Pharmaceutical compositions

Abstract

A pharmaceutical composition can include a lipophilic oil. The pharmaceutical composition can further include an analgesic agent, anesthetic agent, anti-inflammatory agent, or a mixture thereof dispersed in the lipophilic oil. The pharmaceutical composition can further include a structuring agent at least a portion of which is not dissolved in the lipophilic oil and forms a gel.

Description

PHARMACEUTICAL COMPOSITIONSCROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application Serial No. 63 / 513,329 entitled “PHARMACEUTICAL COMPOSITIONS,” filed July 12, 2023, the disclosure of which is incorporated herein in its entirety by reference.BACKGROUND

[0002] Administration of therapeutic agents takes many different forms. One strategy is to locate a therapeutic agent in a delivery vehicle to control the location of delivery, the release rate of the therapeutic agent, or the like.SUMMARY OF THE DISCLOSURE

[0003] A problem that the instant disclosure seeks to solve is to provide an injectable or implantable composition that can provide days to months of therapeutic agent delivery that is both injectable and viscous enough to be manually implanted and remain at the administration site long enough to provide a desired effect. The disclosure therefore relates to a pharmaceutical composition, comprising:DETAILED DESCRIPTION OF THE DISCLOSURE

[0004] Reference will now be made in detail to certain aspects of the disclosed subject matter. While the disclosed subject matter will be described in conjunction with the enumerated claims, it will be understood that the exemplified subject matter is not intended to limit the claims to the disclosed subject matter.

[0005] As used herein the terms “drug” and “therapeutic agent” are interchangeably used.

[0006] 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 not dissolved in the lipophilic oil. These components can form a semi-solid oleogel consisting of drug-loaded lipophilic oil entrapped in asupramolecular network of self-assembled structures, for example, molecular aggregates, crystals, and the like. The pharmaceutical composition can be used in both human and veterinary applications.

[0007] The composition can take the form of an injectable semi-solid gel, paste, or implantable solid. In the form of a semi-solid gel or paste, the composition can be applied to a surgical site / wound, and because of its viscosity, the gel remains where initially applied. Upon closing the surgical site / wound, the semi-solid gel can intercalate within natural crevices and smear between compressed tissues. The self-assembled supramolecular network created by the structuring agent prevents the drug-oil phase from migrating away from the site of administration, which facilitates safer and more effective localized treatment. The structuring agent network also shields the drug-loaded oil from the surrounding in vivo environment (e.g., a surrounding aqueous in vivo environment) which enables the prolonged diffusion-based drug release from the oil into the aqueous environment. The composition can be biodegradable and can, therefore, be naturally resorbed by the body over time.

[0008] Depending on the concentration and unique properties of the structuring agent, the composition can be tuned to have various mechanical properties. If the mechanical properties are too robust, the composition may not be injectable through small bore needles (e.g., >23 gauge), which would only allow it to be manually implanted into a surgical wound cavity. For some therapeutic agents, the mechanical properties need to be optimized so that it can be injectable through an acceptable needle size (18-25 gauge) but remains viscous enough so it is retained at the site of implantation.

[0009] The structuring agent is useful to provide adequate structure and mechanical properties to the composition. For example, if the therapeutic agent or drug is simply loaded into a plain lipophilic oil carrier (e.g., medium-chain triglycerides), the resulting solution will be a thin and flowable liquid like an aqueous solution. Therefore, if the solution (lacking the structuring agent) is injected or implanted directly into a surgical wound cavity, the solution can migrate and be eliminated from the site of administration, therefore lowering the effectiveness of the therapeutic agent. Additionally, rapid elimination of the drug can increase the risk of systemic toxicity for certain therapeutics (e.g., cardiotoxicity or neurotoxicity), which can be life-threatening. Some currentclinically available options include solid, implantable technologies that can only be implanted into surgical sites, which significantly limits their clinical applications. A problem that the instant disclosure seeks to solve is to provide a safe injectable or implantable composition that can provide 2-14 days of therapeutic benefit that is both injectable and viscous enough to be instilled into a surgical site, while also being able to remain at the site it is implanted to for an amount of time sufficient to provide the desired local therapeutic effect.

[0010] Although administration at a surgical site / wound is mentioned, it is possible to administer the pharmaceutical composition at different locations such as topically on skin. Additionally, the pharmaceutical composition can be encapsulated in a pill, tablet, or the like and ingested. Administration can also be accomplished through transdermal, oral, rectal, methods or the like.

[0011] The lipophilic oil of the composition can be chosen from many suitable oils. For example, the lipophilic oil can include a monoglyceride, diglyceride, triglyceride, sesame oil, soybean oil, castor oil, tributyrin oil, vegetable oil, or a mixture thereof. For example, the lipophilic oil can include a mixture of a medium chain triglyceride oil and castor oil in which either independently ranges from 5 wt% to 98 wt%, 30 wt% to 70 wt%, less than, equal to, or greater than 5 wt%, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or about 98 wt%. Sesame oil generally includes 41 wt% linoleic acid, 39 wt% oleic acid, 8 wt% palmitic acid, 5 wt% stearic acid, and trace amounts of other organic acids. Per 100 g, soybean oil has 16 g of saturated fat, 23 g of monounsaturated fat, and 58 g of polyunsaturated fat. The major unsaturated fatty acids in soybean oil triglycerides are 7 to 10 wt% polyunsaturated alpha-linolenic acid, and 51 wt% linoleic acid, and 23 wt% monounsaturated oleic acid. Soybean oil also includes saturated fatty acid such as 4 wt% stearic acid and 10 wt% palmitic acid. Castor oil includes 85 to 95 wt% ricinoleic acid, 2 to 6 wt% oleic acid, 1 to 5 wt% linoleic acid, 0.5 to 1 wt% a-linolenic acid, 0.5 to 1 wt% stearic acid, 0.5 to 1 wt% palmitic acid, 0 to 0.5 wt% dihydroxystearic acid, and 0.2 to 0.5 wt% additional compounds. The tributyrin oil is an ester that is a reaction product of butyric acid and glycerol. The triglyceride can be a long-chain triglyceride, a medium-chain triglyceride, a short-chain triglyceride, or both. Examples of medium-chain triglycerides include an ester that is a reaction product glycerol with any of a C6-C12carboxylic acid (e.g., hexanoic acid, octanoic acid, decanoic acid, lauric acid, or a mixture thereof).

[0012] Medium-chain triglycerides can be particularly well suited as the lipophilic oil. While not intending to be limited to any theory, the benefits of using medium-chain triglycerides are believed to be due to their thin nature and low viscosity, each of which makes it injectable (as compared to castor oil, which often has good drug solubility but is very viscous). Depending on the thereapeutic agent, medium-chain triglycerides can accommodate a range of drug loading and drug release rates. In some examples, medium-chain triglycerides (and sometimes mixed with additional oils) are beneficial in that they exhibit a viscosity that allows it to be injectable, structured to a supramolecular gel using a structuring agent, loaded with a sufficient amount of a drug, and exhibits a good drug release profile.

[0013] A mixture of lipophilic oils can be used. For example, the pharmaceutical composition can include a mixture of medium-chain triglycerides and short-chain triglycerides , medium-chain triglycerides and long-chain triglyceride oils, or short-chain triglycerides and long-chain triglycerides. In some, a mixture of medium-chain triglycerides and short-chain triglycerides is at a 90: 10 (medium-chain triglyceride: short-chain triglyceride). In other examples a mixture of oils can include a 50:50 medium-chain triglyceride:castor oil. As a further example a mixture medium-chain triglycerides and long-chain triglycerides as the lipophilic oil will achieve a higher drug load with reducing viscosity in the overall structure. The structuring agent (alternatively referred to as an organostructuring agent, oleostructuring agent, or supramolecular structuring agent) imparts a structure to the lipophilic oil. For example, the structuring agent helps to form a gel. An example of a type of gel is a supramolecular gel which is a complex of molecules held together by noncovalent interactions such as H-bonding, Pi-Pi interactions, anionic-Pi interactions, cationic-Pi interactions, and van der Waals forces. The process by which a supramolecular assembly forms is called molecular self-assembly. Molecular self-assembly refers to the process by which molecules adopt a defined arrangement without guidance or management from an outside source. The ability for a structuring agent to impart structure to the lipophilic oil can be a function of the structuring agent’s minimum gelling concentration. Below theminimum gelling concentration no gel is formed. In a pharmaceutical composition, it is ideal to use the minimal amount of structural agents to get to the minimum gelling concentration as this minimizes the amount of foreign body reaction and undesired capsule formation. Therefore, when selecting the ideal structuring agent for a given lipophilic oil, it is important to identify structuring agents with lower minimum gelling concentrations as to minimize the foreign body reaction while achieving the desired physical properties of the gel.

