Pharmaceutical composition for treating pain

Abstract

The present application relates to pharmaceutical compositions for the treatment of pain. The pharmaceutical composition may comprise a lipophilic oil. The pharmaceutical composition may also include an analgesic, an anesthetic, an anti-inflammatory agent, or a mixture thereof dispersed in the lipophilic oil. The pharmaceutical composition may also include a structuring agent, at least a portion of which is insoluble in the lipophilic oil and forms a gel.

Description

[0001] This application is a divisional application of the Chinese patent application with application number 202380023719.4 and the invention name “Pharmaceutical composition for treating pain”. The original application is the PCT international application PCT / US2023 / 061464 filed on January 27, 2023, which entered the Chinese national phase on August 26, 2024.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of priority to U.S. Provisional Patent Application Serial No. 63 / 267,256, filed on January 28, 2022, entitled “PHARMACEUTICAL COMPOSITIONS FORTREATING PAIN,” the disclosure of which is incorporated herein by reference in its entirety. Background Art

[0004] Local anesthetics are widely used in surgery to numb the surgical site and relieve postoperative pain, but because of their short duration of action, they cannot provide analgesia for the entire period of severe pain a patient experiences. As the anesthesia wears off, opioids are given to control this pain, most often for three or more days, until less potent analgesics can control the pain. Summary of the Invention

[0005] The problem that the present disclosure seeks to solve is to provide an injectable or implantable composition that can provide robust pain relief for 2 to 14 days, which composition is both injectable and viscous enough to be manually implanted into the surgical site and remains at the site of application long enough to provide a local anesthetic effect. Accordingly, the present disclosure relates to a pharmaceutical composition comprising:

[0006] lipophilic oils;

[0007] a drug, a salt thereof, or a prodrug thereof (e.g., an analgesic, an anesthetic, an anti-inflammatory agent, or a mixture of these) dispersed in the lipophilic oil; and

[0008] A structurant, at least a portion of which is insoluble in the lipophilic oil and forms a gel.

[0009] The present disclosure also relates to pharmaceutical compositions comprising:

[0010] medium-chain triglycerides;

[0011] an anesthetic comprising bupivacaine, ropivacaine, or both, present in an amount sufficient to reduce pain in a subject, dispersed in a medium chain triglyceride; and

[0012] Structuring agents comprising tristearin, distearin, monostearin, dibehenin, cholesterol, trimyristin, dimyristin, monomyristin, trilaurin, dilaurin, monolaurin, tripalmitin, dipalmitin, monopalmitin, cholesterol, polyglycerol esters of fatty acids, polyglycerol esters of fatty acids, or mixtures thereof.

[0013] The present disclosure relates to a kit comprising:

[0014] syringes; and

[0015] The pharmaceutical composition of the present disclosure is configured in a syringe.

[0016] The present disclosure also relates to a method of preparing a pharmaceutical composition, the method comprising:

[0017] a) mixing a lipophilic oil, an analgesic, and an anesthetic at a temperature above 25° C. with stirring to form a first mixture;

[0018] 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

[0019] c) cooling the second mixture to form the pharmaceutical composition.

[0020] The present disclosure relates to methods of treating a subject with a composition of the present disclosure comprising administering the composition to a subject in need thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] The drawings generally illustrate various embodiments of the present disclosure by way of example and not by way of limitation.

[0022] Figure 1 is a graph showing drug release profiles of various oils.

[0023] Figure 2 is a graph showing drug release profiles of various oils.

[0024] Figure 3 is a graph showing the viscosity of various oils.

[0025] Figure 4 is a graph showing the effect of different oil components on viscosity.

[0026] Figure 5 is a graph showing viscosity curves of various formulations.

[0027] Figure 6 is a graph showing the viscosity of the formulation at body temperature.

[0028] Figures 7A to 7D is a series of graphs showing storage modulus values ​​for various formulations.

[0029] Figure 8A and 8B is a graph showing the peak melting and peak crystallization characteristics of various formulations.

[0030] Figure 9A and 9B is a graph showing rat sciatic nerve block data for various formulations.

[0031] Figure 10 is a graph showing efficacy data for various formulations in a porcine incisional wound model.

[0032] Figure 11 is a graph showing the solubility of bupivacaine in various blends of MCT oil and castor oil.

[0033] Figure 12 is a graph showing the solubility of bupivacaine and various lipophilic salts of bupivacaine in MCT oil.

[0034] Figure 13 is a graph showing the release characteristics of bupivacaine and various lipophilic salts of bupivacaine in MCT oil. DETAILED DESCRIPTION

[0035] 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.

[0036] 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 semisolid oleogel composed of a drug-loaded lipophilic oil, which is entrapped in a supramolecular network (e.g., molecular aggregates, crystals, etc.) of a self-assembled structure. The pharmaceutical composition can be used for both human and veterinary pain management applications. Possible clinical uses include, but are not limited to, neuraxial, regional, and local anesthesia for the treatment of surgical, postoperative, and injury-related pain, and local infiltration anesthesia for myofascial pain (e.g., trigger points) and chronic pain.

[0037] The pharmaceutical compositions described herein can be used for postoperative pain management as an alternative to medications containing opioids for postoperative pain management. The pharmaceutical compositions can completely replace medications containing opioids, or they can be used in combination with medications containing opioids to reduce the amount of opioids used in postoperative pain management.

[0038] Composition can take the form of injectable semisolid gel, paste or implantable solid agent.With the form of semisolid gel or paste, composition can be applied to surgical site / wound, and due to its viscosity, gel retains the place that initially applies.After closing surgical site / wound, semisolid gel can be embedded in natural gap and be applied between squeezed tissue (compressed tissue).The self-assembly supramolecular network produced by structurant prevents drug-oil phase from migrating from the position of using, and this helps safer and more effective local treatment.Structurant network will also protect the oil of load drug from the impact of surrounding internal environment (for example, surrounding aqueous internal environment), and this makes the medicine based on long-term diffusion can be discharged in aqueous environment from oil.Composition can be biodegradable, and therefore can be naturally absorbed by body in time.

[0039] Depending on the concentration and unique properties of the structuring agent, the composition can be adjusted to have a variety of mechanical properties. Adjustment of mechanical properties is relevant to the creation of long-acting local anesthetic drugs that represent an improvement over many currently clinically available technologies. 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 used 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 allow it to be retained at the implant site.

[0040] Structuring agents can be used to provide sufficient structure and mechanical properties for the composition. For example, if a therapeutic agent or drug (e.g., 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 dilute and flowable liquid, such as an aqueous solution. Therefore, if the solution (lacking a structuring agent) is injected or directly implanted into the surgical wound cavity, the solution can migrate and be eliminated from the application site, thereby reducing its effectiveness in controlling pain at the target site. In addition, the rapid elimination of the drug increases the risk of systemic toxicity (e.g., cardiotoxicity or neurotoxicity), which may be life-threatening. Therefore, as an example, a favorable long-acting local anesthetic composition should be both injectable and viscous enough to be manually implanted into the surgical site. Some currently available clinical options include solid implantable technologies that can only be implanted into the surgical site, which significantly limits its clinical application. Injectable compositions can be used as nerve blocks for extended duration of regional anesthesia, which has become widely popular due to the non-opioid management of postoperative pain; however, the current injectable option only lasts for less than 24 hours. Therefore, 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, which composition is both injectable and viscous enough to be manually implanted into a surgical site, while also being able to remain at its implantation site for an amount of time sufficient to provide local analgesia.

