Precipitation-resistant small molecule drug formulations

Abstract

To provide formulations that provide a solution to the problem of small molecule precipitation at the injection site when administered as a highly-concentrated formulation.SOLUTION: A formulation comprises: (a) a biocompatible non-aqueous solvent; and (b) a small molecule drug or a salt thereof, solubilized within the non-aqueous solvent; and (c) 1% to 30% w / w of a surfactant which attenuates the precipitation of the small molecule drug when injected into a subject.SELECTED DRAWING: Figure 2

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 514,474, filed June 2, 2017, which is incorporated by reference in its entirety.

[0002] A. Field of the Invention The present invention relates generally to pharmaceutical formulations, and more specifically to therapeutic formulations of small molecule drugs with improved solubility, stability, and bioavailability, and methods of using such pharmaceutical formulations to treat various diseases, conditions, and disorders. [Background technology]

[0003] B. Description of Related Art Although many small molecule drugs are orally bioavailable, parenteral infusions are also used in situations where the drug has insufficient oral bioavailability, where the patient cannot tolerate the drug orally, or where a more rapid onset of drug action is required. For example, administration of benzodiazepines for emergency treatment of epileptic seizures, administration of catecholamines for allergic reactions, and administration of "triptans" for the treatment of migraines represent situations where oral administration is not efficient or recommended, and thus the drug must be administered by a route other than oral, often parenteral administration.

[0004] The standard practice for preparing formulations containing small molecule drugs is to develop an aqueous solution for parenteral injection. The main reason is that the human body is largely composed of water, including plasma, and is an aqueous environment. Therefore, it is a natural tendency to administer drug formulations that are compatible with the environment the drug is intended to reach. However, some small molecule drugs have limited solubility and poor stability in such aqueous environments. This problem has been at least partially solved by including co-solvents and / or stabilizers in the formulation to more effectively solubilize and stabilize small molecule drugs in aqueous solutions.

[0005] Some examples of problems associated with parenteral injection of small molecule drugs can be seen for diazepam. This drug is used for emergency treatment of epileptic seizures, but its poor water solubility prevents its use. For this reason, the currently available emergency treatment consists of a rectal gel. Attempts have also been made to develop large volume (up to 3 mL) intramuscular injections based on aqueous formulations with cosolvents (larger volumes are necessary due to the low solubility of diazepam). However, development of this drug has been limited by the difficulty of delivering large volumes of intramuscular injections deep into patients experiencing convulsions and by the pain associated with such large doses.

[0006] Furthermore, due to stability issues of small molecule drugs in aqueous environments, current products are often sold as lyophilized powders that require reconstitution in an aqueous carrier prior to injection, allowing for a longer shelf life of the drug. Some products are still sold as liquids that require further dilution with sterile water, phosphate buffer, or isotonic saline prior to injection.

[0007] Due to the limited water solubility of therapeutically relevant benzodiazepine drugs (e.g., diazepam), there have been previous attempts to formulate these drugs as non-aqueous compositions. For example, U.S. Patent No. 8,946,208 (Castile et al.) describes a composition for intranasal administration in which a small molecule drug (e.g., diazepam) is dissolved in a non-aqueous vehicle that includes propylene glycol and one additional non-aqueous solvent selected from the group including N-methylpyrrolidone (NMP) and dimethylsulfoxide (DMSO). The pharmaceutical composition for intranasal administration described by Castile et al. can be highly concentrated, with examples citing diazepam concentrations ranging up to 200 mg / mL, and a preferred embodiment for a 50 mg / mL concentration. The nasal spray formulation described by Castile et al. does not address the problem of poor water solubility encountered by drugs when administered to patients, specifically the problem of low bioavailability that occurs when formulations such as highly concentrated injection formulations are administered to patients.

[0008] Another example is non-aqueous small molecule compositions for parenteral injection as described in U.S. Pat. No. 9,125,805 ('805 patent). The '805 patent discloses compositions including concentrated diazepam formulations (e.g., 50 and 100 mg / mL solutions) solubilized in non-aqueous solvents, including DMSO and NMP, with examples showing excellent long-term stability under accelerated storage conditions (40° C. / 75% relative humidity). However, while these formulations may show excellent long-term stability when stored in pharma- ceutical relevant container closure systems (e.g., vials, pre-filled syringes), they show poor bioavailability when injected into patients due to diazepam's extremely low water solubility at physiological pH, which leads to precipitation of the drug at the injection site.

[0009] The technology described in this application builds on previous discoveries by Xeris Pharmaceuticals (e.g., Patent '805) that solved the problem of poor water solubility and stability of many small molecule drugs, enabling the development of injectables using aprotic polar solvents. However, although these formulations had excellent solubility of poorly water soluble drugs such as diazepam (>50 mg / mL) combined with excellent long-term storage stability in vials and pre-filled syringes, bioavailability of the active pharmaceutical ingredient (API) after injection was minimal due to precipitation of the drug at the injection site.

[0010] Thus, there remains a need for formulations that address the poor water solubility and stability of small molecules, including benzodiazepines, while providing improved bioavailability of highly concentrated formulations when administered parenterally to patients. [Prior art documents] [Patent documents]

[0011] [Patent Document 1] U.S. Patent No. 8,946,208 [Patent Document 2] U.S. Patent No. 9,125,805 Summary of the Invention

[0012] overview The problem of small molecule (e.g., diazepam) precipitation at the injection site when administered as a highly concentrated formulation is solved by including at least one surfactant in the non-aqueous formulation, which prevents small molecule precipitation and improves drug bioavailability by increasing absorption into the systemic circulation. The present invention provides a solution to the current problems faced when using small molecule drugs in therapeutic applications such as those described above. The solution is premised on solubilizing and stabilizing the small molecule drug in a non-aqueous environment, and then injecting the solubilized drug directly into the patient by parenteral administration, without the need for a reconstitution and / or dilution step before administration. The formulation can be in a liquid dosage form. The formulation can be stored for an extended period of time after preparation (even in an injection device) and can be injected directly into a subject (e.g., a human) without the reconstitution or dilution step observed in current products. In fact, this solution does not meet the prevailing industry standard. In this regard, our solution provides a more stable drug environment and a more efficient and effective approach to providing life-saving drugs to subjects in need of treatment. Importantly, our findings are broadly applicable for the delivery of a wide variety of small molecule drugs that have poor or limited stability and solubility in aqueous environments, such as diazepam.

[0013] The non-aqueous vehicles described in this application are suitable for preparing pharmaceutical compositions for intradermal delivery of a wide range of drug compounds. In view of this specification, one skilled in the art can determine whether a particular aprotic polar solvent system is suitable for use in combination with a particular drug. For example, this can be done by measuring the solubility of the drug compound in the vehicle. Solubility can be tested by adding an excess amount of drug to the vehicle and stirring the mixture at room temperature for 24 hours. Undissolved drug is then removed by filtration or centrifugation, and the solution is assayed for dissolved drug content by a suitable analytical method, such as high performance liquid chromatography (HPLC).

[0014] Without wishing to be bound by theory, it is believed that the use of surfactants in aprotic polar solvent formulations improves bioavailability by preventing precipitation of highly concentrated small molecule (e.g., benzodiazepine) formulations when injected into a patient. Specifically, it is believed that surfactants improve solubility by encapsulating drugs such as diazepam in micelles, so that when injected into an aqueous environment, the surfactants promote diffusion of diazepam away from the injection site, allowing for rapid absorption and greater bioavailability. When highly concentrated diazepam formulations are injected into an aqueous environment at physiological pH without the use of surfactants, the diazepam partially precipitates and is gradually resolubilized and absorbed.

[0015] One embodiment of the present invention relates to a stable precipitation-resistant formulation for parenteral injection. The formulation can include: (a) a biocompatible non-aqueous solvent; (b) a small molecule drug or salt thereof solubilized in the non-aqueous solvent; and (c) 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15% to 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30% w / w (including all values ​​and ranges therebetween) of a surfactant, where the surfactant reduces precipitation of the small molecule drug when injected into a subject. In one aspect, the surfactant is present in a molar ratio of surfactant:small molecule drug of 0.5:1 to 4:1, or 1:1 to 2:1. The surfactant may be sodium deoxycholate, polysorbate 80, polysorbate 20, dodecyl maltoside, sodium dodecyl sulfate, sodium tetradecyl sulfate, alcohol ethoxylate, alkyl dimethylamine oxide, or alkyl betaine. In an aspect, the liquid formulation comprises a water content of less than 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1% by weight. The formulation of claim 1, wherein the amount of liquid formulation to be parenterally injected is 3 mL or less. The formulation may be contained within a device for dispensing the formulation. In an aspect, the device is a syringe, a pen injection device, an autoinjector device, an external or implantable pump, or a perfusion bag. The biocompatible non-aqueous solvent may be an aprotic polar solvent, an alkyl or aryl benzoate solvent, a lipid solvent, a protic solvent, or a mixture thereof. In some aspects, the formulation comprises an aprotic polar solvent, where the aprotic polar solvent is dimethylsulfoxide (DMSO), dimethylformamide (DMF), ethyl acetate, n-methylpyrrolidone (NMP), dimethylacetamide (DMA), propylene carbonate, or a mixture thereof. In certain aspects, the aprotic polar solvent is DMSO, NMP, or a mixture thereof. The formulation can also comprise an aryl or alkyl benzoate solvent, where the aryl or alkyl benzoate solvent is ethyl benzoate, benzyl benzoate, or a mixture thereof.The formulation can include 0.5, 5, 10, 20, 40, 80, 160, 320 mg / mL to 350, 400, 450, 500, 550, 600, 650, 700, 750 mg / mL (including all values ​​and ranges therebetween) of the small molecule drug. In some aspects, the volume of the liquid formulation to be parenterally infused is 1 μL to 10 μL, 10 μL to 100 μL, or 100 μL to 1 mL. In some aspects, the small molecule drug is a benzodiazepine. In certain aspects, the benzodiazepine is diazepam. The formulation can include 25, 50, 75, 100, 125, 150 mg / mL to 175, 200, 225, 250, 275, 300 mg / mL of the benzodiazepine (including all values ​​and ranges therebetween). The solvent can be, but is not limited to, DMSO, NMP, or a mixture thereof.