[0014] The structuring agent is present in a concentration in a range of from about 0.1 % (w / v) to about 25 % (w / v) of the pharmaceutical composition based on the volume of the lipophilic oil, 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), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7,7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16,16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, or about 25 % (w / v). The structuring agent or mixture of structuring agents used can depend on several factors such as the melting point of the structuring agent. For example, a melting point of the structuring agent can be in a range of from 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, 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.

[0015] Examples of suitable structuring agents include a monoglyceride, a diglyceride, a triglyceride, a polyglycerol ester of a fatty acid, or a mixture thereof. Polyglycerols used herein can be a diglycerol or triglycerol and can be fully or partially esterified with saturated or unsaturated fatty acid moieties. The fatty acid can include caprylic acid (C8), capric acid (CIO), lauric acid (Cl 2), myristic acid (C14), palmitic acid (C16), stearic acid (C18), arachidonic acid (C20), behenic acid (C22), or a mixture 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 a mixture thereof.

[0016] At least a portion of the structuring agent is phase separated in the lipophilic oil. Thus, for example, a portion of the structuring agent can be partially dissolved in the lipophilic oil (first phase), while a second portion is not dissolved in the lipophilic oil (second phase). The phase separation of the structuring agent allows the structuring agent to help the pharmaceutical composition achieve the supramolecular gel within the lipophilic oil. If the structuring agent is too soluble in the lipophilic oil, it will dissolve therein and the supramolecular gel cannot be formed. If the structuring agent is too insoluble, it will not interact with the lipophilic oil and the pharmaceutical composition will take the form of a heterogenous unstable gel with the structuring agent precipitated out.

[0017] The supramolecular gel itself can be characterized as a semisolid composition (alternatively referred to as a quasi-solid or a semiliquid). While similar to solids in some respects, such as having the ability to support their own weight and hold their shapes, a semi-solid composition also shares some properties of liquids, such as conforming in shape to something applying pressure to it and the ability to flow under pressure. Selecting the proper structuring agent also impacts the viscosity of the pharmaceutical composition. A proper viscosity allows the pharmaceutical composition to substantially remain in a desired location in the body. An example of a suitable viscosity at 37 °C is in the range of aboutl,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, less than, equal to, or greater than about 10,000, 15,000, 20,000, 25,000, 30,000, 35,000, 40,000, 45,000, 50,000, 55,000, 60,000, 65,000, 70,000, 80,000, 85,000, 90,000, 95,000, 100,00, 105,000, 110,000, 115,000, 120,000, 125,000, 130,000, 135,000, 140,000, 145,000, 150,000, 155,000, 160,000, 165,000, 170,000, 175,000, 180,000, 185,000, 190,000, 195,000, 200,000, 205,000, 210,000, 215,000, 220,000, 225,000, 230,000, 235,000, 240,000, 245,000, 250,000, 255,000, 260,000, 265,000, 270,000, 275,000, 280,000, 285,000, 290,000, 295,000, 300,000, 305,000, 310,000, 315,000, 320,000, 325,000, 330,000, 335,000, 340,000, 345,000, 350,000, 355,000, 360,000, 365,000, 370,000, 375,000, 380,000, 385,000, 390,000, 395,000, 400,000, 405,000, 410,000, 415,000, 420,000,425,000, 430,000, 435,000, 440,000, 445,000, 450,000, 455,000, 460,000, 465,000, 470,000, 475,000, 480,000, 485,000, 490,000, 495,000, 500,000, 600,00, 605,000, 610,000, 615,000, 620,000, 625,000, 630,000, 635,000, 640,000, 645,000, 650,000, 655,000, 660,000, 665,000, 670,000, 675,000, 680,000, 685,000, 690,000, 695,000, 700,000, 705,000, 710,000, 715,000, 720,000, 725,000, 730,000, 735,000, 740,000, 745,000, 750,000, 755,000, 760,000, 765,000, 770,000, 775,000, 780,000, 785,000, 790,000, 795,000, 800,000, 805,000, 810,000, 815,000, 820,000, 825,000, 830,000, 835,000, 840,000, 845,000, 850,000, 855,000, 860,000, 865,000, 870,000, 875,000, 980,000, 985,000, 990,000, 995,000, 1,000,000 cP.

[0018] If the viscosity is too low, the pharmaceutical composition will disperse beyond the desired location. Additionally, if the viscosity is too low, an undesired release rate of the drug can result. Conversely, if the viscosity is too high, it can be impossible to inject the pharmaceutical composition to the desired location. This may leave manual application (e.g., by hand or using an instrument to apply or spread the composition to the site) as the only viable option. However, even manual application may be impractical if the viscosity is too high. For Newtonian fluids / materials, the viscosities required to maintain material retention at the application site are generally too high to enable injection through clinically relevant needle sizes (18g-25g needles).

[0019] An alternative method used to deliver viscous pharmaceutical formulations is through solvent exchange. Solvent exchange works by reducing pharmaceutical formulation’s viscosity, making them easier to administer. The pharmaceutical formulation is initially prepared in a highly viscous state, which can be challenging to inject through standard needles. A biocompatible solvent, which is often less viscous, is added to the viscous formulation. Common solvents include ethanol, benzyl alcohol or specific biocompatible organic solvents. The viscous formulation and the added solvent are thoroughly mixed to create a uniform solution or dispersion. This process often involves mechanical mixing or the use of specialized equipment to ensure complete homogenization. The addition of the solvent reduces the overall viscosity of the formulation, making it less thick and more fluid. This lower viscosity state is crucial for enabling easier injection through conventional syringes and needles. The reduced viscosity formulation can now be drawn into a syringe and injected intothe patient. This step requires less force and minimizes discomfort during administration. In some cases, the solvent may be removed after injection, especially if it’s an organic solvent. This can be achieved through processes like evaporation or dilution with bodily fluids. Once inside the body, the formulation may revert to its original viscous state. This can be advantageous for controlled release of the drug, as the viscosity can help retain the formulation at the site of injection, leading to prolonged drug release.

[0020] However, certain tissues are highly sensitive to organic solvents used for solvent exchange, limiting its application in these scenarios. For example, alcohols and organic solvents are known to cause neurotoxicity and are not safe to use in formulations being administered near peripheral nerves.

[0021] A particular disadvantage to not being able to inject through these needles is that such compositions cannot be used as a subcutaneous injection, either self-administered or by a health care provider. To overcome this, the pharmaceutical compositions disclosed are engineered to be shear-thinning, which is defined as the ability of a material to decrease in viscosity with increasing shear. Such compositions can be pre-loaded into syringes, extruded upon application of shear, and regain their viscosities upon cessation of mechanical load, a process known as self-healing. This shear-thinning and self- healing mechanisms enables injectability of the semi-solid formulation without requiring organic solvents. This self-healing behavior allows for both improved application and material retention thus improving the usefulness and efficacy of the pharmaceutical product while also exhibiting the prolonged drug release characteristics described herein. As an example, when sheared at sweeps ranging from 0.01 hz to 200 hz, the viscosities at 37 °C can go 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, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or about 10,000 cP. Unless otherwise specified, all viscosity values described herein are obtained at 37 °C, by a HAAKE Mars 60 rheometer, available from Thermo-Fisher Scientific, Waltman MA.

