, etidocaine, their salts, or mixtures of these. Amide-based anesthetics may include the free base form of the amide-based anesthetic, the hydrochlorinated form of the amide-based anesthetic, or additional salt forms or ion pairs (including lipophilic salts) of the amide-based anesthetic. Lipophilic salts of amide-based anesthetics involve pairing a protonated amide-based anesthetic with a lipophilic counterion, which can increase the solubility of the amide-based anesthetic in lipophilic oils. This can be beneficial for increasing the loading of the anesthetic in the pharmaceutical composition. For example, lipophilic salts or ion pairs of amide-based anesthetics may include dioctylsulfosuccinate counterions. As an example, a lipophilic salt or ion pair of an amide-based anesthetic can be ropivacaine dioctylsulfosuccinate. As another example, an amide-based local anesthetic is an ion pair or salt that includes bupivacaine butyrate, bupivacaine palmitate, bupivacaine laurate, bupivacaine myristate, bupivacaine stearate, bupivacaine hydroxystearate, bupivacaine oleate, bupivacaine ricinoleate, bupivacaine dioctylsulfosuccinate.

[0059] Although any of the above amide-based anesthetics are desirable, it may also be desirable to use ropivacaine because it has several known clinical advantages, such as good patient safety and good analgesic properties (e.g., sensory selectivity). However, ropivacaine generally exhibits poor solubility in lipophilic oils (including but not limited to medium-chain triglycerides). The relatively poor solubility extends to the free base and hydrochlorinated forms of ropivacaine. However, unexpectedly, it has been shown that ropivacaine dioctylsulfosuccinate exhibits suitable solubility in lipophilic oils (such as medium-chain triglycerides) such that a sufficient amount of ropivacaine dissolves in the lipophilic oil and is released at an acceptable rate.

[0060] Some suitable examples of anti-inflammatory agents may include aspirin, celecoxib, diclofenac, diflunisal, etodolac, ibuprofen, indomethacin, ketoprofen, ketorolac, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin, or a mixture thereof.

[0061] The pharmaceutical composition may comprise an adjuvant. In the context of a medicament, an adjuvant refers to a medicament having analgesic properties in the case of a primary indication other than pain. Some examples of suitable adjuvants include barbiturate, opiate, anti-inflammatory agent, cannabinoid, sympatholytic, or a mixture thereof. Some other examples of suitable adjuvants include corticosteroid, dexamethasone, pethidine, tubocurarine chloride, meloxicam, dexmedetomidine, or a mixture thereof.

[0062] If the excipient contains cannabinoids, suitable cannabinoids can be cannabidiol (CBD). However, some other cannabinoids may 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 (CBDA), cannabidiol monomethylether (CBDM), 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), THC-C4, tetrahydrocannabivarinic acid (THCVA), tetrahydrocannabivarin,THCV), tetrahydrocannabiorcolic acid (THCA-C1), tetrahydrocannabiorcol (THC-C1), Δ7-cis-iso-tetrahydrocannabivarin, Δ8-tetrahydrocannabinolic acid (Δ8-THCA), cannabinovarinodiolic (CBNDVA), cannabinovarinodiol (CBNDV), Δ8-tetrahydrocannabinol (Δ8-THC), Δ9-tetrahydrocannabinol (Δ9-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 methyl ether (CBNM), cannabinol-C4 (CBN-C4), cannabivarin (CBV), cannabinol-C2 (CBN-C2), cannabinorcol (CBN-C1), cannabinodiol (CBND), cannabinodiolic acid (CBNDA), cannabinodivarin (CBDV), cannabitriol (CBT), 10-ethoxy-9-hydroxy-Δ8a-tetrahydrocannabinol, 8,9-dihydroxy-Δ6a(10a)-tetrahydrocannabinol (8,9-Di-OH-CBT-C5), cannabitriolvarin (CBTV), ethoxy-cannabitriolvarin (CBTVE), dehydrocannabifuran,DCBF), cannabifuran (CBF), cannabichromanon (CBCN), cannabicitran (CBT), 10-oxo-Δ6a(10a)-tetrahydrocannabinol (OTHC), A9-cis-tetrahydrocannabinol (cis-THC), cannabiripsol (CBR), 3,4,5,6-tetrahydro-7-hydroxy-α-α-2-trimethyl-9-n-propyl-2,6-methano-2H-1-benzoxocin-5-methanol (OH-iso-HHCV), trihydroxy-Δ-9-tetrahydrocannabinol (triOH-THC), yangonin, epigallocatechin gallate, isobutyl amide of dodeca-2E,4E,8Z,10Z-tetraenoic acid, and isobutyl amide of dodeca-2E,4E-dienoic acid, mixtures thereof, or mixtures of any of the foregoing with cannabidiol.,

[0063] Relative to a comparative pharmaceutical composition that differs only in that it does not contain excipients, the inclusion of excipients can provide a synergistic effect because it can reduce the amount of the drug that is considered to be a therapeutically effective amount and that needs to be added.

[0064] In some aspects, the pharmaceutical composition can include a rheology modifier. When present, based on the volume of the lipophilic oil, the rheology modifier can be present in the pharmaceutical composition at: about 0.5% (w / v) to about 10% (w / v), about 1% (w / v) to about 6% (w / v), about 1.5% (w / v) to about 3% (w / v), less than, equal to, or greater than about 0.5% (w / v), 1% (w / v), 1.5% (w / v), 2% (w / v), 2.5% (w / v), 3% (w / v), 3.5% (w / v), 4% (w / v), 4.5% (w / v), 5% (w / v), 5.5% (w / v), 6% (w / v), 6.5% (w / v), 7% (w / v), 7.5% (w / v), 8% (w / v), 8.5% (w / v), 9% (w / v), 9.5% (w / v), or about 10% (w / v).

