Pharmaceutical composition for treating pain

Abstract

An injectable or implantable composition is provided that is sufficiently viscous to be injectable and manually implanted at a surgical site, remains at the site of administration long enough to provide a local anesthetic effect, and is capable of providing a potent analgesic effect for 2-14 days.SOLUTION: An injectable pharmaceutical composition is provided that includes an analgesic, anesthetic, anti-inflammatory agent, or mixture thereof dispersed in a lipophilic oil, and may include a structuring agent that is at least partially insoluble in the lipophilic oil and forms a gel.SELECTED DRAWING: Figure 1

Description

[Background technology]

[0001] Local anesthetics are widely used in surgery to anesthetize the surgical site and reduce postoperative pain, but their short duration of action means they cannot provide pain relief for the duration of the patient's severe pain. Once the anesthesia wears off, opioid drugs are administered to suppress the pain, which usually lasts for three days or more before the pain can be controlled with less effective painkillers. Summary of the Invention

[0002] The problem that the present disclosure seeks to solve is to provide an injectable or implantable composition that is viscous enough to be injectable and manually implanted at a surgical site, that remains at the administration site long enough to provide a local anesthetic effect, and that can provide potent analgesic effects for 2 to 14 days. lipophilic oil, a drug, its salt, or prodrug (e.g., an analgesic, an anesthetic, an anti-inflammatory, or a mixture thereof) dispersed in the lipophilic oil; and a structuring agent at least partially insoluble in said lipophilic oil and forming a gel; The present invention relates to a pharmaceutical composition comprising:

[0003] The present disclosure also provides medium chain triglycerides, an anesthetic agent comprising bupivacaine, ropivacaine, or both, present in an amount sufficient to relieve pain in a subject and dispersed about the medium-chain triglycerides; and structuring agents including tristearin, glyceryl distearate, glycerol monostearate, glyceryl dibehenate, cholesterol, trimyristin, glyceryl dimyristin, glyceryl monomyristin, trilaurin, glyceryl dilaurin, glyceryl monolaurin, tripalmitin, glyceryl dipalmitin, glyceryl monopalmitin, cholesterol, polyglyceride esters of fatty acids, polyglycerol esters of fatty acids, or mixtures thereof; The present invention relates to a pharmaceutical composition comprising:

[0004] The present disclosure provides: syringes, and a pharmaceutical composition of the present disclosure disposed within said syringe; The present invention relates to a kit comprising:

[0005] The present disclosure also relates to a method for producing a pharmaceutical composition, said method comprising: a) mixing a lipophilic oil and an analgesic, an anesthetic agent with stirring at a temperature above 25°C to form a first mixture; b) mixing a structuring agent with the first mixture with stirring and heating at a temperature above 25°C to form a second mixture; and c) cooling the second mixture to form a pharmaceutical composition. Includes.

[0006] The present disclosure relates to a method of treating a subject with a composition of the present disclosure, comprising administering the composition to a subject in need thereof. [Brief explanation of the drawings]

[0007] The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments of the present disclosure. [Figure 1] 1 is a graph showing the drug release profile of various oils. [Figure 2] 1 is a graph showing the drug release profile of various oils. [Figure 3] 1 is a graph showing the viscosity of various oils. [Figure 4] 1 is a graph showing the effect of changes in oil components on viscosity. [Figure 5] 1 is a graph showing viscosity curves of various formulations. [Figure 6] 1 is a graph showing the viscosity of the formulation at body temperature. [Figure 7] 7A-7D are a series of graphs showing storage modulus values ​​for various formulations. [Figure 8A] 1 is a graph showing the peak melting profiles of various formulations. [Figure 8B] 1 is a graph showing peak crystallization profiles of various formulations. [Figure 9A] 1 is a graph showing rat sciatic nerve block data for various formulations. [Figure 9B] 1 is a graph showing rat sciatic nerve block data for various formulations. [Figure 10] 1 is a graph showing efficacy data for various formulations in a porcine incision wound model. [Figure 11] 1 is a graph showing the solubility of bupivacaine in various mixtures of MCT oil and castor oil. [Figure 12] 1 is a graph showing the solubility of bupivacaine and various lipophilic salts of bupivacaine in MCT oil. [Figure 13] 1 is a graph showing the release profile of bupivacaine and various lipophilic salts of bupivacaine in MCT oil. DETAILED DESCRIPTION OF THE INVENTION

[0008] Detailed Description of Disclosure 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 illustrated subject matter is not intended to limit the claims to the disclosed subject matter.

[0009] The present disclosure relates to pharmaceutical compositions comprising a lipophilic oil component; a therapeutic agent dispersed in the lipophilic oil component, or a mixture thereof; and a structuring agent, at least a portion of which is insoluble in the lipophilic oil. These components can form a semi-solid oleogel consisting of the lipophilic oil containing the drug entrapped within a supramolecular network of self-assembled structures, such as molecular aggregates or crystals. The pharmaceutical compositions can be used for pain control in both human and veterinary medicine. Clinical applications include, but are not limited to, neuraxial, regional, and local anesthesia for the treatment of pain associated with surgery, post-operative, and trauma, as well as local infiltration anesthesia for myofascial pain (e.g., trigger point pain) and chronic pain.

[0010] The pharmaceutical compositions described herein can be used for postoperative pain control as a replacement for opioid-containing medications used for postoperative pain control. The described pharmaceutical compositions can be a complete substitute for opioid-containing medications, or can be used in combination with opioid-containing medications to reduce the amount of opioids used for postoperative pain control.

[0011] The composition can take the form of an injectable semi-solid gel, paste, or implantable solid. In semi-solid gel or paste form, the composition can be applied to the surgical site / wound, and its viscosity allows the gel to remain in place where initially applied. Upon closure of the surgical site / wound, the semi-solid gel penetrates natural crevices and seeps into the compressed tissues. The self-assembled supramolecular network generated by the structuring agent prevents the drug-oil phase from migrating from the administration site, thereby promoting safer and more effective localized treatment. The structuring agent network also protects the drug-laden oil from the surrounding in vivo environment (e.g., the surrounding aqueous in vivo environment), allowing for extended drug release via diffusion from the oil into the aqueous environment. The composition can be biodegradable, allowing for natural absorption by the body over time.

[0012] Depending on the concentration and inherent properties of the structuring agent, compositions can be tailored to have a variety of mechanical properties. Tailoring mechanical properties is relevant to the development of long-acting local anesthetic products, which represent an improvement over many currently clinically available technologies. If the mechanical properties are too rigid, the composition cannot be injected through small-bore needles (e.g., >23 gauge) and can only be implanted manually into the surgical wound. Some long-acting local anesthetic products for postoperative pain require optimized mechanical properties to be injectable through acceptable needle sizes (18–25 gauge) while maintaining sufficient viscosity to remain at the implantation site.

[0013] Structuring agents help impart appropriate structural and mechanical properties to the composition. For example, if a therapeutic agent or drug (e.g., an analgesic, anesthetic, anti-inflammatory, or a mixture thereof) is simply placed in a simple lipophilic oil carrier (e.g., a medium-chain triglyceride), the resulting solution will be thin and mobile, similar to an aqueous solution. Therefore, if the solution (without a structuring agent) is injected or implanted directly into a surgical wound cavity, the solution may migrate and disappear from the administration site, resulting in reduced effectiveness of pain control at the target site. Furthermore, rapid drug excretion increases the risk of systemic toxicity (e.g., cardiotoxicity or neurotoxicity), which can be life-threatening. Therefore, by way of example, an advantageous long-acting local anesthetic composition should be both injectable and sufficiently viscous to be manually implanted into the surgical site. Current clinically available options include solid implantation techniques that can only be implanted into the surgical site, which severely limits clinical application. Injectable compositions can be used as long-lasting nerve blocks for local anesthesia, a popular technique for non-opioid management of postoperative pain, but current injectable options last less than 24 hours. Therefore, the problem addressed by this disclosure is to provide a safe injectable or implantable composition that is viscous enough to be injectable and manually implanted at the surgical site, that can remain at the implanted site long enough to provide local analgesic effects, and that can provide potent pain relief (e.g., analgesia) for 2 to 14 days.

