Hydrocortisone sodium phosphate and monothioglycerol aqueous pharmaceutical formulation

Abstract

The present disclosure provides an aqueous formulation comprising hydrocortisone sodium phosphate and monothioglycerol. In some embodiments, the formulation comprises monobasic sodium phosphate, dibasic sodium phosphate, or disodium EDTA. The present disclosure further provides a method of treating a disease or disorder in a subject by administering the aqueous formulation.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is an international application claiming priority to U.S. Provisional Patent Application No. 63 / 321,997, filed March 21, 2022, No. 63 / 322,934, filed March 23, 2022, and No. 63 / 387,727, filed December 16, 2022, each of which is incorporated by reference in its entirety herein.

[0002] The present invention relates generally to hydrocortisone and hydrocortisone prodrugs, as well as pharma- ceutically acceptable salts thereof, and related formulations. [Background technology]

[0003] Hydrocortisone is the name of the hormone cortisol when supplied as a medicine. It is used by mouth, intravenous injection, or topical application. It is used as an immunosuppressant given by injection in the treatment of severe allergic reactions such as anaphylaxis and angioedema. It can be used topically for allergic rashes, eczema, psoriasis, pruritus, and other inflammatory skin disorders.

[0004] Therapeutic hydrocortisone is a synthetic or semi-synthetic analog of the natural hydrocortisone hormone produced by the adrenal glands, with predominantly glucocorticoid and mild mineralocorticoid actions. As a glucocorticoid receptor agonist, hydrocortisone promotes protein catabolism, gluconeogenesis, capillary wall stability, renal excretion of calcium, and suppresses immune and inflammatory responses. Summary of the Invention [Means for solving the problem]

[0005] In one aspect, the present disclosure provides an aqueous pharmaceutical formulation comprising about 50 to about 150 mg / mL hydrocortisone sodium phosphate, about 2.5 to about 50 mg / mL monothioglycerol, and water. In one embodiment, the aqueous pharmaceutical formulation comprises about 120 to about 130 mg / mL hydrocortisone sodium phosphate, about 127 mg / mL to about 141 mg / mL hydrocortisone sodium phosphate, about 130 to about 140 mg / mL hydrocortisone sodium phosphate, or about 140 to about 150 mg / mL hydrocortisone sodium phosphate. In one embodiment, the aqueous pharmaceutical formulation comprises about 127 mg / mL to about 141 mg / mL hydrocortisone sodium phosphate. In one embodiment, the aqueous pharmaceutical formulation comprises about 130 to about 135 mg / mL hydrocortisone sodium phosphate, or about 135 to about 140 mg / mL hydrocortisone sodium phosphate. In one embodiment, the aqueous pharmaceutical formulation comprises about 127 mg / mL hydrocortisone sodium phosphate, about 128 mg / mL hydrocortisone sodium phosphate, about 129 mg / mL hydrocortisone sodium phosphate, about 130 mg / mL hydrocortisone sodium phosphate, about 131 mg / mL hydrocortisone sodium phosphate, about 132 mg / mL hydrocortisone sodium phosphate, about 133 mg / mL hydrocortisone sodium phosphate, about 134 mg / mL hydrocortisone sodium phosphate, about 135 mg / mL hydrocortisone sodium phosphate, about 136 mg / mL hydrocortisone sodium phosphate, about 137 mg / mL hydrocortisone sodium phosphate, about 138 mg / mL hydrocortisone sodium phosphate, about 139 mg / mL hydrocortisone sodium phosphate, about 140 mg / mL hydrocortisone sodium phosphate, or about 141 mg / mL hydrocortisone sodium phosphate.In one embodiment, the aqueous pharmaceutical formulation comprises about 134 mg / mL hydrocortisone sodium phosphate, about 134.1 mg / mL hydrocortisone sodium phosphate, about 134.2 mg / mL hydrocortisone sodium phosphate, about 134.3 mg / mL hydrocortisone sodium phosphate, about 134.4 mg / mL hydrocortisone sodium phosphate, about 134.5 mg / mL hydrocortisone sodium phosphate, about 134.6 mg / mL hydrocortisone sodium phosphate, about 134.7 mg / mL hydrocortisone sodium phosphate, about 134.8 mg / mL hydrocortisone sodium phosphate, about 134.9 mg / mL hydrocortisone sodium phosphate, or about 135 mg / mL hydrocortisone sodium phosphate. In one embodiment, the liquid pharmaceutical formulation contains about 2.5 to about 3.5 mg / mL monothioglycerol, about 3.5 to about 4.5 mg / mL monothioglycerol, about 3.5 to about 5.5 mg / mL monothioglycerol, about 4.5 to about 5.5 mg / mL monothioglycerol, about 5.5 to about 6.5 mg / mL monothioglycerol, about 6.5 to about 7.5 mg / mL monothioglycerol, about 7.5 to about 8.5 mg / mL monothioglycerol, about 8.5 to about 9.5 mg / mL monothioglycerol, about 9.5 to about 10.5 mg / mL monothioglycerol, about 10.5 to about 11.5 mg / mL monothioglycerol, or about 11.5 to about 12.5 mg / mL monothioglycerol. In one embodiment, the liquid pharmaceutical formulation contains about 4 to about 4.25 mg / mL monothioglycerol, about 4.25 to about 4.5 mg / mL monothioglycerol, about 4.5 to about 4.75 mg / mL monothioglycerol, about 4.75 to about 5 mg / mL monothioglycerol, about 5 to about 5.25 mg / mL monothioglycerol, about 5.25 to about 5.5 mg / mL monothioglycerol, about 5.5 to about 5.75 mg / mL monothioglycerol, or about 5.75 to about 6 mg / mL monothioglycerol.In one embodiment, the liquid pharmaceutical formulation contains about 4.5 mg / mL monothioglycerol, about 4.6 mg / mL monothioglycerol, about 4.7 mg / mL monothioglycerol, about 4.8 mg / mL monothioglycerol, about 4.9 mg / mL monothioglycerol, about 5 mg / mL monothioglycerol, about 5.1 mg / mL monothioglycerol, about 5.2 mg / mL monothioglycerol, about 5.3 mg / mL monothioglycerol, about 5.4 mg / mL monothioglycerol, or about 5.5 mg / mL monothioglycerol. In one embodiment, the liquid pharmaceutical formulation contains about 0.5 to about 2.5 mg / mL monobasic sodium phosphate. In one embodiment, the liquid pharmaceutical formulation contains about 5 to about 25 mg / mL dibasic sodium phosphate. In one embodiment, the liquid pharmaceutical formulation contains about 0.1 to about 1 mg / mL disodium EDTA. In one embodiment, the liquid medical formulation contains about 0.1 to about 0.22 mg / mL of disodium EDTA. In one embodiment, the liquid medical formulation has a pH of about 7.5 to about 9.5 or about 7.5 to about 8.5. In one embodiment, the liquid medical formulation has a pH of about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, about 8.0, about 8.1, about 8.2, about 8.3, about 8.4, about 8.5, about 8.6, about 8.7, about 8.8, about 8.9, or about 9. In one embodiment, when formulated, the pharmaceutical formulation contains no, less than 0.2%, or no more than 0.2% organic impurities; no, less than 0.15%, or no more than 0.15% organic impurities; no, less than 0.10%, or no more than 0.10% organic impurities; or no, less than 0.05%, or no more than 0.05% organic impurities. In one embodiment, when stored at about 25° C. for about 3 months, the formulation contains no, less than 0.2%, or no more than 0.2% organic impurities; or no, less than 0.07%, or no more than 0.07% organic impurities.In one embodiment, the formulation is free of, contains less than 0.60% or does not exceed 0.60% organic impurities; or free of, contains less than 0.20% or does not exceed 0.20% organic impurities when stored at about 25° C. for about 6 months. In one embodiment, the formulation is stored at about 60% relative humidity. In one embodiment, the formulation is stored against at least one pharma- ceutically acceptable non-glass surface selected from a stopper surface, a needle surface, a needle tip cap surface, a needle shield surface, a septum surface, a syringe plunger surface, a plastic syringe surface, an injector surface, or a rubber surface.

[0006] In one embodiment, the aqueous pharmaceutical formulation is for use in the treatment of a disease, condition, or disorder alleviated by hydrocortisone or hydrocortisone sodium phosphate, in one embodiment, the disease, condition, or disorder comprises one or more of asthma, allergic reactions, severe shock due to injury or infection, adrenal insufficiency, inflammation, atopic dermatitis, contact dermatitis, drug hypersensitivity reactions, perennial or seasonal allergic rhinitis, serum sickness, transfusion reactions, gastrointestinal disease, trichinellosis with neurological or myocardial impairment, tuberculous meningitis with subarachnoid block or impending block, neoplastic disease, palliative management of leukemia and / or lymphoma, renal disease, proteinuria in idiopathic nephrotic syndrome, proteinuria due to lupus erythematosus, dermatomyositis, temporal arteritis, polymyositis, joint and / or tendon swelling, joint and / or tendon pain, tennis elbow, golfer's elbow, and systemic lupus erythematosus. In one embodiment, the disease, condition, or disorder is a skin disease selected from bullous dermatitis herpetiformis, exfoliative erythroderma, mycosis fungoides, pemphigus, and severe erythema multiforme (Stevens-Johnson syndrome); an endocrine disorder selected from primary or secondary adrenal cortical insufficiency, congenital adrenal hyperplasia, hypercalcemia associated with cancer, and nonsuppurative thyroiditis; an endocrine disorder selected from acquired (autoimmune) hemolytic anemia, congenital (erythrocytic) hypoplastic anemia (Diamond-Blackfan anemia), selected cases of idiopathic thrombocytopenic purpura in adults, pure red cell aplasia, and secondary thrombocytopenia. The diseases, conditions, or disorders include blood disorders that are caused by adrenal gland inflammation; acute exacerbations of multiple sclerosis; nervous system conditions selected from primary or metastatic brain tumors, and cerebral edema associated with craniotomy; eye diseases selected from sympathetic ophthalmia, uveitis, and ocular inflammatory conditions; respiratory diseases selected from beryllium disease, fulminant or disseminated pulmonary tuberculosis, idiopathic eosinophilic pneumonia, and symptomatic sarcoidosis; rheumatic disorders selected from acute gouty arthritis, acute rheumatic carditis, ankylosing spondylitis, psoriatic arthritis, and rheumatoid arthritis; and adrenal insufficiency selected from primary adrenal insufficiency, acute adrenal insufficiency, and secondary adrenal insufficiency. In one embodiment, the disease, condition, or disorder includes adrenal insufficiency selected from primary adrenal insufficiency, acute adrenal insufficiency, and secondary adrenal insufficiency. In one embodiment, the disease, condition, or disorder includes acute adrenal insufficiency that occurs in a patient with primary adrenal insufficiency or secondary adrenal insufficiency.

[0007] In another aspect, the disclosure provides a method of treating a disease, condition, or disorder alleviated by administration of hydrocortisone or hydrocortisone sodium phosphate in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the aqueous pharmaceutical formulation described above. In one embodiment, the disease, condition, or disorder comprises one or more of asthma, acute exacerbation of asthma, allergic reactions, severe shock due to injury or infection, adrenal insufficiency, inflammation, atopic dermatitis, contact dermatitis, drug hypersensitivity reactions, perennial or seasonal allergic rhinitis, serum sickness, transfusion reactions, gastrointestinal disease, trichinellosis with neurological or myocardial impairment, tuberculous meningitis with subarachnoid block or impending block, neoplastic disease, palliative management of leukemia and / or lymphoma, renal disease, proteinuria in idiopathic nephrotic syndrome, proteinuria due to lupus erythematosus, dermatomyositis, temporal arteritis, polymyositis, joint and / or tendon swelling, joint and / or tendon pain, tennis elbow, golfer's elbow, systemic lupus erythematosus, acute exacerbation of inflammatory bowel disease, and infantile spasms. In one embodiment, the disease, condition, or disorder is a skin disease selected from bullous dermatitis herpetiformis, exfoliative erythroderma, mycosis fungoides, pemphigus, and severe erythema multiforme (Stevens-Johnson syndrome); an endocrine disorder selected from primary or secondary adrenal cortical insufficiency, congenital adrenal hyperplasia, hypercalcemia associated with cancer, and nonsuppurative thyroiditis; an endocrine disorder selected from acquired (autoimmune) hemolytic anemia, congenital (erythrocytic) hypoplastic anemia (Diamond-Blackfan anemia), selected cases of idiopathic thrombocytopenic purpura in adults, pure red cell aplasia, and secondary thrombocytopenia. In one embodiment, the disease, condition, or disorder includes adrenal insufficiency selected from primary adrenal insufficiency, acute adrenal insufficiency, and secondary adrenal insufficiency. In one embodiment, the disease, condition, or disorder includes adrenal insufficiency selected from primary adrenal insufficiency, acute adrenal insufficiency, and secondary adrenal insufficiency. In one embodiment, the disease, condition, or disorder includes adrenal insufficiency selected from primary adrenal insufficiency, acute adrenal insufficiency, and secondary adrenal insufficiency.In one embodiment, the disease, condition, or disorder comprises acute adrenal insufficiency occurring in patients with primary adrenal insufficiency or secondary adrenal insufficiency. In one embodiment, the therapeutic amount is about 0.5 mL to about 0.6 mL, about 0.6 mL to about 0.7 mL, about 0.7 mL to about 0.8 mL, about 0.8 mL to about 0.9 mL, about 0.9 mL to about 1.0 mL, about 1.0 mL to about 1.2 mL, about 1.0 mL to about 1.1 mL, about 1.1 mL to about 1.2 mL, about 1.2 mL to about 1.3 mL, about 1.3 mL to about 1.4 mL, or about 1.4 mL to about 1.5 mL of the aqueous pharmaceutical formulation. In one embodiment, the therapeutic amount is about 0.5 mL, about 0.6 mL, about 0.7 mL, about 0.8 mL, about 0.9 mL, about 1.0 mL, about 1.1 mL, about 1.2 mL, about 1.3 mL, about 1.4 mL, or about 1.5 mL of the aqueous pharmaceutical formulation. In one embodiment, the therapeutic amount is administered to the patient using an emergency / rescue autoinjector device. In one embodiment, the patient cannot receive hydrocortisone or its medications in an oral treatment. In one embodiment, the therapeutic amount is administered intravenously. In one embodiment, the therapeutic amount is administered intramuscularly. In one embodiment, the therapeutic amount is about 5,500 to 5,575 h. * Mean AUC in ng / mL 0-inf In one embodiment, the therapeutic amount is about 5,275 to 5,375 h. * Mean AUC in ng / mL 0-t and a t of about 0.5-12.5 hours. In one embodiment, the patient has a C of hydrocortisone of about 800-1600 ng / mL, about 900-1600 ng / mL, about 1000-1600 ng / mL, about 1000-1500 ng / mL, about 1100-1500 ng / mL, about 1100-1400 ng / mL, or about 1200-1300 ng / mL about 30 minutes, about 45 minutes, about 1.0 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, about 2.0 hours, about 2.25 hours, about 2.5 hours, about 2.75 hours, about 3.0 hours, about 3.25 hours, about 3.5 hours, or about 4.0 hours after a therapeutic dose is administered. max In one embodiment, the therapeutic amount is a median T maxIn one embodiment, hydrocortisone is administered to a patient at a mean T of about 1.8 to 2.1 hours. 1 / 2 el In one embodiment, the aqueous pharmaceutical formulation exhibits a higher exposure following administration to a patient as compared to a hydrocortisone reference formulation. In one embodiment, the aqueous pharmaceutical formulation achieves a higher area under the curve (AUC) following administration to a patient as compared to a hydrocortisone reference enumerated formulation. In one embodiment, the aqueous pharmaceutical formulation achieves a higher maximum (or peak) serum concentration (C) following administration to a patient as compared to a hydrocortisone reference enumerated formulation. max In one embodiment, the aqueous pharmaceutical formulation achieves a faster maximum (or peak) serum concentration (C) after administration to a patient than a hydrocortisone reference formulation. max ). In one embodiment, the hydrocortisone reference formulation is administered intravenously to the patient. In one embodiment, the hydrocortisone reference formulation is administered intramuscularly to the patient. In one embodiment, the hydrocortisone reference formulation comprises hydrocortisone sodium succinate. In one embodiment, the hydrocortisone reference formulation does not comprise an antioxidant. In one embodiment, the hydrocortisone reference formulation comprises an aqueous formulation comprising about 67 mg / mL hydrocortisone sodium succinate, about 4.4 mg / mL sodium phosphate dibasic, about 0.4 mg / mL sodium phosphate monobasic, and water, and about 2.0 mL is administered to the patient.

[0008] The foregoing summary, as well as the following detailed description of embodiments of the present invention, will be better understood when read in conjunction with the appended drawings and figures. [Brief description of the drawings]

[0009] [Figure 1] The stability of the three main formulations is shown. [Diagram 2] A typical chromatogram of HCP using the analytical method developed herein is shown. [Figure 3A] 1 shows the acid hydrolysis of HCP using 0.1 N HCl. [Figure 3B] 1 shows alkaline hydrolysis of HCP using 0.1 N NaOH. [Figure 3C] 1 shows the pyrolysis of HCPs using dry heat. [Figure 4] The stability of two formulations (#3 and #7) over a six month period is shown. [Diagram 5] The stability of two formulations (#3 and #10) over a six month period is shown. [Figure 6] 1 is a perspective view of an injector according to an exemplary embodiment of the present invention; [Figure 7] FIG. 7 is a cross-sectional view of the injector of FIG. [Figure 8] FIG. 7 is a cross-sectional view of the injector of FIG. 6 with the needle guard in a retracted position. [Figure 9] 7 is a cross-sectional view of the injector of FIG. 6 with the drug container in an injection position. [Figure 10] FIG. 7 is a cross-sectional view of the injector of FIG. 6 after a drug has been injected. [Figure 11] 7 is a cross-sectional view of the injector of FIG. 6 after injection with the needle guard in the extended position. [Figure 12] 1 depicts cortisol plasma concentration curves for a formulation disclosed herein (ATRS-2001) and Solu-Cortef. [Figure 13] 1 depicts cortisol plasma concentration curves for a formulation disclosed herein (ATRS-2001) and Solu-Cortef. [Figure 14] An equivalent plot for AUClast is provided. [Figure 15] Box plots for AUClast are provided. [Figure 16] Provide an equivalent plot for AUCinf. [Figure 17] Provide a box plot for AUCinf. [Figure 18] An equivalent plot for Cmax is provided. [Figure 19] Box plots for Cmax are provided. [Figure 20] An equivalent plot for Tmax is provided. [Figure 21]Box plots for Tmax are provided. [Figure 22] 1 is a chart demonstrating the effect of pH on hydrocortisone impurity formation under accelerated storage conditions. [Figure 23] 2. Drawing of a 25 ml sterile glass syringe [Figure 24] This is a representative model of an autoinjector assembly. [Diagram 25] 1 is a representative model of an autoinjector assembly assembly drawing. [Figure 26] FIG. 2 is an exploded view of the rear subassembly. [Figure 27] FIG. 2 is an exploded view of the front subassembly. [Figure 28] 1 is a chart demonstrating the increase in water content of the amorphous form compared to that of the crystalline hydrate. [Figure 29] 1 is a chart of mean (±SD) baseline-corrected cortisol plasma concentrations (linear scale) for ATRS-1902 compared to Solu-Cortef. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] Although the above-identified drawings set forth embodiments of the present disclosure, other embodiments are contemplated, as noted in the discussion. The present disclosure represents illustrative embodiments, not limiting. Numerous other modifications and embodiments can be devised by those skilled in the art that fall within the scope and spirit of the principles of the embodiments of the present disclosure.