[0065] In some aspects, the rheology modifier can be a diluent that reduces the viscosity of the pharmaceutical composition. In some instances, in cases where the pharmaceutical composition is intended for injection, the diluent can be beneficial because it can enhance the injectability of the pharmaceutical composition by reducing its viscosity. For example, the diluent can at least temporarily disrupt the supramolecular gel. In addition to improving the injectability of the pharmaceutical composition, at least temporarily disrupting the supramolecular gel can contribute to enhancing the shelf-life stability of the pharmaceutical composition. For example, if the components of the pharmaceutical composition are uniformly distributed relative to each other, the formation of the supramolecular gel can be delayed until deployment in the body. Some examples of suitable diluents can include C2-C 12 alcohols. Some non-limiting examples of alcohols can include ethanol, benzyl alcohol, or mixtures thereof. The benefit of using ethanol or benzyl alcohol is that once the pharmaceutical composition (containing ethanol or benzyl alcohol) is deployed in the body, the ethanol or benzyl alcohol will diffuse in the aqueous environment, causing the viscosity of the pharmaceutical composition to increase and / or the complete formation of the supramolecular gel to occur.

[0066] In other aspects, the rheology modifier can increase the viscosity of the pharmaceutical composition. For example, if a particular combination of a lipophilic oil and a structuring agent interacts well together, or allows the desired drug to be sufficiently dispersed and diffused, but together does not provide a composition with sufficient viscosity, then this can be helpful. Incorporating a rheology modifier to increase the viscosity can make the pharmaceutical composition viable.

[0067] The pharmaceutical composition comprises an effective amount of a compound as described herein and optionally one or more other therapeutic agents in a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" means one or more compatible solid or liquid fillers, diluents, or encapsulating substances suitable for administration to humans or other vertebrates. The term "carrier" denotes a natural or synthetic organic or inorganic component with which the active ingredient is combined to facilitate its application. The components of the pharmaceutical composition can also be mixed with the compound and with each other in such a way that there are no interactions that would significantly impair the desired pharmaceutical efficacy.

[0068] 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 substance from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the composition, being non-harmful to the patient, and being substantially pyrogen-free. Some examples of materials that 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 wax; (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 glycerol, 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) ethanol; (20) phosphate buffer solution; and (21) other non-toxic compatible substances employed in pharmaceutical compositions. The pharmaceutical compositions of the present disclosure are pyrogen-free, i.e., they do not induce a significant temperature increase when administered to a patient.

[0069] The pharmaceutical compositions can be packaged in any suitable manner. For example, the pharmaceutical compositions can be packaged in cans, vessels, etc., such that the pharmaceutical compositions can be accessed and manually applied at the desired location. Alternatively, the pharmaceutical compositions can be configured in the dispensing chamber of a syringe. The syringe can have a needle sized at about 14 to about 30G, about 21 to about 25G, less than, equal to, or greater than about 14G, 15G, 16G, 17G, 18G, 19G, 20G, 21G, 22G, 23G, 24G, 25G, 26G, 27G, 28G, 29G, or 30G. Alternatively, the pharmaceutical compositions can be configured from the syringe without a needle (e.g., via a cone applicator).

[0070] The pharmaceutical composition can be prepared by: a) mixing a lipophilic oil with an analgesic, an anesthetic (or other drugs within the scope of the present disclosure) at a temperature above 25 °C with stirring to form a first mixture; b) mixing a structurant with the first mixture at a temperature above 25 °C with stirring and heating to form a second mixture; and c) cooling the second mixture to form the pharmaceutical composition.

[0071] As an example, the pharmaceutical composition can be prepared by: mixing a lipophilic oil and a drug at a temperature above room temperature (25 °C) with stirring to form a first mixture. For example, the temperature can be from about 50 °C to about 100 °C, from about 60 °C to about 80 °C, less than, equal to, or greater than about 50 °C, 55 °C, 60 °C, 65 °C, 70 °C, 75 °C, 80 °C, 85 °C, 90 °C, 95 °C or 100 °C. The structurant can be added to the first mixture at a temperature above room temperature (25 °C) with stirring and heating to form a second mixture. For example, the temperature can be from about 50 °C to about 100 °C, from about 60 °C to about 80 °C, less than, equal to, or greater than about 50 °C, 55 °C, 60 °C, 65 °C, 70 °C, 75 °C, 80 °C, 85 °C, 90 °C, 95 °C or 100 °C. Then the second mixture can be cooled to form the pharmaceutical composition. Before cooling the second mixture, it can be placed in a tank, vessel or syringe such that a supramolecular gel is formed therein.

[0072] The pharmaceutical composition and / or the tank, vessel or syringe can be sterilized at any time point during the preparation process. However, due to the stability of the pharmaceutical composition, sterilization can occur after the pharmaceutical composition is fully formed (e.g., after cooling). Sterilization can occur using any suitable technique (e.g., ultraviolet treatment, electron beam, x-ray, autoclaving, steam sterilization and dry heat sterilization).

[0073] In operation, the pharmaceutical composition can be administered to a subject. The pharmaceutical composition can be administered at or near an injury or wound or treatment site. An example of an injury or wound can include a surgical site. The pharmaceutical composition can be administered at a distance from the injury or wound. For example, the pharmaceutical composition can be administered to a specific location to block a nerve and thus block pain from a distant injury or wound. In the context of surgery, the pharmaceutical composition can be applied before surgery, during surgery (e.g., at any time before incision closure) or after surgery (e.g., after incision closure).

[0074] As used herein, the term "kit" refers to a package or a product in one or more separate packages (e.g., drugs, kit sets) that contains:

[0075] (i) A pharmaceutical composition comprising an active pharmaceutical ingredient and at least one additional active pharmaceutical ingredient and optionally a medical device. The at least one additional active pharmaceutical ingredient may be present in the pharmaceutical composition, i.e., the kit may comprise one or more packages, wherein each package contains a pharmaceutical composition comprising two or more active pharmaceutical ingredients. The additional active pharmaceutical ingredient may also be present in an additional pharmaceutical composition, i.e., the kit may comprise separate packages of two or more pharmaceutical compositions, wherein each pharmaceutical composition contains one active pharmaceutical ingredient.

[0076] Or

[0077] (ii) A pharmaceutical composition comprising an active pharmaceutical ingredient and a medical device.

[0078] The kit may comprise only one package, or may comprise one or more separate packages. For example, the kit may be a product (e.g., a drug) comprising two or more vials, each vial containing a defined pharmaceutical composition, wherein each pharmaceutical composition comprises at least one active pharmaceutical ingredient. For example, the kit may comprise: (i) a vial containing a defined pharmaceutical composition, and (ii) in addition, tablets, capsules, powders or any other oral dosage form containing at least one additional active pharmaceutical ingredient. The kit may also comprise a leaflet which describes how to administer the pharmaceutical composition and the at least one additional active pharmaceutical ingredient.