[0022] The drug or therapeutic agent can be present in the pharmaceutical composition in a therapeutically effective amount. A “therapeutically effective amount” (or “effective amount”) of a compound with respect to use in treatment,refers to an amount of the compound in a preparation which, when administered as part of a desired dosage regimen (to a mammal, such as a human) alleviates a symptom, ameliorates a condition, or slows the onset of disease conditions according to clinically acceptable standards for the disorder or condition to be treated or the cosmetic purpose, e.g., at a reasonable benefit / risk ratio applicable to any medical treatment.

[0023] The term “prophylactic or therapeutic” treatment is art-recognized and includes administration to the patient of one or more compound of the disclosure. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, (e.g., it protects the host against developing the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (e.g., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).

[0024] The exact amount of the drug or therapeutic agent can vary and is selected depending on the application. As a non-limiting example, the drug can be present in a concentration in a range of from about 0.5% (w / v) to about 40% (w / v), about 1% (w / v) to about 25% (w / v), 2 % (w / v) to about 15 % (w / v) based on a volume of the lipophilic oil, about 3 % (w / v) to about 10 % (w / v), about 5 % (w / v) to about 8 % (w / v), less than, equal to, or greater than about 0.5 % (w / v), 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11,11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28,28.5, 29, 29.5, 30, 30.5, 31, 31.5, 32, 32.5, 33, 33.5, 34, 34.5, 35, 35.5, 36, 36.5, 37, 37.5, 38, 38.5, 39, 39.5, or about 40 % (w / v), based on the volume of the lipophilic oil. Whether an amount is therapeutically effective can be a factor of the amount of time that the therapeutic effects are present in a subject. For example the pharmaceutical composition may be effective for a time in a range of from about 24 hours to about 180 days, about 24 hours to about 90 days, about 24 hours to about 30 days, about 24 hours to about 14 days, 48 hours to about 14 days, from about 72 hours to about 96 hours, from about 72 hours to about 80 hours, less than, equal to, or greater than about 24 hours, 25 hours, 26 hours, 27 hours 28 hours, 29 hours 30 hours, 31 hours, 32 hours, 33 hours, 34 hours, 35 hours, 36 hours, 37 hours, 38 hours, 39 hours, 40 hours, 41 hours, 42hours, 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, about 14 days, about 20 days, about 40 days, about 60 days, about 80 days, about 100 days, about 120 days, about 140 days, about 160 days, or about 180 days. Some pharmaceutical compositions can be designed to be effective to for specified ranges such as 12 hours to 48 hours, 48 hours to 96 hours, 96 hours to 144 hours, 144 hours to 240 hours, or 240 hours to 336 hours. The exact drug release characteristics can be a function of the structure of the pharmaceutical composition. For example, a specific blend of lipophilic oils affects drug release characteristics. For example, a specific ion pair (e.g., lipophilic salt) formed with the therapeutic agent can affect the release characteristics.

[0025] The amount of time that that the pharmaceutical composition is therapeutically effective can be a result of the release rate of the drug from the lipophilic oil. The drug release from lipophilic oil is controlled by diffusion. Depending on the drugs affinity to the specific lipophilic oil or specific blend of lipophilic oils, the drug will preferentially reside in the lipophilic oil and slowly diffuse into the surrounding aqueous medium in a patient’s body depending on its greater affinity to the lipophilic oil than the aqueous medium. The drug release rate is also dependent on the interfacial area between the oil-based carrier and the surrounding aqueous in vivo environment. The aforementioned interfacial area can be controlled by the supramolecular gel provided by the structuring agent. Without any structure, the pharmaceutical composition can freely flow and spread in vivo, this drastically increases its interfacial surface area and, therefore, accelerates its drug release rate. However, if the lipophilic oil is formed into a viscous semi-solid by its supramolecular gel, it will have a significantly reduced ability to spread and increase its interfacial area, therefore reducing the rate of drug release and prolonging the effect of the therapeutic agent.

[0026] Therapeutic agents of various lipophilicity in their base form can be covalently or non-covalently modified to improve their lipophilicity and resultant solubility, drug loading , and releasee base oil. This is achieved by altering the physicochemical properties of the drug (e.g, melting point, polarity, hydrophobicity, lipophilicity, partition coefficient). Using covalent modification, prodrugs of the agents can be synthesized that are significantly more lipophilic and suitable for use in the disclosed composition. This can also be achieved using non-covalent modification. For example, hydrophobic ion pairing can be used to ionically pair charged drug molecules with oppositely-charged molecules with hydrophobic moieties. The resultant complexes are more lipophilic and hydrophobic allowing better encapsulation into and more controlled release from lipid-based formulations. Both covalent and non-covalent modulation of the drug can thus be used to tune drug release of a wide range of hydrophilic to hydrophobic drugs from the system. The desired solubility and partition coefficients from the base oil will be different for different drugs and intended uses. For example, a drug having a log P of less than 2 could be modified by the formation of a prodrug that makes the log P greater than the recited log P values (e.g., at least 2). These examples of covalent and non-covalent chemical modification increase the lipophilicity leading to greater affinity to the base oil leading to slower modified release characteristics. In such an example, the drug having a log P of less than 2 can comprise a hydroxy or amino functional group that can form an ester or an amide, respectively, with a Ci2-C22-carboxylic acid. The resulting Ci2-C22-ester or amide may have the recited log P values (e.g., at least 3).

[0027] Alternatively, or in addition, the drug or prodrug can be modified by pairing it with a hydrophobic counterion that may have the recited log P values. For example, the drug or prodrug can be synthesized to be a docusate salt or can be ion exchanged to form a docusate salt, where the docusate is the counterion of the drug. Other such counterions are known in the art and are contemplated herein.

[0028] As used herein, the partition coefficient, or log P, is a measure of the lipophilicity of a drug and an indication of its ability to cross the cell membrane. It is defined as the ratio between drug distributed between the organic and aqueous layers at equilibrium. The partition coefficient of a drugmay be determined by shaking it with equal parts of two immiscible solvents (the organic layer, which is saturated with water, and the aqueous drug solution) until equilibrium is attained. The content of the drug in one of the layers is determined and the value is calculated. Octanol-water partitioning is the system commonly used for the study. Although the partition coefficient alone may not provide information regarding absorption, it characterizes the lipophilic- hydrophilic balance of a drug and supports the screening of compounds for their biological properties. Combined with LogP, a drugs melting point is also useful for screening compounds for their lipid solubility. Molecules with high melting point tend to be less soluble than predicted from their LogP. Molecules with low melting point tend to be more soluble than predicted from their LogP.

[0029] Therapeutic agents can include any compound having a desired biological or physiological effect, such as an oligonucleotide, peptide, protein, drug, antigen, nutrient, cosmetic, fragrance, flavoring, diagnostic, pharmaceutical, vitamin, or dietary agent and will be formulated at a level sufficient to provide an in vivo concentration at a functional level (including local concentrations for topical compositions). Most preferred therapeutic agents are pharmaceutical agents including drugs, vaccines, and diagnostic agents.

[0030] Therapeutic agents that may be delivered by the present invention include drugs which act on cells and receptors, peripheral nerves, adrenergic receptors, cholinergic receptors, the skeletal muscles, the cardiovascular system, smooth muscles, the blood circulation system, endocrine and hormone system, blood circulatory system, synoptic sites, neuroeffector junctional sites, the immunological system, the reproductive system, the skeletal system, autacoid system, the alimentary and excretory systems, the histamine system, and the central nervous system.