[0016] Certain embodiments relate to methods of administering a formulation of the invention to a subject in need thereof, comprising parenterally injecting the formulation into the subject. In some aspects, the injection is by parenteral or intradermal injection. In some aspects, the formulation is not diluted prior to administration.

[0017] Yet another aspect of the invention relates to a method for treating or preventing a condition by parenterally administering to a subject in need thereof a formulation of the claimed invention having a small molecule drug in an amount effective to treat or prevent the condition.

[0018] An aspect relates to a method for treating or preventing anxiety, muscle spasms, or seizures, comprising parenterally administering a benzodiazepine formulation to a subject in need thereof. The method can include administering an injectable amount of the formulation in a device for dispensing the formulation. The device can be a syringe, a pen injection device, an autoinjector device, an external or implantable pump, or a perfusion bag. In an aspect, the liquid formulation comprises 25 mg / mL to 300 mg / mL of benzodiazepine. In a particular aspect, the benzodiazepine is diazepam. The amount of liquid formulation parenterally injected can be 1 μL to 10 μL, 10 μL to 100 μL, or 100 μL to 1 mL. In an aspect, the liquid formulation is not diluted prior to administration.

[0019] The term "benzodiazepine" as used herein refers to a class of compounds that contain a bicyclic core unit in which a benzene ring is fused with a diazepine ring.Benzodiazepines are widely used lipophilic drugs that act on the central nervous system and cause sedation, anxiety reduction, muscle relaxation, and anticonvulsant effects.Non-limiting examples of benzodiazepines include diazepam, clonazepam, lorazepam, alprazolam, midazolam, and temazepam.

[0020] The term "surfactant" as used herein refers to a surface active agent that can adsorb onto the surface and / or interface of a system and change the surface or interfacial free energy and surface or interfacial tension. Non-limiting functions of surfactants include use as wetting agents, emulsifiers, dispersants, and suspending agents. Surfactants are monomeric amphiphilic molecules that possess a characteristic structure with both a non-polar (hydrophobic) region called the "tail" and a polar (hydrophilic) region called the "head". The hydrophobic tail of a surfactant molecule is generally composed of an unsaturated or saturated hydrocarbon chain or a heterocyclic or aromatic ring system. The hydrophilic head of a surfactant molecule is polar, and depending on the charge group present in the polar head of the surfactant, they can be classified as either nonionic, cationic, anionic, or zwitterionic (amphoteric). If the molecule does not have a charge group on its head, the surfactant is nonionic. If the charge group on the polar head is positive, the molecule is a cationic surfactant, while an anionic surfactant has a negative charge group on the polar head of the molecule. Zwitterionic (or amphoteric) surfactants possess both positively or negatively charged groups and can exist as either cationic or anionic surfactants depending on the pH of the solution. Examples of anionic surfactants include, but are not limited to, carboxylate, phosphate, sulfate, and sulfonate ions. Non-limiting examples of anionic surfactants are sodium dodecyl sulfate (SDS) and sodium tetradecyl sulfate (STS). Non-limiting examples of cationic surfactants include alkyl pyridinium chloride and alkyl trimethyl ammonium bromide. Examples of nonionic surfactants include, but are not limited to, alcohol ethoxylates, while non-limiting examples of zwitterionic surfactants include alkyl dimethyl amine oxides and alkyl betaines.

[0021] The term "dissolution" as used herein refers to the process by which a material in a gas, solid, or liquid state becomes a solute, i.e., a dissolved component, of a solvent, forming a solution of the gas, liquid, or solid in the solvent. In some aspects, a therapeutic agent or excipient, e.g., an ionizable stabilizing excipient, is present in an amount up to its solubility limit or is completely solubilized. The term "dissolve" refers to the incorporation of a gas, liquid, or solid into a solvent to form a solution.

[0022] The term "excipient" as used herein refers to a natural or synthetic substance (a component that is not an active ingredient) that is formulated with the active or therapeutic ingredient of a drug, included for the purposes of stabilizing, bulking, or imparting a therapeutic enhancement to the active ingredient in the final dosage form, such as facilitating drug absorption, reducing viscosity, enhancing solubility, adjusting tonicity, reducing injection site discomfort, lowering the freezing point, or enhancing stability. Excipients may also be useful in the manufacturing process to aid in in vitro stability, for example, to aid in handling of the active agent in question, such as by promoting powder flow or non-stickiness, in addition to preventing denaturation or aggregation over the expected shelf life.

[0023] "Small molecule drugs" in the context of the present invention are bioactive compounds (and their salts) that can produce desired, beneficial, and / or pharmacological effects in a subject. These "small molecule drugs" are organic or inorganic compounds. Therefore, small molecule drugs in the context of the present invention are not polymeric compounds. Typically, small molecule drugs have a molecular weight of less than approximately 1000 Daltons. Some small molecule drugs are "moisture sensitive" in that they are more unstable in the presence of water. Similarly, salts that can be used for small molecule drugs are also known to those skilled in the art and include salts with inorganic acids, organic acids, inorganic bases, or organic bases.

[0024] As used herein, "inhibit" or "reduce" or any variation of these terms includes any measurable decrease or complete inhibition to achieve a desired result.

[0025] As used herein, "effective," or "treat," or "prevent," or any variation of these terms, means adequate to achieve a desired, expected, or intended result.

[0026] As used herein, "chemical stability" refers to an acceptable percentage of degradation products produced by chemical pathways, such as oxidation and / or hydrolysis and / or fragmentation and / or other chemical degradation pathways, when referring to a therapeutic agent.Specifically, a formulation is considered chemically stable if, after one year of storage of the product at the intended storage temperature (e.g., room temperature), or after one year of storage of the product at 25°C and 60% relative humidity (RH), or after one month, preferably three months of storage of the product at 40°C and 75% relative humidity, the degradation products formed are about 20% or less.In some embodiments, a chemically stable formulation forms less than 20%, less than 15%, less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% degradation products after long-term storage of the product at the intended storage temperature.

[0027] As used herein, "physical stability" refers to an acceptable percentage of insoluble precipitates and / or other aggregates (e.g., dimers, trimers, and larger forms) formed when referring to a therapeutic agent. Specifically, a formulation is considered physically stable if, after one year of storage of the product at the intended storage temperature (e.g., room temperature), or after one year of storage of the product at 25°C and 60% relative humidity, or after one month, preferably three months of storage of the product at 40°C and 75% relative humidity, the aggregates formed are about 15% or less. In some embodiments, a physically stable formulation forms less than 15%, less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% aggregates after long-term storage of the product at the intended storage temperature.

[0028] As used herein, "stable formulation" refers to a formulation in which at least about 65% of the therapeutic agent (e.g., peptide or its salt) remains chemically and physically stable after storage at room temperature for 2 months.Particularly preferred formulations are those in which at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the therapeutic agent remains chemically and physically stable under these storage conditions.Particularly preferred stable formulations are those that do not show degradation after irradiation with sterilizing radiation (e.g., gamma, beta, or electron beam).

[0029] As used herein, "parenteral administration" refers to the administration of a therapeutic agent to a patient via a route other than the digestive tract (any administration that is not via the digestive tract).

[0030] As used herein, "parenteral injection" refers to the administration of a therapeutic agent (e.g., a peptide or small molecule) by injection under or through one or more layers of the skin or mucosa of an animal, such as a human. Standard parenteral injections are performed into the subcutaneous, intramuscular, or intradermal regions of an animal, such as a human. These deep locations are targeted because the tissue expands more readily compared to shallow skin sites to accommodate the injection volumes, e.g., 0.1-3.0 cc (mL), required to deliver most therapeutic agents.

[0031] The term "intradermal" includes administration into the epidermal, dermal, or subcutaneous skin layers.

[0032] As used herein, the term "aprotic polar solvent" refers to a polar solvent that does not contain acidic hydrogen and therefore does not act as a hydrogen bond donor. Aprotic polar solvents include, but are not limited to, dimethylsulfoxide (DMSO), dimethylformamide (DMF), ethyl acetate, n-methylpyrrolidone (NMP), dimethylacetamide (DMA), and propylene carbonate.

[0033] As used herein, the term "aprotic polar solvent system" refers to a solution in which the solvent is a single aprotic polar solvent (e.g., neat DMSO) or a mixture of two or more aprotic polar solvents (e.g., a mixture of DMSO and NMP).