[0079] As used herein, the term "medical device" means any instrument, apparatus, implant, in vitro reagent or similar or related article used for diagnosing, preventing or treating a disease with other conditions, and which cannot achieve its purpose through pharmacological action in or on the body.

[0080] As used herein, the medical device may be a syringe, an insulin injection system, an insulin infusion system, an insulin pump or an insulin pen injection device. As used herein, the medical device may be mechanically or electromechanically driven.

[0081] The ingredients in the pharmaceutical composition can be defined as Generally Recognized as Safe (“GRAS”). The complete list of GRAS ingredients can be found in the GRAS Substances (SCOGS) Database maintained by the United States Food and Drug Administration. Approximately 50% to approximately 100% of the ingredients in the pharmaceutical composition can be classified as GRAS ingredients, approximately 75% to approximately 100%, approximately 90% to approximately 100%, less than, equal to, or greater than approximately 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or approximately 100% of the ingredients in the pharmaceutical composition can be classified as GRAS ingredients.

[0082] Examples

[0083] Aspects of the present disclosure can be better understood with reference to the examples provided by way of illustration below. The present disclosure is not limited to the examples given herein.

[0084] Table 1: Materials

[0085]

[0086] Glyceryl trilaurate Sigma Aldrich, St. Louis, MO Glyceryl tributyrate Acros Organics, Carlsbad, CA Bupivacaine free base Cayman Chemical, Ann Arbor, MI Sodium docusate MP Biomedicals, Santa Anna, CA Ropivacaine free base Alpha Aesar, Ward Hill, MA

[0087] Fifteen compositions were prepared. Each composition was prepared by heating medium-chain triglycerides to approximately 70 °C. A drug (bupivacaine free base, ropivacaine docusate or ropivacaine free base) was added to the heated medium-chain triglycerides and stored. Subsequently, a structurant (glyceryl trimyristate, glyceryl tripalmitate, glyceryl trilaurate or glyceryl monostearate) was added under heating and stirred until it was fully dissolved. The resulting solution was aspirated into a syringe, the air bubbles were removed, and the syringe was capped with an airtight seal. When the solution cooled to room temperature (approximately 25 °C), it spontaneously formed a supramolecular gel. The components of the fifteen compositions are provided in Tables 2 to 16 below. In Tables 2 to 16, the concentration values of the structurant and the drug for each composition are expressed as weight per volume (w / v) relative to the volume of the lipophilic oil.

[0088] Table 2: Composition 1

[0089] Function Component Concentration Lipophilic oil Medium-chain triglyceride Structuring agent Glyceryl monostearate 10% to 20% (w / v) Drug Bupivacaine free base 5% (w / v)

[0090] Table 3: Composition 2

[0091] Function Component Concentration Lipophilic oil Medium-chain triglyceride Structuring agent Glyceryl distearate 10% to 20% (w / v) Drug Bupivacaine free base 5% (w / v)

[0092] Table 4: Composition 3

[0093] Function Component Concentration Lipophilic oil Medium-chain triglyceride Structuring agent Glyceryl trimyristate 10% to 20% (w / v) Drug Bupivacaine free base 5% (w / v)

[0094] Table 5: Composition 4

[0095] Function Component Concentration Lipophilic oil Medium-chain triglyceride Structuring agent Glyceryl tripalmitate 5% to 20% (w / v) Drug Bupivacaine free base 5% (w / v)

[0096] Table 6: Composition 5

[0097] Function Component Concentration Lipophilic oil Medium-chain triglyceride Structuring agent Glyceryl monolaurate 10% to 20% (w / v) Drug Bupivacaine free base 5% (w / v)

[0098] Table 7: Composition 6

[0099] Function Component Concentration Lipophilic oil Medium-chain triglyceride Structuring agent Glyceryl monostearate 10% to 20% (w / v) Drug Ropivacaine docusate 5% (w / v)

[0100] Table 8: Composition 7

[0101] Function Component Concentration Lipophilic oil Medium-chain triglyceride Structuring agent Glyceryl distearate 10% to 20% (w / v) Drug Ropivacaine docusate 5% (w / v)

[0102] Table 9: Composition 8

[0103] Function Component Concentration Lipophilic oil Medium-chain triglyceride Structuring agent Glyceryl trimyristate 10% to 20% (w / v) Drug Ropivacaine docusate 5% (w / v)

[0104] Table 10: Composition 9

[0105] Function Component Concentration Lipophilic oil Medium-chain triglyceride Structuring agent Glyceryl tripalmitate 10% to 20% (w / v) Drug Ropivacaine docusate 5% (w / v)

[0106] Table 11: Composition 10

[0107] Function Component Concentration Lipophilic oil Medium-chain triglyceride Structuring agent Glyceryl monolaurate 10% to 20% (w / v) Drug Ropivacaine docusate 5% (w / v)

[0108] Table 12: Composition 11

[0109] Function Component Concentration Lipophilic oil Medium-chain triglyceride Lipophilic oil Glyceryl tributyrate 5% to 10% (w / v) Structuring agent Glyceryl monostearate 10% to 20% (w / v) Drug Ropivacaine free base 5% (w / v)

[0110] Table 13: Composition 12

[0111] Function Component Concentration Lipophilic oil Medium-chain triglyceride Lipophilic oil Glyceryl tributyrate 5% to 10% (w / v) Structuring agent Glyceryl distearate 10% to 15% (w / v) Drug Ropivacaine free base 5% (w / v)

[0112] Table 14: Composition 13

[0113] Function Component Concentration Lipophilic oil Medium-chain triglyceride Lipophilic oil Glyceryl tributyrate 5% to 10% (w / v) Structuring agent Glyceryl trimyristate 10% to 20% (w / v) Drug Ropivacaine free base 5% (w / v)

[0114] Table 15: Composition 14

[0115] Function Component Concentration Lipophilic oil Medium-chain triglyceride Lipophilic oil Glyceryl tributyrate 5% to 10% (w / v) Structurant Tripalmitin 10% to 25% (w / v) Drug Ropivacaine free base 5% (w / v)