[0014] 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 ranging from 5% to 98% by weight, 30% to 70% by weight, or less than, equal to, or greater than 5%, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or about 98% by weight. Sesame oil typically contains 41% by weight of linoleic acid, 39% by weight of oleic acid, 8% by weight of palmitic acid, 5% by weight of stearic acid, and trace amounts of other organic acids. Soybean oil contains 16g saturated fat, 23g monounsaturated fat, and 58g polyunsaturated fat per 100g. The main unsaturated fatty acids in soybean oil triglycerides are 7-10% by weight of polyunsaturated α-linolenic acid, 51% by weight of linoleic acid, and 23% by weight of monounsaturated oleic acid. Soybean oil also contains saturated fatty acids such as 4% by weight of stearic acid and 10% by weight of palmitic acid. Castor oil contains 85-95% by weight of ricinoleic acid, 2-6% by weight of oleic acid, 1-5% by weight of linoleic acid, 0.5-1% by weight of α-linolenic acid, 0.5-1% by weight of stearic acid, 0.5-1% by weight of palmitic acid, 0-0.5% by weight of dihydroxystearic acid, and 0.2-0.5% by weight of additional compounds. Tributyrin oil is an ester that is the 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 esters that are the reaction product of glycerol with any of the C6 to C12 carboxylic acids (e.g., hexanoic acid, octanoic acid, decanoic acid, lauric acid, or mixtures thereof).

[0015] Medium-chain triglycerides are particularly suitable as lipophilic oils. Without intending to be limited by any theory, the advantages of using medium-chain triglycerides are thought to be due to their thin nature and low viscosity, both of which make them injectable (compared to castor oil, which has good drug solubility but a very high viscosity). Furthermore, medium-chain triglycerides have been shown to provide high drug loading and favorable release rates. Thus, medium-chain triglycerides are advantageous in that they exhibit injectable viscosity, can be structured into supramolecular gels using structuring agents, can be loaded with sufficient amounts of drug, and exhibit favorable drug release profiles.

[0016] Mixtures of lipophilic oils can also be used. For example, a pharmaceutical composition can contain a mixture of medium-chain triglycerides and short-chain triglycerides, medium-chain triglycerides and long-chain triglycerides, or short-chain triglycerides and long-chain triglycerides. In some instances, the solubility of a drug such as ropivacaine can be enhanced in a 90:10 mixture of medium-chain triglycerides and short-chain triglycerides (medium-chain triglycerides:short-chain triglycerides). As a further example, a mixture of medium-chain triglycerides and castor oil as the lipophilic oil achieves higher drug loading while reducing the viscosity of the overall structure.

[0017] Structuring agents (also known as organic structuring agents, oleostructuring agents, or supramolecular structuring agents) impart structure to lipophilic oils. For example, structuring agents aid in the formation of gels. One type of gel is a supramolecular gel, which is a complex of molecules held together by non-covalent interactions such as hydrogen bonding, π-π interactions, anion-π interactions, cation-π interactions, and van der Waals forces. The process by which supramolecular assemblies form is called molecular self-assembly. Molecular self-assembly refers to the process by which molecules adopt a defined arrangement without external guidance or control.

[0018] The structuring agent may be present in an amount ranging from about 0.1% (w / v) to about 25% (w / v), about 5% (w / v) to about 25% (w / v), about 10% (w / v) to about 15% (w / v), about 5% (w / v) to 10% (w / v), about 5% (w / v) to 15% (w / v), about 10% (w / v) to 20% (w / v), about 0.1%, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 8 25%, or about 25% (w / v) of the structurant or mixture of structurants. For example, the melting point of the structuring agent can be in the range of about 40°C to about 100°C, about 50°C to about 85°C, about 45°C to about 60°C, about 50°C to about 70°C, or a temperature less than, equal to, or greater than about 40°C, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or about 100°C, respectively.

[0019] Examples of suitable structuring agents include monoglycerides, diglycerides, triglycerides, polyglycerol esters of fatty acids, or mixtures thereof. The polyglycerols used herein can be diglycerol or triglycerol and can be fully or partially esterified with saturated or unsaturated fatty acid moieties. Fatty acids 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. More specific examples of suitable structuring agents include tristearin, glyceryl distearate, glycerol monostearate, glyceryl dibehenate, cholesterol, trimyristin, glyceryl dimyristin, glyceryl monomyristin, trilaurin, glyceryl dilaurin, glyceryl monolaurin, tripalmitin, glyceryl dipalmitin, glyceryl monopalmitin, diglycerol esterified with stearic acid, cholesterol, or mixtures thereof.

[0020] At least a portion of the structurant is phase-separated in the lipophilic oil. Thus, for example, a portion of the structurant is partially soluble in the lipophilic oil (first phase), and a second portion is insoluble in the lipophilic oil (second phase). Due to the phase separation of the structurant, the structurant can help the pharmaceutical composition achieve a supramolecular gel in the lipophilic oil. If the structurant is too soluble in the lipophilic oil, the structurant will dissolve in the oil and will not be able to form a supramolecular gel. If the structurant is too insoluble, it will not interact with the lipophilic oil, and the pharmaceutical composition will form a heterogeneous, unstable gel in which the structurant precipitates.

[0021] The supramolecular gel itself is characterized as a semi-solid composition (also called a quasi-solid or semi-liquid). Semi-solid compositions resemble solids in some ways, such as their ability to support their own weight and retain their shape, but they also share some properties of liquids, such as their ability to conform to the shape of objects subjected to pressure and to flow under pressure. The selection of an appropriate structuring agent also affects the viscosity of the pharmaceutical composition. Appropriate viscosity allows the pharmaceutical composition to remain substantially in the desired location in the body. Examples of suitable viscosities at 37°C include those in the range of about 1,000 cP to about 1,000,000 cP, about 100,000 cP to about 1,000,000 cP, about 5,000 cP to about 200,000 cP, about 10,000 cP to about 100,000 cP, about 50,000 cP to about 150,000 cP, about 10,000 cP to about 500,000 cP, 20,000 cP to about 90,000 cP, and 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, 600,000, 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, 82 Less than, equal to, or greater than 0,000, 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, and 1,000,000 cP, respectively.

[0022] If the viscosity is too low, the pharmaceutical composition will disperse beyond the desired location. Furthermore, if the viscosity is too low, the drug may be released uncontrollably. Conversely, if the viscosity is too high, it may be impossible to inject the pharmaceutical composition into the desired location. In this case, manual application (e.g., applying or spreading the composition to the site by hand or using an instrument) may be the only viable option. However, if the viscosity is too high, manual application may not be practical. The viscosity required to maintain retention of the material at the application site is typically too high to allow injection through clinically relevant needle sizes (18 g to 25 g needles). A particular disadvantage of not being able to inject through these needles is that such solutions cannot be used for nerve blocks. To overcome this, the disclosed pharmaceutical compositions are designed to be shear-thinning. Shear-thinning is defined as the ability of a material to decrease in viscosity as shear increases. Such compositions can be pre-filled into syringes, extruded upon shear application, and regain viscosity when mechanical loading ceases, a process known as self-healing. This self-healing behavior allows for both improved application and material retention, thereby increasing the usefulness and efficacy of pharmaceuticals, as well as the longer drug release characteristics described herein. By way of example, when sheared at a sweep ranging from 0.01 Hz to 200 Hz, the viscosity at 37°C can decrease to less than, equal to, or greater than about 10 cP to about 10,000 cP, about 20 cP to about 5,000 cP, about 20 cP to about 500 cP, about 10 cP, 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, respectively. Unless otherwise specified, all viscosity values ​​reported herein were measured at 37°C using a HAAKE Mars60 rheometer available from Thermo-Fisher Scientific, Inc., Wortman, Massachusetts.

[0023] The drug may be present in the pharmaceutical composition in a therapeutically effective amount. A "therapeutically effective amount" (or "effective amount") of a compound for use in therapy refers to the amount of compound in the formulation that, when administered (to a mammal, such as a human) as part of a desired dosing regimen, alleviates the symptoms, improves the condition, or delays the onset of a disease state in accordance with clinically accepted standards for the disorder or condition being treated, or for cosmetic purposes, e.g., at a reasonable benefit / risk ratio applicable to any medical treatment.

[0024] The term "prophylactic or therapeutic" treatment is art-recognized and includes administration of one or more compounds of the present disclosure to a patient. The treatment is prophylactic (e.g., to protect the host from developing the undesirable condition) when administered before the clinical manifestation of an undesirable condition (e.g., a disease or other undesirable condition in a host animal), and is therapeutic (e.g., aimed at reducing, ameliorating, or stabilizing an existing undesirable condition or its side effects) when administered after the undesirable condition is manifested.

[0025] The exact amount of drug will vary and will be selected depending on the application. As non-limiting examples, the drug may be present in a range of 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) (based on the volume of the lipophilic oil), about 3% (w / v) to about 10% (w / v), about 5% (w / v) to about 8% (w / v), 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, The lipophilic oil may be present at a concentration of less than, equal to, or greater than 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 may be a factor in the length of time that the subject's pain is relieved.For example, the pharmaceutical composition may be administered within a range of 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, 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, or 63 hours. In some embodiments, the composition may be effective to reduce pain in vivo in a subject for less than, equal to, or more than 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, respectively. Some pharmaceutical compositions can be designed to be effective in relieving pain over a specific range, such as 12 to 48 hours, 48 ​​to 96 hours, 96 to 144 hours, 144 to 240 hours, or 240 to 336 hours. The exact drug release profile will vary depending on the structure of the pharmaceutical composition. For example, the specific blend of lipophilic oils will affect the drug release profile. For example, the specific ion pair (e.g., lipophilic salt) formed with the therapeutic agent can affect the release profile.