[0011] The present invention is directed to pharmaceutical formulations comprising hydrocortisone, one or more hydrocortisone prodrugs, such as hydrocortisone esters, and / or any salts thereof, including, but not limited to, stable liquid formulations using hydrocortisone sodium phosphate as the active ingredient.

[0012] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0013] All patents and publications referenced herein are incorporated by reference in their entirety. As used herein, the terms "administer," "administration," or "administering" refer to (1) providing, administering, dispensing, and / or prescribing, either by or under the direction of a medical professional or his / her authorized representative, in accordance with this disclosure, and / or (2) placing, ingesting, or causing to be consumed by a subject, e.g., a mammal, including a human, in accordance with this disclosure.

[0014] As used herein, the terms "co-administration," "co-administer," "administered in combination with," "administered in combination with," "simultaneously," and "co-administration" encompass administration of two or more active pharmaceutical ingredients to a subject such that both active pharmaceutical ingredients and / or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which two or more active pharmaceutical ingredients are present. In some embodiments, co-administration in separate compositions and administration in a composition in which both agents are contained are preferred.

[0015] The term "effective amount" or "therapeutically effective amount" refers to that amount of a compound or combination of compounds described herein that is sufficient to achieve the intended application, including but not limited to disease treatment. The therapeutically effective amount may vary depending on the intended application (in vitro or in vivo), or the subject and disease state to be treated (e.g., the subject's weight, age, and sex), the severity of the disease state, the method of administration, etc., which can be easily determined by one of ordinary skill in the art. The term also applies to a dose that induces a particular response in target cells (e.g., reduction of platelet adhesion and / or cell migration). The particular dose will vary depending on the subject to which the dose is administered, the particular compound selected, the administration regimen to be followed, whether the compound is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system to which the compound is transported.

[0016] A "therapeutic benefit" as the term is used herein encompasses a therapeutic benefit and / or a prophylactic benefit. A prophylactic benefit includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting or reversing the progression of a disease or condition, or any combination thereof.

[0017] As used herein, the terms "treat", "treatment", and / or "treating" may refer to the management of a disease, disorder, or pathological condition, or a symptom thereof, with the intent of curing, ameliorating, stabilizing, and / or controlling the disease, disorder, pathological condition, or a symptom thereof. More specifically, with respect to the control of a disease, disorder, or pathological condition, "control" may include the lack of progression of the condition, as assessed by response to the methods listed herein, and such response may be complete (e.g., putting the disease into remission) or partial (e.g., reducing or improving any symptoms associated with the condition). As used herein, the terms "prevent", "preventing", and / or "prevention" may refer to reducing the risk of developing a disease, disorder, or pathological condition.

[0018] The term "pharmaceutically acceptable salts" refers to salts derived from various organic and inorganic counterions known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Preferred inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Preferred organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, phosphoric acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins. Specific examples include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharma-ceutically acceptable base addition salt is selected from ammonium, potassium, sodium, calcium, and magnesium salts. The term "co-crystal" refers to a molecular complex derived from a number of co-crystal formers known in the art. Unlike salts, co-crystals do not usually involve hydrogen transfer between the co-crystal and the drug, but instead involve intermolecular interactions such as hydrogen bonding, aromatic ring stacking, or dispersion forces between the co-crystal former and the drug in the crystal structure.

[0019] A "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" or "physiologically compatible" carrier or carrier medium is intended to include any solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and inactive ingredients. The use of such pharmaceutically acceptable carriers or pharmaceutically acceptable excipients for active pharmaceutical ingredients is well known in the art. Except insofar as any conventional pharmaceutically acceptable carrier or pharmaceutically acceptable excipient is incompatible with the active pharmaceutical ingredient, its use in the therapeutic compositions of the present invention is contemplated. Additional active pharmaceutical ingredients, such as other drugs, may also be incorporated into the compositions and methods described.

[0020] "Prodrug" refers to a derivative of a compound described herein, whose pharmacological action results from conversion to an active compound by chemical or metabolic processes in vivo. Prodrugs include, but are not limited to, compounds in which an amino acid residue, or a polypeptide chain of two or more (e.g., 2, 3, or 4) amino acid residues, is covalently bonded to a free amino, hydroxyl, or carboxylic acid group of hydrocortisone via an amide or ester bond. Amino acid residues include, but are not limited to, the 20 naturally occurring amino acids commonly designated by one-letter or three-letter symbols, including, for example, 4-hydroxyproline, hydroxylysine, desmosine, isodesmosine, 3-methylhistidine, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine, and methionine sulfone. Additional types of prodrugs are also encompassed. For example, free carboxyl groups can be derivatized as amides or alkyl esters (e.g., methyl esters and acetoxymethyl esters). Prodrug esters as used herein include esters and carbonates formed by reacting one or more hydroxyls of the compounds of the method of the present invention with alkyl, alkoxy, or aryl substituted acylating agents to produce acetates, phosphates, succinates, butyrates, pivalates, methylcarbonates, benzoates, etc., using procedures known to those skilled in the art. As a further example, free hydroxyl groups may be derivatized using groups including, but not limited to, hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyl, as reviewed in Advanced Drug Delivery Reviews, 1996, 19, 115. Carbamate prodrugs of hydroxyl and amino groups are also included, as well as carbonate prodrugs, sulfonate prodrugs, sulfonate esters, and sulfate esters of hydroxyl groups. Free amines may also be derivatized to amides, sulfonamides, or phosphonamides. All of the prodrug moieties described may incorporate groups including, but not limited to, ether, amine, and carboxylic acid functionalities.Furthermore, any compound that can be converted in vivo to provide a bioactive agent (e.g., hydrocortisone) is a prodrug within the scope of the present invention. Various forms of prodrugs are well known in the art. Comprehensive descriptions of prodrugs and prodrug derivatives are described in: (a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al., (Academic Press, 1996); (b) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985); (c) A Textbook of Drug Design and Development, P. Krogsgaard-Larson and H. Bundgaard, eds., (Harwood Academic Publishers, 1991). In general, prodrugs may be designed to improve penetration of the drug across biological membranes to obtain improved drug absorption, to extend the duration of action of the drug (slow release of the parent drug from the prodrug, reduced first pass metabolism of the drug), to target drug action (e.g., organ or tumor targeting, lymphocyte targeting), to modify or improve the water solubility of the drug (e.g., intravenous preparations and eye drops), to improve local drug delivery (e.g., drug delivery to the skin and eye), to improve the chemical / enzymatic stability of the drug, or to reduce off-target drug effects, and more generally to improve the therapeutic efficacy of the compounds utilized in the present invention.

[0021] Unless otherwise stated, chemical structures depicted herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds in which one or more hydrogen atoms are replaced with deuterium or tritium, or compounds in which one or more carbon atoms are replaced with 13 C-rich carbon or 14 Compounds substituted with C-rich carbons are within the scope of the present invention.

[0022] For example, when ranges are used herein to describe physical or chemical properties such as molecular weight or chemical formula, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The use of the term "about" when referring to a numerical value or numerical range means that the stated number or numerical range is an approximation within experimental variation (or within statistical experimental error), and thus the number or numerical range may vary. The variation is typically 0% to 15%, 0% to 10%, 0% to 5%, etc., of the stated number or numerical range.

[0023] As used herein, the term "about" means that amounts, sizes, formulations, parameters, shapes, and other quantities and characteristics are not and need not be exact, but may be approximate and / or larger or smaller, as desired, to reflect tolerances, conversion factors, rounding, measurement errors, and the like, and other factors known to those of skill in the art. In general, amounts, sizes, formulations, parameters, shapes, or other quantities or characteristics are "about" or "approximately" whether or not they are explicitly stated as such. The term "about" generally refers to a particular numerical value that is within an acceptable error range as determined by one of skill in the art, which depends in part on how the numerical value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean a range of ±20%, ±10%, or ±5% of the given numerical value.

[0024] The transitional terms "comprising," "consisting essentially of," and "consisting of," when used in the appended claims, in their original and amended forms, define the claims in terms of whether any additional unrecited claim elements or steps are excluded from the claim. The term "comprising" is intended to be inclusive or open-ended and does not exclude any additional unrecited elements, methods, steps, or materials. The term "consisting of" excludes any element, step, or material other than that specified in the claim, and in the latter case, excludes impurities normally associated with the specified material. The term "consisting essentially of" limits the claim to the specified elements, steps, or materials, and those that do not materially affect the basic and novel characteristics of the claimed invention. All compounds, compositions, formulations, and methods described herein that embody the present invention may be more specifically defined in alternative embodiments by any of the transitional terms "comprising," "consisting essentially of," and "consisting of." The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") includes, for example, any compositional embodiment of a material, method, or process that "consists of" or "consists essentially of" the recited features.

[0025] "Alkyl" refers to a straight or branched hydrocarbon chain radical, containing no unsaturation, consisting solely of carbon and hydrogen atoms, having from one to ten carbon atoms (e.g., (C 10 ) Alkyl or C1~ 10alkyl). Whenever it appears herein, a numerical range, e.g., 1-10, refers to each integer in the given range, e.g., 1-10 carbon atoms means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 10 carbon atoms, but the definition is also intended to cover the occurrence of the term "alkyl" when no numerical range is specifically specified. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butylisobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl, and decyl. The alkyl moiety may be attached to the remainder of the molecule by a single bond, e.g., methyl (Me), ethyl (Et), n-propyl (Pr), 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), and 3-methylhexyl. Unless otherwise stated in the specification, an alkyl group is optionally substituted with one or more of the following substituents, which substituents are independently heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , -S(O) t R a - (wherein t is 1 or 2), -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, N(R a )C(NRa )N(R a )2, -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t N(R a )2 (wherein t is 1 or 2), or PO3(R a ) 2, wherein each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl. The alkyl portion may be branched, straight chain, or cyclic, whether saturated or unsaturated.

[0026] An "alkene" or "alkenyl" moiety refers to a group that consists of at least two carbon atoms and at least one carbon-carbon double bond, and an "alkyne" moiety refers to a group that consists of at least two carbon atoms and at least one carbon-carbon triple bond.

[0027] "Alkenyl" refers to the radical group of a straight or branched hydrocarbon chain, consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having from 2 to 10 carbon atoms (i.e., (C 10 ) alkenyl or C2 10alkenyl). Whenever it appears herein, a numerical range such as "2 to 10" refers to each integer in the given range, for example, "2 to 10 carbon atoms" means that the alkenyl group can be composed of up to 10 carbon atoms, such as 2 carbon atoms, 3 carbon atoms, etc. The alkenyl moiety may be attached to the remainder of the molecule by a single bond, such as, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, and penta-1,4-dienyl. Unless otherwise stated herein, an alkenyl group is optionally substituted by one or more of the following substituents, which are independently alkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR, -O- ... a , -SR a , -S(O) t R a - (wherein t is 1 or 2), -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, N(R a )C(NR a )N(R a )2, -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t N(R a )2 (wherein t is 1 or 2), or PO3(Ra ) 2, wherein each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0028] "Alkenyl-cycloalkyl" refers to an -(alkenyl)cycloalkyl radical, in which the alkenyl and cycloalkyl are as disclosed herein and are optionally substituted by one or more of the substituents described as suitable substituents for alkenyl and cycloalkyl, respectively.

[0029] "Cycloalkyl" refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen and can be saturated or partially unsaturated. Cycloalkyl groups include groups having 3 to 10 ring atoms (i.e., (C3 to C4). 10 ) Cycloalkyl or C3~ 10 cycloalkyl). Whenever it appears herein, a numerical range such as "3 to 10" refers to each integer in the given range, for example, "3 to 10 carbon atoms" means that the cycloalkyl group can consist of up to 10 carbon atoms, such as 3 carbon atoms. Specific examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, and the like. Unless otherwise stated in the specification, cycloalkyl groups are optionally substituted with one or more of the following substituents, which are independently: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, acylsulfonamido, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR, -O- ... a , -SR a , -S(O) t R a- (wherein t is 1 or 2), -S(O) t R a - (wherein t is 1 or 2), -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, N(R a )C(NR a )N(R a )2, -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t N(R a )2 (wherein t is 1 or 2), or PO3(R a ) 2, wherein each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0030] "Cycloalkyl-alkenyl" refers to a -(cycloalkyl)alkenyl radical, in which the cycloalkyl and alkenyl are as disclosed herein, optionally substituted with one or more of the substituents described as suitable substituents for cycloalkyl and alkenyl, respectively.

[0031] "Acyl" refers to the groups (alkyl)-C(O)-, (aryl)-C(O)-, (heteroaryl)-C(O)-, (heteroalkyl)-C(O)-, and (heterocycloalkyl)-C(O)-, which are attached to the parent structure via a carbonyl functionality. When the R radical is heteroaryl or heterocycloalkyl, the hetero ring or chain atoms contribute to the total number of chain or ring atoms. Unless otherwise stated in the specification, the alkyl, aryl, and heteroaryl portions of the acyl group are optionally substituted with one or more of the following substituents, which are independently alkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , -S(O) t R a - (wherein t is 1 or 2), -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, N(R a )C(NR a )N(R a )2, -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t N(R a )2 (wherein t is 1 or 2), or PO3(R a ) 2, wherein each R ais independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0032] "Ester" refers to, but is not limited to, a chemical radical of the formula -COOR, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heteroalicyclic (bonded through a ring carbon). Procedures and specific groups for making esters are known to those of skill in the art and are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3, incorporated herein by reference in its entirety. rd Ed., John Wiley & Sons, New York, NY, 1999. Unless otherwise stated herein, the ester groups are optionally substituted with one or more of the following substituents, which are independently: alkyl, acylsulfonamido, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR, -O- ... a , -SR a , -S(O) t R a - (wherein t is 1 or 2), -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, N(Ra )C(NR a )N(R a )2, -N(R a )S(O) t R a (Wherein, t is 1 or 2), -S(O) t or a (Wherein, t is 1 or 2), -S(O) t N(R a )2 (wherein t is 1 or 2), or PO3(R a )2, where each R a is independently hydrogen, including alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0033] "Ester" also refers to, but is not limited to, phosphate. "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, such as trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. The alkyl portion of the fluoroalkyl radical may be optionally substituted as defined above for an alkyl group.

[0034] "Isomers" are different compounds that have the same molecular formula. "Stereoisomers" are isomers that differ only in the way the atoms are arranged in space, i.e., have different stereochemical configurations. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The term "(±)" is used to designate a racemic mixture where appropriate.

[0035] "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is designated according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be designated by either (R) or (S). Resolved compounds of unknown absolute configuration can be designated as (+) or (-) depending on the direction (dextrorotatory or levorotatory) that they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and can therefore give rise to enantiomers, diastereomers, and other stereoisomers that can be defined in terms of absolute stereochemistry as (R) or (S). The chemical compounds, pharmaceutical compositions, and methods of the invention are meant to include all such possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Optically active (R) and (S) isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers.

[0036] "Moiety" refers to a specific segment or functional group of a molecule. A chemical moiety is often recognized as a chemical substance that is embedded within or appended to a molecule. "Tautomers" are structurally distinct isomers that interconvert by tautomerization. "Tautomerization" is a form of isomerization and includes prototropic or proton shift tautomerization, which are considered a subset of acid-base chemistry. "Prototropic tautomerization" or "proton shift tautomerization" involves the migration of a proton with a change in bond order, often involving the exchange of a single bond with an adjacent double bond. When tautomerization is possible (e.g., in solution), a chemical equilibrium of tautomers can be reached. Examples of tautomerization include keto-enol tautomerization. A specific example of keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers.

[0037] "Substituted" means that the referenced group may be bonded with one or more additional groups, radicals or moieties individually and independently selected from, for example, acyl, alkyl, alkylaryl, cycloalkyl, aralkyl, aryl, carbohydrate, carbonate, heteroaryl, heterocycloalkyl, hydroxamate, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, ester, thiocarbonyl, isocyanato, thiocyanato, isothiocyanato, nitro, oxo, perhaloalkyl, perfluoroalkyl, phosphate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, and amino, including mono- and di-substituted amino groups and protected derivatives thereof. The substituents themselves may be substituted, for example, the cycloalkyl substituent itself may have a halide substituent at one or more of its ring carbons. The term "optionally substituted" means optional substitution with the specified group, radical, or moiety.

[0038] Detailed Description formulation In one embodiment, the present invention relates to pharmaceutical formulations comprising hydrocortisone, one or more hydrocortisone prodrugs, such as hydrocortisone esters, and / or any salts thereof.

[0039] Hydrocortisone is the name of the hormone cortisol when supplied as a medicine. It is used by mouth, intravenous injection, or topical application. It is used as an immunosuppressant given by injection in the treatment of severe allergic reactions such as anaphylaxis and angioedema. It can be used topically for allergic rashes, eczema, psoriasis, pruritus, and other inflammatory skin disorders.

[0040] Therapeutic hydrocortisone is a synthetic or semi-synthetic analog of the natural hydrocortisone hormone produced by the adrenal glands, with predominantly glucocorticoid and mild mineralocorticoid actions. As a glucocorticoid receptor agonist, hydrocortisone promotes protein catabolism, gluconeogenesis, capillary wall stability, renal excretion of calcium, and suppresses immune and inflammatory responses.

[0041] The empirical formula for hydrocortisone is C 21 H 30 O5. Molecular weight is 362.46 g / mol. Structural formula:

[0042] [ka]

[0043] Hydrocortisone is available as a crystalline white powder and has a bitter taste. Its melting point is 220°C. It is insoluble in water, with a reported solubility in water of approximately 0.32 mg / mL. Its reported solubility in propylene glycol is 12.7 mg / mL. The octanol / water partition coefficient value for hydrocortisone is 1.61. It is light sensitive and unstable in strong acids and alkalis.

[0044] Hydrocortisone sodium phosphate is an organic salt. Its molecular formula is C21 H 29 Na2O8P, its molecular weight is 486.4 g / mol and it has the following structure:

[0045] [ka]

[0046] Any antioxidant suitable for parenteral administration can be used in the formulations of the present invention. In some embodiments, the antioxidant is one or more of butylated hydroxytoluene (BHT), tocopherol, butylated hydroxyanisole (BHA), ascorbyl palmitate, ascorbic acid and its salts, vitamin E, niacinamide, methionine, monothioglycerol, sodium bisulfite, cysteine, sodium dithionite, gentisic acid, and / or sodium glutamate. In one embodiment, an aqueous formulation of the present disclosure comprising about 0.50%-2.5% w / v monothioglycerol is stable at room temperature or elevated temperatures for up to about 24 months. In one embodiment, an aqueous hydrocortisone formulation without an antioxidant is not stable at elevated temperatures, but only for a short period of time at room temperature. Specifically, a formulation comprising hydrocortisone sodium succinate, sodium phosphate monobasic anhydrous, and sodium phosphate dibasic dry without an antioxidant is only FDA approved for storage at room temperature for 3 days when reconstituted with sterile water.