[0116] Table 16: Composition 15

[0117] Function Component Concentration Lipophilic oil Medium-chain triglyceride Lipophilic oil Tributyrin 5% to 10% (w / v) Structurant Trilaurin 10% to 15% (w / v) Drug Ropivacaine free base 5% (w / v)

[0118] Table 17: Composition 15

[0119] Function Component Concentration Lipophilic oil Medium-chain triglyceride Lipophilic oil Castor oil 10% to 50% (w / v) Structurant Tristearin 3% to 15% (w / v) Drug Bupivacaine free base 5% (w / v)

[0120] Table 18: Composition 15

[0121] Function Component Concentration Lipophilic oil Medium-chain triglyceride - Lipophilic oil Castor oil 10% to 50% (w / v) Structurant Tripalmitin 10% to 15% (w / v) Drug Bupivacaine free base 5% (w / v)

[0122] Table 19: Composition 15

[0123] Function Component Concentration Lipophilic oil Medium-chain triglyceride Lipophilic oil Castor oil 10% to 50% (w / v) Structurant Tristearin 3% to 15% (w / v) Drug Bupivacaine oleate 5% (w / v)

[0124] Example 2

[0125] The ability of an MCT-only formulation containing bupivacaine free base and MCT oil, and an oleogel formulation containing bupivacaine free base, MCT oil (lipophilic oil), and glyceryl monostearate (structurant) to release bupivacaine free base over time was investigated. As Figure 1 shown, the release of bupivacaine free base was slower in the oleogel formulation.

[0126] The controlled release of the formulation was evaluated by placing 0.5 mL of the formulation in a dialysis bag (10 kDa) and immersing it in a 50 mL bath of phosphate buffered saline (1×; pH 7.4). The sample was placed in a rotary incubator (1 Hz) at 37 °C. At specified time points, 2 mL of the saline was removed and analyzed using ultraviolet-visible spectrophotometry (272 nm). The entire bath medium was replaced at each time point until no more drug eluted from the system.

[0127] Example 3

[0128] The drug release over time of an oleogel formulation containing bupivacaine free base, MCT oil, and glyceryl monostearate (structurant), and an oleogel formulation containing bupivacaine free base, a lipophilic oil mixture consisting of 75 wt% MCT oil and 25 wt% castor oil, and glyceryl monostearate (structurant) was investigated.

[0129] As shown in Figure 2 the release of bupivacaine free base was slower in the formulation containing a mixture of 75 wt% MCT oil and 25 wt% castor oil. The drug release curve was measured according to the protocol of Example 2.

[0130] Example 4

[0131] The viscosities of various oils used in the formulations described herein at 37 °C were investigated. The oils studied included castor oil, MCT oil, and blends of both castor oil and MCT oil (e.g., 50%, 40%, 30%, and 20% castor oil, balance MCT). As shown in Figure 3As shown, the viscosity of the blend of MCT:castor oil is significantly lower than that of castor oil alone and is closer to the viscosity value of MCT alone. Given that the drug solubility of bupivacaine and other local anesthetics in castor oil is higher than that in MCT, blending these two oils can achieve both good drug solubility (and thus, good drug loading capacity) and a low viscosity suitable for injection. For example, these properties mean that 30% to 50% castor oil can be included to obtain higher drug loading and slower drug release without significantly changing the base viscosity of the oil.

[0132] A rheometer was used to measure the rheological properties of each formulation. Using a 35 mm parallel plate with a 0.5 mm gap, approximately 0.5 mL of the formulation was injected onto the rheometer plate through an 18G needle for analysis. A rotational ramp test was performed at 20 °C, and a ramp was made between shear rates of 1 to 200 Hz to obtain a viscosity curve.

[0133] Example 5

[0134] The viscosity of a formulation containing 25 wt% castor oil and 20 wt% structuring agent at 37 °C was measured. The structuring agent included monostearate, monopalmitate, and their blends. Figure 4 The effect of viscosity with changing the weight % of monostearate in the mixture of monostearate and monopalmitate is shown. As shown, formulations with only monostearate or only monopalmitate were significantly weaker than gels made from blends of the two. Viscosity was measured according to the protocol of Example 4.

[0135] Example 6

[0136] The shear rate of a formulation containing 25% monostearate & monopalmitate, 100% MCT, and 5% bupivacaine was studied. As Figure 5 shown, the viscosity curve shows that the viscosity decreases with increasing shear rate. This property can be called "shear thinning", which means that the formulation improves injectability and produces in-situ gelation. Viscosity was measured according to the protocol of Example 4.

[0137] Example 7

[0138] The viscosity of a formulation containing MCT (60:40 monostearate:monopalmitate mixture ("GMSP") and bupivacaine free base) at 20 °C and 37 °C (to simulate body temperature) was measured. As Figure 6 shown, a gel strong enough can be obtained. Viscosity was measured according to the protocol of Example 4.

[0139] Example 8

[0140] Rheograms using different structuring agents are shown here. Figures 7A to 7DShows how some formulations significantly weaken at 37 °C. If the gel disintegrates when placed at 37 °C, then it becomes less useful as an injectable depot sustained release drug delivery system. Viscosity was measured according to the protocol of Example 4. The crossover point and the average storage modulus (G’) in the linear viscoelastic region were then obtained from the software and further analyzed.

[0141] Example 9

[0142] The DSC melting and crystallization temperatures are shown in Tables 20 and 21, respectively. As shown, GMS has a melting peak and a crystallization peak above 37 °C. Among the foregoing rheograms ( Figures 7A to 7D ), those are the highest obtained from all the gelling agents. The above results are supported. The GMSP gel is more thermally stable, making it more useful.

[0143] Table 20

[0144]

[0145] Table 21

[0146]

[0147] In Tables 20 and 21:

[0148] GMS = glyceryl monostearate

[0149] PMF = polyglycerol ester of fatty acids (fatty acids with 18C length)

[0150] TM = glyceryl trimyristate

[0151] TP = glyceryl tripalmitate

[0152] Example 10

[0153] Figure 8A and 8B shows the peak melting and peak crystallization characteristics of various formulations. The thermal properties of the organogels (e.g., lipophilic oils and structuring agents) were determined using differential scanning calorimetry (DSC). At room temperature, approximately 25 mg of the organogel was loaded into a standard aluminum crucible (25 μL) with a center-punched lid. The sample was heated from 20 °C to 100 °C at a scan rate of 10 °C / minute, then subsequently held isothermally at 100 °C for 5 minutes and then cooled to -20 °C.