[0026] The length of time a pharmaceutical composition exerts its therapeutic effect depends on the release rate of the drug from the lipophilic oil. Drug release from the lipophilic oil is controlled by diffusion. Depending on the drug's affinity for a particular lipophilic oil or a particular 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 due to its higher affinity for the lipophilic oil than for the aqueous medium. The drug release rate also depends on the interfacial area between the oily carrier and the surrounding aqueous in vivo environment. This interfacial area can be controlled by the supramolecular gel provided by the structuring agent. Without structure, the pharmaceutical composition can flow and spread freely in the body, which greatly increases the interfacial surface area and therefore greatly accelerates the drug release rate. However, when the lipophilic oil is formed into a viscous semi-solid by the supramolecular gel, its ability to diffuse and increase the interfacial area is greatly reduced, thereby slowing the drug release rate and prolonging the effect of locally controlled non-opioid analgesics (when the drug is used as an analgesic or anesthetic).

[0027] Therapeutic agents include analgesics, anesthetics, and anti-inflammatory agents. Various lipophilic therapeutic agents in their base form can be covalently or noncovalently modified to improve their lipophilicity and, consequently, their solubility and drug loading capacity in the base oil. This is achieved by altering the physicochemical properties of the drug (e.g., melting point, polarity, hydrophobicity, partition coefficient). Covalent modification can be used to synthesize prodrugs of drugs that are much more lipophilic and suitable for use in the compositions of the present disclosure. This can also be achieved using noncovalent modification. For example, hydrophobic ion pairing can be used to ion-pair a charged drug molecule with an oppositely charged molecule bearing a hydrophobic moiety. The resulting complex is more lipophilic and hydrophobic, resulting in improved encapsulation in and more controlled release from lipid-based formulations. Therefore, both covalent and noncovalent modulation of drug attachment can be used to tailor the drug release of naturally lipophilic or naturally hydrophobic drugs from the system. The desired solubility and partition coefficient from the base oil vary depending on the drug and application. For example, drugs with a logP of less than 2 can be modified by forming a prodrug that increases the logP above the stated logP value (e.g., at least 2). These examples of covalent and non-covalent chemical modifications increase lipophilicity, enhance affinity to the base oil, and result in slower modified release characteristics. In such examples, drugs with a logP of less than 2 can be modified by forming a prodrug that increases the logP above the stated logP value (e.g., at least 2). 12 ~C 22 The resulting C may contain hydroxy or amino functional groups that can form esters or amides, respectively, with carboxylic acids. 12 ~C 22The ester or amide may have a recited logP value (e.g., at least 3). Alternatively, or in addition, the drug or prodrug may be modified by combining it with a hydrophobic counterion that may have a recited logP value. For example, the drug or prodrug may be synthesized as a docusate salt or ion-exchanged to form a docusate salt. In this case, docusate is the counterion to the drug. Other such counterions are known in the art and are contemplated herein. Thus, in addition to the analgesic, anesthetic, and anti-inflammatory agents described herein, the pharmaceutical compositions described herein may be formulated to include one or more adjuvant agents (which may also be covalently or non-covalently modified). Examples include, but are not limited to, sympatholytics (e.g., dexmedetomidine, clonidine), anxiolytics (e.g., midazolam), anti-inflammatory agents (e.g., dexamethasone, NSAIDs, COX-2 inhibitors), and cannabinoids (e.g., cannabidiol).

[0028] The partition coefficient, or logP, used herein, is a measure of a drug's lipophilicity and its ability to cross cell membranes. It is defined as the ratio of drug partitioning between the organic and aqueous layers at equilibrium. Drug partition coefficients can be measured by adding equal volumes of two immiscible solvents (a water-saturated organic layer and an aqueous drug solution) and shaking until equilibrium is reached. The drug content in one layer is measured and the value is calculated. Octanol-water partitioning is a commonly used system for this test. While the partition coefficient alone may not provide information about absorption, it characterizes the balance of a drug's lipophilicity and hydrophilicity, aiding in the screening of a compound's biological properties. When combined with LogP, a drug's melting point can also be useful in screening a compound's lipid solubility. Molecules with high melting points tend to be less soluble than predicted by LogP. Molecules with low melting points tend to be more soluble than predicted by LogP.

[0029] As understood herein, an analgesic is any member of a group of drugs used to achieve analgesia, i.e., pain relief. These are distinct from anesthetics, which temporarily affect sensation and, in some cases, eliminate it. Examples of suitable analgesics include nonsteroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors, or mixtures thereof. Non-limiting examples of NSAIDs include ibuprofen, naproxen, diclofenac, mefenamic acid, indomethacin, cannabidiol, ion pairs thereof, salts thereof, or mixtures thereof. Non-limiting examples of COX-2 inhibitors include etoricoxib, meloxicam, celecoxib, ion pairs thereof, salts thereof, or mixtures thereof.

[0030] As understood herein, an anesthetic agent refers to any agent that causes localized or total loss of sensation, including pain. Anesthetics achieve their effect by acting on the brain and peripheral nervous system to inhibit responses to sensory stimuli. The state of unresponsiveness induced in this way is known as anesthesia. General anesthesia involves the loss of consciousness, usually for the purpose of pain relief during surgery. Regional anesthesia involves the loss of sensation and motor function in an area of ​​the body by blocking nerve conduction.

[0031] While this disclosure describes the use of local anesthetics, general anesthetics can also be included. Suitable examples of local anesthetics include ester anesthetics, amide anesthetics, or mixtures thereof. Non-limiting examples of ester anesthetics include procaine, amethocaine, benzocaine, tetracaine, or mixtures thereof. Non-limiting examples of amide anesthetics include lidocaine, prilocaine, bupivacaine, levobupivacaine, ropivacaine, mepivacaine, dibucaine, etidocaine, salts thereof, or mixtures thereof. Amide anesthetics may include the free base form of the amide anesthetic, the hydrochloride form of the amide anesthetic, or additional salt forms or ion pairs of the amide anesthetic, including lipophilic salts. Lipophilic salts of amide anesthetics comprise a protonated amide anesthetic paired with a lipophilic counterion, which can increase the solubility of the amide anesthetic in lipophilic oils. This can be beneficial for increasing the loading of the anesthetic in pharmaceutical compositions. For example, a lipophilic salt or ion pair of an amide anesthetic can include a docusate counterion. As an example, a lipophilic salt or ion pair of an amide anesthetic can be ropivacaindocusate. As a further example, the amide local anesthetic is an ion pair or salt including those of bupivacaine butyrate, bupivacaine palmitate, bupivacaine laurate, bupivacaine myristate, bupivacaine stearate, bupivacaine hydroxystearate, bupivacaine oleate, bupivacaine ricinoleate, and bupivacaindocusate.

[0032] While all of the aforementioned amide anesthetics are desirable, ropivacaine is preferred due to its several known clinical advantages, including patient safety and favorable analgesic properties, such as sensory selectivity. However, ropivacaine typically has poor solubility in lipophilic oils (including, but not limited to, medium-chain triglycerides). This relatively poor solubility also applies to the free base and hydrochloride forms of ropivacaine. Surprisingly, however, ropivacaine indoxate has been shown to exhibit adequate solubility in lipophilic oils, such as medium-chain triglycerides, allowing sufficient amounts of ropivacaine to dissolve in the lipophilic oil and be released at an acceptable rate.

[0033] Suitable examples of anti-inflammatory agents include aspirin, celecoxib, diclofenac, diflunisal, etodolac, ibuprofen, indomethacin, ketoprofen, ketorolac, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin, or mixtures thereof.

[0034] The pharmaceutical composition can include an adjuvant. In the context of drugs, an adjuvant refers to a drug that has an analgesic effect and has a primary indication other than pain. Examples of suitable adjuvants include barbiturates, opiates, anti-inflammatory agents, cannabinoids, sympatholytic agents, or mixtures thereof. Further examples of suitable adjuvants include corticosteroids, dexamethasone, pethidine, tubocurarine chloride, meloxicam, dexmedetomidine, or mixtures thereof.