[0047] Pharmaceutical Compositions In some embodiments, the concentration of hydrocortisone, hydrocortisone prodrug, i.e., hydrocortisone ester, or pharma- ceutically acceptable salt thereof, as described herein, is, for example, less than or not more than 100%, less than or not more than 90%, less than or not more than 80%, less than or not more than 70%, less than or not more than 60%, less than or not more than 50%, less than or not more than 40%, w / w, w / v, or v / v, of the pharmaceutical formulations described herein. , less than 30% or not more than 30%, less than 20% or not more than 20%, less than 19% or not more than 19%, less than 18% or not more than 18%, less than 17% or not more than 17%, less than 16% or not more than 16%, less than 15% or not more than 15%, less than 14% or not more than 14%, less than 13% or not more than 13%, less than 12% or not more than 12%, less than 11% or not more than 11%, less than 10% or not more than 10%, less than 9% or not more than 9%, less than 8% Less than or not exceeding 8%, Less than 7% or not exceeding 7%, Less than 6% or not exceeding 6%, Less than 5% or not exceeding 5%, Less than 4% or not exceeding 4%, Less than 3% or not exceeding 3%, Less than 2% or not exceeding 2%, Less than 1% or not exceeding 1%, Less than 0.5% or not exceeding 0.5%, Less than 0.4% or not exceeding 0.4%, Less than 0.3% or not exceeding 0.3%, Less than 0.2% or not exceeding 0.2%, Less than 0.1% or not exceeding 0.1%, Less than 0.09%, or or not exceeding 0.09%, less than 0.08% or not exceeding 0.08%, less than 0.07% or not exceeding 0.07%, less than 0.06% or not exceeding 0.06%, less than 0.05% or not exceeding 0.05%, less than 0.04% or not exceeding 0.04%, less than 0.03% or not exceeding 0.03%, less than 0.02% or not exceeding 0.02%, less than 0.01% or not exceeding 0.01%, less than 0.009% or not exceeding 0.009%, less than 0.008% or not exceeding 0.008%, 0.Less than 0.007% or not exceeding 0.007%, Less than 0.006% or not exceeding 0.006%, Less than 0.005% or not exceeding 0.005%, Less than 0.004% or not exceeding 0.004%, Less than 0.003% or not exceeding 0.003%, Less than 0.002% or not exceeding 0.002%, Less than 0.001% or not exceeding 0.001%, Less than 0.0009% or not exceeding 0.0009%, Less than 0.0008% , or not exceeding 0.0008%, less than 0.0007% or not exceeding 0.0007%, less than 0.0006% or not exceeding 0.0006%, less than 0.0005% or not exceeding 0.0005%, less than 0.0004% or not exceeding 0.0004%, less than 0.0003% or not exceeding 0.0003%, less than 0.0002% or not exceeding 0.0002%, or less than 0.0001% or not exceeding 0.0001%.

[0048] In some embodiments, the concentration of hydrocortisone, hydrocortisone prodrug, i.e., hydrocortisone ester, or pharma- ceutically acceptable salt thereof, as described herein, is greater than 90%, greater than 80%, greater than 70%, greater than 60%, greater than 50%, greater than 40%, greater than 30%, greater than 20%, greater than 19.75%, greater than 19.50%, greater than 19.25%, greater than 19%, greater than 18.75%, greater than 18.50%, greater than 18.25%, greater than 18%, greater than 17.75%, greater than 17.50%, greater than 17.25%, greater than 17%, greater than 16.75%, greater than 16.50%, greater than 16.25%, greater than 16%, greater than 15.75%, greater than 15.50%, greater than 15.25%, w / w, w / v, or v / v, of the pharmaceutical formulations described herein. More than 15%, more than 14.75%, more than 14.50%, more than 14.25% More than 14%, more than 13.75%, more than 13.50%, more than 13.25% More than 13%, more than 12.75%, more than 12.50%, more than 12.25% More than 12%, more than 11.75%, more than 11.50%, more than 11.25% More than 11%, more than 10.75%, more than 10.50%, more than 10.25% More than 10%, more than 9.75%, more than 9.50%, more than 9.25% More than 9%, more than 8.75%, more than 8.50%, more than 8.25% More than 8%, more than 7.75%, more than 7.50%, more than 7.25% Over 7%, over 6.75%, over 6.50%, over 6.25% Over 6%, over 5.75%, over 5.50%, over 5.25% More than 5%, more than 4.75%, more than 4.50%, more than 4.25%, more than 4%, more than 3.75%, more than 3.50%, more than 3.25%, more than 3%, more than 2.75%, more than 2.50%, more than 2.25%, more than 2%, more than 1.75%, 1. More than 50%, more than 125%, more than 1%, more than 0.5%, more than 0.4%, more than 0.3%, more than 0.2%, more than 0.1%, more than 0.09%, more than 0.08%, more than 0.07%, more than 0.06%, more than 0.05%, more than 0.04%, 0. greater than 0.03%, greater than 0.02%, greater than 0.01%, greater than 0.009%, greater than 0.008%, greater than 0.007%, greater than 0.006%, greater than 0.005%, greater than 0.004%, greater than 0.003%, greater than 0.002%, greater than 0.001%, greater than 0.0009%, greater than 0.0008%, greater than 0.0007%, greater than 0.0006%, greater than 0.0005%, greater than 0.0004%, greater than 0.0003%, greater than 0.0002%, or greater than 0.0001%.

[0049] In some embodiments, the concentration of hydrocortisone, hydrocortisone prodrug, i.e., hydrocortisone ester, or a pharma- ceutically acceptable salt thereof, w / w, w / v, or v / v, of the pharmaceutical formulations described herein is from about 0.0001% to about 50%, from about 0.001% to about 40%, from about 0.01% to about 30%, from about 0.02% to about 29%, from about 0.03% to about 28%, from about 0.04% to about 27%, , about 0.05% to about 26%, about 0.06% to about 25%, about 0.07% to about 24%, about 0.08% to about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12%, or about 1% to about 10%.

[0050] In some embodiments, the concentration of hydrocortisone, hydrocortisone prodrug, i.e., hydrocortisone ester, or a pharma- ceutically acceptable salt thereof, w / w, w / v, or v / v, of the pharmaceutical formulations described herein is within the range of about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, or about 0.1% to about 0.9%.

[0051] In some embodiments, the amount of each of the active pharmaceutical ingredient and / or inactive pharmaceutical ingredient, e.g., hydrocortisone, hydrocortisone prodrug, i.e., hydrocortisone ester, or pharma- ceutically acceptable salts thereof, and / or antioxidants provided in the pharmaceutical compositions of the present invention is less than or equal to 10 g, or not more than 10 g, less than or equal to 9.5 g, or not more than 9.5 g, less than or equal to 9.0 g, less than or equal to 8.5 g, or not more than 8.5 g, in the pharmaceutical formulations described herein. not exceeding, equal to or less than 8.0g, equal to or less than 7.5g, equal to or less than 7.5g, equal to or less than 7.0g, equal to or less than 6.5g, equal to or less than 6.0g, equal to or less than 5.5g, equal to or less than 5.0g, equal to or less than 5.0g, equal to or less than 4.5g, equal to or less than 4.0g, not more than 0g, equal to or less than 3.5g, equal to or less than 3.5g, equal to or less than 3.0g, equal to or less than 2.5g, equal to or less than 2.0g, equal to or less than 1.5g, equal to or less than 1.0g, equal to or less than 0.95g, equal to or less than 0.95g, equal to or less than 0.9g, equal to or less than 0.85g, or not exceeding 0.85g, equal to or less than 0.8g or not exceeding 0.8g, equal to or less than 0.75g or not exceeding 0.75g, equal to or less than 0.7g or not exceeding 0.7g, equal to or less than 0.65g or not exceeding 0.65g, equal to or less than 0.6g or not exceeding 0.6g, equal to or less than 0.55g or not exceeding 0.55g, equal to or less than 0.5g or not exceeding 0.5g, equal to or less than 0.45g or not exceeding 0.less than or equal to 4g, or not more than 0.4g, less than or equal to 0.35g, less than or equal to 0.35g, less than or equal to 0.3g, less than or equal to 0.25g, less than or equal to 0.25g, less than or equal to 0.2g, less than or equal to 0.15g, less than or equal to 0.1g, less than or equal to 0.09g, less than or equal to 0.08g, Not more than 0.08g, equal to or less than 0.07g or not more than 0.07g, equal to or less than 0.06g or not more than 0.06g, equal to or less than 0.05g or not more than 0.05g, equal to or less than 0.04g or not more than 0.04g, equal to or less than 0.03g or not more than 0.03g, equal to or less than 0.02g or not more than 0.02g, equal to or less than 0.01g or not more than 0.01g, equal to or less than 0.009g or not more than 0.009g , equal to or less than 0.008g or not exceeding 0.008g, equal to or less than 0.007g or not exceeding 0.007g, equal to or less than 0.006g or not exceeding 0.006g, equal to or less than 0.005g or not exceeding 0.005g, equal to or less than 0.004g or not exceeding 0.004g, equal to or less than 0.003g or not exceeding 0.003g, equal to or less than 0.002g or not exceeding 0.002g, equal to or less than 0.001g or 0. Not more than 0.001g, not more than or equal to 0.0009g, not more than 0.0009g, not more than 0.0008g, not more than 0.0008g, not more than 0.0007g, not more than 0.0007g, not more than 0.0006g, not more than 0.0006g, not more than 0.0005g, not more than 0.0005g, not more than 0.0004g, not more than 0.0004g, not more than 0.0003g, not more than 0.Less than or equal to 0002g, but not more than 0.0002g, or less than or equal to 0.0001g, but not more than 0.0001g.

[0052] In some embodiments, the amount of each of the active pharmaceutical ingredient and / or inactive pharmaceutical ingredient, e.g., hydrocortisone, hydrocortisone prodrug, i.e., hydrocortisone ester, or pharma- ceutically acceptable salts thereof, and / or antioxidants provided in the pharmaceutical compositions of the present invention is greater than 0.0001 g, greater than 0.0002 g, greater than 0.0003 g, greater than 0.0004 g, greater than 0. More than 0005g, more than 0.0006g, more than 0.0007g, more than 0.0008g, more than 0.0009g, more than 0.001g, more than 0.0015g, more than 0.002g, more than 0.0025g, more than 0.003g, 0.0035 More than g, more than 0.004g, more than 0.0045g, more than 0.005g, more than 0.0055g, more than 0.006g, more than 0.0065g, more than 0.007g, more than 0.0075g, more than 0.008g, more than 0.0085g, 0.0 More than 0.09g, more than 0.0095g, more than 0.01g, more than 0.015g, more than 0.02g, more than 0.025g, more than 0.03g, more than 0.035g, more than 0.04g, more than 0.045g, more than 0.05g, more than 0.055g, 0. More than 0.06g, More than 0.065g, More than 0.07g, More than 0.075g, More than 0.08g, More than 0.085g, More than 0.09g, More than 0.095g, More than 0.1g, More than 0.15g, More than 0.2g, More than 0.25g, More than 0.3g, 0 More than .35g, more than 0.4g, more than 0.45g, more than 0.5g, more than 0.55g, more than 0.6g, more than 0.65g, more than 0.7g, more than 0.75g, more than 0.8g, more than 0.85g, more than 0.9g, more than 0.95g, more than 1g, 1.5 More than g, more than 2g, more than 2.5, more than 3g, more than 3.5, more than 4g, more than 4.5g, more than 5g, more than 5.5g, more than 6g, more than 6.5g, more than 7g, more than 7.5g, more than 8g, more than 8.5g, more than 9g, more than 9.5g, or more than 10g.

[0053] Each of the active pharmaceutical ingredients according to the present invention is effective over a wide dosage range. For example, in the treatment of adult humans, dosages independently range from 0.01 to 1000 mg, 0.5 to 100 mg, 1 to 50 mg per day, and 5 to 40 mg per day are examples of dosages that may be used. Effective dosages of 50 to 200 mg per week are also examples of dosages that may be used. In one embodiment, an effective weekly dosage is about 50 mg. In one embodiment, an effective weekly dosage is about 100 mg. In one embodiment, an effective weekly dosage is about 150 mg. In one embodiment, an effective weekly dosage is about 200 mg. In one embodiment, an effective weekly dosage is about 250 mg.

[0054] The exact dosage will depend on the route of administration, the form in which the compound is administered, the sex and age of the subject being treated, the weight of the subject being treated, and the preference and experience of the attending physician. Clinically established dosages of hydrocortisone, hydrocortisone prodrugs, i.e., hydrocortisone esters, or pharma- ceutically acceptable salts thereof, such as hydrocortisone phosphate, may also be used as appropriate.

[0055] In some embodiments, the concentration of hydrocortisone sodium phosphate ranges from 50 mg / mL to 200 mg / mL. In some embodiments, the concentration of BHT ranges from 0.01% to 0.1%. In some embodiments, the concentration of monothioglycerol ranges from 0.1 mg / mL to 10 mg / mL.

[0056] Injectable pharmaceutical composition In some embodiments, a pharmaceutical composition for injection is provided that contains an active pharmaceutical ingredient or a combination of active pharmaceutical ingredients, such as, for example, a hydrocortisone ester, e.g., hydrocortisone sodium phosphate, and a pharmaceutical excipient suitable for injection.

[0057] Forms in which the compositions of the present invention can be incorporated for administration by injection include aqueous or oily suspensions or emulsions, including sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles.

[0058] Aqueous solutions in physiological saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol, and liquid polyethylene glycol (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be used. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin to maintain the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be brought about by various antibacterial and antifungal preservatives or preservatives, such as parabens, chlorobutanol, phenol, sorbic acid, and thimerosal.

[0059] Sterile injectables are prepared by incorporating the pharmaceutical active ingredient or combination of pharmaceutical active ingredients in the required amount in a suitable solvent with various other ingredients as listed above, as necessary, followed by filtration sterilization.Generally, dispersions are prepared by incorporating various sterilized active ingredients into a sterile vehicle that contains a basic dispersion medium and other ingredients as listed above.In the case of sterile powders for preparing sterile injectables, a specific desired preparation method is vacuum drying and freeze-drying technology, which obtains powders of active ingredients plus any additional desired ingredients from the solution that has been previously sterilized.

[0060] Administration of the active pharmaceutical ingredient or combination of active pharmaceutical ingredients or pharmaceutical compositions thereof may be accomplished by any method that allows delivery of the compound to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intradermal, intravascular, intraperitoneal, or infusion), topically (e.g., transdermal administration), rectal administration, local delivery by catheter or stent, or via inhalation. The active pharmaceutical ingredient or combination of active pharmaceutical ingredients may also be administered intraadiposally or intrathecally. In one embodiment, the hydrocortisone sodium phosphate formulations described herein may be administered by an emergency / rescue autoinjector device.

[0061] The pharmaceutical formulations described herein may be injected using an injector. The formulations may be injected subcutaneously or intramuscularly. In some embodiments, the injector is a single-use device that is disposed of or reused after a single dose is administered. In other embodiments, the injector is a multi-dose injector. Some injectors contemplated for use with the formulations described herein are disclosed in U.S. Patent Nos. 8,021,335, 8,814,834, 8,945,063, and 10,300,207, all of which are incorporated herein by reference.

[0062] 5-11, an injector, generally designated 30, is shown in accordance with an exemplary embodiment of the present invention. The injector 30 may be an autoinjector. The injector 30 may include a housing 32. An end cap 34 may be coupled to the housing 30. The injector 30 may include a needle 74 fluidly coupled to a formulation container 72 (e.g., a syringe). A plunger 70 may be movable relative to the formulation container 72 to force the formulation out of the needle 74 during injection. A ram 58 may be operatively associated with the plunger 70 such that axial movement of the ram 58 causes movement of the plunger 70. An energy source 66 (e.g., a biasing element, a spring) may move the plunger 70 when the injector 30 is triggered.

[0063] The needle guard 78 may be movably coupled to the housing 32. The needle guard 78 is movable between an extended position (FIG. 7) and a retracted position (FIG. 8). The needle guard 78 may be movable when a distal end of the needle guard 78 is pressed against an injection site. Movement of the needle guard 78 relative to the housing 32 may trigger the injector 30 to begin an injection sequence.

[0064] The formulation container 72 may be movable relative to the housing 32 between a storage position ( FIG. 7 ) and an injection position ( FIG. 9 ). The formulation container 72 may be moved to the injection position after the needle guard 78 triggers the injector 30. A second energy source 56 (e.g., a biasing element or spring) may move the formulation container 72 from the storage position to the injection position. Once the formulation container 72 is in the injection position, the energy source 66 may move the ram 58 to dispense the formulation through the needle 74. Once the formulation has been dispensed, the needle guard 78 may return to the extended position ( FIG. 11 ).

[0065] kit The present invention also provides kits. The kits include the active pharmaceutical ingredient or combination of active pharmaceutical ingredients, either alone or in combination, in suitable packaging and include documentation that may include instructions for use, clinical trial descriptions, and a list of side effects. Such kits may also include information such as scientific literature references, package insert information, clinical trial results, and / or summaries of these and the like, that show or establish the activity and / or benefits of the composition and / or describe dosing, administration, side effects, drug interactions, or other information useful to the medical practitioner. Such information may be based on the results of various studies, for example, studies using laboratory animals, including in vivo models, and studies based on human clinical trials. The kits may further contain another active pharmaceutical ingredient. In selected embodiments, the active pharmaceutical ingredient or combination of active pharmaceutical ingredients is provided as a separate composition in a separate container within the kit. In selected embodiments, the active pharmaceutical ingredient or combination of active pharmaceutical ingredients is provided as a single composition in a container within the kit. Suitable packaging and additional items for use (e.g., measuring cups for liquid preparations, foil packaging to minimize exposure to air, etc.) are known in the art and can be included in the kit.

[0066] The kits described herein may be provided, marketed and / or promoted to healthcare professionals, including physicians, nurses, pharmacists, formulary personnel, etc. The kits may also, in selected embodiments, be sold directly to consumers.

[0067] In some embodiments, the present invention provides kits that include compositions that include a therapeutically effective amount of an active pharmaceutical ingredient (e.g., hydrocortisone sodium phosphate) or a combination of active pharmaceutical ingredients, or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. These compositions are typically pharmaceutical compositions. The kits are for simultaneous or separate co-administration of the active pharmaceutical ingredients or combination of active pharmaceutical ingredients.

[0068] In some embodiments, the present invention provides a kit comprising a composition comprising a therapeutically effective amount of hydrocortisone sodium phosphate alone or in combination with an active pharmaceutical ingredient, or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug in a pre-filled syringe (PFS) or vial in oil and in combination with an antioxidant.In some embodiments, the pre-filled syringe or vial is transparent.

[0069] The kit includes suitable packaging to protect the prefilled syringe or vial from light. In some embodiments, it includes an autoinjector. In other embodiments, it includes an autoinjector with a viewing window that allows for inspection of the drug prior to injection. In yet other embodiments, the autoinjector is in a carton to prevent light access to the drug.

[0070] Prefilled syringe or vial can contain one dose or multiple doses.In some embodiments, the prefilled syringe or vial that contains multiple doses is larger, i.e. has a larger volume than the prefilled syringe or vial that contains only one dose.In some embodiments, the surface area to volume ratio of prefilled syringe or vial is smaller as the prefilled syringe or vial is larger in volume.

[0071] Such kits may include information such as scientific literature references, package insert information, clinical trial results, and / or summaries of these and the like that indicate or establish the activity and / or benefits of the composition and / or describe dosing, administration, side effects, drug interactions, or other information useful to healthcare professionals and / or patients. Such information may instruct the user to store the prefilled syringe or the prefilled syringe and autoinjector in the carton to protect the pharmaceutical ingredients from light.