[0154] The peak temperature and the enthalpy of melting or the area under the curve were obtained using this method.

[0155] Example 11

[0156] Figure 9A and 9B shows the rat sciatic nerve block data. Figure 9B shows the same data as Figure 9A but with different y-axis and x-axis values. As shown, bupivacaine in the oil gel has the longest-lasting effect. More importantly, the oil gel has a longer-lasting effect than MCT oil without a structuring agent, and both of them have the same dose of bupivacaine. By turning the oil into a gel, the release of the drug in the body is greatly prolonged.

[0157] This longitudinal experiment, in which seventeen male CD Sprague Dawley rats weighing 360 to 420 grams underwent sciatic nerve block under one of the following four different treatments: 0.3 mL of 0.5% bupivacaine HCl (1.5 mg bupivacaine), 0.3 mL of 1.33% liposomal bupivacaine (4 mg bupivacaine), 0.2 mL of 5% bupivacaine in MCT oil (10 mg bupivacaine), or 0.2 mL of 5% bupivacaine oil gel (w / v) (bupivacaine / oil gel) (10 mg bupivacaine) using 20% GMS (w / v) (GMS / MCT). Each group contained 5 animals except for the 0.5% bupivacaine HCl group, which contained 2 animals because the anesthetic effect of bupivacaine HCl was well understood. Once the animals recovered from the surgery, they were moved into individual acrylic enclosures on a heated transparent glass surface to undergo the Hargreaves pain assay.

[0158] Method for Hargreaves: At the designated time points, noxious heat was applied to the mid-plantar part of the right hind paw and manually turned off when the paw withdrew. The paw withdrawal latency was measured three times for each animal at each time point and averaged.

[0159] Example 12

[0160] Figure 10 is a graph showing the pig potency data. Alevatrix 001 = 100% MCT. Alevatrix 002 = 75:25 MCT:castor oil. The 002 castor blend group shows a better bupivacaine release curve.

[0161] Thirty pigs weighing 10 to 13 kg each were subjected to subcutaneous injection of each preparation. At the designated time points, the von Frey method was performed at approximately 0.5 cm from the injection site. Among them, filaments with increasing diameters were applied in ascending order until a withdrawal response was observed, where the filament of 60 g force was the maximum. The withdrawal response was considered as a movement away from the stimulus - either by leaving or by wriggling the flank away. After the operation, if the flank withdrawal force ≤ 8 g, pain (allodynia) was considered to be present.

[0162] Treatment group (n = 6); the administration volume of the low dose (L) was 2.5 mL. The administration volume of the high dose (H) was 5 mL.

[0163] Example 13

[0164] The solubility of bupivacaine in a blend of MCT oil and castor oil was investigated. As Figure 11 shown, in the case of a specific blend of oils, the drug loading is increased and the drug release is also slowed down because the drug has a higher affinity for the oil blend. The higher the drug affinity, the higher the drug loading and the slower the release. The maximum solubility of the oil blend was determined by adding 300 mg of bupivacaine free base to 3 mL of the MCT:castor oil mixture. The mixture was rotated overnight on a nutating shaker in an oven at 37 °C to achieve complete dissolution. After rotation, the sample was centrifuged at 2000 × g for 5 minutes. Next, 30 μL of the sample supernatant was taken and dissolved in 1470 μL of ethanol, and analyzed using ultraviolet-visible spectrophotometry (272 nm).

[0165] Example 14

[0166] Figure 12 shown the solubility of bupivacaine in a preparation containing MCT oil and glyceryl monostearate as a structuring agent in the presence and absence of anions (shown on the x-axis of Figure 12 ). As shown, docusate increased the solubility of bupivacaine. The solubility was determined according to the protocol of Example 13.

[0167] Example 15

[0168] shown the release of bupivacaine in a preparation containing MCT oil and glyceryl monostearate as a structuring agent in the presence and absence of anions (for increasing hydrophobicity). As Figure 13As shown, the release of bupivacaine with polyethylene glycol 15 hydroxystearate is prolonged. The controlled release of the formulation was evaluated by placing 0.5 mL of the formulation in a dialysis bag (10 kDa) and immersing it in a 50 mL bath of phosphate buffered saline (1×; pH 7.4). The sample was placed in a rotary incubator (1 Hz) at 37°C. At the designated time points, 2 mL of the saline was removed and analyzed using ultraviolet-visible spectrophotometry (272 nm). The entire bath medium was replaced at each time point until no more drug eluted from the system.

[0169] The terms and expressions that have been employed are used as descriptive terms and not as restrictive terms, and it is not intended to use such terms and expressions to exclude any equivalents or portions thereof of the features shown and described, but rather it should be recognized that various modifications are possible within the scope of the aspects of the present disclosure. Accordingly, it is to be understood that although the present disclosure has been specifically disclosed by specific aspects and optional features, those of ordinary skill in the art can utilize modifications and variations of the concepts disclosed herein, and such modifications and variations are considered to be within the scope of the aspects of the present disclosure.

[0170] Exemplary aspects

[0171] The following exemplary aspects are provided, and the numbers should not be construed as indicating a level of importance:

[0172] Aspect 1 provides a pharmaceutical composition comprising:

[0173] a lipophilic oil;

[0174] a therapeutic agent, a salt thereof, an ion pair thereof, or a prodrug thereof dispersed in the lipophilic oil; and

[0175] a structuring agent, at least a portion of which is insoluble in the lipophilic oil and forms a gel.

[0176] Aspect 2 provides the pharmaceutical composition according to aspect 1, wherein the lipophilic oil comprises a monoglyceride, a diglyceride, a triglyceride, a medium-chain triglyceride oil, a sesame oil, a soybean oil, a castor oil, a vegetable oil, a tributyrin oil, or a mixture thereof.

[0177] Aspect 3 provides the pharmaceutical composition according to aspect 2, wherein the triglyceride is a saturated triglyceride, a monounsaturated triglyceride, or a polyunsaturated triglyceride.