[0031] Examples of therapeutic agents which may be delivered include, but are not limited to, antibacterial agents such as P-lactams or macrocyclic peptide antibiotics, anti fungal agents such as polyene macrolides (e.g. amphotericin B) or azole antifungals, anticancer and / or anti viral drugs such as nucleoside analogues, paclitaxel and derivatives thereof, anti inflammatory drugs, such as non-steroidal anti inflammatory drugs and corticosteroids, cardiovascular drugs including cholesterol lowering and blood-pressure lowing agents, analgesics, antipsychotics and antidepressants including serotonin uptakeinhibitors, prostaglandins and derivatives, vaccines, and bone modulators. Diagnostic agents include radionuclide labelled compounds and contrast agents including X-ray, ultrasound and MRI contrast enhancing agents. Nutrients include vitamins, coenzymes, dietary supplements etc.

[0032] Particularly suitable therapeutic agents include those which would normally have a short residence time in the body due to rapid breakdown or excretion and those with poor oral bioavailability. These include peptide, protein and nucleic acid based active agents, hormones and other naturally occurring agents in their native or modified forms. By administering such agents in the form of a depot composition formed from the pharmaceutical compositionof the present invention, the agents are provided at a sustained level for a length of time which may stretch to days, weeks or even several months in spite of having rapid clearance rates. This offers obvious advantages in terms of stability and patient compliance over dosing multiple times each day for the same period. In one preferred embodiment, the therapeutic agent thus has a biological half life (upon entry into the blood stream) of less than 1 day, preferably less than 12 hours and more preferably less than 6 hours. In some cases this may be as low as 1-3 hours or less. Suitable agents are also those with poor oral bioavailability relative to that achieved by injection, for where the active agent also or alternatively has a bioavailability of below 0.1%, especially below 0.05% in oral formulations.

[0033] Peptide and protein based active agents include human and veterinary drugs selected from the group consisting of adrenocorticotropic hormone (ACTH) and its fragments, angiotensin and its related peptides, antibodies and their fragments, antigens and their fragments, atrial natriuretic peptides, bioadhesive peptides, Bradykinins and their related peptides, calcitonins and their related peptides, cell surface receptor protein fragments, chemotactic peptides, cyclosporins, cytokines, Dynorphins and their related peptides, endorphins and P-lidotropin fragments, enkephalin and their related proteins, enzyme inhibitors, immunostimulating peptides and polyaminoacids, fibronectin fragments and their related peptides, gastrointestinal peptides, gonadotrophin-releasing hormone (GnRH) agonists and antagonist, glucagons like peptides, growth hormone releasing peptides, immunostimulating peptides, insulins and insulin-like growth factors, interleukins, luthenizing hormonereleasing hormones (LHRH) and their related peptides, melanocyte stimulating hormones and their related peptides, nuclear localization signal related peptides, neurotensins and their related peptides, neurotransmitter peptides, opioid peptides, oxytocins, vasopressins and their related peptides, parathyroid hormone and its fragments, protein kinases and their related peptides, somatostatins and their related peptides, substance P and its related peptides, transforming growth factors (TGF) and their related peptides, tumor necrosis factor fragments, toxins and toxoids and functional peptides such as anticancer peptides including angiostatins, antihypertension peptides, anti-blood clotting peptides, and antimicrobial peptides; selected from the group consisting of proteins such as immunoglobulins, angiogenins, bone morphogenic proteins, chemokines, colony stimulating factors (CSF), cytokines, growth factors, interferons (Type I and II), interleukins, leptins, leukaemia inhibitory factors, stem cell factors, transforming growth factors and tumor necrosis factors.

[0034] Cationic peptides are suitable for use where a portion of the composition comprises an anionic amphiphile such as a fatty acid. In this embodiment, preferred peptides include octreotide, lanreotide, calcitonin, oxytocin, interferon-beta and -gamma, interleukins 4, 5, 7 and 8 and other peptides having an isoelectric point above pH 7, especially above pH 8.

[0035] Some particular therapeutic agents are those suitable for systemic administration including antibacterials (including amicacin, monocycline anddoxycycline), local and systemic analgesics (including bupivacaine, tramadol, fentanyl, morphine, hydromorphone, methadone, oxycodone, codeine, asperine, acetaminophen), NS AIDS (such as ibuprofene, naproxene, keteprofene, indomethansine, sulindac, tolmethin, salysylic acids such as salisylamide, diflunisal), Coxl or Cox2 inhibitors (such as celecoxib, rofecoxib, valdecoxib) anticancer agents (including octreotide, lanreotide, buserelin, luprorelin, goserelin, triptorelin, avorelin, deslorein, abarelix, degarelix, fulvestrant, interferon alpha, interferon beta, darbepoetin alpha, epoetin alpha, beta, delta, and paclitaxel), antipsychotics (like bromperidol, risperidone, olanzapine, iloperidone, paliperadone, pipotiazine and zuclopenthixol), antivirals, anticonvulsants (for instance tiagabine topiramate or gabapentin) or nicotine, hormones (such as testosterone, and testosterone undecanoate, medroxyprogesterone, estradiol) growth hormones (like human growthhormone), and growth factors (like granulocyte macrophage colony-stimulating factor)

[0036] Other therapeutic agents suitable for inclusion include Antihistamines, Mast cell stabilizers, Nonsteroidal anti-inflammatory drugs (NSAIDs), Corticosteroids (e.g. to treat allergic conjunctivitis), Anti-Glaucoma actives including inflow suppressing / inhibiting agents (beta blocking agents: timolol, betaxolol, carteolol, levobunolol, etc., topical carbonic anhydrase inhibitors: dorzolamide, brinzolamide, sympathomimetics: epinephrine, dipivefrin, clonidine, apraclonidine, brimonidine), outflow facilitating agents (parasympathomimetics (cholinergic agonists): pilocarpine prostaglandin analogues and related compounds: atanoprost, travoprost, bimatoprost, unoprostone).

[0037] Other therapeutic agents that can be incorporated into the pharmaceutical compositions described herein include any drug having or that can be modified to have a log P of at least 3, at least 4, at least 5 . The drug can be modified to have the recited log P values by making a prodrug of the drug of interest or by making a salt of the drug, wherein the salt of the drug has the recited log P values. Thus, for example, a drug having a log P of less than 3 could be modified by the formation of a prodrug having a functional group that makes the log P of the prodrug be the recited log P values (e.g., at least 3). In such an example, the drug having a log P of less than 3 can comprise a hydroxy or amino functional group that can form an ester or an amide, respectively, with a Ci2-C22-carboxylic acid. The resulting Ci2-C22-ester or amide may have the recited log P values (e.g., at least 3). Alternatively, or in addition, the drug or prodrug can be modified by making it a salt that may have the recited log P values. For example, the drug or prodrug can be synthesized to be a docusate salt or can be ion exchanged to form a docusate salt, where the docusate is the counterion of the salt. Other such counterions are known in the art and are contemplated herein. Accordingly, in addition to the analgesic agents, anesthetic agents, and anti-inflammatory agents described herein, the pharmaceutical compositions described herein can also be formulated to contain one or more antidepressants, antipsychotics, antianxiolitics, and anticancer agents.

[0038] Examples of antidepressants include, but are not limited to, agomelatine, Allegron (nortriptyline), Alventa XL (venlafaxine), Amphero XL(venlafaxine), amitriptyline, Brintellix (vortioxetine), Cipralex (escitalopram), Cipramil (citalopram), citalopram, clomipramine, Cymbalta (duloxetine), Depefex XL (venlafaxine), dosulepin, doxepin, duloxetine, Edronax (reboxetine), Efexor XL (venlafaxine), escitalopram, Faverin (fluvoxamine), fluoxetine, fluvoxamine, Foraven XL (venlafaxine), imipramine, isocarboxazid, lofepramine, Lomont (lofepramine), Lustral (sertraline), Maj oven XL (venlafaxine), Manerix (moclobemide), mianserin, mirtazapine, moclobemide, Molipaxin (trazodone), Nardil (phenelzine), nortriptyline, Olena (fluoxetine), Oxactin (fluoxetine), Parnate (tranylcypromine), paroxetine, phenelzine, Politid XL (venlafaxine), Prothiaden (dosulepin), Prozac (fluoxetine), Prozep (fluoxetine), reboxetine, Seroxat (paroxetine), sertraline, Sinepin (doxepin), Sunveniz XL (venlafaxine), Surmontil (trimipramine), Tonpular XL (venlafaxine), tranylcypromine, trazodone, trimipramine, Valdoxan (agomelatine), Venadex XL (venlafaxine), Venaxx XL (venlafaxine), Vencarm XL (venlafaxine), Venlablue XL (venlafaxine), venlafaxine, Venladex XL (venlafaxine), Venlasoz XL (venlafaxine), Venlalic XL (venlafaxine), Vensir XL (venlafaxine), ViePax XL (venlafaxine), vortioxetine, and Zispin (mirtazapine). Some of the foregoing antidepressants may have a log P of less than 3 (e.g., agomelatine, which is calculated to have a log P of about 2.0 to about 2.8) but can be modified as described herein to have a log P of at least 3.