[0035] Where the adjuvant comprises a cannabinoid, a suitable cannabinoid may be cannabidiol (CBD), although other cannabinoids include cannabigerolic acid (CBGA), cannabigerolic acid monomethyl ether (CBGAM), cannabigerol (CBG), cannabigerol monomethyl ether (CBGM), cannabigerovaric acid (CBGVA), cannabigerovarin (CBGV), cannabichromenic acid (CBCA), cannabichromene (CBC), cannabichromevaric acid (CBCVA), cannabichromevarin (CBCV), cannabidiolic acid (CBDA), cannabidiol monomethyl ether (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), tetrahydrocannabinol C4 (THC-C4), tetrahydrocannabivarinic acid tetrahydrocannabivarin (THCV), tetrahydrocannabiorcholic acid (THCA-C1), tetrahydrocannabiorcholic acid (THC-C1), Δ7-cis-iso-tetrahydrocannabivarin, Δ8-tetrahydrocannabinolic acid (Δ8-THCA), cannabivarinodiol acid (CBNDVA), cannabivarinodiol (CBNDV), Δ8-tetrahydrocannabinol (Δ8-THC), Δ9-tetrahydrocannabinol (Δ9-THC), cannabicyclolic acid (CBLA) , cannabicyclol (CBL), cannabicyclovalin (CBLV), cannabielsonic acid A (CBEA-A), cannabielsonic acid B (CBEA-B), cannabielson (CBE), cannabivarinselsoin (CBEV), cannabivarinselsoin acid (CBEVA), cannabielsonic acid (CBEA), cannabielvarinsoin (CBLV), cannabielvarinsoin acid (CBLVA), cannabinolic acid (CBNA),Cannabinol (CBN), cannabivaric acid (CBNVA), cannabinol methyl ether (CBNM), cannabinol-C4 (CBN-C4), cannabivarin (CBV), cannabino-C2 (CBN-C2), cannabiolchol (CBN-C1), cannabinodiol (CBND), cannabinodivalin (CBNDA), cannabinodivalin (CBDV), cannabidiol (CBT), 10-ethoxy-9-hydroxy-Δ8a-tetrahydrocannabinol, 8,9-dihydroxy-Δ6a(10a)-tetrahydrocannabinol (8,9-di-OH-CBT-C5), cannabidiol valine (CBTV), ethoxycannabidiol valine (CBTVE), dehydrocannabifuran (DCBF), cannbifuran (CBF) ), cannabichromanone (CBCN), cannabiditran (CBT), 10-oxo-Δ6a(10a)-tetrahydrocannabinol (OTHC), Δ9-cis-tetrahydrocannabinol (cis-THC), cannabilipsol (CBR), 3,4,5,6-tetrahydro-7-hydroxy-α-α-2-trimethyl-9-n-propyl-2,6-methano-2H-1-benzoxocine-5-methanol (OH-iso-HHCV), trihydroxy-delta-9-tetrahydrocannabinol (triOH-THC), yangonin, epigallocatechin gallate, dodeca-2E,4E,8Z,10Z-tetraenoic acid isobutyramide, and dodeca-2E,4E-dienoic acid isobutyramide, mixtures thereof, or mixtures of any of the foregoing with cannabidiol.

[0036] The inclusion of an adjuvant has a synergistic effect in that it reduces the amount of drug that needs to be added to be considered a therapeutically effective amount, compared to a comparative pharmaceutical composition that differs only in the absence of an adjuvant.

[0037] In some embodiments, the pharmaceutical composition can include a rheology modifier, which, if present, can be present in an amount of less than, equal to, or greater than 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), about 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, or about 10% (w / v) of the pharmaceutical composition based on the volume of lipophilic oil.

[0038] In some embodiments, the rheology modifier may be a diluent that reduces the viscosity of the pharmaceutical composition. For example, if the pharmaceutical composition is intended for injection, the diluent may be beneficial in that it can increase the injectability of the pharmaceutical composition by reducing the viscosity of the pharmaceutical composition. For example, the diluent may at least temporarily disrupt the supramolecular gel. In addition to increasing the injectability of the pharmaceutical composition, at least temporarily disrupting the supramolecular gel may help increase the shelf-life stability of the pharmaceutical composition. For example, if the components of the pharmaceutical composition are uniformly distributed with each other, the formation of the supramolecular gel may be delayed until deployment in vivo. Examples of suitable diluents include C2-C3. 12 Examples of suitable pharmaceutical compositions include alcohols. Non-limiting examples of alcohols include ethanol, benzyl alcohol, or a mixture thereof. The advantage of using ethanol or benzyl alcohol is that when a pharmaceutical composition containing ethanol or benzyl alcohol is placed in the body, the viscosity of the pharmaceutical composition increases and / or a supramolecular gel is completely formed as the ethanol or benzyl alcohol diffuses into the aqueous environment.

[0039] In other aspects, rheology modifiers can increase the viscosity of a pharmaceutical composition. This is useful, for example, when a particular combination of lipophilic oil and structuring agent interacts well with each other or allows for proper dispersion and diffusion of a desired drug, but together does not result in a composition with the appropriate viscosity. Inclusion of a rheology modifier to increase viscosity can make a pharmaceutical composition viable.

[0040] Pharmaceutical compositions comprise an effective amount of a compound described herein and, optionally, one or more other therapeutic agents contained in a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers, diluents, or encapsulating substances suitable for administration to humans or other vertebrates. The term "carrier" refers to an organic or inorganic, natural or synthetic component with which an active ingredient is combined to facilitate application. The components of the pharmaceutical composition can also be mixed with the compound, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficiency.

[0041] As used herein, the phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting a chemical substance of interest 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, not injurious to the patient, and substantially non-pyrogenic. Examples of substances that can be used 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 carboxymethylcellulose, ethyl cellulose, and cellulose acetate; (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; and (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) buffers 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, and (21) other non-toxic, compatible substances used in pharmaceutical compositions. The pharmaceutical compositions of the present disclosure are non-pyrogenic, i.e., they do not cause a significant temperature increase when administered to a patient.

[0042] The pharmaceutical composition can be packaged in any suitable manner. For example, the pharmaceutical composition can be packaged in a bottle, container, or the like, so that the pharmaceutical composition can be accessed and manually applied to the desired location. Alternatively, the pharmaceutical composition can be placed in the dispensing chamber of a syringe. The syringe can have a needle ranging from about 14 to about 30 gauge, about 21 to about 25 gauge, or 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 30 gauge. Alternatively, the pharmaceutical composition can be dispensed from the syringe without a needle (e.g., via a cone applicator).

[0043] The pharmaceutical composition can be made by a) mixing a lipophilic oil with an analgesic, anesthetic (or other drug within the scope of this disclosure) at a temperature above 25°C with stirring to form a first mixture, b) mixing a structuring agent with the first mixture with stirring and heating at a temperature above 25°C to form a second mixture, and c) cooling the second mixture to form the pharmaceutical composition.

[0044] As an example, a pharmaceutical composition can be prepared by mixing a lipophilic oil and a drug with stirring at a temperature above room temperature (25°C) to form a first mixture. For example, the temperature can be in the range of about 50°C to about 100°C, about 60°C to about 80°C, or a temperature less than, equal to, or greater than about 50°C, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100°C. A structuring agent can be added to the first mixture with stirring and heating at a temperature above room temperature (25°C) to form a second mixture. For example, the temperature can be in the range of about 50°C to about 100°C, about 60°C to about 80°C, or a temperature less than, equal to, or greater than about 50°C, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100°C. The pharmaceutical composition can then be formed by cooling the second mixture. Before the second mixture cools, it can be placed in a bottle, container, or syringe to allow the supramolecular gel to form therein.

[0045] The pharmaceutical composition and / or bottle, container, or syringe can be sterilized at any point during the manufacturing process. However, due to the stability of the pharmaceutical composition, sterilization can be performed after the pharmaceutical composition is fully formed (e.g., after cooling). Sterilization can be performed using any suitable technique, such as ultraviolet treatment, electron beam, X-ray, autoclave, steam sterilization, dry heat sterilization, etc.

[0046] In practice, the pharmaceutical composition can be administered to a subject. The pharmaceutical composition can be administered at or near the injury, wound, or treatment site. Examples of injuries and wounds include surgical sites. The pharmaceutical composition can be administered distal to the injury or wound. For example, pain from a distal injury or wound can be blocked by administering the pharmaceutical composition to a specific location that blocks nerves. In the context of surgery, the pharmaceutical composition can be applied pre-operatively, intra-operatively (e.g., any time before the incision is closed), or post-operatively (e.g., after the incision is closed).