[0041] The lipophilic oil of composition can be selected from many suitable oils.For example, lipophilic oil can comprise monoglyceride, diglyceride, triglyceride, sesame oil, soybean oil, castor oil, tributyrin oil, vegetable oil or its mixture.For example, lipophilic oil can comprise the mixture of medium chain triglyceride oil and castor oil, wherein independently of one another is 5 weight % to 98 weight %, 30 weight % to 70 weight %, less than, equal to or greater than 5 weight %, 10 weight %, 15 weight %, 20 weight %, 25 weight %, 30 weight %, 35 weight %, 40 weight %, 45 weight %, 50 weight %, 55 weight %, 60 weight %, 65 weight %, 70 weight %, 75 weight %, 80 weight %, 85 weight %, 90 weight % or about 98 weight %.Sesame oil generally comprises other organic acids of 41 weight % linoleic acid, 39 weight % oleic acid, 8 weight % palmitic acid, 5 weight % stearic acid and trace. Every 100g soybean oil has 16g of saturated fat, 23g of monounsaturated fat and 58g of polyunsaturated fat.The main unsaturated fatty acids in soybean oil triglyceride are 7% by weight to 10% by weight polyunsaturated α-linolenic acid and 51% by weight linoleic acid and 23% by weight monounsaturated oleic acid.Soybean oil also includes saturated fatty acids, for example 4% by weight stearic acid and 10% by weight palmitic acid.Castor oil includes 85% by weight to 95% by weight ricinoleic acid, 2% by weight to 6% by weight oleic acid, 1% by weight to 5% by weight linoleic acid, 0.5% by weight to 1% by weight α-linolenic acid, 0.5% by weight to 1% stearic acid, 0.5% by weight to 1% by weight palmitic acid, 0% by weight to 0.5% dihydroxystearic acid and 0.2% by weight to 0.5% by weight other compounds.Tributyrin oil is an ester that is the reaction product of butyric acid and glycerol.Triglyceride can be medium chain triglyceride, short chain triglyceride or the two thereof. Some examples of medium chain triglycerides include esters that are the reaction product of glycerol and any of the C6-C12 carboxylic acids (eg, caproic acid, caprylic acid, capric acid, lauric acid, or mixtures thereof).

[0042] Medium chain triglycerides can be especially suitable as lipophilic oil.Although not intended to be restricted by any theory, the benefit of using medium chain triglycerides is considered to be due to its rare character and low viscosity, this rare character and low viscosity each all make its injectable (compared with castor oil, it has good drug solubility, but very sticky).In addition, show that medium chain triglycerides provides high drug load and good release rate.Therefore, medium chain triglycerides is useful, because they show the viscosity that makes its injectable, use structuring agent to be structured into supramolecular gel, load with q.s of medicine, and show good drug release curve.

[0043] The mixture of lipophilic oil can be used.For example, pharmaceutical composition may include following mixture: medium-chain triglyceride and short-chain triglyceride, medium-chain triglyceride and long-chain triglyceride oil or short-chain triglyceride and long-chain triglyceride.In some instances, with the medium-chain triglyceride of 90:10 (medium-chain triglyceride: short-chain triglyceride) and the mixture of short-chain triglyceride, the solubility of medicine (such as ropivacaine) can improve.As another example, the mixture of medium-chain triglyceride and castor oil will realize higher drug load as lipophilic oil, reduces the viscosity in the overall structure simultaneously.

[0044] Structuring agents (or alternatively referred to as organic structuring agents, oil structuring agents or supramolecular structuring agents) impart structure to lipophilic oils. For example, structuring agents help to form gels. An example of a type of gel 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 supramolecular assemblies are formed is called molecular self-assembly. Molecular self-assembly refers to the process by which molecules are arranged without guidance or management from an external source.

[0045] The structuring agent is present in the pharmaceutical composition at a concentration of 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), less than, equal to, or greater than about 0.1% (w / v), based on the volume of the lipophilic oil.

[0046] 0.5,1,1.5,2,2.5,3,3.5,4,4.5,5,5.5,6,6.5,7,7.5,8,8.5,9,9.5,10,10.5,11,11.5,12,12.5,13,13.5,14,14.5,15,15.5,16,16.5,17,17.5,18,18.5,19,19.5,20,20.5,21,21.5,22,22.5,23,23.5,24,24.5

[0047] or about 25% (w / v). The structurant or mixture of structurants used may depend on several factors, such as the melting point of the structurant. For example, the structurant may have a melting point of 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.

[0048] Some examples of suitable structurants include polyglycerol esters of monoglycerides, diglycerides, triglycerides, fatty acids, or their mixtures. The polyglycerol used herein can be diglycerol or triglycerol, and can be esterified completely or partially with saturated or unsaturated fatty acid moieties. Fatty acid 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 their mixtures. Some more specific examples of suitable structurants include tristearin, distearin, monostearin, dibehenin, cholesterol, trimyristin, dimyristin, monomyristin, trilaurin, dilaurin, monolaurin, tripalmitin, dipalmitin, monopalmitin, diglycerol esterified with stearic acid, cholesterol, or their mixtures.

[0049] At least a portion of the structuring agent phase separates in the lipophilic oil. Thus, for example, a portion of the structuring agent may be partially soluble 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 allows the structuring agent to contribute to the formation of a supramolecular gel 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 difficult to dissolve, it will not interact with the lipophilic oil, and the pharmaceutical composition will exhibit the form of a heterogeneous unstable gel and the structuring agent will separate out.

[0050] Supramolecular gels themselves can be characterized as semisolid compositions (or quasi-solids or semi-liquids). Although similar to solids in some respects (e.g., having the ability to support their own weight and maintain their shape), semisolid compositions also share some properties of liquids (e.g., conforming to the shape of something to which pressure is applied and being able to flow under pressure). Selecting an appropriate structuring agent can also affect the viscosity of the pharmaceutical composition. An appropriate viscosity allows 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, from 20,000 cP to about 90,000 cP, less than, equal to, or greater than about

[0051] 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, 1,000,000cP. ,

[0052] If the viscosity is too low, the pharmaceutical composition will be dispersed beyond the desired location. In addition, if the viscosity is too low, uncontrolled drug release may result. On the contrary, if the viscosity is too high, it is impossible to inject the pharmaceutical composition into 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 usually too high to be injected by a clinically relevant needle size (18G to 25G needle). The specific disadvantage of not being able to be injected by these needles is that such solutions cannot be used as nerve blocks. To overcome this, the disclosed pharmaceutical composition is modified to be shear-thinning, which is defined as the ability of a material to reduce viscosity as shear increases. Such a composition can be preloaded into a syringe, extruded after applying shear, and recovers its viscosity after the mechanical load stops, a process called self-repairing. This self-repairing behavior allows for improved application and material retention, thereby improving the usefulness and efficacy of the drug product, while also exhibiting the extended drug release characteristics described herein. As an example, when sheared at a sweep 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,

[0053] 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

[0054] Or about 10,000 cP. Unless otherwise stated, all viscosity values ​​stated herein were obtained at 37°C on a HAAKE Mars 60 rheometer obtained from Thermo-Fisher Scientific, Waltman MA.

[0055] The drug may be present in a pharmaceutical composition in a therapeutically effective amount. For use in therapy, a "therapeutically effective amount" (or "effective amount") of a compound refers to that amount of the compound in a formulation that, when administered as part of a desired dosage regimen (to a mammal, such as a human), alleviates symptoms, ameliorates symptoms, or slows the onset of a disease condition according to clinically acceptable standards (e.g., at a reasonable benefit / risk ratio applicable to any medical treatment) for the disorder or condition being treated or for cosmetic purposes.

[0056] The terms "prophylactic or therapeutic" treatment are art-recognized and include administering one or more compounds of the present disclosure to a patient. If it is administered before the clinical manifestation of an undesirable condition (e.g., a disease or other undesirable condition of the host animal), the treatment is prophylactic (i.e., it protects the host from developing the undesirable condition), while if it is administered after the manifestation of the undesirable condition, the treatment is therapeutic (i.e., it is intended to reduce, alleviate, or stabilize an existing undesirable condition or its side effects).

[0057] The exact amount of drug can vary and be selected based on the application. As a non-limiting example, the drug can be present in the following concentrations based on the volume of the lipophilic oil: 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), based on the volume of the lipophilic oil.