[0072] In some embodiments, the invention provides kits comprising: (1) a composition comprising a therapeutically effective amount of an active pharmaceutical ingredient (e.g., hydrocortisone sodium phosphate), or a combination of active pharmaceutical ingredients, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof; and (2) a diagnostic test for determining whether a patient requires administration of hydrocortisone sodium phosphate. Dosage and Administration Regimen The amount of pharmaceutical composition administered using the methods herein, such as the dosage of hydrocortisone sodium phosphate, depends on the subject, e.g., human or mammal, being treated, the severity of the disorder or condition, the rate of administration, the quality of the active pharmaceutical ingredient, and the discretion of the prescribing physician. Dosages in the range of 50-100 mg per week for administration to humans may be sufficient to achieve effective therapeutic levels. Sometimes, dosages of 50-100 mg per week may be required for several weeks to achieve the desired therapeutic level. However, effective dosages range from about 0.001 to about 100 mg per kg of body weight per day, e.g., from about 1 to about 35 mg / kg / day, in single or divided doses. For a 70 kg human, this would be about 0.05 to 7 g / day, e.g., from about 0.05 to about 2.5 g / day. In some cases, dosage levels below the lower limit of the aforementioned range may be more than sufficient, while in other cases even larger doses may be employed without causing adverse side effects, for example, by dividing such larger doses into several smaller doses to be administered throughout the day. Dosages of pharmaceutical compositions and active pharmaceutical ingredients are given in mg per kg body weight or m2 of body surface area. 2 The dosage may be provided in mg per serving.

[0073] In some embodiments, the pharmaceutical composition or active pharmaceutical ingredient is administered in multiple doses. In one embodiment, the pharmaceutical composition is administered in multiple doses. Administration may be once, twice, three times, four times, five times, six times, or more than six times per day. Administration may be monthly, biweekly, weekly, or every other day. In other embodiments, the pharmaceutical composition is administered from about once to about six times per day. In some embodiments, the pharmaceutical composition is administered once per day, while in other embodiments, the pharmaceutical composition is administered twice per day, and in other embodiments, the pharmaceutical composition is administered three times per day.

[0074] Administration of the active pharmaceutical ingredient can continue for as long as necessary. In selected embodiments, the pharmaceutical composition is administered for more than 1 day, more than 2 days, more than 3 days, more than 4 days, more than 5 days, more than 6 days, more than 7 days, more than 14 days, or more than 28 days. Other embodiments require that the pharmaceutical composition be administered for more than 1 week, more than 2 weeks, more than 3 weeks, more than 4 weeks, more than 5 weeks, more than 6 weeks, more than 7 weeks, more than 14 weeks, or more than 28 weeks. In some embodiments, the pharmaceutical composition is administered for less than or not more than 28 days, less than or not more than 14 days, less than or not more than 7 days, less than or not more than 6 days, less than or not more than 5 days, less than or not more than 4 days, less than or not more than 3 days, less than or not more than 2 days, or less than or not more than 1 day. In some embodiments, the pharmaceutical composition is administered chronically on an ongoing basis, for example, for the treatment of chronic effects. In some embodiments, administration of the pharmaceutical composition continues for less than about 7 days, or for no more than about 7 days. In yet other embodiments, administration continues for more than about 6, 10, 14, 28 days, 2 months, 6 months, or 1 year. In some cases, continuous administration is achieved and maintained for as long as necessary.

[0075] In some embodiments, an effective dose of an active pharmaceutical ingredient disclosed herein is from about 1 mg to about 500 mg, from about 10 mg to about 300 mg, from about 20 mg to about 250 mg, from about 25 mg to about 200 mg, from about 50 mg to about 200 mg, from about 10 mg to about 200 mg, from about 20 mg to about 150 mg, from about 30 mg to about 120 mg, from about 10 mg to about 90 mg, from about 20 mg to about 80 mg, from about 30 mg to about 70 mg, from about 40 mg to about 60 mg, from about 45 mg to about 55 mg, from about 50 mg to about 60 mg, from about 50 mg to about 70 mg, from about 60 mg to about 80 mg, from about 70 mg to about 90 mg, from about 80 mg to about 100 mg, from about 90 mg to about 100 mg, from about 100 mg to about 120 mg, from about 10 mg to about 150 mg, from about 150 mg to about 200 mg, from about 150 mg to about 30 mg, from about 150 mg to about 40 mg, from about 150 mg to about 50 mg, from about 150 mg to about 60 mg, from about 150 mg to about 120 mg, from about 150 mg to about 200 mg, from about 150 mg to about 30 mg, from about 150 mg to about 40 mg, from about 150 mg to about 50 mg, from about 150 mg to about 50 mg, from about 150 mg to about 60 mg, from about 150 mg to about 120 mg, from about 150 mg to about 200 mg, from about 150 mg to about g to about 100 mg, about 48 mg to about 52 mg, about 50 mg to about 150 mg, about 60 mg to about 140 mg, about 70 mg to about 130 mg, about 80 mg to about 120 mg, about 90 mg to about 110 mg, about 95 mg to about 105 mg, about 150 mg to about 250 mg, about 160 mg to about 240 mg, about 170 mg to about 230 mg, about 180 mg to about 220 mg, about 190 mg to about 210 mg, about 195 mg to about 205 mg, or about 198 mg to about 202 mg. In some embodiments, the effective dosage of an active pharmaceutical ingredient disclosed herein is less than about or not more than about 25 mg, or less than or not more than about 50 mg, less than or not more than about 75 mg, less than or not more than about 100 mg, less than or not more than about 125 mg, less than or not more than about 150 mg, less than or not more than about 175 mg, less than or not more than about 200 mg, less than or not more than about 225 mg, or less than or not more than about 250 mg. In some embodiments, the effective dosage of an active pharmaceutical ingredient disclosed herein is greater than about 25 mg, greater than about 50 mg, greater than about 75 mg, greater than about 100 mg, greater than about 125 mg, greater than about 150 mg, greater than about 175 mg, greater than about 200 mg, greater than about 225 mg, or greater than about 250 mg.

[0076] In some embodiments, an effective dosage of an active pharmaceutical ingredient disclosed herein is in the range of about 0.01 mg / kg to about 200 mg / kg, or about 0.1 to 100 mg / kg, or about 1 to 50 mg / kg. In some embodiments, the active pharmaceutical ingredient is administered at a dosage of 10 to 200 mg BID, including 50, 60, 70, 80, 90, 100, 150, or 200 mg BID. In some embodiments, the active pharmaceutical ingredient is administered at a dosage of 10 to 500 mg BID, including 1, 5, 10, 15, 25, 50, 75, 100, 150, 200, 300, 400, or 500 mg BID.

[0077] In some cases, dosage levels below the lower limit of the aforementioned range may be more than sufficient, while in other cases, even larger doses may be employed without causing adverse side effects, for example, by dividing such larger doses into several smaller doses for administration throughout the day.As will be understood by those skilled in the art, the actual dosage administered will depend on the condition being treated, the age, health and weight of the recipient, the type of concurrent treatment, if any, and the frequency of treatment.Furthermore, the effective dosage may be determined by those skilled in the art based on routine empirical activity testing to measure the biological activity of the compound in bioassays, and thus the appropriate dosage to be administered may be established.

[0078] An effective amount of the combination of active pharmaceutical ingredients may be administered by any of the acceptable modes of administration for drugs having similar utilities, including rectal, buccal, intranasal, transdermal routes, by intraarterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, intradermally, orally, topically, or as an inhalant, either in single or multiple doses.

[0079] In some embodiments, the compositions described herein further comprise controlled, sustained, or extended release therapeutic dosage forms for administration of the compounds described herein, which include incorporating the compounds into a suitable delivery system in the formation of a particular composition. The dosage forms control the release of the compound so that an effective concentration of the compound in the bloodstream is maintained over an extended period of time, and the concentration in the blood remains relatively constant, improving therapeutic outcomes and / or minimizing side effects. Additionally, the controlled release system provides minimal peak-to-trough fluctuations in the plasma levels of the compound.

[0080] The following clauses describe specific embodiments. Clause 1. A pharmaceutical formulation comprising hydrocortisone, a hydrocortisone prodrug, and / or a pharma- ceutically acceptable salt of any one thereof, and one or more inactive ingredients.

[0081] Clause 2. The pharmaceutical formulation of clause 1, wherein the hydrocortisone prodrug is a hydrocortisone ester. Clause 3. The pharmaceutical formulation of clause 1 or 2, wherein the hydrocortisone prodrug or a pharma- ceutically acceptable salt thereof is selected from hydrocortisone sodium phosphate, hydrocortisone sodium succinate, hydrocortisone hydrogen succinate, hydrocortisone butyrate, hydrocortisone acetate.

[0082] Clause 4. The pharmaceutical formulation of clause 1 or 2, wherein the hydrocortisone prodrug or a pharma- ceutically acceptable salt thereof is hydrocortisone sodium phosphate. Clause 5. The pharmaceutical formulation of clause 4, wherein the concentration of hydrocortisone sodium phosphate in the pharmaceutical formulation is between about 5 mg / mL and about 100 mg / mL.

[0083] Clause 6. The pharmaceutical formulation of clause 4, wherein the concentration of hydrocortisone sodium phosphate in the pharmaceutical formulation is between about 50 mg / mL and about 100 mg / mL. Clause 7. The pharmaceutical formulation of clause 4, wherein the concentration of hydrocortisone sodium phosphate in the pharmaceutical formulation is between about 25 mg / mL and about 75 mg / mL.

[0084] Clause 8. The pharmaceutical formulation of clause 4, wherein the concentration of hydrocortisone sodium phosphate in the pharmaceutical formulation is about 50 mg / mL, about 51 mg / mL, about 52 mg / mL, about 53 mg / mL, about 54 mg / mL, about 55 mg / mL, about 56 mg / mL, about 57 mg / mL, about 58 mg / mL, about 59 mg / mL, about 60 mg / mL, about 61 mg / mL, about 62 mg / mL, about 63 mg / mL, about 64 mg / mL, about 65 mg / mL, about 66 mg / mL, about 67 mg / mL, about 68 mg / mL, about 69 mg / mL, or about 70 mg / mL.

[0085] Clause 9. The pharmaceutical formulation of any one of clauses 1 to 8, wherein the one or more inactive ingredients are selected from buffers, chelating agents, antioxidants, pH adjusters, and solvents. Clause 10. The pharmaceutical formulation of clause 9, wherein the buffering agent is selected from sodium phosphate monobasic anhydrous and sodium phosphate dibasic anhydrous.

[0086] Clause 11. The pharmaceutical formulation of clause 9, wherein the chelating agent is disodium EDTA. Clause 12. The pharmaceutical formulation of clause 9, wherein the antioxidant is monothioglycerol. Clause 13. The pharmaceutical formulation according to clause 9, wherein the pH adjuster is selected from sodium hydroxide and HCl.

[0087] Clause 14. The pharmaceutical formulation according to clause 9, wherein the solvent is water. Clause 101. An aqueous pharmaceutical formulation comprising about 50 to about 150 mg / mL of hydrocortisone sodium phosphate, about 2.5 to about 12.5 mg / mL of monothioglycerol, and water.

[0088] Clause 102. An aqueous pharmaceutical formulation comprising about 60 to about 135 mg / mL of hydrocortisone sodium phosphate, about 5 to about 10 mg / mL of monothioglycerol, and water. Clause 201. The liquid pharmaceutical formulation according to clause 101 or 102, comprising about 50 to about 60 mg / mL of hydrocortisone sodium phosphate, about 60 to about 70 mg / mL of hydrocortisone sodium phosphate, or about 70 to about 80 mg / mL of hydrocortisone sodium phosphate.

[0089] Clause 301. The liquid pharmaceutical formulation according to clause 101 or 102, comprising about 60 to about 65 mg / mL of hydrocortisone sodium phosphate, or about 65 to about 70 mg / mL of hydrocortisone sodium phosphate.

[0090] Clause 401. The aqueous pharmaceutical formulation according to clause 101 or 102, comprising about 120 to about 130 mg / mL of hydrocortisone sodium phosphate, about 130 to about 140 mg / mL of hydrocortisone sodium phosphate, or about 140 to about 150 mg / mL of hydrocortisone sodium phosphate.

[0091] Clause 501. The liquid pharmaceutical formulation according to clause 101 or 102, comprising about 130 to about 135 mg / mL of hydrocortisone sodium phosphate, or about 135 to about 140 mg / mL of hydrocortisone sodium phosphate.

[0092] Article 601. About 50 mg / mL hydrocortisone sodium phosphate, about 55 mg / mL hydrocortisone sodium phosphate, about 60 mg / mL hydrocortisone sodium phosphate, about 65 mg / mL hydrocortisone sodium phosphate, about 70 mg / mL hydrocortisone sodium phosphate, about 75 mg / mL hydrocortisone sodium phosphate, about 80 mg / mL hydrocortisone sodium phosphate, about 85 mg / mL hydrocortisone sodium phosphate, about 90 mg / mL hydrocortisone sodium phosphate, about 95 mg / mL hydrocortisone sodium phosphate, about 100 mg / mL hydrocortisone sodium phosphate, about 103. The aqueous pharmaceutical formulation of clause 101 or 102, comprising 105 mg / mL hydrocortisone sodium phosphate, about 110 mg / mL hydrocortisone sodium phosphate, about 115 mg / mL hydrocortisone sodium phosphate, about 120 mg / mL hydrocortisone sodium phosphate, about 125 mg / mL hydrocortisone sodium phosphate, about 130 mg / mL hydrocortisone sodium phosphate, about 135 mg / mL hydrocortisone sodium phosphate, about 140 mg / mL hydrocortisone sodium phosphate, about 145 mg / mL hydrocortisone sodium phosphate, or about 150 mg / mL hydrocortisone sodium phosphate.

[0093] Article 701. An aqueous pharmaceutical formulation comprising about 60 mg / mL of hydrocortisone sodium phosphate, about 2.5 to about 12.5 mg / mL of monothioglycerol, and water. Article 702. An aqueous pharmaceutical formulation comprising about 61 mg / mL of hydrocortisone sodium phosphate, about 2.5 to about 12.5 mg / mL of monothioglycerol, and water.

[0094] Article 703. An aqueous pharmaceutical formulation comprising about 62 mg / mL of hydrocortisone sodium phosphate, about 2.5 to about 12.5 mg / mL of monothioglycerol, and water. Article 704. An aqueous pharmaceutical formulation comprising about 63 mg / mL of hydrocortisone sodium phosphate, about 2.5 to about 12.5 mg / mL of monothioglycerol, and water.

[0095] Article 705. An aqueous pharmaceutical formulation comprising about 64 mg / mL of hydrocortisone sodium phosphate, about 2.5 to about 12.5 mg / mL of monothioglycerol, and water. Article 706. An aqueous pharmaceutical formulation comprising about 65 mg / mL of hydrocortisone sodium phosphate, about 2.5 to about 12.5 mg / mL of monothioglycerol, and water.

[0096] Article 707. An aqueous pharmaceutical formulation comprising about 66 mg / mL of hydrocortisone sodium phosphate, about 2.5 to about 12.5 mg / mL of monothioglycerol, and water. Article 708. An aqueous pharmaceutical formulation comprising about 67 mg / mL of hydrocortisone sodium phosphate, about 2.5 to about 12.5 mg / mL of monothioglycerol, and water.

[0097] Article 709. An aqueous pharmaceutical formulation comprising about 68 mg / mL of hydrocortisone sodium phosphate, about 2.5 to about 12.5 mg / mL of monothioglycerol, and water. Article 710. An aqueous pharmaceutical formulation comprising about 69 mg / mL of hydrocortisone sodium phosphate, about 2.5 to about 12.5 mg / mL of monothioglycerol, and water.

[0098] Clause 711. An aqueous pharmaceutical formulation comprising about 70 mg / mL of hydrocortisone sodium phosphate, about 2.5 to about 12.5 mg / mL of monothioglycerol, and water. Clause 801. An aqueous pharmaceutical formulation comprising about 67 mg / mL of hydrocortisone sodium phosphate, about 2.5 to about 12.5 mg / mL of monothioglycerol, and water.

[0099] Clause 802. An aqueous pharmaceutical formulation comprising about 67.1 mg / mL of hydrocortisone sodium phosphate, about 2.5 to about 12.5 mg / mL of monothioglycerol, and water. Clause 803. An aqueous pharmaceutical formulation comprising about 67.2 mg / mL of hydrocortisone sodium phosphate, about 2.5 to about 12.5 mg / mL of monothioglycerol, and water.

[0100] Clause 804. An aqueous pharmaceutical formulation comprising about 67.3 mg / mL of hydrocortisone sodium phosphate, about 2.5 to about 12.5 mg / mL of monothioglycerol, and water. Clause 805. An aqueous pharmaceutical formulation comprising about 67.4 mg / mL of hydrocortisone sodium phosphate, about 2.5 to about 12.5 mg / mL of monothioglycerol, and water.

[0101] Clause 806. An aqueous pharmaceutical formulation comprising about 67.5 mg / mL of hydrocortisone sodium phosphate, about 2.5 to about 12.5 mg / mL of monothioglycerol, and water. Clause 807. An aqueous pharmaceutical formulation comprising about 67.6 mg / mL of hydrocortisone sodium phosphate, about 2.5 to about 12.5 mg / mL of monothioglycerol, and water.

[0102] Clause 808. An aqueous pharmaceutical formulation comprising about 67.7 mg / mL of hydrocortisone sodium phosphate, about 2.5 to about 12.5 mg / mL of monothioglycerol, and water. Article 809. An aqueous pharmaceutical formulation comprising about 67.8 mg / mL of hydrocortisone sodium phosphate, about 2.5 to about 12.5 mg / mL of monothioglycerol, and water.

[0103] Clause 810. An aqueous pharmaceutical formulation comprising about 67.9 mg / mL of hydrocortisone sodium phosphate, about 2.5 to about 12.5 mg / mL of monothioglycerol, and water. Clause 811. An aqueous pharmaceutical formulation comprising about 68 mg / mL of hydrocortisone sodium phosphate, about 2.5 to about 12.5 mg / mL of monothioglycerol, and water.

[0104] Article 901. An aqueous pharmaceutical formulation comprising about 130 mg / mL of hydrocortisone sodium phosphate, about 2.5 to about 12.5 mg / mL of monothioglycerol, and water. Article 902. An aqueous pharmaceutical formulation comprising about 131 mg / mL of hydrocortisone sodium phosphate, about 2.5 to about 12.5 mg / mL of monothioglycerol, and water.

[0105] Article 903. An aqueous pharmaceutical formulation comprising about 132 mg / mL of hydrocortisone sodium phosphate, about 2.5 to about 12.5 mg / mL of monothioglycerol, and water. Article 904. An aqueous pharmaceutical formulation comprising about 133 mg / mL of hydrocortisone sodium phosphate, about 2.5 to about 12.5 mg / mL of monothioglycerol, and water.

[0106] Article 905. An aqueous pharmaceutical formulation comprising about 134 mg / mL of hydrocortisone sodium phosphate, about 2.5 to about 12.5 mg / mL of monothioglycerol, and water. Article 906. An aqueous pharmaceutical formulation comprising about 135 mg / mL of hydrocortisone sodium phosphate, about 2.5 to about 12.5 mg / mL of monothioglycerol, and water.