[0047] As used herein, the term "kit" refers to an article of manufacture (e.g., pharmaceutical product, kit of parts) that includes one package or one or more separate packages of the following: (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. That is, the kit may include one or more packages each containing one pharmaceutical composition containing two or more active pharmaceutical ingredients. The additional active pharmaceutical ingredients may be present in additional pharmaceutical compositions. That is, the kit may include separate packages of two or more pharmaceutical compositions, each pharmaceutical composition containing one active pharmaceutical ingredient.

[0048] or (ii) A pharmaceutical composition comprising an active pharmaceutical ingredient and a medical device. A kit may include only one package, or it may include one or more individual packages. For example, a kit may be a product (e.g., a pharmaceutical product) that includes two or more vials, each containing a specified pharmaceutical composition, each containing at least one active pharmaceutical ingredient. For example, a kit may include (i) a vial containing a specified pharmaceutical composition, and (ii) a tablet, capsule, powder, or other oral dosage form that further contains at least one additional active pharmaceutical ingredient. The kit may further include a package leaflet that describes how to administer the pharmaceutical composition and at least one additional active pharmaceutical ingredient.

[0049] As used herein, the term "medical device" means any instrument, apparatus, implant, extracorporeal reagent, or similar or related article used in the diagnosis, prevention, or treatment of disease or other condition, which does not achieve its purpose by pharmacological action within or on the body.

[0050] A medical device as used herein may be a syringe, an insulin injection system, an insulin infusion system, an insulin pump, or an insulin pen injection device. A medical device as used herein may be mechanically or electromechanically driven.

[0051] Ingredients in a pharmaceutical composition can be defined as generally recognized as safe ("GRAS"). A complete list of GRAS ingredients can be found in the GRAS Substances (SCOGS) database maintained by the U.S. Food and Drug Administration. About 50% to about 100% of the ingredients in a pharmaceutical composition can be classified as GRAS ingredients, and less than, equal to, or more than about 75% to about 100%, about 90% to about 100%, about 50%, 55, 60, 65, 70, 75, 80, 85, 90, 95, or about 100%, respectively, of the ingredients in a pharmaceutical composition can be classified as GRAS ingredients.

[0052] Example Various aspects of the present disclosure may be better understood by reference to the following examples, which are provided for illustrative purposes only and are not intended to limit the disclosure to the examples described herein.

[0053] [Table 1]

[0054] Fifteen compositions were prepared. Each composition was prepared by heating medium-chain triglycerides to approximately 70°C. The drug (bupivacaine free base, ropivacaine indoxate, or ropivacaine free base) was added to the heated medium-chain triglycerides and stored. The structuring agent (trimyristin, tripalmitin, trilaurin, or glycerol monostearate) was then added with heating and stirring until fully dissolved. The resulting solution was drawn up into a syringe, air bubbles were removed, and the syringe was sealed with an airtight seal. The solution was allowed to cool to room temperature (approximately 25°C), allowing the spontaneous formation of a supramolecular gel. The components of the 15 compositions are listed below in Tables 2-16. In Tables 2-16, the concentration values ​​of the structuring agent and drug for each composition are expressed as weight relative to the volume of lipophilic oil (w / v).

[0055] [Table 2]

[0056] [Table 3]

[0057] [Table 4]

[0058] [Table 5]

[0059] [Table 6]

[0060] Table 7

[0061] Table 8

[0062] Table 9

[0063] Table 10

[0064] Table 11

[0065] Table 12

[0066] Table 13

[0067] Table 14

[0068] Table 15

[0069] Table 16

[0070] [Table 17]

[0071] [Table 18]

[0072] [Table 19]

[0073] Example 2 The time-release performance of bupivacaine free base was investigated for an MCT-only formulation containing bupivacaine free base and MCT oil, and an oleogel formulation containing bupivacaine free base, MCT oil (a lipophilic oil), and glyceryl monostearate (a structuring agent). As shown in Figure 1, the oleogel formulation slowed the release of bupivacaine free base.

[0074] The controlled release of the formulations was evaluated by placing 0.5 mL of the formulation in a dialysis bag (10 kDa) and immersing it in a sink of 50 mL of phosphate-buffered saline (1x; pH 7.4). The sample was placed in a rotating incubator (1 Hz) at 37 °C. At designated time points, 2 mL of saline was removed and analyzed using a UV-visible spectrophotometer (272 nm). The entire sink medium was replaced at each time point until no more drug was eluted from the system.

[0075] Example 3 Drug release over time was investigated for oleogel formulations containing bupivacaine free base, MCT oil, and glyceryl monostearate (a structuring agent), as well as for oleogel formulations containing bupivacaine free base, a lipophilic oil mixture consisting of 75% MCT oil and 25% castor oil (by weight), and glyceryl monostearate (a structuring agent). As shown in Figure 2, the formulation containing the mixture of 75% MCT oil and 25% castor oil (by weight) exhibited a slower release of bupivacaine free base. Drug release profiles were measured according to the protocol in Example 2.

[0076] Example 4 The viscosity of various oils used in the formulations described herein was investigated at 37°C. The oils investigated included castor oil, MCT oil, and a blend of castor oil and MCT oil (e.g., 50%, 40%, 30%, and 20% castor oil, with the remainder being MCT). As shown in Figure 3, the MCT:castor oil blend had a significantly lower viscosity than castor oil alone, approaching the viscosity value of MCT alone. Because bupivacaine and other local anesthetics have higher drug solubility in castor oil than in MCT, blending these two oils can achieve both good drug solubility (and thus drug loading) and a low viscosity suitable for injection. For example, these properties mean that the inclusion of 30%–50% castor oil can increase drug loading and delay drug release without significantly altering the base viscosity of the oil.

[0077] The rheological properties of each formulation were measured using a rheometer. Using a 35 mm parallel plate set with a 0.5 mm gap, approximately 0.5 mL of formulation was injected into the rheometer plate through an 18 G needle and analyzed. Rotational acceleration tests were performed at 20 °C, and viscosity curves were obtained by varying the shear rate between 1 and 200 Hz.

[0078] Example 5 The viscosity of formulations containing 25% by weight castor oil and 20% by weight structuring agent was measured at 37°C. The structuring agents included monostearate, monopalmitate, and a mixture thereof. Figure 4 shows the effect on viscosity of varying the weight percent of monostearate in a mixture of monostearate and monopalmitate. As shown, formulations containing only monostearate or only monopalmitate are significantly softer than gels made by blending the two. Viscosity was measured according to the protocol in Example 4.

[0079] Example 6 The shear rate of a formulation containing 25% monostearate and monopalmitate, 100% MCT, and 5% bupivacaine was tested. As shown in Figure 5, the viscosity curves indicate a decrease in viscosity as the shear rate increases. This property is called "shear thinning," meaning that the formulation exhibits improved injectability and in situ gelation. Viscosity was measured according to the protocol in Example 4.

[0080] Example 7 The viscosity of a formulation containing MCT, a 60:40 monostearate:monpalmitate mixture ("GMSP"), and bupivacaine free base was measured at 20° C. and 37° C. (mimicking body temperature). A sufficiently strong gel was obtained, as shown in Figure 6. Viscosity was measured according to the protocol in Example 4.

[0081] Example 8 Rheology graphs using various structuring agents are shown here. Figures 7A-7D show how some formulations weaken significantly at 37°C. If the gels break down at 37°C, their usefulness as injectable depot sustained-release drug delivery systems is diminished. Viscosity was measured according to the protocol in Example 4. The average storage modulus (G') and crossover point in the linear viscoelastic region were then obtained from the software and further analyzed.

[0082] Example 9 The DSC melting point and crystallization temperature are shown in Tables 20 and 21, respectively. As shown, GMS has a melting peak and a crystallization peak above 37°C. These are the highest peaks among all gelling agents in the previous rheology graphs (Figures 7A-7D). This confirms the results above. GMSP gels are more heat resistant and therefore more useful.

[0083] [Table 20]

[0084] [Table 21]

[0085] In Tables 20 and 21: GMS = glyceryl monostearate PMF = Polyglyceride esters of fatty acids (18C-long fatty acids) TM = trimyristin TP = Tripalmitin Example 10 Figures 8A and 8B show the peak melting and peak crystallization profiles of various formulations. The thermal properties of the oleogel (e.g., lipophilic oil and structuring agent) were measured using differential scanning calorimetry (DSC). Approximately 25 mg of oleogel was loaded into a standard aluminum crucible (25 μL) with a lid and a central hole at room temperature. The sample was heated from 20°C to 100°C at a scan rate of 10°C / min, followed by an isothermal hold at 100°C for 5 minutes before cooling to -20°C.

[0086] Using this method, the area under the curve, and thus the enthalpy of fusion and peak temperature were obtained. Example 11 Figures 9A and 9B show sciatic nerve block data from rats. Figure 9B shows the same data as Figure 9A, but with different y- and x-axis values. As shown, bupivacaine in oleogel has the longest effect. More importantly, oleogel has a longer effect than MCT oil without a structuring agent, both at the same dose of bupivacaine. Gelling the oil significantly prolongs drug release in the body.