[0058] 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

[0059] or about 40% (w / v). Whether an amount is therapeutically effective can be a factor of the amount of time that pain is relieved in a subject. For example, a pharmaceutical composition can be effective in reducing pain in a subject for a period of time from about 24 hours to about 14 days, from about 48 hours to about 14 days, from about 72 hours to about 96 hours, from about 72 hours to about 80 hours, less than, equal to, or greater than about 24 hours, 25 hours, 26 hours, 27 hours, 28 hours, 29 hours, 30 hours, 31 hours, 32 hours, 33 hours, 34 hours, 35 hours, 36 hours, 37 hours, 38 hours, 39 hours, 40 hours, 41 hours, 42 hours, 43 hours, 44 hours, 45 hours, 46 hours, 47 hours, 48 ​​hours, 49 hours, 50 hours, 51 hours, 52 hours, 53 hours, 54 hours, 55 hours. , 56 hours, 57 hours, 58 hours, 59 hours, 60 hours, 61 hours, 62 hours, 63 hours, 64 hours, 65 hours, 66 hours, 67 hours, 68 hours, 69 hours, 70 hours, 71 hours, 72 hours, 73 hours, 74 hours, 75 hours, 76 hours, 77 hours, 78 hours, 79 hours, 80 hours, 81 hours, 82 hours, 83 hours, 84 hours, 85 hours, 86 hours, 87 hours, 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. In some embodiments, the present invention provides the pharmaceutical composition of the present invention.Some pharmaceutical compositions can be designed to effectively alleviate pain and continue specific scope, for example 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. Definite drug release characteristics can be the function of pharmaceutical composition structure.For example, the blend of specific lipophilic oil affects drug release characteristics.For example, the specific ion pair (for example, lipophilic salt) formed by therapeutic agent can affect release characteristics.

[0060] The amount of time that pharmaceutical composition is effective for treatment can be the result of the release rate of drug from lipophilic oil.Drug is released from lipophilic oil and is controlled by diffusion.According to the affinity of drug to specific lipophilic oil or the blend of specific lipophilic oil, drug will be preferentially present in lipophilic oil and slowly diffuse into the surrounding aqueous medium in patient's body, which depends on its affinity to lipophilic oil being greater than to aqueous medium.Drug release rate also depends on the interfacial area between oil-based carrier and surrounding aqueous in vivo environment.Above-mentioned interfacial area can be controlled by the supramolecular gel provided by structuring agent.In the case of any structure, pharmaceutical composition can flow freely and diffuse in vivo, which significantly increases its interfacial surface area, and therefore significantly accelerates its drug release rate.However, if lipophilic oil forms viscous semisolid by its supramolecular gel, it will have significantly reduced diffusion ability and increase its interfacial area, therefore reduce the rate of drug release and prolong the effect of local controlled non-opioid pain management (if drug is used as analgesic or anesthetic).

[0061] Therapeutic agents include analgesics, anesthetics, and anti-inflammatory agents. The various lipophilic therapeutic agents in their basic form can be covalently or non-covalently modified to increase their lipophilicity and the resulting solubility and drug loading capacity in the base oil. This is achieved by changing the physicochemical properties of the drug (e.g., melting point, polarity, hydrophobicity, partition coefficient). Using covalent modification, prodrugs of pharmaceutical agents 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 charged drug molecules with oppositely charged molecules having a hydrophobic portion. The resulting complex is more lipophilic and hydrophobic, making it better encapsulated in lipid-based formulations and released more controlled from lipid-based formulations. Therefore, both covalent and non-covalent regulation 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 expected solubility and partition coefficient from the base oil will also be different. For example, a drug with a log P of less than 2 can be modified by forming a prodrug with a log P greater than a reported 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, thereby resulting in a slower modified release profile. In one such example, a drug with a log P of less than 2 can contain hydroxyl or amino functional groups, which can be combined with C 12 -C 22 Carboxylic acids form esters or amides. 12 -C 22Ester or amide can have the log P value of record (for example, at least 3).As an alternative or supplement, medicine or prodrug can be modified by being paired with the hydrophobic counterion that can have the log P value of record.For example, medicine or prodrug can be synthesized as docusate salt, or can be ion exchanged to form docusate salt, wherein docusate is the counterion of medicine.Other such counterions are known in the art, and are considered in this article.Therefore, except analgesics, anesthetics and anti-inflammatory agents described herein, pharmaceutical composition described herein can also be formulated to contain one or more adjuvants, and described adjuvant agent (adjuvant agent) can also be through covalent or non-covalent modification.Some examples include but are not limited to sympatholytics (for example, dexmedetomidine (dexmedetomidine), clonidine (clonidine)), antianxiety agents (for example, midazolam (midazolam)), anti-inflammatory agents (for example, dexamethasone (dexamethasone), NSAID, COX-2 inhibitor) and cannabinoids (for example, cannabidiol).

[0062] As used herein, the partition coefficient or log P is a measure of the lipophilicity of a drug and an indicator of its ability to pass through a cell membrane. It is defined as the ratio between the drug distributed between the organic layer and the aqueous layer when in equilibrium. The partition coefficient of a drug can be determined by shaking it with equal parts of two mutually immiscible solvents (the organic layer saturated with water and the aqueous drug solution) until equilibrium is reached. The content of the drug in one of the layers is determined and the value is calculated. Octanol-water distribution is a system commonly used in this research. Although a single partition coefficient may not provide information about absorption, it characterizes the lipophilic-hydrophilic balance of the drug and supports screening compounds for the biological properties of the compound. In combination with Log P, the drug melting point can also be used to screen compounds for the lipid solubility of the compound. Molecules with high melting points tend to be more difficult to dissolve than predicted according to their Log P. Molecules with low melting points tend to be more soluble than predicted according to Log P.

[0063] As understood herein, analgesics are any member of the drug group for achieving analgesia (relieving pain). They are different from anesthetics, and they temporarily affect sensation and eliminate sensation in some cases. Some examples of suitable analgesics may include nonsteroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors, or their mixtures. Some non-limiting examples of NSAIDs may include ibuprofen, naproxen, diclofenac, mefenamic acid, indomethacin, cannabidiol, its ion pair, its salt, or a mixture thereof. Some non-limiting examples of COX-2 inhibitors may include etoricoxib, meloxicam, celecoxib, its ion pair, its salt, or a mixture thereof.

[0064] As understood herein, an anesthetic refers to any agent that produces a loss of local or systemic sensation (including pain). Anesthetics achieve this effect by acting on the brain or peripheral nervous system to suppress the response to sensory stimuli. Therefore, the induced unresponsive state is called anesthesia. General anesthesia involves loss of consciousness, usually for the purpose of relieving surgical pain. Local anesthesia involves loss of sensation and / or motor function in one area of ​​the body by blocking conduction in the nerves.

[0065] 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 their mixtures. Some non-limiting examples based on ester-based anesthetics include procaine, amethocaine, benzocaine, tetracaine or their mixtures. Some non-limiting examples based on amide-based anesthetics include lidocaine, prilocaine, bupivacaine, levobupivacaine, ropivacaine, mepivacaine, dibucaine, etidocaine, its salt or a mixture of these. Anesthetics based on amides may include the free base form of the anesthetic based on amides, the hydrochloride form of the anesthetic based on amides or other salt forms or ion pairs (including lipophilic salts) of the anesthetic based on amides. The lipophilic salt of the anesthetic based on amide involves pairing the protonated anesthetic based on amide with a lipophilic counterion, which can improve the solubility of the anesthetic based on amide in lipophilic oils. This can be beneficial to improving the load of the anesthetic in the pharmaceutical composition. For example, the lipophilic salt or ion pair of the anesthetic based on amide can include the docusate counterion. As an example, the lipophilic salt or ion pair of the anesthetic based on amide can be ropivacaine docusate. As another example, the local anesthetic based on amide is an ion pair or salt comprising bupivacaine butyrate, bupivacaine palmitate, bupivacaine laurate, bupivacaine myristate, bupivacaine stearate, bupivacaine hydroxystearate, bupivacaine oleate, bupivacaine ricinoleate, and docusate bupivacaine.

[0066] Although any one in the above-mentioned anesthetic based on amide is all expectation, it is also possible to expect to use ropivacaine, because it comprises several known clinical advantages, for example good patient safety and good analgesic properties (for example sensory selectivity).But ropivacaine shows poor solubility conventionally in lipophilic oil (including but not limited to medium chain triglyceride).Relative poor solubility extends to free alkali and the hydrochloride form of ropivacaine.But, unexpectedly show that docusate ropivacaine shows suitable solubility in lipophilic oil (for example medium chain triglyceride), so that a sufficient amount of ropivacaine is dissolved in the lipophilic oil and discharges at an acceptable rate.

[0067] Some suitable examples of anti-inflammatory agents can include aspirin, celecoxib, diclofenac, diflunisal, etodolac, ibuprofen, indomethacin, ketoprofen, ketorolac, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin, or mixtures thereof.