[0039] Examples of antipsychotics include, but are not limited to, Abilify (aripiprazole), Alaquet (quetiapine), amisulpride, Anquil (benperidol), aripiprazole, Arpoya (aripiprazole), Asenapine, Atrolak (quetiapine), benperidol, Biquelle (quetiapine), Brancico (quetiapine), cariprazine, Chloractil (chlorpromazine), chlorpromazine, Clopixol (zuclopenthixol), Clopixol Acuphase (zuclopenthixol), clozapine, Clozaril (clozapine), Denzapine (clozapine), Depixol (flupentixol), Dolmatil (sulpiride), Fluanxol (flupentixol), flupentixol, Haldol (haloperidol), Halkid (haloperidol), haloperidol, Invega (paliperidone), Largactil (chlorpromazine), Latuda (lurasidone), levomepromazine, lurasidone, Mintreleg (quetiapine), Neulactil (pericyazine), Nozinan (levomepromazine), olanzapine, Orap (pimozide), paliperidone, periciazine, pimozide, prochlorperazine, promazine, quetiapine, Reagila (cariprazine), Risperdal (risperidone), risperidone, Seroquel (quetiapine), Solian (amisulpride), Stelazine (trifluoperazine), Stemetil (prochlorperazine), sulpiride,Sulpor (sulpiride), Sy crest (asenapine), Tenprolide (quetiapine), Trevi eta (paliperidone), trifluoperazine, Zalasta (olanzapine), Zaluron (quetiapine), Zaponex (clozapine), zuclopenthixol, zuclopenthixol dihydrochloride, and Zyprexa (olanzapine). Some of the foregoing antidepressants may have a log P of less than 3 (e.g., amisulpride, which is calculated to have a log P of about 0.25 to about 1.5) but can be modified as described herein to have a log P of at least 3.

[0040] The pharmaceutical composition can include an adjuvant. In the context of drug, an adjuvant refers to drugs with a primary indication that may differ from that of the therapeutic agent. Examples of suitable adjuvants include a barbiturate, an opiate, an anti-inflammatory agent, a cannabinoid, a sympatholytic agent or a mixture thereof. Further examples of suitable adjuvants include corticosteroid, dexamethasone, pethidine, tubocurarine chloride, meloxicam, dexmedetomidine or a mixture thereof.

[0041] If the adjuvant includes a cannabinoid, a suitable cannabinoid can be cannabidiol (CBD). However it is possible that other cannabinoids can include cannabigerolic acid (CBGA), cannabigerolic acid monomethylether (CBGAM), cannabigerol (CBG), cannabigerol monomethylether (CBGM), cannabigerovarinic acid (CBGVA), cannabigerovarin (CBGV), cannabichromenic acid (CBCA), cannabichromene (CBC), cannabichromevarinic acid (CBCVA), cannabichromevarin (CBCV), cannabidiolic acid (CBD A), cannabidiol monomethylether (CBDM), cannabidiol-C4 (CBD-C4), cannabidivarinic acid (CBDVA), cannabidivarin (CBDV), cannabidiorcol (CBD-C1), tetrahydrocannabinolic acid A (THCA-A), tetrahydrocannabinolic acid B (THCA-B), tetrahydrocannabinolic acid (THCA), tetrahydrocannabinol (THC), tetrahydrocannabinolic acid C4 (THCA-C4), tetrahydrocannbinol C4 (THC-C4), tetrahydrocannabivarinic acid (THCVA), tetrahydrocannabivarin (THCV), tetrahydrocannabiorcolic acid (THCA-C1), tetrahydrocannabiorcol (THC-C1), A7-cis-iso-tetrahydrocannabivarin, A8- tetrahydrocannabinolic acid (A8-THCA), cannabivarinodiolic (CBNDVA), cannabivarinodiol (CBNDV), A8-tetrahydrocannabinol (A8-THC), A9- tetrahydrocannabinol (A9-THC), cannabicyclolic acid (CBLA), cannabicyclol (CBL), cannabicyclovarin (CBLV), cannabielsoic acid A (CBEA-A), cannabielsoic acid B (CBEA-B), cannabielsoin (CBE), cannabivarinselsoin(CBEV), cannabivarinselsoinic acid (CBEVA), cannabielsoic acid (CBEA), cannabielvarinsoin (CBLV), cannabielvarinsoinic acid (CBLVA), cannabinolic acid (CBNA), cannabinol (CBN), cannabivarinic acid (CBNVA), cannabinol methylether (CBNM), cannabinol-C4 (CBN-C4), cannabivarin (CBV), cannabino-C2 (CBN-C2), cannabiorcol (CBN-C1), cannabinodiol (CBND), cannabinodiolic acid (CBND A), cannabinodivarin (CBDV), cannabitriol (CBT), 10-ethoxy-9-hydroxy-A8a-tetrahydrocannabinol, 8,9-dihydroxy-A6a(10a)- tetrahydrocannabinol (8,9-Di-OH-CBT-C5), cannabitriolvarin (CBTV), ethoxy- cannabitriolvarin (CBTVE), dehydrocannabifuran (DCBF), cannbifuran (CBF), cannabichromanon (CBCN), cannabicitran (CBT), 10-oxo-A6a(10a)- tetrahydrocannabinol (OTHC), A9-cis-tetrahydrocannabinol (cis-THC), cannabiripsol (CBR), 3,4,5,6-tetrahydro-7-hydroxy-alpha-alpha-2-trimethyl-9-n- propyl-2,6-methano-2H-l-benzoxocin-5-methanol (OH-iso-HHCV), trihydroxy - delta-9-tetrahydrocannabinol (triOH-THC), yangonin, epigallocatechin gallate, dodeca-2E,4E,8Z,10Z-tetraenoic acid isobutylamide, and dodeca-2E,4E-dienoic acid isobutyl ami de, a mixture thereof, or a mixture of any of the foregoing with cannabidiol.

[0042] Including the adjuvant can provide a synergistic effect in that the amount of the drug that needs to be added to be considered a therapeutically effective amount can be decreased, relative to a comparative pharmaceutical composition differing only by being free of the adjuvant.

[0043] In some aspects, the pharmaceutical composition can include a rheological modifier. Where present, the rheological modifier can be present in a range of from about 0.5 % (w / v) to about 10 % (w / v) of the pharmaceutical composition based on the volume of the lipophilic oil, 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, 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).

[0044] In some aspects, the rheological modifier can be a thinning agent that reduces the viscosity of the pharmaceutical composition. In examples, where the pharmaceutical composition is intended to be injected, the thinning agent can be beneficial in that it can enhance the injectability of the pharmaceutical composition by making it less viscous. For example, the thinning agent can at least temporarily disrupt the supramolecular gel. In addition to increasing theinjectability of the pharmaceutical composition, at least temporarily disrupting the supramolecular gel can help to enhance the shelf-life stability of the pharmaceutical composition. For example, if the components of the pharmaceutical composition are homogenously distributed with respect to each other the formation of the supramolecular gel can be delayed until deployed in vivo. Examples of suitable thinning agents can include a C2-Ci2-alcohol. Nonlimiting examples of alcohols can include ethanol, benzyl alcohol, or a mixture thereof. A benefit of using ethanol or benzyl alcohol is that once the pharmaceutical composition, including ethanol or benzyl alcohol, is deployed in vivo the ethanol or benzyl alcohol will diffuse in the aqueous environment allowing for the viscosity of the pharmaceutical composition to increase and / or for complete formation of the supramolecular gel to occur.