[0107] Article 907. An aqueous pharmaceutical formulation comprising about 136 mg / mL of hydrocortisone sodium phosphate, about 2.5 to about 12.5 mg / mL of monothioglycerol, and water. Article 908. An aqueous pharmaceutical formulation comprising about 137 mg / mL of hydrocortisone sodium phosphate, about 2.5 to about 12.5 mg / mL of monothioglycerol, and water.

[0108] Article 909. An aqueous pharmaceutical formulation comprising about 138 mg / mL of hydrocortisone sodium phosphate, about 2.5 to about 12.5 mg / mL of monothioglycerol, and water. Article 910. An aqueous pharmaceutical formulation comprising about 139 mg / mL of hydrocortisone sodium phosphate, about 2.5 to about 12.5 mg / mL of monothioglycerol, and water.

[0109] Article 911. An aqueous pharmaceutical formulation comprising about 140 mg / mL of hydrocortisone sodium phosphate, about 2.5 to about 12.5 mg / mL of monothioglycerol, and water. Clause 1001. An aqueous pharmaceutical formulation comprising about 134 mg / mL hydrocortisone sodium phosphate, about 134.1 mg / mL hydrocortisone sodium phosphate, about 134.2 mg / mL hydrocortisone sodium phosphate, about 134.3 mg / mL hydrocortisone sodium phosphate, about 134.4 mg / mL hydrocortisone sodium phosphate, about 134.5 mg / mL hydrocortisone sodium phosphate, about 134.6 mg / mL hydrocortisone sodium phosphate, about 134.7 mg / mL hydrocortisone sodium phosphate, about 134.8 mg / mL hydrocortisone sodium phosphate, about 134.9 mg / mL hydrocortisone sodium phosphate, or about 135 mg / mL hydrocortisone sodium phosphate, about 2.5 to about 12.5 mg / mL monothioglycerol, and water.

[0110] Clause 1101. The liquid pharmaceutical formulation according to any one of clauses 101 to 1001, comprising about 2.5 to about 3.5 mg / mL of monothioglycerol, about 3.5 to about 4.5 mg / mL of monothioglycerol, about 4.5 to about 5.5 mg / mL of monothioglycerol, about 5.5 to about 6.5 mg / mL of monothioglycerol, about 6.5 to about 7.5 mg / mL of monothioglycerol, about 7.5 to about 8.5 mg / mL of monothioglycerol, about 8.5 to about 9.5 mg / mL of monothioglycerol, about 9.5 to about 10.5 mg / mL of monothioglycerol, about 10.5 to about 11.5 mg / mL of monothioglycerol, or about 11.5 to about 12.5 mg / mL of monothioglycerol.

[0111] Clause 1201. The liquid medical formulation according to any one of clauses 101 to 1001, comprising about 4 to about 4.25 mg / mL of monothioglycerol, about 4.25 to about 4.5 mg / mL of monothioglycerol, about 4.5 to about 4.75 mg / mL of monothioglycerol, about 4.75 to about 5 mg / mL of monothioglycerol, about 5 to about 5.25 mg / mL of monothioglycerol, about 5.25 to about 5.5 mg / mL of monothioglycerol, about 5.5 to about 5.75 mg / mL of monothioglycerol, or about 5.75 to about 6 mg / mL of monothioglycerol.

[0112] Article 1301. The liquid pharmaceutical formulation according to any one of Articles 101 to 1001, comprising about 9 to about 9.25 mg / mL of monothioglycerol, about 9.25 to about 9.5 mg / mL of monothioglycerol, about 9.5 to about 9.75 mg / mL of monothioglycerol, about 9.75 to about 10 mg / mL of monothioglycerol, about 10 to about 10.25 mg / mL of monothioglycerol, about 10.25 to about 10.5 mg / mL of monothioglycerol, about 10.5 to about 10.75 mg / mL of monothioglycerol, or about 10.75 to about 11 mg / mL of monothioglycerol.

[0113] Clause 1401. The liquid pharmaceutical formulation according to any one of clauses 101 to 1001, comprising about 4.5 mg / mL monothioglycerol. Clause 1402. The liquid pharmaceutical formulation according to any one of clauses 101 to 1001, comprising about 4.6 mg / mL monothioglycerol.

[0114] Clause 1403. The liquid pharmaceutical formulation according to any one of clauses 101 to 1001, comprising about 4.7 mg / mL monothioglycerol. Clause 1404. The liquid pharmaceutical formulation according to any one of clauses 101 to 1001, comprising about 4.8 mg / mL monothioglycerol.

[0115] Clause 1405. The liquid pharmaceutical formulation according to any one of clauses 101 to 1001, comprising about 4.9 mg / mL monothioglycerol. Clause 1406. The liquid pharmaceutical formulation according to any one of clauses 101 to 1001, comprising about 5 mg / mL monothioglycerol.

[0116] Clause 1407. The liquid pharmaceutical formulation according to any one of clauses 101 to 1001, comprising about 5.1 mg / mL monothioglycerol. Clause 1408. The liquid pharmaceutical formulation according to any one of clauses 101 to 1001, comprising about 5.2 mg / mL monothioglycerol.

[0117] Clause 1409. The liquid pharmaceutical formulation according to any one of clauses 101 to 1001, comprising about 5.3 mg / mL monothioglycerol. Clause 1410. The liquid pharmaceutical formulation according to any one of clauses 101 to 1001, comprising about 5.4 mg / mL monothioglycerol.

[0118] Clause 1411. The liquid pharmaceutical formulation according to any one of clauses 101 to 1001, comprising about 5.5 mg / mL monothioglycerol. Clause 1501. The liquid pharmaceutical formulation according to any one of clauses 101 to 1001, comprising about 9.5 mg / mL monothioglycerol.

[0119] Clause 1502. The liquid pharmaceutical formulation according to any one of clauses 101 to 1001, comprising about 9.6 mg / mL monothioglycerol. Clause 1503. The liquid pharmaceutical formulation according to any one of clauses 101 to 1001, comprising about 9.7 mg / mL monothioglycerol.

[0120] Clause 1504. The liquid pharmaceutical formulation according to any one of clauses 101 to 1001, comprising about 9.8 mg / mL monothioglycerol. Clause 1505. The liquid pharmaceutical formulation according to any one of clauses 101 to 1001, comprising about 9.9 mg / mL monothioglycerol.

[0121] Clause 1506. The liquid pharmaceutical formulation according to any one of clauses 101 to 1001, comprising about 10 mg / mL monothioglycerol. Clause 1601. The liquid pharmaceutical formulation according to any one of clauses 101 to 1001, comprising about 10.1 mg / mL monothioglycerol.

[0122] Clause 1602. The liquid pharmaceutical formulation according to any one of clauses 101 to 1001, comprising about 10.2 mg / mL monothioglycerol. Clause 1603. The liquid pharmaceutical formulation according to any one of clauses 101 to 1001, comprising about 10.3 mg / mL of monothioglycerol.

[0123] Clause 1604. The liquid pharmaceutical formulation according to any one of clauses 101 to 1001, comprising about 10.4 mg / mL monothioglycerol. Clause 1605. The liquid pharmaceutical formulation according to any one of clauses 101 to 1001, comprising about 10.5 mg / mL monothioglycerol.

[0124] Clause 1701. The liquid pharmaceutical formulation according to any one of clauses 101 to 1606, further comprising about 0.5 to about 2.5 mg / mL of monobasic sodium phosphate. Clause 1702. The liquid pharmaceutical formulation according to any one of clauses 101 to 1606, further comprising about 0.5 mg / mL of monobasic sodium phosphate.

[0125] Clause 1703. The liquid pharmaceutical formulation according to any one of clauses 101 to 1606, further comprising about 0.6 mg / mL of monobasic sodium phosphate. Clause 1704. The liquid pharmaceutical formulation according to any one of clauses 101 to 1606, further comprising about 0.7 mg / mL of monobasic sodium phosphate.

[0126] Clause 1705. The liquid pharmaceutical formulation according to any one of clauses 101 to 1606, further comprising about 0.8 mg / mL of monobasic sodium phosphate. Clause 1706. The liquid pharmaceutical formulation according to any one of clauses 101 to 1606, further comprising about 0.9 mg / mL of monobasic sodium phosphate.

[0127] Clause 1707. The liquid pharmaceutical formulation according to any one of clauses 101 to 1606, further comprising about 1 mg / mL of monobasic sodium phosphate. Clause 1708. The liquid pharmaceutical formulation according to any one of clauses 101 to 1606, further comprising about 1.1 mg / mL of monobasic sodium phosphate.

[0128] Clause 1709. The liquid pharmaceutical formulation according to any one of clauses 101 to 1606, further comprising about 1.2 mg / mL of monobasic sodium phosphate. Clause 1710. The liquid pharmaceutical formulation according to any one of clauses 101 to 1606, further comprising about 1.3 mg / mL of monobasic sodium phosphate.

[0129] Clause 1711. The liquid pharmaceutical formulation according to any one of clauses 101 to 1606, further comprising about 1.4 mg / mL of monobasic sodium phosphate. Clause 1712. The liquid pharmaceutical formulation according to any one of clauses 101 to 1606, further comprising about 1.5 mg / mL of monobasic sodium phosphate.

[0130] Clause 1713. The liquid pharmaceutical formulation according to any one of clauses 101 to 1606, further comprising about 1.6 mg / mL of monobasic sodium phosphate. Clause 1714. The liquid pharmaceutical formulation according to any one of clauses 101 to 1606, further comprising about 1.7 mg / mL of monobasic sodium phosphate.

[0131] Clause 1715. The liquid pharmaceutical formulation according to any one of clauses 101 to 1606, further comprising about 1.8 mg / mL of monobasic sodium phosphate. Clause 1716. The liquid pharmaceutical formulation according to any one of clauses 101 to 1606, further comprising about 1.9 mg / mL of monobasic sodium phosphate.

[0132] Clause 1717. The liquid pharmaceutical formulation according to any one of clauses 101 to 1606, further comprising about 2 mg / mL of monobasic sodium phosphate. Clause 1718. The liquid pharmaceutical formulation according to any one of clauses 101 to 1606, further comprising about 2.1 mg / mL of monobasic sodium phosphate.

[0133] Clause 1719. The liquid pharmaceutical formulation according to any one of clauses 101 to 1606, further comprising about 2.2 mg / mL of monobasic sodium phosphate. Clause 1720. The liquid pharmaceutical formulation according to any one of clauses 101 to 1606, further comprising about 2.3 mg / mL of monobasic sodium phosphate.

[0134] Clause 1721. The liquid pharmaceutical formulation according to any one of clauses 101 to 1606, further comprising about 2.4 mg / mL of monobasic sodium phosphate. Clause 1722. The liquid pharmaceutical formulation according to any one of clauses 101 to 1606, further comprising about 2.5 mg / mL of monobasic sodium phosphate.

[0135] Clause 1801. The liquid pharmaceutical formulation according to any one of clauses 101 to 1722, further comprising about 5 to about 25 mg / mL of dibasic sodium phosphate. Clause 1802. The liquid pharmaceutical formulation according to any one of clauses 101 to 1722, further comprising about 5 mg / mL of dibasic sodium phosphate.

[0136] Clause 1803. The liquid pharmaceutical formulation according to any one of clauses 101 to 1722, further comprising about 6 mg / mL of dibasic sodium phosphate. Clause 1804. The liquid pharmaceutical formulation according to any one of clauses 101 to 1722, further comprising about 7 mg / mL of dibasic sodium phosphate.

[0137] Clause 1805. The liquid pharmaceutical formulation according to any one of clauses 101 to 1722, further comprising about 8 mg / mL of dibasic sodium phosphate. Clause 1806. The liquid pharmaceutical formulation according to any one of clauses 101 to 1722, further comprising about 9 mg / mL of dibasic sodium phosphate.

[0138] Clause 1807. The liquid pharmaceutical formulation according to any one of clauses 101 to 1722, further comprising about 10 mg / mL of dibasic sodium phosphate. Clause 1808. The liquid pharmaceutical formulation according to any one of clauses 101 to 1722, further comprising about 11 mg / mL of dibasic sodium phosphate.

[0139] Clause 1809. The liquid pharmaceutical formulation according to any one of clauses 101 to 1722, further comprising about 12 mg / mL of dibasic sodium phosphate. Clause 1810. The liquid pharmaceutical formulation according to any one of clauses 101 to 1722, further comprising about 13 mg / mL of dibasic sodium phosphate.

[0140] Clause 1811. The liquid pharmaceutical formulation according to any one of clauses 101 to 1722, further comprising about 14 mg / mL of dibasic sodium phosphate. Clause 1812. The liquid pharmaceutical formulation according to any one of clauses 101 to 1722, further comprising about 15 mg / mL of dibasic sodium phosphate.

[0141] Clause 1813. The liquid pharmaceutical formulation according to any one of clauses 101 to 1722, further comprising about 16 mg / mL of dibasic sodium phosphate. Clause 1814. The liquid pharmaceutical formulation according to any one of clauses 101 to 1722, further comprising about 17 mg / mL of dibasic sodium phosphate.

[0142] Clause 1815. The liquid pharmaceutical formulation according to any one of clauses 101 to 1722, further comprising about 18 mg / mL of dibasic sodium phosphate. Clause 1816. The liquid pharmaceutical formulation according to any one of clauses 101 to 1722, further comprising about 19 mg / mL of dibasic sodium phosphate.

[0143] Clause 1817. The liquid pharmaceutical formulation according to any one of clauses 101 to 1722, further comprising about 20 mg / mL of dibasic sodium phosphate. Clause 1818. The liquid pharmaceutical formulation according to any one of clauses 101 to 1722, further comprising about 21 mg / mL of dibasic sodium phosphate.

[0144] Clause 1819. The liquid pharmaceutical formulation according to any one of clauses 101 to 1722, further comprising about 22 mg / mL of dibasic sodium phosphate. Clause 1820. The liquid pharmaceutical formulation according to any one of clauses 101 to 1722, further comprising about 23 mg / mL of dibasic sodium phosphate.

[0145] Clause 1821. The liquid pharmaceutical formulation according to any one of clauses 101 to 1722, further comprising about 24 mg / mL of dibasic sodium phosphate. Clause 1822. The liquid pharmaceutical formulation according to any one of clauses 101 to 1722, further comprising about 25 mg / mL of dibasic sodium phosphate.

[0146] Clause 1901. The liquid pharmaceutical formulation according to any one of clauses 101 to 1822, further comprising about 0.1 to about 1 mg / mL of disodium EDTA. Clause 1902. The liquid pharmaceutical formulation according to any one of clauses 101 to 1822, further comprising about 0.1 mg / mL of disodium EDTA.

[0147] Clause 1903. The liquid pharmaceutical formulation according to any one of clauses 101 to 1822, further comprising about 0.2 mg / mL of disodium EDTA. Clause 1904. The liquid pharmaceutical formulation according to any one of clauses 101 to 1822, further comprising about 0.3 mg / mL of disodium EDTA.

[0148] Clause 1905. The liquid pharmaceutical formulation according to any one of clauses 101 to 1822, further comprising about 0.4 mg / mL of disodium EDTA. Clause 1906. The liquid pharmaceutical formulation according to any one of clauses 101 to 1822, further comprising about 0.5 mg / mL of disodium EDTA.

[0149] Clause 1907. The liquid pharmaceutical formulation according to any one of clauses 101 to 1822, further comprising about 0.6 mg / mL of disodium EDTA. Clause 1908. The liquid pharmaceutical formulation according to any one of clauses 101 to 1822, further comprising about 0.7 mg / mL of disodium EDTA.

[0150] Clause 1909. The liquid pharmaceutical formulation according to any one of clauses 101 to 1822, further comprising about 0.8 mg / mL of disodium EDTA. Clause 1910. The liquid pharmaceutical formulation according to any one of clauses 101 to 1822, further comprising about 0.9 mg / mL of disodium EDTA.

[0151] Clause 1911. The liquid pharmaceutical formulation according to any one of clauses 101 to 1822, further comprising about 1 mg / mL of disodium EDTA. Clause 2001. The liquid pharmaceutical formulation according to any one of clauses 101 to 1911, wherein the pharmaceutical formulation has a pH of about 7.5 to about 9.5.

[0152] Clause 2002. The aqueous pharmaceutical formulation according to any one of clauses 101 to 1911, wherein the pharmaceutical formulation has a pH of about 7.5 to about 8. Clause 2003. The aqueous pharmaceutical formulation according to any one of clauses 101 to 1911, wherein the pharmaceutical formulation has a pH of about 8 to about 8.5.

[0153] Clause 2004. The aqueous pharmaceutical formulation according to any one of clauses 101 to 1911, wherein the pharmaceutical formulation has a pH of about 8.5 to about 9. Clause 2101. The aqueous pharmaceutical formulation according to any one of clauses 101 to 1911, wherein the pharmaceutical formulation has a pH of about 7.5.

[0154] Clause 2102. The aqueous pharmaceutical formulation according to any one of clauses 101 to 1911, wherein the pharmaceutical formulation has a pH of about 7.6. Clause 2103. The aqueous pharmaceutical formulation according to any one of clauses 101 to 1911, wherein the pharmaceutical formulation has a pH of about 7.7.

[0155] Clause 2104. The aqueous pharmaceutical formulation according to any one of clauses 101 to 1911, wherein the pharmaceutical formulation has a pH of about 7.8. Clause 2105. The aqueous pharmaceutical formulation according to any one of clauses 101 to 1911, wherein the pharmaceutical formulation has a pH of about 7.9.

[0156] Clause 2106. The aqueous pharmaceutical formulation according to any one of clauses 101 to 1911, wherein the pharmaceutical formulation has a pH of about 8. Clause 2107. The aqueous pharmaceutical formulation according to any one of clauses 101 to 1911, wherein the pharmaceutical formulation has a pH of about 8.1.

[0157] Clause 2108. The aqueous pharmaceutical formulation according to any one of clauses 101 to 1911, wherein the pharmaceutical formulation has a pH of about 8.2. Clause 2109. The aqueous pharmaceutical formulation according to any one of clauses 101 to 1911, wherein the pharmaceutical formulation has a pH of about 8.3.

[0158] Clause 2110. The aqueous pharmaceutical formulation according to any one of clauses 101 to 1911, wherein the pharmaceutical formulation has a pH of about 8.4. Clause 2111. The aqueous pharmaceutical formulation according to any one of clauses 101 to 1911, wherein the pharmaceutical formulation has a pH of about 8.5.

[0159] Clause 2112. The aqueous pharmaceutical formulation according to any one of clauses 101 to 1911, wherein the pharmaceutical formulation has a pH of about 8.6. Clause 2113. The aqueous pharmaceutical formulation according to any one of clauses 101 to 1911, wherein the pharmaceutical formulation has a pH of about 8.7.

[0160] Clause 2114. The aqueous pharmaceutical formulation according to any one of clauses 101 to 1911, wherein the pharmaceutical formulation has a pH of about 8.8. Clause 2115. The aqueous pharmaceutical formulation according to any one of clauses 101 to 1911, wherein the pharmaceutical formulation has a pH of about 8.9.

[0161] Clause 2116. The aqueous pharmaceutical formulation according to any one of clauses 101 to 1911, wherein the pharmaceutical formulation has a pH of about 9. Clause 2201. The liquid pharmaceutical formulation according to any one of clauses 1 to 2116, wherein the formulation, upon formulation, is free of impurities or contains less than 0.05% or not more than 0.05% impurities.