[0068] The pharmaceutical composition may include an excipient. In the context of a pharmaceutical, an excipient refers to a drug with analgesic properties in the case of a primary indication other than pain. Some examples of suitable excipients include barbiturates, opiates, anti-inflammatory agents, cannabinoids, sympatholytics, or mixtures thereof. Other examples of suitable excipients include corticosteroids, dexamethasone, pethidine, myostatin, meloxicam, dexmedetomidine, or mixtures thereof.

[0069] If the excipient comprises a cannabinoid, a suitable cannabinoid may be cannabidiol (CBD). However, other cannabinoids may include cannabigerolic acid (CBGA), cannabigerolic acid monomethylether (CBGAM), cannabigerol (CBG), cannabigerol monomethylether (CBGM), cannabigerovarinicacid (CBGVA), cannabigerovarin (CBGV), cannabichromenic acid (CBCA), cannabichromene (CBC), cannabichromevarinicacid (CBCVA), cannabichromevarin (CBCV), cannabidiolic acid (CBDA), cannabidiol monomethylether (CBDM), cannabidiol-C4 (CBD-C4), cannabidivarinic acid (CBD), and cannabichromenic acid (CBD). 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 (THCVA), tetrahydrocannabivarin (TEV), tetrahydrocannabinol (THC-C4 ...THCV), tetrahydrocannabircolic acid (THCA-C1), tetrahydrocannabiorcol (THC-C1), Δ7-cis-iso-tetrahydrocannabinol, Δ8-tetrahydrocannabinolic acid (Δ8-THCA), cannabivarinodiolic (CBNDVA), cannabivarinodiol (CBNDV), Δ8-tetrahydrocannabinol (Δ8-THC), Δ9-tetrahydrocannabinol (Δ9-THC), cannabicyclolic acid (CBLA), cannabicyclol (CBL), cannabicyclovarin (CBLV), hexahydrocannabielsoic acid A (CBEA-A), hexahydrocannabifurcolic acid B (CBEA-B), hexahydrocannabielsoin (CBE), cannabivarinselsoin (CBEV), cannabivarinselsoinic acid (CBEVA), hexahydrocannabinofuric acid (cannabielsoic acid, CBEA), cannabielvarinsoin (CBLV), cannabielvarinsoinic acid (CBLVA), cannabinolic acid (CBNA), cannabinol (CBN), cannabivarinic acid (CBNVA), cannabinol methylether (CBNM), cannabinol-C4 (CBN-C4), cannabivarin (CBV), cannabino-C2 (CBN-C2), cannabiorcol (CBN-C1), cannabinodiol (CBND), cannabinodiolic acid (CBNVA), 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-cannabitriol (CBTVE), dehydrocannabifuran (dehydrocannabifuran),DCBF), cannbifuran (CBF), cannabichromanone (CBCN), cannabipyran cycloalkane (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-benzoxazin-5-ol (OH-iso-HHCV), trihydroxy-Δ-9-tetrahydrocannabinol (triOH-THC), yangonin, epigallocatechin gallate / salt gallate), dodecane-2E,4E,8Z,10Z-tetraenoic acid isobutylamide, and dodecane-2E,4E-dienoic acid isobutylamide, mixtures thereof, or a mixture of any of the foregoing with cannabidiol.

[0070] The inclusion of an excipient may provide a synergistic effect relative to a comparative pharmaceutical composition that differs only in that it does not contain the excipient because the amount of drug that needs to be added to be considered a therapeutically effective amount may be reduced.

[0071] In some aspects, the pharmaceutical composition may include a rheology modifier. If present, the rheology modifier may 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).

[0072] In some aspects, the rheology modifier can be a diluent that reduces the viscosity of the pharmaceutical composition. In some instances, where the pharmaceutical composition is intended to be injected, the diluent can be beneficial because it can enhance the injectability of the pharmaceutical composition by reducing the viscosity of the pharmaceutical composition. 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 help enhance the shelf life stability of the pharmaceutical composition. For example, if the components of the pharmaceutical composition are evenly distributed relative to each other, the formation of the supramolecular gel can be delayed until deployment in vivo. Some examples of suitable diluents can include C2-C 12 Alcohol. Some non-limiting examples of alcohols include ethanol, benzyl alcohol, or mixtures thereof. The benefit of using ethanol or benzyl alcohol is that once the pharmaceutical composition (including ethanol or phenylpropanol) is utilized in vivo, the ethanol or phenylpropanol will diffuse in the aqueous environment, resulting in an increase in the viscosity of the pharmaceutical composition and / or complete formation of the supramolecular gel.

[0073] In other aspects, rheology modifiers can increase the viscosity of a pharmaceutical composition. For example, this can be helpful if a particular combination of a lipophilic oil and a structurant together interacts well, or allows for adequate dispersion and diffusion of the desired drug, but together do not provide a composition with sufficient viscosity. Including a rheology modifier to increase viscosity can make the pharmaceutical composition workable.

[0074] 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 materials suitable for administration to humans or other vertebrates. The term "carrier" refers to a natural or synthetic organic or inorganic ingredient with which the active ingredient is combined to facilitate application. The components of the pharmaceutical composition may also be mixed with the compound, and with each other, in a manner such that there is no interaction that would significantly impair the desired drug efficacy.

[0075] As used herein, the phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, which is involved in carrying or transporting the subject chemical from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the composition, not harmful to the patient, and substantially non-pyrogenic. Some examples of materials 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, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, castor oil, Chinese herbal medicine, and so on. (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) buffers, 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 buffered saline; and (21) other non-toxic compatible substances employed in the pharmaceutical composition. The pharmaceutical composition of the present disclosure is pyrogen-free, i.e., does not induce a significant temperature increase when administered to a patient.

[0076] The pharmaceutical composition can be packaged in any suitable manner. For example, the pharmaceutical composition can be packaged in a tank, a vessel, etc. so that the pharmaceutical composition can be obtained and manually applied at the desired position. Alternatively, the pharmaceutical composition can be configured in the distribution chamber of a syringe. The syringe can have a needle having a size of 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 composition can be configured from a syringe without a needle (for example, by a cone applicator).

[0077] The pharmaceutical composition can be prepared by: a) mixing a lipophilic oil with an analgesic, anesthetic (or other drug within the scope of the present disclosure) at a temperature above 25° C. with stirring to form a first mixture; b) mixing a structuring agent 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.

[0078] As an example, a pharmaceutical composition can be prepared by mixing a lipophilic oil and a drug under stirring at a temperature above room temperature (25°C) 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. A structuring agent can be added to the first mixture under stirring and heating at a temperature above room temperature (25°C) 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. The second mixture can then be cooled to form a pharmaceutical composition. Before cooling the second mixture, it may be placed in a jar, container, or syringe so that a supramolecular gel forms therein.

[0079] The pharmaceutical composition and / or the canister, vessel, or syringe can be sterilized at any 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).

[0080] In operation, the pharmaceutical composition can be administered to the subject. The pharmaceutical composition can be administered at or near the injury or wound or treatment site. An example of an injury or wound may 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 at a specific location to block nerves and thus block pain from a distant injury or wound. In the context of surgery, the pharmaceutical composition can be applied before surgery, during the surgical procedure (e.g., any time before incision closure), or after surgery (e.g., after incision closure).

[0081] As used herein, the term "kit" refers to a package or one or more separately packaged products (e.g., a medication, a kit of parts) comprising:

[0082] (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, each package containing a pharmaceutical composition comprising two or more active pharmaceutical ingredients. The additional active pharmaceutical ingredient may also be present in separate pharmaceutical compositions, i.e., the kit may comprise separate packages of two or more pharmaceutical compositions, each containing one active pharmaceutical ingredient.

[0083] or

[0084] (ii) A pharmaceutical composition comprising an active pharmaceutical ingredient and a medical device.

[0085] A medicine box may comprise only one package, or may comprise one or more separate packages. For example, a medicine box may be a product (e.g., a drug) comprising two or more vials, each vial comprising a defined pharmaceutical composition, wherein each pharmaceutical composition comprises at least one active pharmaceutical ingredient. For example, a medicine box may comprise: (i) a vial containing a defined pharmaceutical composition, and (ii) in addition, a tablet, capsule, powder, or any other oral dosage form containing at least one additional active pharmaceutical ingredient. The medicine box may also comprise a package insert (leaflet) which describes how to administer the pharmaceutical composition and at least one additional active pharmaceutical ingredient.