[0087] In this longitudinal study, 17 male CD Sprague-Dawley rats weighing 360–420 g underwent sciatic nerve block with one of 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), and 0.2 mL of 5% bupivacaine oleogel (w / v) in 20% GMS (w / v) (GMS / MCT) (bupivacaine / oleogel) (10 mg bupivacaine). Each group consisted of five rats, except for 0.5% bupivacaine HCl, which had only two rats because the anesthetic effects of bupivacaine HCl are well understood. Once the rats had recovered from surgery, they were transferred to individual acrylic enclosures on a heated clear glass surface for the Hargreaves pain assay.

[0088] Hargreaves method: At designated time points, a heat hazardous device was placed on the mid-plantar area of ​​the right hind paw and manually turned off when the paw was withdrawn. Paw withdrawal latency was measured three times per animal and time point and averaged.

[0089] Example 12 Figure 10 is a graph showing porcine efficacy data. Alevatrix 001 = 100% MCT. Alevatrix 002 = 75:25 MCT:castor oil. The 002 castor oil blend group demonstrated a better bupivacaine release profile.

[0090] Thirty pigs weighing 10-13 kg were injected subcutaneously with each formulation. At designated time points, a von Frey maneuver was performed approximately 0.5 cm from the injection site. A filament was applied to this site, with the diameter of the applied filament gradually increasing until a withdrawal response was observed. A maximum force of 60 grams was used. A withdrawal response was considered to be an action of moving away from the stimulus, such as walking away or twisting the flank. After surgery, pain (allodynia) was considered to be present if the withdrawal force in the flank was ≤8 g.

[0091] Treatment group (n=6); Low dose (L) dose was 2.5 mL. High dose (H) dose was 5 mL. Example 13 The solubility of bupivacaine in blends of MCT oil and castor oil was investigated. As shown in Figure 11, certain oil blends increase drug loading and slow drug release due to increased drug affinity for the oil blend. Higher drug affinity leads to higher drug loading and slower release. The maximum solubility of the oil blends 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 rotary shaker in a 37°C oven to ensure complete dissolution. After rotation, the sample was centrifuged at 2000 x g for 5 minutes. Next, 30 μL of the sample supernatant was collected, dissolved in 1470 μL of ethanol, and analyzed using a UV-visible spectrophotometer (272 nm).

[0092] Example 14 The solubility of bupivacaine in formulations containing MCT oil and glycerol monostearate as a structuring agent, with or without an anion (as indicated on the x-axis of Figure 12), is shown in Figure 12. As shown, docusate increases the solubility of bupivacaine. Solubility was measured according to the protocol in Example 13.

[0093] Example 15 Bupivacaine release has been demonstrated in formulations containing MCT oil and glycerol monostearate as a structuring agent, with or without an anion to enhance hydrophobicity. As shown in Figure 13, the release of bupivacaine with docusate is prolonged. The controlled release of the formulations was evaluated by placing 0.5 mL of the formulation in a dialysis bag (10 kDa) and immersing it in a sink of 50 mL of phosphate-buffered saline (1x; pH 7.4). The samples were placed in a rotating incubator (1 Hz) at 37°C. At designated time points, 2 mL of saline was removed and analyzed using a UV-visible spectrophotometer (272 nm). The entire sink medium was replaced at each time point until no more drug was eluted from the system.

[0094] The terms and expressions used are used as terms of description rather than limitation, and the use of such terms and expressions is not intended to exclude equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the aspects of the present disclosure. Thus, while the present disclosure has been specifically disclosed by certain embodiments and optional features, it will be understood that those skilled in the art may resort to modifications and variations of the concepts disclosed herein, and that such modifications and variations are deemed to be within the scope of the aspects of the present disclosure.

[0095] Exemplary Embodiments Below are exemplary embodiments, the numbering of which should not be construed as an indication of importance.

[0096] Aspect 1 is lipophilic oil, a therapeutic agent, a salt, an ion pair, or a prodrug thereof dispersed in said lipophilic oil; and a structuring agent at least partially insoluble in said lipophilic oil and forming a gel; The present invention provides a pharmaceutical composition comprising:

[0097] Aspect 2 provides the pharmaceutical composition of Aspect 1, wherein the lipophilic oil comprises a monoglyceride, a diglyceride, a triglyceride, a medium chain triglyceride oil, sesame oil, soybean oil, castor oil, a vegetable oil, a tributyrin oil, or a mixture thereof.

[0098] Aspect 3 provides the pharmaceutical composition of Aspect 2, wherein the triglyceride is a saturated triglyceride, a monounsaturated triglyceride, or a polyunsaturated triglyceride. Aspect 4 provides the pharmaceutical composition of Aspect 2, wherein the triglyceride comprises a medium chain triglyceride, a short chain triglyceride, a long chain triglyceride, or a mixture thereof.

[0099] Aspect 5 provides the pharmaceutical composition of aspect 4, wherein the triglyceride comprises a medium chain triglyceride. Aspect 6 provides the pharmaceutical composition of Aspect 5, wherein the medium chain triglyceride comprises a glyceride of a C6 to C12 carboxylic acid, or a mixture thereof.

[0100] Aspect 7 provides the pharmaceutical composition of Aspect 1, wherein the structuring agent has a melting point in the range of about 40°C to about 100°C. Aspect 8 provides the pharmaceutical composition of aspect 7, wherein the structuring agent has a melting point in the range of about 50°C to about 85°C.

[0101] Aspect 9 provides the pharmaceutical composition of aspect 8, wherein the structuring agent has a melting point in the range of about 60°C to about 70°C. Aspect 10 provides the pharmaceutical composition of aspect 1, wherein the structuring agent comprises a monoglyceride, a diglyceride, a triglyceride, a polyglyceride ester of a fatty acid, or a mixture thereof.

[0102] Example 11 provides the pharmaceutical composition of Example 1, wherein the structuring agent comprises tristearin, glyceryl distearate, glycerol monostearate, glyceryl dibehenate, cholesterol, trimyristin, glyceryl dimyristin, glyceryl monomyristin, trilaurin, glyceryl dilaurin, glyceryl monolaurin, tripalmitin, glyceryl dipalmitin, glyceryl monopalmitin, cholesterol, polyglyceride esters of fatty acids, polyglycerol esters of fatty acids, or mixtures thereof.

[0103] Aspect 12 provides the pharmaceutical composition of aspect 11, wherein the structuring agent comprises glycerol monostearate, glyceryl distearate, tristearin, glycerol monopalmitin, glycerol dipalmitin, tripalmitin, glycerol monomyristin, glycerol dimyristin, trimyristin, or a mixture thereof.

[0104] Example 13 provides the pharmaceutical composition of Example 1, wherein the structuring agent is present in a concentration ranging from about 0.1% (w / v) to about 25% (w / v) of the pharmaceutical composition, based on the volume of the lipophilic oil.

[0105] Aspect 14 provides the pharmaceutical composition of aspect 13, wherein the structuring agent is present in a concentration ranging from about 3% (w / v) to about 20% (w / v) of the pharmaceutical composition, based on the volume of the lipophilic oil.

[0106] Example 15 provides the pharmaceutical composition of Example 13, wherein the structuring agent is present in a concentration ranging from about 3% (w / v) to about 10% (w / v) of the pharmaceutical composition, based on the volume of the lipophilic oil.

[0107] Aspect 16 provides the pharmaceutical composition of Aspect 1, wherein the therapeutic agent comprises an analgesic, an anesthetic, an anti-inflammatory, a sympatholytic, an anxiolytic, a cannabinoid, or a mixture thereof dispersed in the lipophilic oil.

[0108] Aspect 17 provides the pharmaceutical composition of aspect 16, wherein the analgesic, anesthetic, or both are present in an amount sufficient to reduce pain in the subject. Aspect 18 provides the pharmaceutical composition of aspect 17, wherein the pharmaceutical composition comprises an analgesic agent.

[0109] Aspect 19 provides the pharmaceutical composition of aspect 18, wherein the analgesic agent comprises a nonsteroidal anti-inflammatory drug, a COX-2 inhibitor, or a mixture thereof. Aspect 20 provides the pharmaceutical composition of aspect 19, 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.

[0110] Aspect 21 provides the pharmaceutical composition of aspect 19, wherein the COX-2 inhibitor comprises etoricoxib, meloxicam, celecoxib, an ion pair thereof, a salt thereof, or a mixture thereof.