[0162] Clause 2202. The liquid medical formulation according to any one of clauses 101 to 2116, wherein the formulation, upon formulation, is free of impurities or contains less than 0.04% or not more than 0.04% of impurities.

[0163] Clause 2203. The liquid medical formulation according to any one of clauses 101 to 2116, wherein the formulation, upon formulation, is free of impurities or contains less than 0.03% or not more than 0.03% of impurities.

[0164] Clause 2204. The liquid medical formulation according to any one of clauses 101 to 2116, wherein the formulation, upon formulation, is free of impurities or contains less than 0.02% or not more than 0.02% of impurities.

[0165] Clause 2205. The liquid medical formulation according to any one of clauses 101 to 2116, wherein the formulation, upon formulation, is free of impurities or contains less than 0.01% or not more than 0.01% of impurities.

[0166] Clause 2206. The liquid pharmaceutical formulation according to any one of clauses 1 to 2116, wherein the formulation, upon formulation, is free of impurities or contains less than 0.1% or not more than 0.1% of impurities. Clause 2207. The liquid medical formulation according to any one of clauses 101 to 2116, wherein the formulation, upon formulation, is free of impurities or contains less than 0.09% or not more than 0.09% of impurities.

[0167] Clause 2208. The liquid medical formulation according to any one of clauses 101 to 2116, wherein the formulation, upon formulation, is free of impurities or contains less than 0.08% or not more than 0.08% impurities.

[0168] Clause 2209. An aqueous pharmaceutical formulation according to any one of clauses 101 to 2116, wherein the formulation, upon formulation, is free of impurities or contains less than 0.07% or not more than 0.07% of impurities.

[0169] Clause 2210. The liquid medical formulation according to any one of clauses 101 to 2116, wherein the formulation, upon formulation, is free of impurities or contains less than 0.06% or not more than 0.06% of impurities.

[0170] Clause 2211. The liquid pharmaceutical formulation according to any one of clauses 1 to 2116, wherein the formulation, upon formulation, is free of impurities or contains less than 0.5% or not more than 0.5% of impurities. Clause 2212. The liquid medical formulation according to any one of clauses 101 to 2116, wherein the formulation, upon formulation, is free of impurities or contains less than 0.45% or not more than 0.45% of impurities.

[0171] Clause 2213. The liquid medical formulation according to any one of clauses 101 to 2116, wherein the formulation, upon formulation, is free of impurities or contains less than 0.4% or not more than 0.4% of impurities.

[0172] Clause 2214. The liquid medical formulation according to any one of clauses 101 to 2116, wherein the formulation, upon formulation, is free of impurities or contains less than 0.35% or not more than 0.35% of impurities.

[0173] Clause 2215. The liquid medical formulation according to any one of clauses 101 to 2116, wherein the formulation, upon formulation, is free of impurities or contains less than 0.3% or not more than 0.3% of impurities.

[0174] Clause 2216. The liquid pharmaceutical formulation according to any one of clauses 1 to 2116, wherein the formulation, upon formulation, is free of impurities or contains less than 0.25% or not more than 0.25% of impurities.

[0175] Clause 2217. The liquid pharmaceutical formulation according to any one of clauses 101 to 2116, wherein the formulation, upon formulation, is free of impurities or contains less than 0.2% or not more than 0.2% of impurities.

[0176] Clause 2218. The liquid medical formulation according to any one of clauses 101 to 2116, wherein the formulation, upon formulation, is free of impurities or contains less than 0.15% or not more than 0.15% of impurities.

[0177] Clause 2219. The liquid medical formulation according to any one of clauses 101 to 2116, wherein the formulation, upon formulation, is free of impurities or contains less than 0.14% or not more than 0.14% of impurities.

[0178] Clause 2220. An aqueous pharmaceutical formulation according to any one of clauses 101 to 2116, wherein the formulation, upon formulation, is free of impurities or contains less than 0.13%, less than 0.12%, or less than 0.11%, or does not exceed 0.13%, does not exceed 0.12%, or does not exceed 0.11% of impurities.

[0179] Clause 2301. An aqueous pharmaceutical formulation according to any one of clauses 101 to 2205, wherein the formulation is free of impurities or contains less than 0.07% or not more than 0.07% impurities when stored at 25°C for about 3 months.

[0180] Clause 2302. An aqueous pharmaceutical formulation according to any one of clauses 101 to 2205, wherein the formulation is free of impurities or contains less than 0.06% or not more than 0.06% impurities when stored at 25°C for about 3 months.

[0181] Clause 2303. An aqueous pharmaceutical formulation according to any one of clauses 101 to 2205, wherein the formulation is free of impurities or contains less than 0.05% or not more than 0.05% impurities when stored at 25°C for about 3 months.

[0182] Clause 2304. An aqueous pharmaceutical formulation according to any one of clauses 101 to 2205, wherein the formulation is free of impurities or contains less than 0.04% or not more than 0.04% impurities when stored at 25°C for about 3 months.

[0183] Clause 2305. An aqueous pharmaceutical formulation according to any one of clauses 101 to 2205, wherein the formulation is free of impurities or contains less than 0.03% or not more than 0.03% of impurities when stored at 25°C for about 3 months.

[0184] Clause 2306. An aqueous pharmaceutical formulation according to any one of clauses 101 to 2205, wherein the formulation is free of impurities or contains less than 0.02% or not more than 0.02% impurities when stored at 25°C for about 3 months.

[0185] Clause 2307. An aqueous pharmaceutical formulation according to any one of clauses 101 to 2205, wherein the formulation is free of impurities or contains less than 0.01% or not more than 0.01% impurities when stored at 25°C for about 3 months.

[0186] Clause 2308. The liquid medical formulation according to any one of clauses 101 to 2205, wherein the formulation contains between 0.01% impurities and less than 0.07%, or not more than 0.07%, of impurities when stored at 25°C for about 3 months.

[0187] Clause 2309. The liquid medical formulation according to any one of clauses 101 to 2205, wherein the formulation contains between 0.01% impurities and less than 0.06%, or not more than 0.06%, of impurities when stored at 25°C for about 3 months.

[0188] Clause 2310. The liquid medical formulation according to any one of clauses 101 to 2205, wherein the formulation contains between 0.01% impurities and less than 0.05%, or not more than 0.05%, of impurities when stored at 25°C for about 3 months.

[0189] Clause 2311. An aqueous pharmaceutical formulation according to any one of clauses 101 to 2205, wherein the formulation contains between 0.01% impurities and less than 0.04%, or not more than 0.04%, of impurities when stored at 25°C for about 3 months.

[0190] Clause 2312. An aqueous pharmaceutical formulation according to any one of clauses 101 to 2205, wherein the formulation contains between 0.01% impurities and less than 0.03%, or not more than 0.03%, of impurities when stored at 25°C for about 3 months.

[0191] Clause 2313. An aqueous pharmaceutical formulation according to any one of clauses 101 to 2205, wherein the formulation contains between 0.01% impurities and less than 0.02%, or not more than 0.02%, of impurities when stored at 25°C for about 3 months.

[0192] Clause 2314. An aqueous pharmaceutical formulation according to any one of clauses 101 to 2205, wherein the formulation contains between 0.01% impurities and less than 0.1%, or not more than 0.1%, of impurities when stored at 25°C for about 3 months.

[0193] Clause 2315. An aqueous pharmaceutical formulation according to any one of clauses 101 to 2205, wherein the formulation contains between 0.01% impurities and less than 0.15%, or not more than 0.15%, of impurities when stored at 25°C for about 3 months.

[0194] Clause 2316. An aqueous pharmaceutical formulation according to any one of clauses 101 to 2205, wherein the formulation contains between 0.01% impurities and less than 0.2%, or not more than 0.2%, of impurities when stored at 25°C for about 3 months.

[0195] Clause 2317. An aqueous pharmaceutical formulation according to any one of clauses 101 to 2205, wherein the formulation contains between 0.01% impurities and less than 0.25%, or not more than 0.25%, of impurities when stored at 25°C for about 3 months.

[0196] Clause 2318. An aqueous pharmaceutical formulation according to any one of clauses 101 to 2205, wherein the formulation contains between 0.01% impurities and less than 0.3%, or not more than 0.3%, of impurities when stored at 25°C for about 3 months.

[0197] Clause 2319. An aqueous pharmaceutical formulation according to any one of clauses 101 to 2205, wherein the formulation contains from 0.01% impurities to less than 0.35%, less than 0.4%, or less than 0.5%, or does not exceed 0.35%, does not exceed 0.4%, or does not exceed 0.5%, when stored at 25°C for about 3 months.

[0198] Clause 2401. The liquid medical formulation of any one of claims 101 to 2307, wherein the formulation is free of impurities or contains less than 0.20% or not more than 0.20% impurities when stored at 25°C for about 6 months.

[0199] Clause 2402. The liquid medical formulation of any one of claims 101 to 2307, wherein the formulation is free of impurities or contains less than 0.19% or not more than 0.19% impurities when stored at 25°C for about 6 months.

[0200] Clause 2403. The liquid medical formulation of any one of claims 101 to 2307, wherein the formulation is free of impurities or contains less than 0.18% or not more than 0.18% impurities when stored at 25°C for about 6 months.

[0201] Clause 2404. The liquid medical formulation of any one of claims 101 to 2307, wherein the formulation is free of impurities or contains less than 0.17% or not more than 0.17% impurities when stored at 25°C for about 6 months.

[0202] Clause 2405. The liquid pharmaceutical formulation of any one of claims 101 to 2307, wherein the formulation is free of impurities or contains less than 0.16% or not more than 0.16% impurities when stored at 25°C for about 6 months.

[0203] Clause 2406. The liquid medical formulation of any one of claims 101 to 2307, wherein the formulation is free of impurities or contains less than 0.15% or not more than 0.15% impurities when stored at 25°C for about 6 months.

[0204] Clause 2407. The liquid medical formulation of any one of claims 101 to 2307, wherein the formulation is free of impurities or contains less than 0.14% or not more than 0.14% impurities when stored at 25°C for about 6 months.

[0205] Clause 2408. The liquid medical formulation of any one of claims 101 to 2307, wherein the formulation is free of impurities or contains less than 0.13% or not more than 0.13% impurities when stored at 25°C for about 6 months.

[0206] Clause 2409. The liquid medical formulation of any one of claims 101 to 2307, wherein the formulation is free of impurities or contains less than 0.12% or not more than 0.12% impurities when stored at 25°C for about 6 months.

[0207] Clause 2410. The liquid medical formulation of any one of claims 101 to 2307, wherein the formulation is free of impurities or contains less than 0.11% or not more than 0.11% impurities when stored at 25°C for about 6 months.

[0208] Clause 2411. The liquid medical formulation of any one of claims 101 to 2307, wherein the formulation is free of impurities or contains less than 0.10% or not more than 0.10% impurities when stored at 25°C for about 6 months.

[0209] Clause 2412. The liquid medical formulation of any one of claims 101 to 2307, wherein the formulation is free of impurities or contains less than 0.09% or not more than 0.09% impurities when stored at 25°C for about 6 months.

[0210] Clause 2413. The liquid pharmaceutical formulation of any one of claims 101 to 2307, wherein the formulation is free of impurities or contains less than 0.08% or not more than 0.08% impurities when stored at 25°C for about 6 months.

[0211] Clause 2414. The liquid pharmaceutical formulation of any one of claims 101 to 2307, wherein the formulation is free of impurities or contains less than 0.07% or not more than 0.07% impurities when stored at 25°C for about 6 months.

[0212] Clause 2415. The liquid medical formulation of any one of claims 101 to 2307, wherein the formulation contains between 0.01% impurities and less than 0.20%, or not more than 0.20%, of impurities when stored at 25°C for about 6 months.

[0213] Clause 2416. The liquid medical formulation of any one of claims 101 to 2307, wherein the formulation contains between 0.01% impurities and less than 0.19%, or not more than 0.19%, of impurities when stored at 25°C for about 6 months.

[0214] Clause 2417. The liquid medical formulation of any one of claims 101 to 2307, wherein the formulation contains between 0.01% impurities and less than 0.18%, or not more than 0.18%, of impurities when stored at 25°C for about 6 months.

[0215] Clause 2418. The liquid medical formulation of any one of claims 101 to 2307, wherein the formulation contains between 0.01% impurities and less than 0.17%, or not more than 0.17%, of impurities when stored at 25°C for about 6 months.

[0216] Clause 2419. The liquid medical formulation of any one of claims 101 to 2307, wherein the formulation contains between 0.01% impurities and less than 0.16%, or not more than 0.16%, of impurities when stored at 25°C for about 6 months.

[0217] Clause 2420. The liquid medical formulation of any one of claims 101 to 2307, wherein the formulation contains between 0.01% impurities and less than 0.15%, or not more than 0.15%, of impurities when stored at 25°C for about 6 months.

[0218] Clause 2421. The liquid medical formulation of any one of claims 101 to 2307, wherein the formulation contains between 0.01% impurities and less than 0.14%, or not more than 0.14%, of impurities when stored at 25°C for about 6 months.

[0219] Clause 2422. The liquid medical formulation of any one of claims 101 to 2307, wherein the formulation contains between 0.01% impurities and less than 0.13%, or not more than 0.13%, of impurities when stored at 25°C for about 6 months.

[0220] Clause 2423. The liquid medical formulation of any one of claims 101 to 2307, wherein the formulation contains between 0.01% impurities and less than 0.12%, or not more than 0.12%, of impurities when stored at 25°C for about 6 months.

[0221] Clause 2424. The liquid medical formulation of any one of claims 101 to 2307, wherein the formulation contains between 0.01% impurities and less than 0.11%, or not more than 0.11%, of impurities when stored at 25°C for about 6 months.

[0222] Clause 2425. The liquid medical formulation of any one of claims 101 to 2307, wherein the formulation contains between 0.01% impurities and less than 0.10%, or not more than 0.10%, of impurities when stored at 25°C for about 6 months.

[0223] Clause 2426. The liquid medical formulation of any one of claims 101 to 2307, wherein the formulation contains between 0.01% impurities and less than 0.09%, or not more than 0.09%, of impurities when stored at 25°C for about 6 months.

[0224] Clause 2427. The liquid medical formulation of any one of claims 101 to 2307, wherein the formulation contains between 0.01% impurities and less than 0.08%, or not more than 0.08%, of impurities when stored at 25°C for about 6 months.

[0225] Clause 2428. The liquid medical formulation of any one of claims 101 to 2307, wherein the formulation contains between 0.01% impurities and less than 0.07%, or not more than 0.07%, of impurities when stored at 25°C for about 6 months.

[0226] Clause 2429. The liquid medical formulation of any one of claims 101 to 2307, wherein the formulation contains between 0.01% impurities and less than 0.25%, or not more than 0.25%, of impurities when stored at 25°C for about 6 months.

[0227] Clause 2430. The liquid medical formulation of any one of claims 101 to 2307, wherein the formulation contains between 0.01% impurities and less than 0.3%, or not more than 0.3%, of impurities when stored at 25°C for about 6 months.

[0228] Clause 2431. The liquid medical formulation of any one of claims 101 to 2307, wherein the formulation contains between 0.01% impurities and less than 0.35%, or not more than 0.35%, of impurities when stored at 25°C for about 6 months.

[0229] Clause 2432. The liquid medical formulation of any one of claims 101 to 2307, wherein the formulation contains between 0.01% impurities and less than 0.4%, or not more than 0.4%, of impurities when stored at 25°C for about 6 months.

[0230] Clause 2433. The liquid medical formulation of any one of claims 101 to 2307, wherein the formulation contains between 0.01% impurities and less than 0.45%, or not more than 0.45%, of impurities when stored at 25°C for about 6 months.

[0231] Clause 2434. The liquid medical formulation of any one of claims 101 to 2307, wherein the formulation contains between 0.01% impurities and less than 0.5%, or not more than 0.5%, of impurities when stored at 25°C for about 6 months.

[0232] Article 2501. The liquid medical formulation according to any one of Articles 101 to 2428, wherein the formulation is free of impurities or contains less than 0.35% or not more than 0.35% of impurities when stored at 40°C for about one month.

[0233] Clause 2601. The liquid medical formulation according to any one of clauses 101 to 2428, wherein the formulation is free of impurities or contains less than 0.7% or not more than 0.7% of impurities when stored at 40°C for about 2 months.

[0234] Article 2701. The liquid medical formulation according to any one of Articles 101 to 2428, wherein the formulation is free of impurities or contains less than 1.5% or not more than 1.5% of impurities when stored at 40°C for about 3 months.

[0235] Clause 2801. The liquid medical formulation according to any one of clauses 101 to 2428, wherein the formulation is free of impurities or contains less than 2% or not more than 2% of impurities when stored at 40°C for about 6 months.

[0236] Clause 2901. The aqueous pharmaceutical formulation according to any one of clauses 2301-2801, wherein the impurity concentration is measured during storage for at least one pharma- ceutically acceptable surface selected from a stopper surface, a needle surface, a needle tip cap surface, a needle shield surface, a septum surface, a syringe plunger surface, a glass syringe surface, a plastic syringe surface (e.g., neoprene, polyisoprene, silicone), an injector surface, a rubber surface, etc. Any surface may comprise any material known in the art, such as, but not limited to, neoprene, polyisoprene, silicone, etc.

[0237] Clause 3001. The liquid pharmaceutical formulation according to any one of clauses 2201 to 2901, wherein the impurities include hydrocortisone. Clause 3002. The liquid pharmaceutical formulation according to any one of clauses 2201 to 2901, wherein the impurities consist essentially of hydrocortisone.

[0238] Clause 3003. The preparation contains: no hydrocortisone, less than 0.01%, or not more than 0.01% hydrocortisone; no hydrocortisone, less than 0.025%, or not more than 0.025% hydrocortisone; no hydrocortisone, less than 0.05%, or not more than 0.05% hydrocortisone; no hydrocortisone, less than 0.1%, or not more than 0.1% hydrocortisone; no hydrocortisone, less than 0.15%, or not more than 0.15% hydrocortisone; no hydrocortisone, less than 0.2%, or not more than 0.2% hydrocortisone; hydrocortisone The aqueous pharmaceutical formulation according to any one of clauses 2201 to 2901, comprising: no hydrocortisone, less than 0.25%, or not more than 0.25% hydrocortisone; no hydrocortisone, less than 0.3%, or not more than 0.3% hydrocortisone; no hydrocortisone, less than 0.35%, or not more than 0.35% hydrocortisone; no hydrocortisone, less than 0.4%, or not more than 0.4% hydrocortisone; no hydrocortisone, less than 0.45%, or not more than 0.45% hydrocortisone; or no hydrocortisone, less than 0.5%, or not more than 0.5% hydrocortisone.

[0239] Clause 3101. The liquid pharmaceutical formulation according to any one of clauses 101 to 3003, wherein any formulation component concentration can be expressed as % w / v using the conversion factor of 1 mg / mL = 0.1% w / v.

[0240] Clause 3201. A method of treating a disease, condition, or disorder that is alleviated by administering hydrocortisone or hydrocortisone sodium phosphate in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of an aqueous pharmaceutical formulation according to any one of clauses 101 to 3101.

[0241] Clause 3301. The method of clause 3201, wherein the disease, condition, or disorder includes one or more of joint and / or tendon swelling, joint and / or tendon pain, tennis elbow, and / or golfer's elbow.