[0086] As used herein, the term "medical device" means any instrument, apparatus, implant, in vitro reagent, or similar or related article used for the diagnosis, prevention, or treatment of disease with other conditions, and which does not achieve its purpose through pharmacological action in or on the body.

[0087] As used herein, a 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, a medical device may be mechanically or electromechanically driven.

[0088] The ingredients in the pharmaceutical composition can be defined as Generally Recognized as Safe ("GRAS (Generally Recognized as Safe)"). A complete list of GRAS ingredients can be found in the GRAS Substances (SCOGS) database maintained by the United States Food and Drug Administration. About 50% to about 100% of the ingredients in the pharmaceutical composition can be classified as GRAS ingredients, and about 75% to about 100%, about 90% to about 100%, less than, equal to, or greater than about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or about 100% of the ingredients in the pharmaceutical composition can be classified as GRAS ingredients.

[0089] Example

[0090] Various aspects of the present disclosure may be better understood with reference to the following examples which are provided by way of illustration.The present disclosure is not limited to the examples given herein.

[0091] Table 1: Materials

[0092]

[0093]

[0094] Fifteen compositions were prepared. Each composition was prepared by heating medium-chain triglycerides to about 70°C. The drug (bupivacaine free base, ropivacaine docusate, or ropivacaine free base) was added to the heated medium-chain triglycerides and stored. Subsequently, a structuring agent (trimyristin, tripalmitin, trilaurin, or monostearin) was added under heating and stirred until fully dissolved. The resulting solution was drawn into a syringe, the bubbles were removed, and the syringe was sealed with an airtight seal. When the solution cooled to room temperature (about 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 structuring agent and drug of each composition are expressed as weight (w / v) relative to the volume of the lipophilic oil.

[0095] Table 2: Composition 1

[0096] Function Components concentration lipophilic oil Medium-chain triglycerides - Structuring agent Glyceryl Monostearate 10% to 20% (w / v) drug Bupivacaine free base 5% (w / v)

[0097] Table 3: Composition 2

[0098] Function Components concentration lipophilic oil Medium-chain triglycerides - Structuring agent Glyceryl Distearate 10% to 20% (w / v) drug Bupivacaine free base 5% (w / v)

[0099] Table 4: Composition 3

[0100] Function Components concentration lipophilic oil Medium-chain triglycerides - Structuring agent Trimyristin 10% to 20% (w / v) drug Bupivacaine free base 5% (w / v)

[0101] Table 5: Composition 4

[0102] Function Components concentration lipophilic oil Medium-chain triglycerides - Structuring agent Tripalmitin 5% to 20% (w / v) drug Bupivacaine free base 5% (w / v)

[0103] Table 6: Composition 5

[0104] Function Components concentration lipophilic oil Medium-chain triglycerides - Structuring agent Glyceryl Monolaurate 10% to 20% (w / v) drug Bupivacaine free base 5% (w / v)

[0105] Table 7: Composition 6

[0106] Function Components concentration lipophilic oil Medium-chain triglycerides - Structuring agent Glyceryl Monostearate 10% to 20% (w / v) drug Ropivacaine docusate 5% (w / v)

[0107] Table 8: Composition 7

[0108] Function Components concentration lipophilic oil Medium-chain triglycerides - Structuring agent Glyceryl Distearate 10% to 20% (w / v) drug Ropivacaine docusate 5% (w / v)

[0109] Table 9: Composition 8

[0110] Function Components concentration lipophilic oil Medium-chain triglycerides - Structuring agent Trimyristin 10% to 20% (w / v) drug Ropivacaine docusate 5% (w / v)

[0111] Table 10: Composition 9

[0112] Function Components concentration lipophilic oil Medium-chain triglycerides - Structuring agent Tripalmitin 10% to 20% (w / v) drug Ropivacaine docusate 5% (w / v)

[0113] Table 11: Composition 10

[0114] Function Components concentration lipophilic oil Medium-chain triglycerides - Structuring agent Glyceryl Monolaurate 10% to 20% (w / v) drug Ropivacaine docusate 5% (w / v)

[0115] Table 12: Composition 11

[0116] Function Components concentration lipophilic oil Medium-chain triglycerides - lipophilic oil Tributyrin 5% to 10% (w / v) Structuring agent Glyceryl Monostearate 10% to 20% (w / v) drug Ropivacaine free base 5% (w / v)

[0117] Table 13: Composition 12

[0118] Function Components concentration lipophilic oil Medium-chain triglycerides - lipophilic oil Tributyrin 5% to 10% (w / v) Structuring agent Glyceryl Distearate 10% to 15% (w / v) drug Ropivacaine free base 5% (w / v)

[0119] Table 14: Composition 13

[0120] Function Components concentration lipophilic oil Medium-chain triglycerides - lipophilic oil Tributyrin 5% to 10% (w / v) Structuring agent Trimyristin 10% to 20% (w / v) drug Ropivacaine free base 5% (w / v)

[0121] Table 15: Composition 14

[0122] Function Components concentration lipophilic oil Medium-chain triglycerides - lipophilic oil Tributyrin 5% to 10% (w / v) Structuring agent Tripalmitin 10% to 25% (w / v) drug Ropivacaine free base 5% (w / v)

[0123] Table 16: Composition 15

[0124] Function Components concentration lipophilic oil Medium-chain triglycerides - lipophilic oil Tributyrin 5% to 10% (w / v) Structuring agent Trilaurin 10% to 15% (w / v) drug Ropivacaine free base 5% (w / v)

[0125] Table 17: Composition 15

[0126] Function Components concentration lipophilic oil Medium-chain triglycerides - lipophilic oil castor oil 10% to 50% (w / v) Structuring agent Glyceryl Tristearate 3% to 15% (w / v) drug Bupivacaine free base 5% (w / v)

[0127] Table 18: Composition 15

[0128] Function Components concentration lipophilic oil Medium-chain triglycerides - lipophilic oil castor oil 10% to 50% (w / v) Structuring agent Tripalmitin 10% to 15% (w / v) drug Bupivacaine free base 5% (w / v)

[0129] Table 19: Composition 15

[0130] Function Components concentration lipophilic oil Medium-chain triglycerides - lipophilic oil castor oil 10% to 50% (w / v) Structuring agent Glyceryl Tristearate 3% to 15% (w / v) drug Bupivacaine oleate 5% (w / v)

[0131] Example 2

[0132] 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) were investigated for their ability to release bupivacaine free base over time. Figure 1 As shown in , bupivacaine free base is released more slowly in the oil gel formulation.

[0133] 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 tank of phosphate buffered saline (1×; pH 7.4). The sample was placed in a rotating incubator (1 Hz) at 37°C. At the designated time points, 2 mL of saline was removed and analyzed using UV-visible spectrophotometry (272 nm). The entire tank medium was replaced at each time point until the drug no longer eluted from the system.

[0134] Example 3

[0135] The drug release over time of an oleogel formulation comprising bupivacaine free base, MCT oil, and glyceryl monostearate (structurant), and an oleogel formulation comprising bupivacaine free base, a lipophilic oil mixture consisting of 75 wt% MCT oil and 25 wt% castor oil, and glyceryl monostearate (structurant) was studied.

[0136] As in Figure 2 As shown in , the release of bupivacaine free base was slower in the formulation comprising a mixture of 75 wt% MCT oil and 25 wt% castor oil. The drug release profile was measured according to the protocol of Example 2.

[0137] Example 4

[0138] The viscosity of various oils used in the formulations described herein was studied at 37°C. The oils studied included castor oil, MCT oil, and blends of castor oil and MCT oil (e.g., 50%, 40%, 30%, and 20% castor oil with the balance being MCT). Figure 3As shown, the viscosity of the MCT:castor blend 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 in MCT, blending these two oils can achieve both good drug solubility (and thus, good drug loading capacity) and low viscosity suitable for injection. For example, these properties mean that 30% to 50% castor oil can be included to achieve higher drug loading and slower drug release without significantly changing the base viscosity of the oil.

[0139] The rheological properties of each formulation were measured using a rheometer. Approximately 0.5 mL of the formulation was injected onto the rheometer plate using an 18G needle using a 35 mm parallel plate with a 0.5 mm gap. A rotating ramp test was performed at 20°C, with a shear rate ramp between 1 and 200 Hz to obtain a viscosity curve.