[0034] As used herein, "residual moisture" may refer to the residual moisture in a drug powder after preparation by the manufacturer / supplier. Typical powders often have a residual moisture content ranging up to 10% (w / w). When these powders are dissolved in an aprotic polar solvent system, the residual moisture in the powder is incorporated into the formulation. Additionally, the aprotic polar solvent may also contain a certain level of residual moisture. For example, a freshly opened bottle of USP grade DMSO typically contains up to 0.1% (w / w) moisture. Residual moisture is distinct from "added moisture," where water is intentionally added to the formulation, for example, to serve as a co-solvent or to depress the freezing point of the aprotic polar solvent system. Moisture may also be introduced into the formulation during the addition of ionizable stabilizing excipients (e.g., through the addition of a mineral acid from an aqueous stock solution (e.g., 1 N HCl)). The "total moisture" (% w / w unless otherwise stated) in the formulation immediately after preparation is due to contributions from both residual moisture and added moisture.

[0035] The use of the terms "a" or "an" when used in the claims and / or specification in connection with the term "comprising" may mean "one," but is also consistent with the meanings of "one or more," "at least one," and "one or more than one."

[0036] The terms "comprising" (and any form of "comprising", such as "comprise" and "comprises"), "having" (and any form of "having", such as "have" and "has"), "including" (and any form of "including", such as "includes" and "include"), or "containing" (and any form of "containing", such as "contains" and "contain") are all inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0037] The terms "about" or "approximately" or "substantially unchanged" are defined as close to the meaning understood by those of ordinary skill in the art, and in one non-limiting embodiment, the term is defined as within 10%, preferably within 5%, more preferably within 1%, and most preferably within 0.5%. Additionally, "substantially non-aqueous" means less than 5%, 4%, 3%, 2%, 1%, or less water by weight or volume.

[0038] As used herein, a "pharmacologically acceptable" ingredient, excipient, or component is an ingredient, excipient, or component that is suitable for use with humans and / or animals without undue adverse side effects (such as toxicity, irritation, and allergic reactions), commensurate with a reasonable benefit / risk ratio.

[0039] As used herein, "pharmaceutically acceptable carrier" means a pharmaceutically acceptable solvent, suspending agent, or vehicle for delivering a drug compound of the present invention to a mammal, such as a human.

[0040] Other objects, features, and advantages of the present invention will become apparent from the following detailed description. However, it should be understood that the detailed description and examples, while showing specific embodiments of the present invention, are given by way of example only. In addition, it is contemplated that changes and modifications in the spirit and scope of the present invention will become apparent to those skilled in the art from the detailed description of the present invention. Other aspects of the present invention are discussed throughout this application. Any aspect discussed with respect to one aspect of the present invention also applies to other aspects of the present invention, and vice versa. It is understood that each aspect described herein is an aspect of the present invention that is applicable to all aspects of the present invention. It is contemplated that any aspect discussed herein can be implemented with respect to any method or composition of the present invention, and vice versa. Furthermore, the compositions and kits of the present invention can be used to achieve the methods of the present invention. [The present invention 1001] (a) a biocompatible non-aqueous solvent; and (b) a small molecule drug or a salt thereof solubilized in the non-aqueous solvent; and (c) a surfactant, between 1% and 30% w / w, that reduces precipitation of the small molecule drug when injected into a subject. 23. A stable, precipitation-resistant formulation for parenteral injection comprising: [The present invention 1002] The formulation of claim 1001, wherein the surfactant is present in a molar ratio of surfactant:small molecule drug of 0.5:1 to 4:1, or 1:1 to 2:1. [The present invention 1003] The formulation of invention 1001, wherein the surfactant is sodium deoxycholate, polysorbate 80, polysorbate 20, dodecyl maltoside, sodium dodecyl sulfate, sodium tetradecyl sulfate, alcohol ethoxylate, alkyl dimethylamine oxide, or alkyl betaine. [The present invention 1004] The formulation of claim 10, wherein the liquid formulation comprises a water content of less than 10% by weight. [The present invention 1005] The formulation of invention 1001, wherein the volume of the liquid formulation injected parenterally is 3 mL or less. [The present invention 1006] The formulation of the present invention 1001 further contained within a device for dispensing the formulation. [The present invention 1007] The formulation of the present invention 1006, wherein the device is a syringe, a pen injection device, an autoinjector device, an external or implantable pump, or a perfusion bag. [The present invention 1008] The formulation of any of claims 1001 to 1007, wherein the biocompatible non-aqueous solvent is an aprotic polar solvent, an alkyl or aryl benzoate solvent, a lipid solvent, a protic solvent, or a mixture thereof. [The present invention 1009] An aprotic polar solvent that is dimethylsulfoxide (DMSO), dimethylformamide (DMF), ethyl acetate, n-methylpyrrolidone (NMP), dimethylacetamide (DMA), propylene carbonate, or a mixture thereof. The formulation of the present invention 1008 comprising: [The present invention 1010] The formulation of the present invention 1009, wherein the aprotic polar solvent is DMSO, NMP, or a mixture thereof. [The present invention 1011] Aryl or alkyl benzoate solvents, such as ethyl benzoate, benzyl benzoate, or mixtures thereof The formulation of the present invention 1008 comprising: [The present invention 1012] The formulation of any of claims 1001 to 1007, wherein the liquid formulation has a water content of less than 10% by weight. [The present invention 1013] The formulation of any of claims 1001 to 1007, wherein the liquid formulation contains 0.5 mg / mL to 750 mg / mL of a low molecular weight drug. [The present invention 1014] The formulation of any one of claims 1001 to 1007, wherein the amount of the liquid formulation to be parenterally injected is 1 µL to 10 µL. [The present invention 1015] The formulation of any one of claims 1001 to 1007, wherein the amount of the liquid formulation to be parenterally injected is 10 µL to 100 µL. [The present invention 1016] The formulation of any one of claims 1001 to 1007, wherein the amount of the liquid formulation to be parenterally injected is 100 µL to 1 mL. [The present invention 1017] The formulation of any one of claims 1001 to 1007, wherein the low molecular weight drug is a benzodiazepine. [The present invention 1018] The formulation of the present invention 1017, wherein the benzodiazepine is diazepam. [The present invention 1019] 1017. The formulation of claim 1017, wherein the liquid formulation comprises 25 mg / mL to 300 mg / mL of a benzodiazepine. [The present invention 1020] The formulation of the present invention, wherein the solvent is DMSO, NMP, or a mixture thereof. [The present invention 1021] A method of administering any one of the formulations of the present inventions 1001 to 1020 to a subject in need thereof, comprising a step of parenterally injecting the formulation into the subject. [The present invention 1022] The method of claim 1021, wherein the injection is by parenteral injection or intradermal injection. [The present invention 1023] The method of claim 1021, wherein the formulation is not diluted prior to administration. [The present invention 1024] A method for treating or preventing a condition, comprising the step of parenterally administering to a subject in need thereof any of the formulations of the present inventions 1001 to 1020 in an amount effective to treat or prevent the condition. [The present invention 1025] A method for treating or preventing anxiety, muscle spasms, or seizures, comprising parenterally administering to a subject in need thereof a formulation of the present invention comprising a benzodiazepine. [The present invention 1026] The method of claim 1025, further comprising an injectable volume within the device for dispensing the liquid formulation. [The present invention 1027] The method of claim 1026, wherein the device is a syringe, a pen injection device, an autoinjector device, an external or implantable pump, or a perfusion bag. [The present invention 1028] The method of claim 1025, wherein the liquid formulation comprises 25 mg / mL to 300 mg / mL of a benzodiazepine. [The present invention 1029] The method of claim 1025, wherein the benzodiazepine is diazepam. [The present invention 1030] The method of claim 1025, wherein the amount of the liquid formulation parenterally injected is 1 μL to 10 μL. [The present invention 1031] The method of claim 1025, wherein the amount of the liquid formulation to be parenterally injected is 10 μL to 100 μL. [The present invention 1032] The method of claim 1025, wherein the amount of the liquid formulation injected parenterally is 100 μL to 1 mL. [The present invention 1033] The method of claim 1025, wherein the liquid formulation is not diluted prior to administration. [Brief description of the drawings]

[0041] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of the specification embodiments presented herein.

[0042] [Figure 1] FIG. 1 shows the stability of diazepam dissolved in DMSO through several freeze-thaw cycles. [Diagram 2] FIG. 1 shows the pharmacokinetic profile of diazepam in a DMSO formulation compared to the Diastat® marketed formulation. [Diagram 3] FIG. 1 shows the pharmacokinetic profiles of diazepam and nordiazepam in a DMSO formulation containing 10% (w / v) SDS compared to Hospira's IM formulation. [Figure 4] Diazepam plasma concentrations in minipigs following diazepam administration. [Diagram 5] Percentage of diazepam remaining after 20 days storage at 75°C. [Figure 6] Percentage of diazepam remaining after 30 days storage under various storage conditions. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0043] explanation The following discussion relates to various aspects of the present invention. The term "invention" is not intended to refer to a particular aspect or otherwise limit the scope of the present disclosure. Although one or more of these aspects may be preferred, the disclosed aspects should not be interpreted or otherwise used as limiting the scope of the disclosure, including the claims. Furthermore, those skilled in the art will understand that the following description has broad application, and the discussion of any aspect is intended to be merely an example of that aspect, and is not intended to imply that the scope of the disclosure, including the claims, is limited to that aspect.