[0178] Aspect 4 provides the pharmaceutical composition according to aspect 2, wherein the triglyceride comprises a medium-chain triglyceride, a short-chain triglyceride, a long-chain triglyceride, or a mixture thereof.

[0179] Aspect 5 provides the pharmaceutical composition described in Aspect 4, wherein the triglyceride comprises medium-chain triglycerides.

[0180] Aspect 6 provides the pharmaceutical composition described in Aspect 5, wherein the medium-chain triglycerides comprise glycerides of C6-C12 carboxylic acids or mixtures thereof.

[0181] Aspect 7 provides the pharmaceutical composition described in Aspect 1, wherein the melting point of the structurant is from about 40 °C to about 100 °C.

[0182] Aspect 8 provides the pharmaceutical composition described in Aspect 7, wherein the melting point of the structurant is from about 50 °C to about 85 °C.

[0183] Aspect 9 provides the pharmaceutical composition described in Aspect 8, wherein the melting point of the structurant is from about 60 °C to about 70 °C.

[0184] Aspect 10 provides the pharmaceutical composition described in Aspect 1, wherein the structurant comprises monoglycerides, diglycerides, triglycerides, polyglycerol esters of fatty acids, or mixtures thereof.

[0185] Aspect 11 provides the pharmaceutical composition described in Aspect 1, wherein the structurant comprises glyceryl tristearate, glyceryl distearate, glyceryl monostearate, glyceryl dibehenate, cholesterol, glyceryl trimyristate, glyceryl dimyristate, glyceryl monomyristate, glyceryl trilaurate, glyceryl dilaurate, glyceryl monolaurate, glyceryl tripalmitate, glyceryl dipalmitate, glyceryl monopalmitate, cholesterol, polyglycerol esters of fatty acids, polyglycerols of fatty acids, or mixtures thereof.

[0186] Aspect 12 provides the pharmaceutical composition described in Aspect 11, wherein the structurant comprises glyceryl monostearate, glyceryl distearate, glyceryl tristearate, glyceryl monopalmitate, glyceryl dipalmitate, glyceryl tripalmitate, glyceryl monomyristate, glyceryl dimyristate, glyceryl trimyristate, or mixtures thereof.

[0187] Aspect 13 provides the pharmaceutical composition described in Aspect 1, wherein based on the volume of the lipophilic oil, the structurant is present in the pharmaceutical composition at a concentration of from about 0.1% (w / v) to about 25% (w / v).

[0188] Aspect 14 provides the pharmaceutical composition described in Aspect 13, wherein based on the volume of the lipophilic oil, the structurant is present in the pharmaceutical composition at a concentration of from about 3% (w / v) to about 20% (w / v).

[0189] Aspect 15 provides the pharmaceutical composition described in aspect 13, wherein, based on the volume of the lipophilic oil, the structurant is present in the pharmaceutical composition at a concentration of from about 3% (w / v) to about 10% (w / v).

[0190] Aspect 16 provides the pharmaceutical composition described in aspect 1, wherein the therapeutic agent comprises an analgesic, anesthetic, anti-inflammatory agent, sympathetic nerve blocker, anxiolytic, cannabinoid, or a mixture thereof dispersed in the lipophilic oil.

[0191] Aspect 17 provides the pharmaceutical composition described in aspect 16, wherein the analgesic, anesthetic, or both are present in an amount sufficient to relieve pain in a subject.

[0192] Aspect 18 provides the pharmaceutical composition described in aspect 17, wherein the pharmaceutical composition comprises the analgesic.

[0193] Aspect 19 provides the pharmaceutical composition described in aspect 18, wherein the analgesic comprises a non-steroidal anti-inflammatory drug, a COX-2 inhibitor, or a mixture thereof.

[0194] Aspect 20 provides the pharmaceutical composition described in aspect 19, wherein the non-steroidal anti-inflammatory drug comprises ibuprofen, naproxen, diclofenac, mefenamic acid, indomethacin, cannabidiol, its ion pair, its salt, or a mixture thereof.

[0195] Aspect 21 provides the pharmaceutical composition described in aspect 19, wherein the COX-2 inhibitor comprises etoricoxib, meloxicam, celecoxib, its ion pair, its salt, or a mixture thereof.

[0196] Aspect 22 provides the pharmaceutical composition described in aspect 1, wherein the pharmaceutical composition comprises an anesthetic, and the anesthetic is a local anesthetic.

[0197] Aspect 23 provides the pharmaceutical composition described in aspect 22, wherein the anesthetic comprises an ester-based local anesthetic, an amide-based local anesthetic, or a prodrug thereof, or an ion pair thereof, or a salt thereof, or a mixture thereof.

[0198] Aspect 24 provides the pharmaceutical composition described in aspect 23, wherein the ester-based local anesthetic comprises procaine, amethocaine, benzocaine, tetracaine, or a prodrug thereof, or an ion pair thereof, or a salt thereof, or a mixture thereof.

[0199] Aspect 25 provides the pharmaceutical composition described in aspect 23, wherein the amide-based local anesthetic comprises lidocaine, prilocaine, bupivacaine, levobupivacaine, ropivacaine, mepivacaine, dibucaine, etidocaine, a prodrug thereof, or an ion pair thereof, or a salt thereof, or a mixture thereof.

[0200] Aspect 26 provides the pharmaceutical composition described in aspect 25, wherein the amide-based anesthetic comprises bupivacaine, ropivacaine, its salts, its ion pairs, or mixtures thereof.

[0201] Aspect 27 provides the pharmaceutical composition described in aspect 26, wherein the amide-based local anesthetic is an ion pair or a salt, which comprises bupivacaine butyrate, bupivacaine palmitate, bupivacaine laurate, bupivacaine myristate, bupivacaine stearate, hydroxybupivacaine stearate, bupivacaine oleate, bupivacaine ricinoleate, bupivacaine docusate.

[0202] Aspect 28 provides the pharmaceutical composition described in aspect 1, wherein the pharmaceutical composition comprises a mixture of an analgesic, an anesthetic, and an anti-inflammatory agent.

[0203] Aspect 29 provides the pharmaceutical composition described in aspect 1, wherein the pharmaceutical composition comprises a mixture of an analgesic and an anesthetic.