[0140] Example 5

[0141] The viscosity of a formulation containing 25 wt% castor oil and 20 wt% structurant was measured at 37° C. The structurants included monostearate, monopalmitate, and blends thereof. Figure 4 Shown is the effect of viscosity as the weight % of monostearate in the mixture of monostearate and monopalmitate is varied. As shown, the formulations with only monostearate or only monopalmitate are significantly weaker than the gels made from the blend of the two. Viscosity was measured according to the protocol of Example 4.

[0142] Example 6

[0143] The shear rate of a formulation containing 25% monostearate & monopalmitate, 100% MCT, 5% bupivacaine was studied. Figure 5 As shown in FIG, the viscosity curve shows that as the shear rate increases, the viscosity decreases. This property can be called "shear thinning", which means that the formulation has improved injectability and produces in situ gelation. The viscosity was measured according to the protocol of Example 4.

[0144] Example 7

[0145] The viscosity of formulations containing MCT (60:40 monostearate:monopalmitate mixture ("GMSP") and bupivacaine free base) was measured at 20°C and 37°C (to simulate body temperature). Figure 6 As shown in , a sufficiently strong gel can be obtained. The viscosity is measured according to the protocol of Example 4.

[0146] Example 8

[0147] Here the rheology diagrams using different structurants are shown. Figures 7A to 7DThis shows how some formulations become significantly weaker at 37°C. If the gel disintegrates when placed at 37°C, it becomes less useful as an injectable depot sustained-release drug delivery system. Viscosity was measured according to the protocol of Example 4. The average storage modulus (G') in the crossover point and linear viscoelastic region was then obtained from the software and further analyzed.

[0148] Example 9

[0149] 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. Figures 7A to 7D ), the highest values ​​were obtained from all gelling agents. This supports the above results. GMSP gels are more thermally stable, making them more useful.

[0150] Table 20

[0151]

[0152]

[0153] Table 21

[0154]

[0155] In Tables 20 and 21:

[0156] GMS = Glyceryl Monostearate

[0157] PMF = polyglycerol ester of fatty acids (18C length fatty acids)

[0158] TM = trimyristin

[0159] TP = Tripalmitin

[0160] Example 10

[0161] Figure 8A and 8B Peak melting and peak crystallization characteristics of various formulations are shown. Differential scanning calorimetry (DSC) was used to determine the thermal characteristics of oleogels (e.g., lipophilic oils and structurants). At room temperature, approximately 25 mg of oleogel was loaded into a standard aluminum crucible (25 μL) with a central perforated lid. At a scan rate of 10 ° C / min, the sample was heated from 20 ° C to 100 ° C, then subsequently cooled to -20 ° C after isothermal holding at 100 ° C for 5 minutes.

[0162] The peak temperature and the enthalpy of melting or area under the curve were obtained using this method.

[0163] Example 11

[0164] Figure 9A and 9B Rat sciatic nerve block data are shown. Figure 9B Shown with Figure 9A Same data, but with different y-axis and x-axis values. As shown, the bupivacaine in the oleogel had the longest-lasting effect. More importantly, the oleogel had a longer-lasting effect than MCT oil without a structurant, even though both had the same dose of bupivacaine. By converting the oil into a gel, the release of the drug in the body is greatly prolonged.

[0165] This longitudinal experiment involved seventeen male CD Sprague Dawley rats weighing 360 to 420 grams undergoing 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), or 0.2 mL of 5% bupivacaine oleogel (w / v) (bupivacaine / oleogel) (10 mg bupivacaine) with 20% GMS (w / v) (GMS / MCT). Each group contained five animals, except for 0.5% bupivacaine HCl, which contained two animals, as the anesthetic effects of bupivacaine HCl are well understood. Once the animals recovered from surgery, they were moved into individual acrylic enclosures on a heated clear glass surface to undergo the Hargreaves pain test.

[0166] Method for Hargreaves: At designated time points, noxious heat was placed on the mid-plantar portion of the right hind paw and manually turned off upon paw withdrawal. Paw withdrawal latency was measured three times per animal at each time point and averaged.

[0167] Example 12

[0168] Figure 10 Graph showing porcine efficacy data. Alevatrix 001 = 100% MCT. Alevatrix 002 = 75:25 MCT:Castor Oil. The 002 castor blend group showed a better bupivacaine release profile.

[0169] Thirty pigs weighing 10 to 13 kg were injected subcutaneously with each formulation. At the designated time points, the von Frey method was performed approximately 0.5 cm from the injection site. Wires of increasing diameter were applied in ascending order until a flinch reaction was observed, with the 60 gram force wire being the largest. The flinch reaction was considered to be an action away from the stimulus—either by moving away or by twisting the flank away. After surgery, pain was considered to be present (abnormal pain) if the flank withdrawal force was ≤8 g.

[0170] Treatment groups (n=6): low dose (L) administered in a volume of 2.5 mL, high dose (H) administered in a volume of 5 mL.

[0171] Example 13

[0172] The solubility of bupivacaine in a blend of MCT oil and castor oil was studied. Figure 11 As shown in , in the case of a specific oil blend, drug load increases and drug release also slows down because the drug has a higher affinity for the oil blend. The higher the drug affinity, the higher the drug load 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 MCT: castor oil mixture. The mixture was rotated overnight on a nutating shaker in an oven at 37 ° C to allow complete dissolution. After rotation, the sample was spun in a centrifuge 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 UV-visible spectrophotometry (272 nm).

[0173] Example 14

[0174] Figure 12 The presence and absence of anions (in Figure 12

[00145] Figure 10 illustrates the solubility of bupivacaine in a formulation containing MCT oil and glyceryl monostearate as a structuring agent (shown on the x-axis of Figure 10). As shown, docusate increases the solubility of bupivacaine. Solubility was determined according to the protocol of Example 13.

[0175] Example 15

[0176] The release of bupivacaine from a formulation containing MCT oil and glyceryl monostearate as a structuring agent is shown in the presence and absence of anions (to increase hydrophobicity). Figure 13As shown in Figure 2, the release of bupivacaine with docusate 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 tank of phosphate buffered saline (1×; pH 7.4). The sample was placed in a rotating incubator (1 Hz) at 37°C. At the specified time points, 2 mL of saline was removed and analyzed using UV-visible spectrophotometry (272 nm). The entire tank medium was replaced at each time point until the drug no longer eluted from the system.

[0177] The terms and expressions employed are used as terms of description rather than limitation, and it is not intended that such terms and expressions be used to exclude any equivalents of the features shown and described, or portions thereof, but rather that various modifications are possible within the scope of the aspects of the present disclosure. Thus, it should be understood that while the present disclosure has been specifically disclosed with respect to specific aspects and optional features, modifications and variations of the concepts disclosed herein may be utilized by those of ordinary skill in the art, and such modifications and variations are considered to be within the scope of the aspects of the present disclosure.

[0178] Exemplary Aspects

[0179] The following exemplary aspects are provided, the numbering of which should not be construed as indicating a level of importance:

[0180] Aspect 1 provides a pharmaceutical composition comprising:

[0181] lipophilic oils;

[0182] a therapeutic agent, a salt thereof, an ion pair thereof, or a prodrug thereof dispersed in the lipophilic oil; and

[0183] A structurant, at least a portion of which is insoluble in the lipophilic oil and forms a gel.

[0184] Aspect 2 provides the pharmaceutical composition of aspect 1, wherein the lipophilic oil comprises monoglyceride, diglyceride, triglyceride, medium chain triglyceride oil, sesame oil, soybean oil, castor oil, vegetable oil, tributyrin oil, or a mixture of these.

[0185] Aspect 3 provides the pharmaceutical composition of aspect 2, wherein the triglyceride is a saturated triglyceride, a monounsaturated triglyceride, or a polyunsaturated triglyceride.

[0186] Aspect 4 provides the pharmaceutical composition of aspect 2, wherein the triglyceride comprises medium-chain triglycerides, short-chain triglycerides, long-chain triglycerides, or a mixture thereof.

[0187] Aspect 5 provides the pharmaceutical composition of aspect 4, wherein the triglyceride comprises a medium chain triglyceride.