[0044] A. Small Molecule Drugs In addition to benzodiazepines, other non-limiting small molecule drugs that can be used in the context of the present invention include epinephrine, naloxone, naltrexone, remifentanil, ganaxolone, fenfluramine, brivaracetam, apomorphine, carbidopa, levodopa, dihydroergotamine, levothyroxine, hemin, palonosetron, sumatriptan, aprepitant, novantrone, small molecule chemotherapeutic agents (e.g., mitoxantrone), small molecule corticosteroids (e.g., methylprednisolone), small molecule immunosuppressants (e.g., azathioprine, cladribine, cyclophosphamide, methotrexate), small molecule anti-inflammatory agents (e.g., salicylic acid, acetylsalicylic acid, diflunisal, choline magnesium trisalicylate, salicylate, benorylate, flufenamic acid, mefenamic acid, meclofenamic acid, triflu ... acid), diclofenac, fenclofenac, alclofenac, fentiazac, ibuprofen, flurbiprofen, ketoprofen, naproxen, fenoprofen, fenbufen, suprofen, indoprofen, tiaprofenic acid, benoxaprofen, pirprofen, tolmetin, zomepirac, clopinac, indomethacin, sulindac, phenylbutazone, oxyphenbutazone, azapropazone, feprazone, piroxicam, isoxicam), small molecules used to treat neurological disorders (e.g., cimetidine, ranitidine, famotidine, nizatidine, tacrine, donepidil, metrifonate, rivastigmine, selegiline, ilene), imipramine, fluoxetine, olanzapine, sertindole, risperidone, paliperidone, aripiprazole, valproate semisodium, gabapentin, carbamazepine, topiramate, phenyloin, haloperidol), and small molecules used to treat cancer (e.g., vincristine, vinblastine, paclitaxel, docetaxel, cisplatin, irinotecan, topotecan, gemcitabine, temozolomide, imatinib, bortezomib), statins (e.g., atorvastatin, amlodipine, rosuvastatin, sitagliptin, simvastatin, fluvastatin, pitavastatin, lovastatin, pravastatin,simvastatin), and other taxane derivatives. In certain embodiments, small molecules that can be used include small molecules that treat tuberculosis (e.g., rifampicin), small molecule antifungals (e.g., fluconazole), small molecule anxiolytics and small molecule anticonvulsants (e.g., lorazepam), small molecule anticholinergics (e.g., atropine), small molecule β-agonist drugs (e.g., albuterol sulfate), small molecule mast cell stabilizers, and small molecule drugs used to treat allergies (e.g., cromolyn sodium), small molecule anesthetics and small molecule antiarrhythmics (e.g., lidocaine), small molecule antibiotics (e.g., tobramycin, ciprofloxacin), small molecule antimigraine drugs (e.g., sumatriptan), and small molecule antihistamines (e.g., diphenhydramine). Additionally, the amount of small molecule drug in the dosage formulation can vary depending on currently tolerated amounts, the needs of the subject / patient, and so forth.

[0045] With regard to biocompatible non-aqueous solvents, examples include aprotic polar solvents, alkyl or aryl benzoate solvents, lipid solvents, protic solvents, or mixtures thereof. Non-limiting examples of aprotic polar solvents include dimethylsulfoxide (DMSO), dimethylformamide (DMF), ethyl acetate, n-methylpyrrolidone (NMP), dimethylacetamide (DMA), propylene carbonate, or mixtures thereof. However, in some examples, the formulation of the present invention does not need to include the above-mentioned solvents (i.e., other solvents can be used). In one example, for example, the formulation does not include non-aqueous aprotic polar solvents and / or does not include non-aqueous protic solvents (e.g., polyethylene glycol (PEG), propylene glycol (PG), polyvinylpyrrolidone (PVP), methoxypropylene glycol (MPEG), glycerol, glycofurol, and mixtures thereof). As indicated above, increased solubility of small molecule drugs can result in smaller dosages (and thus smaller storage devices and containers) that provide easier and less painful parenteral administration. Non-limiting examples of aryl or alkyl benzoate solvents include methyl benzoate, ethyl benzoate, propyl benzoate, C12-C15 alkyl benzoates where R is a C12-15 alkyl group, C16-17 alkyl benzoates where R is a C16-17 fatty alcohol group, and benzyl benzoate. A non-limiting example of a lipid is triacetin, a triester of glycerol and acetic acid. Non-limiting examples of protic solvents include polyethylene glycol (PEG), propylene glycol (PG), polyvinylpyrrolidone (PVP), methoxypropylene glycol (MPEG), glycerol, glycofurol, or mixtures thereof. In some aspects, the formulation does not include a co-solvent, while in other aspects, the formulation may include a co-solvent. In one example, the formulation may contain one / only one biocompatible non-aqueous solvent (i.e., undiluted or pure form), in other aspects, the formulation contains a mixture of two, three, four, or more biocompatible non-aqueous solvents.In yet another aspect, the formulation may exclude co-solvents, salts, and other components that may aid in dissolving or increase the solubility of the small molecule drug in non-aqueous solvent. For example, the formulation may consist of a small molecule drug and a non-aqueous solvent (or a mixture of non-aqueous solvents), or may essentially consist of a small molecule drug and a non-aqueous solvent (or a mixture of non-aqueous solvents), and still be directly injected into a subject by parenteral administration ("consisting essentially of" in the context of this text means excluding other components that may increase the solubility of the drug in non-aqueous solvents or mixtures of non-aqueous solvents, and may include, for example, preservatives to further preserve the injectable formulation).

[0046] Furthermore, the formulations of the present invention can be non-aqueous or substantially non-aqueous (e.g., less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5% or less total moisture (i.e., moisture present in the formulation when it is first prepared) by weight). In some instances, the small molecule drug is pre-dried in the presence of a buffer before being solubilized in a non-aqueous solvent. As described below, this can increase the stability of the small molecule drug. In some instances, the dried small molecule drug has a pH memory approximately equal to the pH of the small molecule drug in the presence of an aqueous buffer, such that the pH of the small molecule drug solubilized in a biocompatible non-aqueous solvent is approximately equal to the pH of the small molecule drug in the presence of a buffer. The stored pH can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or higher, or can be in the range of 1-3, 2-4, 3-5, 4-6, 5-7, 6-8, 7-9, 8-10, or 9-11. In some aspects, the buffer is a non-volatile buffer (non-limiting examples of which include glycine, citrate, or phosphate buffers, or mixtures thereof). In other examples, the buffer can be a volatile buffer. Additionally, the water content of the small molecule drug can be less than 5%, 4%, 3%, 2%, 1%, 0.5%, or less w / w.

[0047] In some aspects, the formulation comprises 0.5 mg / mL to about 300 mg / mL, 10 mg / mL to 50 mg / mL, 20 mg / mL to 50 mg / mL, 5 mg / mL to 15 mg / mL, or 0.5 mg / mL to 2 mg / mL of the small molecule drug. In some examples, the amount of the small molecule drug can be 400, 500, 600, 700, 800, 900, 1000, 2000, or 3000 mg / mL or more. One unique aspect of the formulations of the present invention is that the formulations can have a high drug load and still have a relatively low dosage (e.g., 0.1 μL, 1 μL, 10 μL, 20 μL, 50 μL, 75 μL, 100 μL, 200 μL, 300 μL, 400 μL, 500 μL, 600 μL, 700 μL, 800 μL, 900 μL, 1 mL, 2 mL, or 3 mL, or more as needed (e.g., 4, 5, 6, 7, 8, 9, 10 mL, or more)). In certain instances, the volume of the liquid formulation to be parenterally injected is 3 mL or less (e.g., 3, 2.5, 2, 1.5, 1, 0.5, 0.1 mL or less), or 0.1 μL to 3 mL, or 0.1 μL to 1 μL, or 1 μL to 10 μL, or 10 μL to 1 mL, or 0.1 μL to 2.5 mL, or 0.1 μL to 2 mL, or 0.1 μL to 1.5 mL, or 0.1 μL to 1 mL, or 0.1 μL to 0.5 mL, or 0.1 μL to 0.1 mL. Another unique aspect of the formulation of the present invention is that it can be stored in a container or device and immediately ready for parenteral injection without the need to reconstitute or dilute the formulation as needed. The device can be a syringe, a pen injection device, an autoinjector device, a device capable of pumping or administering the formulation (eg, an automated or non-automated external pump, an implantable pump, etc.), or a perfusion bag.Similarly, additional ingredients / pharmaceutical excipients are contemplated for use in the formulation, non-limiting examples of which include antioxidants (examples include ascorbic acid, cysteine, methionine, monothioglycerol, sodium thiosulfate, sulfite, BHT, BHA, ascorbyl palmitate, propyl gallate, or vitamin E), chelating agents (examples include EDTA, EGTA, tartaric acid, glycerin, or citric acid), or preservatives (examples include alkyl alcohols, benzyl alcohol, methylparaben, or propylparaben, or mixtures thereof). The formulation may be in a liquid, semisolid, or gel dosage form. As discussed below, the formulation may have a desired viscosity range (in one non-limiting example, such range may be 0.5-15 cps). The formulation may be one in which at least 65% of the small molecule drug in the formulation remains chemically and physically stable when the formulation is stored at room temperature for two months, or one in which at least 80% of the therapeutic agent in the formulation remains chemically and physically stable when the formulation is stored at room temperature for two months.