[0111] Aspect 22 provides the pharmaceutical composition of aspect 1, wherein the pharmaceutical composition comprises an anesthetic, and the anesthetic is a local anesthetic. Aspect 23 provides the pharmaceutical composition of aspect 22, wherein the anesthetic agent comprises an ester-based local anesthetic, an amide-based local anesthetic, or a prodrug, or an ion pair thereof, or a salt thereof, or a mixture thereof.

[0112] Aspect 24 provides the pharmaceutical composition of Aspect 23, wherein the ester local anesthetic comprises procaine, amethocaine, benzocaine, tetracaine, or a prodrug thereof, or an ion pair thereof, or a salt thereof, or a mixture thereof.

[0113] Aspect 25 provides the pharmaceutical composition of Aspect 23, wherein the local amide anesthetic comprises lidocaine, prilocaine, bupivacaine, levobupivacaine, ropivacaine, mepivacaine, dibucaine, etidocaine, a prodrug, or an ion pair thereof, or a salt thereof, or a mixture thereof.

[0114] Aspect 26 provides the pharmaceutical composition of Aspect 25, wherein the amide anesthetic comprises bupivacaine, ropivacaine, a salt thereof, an ion pair thereof, or a mixture thereof. Aspect 27 provides the pharmaceutical composition of Aspect 26, wherein the amide local anesthetic is an ion pair or salt, including those of bupivacaine butyrate, bupivacaine palmitate, bupivacaine laurate, bupivacaine myristate, bupivacaine stearate, bupivacaine hydroxystearate, bupivacaine oleate, bupivacaine ricinoleate, or bupivacaindocusate.

[0115] Embodiment 28 provides the pharmaceutical composition of embodiment 1, comprising a mixture of an analgesic, an anesthetic, and an anti-inflammatory agent. Embodiment 29 provides the pharmaceutical composition of embodiment 1, comprising a mixture of an analgesic and an anesthetic.

[0116] Embodiment 30 provides the pharmaceutical composition of embodiment 1, wherein the analgesic, anesthetic, or both, are present in a concentration ranging from about 2% (w / v) to about 15% (w / v) based on the volume of the lipophilic oil.

[0117] Embodiment 31 provides the pharmaceutical composition of embodiment 30, wherein the analgesic, anesthetic, or both are present in a concentration ranging from about 3% (w / v) to about 10% (w / v) based on the volume of the lipophilic oil.

[0118] Embodiment 32 provides the pharmaceutical composition of embodiment 1, 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.

[0119] Embodiment 33 provides the pharmaceutical composition of embodiment 1, further comprising an adjuvant. Aspect 34 provides the pharmaceutical composition of aspect 33, wherein the adjuvant comprises a corticosteroid, an alpha 2 agonist, pethidine, a barbiturate, an opiate, tubocurarine chloride, a cannabinoid, meloxicam, a salt thereof, or an ion pair thereof, or a mixture thereof.

[0120] Embodiment 35 provides the pharmaceutical composition of embodiment 34, wherein the cannabinoid is cannabidiol (CBD). Aspect 36 provides the pharmaceutical composition of aspect 33, wherein the pharmaceutical composition is effective in reducing pain in a subject using lower concentrations of analgesic, anesthetic, anti-inflammatory, or a mixture thereof, and / or has a longer duration of pain relief compared to a corresponding pharmaceutical composition without the adjuvant.

[0121] Embodiment 37 provides the pharmaceutical composition of embodiment 1, further comprising a rheology modifier comprising a C2 to C12 alcohol. Aspect 38 provides the pharmaceutical composition of aspect 37, wherein the rheology modifier comprises ethanol, benzyl alcohol, or a mixture thereof.

[0122] Aspect 39 provides the pharmaceutical composition of Aspect 38, wherein the C2 to C12 alcohol comprises ethanol, benzyl alcohol, or a mixture thereof, and is present in a range of about 0.5% (w / v) to about 10% (w / v) of the pharmaceutical composition, based on the volume of the lipophilic oil.

[0123] Aspect 40 provides the pharmaceutical composition of Aspect 39, wherein the ethanol, benzyl alcohol, or mixture thereof is present in a range of about 1% (w / v) to about 6% (w / v) of the pharmaceutical composition, based on the volume of the lipophilic oil.

[0124] Aspect 41 provides the pharmaceutical composition of Aspect 1, wherein the pharmaceutical composition is effective to reduce pain in a subject for a period ranging from about 24 hours to about 14 days. Aspect 42 provides the pharmaceutical composition of Aspect 1, wherein the pharmaceutical composition is effective to reduce pain in a subject for a period ranging from about 48 hours to about 96 hours.

[0125] Aspect 43 provides the pharmaceutical composition of Aspect 1, wherein the pharmaceutical composition is effective to reduce pain in a subject for a period ranging from about 96 hours to about 168 hours. Aspect 44 provides the pharmaceutical composition of Aspect 1, wherein the pharmaceutical composition is effective to reduce pain in a subject for a period ranging from about 168 hours to about 336 hours.

[0126] Embodiment 45 provides the pharmaceutical composition of embodiment 1, wherein the composition is a semi-solid composition. Aspect 46 is medium chain triglycerides, Castor oil, an anesthetic agent comprising bupivacaine, an ion pair thereof, or a salt thereof, or both, present in an amount sufficient to relieve pain in a subject and dispersed about the mixture of medium chain triglycerides and castor oil; and a structuring agent comprising tristearin, glyceryl distearate, glycerol monostearate, glyceryl dibehenate, cholesterol, trimyristin, glyceryl dimyristin, glyceryl monomyristin, trilaurin, glyceryl dilaurin, glyceryl monolaurin, tripalmitin, glyceryl dipalmitin, glyceryl monopalmitin, cholesterol, polyglyceride esters of fatty acids, polyglycerol esters of fatty acids, or mixtures thereof; Optionally, the pharmaceutical composition is provided wherein the weight to weight ratio of the medium chain triglyceride to castor oil is about 50:50.

[0127] Aspect 47 provides the pharmaceutical composition of Aspect 1, wherein the viscosity of the composition is in the range of about 10 Pa·s (about 10,000 cP) to about 1000 Pa·s (about 1,000,000 cP) when measured at about 37°C.

[0128] Aspect 48 provides the pharmaceutical composition of Aspect 1, wherein the viscosity of the composition is in the range of about 10 Pa·s (about 10,000 cP) to about 150 Pa·s (about 150,000 cP) when measured at about 37°C.

[0129] Example 49 provides the pharmaceutical composition of Example 1, wherein after shear, the viscosity of the composition ranges from about 10 mPa·s (about 10 cP) to about 10,000 mPa·s (about 10,000 cP) when measured at about 37°C.

[0130] Embodiment 50 provides the pharmaceutical composition of embodiment 1, wherein the viscosity decreases upon shearing, making the composition injectable due to shear thinning behavior. Aspect 51 is syringes, and The pharmaceutical composition of embodiment 1 disposed within the syringe. A kit comprising:

[0131] Aspect 52 provides the kit of aspect 51, wherein the pharmaceutical composition is sealed within the syringe. Embodiment 53 provides the kit of embodiment 51, wherein the syringe further comprises a needle having a size of about 15 to 30 gauge.

[0132] Embodiment 54 provides the kit of embodiment 53, wherein the syringe comprises a needle size of about 21 to about 25 gauge. Embodiment 55 provides a method of making the pharmaceutical composition of embodiment 1, said method comprising: a) mixing a lipophilic oil and an analgesic, anaesthetic agent with stirring and heating to a temperature above 25°C to form a mixture; b) cooling the mixture to form the pharmaceutical composition. Includes.

[0133] Example 56 provides the method of Example 55, wherein the mixing in a) is conducted at a temperature ranging from about 50°C to about 150°C. Example 57 provides the method of Example 56, wherein the mixture is placed in a sealed syringe and cooled in b).

[0134] Example 58 provides the method of example 57, further comprising sterilizing the pharmaceutical composition. Example 59 provides the method of Example 58, wherein the pharmaceutical composition is sterilized after being dispensed into a container, and the sterilization comprises gamma irradiation, electron beam irradiation, X-ray irradiation, heat sterilization, steam sterilization, or a combination thereof.

[0135] Embodiment 60 provides a method of treating a subject with the pharmaceutical composition of embodiment 1, comprising administering said pharmaceutical composition to a subject in need thereof. Example 61 provides the method of Example 60, wherein the pharmaceutical composition is administered to the subject at or near a surgical site.

[0136] Example 62 provides the method of Example 61, wherein the pharmaceutical composition is administered to the subject at or near a wound. Example 63 provides the method of Example 62, wherein the pharmaceutical composition is administered to the subject at a site proximal to a wound.