[0188] Aspect 6 provides the pharmaceutical composition of aspect 5, wherein the medium chain triglyceride comprises a glyceride of a C6-C12 carboxylic acid or a mixture of these.

[0189] Aspect 7 provides the pharmaceutical composition of aspect 1, wherein the structuring agent has a melting point of about 40°C to about 100°C.

[0190] Aspect 8 provides the pharmaceutical composition of aspect 7, wherein the structuring agent has a melting point of about 50°C to about 85°C.

[0191] Aspect 9 provides the pharmaceutical composition of aspect 8, wherein the structuring agent has a melting point of about 60°C to about 70°C.

[0192] Aspect 10 provides the pharmaceutical composition of aspect 1, wherein the structuring agent comprises a monoglyceride, a diglyceride, a triglyceride, a polyglycerol ester of fatty acids, or a mixture thereof.

[0193] Aspect 11 provides the pharmaceutical composition of aspect 1, wherein the structuring agent comprises tristearin, distearin, monostearin, dibehenin, cholesterol, trimyristin, dimyristin, monomyristin, trilaurin, dilaurin, monolaurin, tripalmitin, dipalmitin, monopalmitin, cholesterol, polyglycerol esters of fatty acids, polyglycerol esters of fatty acids, or a mixture of these.

[0194] Aspect 12 provides the pharmaceutical composition of aspect 11, wherein the structuring agent comprises glyceryl monostearate, glyceryl distearate, glyceryl tristearate, glyceryl monopalmitate, glyceryl dipalmitate, glyceryl tripalmitate, glyceryl monomyristate, glyceryl dimyristate, glyceryl trimyristate, or a mixture thereof.

[0195] Aspect 13 provides the pharmaceutical composition of aspect 1, wherein the structuring agent is present in a concentration of about 0.1% (w / v) to about 25% (w / v) of the pharmaceutical composition based on the volume of the lipophilic oil.

[0196] Aspect 14 provides the pharmaceutical composition of aspect 13, wherein the structuring agent is present in a concentration of about 3% (w / v) to about 20% (w / v) of the pharmaceutical composition based on the volume of the lipophilic oil.

[0197] Aspect 15 provides the pharmaceutical composition of aspect 13, wherein the structuring agent is present in a concentration of about 3% (w / v) to about 10% (w / v) of the pharmaceutical composition based on the volume of the lipophilic oil.

[0198] Aspect 16 provides the pharmaceutical composition of aspect 1, wherein the therapeutic agent comprises an analgesic, anesthetic, anti-inflammatory, sympatholytic, anxiolytic, cannabinoid, or a mixture thereof dispersed in the lipophilic oil.

[0199] 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 a subject.

[0200] Aspect 18 provides the pharmaceutical composition of aspect 17, wherein the pharmaceutical composition comprises the analgesic.

[0201] Aspect 19 provides the pharmaceutical composition of aspect 18, wherein the analgesic comprises a nonsteroidal anti-inflammatory drug, a COX-2 inhibitor, or a mixture thereof.

[0202] 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.

[0203] 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.

[0204] Aspect 22 provides the pharmaceutical composition of aspect 1, wherein the pharmaceutical composition comprises an anesthetic, and the anesthetic is a local anesthetic.

[0205] Aspect 23 provides the pharmaceutical composition of 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.

[0206] Aspect 24 provides the pharmaceutical composition of 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.

[0207] Aspect 25 provides the pharmaceutical composition of 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.

[0208] Aspect 26 provides the pharmaceutical composition of aspect 25, wherein the amide-based anesthetic comprises bupivacaine, ropivacaine, a salt thereof, an ion pair thereof, or a mixture thereof.

[0209] Aspect 27 provides the pharmaceutical composition of aspect 26, wherein the amide-based local anesthetic is an ion pair or a salt comprising bupivacaine butyrate, bupivacaine palmitate, bupivacaine laurate, bupivacaine myristate, bupivacaine stearate, bupivacaine hydroxystearate, bupivacaine oleate, bupivacaine ricinoleate, or bupivacaine docusate.

[0210] Aspect 28 provides the pharmaceutical composition of aspect 1, wherein the pharmaceutical composition comprises a mixture of an analgesic, an anesthetic, and an anti-inflammatory agent.

[0211] Aspect 29 provides the pharmaceutical composition of aspect 1, wherein the pharmaceutical composition comprises a mixture of an analgesic and an anesthetic.

[0212] Aspect 30 provides the pharmaceutical composition of aspect 1, wherein the analgesic, anesthetic, or both are present at a concentration of about 2% (w / v) to about 15% (w / v) based on the volume of the lipophilic oil.

[0213] Aspect 31 provides the pharmaceutical composition of aspect 30, wherein the analgesic, anesthetic, or both are present at a concentration of about 3% (w / v) to about 10% (w / v) based on the volume of the lipophilic oil.

[0214] Aspect 32 provides the pharmaceutical composition of aspect 1, wherein the anti-inflammatory agent comprises aspirin, celecoxib, diclofenac, diflunisal, etodolac, ibuprofen, indomethacin, ketoprofen, ketorolac, nasimetone, naproxen, oxaprozin, piroxicam, salicylic acid, sulindac, tolmetin, cannabidiol, a salt thereof, an ion pair thereof, or a mixture thereof.

[0215] Aspect 33 provides the pharmaceutical composition of aspect 1, further comprising an excipient.

[0216] Aspect 34 provides the pharmaceutical composition of aspect 33, wherein the excipient comprises a corticosteroid, an alpha-2-agonist, pethidine, a barbiturate, an opiate, myostatin, a cannabinoid, meloxicam, a salt thereof, or an ion pair thereof, or a mixture thereof.

[0217] Aspect 35 provides the pharmaceutical composition of aspect 34, wherein the cannabinoid is cannabidiol (CBD).

[0218] Aspect 36 provides the pharmaceutical composition of aspect 33, wherein the pharmaceutical composition effectively relieves pain in a subject using a lower concentration of analgesic, anesthetic, anti-inflammatory agent, or a mixture thereof, and / or has a longer-lasting pain relief effect, compared to a corresponding pharmaceutical composition without the excipient.

[0219] Aspect 37 provides the pharmaceutical composition of aspect 1, further comprising a rheology modifier comprising a C2-C12 alcohol.

[0220] Aspect 38 provides the pharmaceutical composition of aspect 37, wherein the rheology modifier comprises ethanol, benzyl alcohol, or a mixture of these.

[0221] Aspect 39 provides the pharmaceutical composition of aspect 38, wherein the C2-C12 alcohol comprises ethanol, benzyl alcohol, or a mixture thereof, and the C2-C12 alcohol is present at about 0.5% (w / v) to about 10% (w / v) of the pharmaceutical composition based on the volume of the lipophilic oil.

[0222] Aspect 40 provides the pharmaceutical composition of aspect 39, wherein the ethanol, benzyl alcohol, or a mixture thereof is present at about 1% (w / v) to about 6% (w / v) of the pharmaceutical composition based on the volume of the lipophilic oil.

[0223] Aspect 41 provides the pharmaceutical composition of aspect 1, wherein the pharmaceutical composition is effective in reducing pain in a subject for a duration of about 24 hours to about 14 days.

[0224] Aspect 42 provides the pharmaceutical composition of aspect 1, wherein the pharmaceutical composition is effective in reducing pain in a subject for a duration of about 48 hours to about 96 hours.

[0225] Aspect 43 provides the pharmaceutical composition of aspect 1, wherein the pharmaceutical composition is effective in reducing pain in a subject for a duration of about 96 hours to about 168 hours.

[0226] Aspect 44 provides the pharmaceutical composition of aspect 1, wherein the pharmaceutical composition is effective in reducing pain in a subject for a duration of about 168 hours to about 336 hours.

[0227] Aspect 45 provides the pharmaceutical composition of aspect 1, wherein the pharmaceutical composition is a semisolid composition.

[0228] Aspect 46 provides a pharmaceutical composition comprising:

[0229] medium-chain triglycerides;

[0230] castor oil;

[0231] an anesthetic comprising bupivacaine, an ion pair thereof, or a salt thereof, or both, present in an amount sufficient to reduce pain in a subject, and dispersed in the medium chain triglyceride and castor oil mixture; and

[0232] a structurant comprising 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;

[0233] Optionally, the wt:wt ratio of medium chain triglycerides to castor oil is about 50:50.