[0242] Clause 3401. The method of clause 3201, wherein the disease, condition, or disorder includes one or more of asthma, an allergic reaction, severe shock due to injury or infection, and / or adrenal insufficiency.

[0243] Clause 3501. The method of clause 3201, wherein the disease, condition, or disorder comprises inflammation. Clause 3601. The method of clause 3201, wherein the disease, condition, or disorder comprises asthma, atopic dermatitis, contact dermatitis, drug hypersensitivity reactions, perennial or seasonal allergic rhinitis, serum sickness, and / or blood transfusion reactions.

[0244] Clause 3701. The method of clause 3201, wherein the disease, condition, or disorder comprises a skin disease selected from bullous dermatitis herpetiformis, exfoliative erythroderma, mycosis fungoides, pemphigus, and severe erythema multiforme (Stevens-Johnson syndrome).

[0245] Clause 3801. The method of clause 3201, wherein the disease, condition, or disorder comprises an endocrine disorder selected from primary or secondary adrenal cortical insufficiency, congenital adrenal hyperplasia, hypercalcemia associated with cancer, and / or nonsuppurative thyroiditis.

[0246] Clause 3901. The method of clause 3201, wherein the disease, condition, or disorder comprises a gastrointestinal disorder. Clause 4001. The method of clause 3201, wherein the disease, condition, or disorder comprises a gastrointestinal disease selected from regional enteritis (systemic therapy) and ulcerative colitis.

[0247] Clause 4101. The method of clause 3201, wherein the disease, condition, or disorder comprises a blood disorder selected from acquired (autoimmune) hemolytic anemia, congenital (erythrocytic) hypoplastic anemia (Diamond-Blackfan anemia), idiopathic thrombocytopenic purpura in adults, pure red cell aplasia, and selected cases of secondary thrombocytopenia.

[0248] Clause 4201. The method of clause 3201, wherein the disease, condition, or disorder comprises one or more of trichinellosis with neurological or myocardial impairment, tuberculous meningitis with subarachnoid block or impending block.

[0249] Clause 4301. The method of clause 3201, wherein the disease, condition, or disorder comprises a neoplastic disease. Clause 4401. The method of clause 3201, wherein the disease, condition, or disorder comprises palliative management of leukemia and / or lymphoma.

[0250] Clause 4501. The method of clause 3201, wherein the disease, condition, or disorder comprises a nervous system condition selected from acute exacerbation of multiple sclerosis, primary or metastatic brain tumors, or cerebral edema associated with craniotomy.

[0251] Clause 4601. The method of clause 3201, wherein the disease, condition, or disorder comprises an ocular disease selected from sympathetic ophthalmia, uveitis, and an ocular inflammatory condition. Clause 4701. The method of clause 3201, wherein the disease, condition, or disorder includes renal disease.

[0252] Clause 4801. The method of clause 3201, wherein the disease, condition, or disorder comprises induction of diuresis or remission of proteinuria in idiopathic nephrotic syndrome or due to lupus erythematosus. Clause 4901. The method of clause 3201, wherein the disease, condition, or disorder comprises a respiratory disease selected from beryllium disease, fulminant or disseminated pulmonary tuberculosis, idiopathic eosinophilic pneumonia, and symptomatic sarcoidosis.

[0253] Clause 5001. The method of clause 3201, wherein the disease, condition, or disorder comprises a rheumatic disorder selected from acute gouty arthritis, acute rheumatic carditis, ankylosing spondylitis, psoriatic arthritis, and rheumatoid arthritis, including juvenile rheumatoid arthritis.

[0254] Clause 5101. The method of clause 3201, wherein the disease, condition, or disorder comprises dermatomyositis, temporal arteritis, polymyositis, and systemic lupus erythematosus. Clause 5201. The method of clause 3201, wherein the disease, condition, or disorder comprises adrenal insufficiency selected from primary adrenal insufficiency, acute adrenal insufficiency, and secondary adrenal insufficiency.

[0255] Article 6001. An aqueous pharmaceutical formulation comprising about 50 to about 150 mg / mL of hydrocortisone sodium phosphate, about 2.5 to about 12.5 mg / mL of monothioglycerol, and water. Clause 6002. The aqueous pharmaceutical formulation of clause 6001, comprising about 50 to about 60 mg / mL of hydrocortisone sodium phosphate, about 60 to about 70 mg / mL of hydrocortisone sodium phosphate, or about 70 to about 80 mg / mL of hydrocortisone sodium phosphate.

[0256] Clause 6003. The aqueous pharmaceutical formulation of clause 6001, comprising about 60 to about 65 mg / mL of hydrocortisone sodium phosphate, or about 65 to about 70 mg / mL of hydrocortisone sodium phosphate.

[0257] Clause 6004. The aqueous pharmaceutical formulation of clause 6001, comprising about 120 to about 130 mg / mL of hydrocortisone sodium phosphate, about 130 to about 140 mg / mL of hydrocortisone sodium phosphate, or about 140 to about 150 mg / mL of hydrocortisone sodium phosphate.

[0258] Clause 6005. The aqueous pharmaceutical formulation of clause 6001, comprising about 130 to about 135 mg / mL of hydrocortisone sodium phosphate, or about 135 to about 140 mg / mL of hydrocortisone sodium phosphate.

[0259] Article 6006. About 50 mg / mL hydrocortisone sodium phosphate, about 55 mg / mL hydrocortisone sodium phosphate, about 60 mg / mL hydrocortisone sodium phosphate, about 65 mg / mL hydrocortisone sodium phosphate, about 70 mg / mL hydrocortisone sodium phosphate, about 75 mg / mL hydrocortisone sodium phosphate, about 80 mg / mL hydrocortisone sodium phosphate, about 85 mg / mL hydrocortisone sodium phosphate, about 90 mg / mL hydrocortisone sodium phosphate, about 95 mg / mL hydrocortisone sodium phosphate, about 100 mg / mL hydrocortisone sodium phosphate. 6001, comprising about 105 mg / mL hydrocortisone sodium phosphate, about 110 mg / mL hydrocortisone sodium phosphate, about 115 mg / mL hydrocortisone sodium phosphate, about 120 mg / mL hydrocortisone sodium phosphate, about 125 mg / mL hydrocortisone sodium phosphate, about 130 mg / mL hydrocortisone sodium phosphate, about 135 mg / mL hydrocortisone sodium phosphate, about 140 mg / mL hydrocortisone sodium phosphate, about 145 mg / mL hydrocortisone sodium phosphate, or about 150 mg / mL hydrocortisone sodium phosphate.

[0260] Clause 6007. The aqueous pharmaceutical formulation of clause 6001, comprising about 60 mg / mL hydrocortisone sodium phosphate, about 61 mg / mL hydrocortisone sodium phosphate, about 62 mg / mL hydrocortisone sodium phosphate, about 63 mg / mL hydrocortisone sodium phosphate, about 64 mg / mL hydrocortisone sodium phosphate, about 65 mg / mL hydrocortisone sodium phosphate, about 66 mg / mL hydrocortisone sodium phosphate, about 67 mg / mL hydrocortisone sodium phosphate, about 68 mg / mL hydrocortisone sodium phosphate, about 69 mg / mL hydrocortisone sodium phosphate, or about 70 mg / mL hydrocortisone sodium phosphate.

[0261] Clause 6008. The aqueous pharmaceutical formulation of clause 6001, comprising about 67 mg / mL hydrocortisone sodium phosphate, about 67.1 mg / mL hydrocortisone sodium phosphate, about 67.2 mg / mL hydrocortisone sodium phosphate, about 67.3 mg / mL hydrocortisone sodium phosphate, about 67.4 mg / mL hydrocortisone sodium phosphate, about 67.5 mg / mL hydrocortisone sodium phosphate, about 67.6 mg / mL hydrocortisone sodium phosphate, about 67.7 mg / mL hydrocortisone sodium phosphate, about 67.8 mg / mL hydrocortisone sodium phosphate, about 67.9 mg / mL hydrocortisone sodium phosphate or about 68 mg / mL hydrocortisone sodium phosphate.

[0262] Clause 6009. The aqueous pharmaceutical formulation of clause 6001, comprising about 130 mg / mL hydrocortisone sodium phosphate, about 131 mg / mL hydrocortisone sodium phosphate, about 132 mg / mL hydrocortisone sodium phosphate, about 133 mg / mL hydrocortisone sodium phosphate, about 134 mg / mL hydrocortisone sodium phosphate, about 135 mg / mL hydrocortisone sodium phosphate, about 136 mg / mL hydrocortisone sodium phosphate, about 137 mg / mL hydrocortisone sodium phosphate, about 138 mg / mL hydrocortisone sodium phosphate, about 139 mg / mL hydrocortisone sodium phosphate, or about 140 mg / mL hydrocortisone sodium phosphate.

[0263] Clause 6010. The aqueous pharmaceutical formulation of clause 6001, comprising about 134 mg / mL hydrocortisone sodium phosphate, about 134.1 mg / mL hydrocortisone sodium phosphate, about 134.2 mg / mL hydrocortisone sodium phosphate, about 134.3 mg / mL hydrocortisone sodium phosphate, about 134.4 mg / mL hydrocortisone sodium phosphate, about 134.5 mg / mL hydrocortisone sodium phosphate, about 134.6 mg / mL hydrocortisone sodium phosphate, about 134.7 mg / mL hydrocortisone sodium phosphate, about 134.8 mg / mL hydrocortisone sodium phosphate, about 134.9 mg / mL hydrocortisone sodium phosphate or about 135 mg / mL hydrocortisone sodium phosphate.

[0264] Article 6011. The liquid pharmaceutical formulation according to any one of Articles 6001 to 6010, comprising about 2.5 to about 3.5 mg / mL of monothioglycerol, about 3.5 to about 4.5 mg / mL of monothioglycerol, about 4.5 to about 5.5 mg / mL of monothioglycerol, about 5.5 to about 6.5 mg / mL of monothioglycerol, about 6.5 to about 7.5 mg / mL of monothioglycerol, about 7.5 to about 8.5 mg / mL of monothioglycerol, about 8.5 to about 9.5 mg / mL of monothioglycerol, about 9.5 to about 10.5 mg / mL of monothioglycerol, about 10.5 to about 11.5 mg / mL of monothioglycerol, or about 11.5 to about 12.5 mg / mL of monothioglycerol.

[0265] Article 6012. The liquid pharmaceutical formulation according to any one of Articles 6001 to 6010, comprising about 4 to about 4.25 mg / mL of monothioglycerol, about 4.25 to about 4.5 mg / mL of monothioglycerol, about 4.5 to about 4.75 mg / mL of monothioglycerol, about 4.75 to about 5 mg / mL of monothioglycerol, about 5 to about 5.25 mg / mL of monothioglycerol, about 5.25 to about 5.5 mg / mL of monothioglycerol, about 5.5 to about 5.75 mg / mL of monothioglycerol, or about 5.75 to about 6 mg / mL of monothioglycerol.

[0266] Article 6013. The liquid pharmaceutical formulation according to any one of Articles 6001 to 6010, comprising about 9 to about 9.25 mg / mL of monothioglycerol, about 9.25 to about 9.5 mg / mL of monothioglycerol, about 9.5 to about 9.75 mg / mL of monothioglycerol, about 9.75 to about 10 mg / mL of monothioglycerol, about 10 to about 10.25 mg / mL of monothioglycerol, about 10.25 to about 10.5 mg / mL of monothioglycerol, about 10.5 to about 10.75 mg / mL of monothioglycerol, or about 10.75 to about 11 mg / mL of monothioglycerol.

[0267] Clause 6014. The liquid pharmaceutical formulation according to any one of clauses 6001 to 6010, comprising about 4.5 mg / mL monothioglycerol, about 4.6 mg / mL monothioglycerol, about 4.7 mg / mL monothioglycerol, about 4.8 mg / mL monothioglycerol, about 4.9 mg / mL monothioglycerol, about 5 mg / mL monothioglycerol, about 5.1 mg / mL monothioglycerol, about 5.2 mg / mL monothioglycerol, about 5.3 mg / mL monothioglycerol, about 5.4 mg / mL monothioglycerol, or about 5.5 mg / mL monothioglycerol.

[0268] Clause 6015. The liquid pharmaceutical formulation according to any one of clauses 6001 to 6010, comprising about 9.5 mg / mL monothioglycerol, about 9.6 mg / mL monothioglycerol, about 9.7 mg / mL monothioglycerol, about 9.8 mg / mL monothioglycerol, about 9.9 mg / mL monothioglycerol, about 10 mg / mL monothioglycerol, about 10.1 mg / mL monothioglycerol, about 10.2 mg / mL monothioglycerol, about 10.3 mg / mL monothioglycerol, about 10.4 mg / mL monothioglycerol, or about 10.5 mg / mL monothioglycerol.

[0269] Clause 6016. The liquid pharmaceutical formulation according to any one of clauses 6001 to 6015, further comprising about 0.5 to about 2.5 mg / mL of monobasic sodium phosphate. Clause 6017. The liquid pharmaceutical formulation according to any one of clauses 6001 to 6016, further comprising about 5 to about 25 mg / mL of dibasic sodium phosphate.

[0270] Clause 6018. The liquid pharmaceutical formulation according to any one of clauses 6001 to 6017, further comprising about 0.1 to about 1 mg / mL of disodium EDTA. Clause 6019. The liquid pharmaceutical formulation according to any one of clauses 6001 to 6018, wherein the pharmaceutical formulation has a pH of about 7.5 to about 9.5.

[0271] Clause 6020. The aqueous pharmaceutical formulation according to any one of clauses 6001 to 6018, wherein the pharmaceutical formulation has a pH of about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, about 8, about 8.1, about 8.2, about 8.3, about 8.4, about 8.5, about 8.6, about 8.7, about 8.8, about 8.9 or about 9.

[0272] Clause 6021. The liquid medical formulation according to any one of clauses 6001 to 6020, wherein the formulation, upon formulation, is free of impurities or contains less than 0.05% or not more than 0.05% of impurities.

[0273] Clause 6022. An aqueous pharmaceutical formulation according to any one of clauses 6001 to 6020, wherein the formulation is free of impurities or contains less than 0.07% or not more than 0.07% of impurities when stored at 25°C for about 3 months.

[0274] Clause 6023. The liquid medical formulation according to any one of clauses 6001 to 6020, wherein when stored at 25°C for about 3 months, the formulation is free of impurities or contains less than 0.01% or not more than 0.01% impurities; free of impurities or contains less than 0.02% or not more than 0.02% impurities; free of impurities or contains less than 0.03% or not more than 0.03% impurities; free of impurities or contains less than 0.04% or not more than 0.04% impurities; free of impurities or contains less than 0.05% or not more than 0.05% impurities; free of impurities or contains less than 0.06% or not more than 0.06% impurities; or free of impurities or contains less than 0.07% or not more than 0.07% impurities.

[0275] Clause 6024. The liquid medical formulation according to any one of clauses 6001 to 6023, wherein the formulation is free of impurities or contains less than 0.20% or not more than 0.20% of impurities when stored at 25°C for about 6 months.

[0276] Article 6025. When stored at 25°C for about 6 months, the drug product is free, contains less than 0.1%, or contains not more than 0.1% impurities; free, contains less than 0.11%, or contains not more than 0.11% impurities; free, contains less than 0.12%, or contains not more than 0.12% impurities; free, contains less than 0.13%, or contains not more than 0.13% impurities; free, contains less than 0.14%, or contains not more than 0.14% impurities; free, contains less than 0.15%, or contains not more than 0.15% impurities The liquid pharmaceutical formulation according to any one of clauses 6001 to 6023, wherein the liquid pharmaceutical formulation contains no impurities or less than 0.15% impurities; no impurities, less than 0.16%, or not more than 0.16% impurities; no impurities, less than 0.17%, or not more than 0.17% impurities; no impurities, less than 0.18%, or not more than 0.18% impurities; no impurities, less than 0.19%, or not more than 0.19% impurities; or no impurities, less than 0.2%, or not more than 0.2% impurities.

[0277] Article 6026. The liquid medical formulation according to any one of articles 6001 to 6025, wherein the formulation is free of impurities or contains less than 0.35% or not more than 0.35% of impurities when stored at 40°C for about one month.

[0278] Article 6027. The liquid medical formulation according to any one of articles 6001 to 6025, wherein the formulation is free of impurities or contains less than 0.7% or not more than 0.7% of impurities when stored at 40°C for about 2 months.

[0279] Article 6028. An aqueous medical formulation according to any one of articles 6001 to 6025, wherein the formulation is free of impurities or contains less than 1.5% or not more than 1.5% of impurities when stored at 40°C for about 3 months.

[0280] Article 6029. The liquid medical formulation according to any one of articles 6001 to 6025, wherein the formulation is free of impurities or contains less than 2% or not more than 2% of impurities when stored at 40°C for about 6 months.

[0281] Clause 6030. A method of treating a disease, condition, or disorder that is alleviated by administering hydrocortisone or hydrocortisone sodium phosphate in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of an aqueous pharmaceutical formulation according to any one of clauses 6001 to 6029.

[0282] Clause 6031. The method of clause 6030, wherein the disease, condition, or disorder comprises one or more of joint and / or tendon swelling, joint and / or tendon pain, tennis elbow, and / or golfer's elbow.

[0283] Clause 6032. The method of clause 6030, wherein the disease, condition, or disorder includes one or more of asthma, an allergic reaction, severe shock due to injury or infection, and / or adrenal insufficiency.

[0284] Clause 6033. The method of clause 6030, wherein the disease, condition, or disorder comprises inflammation. Clause 6034. The method of clause 6030, wherein the disease, condition, or disorder comprises asthma, atopic dermatitis, contact dermatitis, drug hypersensitivity reactions, perennial or seasonal allergic rhinitis, serum sickness, and / or blood transfusion reactions.

[0285] Clause 6035. The method of clause 6030, wherein the disease, condition, or disorder comprises a skin disease selected from bullous dermatitis herpetiformis, exfoliative erythroderma, mycosis fungoides, pemphigus, and severe erythema multiforme (Stevens-Johnson syndrome).

[0286] Clause 6036. The method of clause 6030, wherein the disease, condition, or disorder comprises an endocrine disorder selected from primary or secondary adrenal insufficiency, congenital adrenal hyperplasia, hypercalcemia associated with cancer, and / or nonsuppurative thyroiditis.

[0287] Clause 6037. The method of clause 6030, wherein the disease, condition, or disorder comprises a gastrointestinal disorder. Clause 6038. The method according to clause 6030, wherein the disease, condition or disorder comprises a gastrointestinal disease selected from regional enteritis (systemic therapy) and ulcerative colitis.

[0288] Clause 6039. The method of clause 6030, wherein the disease, condition, or disorder comprises a blood disorder selected from acquired (autoimmune) hemolytic anemia, congenital (erythrocytic) hypoplastic anemia (Diamond-Blackfan anemia), idiopathic thrombocytopenic purpura in adults, pure red cell aplasia, and selected cases of secondary thrombocytopenia.

[0289] Clause 6040. The method of clause 6030, wherein the disease, condition, or disorder comprises one or more of trichinellosis with neurological or myocardial damage, tuberculous meningitis with subarachnoid block or impending block.

[0290] Clause 6041. The method of clause 6030, wherein the disease, condition, or disorder comprises a neoplastic disease. Clause 6042. The method of clause 6030, wherein the disease, condition, or disorder comprises palliative management of leukemia and / or lymphoma.