[0045] In other aspects, the rheological modifier can increase the viscosity of the pharmaceutical composition. This can be helpful, for example, if a particular combination of a lipophilic oil and structuring agent interact well together or allow for adequate dispersion and diffusion of a desired drug but together do not provide a composition having adequate viscosity. Including a rheological modifier to increase the viscosity can make the pharmaceutical composition viable.

[0046] Pharmaceutical compositions contain an effective amount of a compound as described herein and optionally one or more other therapeutic agents included in a pharmaceutically acceptable carrier. The term “pharmaceutically acceptable carrier” means one or more compatible solid or liquid fillers, diluents or encapsulating substances which are suitable for administration to a human or other vertebrate animal. The term “carrier” denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application. The components of the pharmaceutical compositions also can be commingled with the compounds, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficiency.

[0047] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting thesubject chemical from one organ or portion of the body to another organ or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the composition, not injurious to the patient, and substantially non-pyrogenic. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, castor oil, medium chain triglyceride oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer’s solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical compositions. Pharmaceutical compositions of the present disclosure are non-pyrogenic, i.e., do not induce significant temperature elevations when administered to a patient.

[0048] The pharmaceutical composition can be packaged in any suitable manner. For example, the pharmaceutical composition can be packaged in ajar, vessel, or the like such that the pharmaceutical composition can be accessed and manually applied at a desired location. Alternatively, the pharmaceutical composition can be disposed within a dispensing chamber of a syringe. The syringe can have a needle having a size in a range of from about 14 to about 30 gauge, about 21 to about 25 gauge, less than, equal to, or greater than about 14 gauge, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 gauge. Alternatively, the pharmaceutical composition can be disposed from the syringe without a needle (e.g., through a cone applicator).

[0049] The pharmaceutical composition can be manufactured by a) mixing the lipophilic oil and the therapeutic agent under stirring at a temperature above 25 °C to form a first mixture; b) mixing the structuring agent with the first mixture under 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.

[0050] As an example, the pharmaceutical composition can be manufactured by mixing the lipophilic oil and the drug under stirring at a temperature above room temperature (25 °C ) to form a first mixture. For example, the temperature can be in a range of from about 50 °C to about 100 °C, about 60 °C to about 80 °C, less than, equal to, or greater than about 50 °C , 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 °C. The 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 in a range of from about 50 °C to about 100 °C, about 60 °C to about 80 °C, less than, equal to, or greater than about 50 °C, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 °C. The second mixture can then be cooled to form the pharmaceutical composition. Before the second mixture is cooled it can be placed in the jar, vessel, or syringe so that the supramolecular gel forms therein.

[0051] The pharmaceutical composition and / or jar, vessel, or syringe can be sterilized at any point during the manufacturing process. However, as a result of the stability of the pharmaceutical composition, sterilization can occur after the pharmaceutical composition is fully formed (e.g., post cooling). Sterilization can occur using any suitable technique such as ultra violet light treatment, e- beam, x-ray, autoclaving, steam sterilization and dry heat sterilization.

[0052] In operation, the pharmaceutical composition can be administered to a subject. The pharmaceutical composition can be administered at or proximate to an injury or wound or treatment site. An example of an injury or wound can include a surgical site. The pharmaceutical composition can be administered proximal to an injury or wound. In the context of a surgery, the pharmaceutical composition can be applied before a surgery, during the course of surgery (e.g., any time before the incision is closed) or after surgery (e.g., after the incision is closed).

[0053] As used herein, the term “kit” refers to a product (e.g. medicament, kit-of-parts) comprising one package or one or more separate packages of:(i). A pharmaceutical composition containing an active pharmaceutical ingredient and at least one further active pharmaceutical ingredient and optionally a medical device. The at least one further active pharmaceutical ingredient may be present in said pharmaceuticalcomposition, i.e. the kit may comprise one or more packages, wherein each package comprises one pharmaceutical composition which comprises two or more active pharmaceutical ingredients. The further active pharmaceutical ingredient may also be present in a further pharmaceutical composition, i.e. the kit may comprise separate packages of two or more pharmaceutical compositions, wherein each pharmaceutical composition contain one active pharmaceutical ingredient.Or(ii). A pharmaceutical composition containing an active pharmaceutical ingredient and medical device.

[0054] A kit may comprise one package only or may comprise one or more separate packages. For example, the kit may be a product (e.g. medicament) containing two or more vials each containing a defined pharmaceutical composition, wherein each pharmaceutical composition contains at least one active pharmaceutical ingredient. For example, the kit may comprise (i.) a vial containing a defined pharmaceutical composition and (ii). further a tablet, capsule, powder or any other oral dosage form which contains at least one further active pharmaceutical ingredient. The kit may further comprise a package leaflet with instructions for how to administer the pharmaceutical composition and the at least one further active pharmaceutical ingredient. The kit can include one or more syringes, vials, or the like prefilled with pharmaceutical composition and can include one or more of a needle, applicator, catheter tubing, or syringe adapter (e.g., 2-way, 3-way, 4-way).

[0055] As used herein, the term “medical device” means any instrument, apparatus, implant, in vitro reagent or similar or related article that is used to diagnose, prevent, or treat a disease of other condition, and does not achieve its purpose through pharmacological action within or on the body.

[0056] 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.

[0057] The ingredients in the pharmaceutical composition can be defined as being Generally Recognized as Safe (“GRAS”). A full list of GRASingredients 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 being GRAS ingredients, about 75% to about 100%, about 90% to about 100%, less than, equal to, or greater than about 50%, 55, 60, 65, 70, 75, 80, 85, 90, 95, or about 100% of the ingredients in the pharmaceutical composition can be classified as being GRAS ingredients.Exemplary Aspects.

[0058] The following exemplary aspects are provided, the numbering of which is not to be construed as designating levels of importance:

[0059] Aspect 1 provides a pharmaceutical composition, comprising: a lipophilic oil; a therapeutic agent, salt, ion pair thereof, or prodrug thereof dispersed in the lipophilic oil; and a structuring agent at least a portion of which is not dissolved in the lipophilic oil and forms a gel.

[0060] Aspect 2 provides the pharmaceutical composition of Aspect 1, wherein the lipophilic oil comprises a monoglyceride, diglyceride, triglyceride, medium-chain triglyceride oil, sesame oil, soybean oil, castor oil, vegetable oil, tributyrin oil, or a mixture thereof.

[0061] Aspect 3 provides the pharmaceutical composition of Aspect 2, wherein the triglyceride is a saturated triglyceride, a monounsaturated triglyceride, or a polyunsaturated triglyceride.

[0062] Aspect 4 provides the pharmaceutical composition of any of Aspects 2 or 3, wherein the triglyceride comprises a medium-chain triglyceride, a short-chain triglyceride, long-chain triglyceride, or a mixture thereof.

[0063] Aspect 5 provides the pharmaceutical composition of Aspect 4, wherein the triglyceride comprises the medium-chain triglyceride.

[0064] 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 thereof.

[0065] Aspect 7 provides the pharmaceutical composition of any of Aspects 1-6, wherein the structuring agent has a melting point in a range of from about 40 °C to about 100 °C.

[0066] Aspect 8 provides the pharmaceutical composition of Aspect 7, wherein the structuring agent has a melting point in a range of from about 50 °C to about 85 °C.

[0067] Aspect 9 provides the pharmaceutical composition of Aspect 8, wherein the structuring agent has a melting point in a range of from about 50 °C to about 75 °C.