[0048] In one particular aspect of the present invention, a stable liquid formulation for parenteral injection is disclosed, comprising diazepam or a salt thereof, at least one surfactant, and a biocompatible non-aqueous solvent, wherein the diazepam and surfactant are solubilized in the non-aqueous solvent, the total water content of the formulation upon preparation is less than 5% w / w, and the volume of the formulation parenterally injected is 50 μL to 1000 μL, or any range therebetween (e.g., 75 μL, 100 μL, 150 μL, 200 μL, 300 μL, 400 μL, 500 μL, 600 μL, 700 μL, 800 μL, 900 μL, etc.). In a further aspect, the formulation may include additional excipients. As previously described, such formulations may be contained in a container selected from a sealed syringe, a sealed pen injection device, a sealed autoinjector device, or a pump. Similarly, as explained above, diazepam can be dried in the presence of a buffer before being solubilized in a non-aqueous solvent, which can provide the dried diazepam with a pH memory approximately equal to the pH of diazepam in the presence of an aqueous buffer, such that the pH of diazepam solubilized in a biocompatible non-aqueous solvent is approximately equal to the pH of diazepam in the presence of an aqueous buffer (e.g., a non-volatile buffer such as glycine, citrate, or phosphate buffer, or mixtures thereof, as described above).

[0049] Still further, the formulation of the present invention may include one or more other excipients in addition to surfactants. In some embodiments, the other excipients are selected from sugars, starches, sugar alcohols, antioxidants, chelating agents, polymers, and preservatives. Examples of suitable sugar excipients include, but are not limited to, trehalose, glucose, sucrose, and the like. Examples of suitable starches for stabilizing excipients include, but are not limited to, hydroxyethyl starch (HES). Examples of suitable sugar alcohols (also called polyols) include, but are not limited to, mannitol and sorbitol. Examples of suitable antioxidants include, but are not limited to, ascorbic acid, cysteine, methionine, monothioglycerol, sodium thiosulfate, sulfite, BHT, BHA, ascorbyl palmitate, propyl gallate, N-acetyl-L-cysteine ​​(NAC), and vitamin E. Examples of suitable chelating agents include, but are not limited to, EDTA, EDTA disodium salt (edetate disodium), tartaric acid and its salts, glycerin, and citric acid and its salts. Examples of suitable inorganic salts include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, calcium sulfate, and magnesium sulfate. Examples of suitable preservatives include, but are not limited to, benzyl alcohol, methylparaben, propylparaben, and mixtures thereof. Additional formulation components include local anesthetics, such as lidocaine or procaine.In some embodiments, the additional stabilizing excipient is from about 0.05% (w / v) to about 60% (w / v), from about 1% (w / v) to about 50% (w / v), from about 1% (w / v) to about 40% (w / v), from about 1% (w / v) to about 30% (w / v), from about 1% (w / v) to about 20% (w / v), from about 5% (w / v) to about 60% (w / v), from about 5% (w / v) to about 50% (w / v), from about 5% (w / v) to about 40% (w / v), from about 5% (w / v) to about 30% (w / v), from about 5% (w / v) to about 20% (w / v), from about 10% (w / v) to about 60% (w / v), from about 10% (w / v) to about 50% (w / v), from about 10% (w / v) to about 50% (w / v), (w / v) to about 40% (w / v), about 10% (w / v) to about 30% (w / v), or about 10% (w / v) to about 20% (w / v). In some embodiments, the additional stabilizing excipient is present in the formulation in an amount that is about, at most, or at least 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60% (w / v).

[0050] B. Manufacturing method In some embodiments, the present invention also provides a method for formulating a composition comprising a small molecule drug with one or more of the following pharma- ceutically acceptable solvents; surfactants; carriers; solubilizers; emulsifiers; preservatives; and / or other excipients. Such compositions can contain an effective amount of at least one small molecule drug. Thus, the use of one or more small molecule drugs in the preparation of pharmaceutical compositions of medicines is also included. Acceptable formulation components for pharmaceutical preparations are non-toxic to recipients at the dosages and concentrations used. The formulation components are present in concentrations that are acceptable to the site of administration. Pharmaceutical compositions used for in vivo administration are typically sterile. Sterilization can be achieved by filtration through a sterile filtration membrane.

[0051] Once the pharmaceutical composition of the present invention is formulated, it can be stored in a sterile vial as a solution. Such formulations can be stored in a ready-to-use form. The components used to formulate the pharmaceutical composition are preferably of high purity and substantially free of potentially harmful contaminants (e.g., at least National Food (NF) grade, generally at least analytical grade, more typically at least pharmaceutical grade). Moreover, compositions intended for in vivo use are usually sterile.

[0052] A therapeutically effective dose may be readily determined by one of ordinary skill in the art and will depend on the severity and course of the disease, the patient's health and response to treatment, the patient's age, weight, size, sex, medical history, and the judgment of the treating physician.

[0053] Another aspect of the invention relates to a method of stably formulating a small molecule drug (e.g., a benzodiazepine drug) comprising dissolving the drug (e.g., a benzodiazepine) and a surfactant (and any other additional excipients) in DMSO (the order of dissolution may or may not be important).

[0054] C. Treatment Method In a further aspect of the present invention, a method for treating or preventing a condition, disease, disorder, etc. is disclosed, comprising administering to a subject in need thereof an effective amount of a formulation of the present invention to treat or prevent the condition, disease, disorder, etc. Any suitable dosage of a therapeutic agent (e.g., a small molecule) can be administered in the method of the present invention. Depending on the small molecules that make up the therapeutic formulation, use will be tailored by the indications for which they are approved.

[0055] As a non-limiting example, benzodiazepines such as diazepam are indicated for short-term relief of symptoms of anxiety disorders or for the management of anxiety disorders. Indications also include relief of symptoms of acute alcohol withdrawal, including tremors, impeding or acute delirium tremens, hallucinations, and acute agitation, and use as an adjunct to relieve skeletal muscle spasms. Further indications include status epilepticus and severe recurrent or convulsive seizures. Injectable diazepam can also be used in the management of selected patients with epilepsy on a stable regimen of AEDs, who may require discontinuous use of diazepam to control bouts of increased seizure activity.

[0056] The dosage administered will, of course, vary depending on known factors such as the pharmacological characteristics of the particular compound, salt, or combination; the age, health, or weight of the subject; the nature and extent of the symptoms; the drug and patient's metabolic characteristics, the type of concomitant treatment; the frequency of treatment; or the desired effect. In one aspect, epileptic seizures can be treated by administering a formulation described herein that includes an effective amount of diazepam.

[0057] Benzodiazepines such as diazepam are well known for their use in treating seizures, but can also be used to prevent seizures. One reported example describing the use of benzodiazepines as a prophylactic / preventative measure to eliminate the occurrence of seizures is the use of diazepam to prevent febrile seizures. Shinnar et al., Pediatric Epilepsy: Diagnosis and Therapy, Chapter 19, February Seizures, 2007, 3:293-301 (hereinafter "Shinnar") teaches that diazepam can be administered at the time of fever but before the onset of a seizure to prevent febrile seizures. Shinnar states: "Febrile status epilepticus represents only 5% of febrile seizures, yet accounts for approximately one-quarter of all episodes of pediatric status epilepticus and more than two-thirds of cases of status epilepticus at age 2 years" (Shinnar, p. 293). "Two different approaches to the treatment of febrile seizures have developed based on the perceived immediate and long-term risks of febrile seizures. One approach is based on the older idea that febrile seizures are harmful and may lead to the development of epilepsy; this approach aims to prevent febrile seizures by using either intermittent or long-term treatment with drugs. Preventing febrile seizures The second approach is based on epidemiological data that febrile seizures are benign; the sole concern is to focus on arresting febrile seizures to prevent status epilepticus." (Shinnar, p. 297, emphasis added). "In general, At the onset of a febrile illness Diazepam is given orally or rectally to Reduces the chance of febrile seizures , demonstrating statistically significant, but clinically modest, power (Shinnar, p. 298, emphasis added).

[0058] Knudsen, Archives of Disease in Childhood, 1985 Vol. 60, pp. 1045-1049 (hereinafter "Knudsen") teaches that parenterally administered diazepam provides effective prophylactic seizure control and reduces the incidence of relapse in high and intermediate risk children. Knudsen states: "Our recent studies have demonstrated that short-term diazepam prophylaxis reduces the 18-month relapse rate for 39% to 12%; Thus preventing two-thirds of all further febrile convulsions "Stratification revealed a remarkably wide range of relapse rates in untreated children, uniformly low relapse rates in response to diazepam prophylaxis during fever, and substantial differences in the efficacy of prophylaxis in terms of risk reduction" (Knudson, p. 1048, emphasis added).

[0059] As described in the prior art, parenterally administered diazepam, such as that commercially available under the trade name Diastat®, is administered for the prevention of seizures.