[0204] Aspect 30 provides the pharmaceutical composition described in aspect 1, wherein based on the volume of the lipophilic oil, the analgesic, the anesthetic, or both are present at a concentration of about 2% (w / v) to about 15% (w / v).

[0205] Aspect 31 provides the pharmaceutical composition described in aspect 30, wherein based on the volume of the lipophilic oil, the analgesic, the anesthetic, or both are present at a concentration of about 3% (w / v) to about 10% (w / v).

[0206] Aspect 32 provides the pharmaceutical composition described in aspect 1, wherein the anti-inflammatory agent comprises aspirin, celecoxib, diclofenac, diflunisal, etodolac, ibuprofen, indomethacin, ketoprofen, ketorolac, nabumetone, naproxen, oxaprozin, piroxicam, diacetylsalicylic acid, sulindac, tolmetin, cannabidiol, its salts, its ion pairs, or mixtures thereof.

[0207] Aspect 33 provides the pharmaceutical composition described in aspect 1, which further comprises excipients.

[0208] Aspect 34 provides the pharmaceutical composition described in aspect 33, wherein the excipients comprise corticosteroids, α-2-agonists, pethidine, barbiturates, opiates, tubocurarine chloride, cannabinoids, meloxicam, its salts, or its ion pairs, or mixtures thereof.

[0209] Aspect 35 provides the pharmaceutical composition described in aspect 34, wherein the cannabinoid is cannabidiol (CBD).

[0210] Aspect 36 provides the pharmaceutical composition described in aspect 33, wherein the pharmaceutical composition uses a lower concentration of an analgesic, anesthetic, anti-inflammatory agent, or a mixture thereof compared to the corresponding pharmaceutical composition without the excipient to effectively relieve pain in a subject, and / or has a longer-lasting pain relief effect.

[0211] Aspect 37 provides the pharmaceutical composition described in aspect 1, which further comprises a rheology modifier containing a C2-C12 alcohol.

[0212] Aspect 38 provides the pharmaceutical composition described in aspect 37, wherein the rheology modifier comprises ethanol, benzyl alcohol, or a mixture thereof.

[0213] Aspect 39 provides the pharmaceutical composition described in aspect 38, wherein the C2-C12 alcohol comprises ethanol, benzyl alcohol, or a mixture thereof, and based on the volume of the lipophilic oil, the C2-C12 alcohol is present in the pharmaceutical composition at about 0.5% (w / v) to about 10% (w / v).

[0214] Aspect 40 provides the pharmaceutical composition described in aspect 39, wherein based on the volume of the lipophilic oil, the ethanol, benzyl alcohol, or a mixture thereof is present in the pharmaceutical composition at about 1% (w / v) to about 6% (w / v).

[0215] Aspect 41 provides the pharmaceutical composition described in aspect 1, wherein the duration of effective pain relief of the pharmaceutical composition in a subject is about 24 hours to about 14 days.

[0216] Aspect 42 provides the pharmaceutical composition described in aspect 1, wherein the duration of effective pain relief of the pharmaceutical composition in a subject is about 48 hours to about 96 hours.

[0217] Aspect 43 provides the pharmaceutical composition described in aspect 1, wherein the duration of effective pain relief of the pharmaceutical composition in a subject is about 96 hours to about 168 hours.

[0218] Aspect 44 provides the pharmaceutical composition described in aspect 1, wherein the duration of effective pain relief of the pharmaceutical composition in a subject is about 168 hours to about 336 hours.

[0219] Aspect 45 provides the pharmaceutical composition described in aspect 1, wherein the pharmaceutical composition is a semi-solid composition.

[0220] Aspect 46 provides a pharmaceutical composition comprising:

[0221] medium-chain triglycerides;

[0222] castor oil;

[0223] An anesthetic agent, which comprises bupivacaine, its ion pair, or its salt, or both, and is present in an amount sufficient to relieve pain in a subject, and is dispersed in the medium-chain triglyceride and castor oil mixture; and

[0224] A structurant, which comprises glyceryl tristearate, glyceryl distearate, glyceryl monostearate, glyceryl dibehenate, cholesterol, glyceryl trimyristate, glyceryl dimyristate, glyceryl monomyristate, glyceryl trilaurate, glyceryl dilaurate, glyceryl monolaurate, glyceryl tripalmitate, glyceryl dipalmitate, glyceryl monopalmitate, cholesterol, polyglycerol esters of fatty acids, polyglycerol esters of fatty acids, or mixtures thereof, wherein

[0225] Optionally, the wt:wt ratio of the medium-chain triglyceride to castor oil is about 50:50.

[0226] Aspect 47 provides the pharmaceutical composition according to aspect 1, wherein when measured at about 37 °C, the viscosity of the composition is about 10,000 cP to about 1,000,000 cP.

[0227] Aspect 48 provides the pharmaceutical composition according to aspect 1, wherein when measured at about 37 °C, the viscosity of the composition is about 10,000 cP to about 150,000 cP.

[0228] Aspect 49 provides the pharmaceutical composition according to aspect 1, wherein after shearing, when measured at about 37 °C, the viscosity of the composition is about 10 cP to about 10,000 cP.

[0229] Aspect 50 provides the pharmaceutical composition according to aspect 1, wherein after shearing, the viscosity is reduced by shear-thinning behavior so as to be injectable.

[0230] Aspect 51 provides a kit, which comprises:

[0231] A syringe; and

[0232] The pharmaceutical composition according to aspect 1, which is configured within the syringe.

[0233] Aspect 52 provides the kit according to aspect 51, wherein the pharmaceutical composition is sealed within the syringe.

[0234] Aspect 53 provides the kit according to aspect 51, wherein the syringe further comprises a needle sized about 15 to 30G.

[0235] Aspect 54 provides the kit according to aspect 53, wherein the syringe comprises a needle sized about 21 to about 25G.

[0236] Aspect 55 provides a method for preparing the pharmaceutical composition described in aspect 1, the method comprising:

[0237] a) mixing a lipophilic oil and an analgesic and anesthetic at a temperature above 25°C with stirring and heating to form a mixture;

[0238] b) cooling the mixture to form the pharmaceutical composition.

[0239] Aspect 56 provides the method according to aspect 55, wherein the mixing in a) is carried out at a temperature of about 50°C to about 150°C.

[0240] Aspect 57 provides the method according to aspect 56, wherein in b) the mixture is placed in a sealed syringe for cooling.