[0234] Aspect 47 provides the pharmaceutical composition of aspect 1, wherein the viscosity of the composition is from about 10,000 cP to about 1,000,000 cP when measured at about 37°C.

[0235] Aspect 48 provides the pharmaceutical composition of aspect 1, wherein the viscosity of the composition is from about 10,000 cP to about 150,000 cP when measured at about 37°C.

[0236] Aspect 49 provides the pharmaceutical composition of aspect 1, wherein after shearing, the composition has a viscosity of about 10 cP to about 10,000 cP when measured at about 37°C.

[0237] Aspect 50 provides the pharmaceutical composition of aspect 1, wherein upon shearing, the viscosity decreases by shear thinning behavior to render it injectable.

[0238] Aspect 51 provides a kit comprising:

[0239] syringes; and

[0240] The pharmaceutical composition according to aspect 1 is disposed in the syringe.

[0241] Aspect 52 provides the kit of aspect 51, wherein the pharmaceutical composition is sealed within the syringe.

[0242] Aspect 53 provides the kit of aspect 51, wherein the syringe further comprises a needle having a size gauge of about 15 to 30 G.

[0243] Aspect 54 provides the kit of aspect 53, wherein the syringe comprises a needle having a gauge of about 21 to about 25G.

[0244] Aspect 55 provides a method for preparing the pharmaceutical composition of aspect 1, the method comprising:

[0245] a) mixing a lipophilic oil with an analgesic and an anesthetic at a temperature above 25° C. with stirring and heating to form a mixture;

[0246] b) cooling the mixture to form the pharmaceutical composition.

[0247] Aspect 56 provides the method of aspect 55, wherein the mixing in a) is performed at a temperature of about 50°C to about 150°C.

[0248] Aspect 57 provides the method of aspect 56, wherein in b) the mixture is placed in a sealed syringe to cool.

[0249] Aspect 58 provides the method of aspect 57, further comprising sterilizing the pharmaceutical composition.

[0250] Aspect 59 provides the method of aspect 58, wherein sterilization occurs after sterilizing the pharmaceutical composition after dispensing the pharmaceutical composition into the container, wherein sterilization comprises gamma irradiation, electron beam irradiation, x-ray irradiation, heat sterilization, steam sterilization, or a combination thereof.

[0251] Aspect 60 provides a method of treating a subject with the pharmaceutical composition of aspect 1, comprising administering the pharmaceutical composition to the subject in need thereof.

[0252] Aspect 61 provides the method of aspect 60, wherein the pharmaceutical composition is administered to the subject at or near a surgical site.

[0253] Aspect 62 provides the method of aspect 61, wherein the pharmaceutical composition is administered to the subject at or near a wound.

[0254] Aspect 63 provides the method of aspect 62, wherein the pharmaceutical composition is administered to the subject at a site proximate to a wound.

[0255] Aspect 64 provides the method of aspect 63, wherein the site proximate to the wound is a site that results in nerve blockage.

[0256] Aspect 65 provides the method of aspect 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.

[0257] Aspect 66 provides the method of aspect 61, wherein administering the pharmaceutical composition comprises injecting the pharmaceutical composition by syringe through a needle having a size gauge of about 18 to 30G, applying the pharmaceutical composition at or near a wound or surgical site, or a combination thereof.

[0258] Aspect 67 provides the method of aspect 62, wherein the pharmaceutical composition is administered to the subject before undergoing surgery, during surgery, or after the subject has undergone surgery.

[0259] Aspect 68 provides the method of aspect 67, further comprising administering a non-opioid analgesic to the subject 48 to 120 hours after administering the pharmaceutical composition to the subject.

[0260] Aspect 69 provides the method of aspect 68, further comprising administering a non-opioid analgesic to the subject 72 to 120 hours after administering the pharmaceutical composition to the subject.

[0261] Throughout this document, values ​​expressed in range format should be interpreted in a flexible manner to include not only the numerical values ​​explicitly stated as limits of the range, but also all individual numerical values ​​or subranges encompassed within the range, as if each numerical value and subrange were explicitly stated. 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 indicated range. Unless otherwise noted, the expression "about X to Y" has the same meaning as "about X to about Y." Similarly, unless otherwise noted, the expression "about X, Y, or about Z" has the same meaning as "about X, about Y, or about Z."

[0262] In this document, nouns without quantifiers are used to include one or more unless the context clearly dictates otherwise. 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". In addition, it should be understood that the words or terms used herein and not otherwise defined are for descriptive purposes only and not for limiting purposes. The use of any section headings is intended to assist in reading the document and is not to be construed as limiting; information related to a section heading may appear within or outside that particular section.

[0263] In the methods described herein, unless a time or sequence of operations is explicitly enumerated, the actions may be performed in any order without departing from the principles of the present disclosure. Furthermore, unless the claim language explicitly states that specified actions are to be performed separately, they may be performed simultaneously. For example, a claimed action of performing X and a claimed action of performing Y may be performed simultaneously within a single operation, and the resulting process would fall within the literal scope of the claimed process.

[0264] As used herein, the term "about" can allow for a certain degree of variability in values ​​or ranges, for example, within 10%, within 5%, or within 1% of the value or range limits, and includes the exact value or range. 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 greater, or 100%. As used herein, the term "substantially free" can mean having no or insignificant amounts of a material such that the amount of material present does not affect the material properties of the composition containing the material, such that from about 0% to about 5% by weight, or from about 0% to about 1% by weight, or about 5% by weight or less, 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 about 0.001% by weight or less, or about 0% by weight of the composition is the material.

Claims

1. An injectable pharmaceutical composition comprising: lipophilic oils; a hydrophobic ion pairing agent and an anesthetic agent dispersed in the lipophilic oil; and a structurant, at least a portion of which is insoluble in the lipophilic oil and forms a gel, wherein The pharmaceutical composition does not contain a rheology modifier.

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

70.

3. The injectable pharmaceutical composition of claim 1, wherein the lipophilic oil comprises monoglycerides, diglycerides, triglycerides, medium chain triglyceride oils, sesame oil, soybean oil, castor oil, vegetable oils, tributyrin oil, or mixtures thereof.

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

5. The injectable pharmaceutical composition of claim 1, wherein the structuring agent comprises monoglycerides, diglycerides, triglycerides, polyglycerol esters of fatty acids, or mixtures thereof.

6. The injectable pharmaceutical composition of claim 1 , wherein the structuring agent 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, polyglyceryl esters of fatty acids, polyglyceryl esters of fatty acids, or mixtures thereof.

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

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

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

10. 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 docusate, or a mixture thereof.

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

12. The injectable pharmaceutical composition of claim 1, wherein the pharmaceutical composition is a nerve block composition.

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

14. The injectable pharmaceutical composition of claim 1, wherein the pharmaceutical composition is effective in reducing pain in a subject for a period of time ranging from about 24 hours to about 14 days.

15. An injectable pharmaceutical composition comprising: medium-chain triglycerides; castor oil; an anesthetic present in an amount sufficient to reduce pain in a subject and dispersed in the mixture of medium chain triglycerides and castor oil, the anesthetic comprising bupivacaine butyrate, bupivacaine palmitate, bupivacaine laurate, bupivacaine myristate, bupivacaine stearate, bupivacaine hydroxystearate, bupivacaine oleate, bupivacaine ricinoleate, or bupivacaine docusate; and a structurant comprising 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; The pharmaceutical composition does not contain a rheology modifier.

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

70.

17. The injectable pharmaceutical composition of claim 15, wherein upon shearing, the viscosity decreases by shear thinning behavior to render it injectable.

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

19. An injectable pharmaceutical composition comprising: from about 3% to about 12% bupivacaine by weight of the pharmaceutical composition; from about 3% to about 30% by weight of the pharmaceutical composition of oleic acid, ricinoleic acid, docusate, or a mixture thereof; from about 26% to about 46.5% by weight of the pharmaceutical composition of medium chain triglyceride oil; From about 26% to about 46.5% by weight of the pharmaceutical composition of castor oil; and About 1% to about 6% by weight of the pharmaceutical composition of tristearin, wherein The pharmaceutical composition does not contain a rheology modifier, and The wt:wt ratio of the medium chain triglycerides to castor oil was about 50:

50.

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

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