[0060] D. Method of Administration Also disclosed is a method of administering the formulation of the present invention by parenterally administering the formulation to a subject in need thereof. Administration can be performed without the need to reconstitute and / or dilute the formulation. Furthermore, administration can be performed by a syringe, a pen injection device, an autoinjector device, a pump, or a perfusion bag. Similarly, the formulation can be stored in said syringe, pen injection device, autoinjector device, pump, or perfusion bag, and can be used immediately (again, without the need to reconstitute and / or dilute the formulation). Additionally, and as noted above, the amount of formulation administered can range from 1 μL, 10 μL, 20 μL, 50 μL, 75 μL, 100 μL, 200 μL, 300 μL, 400 μL, 500 μL, 600 μL, 700 μL, 800 μL, 900 μL, 1 mL, 2 mL, 3 mL, 4 mL, 5 mL, 6 mL, 7 mL, 8 mL, 9 mL, or 10 mL, or more, as appropriate. In some aspects, the formulation is one in which the small molecule drug remains stable and solubilized (i.e., there is no coalescence or crystallization of the small molecule drug) when stored at room temperature (approximately 20-25° C.) for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. EXAMPLES

[0061] E. Working Example The following examples and figures are included to illustrate certain aspects of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples or figures represent techniques discovered by the inventors to function well in the practice of the invention and therefore may be considered to constitute modes for its practice. However, those of skill in the art will appreciate, in light of this disclosure, that many changes can be made in the specific embodiments disclosed and still obtain the same or similar results without departing from the spirit and scope of the invention.

[0062] Some aspects of the present disclosure will be described in more detail by specific examples.The following examples are provided for illustrative purposes and are not intended to limit the present invention in any manner.For example, those skilled in the art will easily recognize that various parameters that are not important can be changed or modified, and still produce essentially the same results.

[0063] Example 1 In this example, 1% (w / v) or 2% (w / v) sodium deoxycholate (SDC) (CAS 302-95-4) was dissolved in dimethylsulfoxide (DMSO) (CAS 67-68-5) alone or in DMSO containing 5% (v / v) benzyl alcohol (BA) (CAS 100-51-6), followed by dissolution of diazepam (CAS 439-14-5) to a concentration of 100 mg / mL. Using an anti-precipitation assay coupled with reverse phase high performance liquid chromatography (RP-HPLC), diazepam formulations were screened for their ability to prevent diazepam precipitation.

[0064] The anti-precipitation assay used to screen diazepam formulations consisted of diluting diazepam into simulated extracellular fluid (SEF) to provide a 50x dilution of the formulation solvent. SEF consisted of 0.7 mM magnesium chloride (CAS 7786-30-3), 1.2 mM calcium chloride (CAS 10043-52-4), 2.0 mM potassium chloride (CAS 7447-40-7), 2.0 mM monopotassium phosphate (CAS 7778-77-0), 0.5 mM sodium sulfate (CAS 7757-82-6), 104 mM sodium chloride (CAS 7440-23-5), and 28.3 mM sodium bicarbonate (CAS 144-55-8). After diluting the diazepam formulation into SEF, the samples were mixed by inversion several times and allowed to equilibrate for 10 minutes. The precipitate was collected by centrifugation and the soluble diazepam content was measured in the supernatant by RP-HPLC. Greater solubility in the supernatant is expected to lead to better dissolution of diazepam away from the injection site after subcutaneous administration.

[0065] The RP-HPLC method used to determine soluble diazepam was isocratic with a mobile phase consisting of 20% (v / v) 3.2 mM ammonium formate (CAS 540-69-2) and 80% (v / v) methanol (CAS 67-56-1). A C18 column (Luna™, Phenomenex, 3.9 mm ID x 150 mm length, 5 micron particle size) was used with a column temperature of 40°C, a flow rate of 0.6 mL / min, a sample injection volume of 5-μL, and a detection wavelength of 230-nm.

[0066] Sample formulations containing SDC significantly improved diazepam recovery in the antiprecipitation assay (Table 1). Samples without SDC had 11.4% and 9.1% diazepam recovery, respectively, with and without the addition of BA to the formulation. Adding 1% (w / v) SDC to the formulation improved diazepam recovery by 2.6-fold, and 2% (w / v) SDC improved recovery by 4.1-fold. The improvement in recovery of soluble diazepam measured using the antiprecipitation assay and RP-HPLC is expected to translate into improved dissolution of diazepam from the injection site following subcutaneous administration and prevention of diazepam precipitation. Thus, improved dissolution is expected to result in a more favorable pharmacokinetic profile with rapid absorption and slow excretion.

[0067] (Table 1) Diazepam formulations prepared with sodium deoxycholate in DMSO prevented diazepam precipitation in SEF. TIFF0007660603000001.tif32141

[0068] Example 2 In this example, 1%, 10%, 20%, or 30% (v / v) polysorbate 80 (PS80) (CAS 9005-65-5) was dispersed in DMSO with 5% (v / v) BA, followed by dissolving diazepam at concentrations of 50, 75, or 100 mg / mL. Diazepam formulations containing PS80 were screened for their ability to prevent diazepam precipitation using an anti-precipitation assay followed by RP-HPLC (as detailed in Example 1 above).

[0069] Sample formulations containing PS80 significantly improve diazepam recovery in the antiprecipitation assay (Table 2). When diazepam was dissolved at 100 mg / mL in DMSO with 5% BA and increasing concentrations of PS80 (up to 30% (v / v)), the highest concentration of PS80 provided the best diazepam recovery. 30% (v / v) PS80 improved diazepam recovery 7.9-fold. When diazepam was dissolved at 75 mg / mL in DMSO with 5% (v / v) BA and increasing concentrations of PS80 (up to 30% (v / v)), the highest concentration of PS80 provided the best diazepam recovery. 30 percent PS80 improved diazepam recovery 8.4-fold. Similarly, when diazepam was dissolved at 50 mg / mL in DMSO and 5% (v / v) BA and 20% (v / v) PS80, diazepam recovery was improved 8.8-fold.

[0070] The data in Table 2 show that at a fixed concentration of diazepam (either 50, 75 or 100 mg / mL), the percent of recoverable diazepam increases with PS80 concentration. The data show that there is an optimal ratio between PS80 and diazepam that maximizes diazepam solubility in SEF. In the case of PS80, an approximately 1:1 molar ratio of diazepam and PS80 prevents precipitation in SEF.

[0071] (Table 2) Diazepam formulations prepared with PS80 in DMSO prevented diazepam precipitation in SEF. TIFF0007660603000002.tif75132

[0072] Example 3 In this example, 1%, 5%, 10%, or 17.7% (w / v) dodecylmaltoside (DM) (CAS 69227-93-6) was dissolved in DMSO with 5% (v / v) BA), followed by dissolving diazepam at concentrations of 50, 75, or 100 mg / mL. Diazepam formulations containing DM were screened for their ability to prevent diazepam precipitation using an anti-precipitation assay and RP-HPLC (as detailed in Example 1 above).

[0073] Percent diazepam recovery data for formulations prepared with DM is shown in Table 3. For each concentration of diazepam (50, 75 or 100 mg / mL), increasing concentrations of DM increased the percent of diazepam that remained soluble when the formulation was diluted into SEF. For example, diazepam dissolved at 50 mg / mL in DMSO with 5% BA and 17.7% (w / v) DM had nearly 100% diazepam solubility in SEF. As with PS80, the data in Table 3 suggests that there is an ideal ratio that prevents diazepam precipitation, in this example, the ratio of DM to diazepam is about 2:1.

[0074] (Table 3) Diazepam formulations prepared with DM in DMSO prevented diazepam precipitation in SEF. TIFF0007660603000003.tif76128

[0075] Example 4 In this example, 0% or 2% (v / v) polysorbate 20 (PS20) (CAS 9005-64-5) was dispersed in DMSO with 5% (v / v) BA or in DMSO with 5% (v / v) BA and 5% (v / v) NMP, followed by dissolving diazepam at a drug concentration of 100 mg / mL. Diazepam formulations containing PS20 were screened for their ability to prevent diazepam precipitation using an anti-precipitation assay and RP-HPLC (as detailed in Example 1 above).

[0076] Diazepam formulations containing PS20 significantly improved diazepam recovery in the antiprecipitation assay (Table 4). The inclusion of 1% (v / v) PS20 was insufficient to prevent diazepam precipitation compared to formulations without excipients. However, the inclusion of 2% (v / v) PS20 improved diazepam recovery by 2.9-fold. Diazepam formulations containing PS20 and 5% (v / v) NMP were significantly more effective in preventing diazepam precipitation compared to those without NMP. 1% (v / v) PS20 and 5% (v / v) NMP in the formulation improved diazepam recovery by 4.1-fold, and the inclusion of 2% (v / v) PS20 and 5% (v / v) NMP improved recovery by 5.4-fold.

[0077] (Table 4) Diazepam formulations prepared with PS20 in DMSO prevented diazepam precipitation in SEF. TIFF0007660603000004.tif44150

[0078] Example 5 In this example, 10% (w / v) or less sodium dodecyl sulfate (SDS) (CAS 151-21-3) was dissolved in DMSO with 5% (v / v) BA, followed by dissolving diazepam at concentrations of 50, 75 or 100 mg / mL. Diazepam formulations containing SDS were screened for their ability to prevent diazepam precipitation using an anti-precipitation assay and RP-HPLC (as detailed in Example 1 above).

[0079] Percent diazepam recovery data after dilution of formulations prepared with SDS into SEF is shown in Table 5. For each concentration of diazepam (50, 75, or 100 mg / mL), increasing concentrations of SDS increased the percent of diazepam that remained soluble when diluted into SEF. When 100 mg / mL of diazepam was dissolved in DMSO with 5% (v / v) BA and 10% (w / v) SDS and diluted into SEF, the amount of diazepam recovered improved 8.2-fold compared to diazepam in DMSO and 5% (v / v) BA without SDS. As the concentration of diazepam was reduced, the amount of SDS required to maintain diazepam solubility when diluted into SEF also decreased. The data in Table 5 suggests that there is an ideal ratio to prevent diazepam precipitation, and in this example, the molar ratio of SDS to diazepam was approximately 1:1.