[0068] Aspect 10 provides the pharmaceutical composition of any of Aspects 1-9, wherein the structuring agent comprises a monoglyceride, a diglyceride, a triglyceride, polyglyceride ester of a fatty acid, or a mixture thereof.

[0069] Aspect 11 provides the pharmaceutical composition of any of Aspects 1-10, wherein the structuring agent comprises tri stearin, glyceryl distearate, glycerol monostearate, glyceryl dibehenate, cholesterol, trimyristin, glyceryl dimyristin, glyceryl monomyristin, trilaurin, glyceryl dilaurin, glyceryl monolaurin, tripalmitin, glyceryl dipalmitin, glyceryl monopalmitin, cholesterol, a polyglyceride ester of a fatty acid, a polyglycerol ester of a fatty acid, or a mixture thereof.

[0070] Aspect 12 provides the pharmaceutical composition of Aspect 11, wherein the structuring agent comprises glycerol monostearate, glyceryl di stearate, tri stearin, glycerol monopalmitin, glycerol dipalmitin, tripalmitin, glycerol monomyristin, glycerol dimyristin, trimyristin, or a mixture thereof.

[0071] Aspect 13 provides the pharmaceutical composition of any of Aspects 1-12, wherein the structuring agent is present in a concentration in a range of from about 0.1 % (w / v) to about 25 % (w / v) of the pharmaceutical composition based on the volume of the lipophilic oil.

[0072] Aspect 14 provides the pharmaceutical composition of Aspect 13, wherein the structuring agent is present in a concentration in a range of from about 3% (w / v) to about 20% (w / v) of the pharmaceutical composition based on the volume of the lipophilic oil.

[0073] Aspect 15 provides the pharmaceutical composition of any of Aspects 13 or 14, wherein the structuring agent is present in a concentration in arange of from about 3% (w / v) to about 10 % (w / v) of the pharmaceutical composition based on the volume of the lipophilic oil.

[0074] Aspect 16 provides the pharmaceutical composition of any of Aspects 1-15, wherein the therapeutic agent comprises hydrophilic small molecule drugs, lipophilic small molecule drugs, amphiphilic small molecule drugs, peptides, proteins, oligonucleotides and mixtures thereof..

[0075] Aspect 17 provides the pharmaceutical composition of any of Aspects 1-16, further comprising an adjuvant.

[0076] Aspect 18 provides the pharmaceutical composition of Aspect 17, wherein the adjuvant comprises a corticosteroid, alpha-2-agonist, pethidine, barbiturate, opiate, tubocurarine chloride, a cannabinoid, meloxicam, a salt thereof, or ion pair thereof, or a mixture thereof.

[0077] Aspect 19 provides the pharmaceutical composition of Aspect 18, wherein the cannabinoid is cannabidiol (CBD).

[0078] Aspect 20 provides the pharmaceutical composition of any of Aspects 1-19, further comprising a rheological modifier comprising C2-C12- alcohol.

[0079] Aspect 21 provides the pharmaceutical composition of Aspect 20, wherein the rheological modifier comprises ethanol, benzyl alcohol, or a mixture thereof.

[0080] Aspect 22 provides the pharmaceutical composition of Aspect 21, wherein the C2-C12 alcohol comprises ethanol, benzyl alcohol, or a mixture thereof and is present in a range of from about 0.5 % (w / v) to about 10 % (w / v) of the pharmaceutical composition based on the volume of the lipophilic oil.

[0081] Aspect 23 provides the pharmaceutical composition of Aspect 22, wherein the ethanol, benzyl alcohol, or a mixture thereof is present in a range of from about 1 % (w / v) to about 6 % (w / v) of the pharmaceutical composition based on the volume of the lipophilic oil.

[0082] Aspect 24 provides the pharmaceutical composition of any of Aspects 1-23, wherein a viscosity of the composition is in a range of from about 1,000 cP to about 1,000,000 cP, when measured at about 37 °C.

[0083] Aspect 25 provides the pharmaceutical composition of any of Aspects 1-24, wherein a viscosity of the composition is in a range of from about 1,000 cP to about 150,000 cP, when measured at about 37 °C.

[0084] Aspect 26 provides the pharmaceutical composition of any of Aspects 1-25, wherein following shearing, a viscosity of the composition is in a range of from about 10 cP to about 10,000 cP when measured at about 37 °C.

[0085] Aspect 27 provides the pharmaceutical composition of any of Aspects 1-26, wherein following shearing, the viscosity reduces to allow injectability by a shear-thinning behavior.

[0086] Aspect 28 provides a kit comprising: a syringe; and the pharmaceutical composition of Aspect 1, disposed within the syringe.

[0087] Aspect 29 provides the kit of Aspect 28, wherein the pharmaceutical composition is sealed within the syringe.

[0088] Aspect 30 provides the kit of Aspect 29, wherein the syringe further comprises a needle having a size of about 15-30 gauge.

[0089] Aspect 31 provides the kit of Aspect 30, wherein the syringe comprises a needle size of about 21 to about 25 gauge.

[0090] Aspect 32 provides a method of manufacturing the pharmaceutical composition of any of Aspects 1-31, the method comprising: a) mixing the lipophilic oil and the therapeutic agent under stirring and heating at a temperature above 25 °C to form a mixture; b) cooling the mixture to form the pharmaceutical composition.

[0091] Aspect 33 provides the method of Aspect 32, wherein mixing at a) is conducted at a temperature in a range of from about 50 °C to about 150 °C.

[0092] Aspect 34 provides the method of Aspect 33, wherein the mixture is placed in a sealed syringe to cool at b).

[0093] Aspect 35 provides the method of Aspect 34, further comprising sterilizing the pharmaceutical composition.

[0094] Aspect 36 provides the method of Aspect 35, wherein sterilization occurs after the pharmaceutical composition it is dispensed in the sealed syringed, wherein sterilization comprises gamma irradiation, electron beam irradiation, x-ray irradiation, heat sterilization, steam sterilization, or a combination thereof.

[0095] Aspect 37 provides a method of treating a subject with the pharmaceutical composition of any of Aspects 1-36, comprising administering the pharmaceutical composition to the subject in need thereof.

[0096] Aspect 38 provides the method of Aspect 37, wherein the pharmaceutical composition is administered to the subject at or proximate to a surgical site.

[0097] Aspect 39 provides the method of Aspect 38, wherein the pharmaceutical composition is administered to the subject at or proximate to a wound.

[0098] Aspect 40 provides the method of Aspect 39, wherein the pharmaceutical compositions is administered to a subject at a site that is proximal to a wound.

[0099] Aspect 41 provides the method of any of Aspects 37-40, wherein a first portion of the pharmaceutical composition is administered to the subject at or proximate to the wound and a second portion of the pharmaceutical composition is administered to the subject at a site proximal to the wound.

[0100] Aspect 42 provides the method of any of Aspects 37-41, wherein administering the pharmaceutical composition comprises injecting the pharmaceutical composition through a syringe, through a needle having a size of about 18-30 gauge, rubbing the pharmaceutical composition at or proximate to a wound or surgical site, or a combination thereof.

[0101] Aspect 43 provides the method of any of Aspects 38-42, wherein the pharmaceutical composition is administered to the subject before surgery is performed, during surgery, or after the subject has had surgery performed.

[0102] Aspect 44 provides the method of any of Aspects 37-43, wherein the pharmaceutical composition is injected intraarticular, intra-tendon, or at a site of inflammation.

[0103] Throughout this document, values expressed in a range format should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, a range of “about 0.1% to about 5%” or “about 0.1% to 5%” should be interpreted to include not just about 0.1% to about 5%, but also the individual values (e.g., 1%,2%, 3%, and 4%) and the sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range. The statement “about X to Y” has the same meaning as “about X to about Y,” unless indicated otherwise. Likewise, the statement “about X, Y, or about Z” has the same meaning as “about X, about Y, or about Z,” unless indicated otherwise.