[0137] Example 64 provides the method of Example 63, wherein the site proximal to the wound is a site where a nerve is blocked. Example 65 provides the method of Example 61, wherein a first portion of the pharmaceutical composition is administered to the subject at or near a wound, and a second portion of the pharmaceutical composition is administered to the subject at a site proximal to the wound.

[0138] Example 66 provides the method of Example 61, wherein administering the pharmaceutical composition comprises injecting the pharmaceutical composition via a syringe through a needle of about 18-30 gauge size, rubbing the pharmaceutical composition into or near a wound or surgical site, or a combination thereof.

[0139] Example 67 provides the method of Example 62, wherein the pharmaceutical composition is administered to the subject before surgery is performed, during surgery, or after the subject has undergone surgery. Example 68 provides the method of Example 67, further comprising administering a non-opioid analgesic to the subject 48 to 120 hours after the pharmaceutical composition is administered to the subject.

[0140] Example 69 provides the method of Example 68, further comprising administering a non-opioid analgesic to the subject 72 to 120 hours after the pharmaceutical composition is administered to the subject. Throughout this specification, values ​​expressed in range format should be interpreted flexibly to include not only the numerical values ​​explicitly recited as the limits of the range, but also all individual numerical values ​​or subranges within that range, as if each numerical value and subrange 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 individual values ​​(e.g., 1%, 2%, 3%, and 4%) and subranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the recited range. The statement "about X to Y" has the same meaning as "about X to about Y" unless otherwise specified. Similarly, the statement "about X, Y, or about Z" has the same meaning as "about X, about Y, or about Z" unless otherwise specified.

[0141] As used herein, the terms "a," "the," and "said" refer to one or more unless the context clearly indicates otherwise. The term "or" is used to refer to a non-exclusive "or" unless otherwise specified. The statements "at least one of A and B" or "at least one of A or B" have the same meaning as "A, B, or A and B." Furthermore, it should be understood that any phrases or terms used herein that are not otherwise defined are for descriptive purposes only and not for limiting purposes. The use of section headings is for ease of reading the document and is not limiting. Information associated with a section heading may appear within or outside that particular section.

[0142] In the methods described herein, unless a temporal or operational order is explicitly recited, actions may be performed in any order without departing from the principles of the present disclosure. Furthermore, certain actions may be performed simultaneously unless express claim language recites them being performed separately. For example, a claimed action of performing X and a claimed action of performing Y may be performed simultaneously in a single operation, and the resulting method would fall within the literal scope of the claimed method.

[0143] As used herein, the term "about" allows for a degree of variation in a value or range, such as within 10%, 5%, or 1% of a stated value or a stated range limit, and includes the exact value or range stated. As used herein, the term "substantially" refers to a large portion or majority, 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 more, or 100%. As used herein, the term "substantially free" can mean completely free or containing only trace amounts, and can mean that the amount of a substance present does not affect the material properties of a composition containing that substance. For example, the substance is from about 0% to about 5% by weight of the composition, or from about 0% to about 1% by weight, or less than about 5% by weight, or less than or equal to about 4.5%, 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 less than about 0.001%, or about 0% by weight.

Claims

1. a lipophilic oil comprising a mixture of at least two oils in a weight to weight ratio of about 75:25 to about 25:75; a hydrophobic ion pairing agent and an anesthetic agent dispersed in said lipophilic oil; and a structuring agent at least partially insoluble in said lipophilic oil and forming a gel; and wherein the injectable pharmaceutical composition does not contain a rheology modifier.

2. 10. The injectable pharmaceutical composition of claim 1, wherein the lipophilic oil comprises a mixture of at least two oils in a weight-to-weight ratio of about 70:30 to about 30:

70.

3. 2. The injectable pharmaceutical composition of claim 1, wherein the lipophilic oil comprises a monoglyceride, a diglyceride, a triglyceride, a medium chain triglyceride oil, sesame oil, soybean oil, castor oil, vegetable oil, tributyrin oil, or a mixture thereof.

4. 10. The injectable pharmaceutical composition of claim 1, wherein the structuring agent has a melting point of about 40°C to about 100°C.

5. 10. The injectable pharmaceutical composition of claim 1, wherein the structuring agent comprises a monoglyceride, a diglyceride, a triglyceride, a polyglyceride ester of a fatty acid, or a mixture thereof.

6. 2. The injectable pharmaceutical composition of claim 1, wherein the structuring agent comprises tristearin, glyceryl distearate, glycerol monostearate, glyceryl dibehenate, cholesterol, trimyristin, glyceryl dimyristin, glyceryl monomyristin, trilaurin, glyceryl dilaurin, glyceryl monolaurin, tripalmitin, glyceryl dipalmitin, glyceryl monopalmitin, cholesterol, polyglyceride esters of fatty acids, polyglycerol esters of fatty acids, or mixtures thereof.

7. 10. The injectable pharmaceutical composition of claim 1, wherein the structuring agent is present in a concentration ranging from about 0.1% (w / v) to about 25% (w / v) of the pharmaceutical composition, based on the volume of the lipophilic oil.

8. 10. The injectable pharmaceutical composition of claim 1, wherein the anesthetic agent comprises bupivacaine.

9. 2. The injectable pharmaceutical composition of claim 1, wherein the hydrophobic ion pairing agent comprises oleic acid, ricinoleic acid, docusate, or a mixture thereof.

10. 2. The injectable pharmaceutical composition of claim 1, wherein the anesthetic and the hydrophobic ion pairing agent together form bupivacaine butyrate, bupivacaine palmitate, bupivacaine laurate, bupivacaine myristate, bupivacaine stearate, bupivacaine hydroxystearate, bupivacaine oleate, bupivacaine ricinoleate, bupivacaine indocsate, or a mixture thereof.

11. 11. The injectable pharmaceutical composition of claim 10, wherein the anesthetic agent and the hydrophobic ion pairing agent together form bupivacaine oleate, bupivacaine ricinoleate, bupivacaine indoxate, or a mixture thereof.

12. 10. The injectable pharmaceutical composition of claim 1, which is a nerve block composition.

13. 13. The injectable pharmaceutical composition of claim 12, wherein the nerve block composition is a sciatic nerve block composition.

14. 10. The injectable pharmaceutical composition of claim 1, which is effective in relieving pain in a subject for a period ranging from about 24 hours to about 14 days.

15. medium chain triglycerides, Castor oil, an anesthetic in an amount sufficient to relieve pain in a subject, the anesthetic being dispersed about the medium chain triglyceride and castor oil mixture and comprising bupivacaine butyrate, bupivacaine palmitate, bupivacaine laurate, bupivacaine myristate, bupivacaine stearate, bupivacaine hydroxystearate, bupivacaine oleate, bupivacaine ricinoleate, or bupivacaindocusate; and structuring agents including tristearin, glyceryl distearate, glycerol monostearate, glyceryl dibehenate, cholesterol, trimyristin, glyceryl dimyristin, glyceryl monomyristin, trilaurin, glyceryl dilaurin, glyceryl monolaurin, tripalmitin, glyceryl dipalmitin, glyceryl monopalmitin, cholesterol, polyglyceride esters of fatty acids, polyglycerol esters of fatty acids, or mixtures thereof; 1. An injectable pharmaceutical composition comprising: the pharmaceutical composition does not contain a rheology modifier; An injectable pharmaceutical composition, wherein the weight:weight ratio of medium chain triglycerides to castor oil is from about 75:25 to about 25:

75.

16. 16. The injectable pharmaceutical composition of claim 15, wherein the weight:weight ratio of medium chain triglycerides to castor oil is about 70:30 to about 30:

70.

17. 16. The injectable pharmaceutical composition of claim 15, which upon shearing exhibits a decrease in viscosity, thereby rendering it injectable due to its shear thinning behavior.

18. 16. A method of treating a subject with the pharmaceutical composition of claim 15, comprising administering the pharmaceutical composition to a subject in need thereof, wherein administration of the pharmaceutical composition to the subject results in a nerve block.

19. 1. An injectable pharmaceutical composition comprising: bupivacaine in the range of about 3% to about 12% by weight of the pharmaceutical composition; oleic acid, ricinoleic acid, docusate, or a mixture thereof, in the range of about 3% to about 30% by weight of the pharmaceutical composition; a medium chain triglyceride oil in the range of about 26% to about 46.5% by weight of the pharmaceutical composition; Castor oil in the range of about 26% to about 46.5% by weight of the pharmaceutical composition; and Tristearin in the range of about 1% to about 6% by weight of the pharmaceutical composition Including, the pharmaceutical composition does not contain a rheology modifier; An injectable pharmaceutical composition, wherein the weight:weight ratio of said medium chain triglycerides to castor oil is about 50:

50.

20. 20. The injectable pharmaceutical composition of claim 19, which is a nerve block composition.

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