[0080] (Table 5) Diazepam formulations prepared with SDS in DMSO prevented diazepam precipitation in SEF. TIFF0007660603000005.tif82147

[0081] Example 6 Diazepam formulations (100 mg / mL) prepared in DMSO and 5% (v / v) BA (and containing various surfactants) were sealed in 2 mL CZ vials (Crystal-Zenith, West Pharmaceuticals, PA, USA) with 13 mm FluroTec stoppers (rubber stoppers coated with fluorocarbon film from West Pharmaceuticals) and stored at 40° C. / 75% relative humidity for 90 days. Diazepam formulations were also prepared with 2% (v / v) PS20, 5% (v / v) BA, and 5% (v / v) NMP in DMSO. The sealed CZ vials were packaged in foil pouches for stability studies. All formulations were compared to 100 mg / mL diazepam dissolved in DMSO (containing 5% (v / v) BA). The stability of the formulations is shown below in Table 6 as percent diazepam remaining (± standard deviation).

[0082] Table 6: Stability of diazepam dissolved in DMSO with various excipients at 40° C. / 75% relative humidity. Stability data is given as the mean (± standard deviation) % purity of the diazepam peak for N=3 replicates. TIFF0007660603000006.tif36142

[0083] Diazepam dissolved in the DMSO-BA solvent system (no additional excipients) experienced a 4.2% decrease in diazepam purity over the first 30 days when stored at 40°C and 75% relative humidity, but remained at approximately 95% over the study period. Diazepam formulations prepared with excipients of 10% (v / v) PS80, 10% (w / v) SDS, and 2% (v / v) PS20 demonstrated residual diazepam peak purity of greater than 97.1% at the end of the 90-day study. These formulations demonstrated enhanced stability compared to diazepam in DMSO and 5% (v / v) benzyl alcohol (no additional excipients). Diazepam formulations prepared with 2% (v / v) PS20 and 5% (v / v) NMP demonstrated stability comparable to that observed in the DMSO-BA solvent system with no added excipients. Finally, the diazepam formulation prepared with 2% (w / v) SDC had a residual diazepam peak purity of 91% at the end of the 90-day stability study.

[0084] Example 7 The stability of diazepam formulations in the DMSO-BA solvent system was studied through 40 freeze-thaw cycles. As described above, diazepam (100 mg / mL) was dissolved in DMSO containing 5% (v / v) BA and sealed in 2 mL CZ vials with 13 mm FluroTec stoppers. Three vials of diazepam formulation were sealed in aluminum foil pouches and stored in a -20°C freezer for 2 hours. After storage, the pouches were placed at room temperature and allowed to thaw for 2 hours. This process was repeated at a rate of 3 freeze-thaw cycles per day, with the third freeze cycle left overnight. After several days of freeze-thaw cycles, 2 μL of diazepam formulation was removed for analysis by RP-HPLC. The data shown in Figure 1 shows the percent diazepam remaining ± standard deviation at 5 freeze-thaw cycle intervals.

[0085] No significant decrease in diazepam was measured after 20 freeze-thaw cycles. However, after 25 cycles, the percent diazepam remaining was significantly different from the pre-frozen samples (bar 0, p<0.05). With each successive interval of 5 freeze-thaw cycles, the percent diazepam remaining decreased. After 40 cycles, there was 81.7±0.5% diazepam remaining.

[0086] Example 8 In this example, the pharmacokinetic (PK) profile of several diazepam-DMSO formulations (with and without excipients) was evaluated in a rat model. Studies were conducted in adult male Sprauge-Dawley rats (HillTop Lab Animals, Inc., Scottsdale, PA) aged 8-10 weeks and weighing 275-325 grams, with at least 5 rats per group. Rats were individually housed in stainless steel cages and identified by number with a permanent marker applied to the tail. Rats were observed twice daily during acclimation and any abnormal health findings were recorded. Animals were provided with standard rodent chow and water during the acclimation period but were fasted overnight prior to the start of the study. Animals were allowed to acclimate for 1 week prior to the study.

[0087] Test articles for the pharmacokinetic study are listed in Table 7. The study included two commercially available diazepam formulations as comparators - Diastat® rectal diazepam (Valeant Pharmaceuticals) and Hospira's intramuscular (IM) diazepam formulation. Rats were weighed before the start of the study and accurately administered the test dose of 3.5 mg / kg. In group 1, Diastat was dosed rectally and in group 2, an IM injection of diazepam was given in the posterior thigh muscle. In groups 3-6, diazepam was dosed subcutaneously (SC) in the interscapular region using one of the four test formulations. Whole blood samples were collected from each rat via the jugular vein at time 0 (pre-dosing), 10, 20, 30, 45, 60, and 120 minutes into vials with K2EDTA. Whole blood samples were centrifuged (3000 rpm, 15 minutes) and plasma was collected. Plasma samples were frozen at -70°C for future diazepam and nordiazepam analysis.

[0088] Table 7. Test articles and dosages administered to rats in pharmacokinetic studies TIFF0007660603000007.tif46149

[0089] Rat plasma samples were assayed for diazepam and nordiazepam concentrations by LC / MS using diazepam-d5 and nordiazepam-d5 as internal standards. To each 25 μL sample, 25 μL of 25 ng / mL diazepam-d5 / nordiazepam-d5 solution and 0.2 mL of water were added. Samples were vortexed and extracted using Evolute® ABN SPE plates (solid phase extraction, Biotage, Charlotte, NC), eluted with methanol, and dried under nitrogen at approximately 40° C. The dry residue was reconstituted with 500 μL of 1:1 methanol:water and mixed by vortexing. Diazepam and nordiazepam were measured using reversed-phase ultra-performance liquid chromatography (RP-UPLC) and mass spectrometry (MS) methods. The gradient method utilizes a chromatographic column (Waters Atlantis dC-18, 3 μm, 2.1 x 50 mm) with 0.1% formic acid in 60:40 (% v / v) acetonitrile:water as the mobile phase. Analyte detection was performed using a UV detector at 280 nm for assay and a mass spectrometer for identity confirmation at a flow rate of 0.25 mL / min. Data obtained were expressed in ng / mL. Diazepam and nordiazepam plasma concentration data were analyzed using PKSolver Software, a menu-driven add-in program for Microsoft Excel.

[0090] Diazepam plasma concentration profiles (mean ± SEM) for Diastat® rectal diazepam, diazepam in DMSO and BA with 2% (w / v) SDC and 5% (v / v), diazepam in DMSO alone, and diazepam in DMSO and BA with 2% (v / v) PS20 and 5% (v / v) are shown in Figure 2. The Diastat® group had a Tmax at 10 minutes, a Cmax of approximately 200 ng / mL, and a rapid drop in plasma concentration over the remaining 110 minutes. Diazepam in DMSO alone had a Tmax at 10 minutes, a Cmax of approximately 70 ng / mL. Unlike Diastat, diazepam in DMSO alone maintained diazepam plasma concentrations at approximately 50 ng / mL over the remaining 110 minutes. The lack of an elimination phase observed in this group (and the other DMSO groups) is believed to be due to partial diazepam precipitation at the injection site, followed by slow absorption. Addition of 2% (v / v) PS20 to a diazepam formulation in DMSO resulted in an increase in diazepam plasma concentrations at 10 min, but not at 10 s, due to partial dose precipitation and slow absorption. max (110 ng / mL) occurred at 120 min (C max The addition of 2% (w / v) SDC to a diazepam formulation in DMSO resulted in an increase in diazepam plasma concentrations 10 min after injection, but not a delayed T max (approximately 110 ng / mL) occurred 60 min after injection (C max Overall, the addition of excipients to diazepam in DMSO formulations additionally increased diazepam plasma concentrations compared to diazepam in DMSO alone at 10 min post-infusion.

[0091] The combined diazepam (DZ) and nordiazepam (NDZ) PK profiles (mean ± SEM) for diazepam intramuscular injection (Hospira IM) and diazepam formulations in DMSO with 10% (w / v) SDS and 5% (v / v) BA are shown in Figure 3. Both diazepam and its metabolite, nordiazepam, are pharmacodynamically active and clinically relevant. Both the commercial comparator and the DMSO-based formulations had a T maxC max were 424 ng / mL and 396 ng / mL, respectively. max The differences were statistically equivalent (p=0.3123). Taken together, Figures 2 and 3 show that judicious choice of excipients can modulate the diazepam PK profile to promote either rapid or delayed / slow absorption.

[0092] Example 9 In this example, the pharmacokinetic (PK) profile of diazepam in DMSO and 30% (w / v) polysorbate 80 after subcutaneous and intramuscular injections was evaluated in the Gottingen minipig model. The study was conducted in female minipigs (Xenometrics, Stilwell, KS) weighing 10-12 kilograms, with three minipigs per group (two groups). The animals were allowed to acclimate for two weeks prior to the study. The animals had a two-week washout period between doses. The minipigs were individually housed in stainless steel cages and identified by number by a placard on the cage. The minipigs were observed twice daily during the study and any abnormal health findings were recorded. The animals were fasted overnight before the start of the study and for four hours after dose administration.