[0241] Aspect 58 provides the method according to aspect 57, which further comprises sterilizing the pharmaceutical composition.

[0242] Aspect 59 provides the method according to aspect 58, wherein the sterilization occurs after the pharmaceutical composition is distributed in a container and after the pharmaceutical composition is sterilized, wherein the sterilization comprises gamma irradiation, electron beam irradiation, x-ray irradiation, heat sterilization, steam sterilization, or a combination of these.

[0243] Aspect 60 provides a method for treating a subject with the pharmaceutical composition described in aspect 1, which comprises administering the pharmaceutical composition to the subject in need thereof.

[0244] Aspect 61 provides the method according to aspect 60, wherein the pharmaceutical composition is administered to the subject at or near the surgical site.

[0245] Aspect 62 provides the method according to aspect 61, wherein the pharmaceutical composition is administered to the subject at or near the wound.

[0246] Aspect 63 provides the method according to aspect 62, wherein the pharmaceutical composition is administered to the subject at a site near the wound.

[0247] Aspect 64 provides the method according to aspect 63, wherein the site near the wound is a site where the nerve is blocked.

[0248] Aspect 65 provides the method according to aspect 61, wherein a first portion of the pharmaceutical composition is administered to the subject at or near the wound, and a second portion of the pharmaceutical composition is administered to the subject at a site near the wound.

[0249] Aspect 66 provides the method as described in aspect 61, wherein administering the pharmaceutical composition comprises injecting the pharmaceutical composition through a needle sized from about 18 to 30G by a syringe, applying the pharmaceutical composition at or near a wound or surgical site, or a combination thereof.

[0250] Aspect 67 provides the method as described in aspect 62, wherein the pharmaceutical composition is administered to the subject before, during, or after the subject has undergone surgery.

[0251] Aspect 68 provides the method as described in aspect 67, further comprising administering a non-opioid analgesic to the subject 48 to 120 hours after administering the pharmaceutical composition to the subject.

[0252] Aspect 69 provides the method as described in aspect 68, further comprising administering a non-opioid analgesic to the subject 72 to 120 hours after administering the pharmaceutical composition to the subject.

[0253] Throughout this document, values expressed in a range format should be interpreted in a flexible manner to include not only the explicitly recited values as the limits of the range, but also all individual values or sub-ranges subsumed within that range as if each value and sub-range were 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 only about 0.1% to about 5%, but also the individual values (e.g., 1%, 2%, 3%, and 4%) and sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range. Unless otherwise indicated, the expression "about X to Y" has the same meaning as "about X to about Y". Similarly, unless otherwise indicated, the expression "about X, Y, or about Z" has the same meaning as "about X, about Y, or about Z".

[0254] In this document, unless the context clearly dictates otherwise, a noun without a quantifier is used to include one or more. Unless otherwise indicated, the term "or" is used to refer to a non-exclusive "or". The expression "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". Additionally, it should be understood that the wording or terms used herein and not otherwise defined are for descriptive purposes only and not for purposes of limitation. The use of any section heading is intended to assist in reading the document and not to be construed as restrictive; information related to a section heading may appear within or outside of that particular section.

[0255] In the methods described herein, unless a time or order of operations is explicitly recited, acts can be performed in any order without departing from the principles of the disclosure. Further, unless the explicit claim language recites the acts separately, they can be performed concurrently. For example, the claimed act of performing X and the claimed act of performing Y can be performed concurrently in a single operation, and the resulting process will fall within the literal scope of the claimed process.

[0256] As used herein, the term "about / approximately" can permit a degree of variability of a value or range, e.g., within 10%, 5%, or 1% of the value or the range limit, and includes the exact value or range. The term "substantially" as used herein means mostly or most, such as 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 greater, or 100%. The term "substantially free of" as used herein can mean having none or having a trace amount such that the amount of the material present does not affect the material properties of the composition containing the material, such that the composition is about 0 wt% to about 5 wt%, 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 wt%, 3.5 wt%, 3 wt%, 2.5 wt%, 2 wt%, 1.5 wt%, 1 wt%, 0.9 wt%, 0.8 wt%, 0.7 wt%, 0.6 wt%, 0.5 wt%, 0.4 wt%, 0.3 wt%, 0.2 wt%, 0.1 wt%, 0.01 wt%, or about 0.001 wt% or less, or about 0 wt% of the material.

Claims

1. An injectable pharmaceutical composition comprising: 3 wt% to 7 wt% of bupivacaine in the pharmaceutical composition; 40 wt% to 45 wt% of medium-chain triglyceride oil in the pharmaceutical composition; 40 wt% to 45 wt% of castor oil in the pharmaceutical composition; 0.5 wt% to 6 wt% of glyceryl tristearate in the pharmaceutical composition, wherein the pharmaceutical composition does not contain a rheology modifier, and the wt:wt ratio of the medium-chain triglyceride to the castor oil is 50:

50.

2. The injectable pharmaceutical composition according to claim 1, wherein the injectable pharmaceutical composition is a nerve block composition.

3. A kit comprising: a syringe containing a needle sized 15G to 30G; and the injectable pharmaceutical composition according to claim 1, which is configured and sealed within the syringe.

4. A method of preparing the pharmaceutical composition according to claim 1, the method comprising: a) mixing bupivacaine, medium-chain triglyceride oil, castor oil, and glyceryl tristearate, an anesthetic agent, at a temperature above 25°C and up to 150°C with stirring and heating to form a mixture; b) placing the mixture into a sealed syringe and cooling the mixture to form the pharmaceutical composition; and c) sterilizing the pharmaceutical composition, wherein sterilization occurs after the pharmaceutical composition is placed into the sealed syringe, wherein sterilization comprises gamma irradiation, electron beam irradiation, x-ray irradiation, heat sterilization, steam sterilization, or a combination thereof.

5. Use of the pharmaceutical composition according to claim 1 in the preparation of a medicament for treating pain in a subject in need thereof, wherein the medicament is formulated for: administering the pharmaceutical composition to the subject before, during, or after the subject has undergone surgery, and administering the pharmaceutical composition comprises injecting the pharmaceutical composition through a syringe through a needle sized 18G to 30G at or adjacent to a wound or surgical site.

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