[0104] In this document, the terms “a,” “an,” or “the” are used to include one or more than one unless the context clearly dictates otherwise. The term “or” is used to refer to a nonexclusive “or” unless otherwise indicated. The statement “at least one of A and B” or “at least one of A or B” has the same meaning as “A, B, or A and B.” In addition, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. Any use of section headings is intended to aid reading of the document and is not to be interpreted as limiting; information that is relevant to a section heading may occur within or outside of that particular section.

[0105] In the methods described herein, the acts can be carried out in any order without departing from the principles of the disclosure, except when a temporal or operational sequence is explicitly recited. Furthermore, specified acts can be carried out concurrently unless explicit claim language recites that they be carried out separately. For example, a claimed act of doing X and a claimed act of doing Y can be conducted simultaneously within a single operation, and the resulting process will fall within the literal scope of the claimed process.

[0106] The term “about” as used herein can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range, and includes the exact stated value or range. The term “substantially” as used herein refers to a majority of, or mostly, as in at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%. The term “substantially free of’ as used herein can mean having none or having a trivial amount of, such that the amount of material present does not affect the material properties of the composition including the material, such that about 0 wt% to about 5 wt% of the composition is the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than or equal to about 4.5 wt%, 4, 3.5, 3,2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less, or about 0 wt%.

Claims

CLAIMSWhat is claimed is:

1. A pharmaceutical composition, comprising: a lipophilic oil; a therapeutic agent, salt thereof, ion pair thereof, or prodrug thereof dispersed in the lipophilic oil; and a structuring agent at least a portion of which is not dissolved in the lipophilic oil and forms a gel.

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

3. The pharmaceutical composition of claim 2, wherein the triglyceride is a saturated triglyceride, a monounsaturated triglyceride, or a polyunsaturated triglyceride.

4. The pharmaceutical composition of claim 2, wherein the triglyceride comprises a medium-chain triglyceride, a short-chain triglyceride, long-chain triglyceride, or a mixture thereof.

5. The pharmaceutical composition of claim 4, wherein the triglyceride comprises the medium-chain triglyceride.

6. The pharmaceutical composition of claim 5, wherein the medium-chain triglyceride comprises a glyceride of a C6-C12 carboxylic acid, or a mixture thereof.

7. The pharmaceutical composition of claim 1, wherein the structuring agent has a melting point in a range of from about 40 °C to about 100 °C.

8. The pharmaceutical composition of claim 7, wherein the structuring agent has a melting point in a range of from about 50 °C to about 85 °C.

9. The pharmaceutical composition of claim 8, wherein the structuring agent has a melting point in a range of from about 65 °C to about 75 °C.

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

11. The pharmaceutical composition of claim 1, wherein the structuring agent comprises tri stearin, glyceryl di stearate, glycerol monostearate, glyceryl dibehenate, cholesterol, trimyristin, glyceryl dimyristin, glyceryl monomyristin, trilaurin, glyceryl dilaurin, glyceryl monolaurin, tripalmitin, glyceryl dipalmitin, glyceryl monopalmitin, cholesterol, a polyglyceride ester of a fatty acid, a polyglycerol ester of a fatty acid, or a mixture thereof.

12. The pharmaceutical composition of claim 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.

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

14. The pharmaceutical composition of claim 13, wherein the structuring agent is present in a concentration in a range of from about 3% (w / v) to about 20% (w / v) of the pharmaceutical composition based on the volume of the lipophilic oil.

15. The pharmaceutical composition of claim 13, wherein the structuring agent is present in a concentration in a range of from about 3% (w / v) to about 10 % (w / v) of the pharmaceutical composition based on the volume of the lipophilic oil.

16. The pharmaceutical composition of claim 1, wherein the therapeutic agent comprises hydrophilic small molecule drugs, lipophilic small molecule drugs, amphiphilic small molecule drugs, peptides, proteins, oligonucleotides and mixtures thereof..

17. The pharmaceutical composition of claim 1, further comprising an adjuvant.

18. The pharmaceutical composition of claim 33, wherein the adjuvant comprises a corticosteroid, alpha-2-agonist, pethidine, barbiturate, opiate, tubocurarine chloride, a cannabinoid, meloxicam, a salt thereof, or ion pair thereof, or a mixture thereof.

19. The pharmaceutical composition of claim 18, wherein the cannabinoid is cannabidiol (CBD).

20. The pharmaceutical composition of claim 1, further comprising a rheological modifier comprising C2-C12-alcohol.

21. The pharmaceutical composition of claim 20, wherein the rheological modifier comprises ethanol, benzyl alcohol, or a mixture thereof.

22. The pharmaceutical composition of claim 21, wherein the C2-C12 alcohol comprises ethanol, benzyl alcohol, or a mixture thereof and is present in a range of from about 0.5 % (w / v) to about 10 % (w / v) of the pharmaceutical composition based on the volume of the lipophilic oil.

23. The pharmaceutical composition of claim 22, wherein the ethanol, benzyl alcohol, or a mixture thereof is present in a range of from about 1 % (w / v) to about 6 % (w / v) of the pharmaceutical composition based on the volume of the lipophilic oil.

24. The pharmaceutical composition of claim 1, wherein a viscosity of the composition is in a range of from about 1,000 cP to about 1,000,000 cP, when measured at about 37 °C.

25. The pharmaceutical composition of claim 1, wherein a viscosity of the composition is in a range of from about 1,000 cP to about 150,000 cP, when measured at about 37 °C.

26. The pharmaceutical composition of claim 1, wherein following shearing, a viscosity of the composition is in a range of from about 10 cP to about 10,000 cP when measured at about 37 °C.

27. The pharmaceutical composition of claim 1, wherein following shearing, the viscosity reduces to allow injectability by a shear-thinning behavior.

28. A kit comprising: a syringe; and the pharmaceutical composition of claim 1, disposed within the syringe.

29. The kit of claim 28, wherein the pharmaceutical composition is sealed within the syringe.

30. The kit of claim 29, wherein the syringe further comprises a needle having a size of about 15-30 gauge.

31. The kit of claim 30, wherein the syringe comprises a needle size of about 21 to about 25 gauge.

32. A method of manufacturing the pharmaceutical composition of claim 1, the method comprising: a) mixing the lipophilic oil and the analgesic agent, anesthetic agent under stirring and heating at a temperature above 25 °C to form a mixture; b) cooling the mixture to form the pharmaceutical composition.

33. The method of claim 32, wherein mixing at a) is conducted at a temperature in a range of from about 50 °C to about 150 °C.

34. The method of claim 33, wherein the mixture is placed in a sealed syringe to cool at b).

35. The method of claim 34, further comprising sterilizing the pharmaceutical composition.

36. The method of claim 35, wherein sterilization occurs after the pharmaceutical composition is dispensed in a container, wherein sterilization comprises gamma irradiation, electron beam irradiation, x-ray irradiation, heat sterilization, steam sterilization, or a combination thereof.

37. A method of treating a subject with the pharmaceutical composition of claim 1, comprising administering the pharmaceutical composition to the subject in need thereof.

38. The method of claim 37, wherein the pharmaceutical composition is administered to the subject at or proximate to a surgical site or site or injury.

39. The method of claim 38, wherein the pharmaceutical composition is administered to the subject at or proximate to a wound.

40. The method of claim 39, wherein the pharmaceutical compositions is administered to a subject at a site that is proximal to a wound.

41. The method of claim 37, wherein a first portion of the pharmaceutical composition is administered to the subject at or proximate to the wound and a second portion of the pharmaceutical composition is administered to the subject at a site proximal to the wound.

42. The method of claim 37, wherein administering the pharmaceutical composition comprises injecting the pharmaceutical composition through asyringe, through a needle having a size of about 18-30 gauge, rubbing the pharmaceutical composition at or proximate to a wound or surgical site, or a combination thereof.

43. The method of claim 38, wherein the pharmaceutical composition is administered to the subject before surgery is performed, during surgery, or after the subject has had surgery performed.

44. The method of claim 37, wherein the pharmaceutical composition is injected intraarticular, intra-tendon, or at a site of inflammation.