[0093] Test articles for the PK study are listed in Table 8. The study included two commercially available diazepam formulations as comparators - Diastat® rectal (PR) diazepam (Valeant Pharmaceuticals) and Hospira's intramuscular (IM) diazepam formulation. Minipigs were weighed before the study began and accurately dosed with a test dose of 1.0 mg / kg. Group 1 was dosed with Diastat rectally and Group 2 received an IM injection of Hospira diazepam in the hind thigh muscle. Group 3 received a subcutaneous dose of the diazepam test formulation behind the ear, while Group 4 received an intramuscular dose of the same formulation in the hind thigh. Animals were dosed such that animals in the same group did not receive two intramuscular doses. Whole blood samples were collected from each minipig via the jugular vein at time 0 (pre-dose), 0.017, 0.083, 0.167, 0.25, 0.5, 0.75, 1.0, 2.0, 4.0, 6.0, 8.0, and 24.0 hours after dose administration into vials with K2EDTA. Whole blood samples were centrifuged (3000 rpm, 15 min) and plasma was collected. Plasma samples were frozen at -70°C for future diazepam analysis.

[0094] Table 8. Test articles and dosages administered to minipigs in pharmacokinetic studies TIFF0007660603000008.tif31156

[0095] Minipig plasma samples were assayed for diazepam concentration by LC / MS using diazepam-d5 as an internal standard. To each 20 μL sample or standard, 500 μL of Trizma base buffer was added, followed by vortex mixing for 1 min. After mixing, 600 μL of ethyl acetate was added to each sample and mixed by inversion 40 times. 600 μL of this solution was transferred to a new collection tube and dried at 60° C. under nitrogen. The dried product was reconstituted in 100 μL of reconstitution solution (1 mM ammonium formate and 0.1% formic acid in 65 / 35 (% v / v) methanol / water), followed by vortex mixing for 1 min. Diazepam content was measured using reversed-phase high-performance liquid chromatography (RP-HPLC) and mass spectrometry (MS) methods. The gradient utilized a chromatographic column (Waters ACE® C18, 3 μm, 4.6 x 30 mm) with mobile phase A being 1 mM ammonium formate and 0.1% formic acid in 65 / 35 (v / v) methanol / water and mobile phase B being 1% acetic acid in 90 / 10 (v / v) methanol / water. Diazepam detection was performed utilizing a UV detector at 280 nm for assay and a mass spectrometer for identity confirmation at a flow rate of 0.25 mL / min. Data obtained was expressed in ng / mL.

[0096] Diazepam plasma concentration profiles (mean ± SEM) for 100 mg / mL diazepam in DMSO with 30% polysorbate 80 (30% (w / v) PS80) administered by intramuscular (IM) or subcutaneous (SC) injection, Hospira diazepam administered by intramuscular injection, and Diastat® rectal diazepam are shown in Figure 4. The Diastat® group had a Tmax at 10 minutes and a Cmax of approximately 271 ng / mL, followed by a rapid drop in plasma concentration over the first 5 hours of the study. The Hospira diazepam group also had a Tmax at 10 minutes and a Cmax of 425.3 ng / mL, followed by a rapid drop in plasma concentration, although not as rapid as Diastat rectal gel. A diazepam formulation in DMSO with 30% PS80 administered by IM injection had a Tmax at 45 minutes, a Cmax of 391.3 ng / mL, and an elimination profile consistent with IM administration of Hospira. SC administration of diazepam in DMSO and 30% (w / v) PS80 produced three peak plasma concentrations, with a true Cmax of 202.0 ng / mL occurring at 4.0 hours. Depending on the route of administration, the pharmacokinetic profile and peak plasma concentrations of diazepam in DMSO with 30% (w / v) polysorbate 80 can have a rapid onset or sustained systemic circulation.

[0097] Example 10 The stability of diazepam in DMSO with 30% (w / v) polysorbate 80 was studied when stored in glass vials at 75° C. for 20 days. Diazepam (100 mg / mL) was dissolved in DMSO containing 30% (w / v) polysorbate 80 and sealed in 10 mL borosilicate glass vials with 20 mm FluroTec stoppers and 20 mm flip-off seals. The vials were stored at 75° C. and three vials were drawn on days 5, 12, and 20. The percent diazepam remaining in each vial was determined by RP-HPLC. The data in FIG. 5 shows the percent diazepam remaining ± standard deviation.

[0098] After 5 and 12 days of storage at 75° C., the percent diazepam remaining was not significantly different from the initial (time zero) measurements (p=0.431). However, after 8 additional days of storage at 75° C. (day 20), the percent diazepam decreased by approximately 6.5% (from 106.98% to 99.99%, p=0.001). Despite the decrease in percent diazepam remaining after storage at 75° C., the results indicate that diazepam at 100 mg / mL is stable in DMSO with 30% polysorbate 80 (w / v).

[0099] Example 11 The stability of diazepam in DMSO with 30% (w / v) polysorbate 80 was studied when stored in glass vials at 4-8°C, 25°C and 60% relative humidity, 30°C, and 40°C and 75% relative humidity. Diazepam (100 mg / mL) was dissolved in DMSO containing 30% (w / v) polysorbate 80 and sealed in 10 mL borosilicate glass vials with 20 mm FluroTec stoppers and 20 mm flip-off seals. The vials were stored in triplicate under the storage conditions described above. The percent diazepam remaining in each vial was determined by RP-HPLC after 30 days of storage. The data in Figure 6 shows the percent diazepam remaining ± standard deviation.

[0100] The initial diazepam content was measured by RP-HPLC at time zero and is shown graphically by the bottom bar labeled "Initial." The percent diazepam remaining at all storage conditions (4-8°C, 25°C / 60% RH, 30°C, and 40°C / 75% RH) was 100%, indicating no loss of diazepam after 30 days of storage.

Claims

1. 1. A stable, precipitation-resistant injectable liquid formulation for parenteral injection, comprising: (a) a biocompatible non-aqueous solvent, the non-aqueous solvent being dimethylsulfoxide (DMSO), dimethylformamide (DMF), ethyl acetate, n-methylpyrrolidone (NMP), dimethylacetamide (DMA), propylene carbonate, or a mixture thereof; (b) a small molecule drug selected from levothyroxine, sumatriptan, or a salt thereof, solubilized in the non-aqueous solvent; and (c) 1% to 30% w / w of a surfactant, the surfactant being sodium deoxycholate, polysorbate 80, polysorbate 20, dodecyl maltoside, sodium dodecyl sulfate, sodium tetradecyl sulfate, an alcohol ethoxylate, an alkyl dimethylamine oxide, or an alkyl betaine, and the surfactant reduces precipitation of the small molecule drug when injected into a subject; and The injectable liquid formulation is parenterally injected into a subject in need thereof by intramuscular, intradermal, or subcutaneous injection.

2. 13. The injectable liquid formulation of claim 1, wherein the surfactant is present in a molar ratio of surfactant:small molecule drug of 0.5:1 to 4:1, or 1:1 to 2:

1.

3. 10. The injectable liquid formulation of claim 1, wherein the volume of the formulation injected parenterally is 3 mL or less.

4. The injectable liquid formulation of claim 1, further contained within a device for dispensing the injectable liquid formulation.

5. The injectable liquid formulation of claim 4, wherein the device is a syringe, a pen injection device, an autoinjector device, an external or implantable pump, or an infusion bag.

6. The injectable liquid formulation of claim 1, wherein the non-aqueous solvent is DMSO, NMP, or a mixture thereof.

7. The injectable liquid formulation of claim 1, wherein the formulation has a water content of less than 10% by weight.

8. The injectable liquid formulation of any one of claims 1 to 7, wherein the injectable liquid formulation contains 0.5 mg / mL to 750 mg / mL of a small molecule drug.

9. The injectable liquid formulation according to any one of claims 1 to 8, wherein the amount of the injectable liquid formulation parenterally injected is between 1 μL and 10 μL.

10. The injectable liquid formulation according to any one of claims 1 to 8, wherein the amount of the injectable liquid formulation parenterally injected is between 10 μL and 100 μL.

11. The injectable liquid formulation according to any one of claims 1 to 8, wherein the amount of the injectable liquid formulation injected parenterally is between 100 μL and 1 mL.

12. The injectable liquid formulation of any one of claims 1 to 11, wherein the small molecule drug is levothyroxine.

13. The injectable liquid formulation of any one of claims 1 to 11, wherein the small molecule drug is sumatriptan.

14. The injectable liquid formulation of any one of claims 1 to 13, wherein the injectable liquid formulation is not diluted prior to administration.

15. The injectable liquid formulation of any one of claims 1 to 14 for treating or preventing a condition.

16. The injectable liquid formulation of claim 15, wherein the injectable liquid formulation is contained within a device for dispensing the injectable liquid formulation.

17. The injectable liquid formulation of claim 16, wherein the device is a syringe, a pen injection device, an autoinjector device, an external or implantable pump, or an infusion bag.

18. The injectable liquid formulation of claim 15, wherein the amount of the injectable liquid formulation injected parenterally is 1 μL to 10 μL.

19. The injectable liquid formulation of claim 15, wherein the amount of the injectable liquid formulation injected parenterally is 10 μL to 100 μL.

20. The injectable liquid formulation of claim 15, wherein the amount of the injectable liquid formulation injected parenterally is 100 μL to 1 mL.

21. The injectable liquid formulation of claim 15, wherein the injectable liquid formulation is not diluted prior to administration.

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