[0291] Clause 6043. The method of clause 6030, wherein the disease, condition, or disorder comprises a nervous system condition selected from the group consisting of: Acute exacerbation of multiple sclerosis; cerebral edema associated with primary or metastatic brain tumors or craniotomy.

[0292] Clause 6044. The method of clause 6030, wherein the disease, condition, or disorder comprises an ocular disease selected from sympathetic ophthalmia, uveitis, and an ocular inflammatory condition. Clause 6045. The method of clause 6030, wherein the disease, condition, or disorder comprises renal disease.

[0293] Clause 6046. The method of clause 6030, wherein the disease, condition, or disorder comprises induction of diuresis or remission of proteinuria in idiopathic nephrotic syndrome or due to lupus erythematosus. Clause 6047. The method of clause 6030, wherein the disease, condition, or disorder comprises a respiratory disease selected from beryllium disease, fulminant or disseminated pulmonary tuberculosis, idiopathic eosinophilic pneumonia, and symptomatic sarcoidosis.

[0294] Clause 6048. The method of clause 6030, wherein the disease, condition, or disorder comprises a rheumatic disorder selected from acute gouty arthritis, acute rheumatic carditis, ankylosing spondylitis, psoriatic arthritis, and rheumatoid arthritis, including juvenile rheumatoid arthritis.

[0295] Clause 6049. The method of clause 6030, wherein the disease, condition, or disorder comprises dermatomyositis, temporal arteritis, polymyositis, and systemic lupus erythematosus. Clause 6050. The method of clause 6030, wherein the disease, condition, or disorder comprises adrenal insufficiency selected from primary adrenal insufficiency, acute adrenal insufficiency, and secondary adrenal insufficiency.

[0296] Clause 6051. The method of clause 6050, wherein the disease, condition, or disorder comprises acute adrenal insufficiency occurring in a patient with primary adrenal insufficiency or secondary adrenal insufficiency. Clause 6052. The method according to any one of clauses 6030 to 6051, wherein the therapeutic amount is about 0.5 mL to about 0.6 mL, about 0.6 mL to about 0.7 mL, about 0.7 mL to about 0.8 mL, about 0.8 mL to about 0.9 mL, about 0.9 mL to about 1.0 mL, about 1.0 mL to about 1.1 mL, about 1.1 mL to about 1.2 mL, about 1.2 mL to about 1.3 mL, about 1.3 mL to about 1.4 mL, or about 1.4 mL to about 1.5 mL of the aqueous pharmaceutical formulation.

[0297] Clause 6053. The method of any one of clauses 6030 to 6051, wherein the therapeutic amount is about 0.5 mL, about 0.6 mL, about 0.7 mL, about 0.8 mL, about 0.9 mL, about 1.0 mL, about 1.1 mL, about 1.2 mL, about 1.3 mL, about 1.4 mL, or about 1.5 mL of the aqueous pharmaceutical formulation.

[0298] Clause 6054. The method of any one of clauses 6030 to 6051, wherein the therapeutic dose is administered to the patient using an emergency / rescue autoinjector device. Clause 6055. The method of any one of clauses 6030 to 6054, wherein the patient cannot be administered hydrocortisone or the drug by oral therapy.

[0299] Clause 6056. The method of any one of clauses 6030 to 6055, wherein the therapeutic amount is administered intravenously. Clause 6057. The method of any one of clauses 6030 to 6055, wherein the therapeutic amount is administered intramuscularly.

[0300] Clause 6058. The method according to any one of clauses 6054 to 6057, wherein the aqueous pharmaceutical formulation exhibits a higher exposure after administration to a patient compared to a hydrocortisone reference-listed drug. Clause 6059. The method according to any one of clauses 6054 to 6058, wherein the aqueous pharmaceutical formulation achieves a greater area under the curve (AUC) after administration to a patient compared to a hydrocortisone reference-enumerated drug.

[0301] Article 6060. The aqueous medicinal preparation, after administration to a patient, has a higher maximum (or peak) serum concentration (C) compared to the hydrocortisone reference listed drug. max ) The method of any one of clauses 6054 to 6059, which achieves the above.

[0302] Article 6061. The aqueous medicinal preparation, after administration to a patient, shall have a faster maximum (or peak) serum concentration (C) than the hydrocortisone reference listed drug. max ) The method of any one of clauses 6054 to 6060, which achieves the above.

[0303] Clause 6062. A method according to any one of clauses 6058 to 6061, wherein the hydrocortisone reference-listed drug is administered intravenously to the patient. Clause 6063. The method of any one of clauses 6058 to 6061, wherein the hydrocortisone reference-listed drug is administered intramuscularly to the patient.

[0304] Clause 6064. The method of any one of clauses 6058 to 6063, wherein the hydrocortisone reference-listed drug comprises hydrocortisone sodium succinate. Clause 6065. The method according to any one of clauses 6058 to 6064, wherein the hydrocortisone reference-listed drug does not contain an antioxidant.

[0305] Clause 6066. The method of any one of clauses 6058 to 6065, wherein the hydrocortisone reference listed drug is Solu-Cortef. Article 7001. An aqueous pharmaceutical formulation comprising about 50 to about 150 mg / mL of hydrocortisone sodium phosphate, about 2.5 to about 50 mg / mL of monothioglycerol, and water.

[0306] Clause 7002. The aqueous pharmaceutical formulation of clause 7001, comprising from about 120 to about 130 mg / mL of hydrocortisone sodium phosphate, from about 127 mg / mL to about 141 mg / mL of hydrocortisone sodium phosphate, from about 130 to about 140 mg / mL of hydrocortisone sodium phosphate, or from about 140 to about 150 mg / mL of hydrocortisone sodium phosphate.

[0307] Clause 7003. The aqueous pharmaceutical formulation of clause 7001, comprising from about 127 mg / mL to about 141 mg / mL of hydrocortisone sodium phosphate. Clause 7004. The aqueous pharmaceutical formulation of clause 7001, comprising about 130 to about 135 mg / mL of hydrocortisone sodium phosphate, or about 135 to about 140 mg / mL of hydrocortisone sodium phosphate.

[0308] Article 7005. Approximately 127 mg / mL 133 mg / mL hydrocortisone sodium phosphate, about 134 mg / mL hydrocortisone sodium phosphate, about 135 mg / mL hydrocortisone sodium phosphate, about 136 mg / mL hydrocortisone sodium phosphate, about 137 mg / mL hydrocortisone sodium phosphate, about 138 mg / mL hydrocortisone sodium phosphate, about 139 mg / mL hydrocortisone sodium phosphate, about 140 mg / mL hydrocortisone sodium phosphate, or about 141 mg / mL hydrocortisone sodium phosphate.

[0309] Clause 7006. The aqueous pharmaceutical formulation of clause 7001, comprising about 134 mg / mL hydrocortisone sodium phosphate, about 134.1 mg / mL hydrocortisone sodium phosphate, about 134.2 mg / mL hydrocortisone sodium phosphate, about 134.3 mg / mL hydrocortisone sodium phosphate, about 134.4 mg / mL hydrocortisone sodium phosphate, about 134.5 mg / mL hydrocortisone sodium phosphate, about 134.6 mg / mL hydrocortisone sodium phosphate, about 134.7 mg / mL hydrocortisone sodium phosphate, about 134.8 mg / mL hydrocortisone sodium phosphate, about 134.9 mg / mL hydrocortisone sodium phosphate or about 135 mg / mL hydrocortisone sodium phosphate.

[0310] Article 7007. The liquid pharmaceutical formulation according to any one of Articles 7001 to 7006, comprising about 2.5 to about 3.5 mg / mL of monothioglycerol, about 3.5 to about 4.5 mg / mL of monothioglycerol, about 3.5 to about 5.5 mg / mL of monothioglycerol, about 4.5 to about 5.5 mg / mL of monothioglycerol, about 5.5 to about 6.5 mg / mL of monothioglycerol, about 6.5 to about 7.5 mg / mL of monothioglycerol, about 7.5 to about 8.5 mg / mL of monothioglycerol, about 8.5 to about 9.5 mg / mL of monothioglycerol, about 9.5 to about 10.5 mg / mL of monothioglycerol, about 10.5 to about 11.5 mg / mL of monothioglycerol, or about 11.5 to about 12.5 mg / mL of monothioglycerol.

[0311] Article 7008. The liquid pharmaceutical formulation according to any one of Articles 7001 to 7007, comprising about 4 to about 4.25 mg / mL of monothioglycerol, about 4.25 to about 4.5 mg / mL of monothioglycerol, about 4.5 to about 4.75 mg / mL of monothioglycerol, about 4.75 to about 5 mg / mL of monothioglycerol, about 5 to about 5.25 mg / mL of monothioglycerol, about 5.25 to about 5.5 mg / mL of monothioglycerol, about 5.5 to about 5.75 mg / mL of monothioglycerol, or about 5.75 to about 6 mg / mL of monothioglycerol.

[0312] Article 7009. The liquid pharmaceutical formulation according to any one of articles 7001 to 7008, comprising about 4.5 mg / mL monothioglycerol, about 4.6 mg / mL monothioglycerol, about 4.7 mg / mL monothioglycerol, about 4.8 mg / mL monothioglycerol, about 4.9 mg / mL monothioglycerol, about 5 mg / mL monothioglycerol, about 5.1 mg / mL monothioglycerol, about 5.2 mg / mL monothioglycerol, about 5.3 mg / mL monothioglycerol, about 5.4 mg / mL monothioglycerol, or about 5.5 mg / mL monothioglycerol.

[0313] Clause 7010. The liquid pharmaceutical formulation according to any one of clauses 7001 to 7009, further comprising about 0.5 to about 2.5 mg / mL of monobasic sodium phosphate. Clause 7011. The liquid pharmaceutical formulation according to any one of clauses 7001 to 7010, further comprising about 5 to about 25 mg / mL of dibasic sodium phosphate.

[0314] Clause 7012. The liquid pharmaceutical formulation according to any one of clauses 7001 to 7011, further comprising about 0.1 to about 1 mg / mL of disodium EDTA. Clause 7013. The liquid pharmaceutical formulation according to any one of clauses 7001 to 7011, further comprising about 0.1 to about 0.22 mg / mL of disodium EDTA.

[0315] Clause 7014. The liquid pharmaceutical formulation according to any one of clauses 7001 to 7013, wherein the pharmaceutical formulation has a pH of about 7.5 to about 9.5, or about 7.5 to about 8.5. Clause 7015. The aqueous pharmaceutical formulation according to any one of clauses 7001 to 7013, wherein the pharmaceutical formulation has a pH of about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, about 8.0, about 8.1, about 8.2, about 8.3, about 8.4, about 8.5, about 8.6, about 8.7, about 8.8, about 8.9 or about 9.

[0316] Clause 7016. The liquid pharmaceutical formulation according to any one of clauses 7001 to 7015, wherein, upon formulation, the pharmaceutical formulation is free of organic impurities or contains less than 0.2% or not more than 0.2% organic impurities; free of organic impurities or contains less than 0.15% or not more than 0.15% organic impurities; free of organic impurities or contains less than 0.10% or not more than 0.10% organic impurities; or free of organic impurities or contains less than 0.05% or not more than 0.05% organic impurities.

[0317] Clause 7017. The liquid pharmaceutical formulation according to any one of clauses 7001 to 7016, wherein when stored at about 25°C for about 3 months, the formulation is free of organic impurities or contains less than 0.2% or not more than 0.2% organic impurities; or is free of organic impurities or contains less than 0.07% or not more than 0.07% organic impurities.

[0318] Clause 7018. The liquid pharmaceutical formulation according to any one of clauses 7001 to 7017, wherein when stored at about 25°C for about 6 months, the formulation is free of organic impurities or contains less than 0.60% or not more than 0.60% organic impurities; or is free of organic impurities or contains less than 0.20% or not more than 0.20% organic impurities.

[0319] Clause 7019. The aqueous pharmaceutical formulation according to clause 7017 or 7018, wherein the formulation is stored at about 60% relative humidity. Clause 7020. The aqueous pharmaceutical formulation according to any one of clauses 7017 to 7019, wherein the formulation is stored against at least one pharma- ceutically acceptable non-glass surface selected from a stopper surface, a needle surface, a needle tip cap surface, a needle shield surface, a septum surface, a syringe plunger surface, a plastic syringe surface, an injector surface or a rubber surface.

[0320] Clause 7021. An aqueous pharmaceutical formulation according to any one of clauses 7001 to 7020 for use in the treatment of a disease, condition or disorder alleviated by hydrocortisone or hydrocortisone sodium phosphate.

[0321] Clause 7022. The aqueous pharmaceutical formulation for use according to clause 7021, wherein the disease, condition or disorder comprises one or more of asthma, allergic reactions, severe shock due to injury or infection, adrenal insufficiency, inflammation, atopic dermatitis, contact dermatitis, drug hypersensitivity reactions, perennial or seasonal allergic rhinitis, serum sickness, transfusion reactions, gastrointestinal diseases, trichinellosis with neurological or myocardial impairment, tuberculous meningitis with subarachnoid block or impending block, neoplastic diseases, palliative management of leukemia and / or lymphoma, renal diseases, proteinuria in idiopathic nephrotic syndrome, proteinuria due to lupus erythematosus, dermatomyositis, temporal arteritis, polymyositis, joint and / or tendon swelling, joint and / or tendon pain, tennis elbow, golfer's elbow and systemic lupus erythematosus.

[0322] Article 7023. The disease, condition, or disorder is selected from among bullous dermatitis herpetiformis, exfoliative erythroderma, mycosis fungoides, pemphigus, and severe erythema multiforme (Stevens-Johnson syndrome); an endocrine disorder selected from among primary or secondary adrenal insufficiency, congenital adrenal hyperplasia, hypercalcemia associated with cancer, and nonsuppurative thyroiditis; a blood disorder selected from among acquired (autoimmune) hemolytic anemia, congenital (erythrocytic) hypoplastic anemia (Diamond-Blackfan anemia), idiopathic thrombocytopenic purpura in adults, pure red cell aplasia, and selected cases of secondary thrombocytopenia; multiple sclerosis; a neurological condition selected from acute exacerbation of chronic inflammatory disease; a neurological condition selected from primary or metastatic brain tumor, and cerebral edema associated with craniotomy; an eye disease selected from sympathetic ophthalmia, uveitis, and ocular inflammatory conditions; a respiratory disease selected from beryllium disease, fulminant or disseminated pulmonary tuberculosis, idiopathic eosinophilic pneumonia, and symptomatic sarcoidosis; a rheumatic disorder selected from acute gouty arthritis, acute rheumatic carditis, ankylosing spondylitis, psoriatic arthritis, and rheumatoid arthritis; and an adrenal insufficiency selected from primary adrenal insufficiency, acute adrenal insufficiency, and secondary adrenal insufficiency.

[0323] Clause 7024. The aqueous pharmaceutical formulation for use according to clause 7023, wherein the disease, condition or disorder comprises adrenal insufficiency selected from primary adrenal insufficiency, acute adrenal insufficiency and secondary adrenal insufficiency.

[0324] Clause 7025. The aqueous pharmaceutical formulation for use according to clause 7023, wherein the disease, condition or disorder comprises acute adrenal insufficiency occurring in patients with primary adrenal insufficiency or secondary adrenal insufficiency.

[0325] Clause 7026. A method of treating a disease, condition, or disorder that is alleviated by administering hydrocortisone or hydrocortisone sodium phosphate in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of an aqueous pharmaceutical formulation according to any one of clauses 7001 to 7020.

[0326] Clause 7027. The method of clause 7026, wherein the disease, condition, or disorder comprises one or more of asthma, acute exacerbation of asthma, allergic reactions, severe shock due to injury or infection, adrenal insufficiency, inflammation, atopic dermatitis, contact dermatitis, drug hypersensitivity reactions, perennial or seasonal allergic rhinitis, serum sickness, transfusion reactions, gastrointestinal disease, trichinellosis with neurological or myocardial impairment, tuberculous meningitis with subarachnoid block or impending block, neoplastic disease, palliative management of leukemia and / or lymphoma, renal disease, proteinuria in idiopathic nephrotic syndrome, proteinuria due to lupus erythematosus, dermatomyositis, temporal arteritis, polymyositis, joint and / or tendon swelling, joint and / or tendon pain, tennis elbow, golfer's elbow, systemic lupus erythematosus, acute exacerbation of inflammatory bowel disease, and infantile spasms.

[0327] Article 7028. The disease, condition, or disorder is a skin disorder selected from among bullous dermatitis herpetiformis, exfoliative erythroderma, mycosis fungoides, pemphigus, and severe erythema multiforme (Stevens-Johnson syndrome); an endocrine disorder selected from among primary or secondary adrenal insufficiency, congenital adrenal hyperplasia, hypercalcemia associated with cancer, and nonsuppurative thyroiditis; a blood disorder selected from among acquired (autoimmune) hemolytic anemia, congenital (erythrocytic) hypoplastic anemia (Diamond-Blackfan anemia), idiopathic thrombocytopenic purpura in adults, pure red cell aplasia, and selected cases of secondary thrombocytopenia. ; an acute exacerbation of multiple sclerosis; a nervous system condition selected from primary or metastatic brain tumors, and cerebral edema associated with craniotomy; an eye disease selected from sympathetic ophthalmia, uveitis, and ocular inflammatory conditions; a respiratory disease selected from beryllium disease, fulminant or disseminated pulmonary tuberculosis, idiopathic eosinophilic pneumonia, and symptomatic sarcoidosis; a rheumatic disorder selected from acute gouty arthritis, acute rheumatic carditis, ankylosing spondylitis, psoriatic arthritis, and rheumatoid arthritis; and adrenal insufficiency selected from primary adrenal insufficiency, acute adrenal insufficiency, and secondary adrenal insufficiency.

[0328] Clause 7029. The method of clause 7028, wherein the disease, condition, or disorder comprises adrenal insufficiency selected from primary adrenal insufficiency, acute adrenal insufficiency, and secondary adrenal insufficiency. Clause 7030. The method of clause 7028, wherein the disease, condition, or disorder comprises acute adrenal insufficiency occurring in a patient with primary adrenal insufficiency or secondary adrenal insufficiency.

[0329] Clause 7031. The method according to any one of clauses 7026 to 7030, wherein the therapeutic amount is about 0.5 mL to about 0.6 mL, about 0.6 mL to about 0.7 mL, about 0.7 mL to about 0.8 mL, about 0.8 mL to about 0.9 mL, about 0.9 mL to about 1.0 mL, about 1.0 mL to about 1.2 mL, about 1.0 mL to about 1.1 mL, about 1.1 mL to about 1.2 mL, about 1.2 mL to about 1.3 mL, about 1.3 mL to about 1.4 mL, or about 1.4 mL to about 1.5 mL of the aqueous pharmaceutical formulation.

[0330] Clause 7032. The method of any one of clauses 7026 to 7030, wherein the therapeutic amount is about 0.5 mL, about 0.6 mL, about 0.7 mL, about 0.8 mL, about 0.9 mL, about 1.0 mL, about 1.1 mL, about 1.2 mL, about 1.3 mL, about 1.4 mL, or about 1.5 mL of the aqueous pharmaceutical formulation.

[0331] Clause 7033. The method according to any one of clauses 7026 to 7032, wherein the therapeutic dose is administered to the patient using an emergency / rescue autoinjector device. Clause 7034. The method of any one of clauses 7026 to 7033, wherein the patient cannot receive hydrocortisone or the drug by oral therapy.

[0332] Clause 7035. The method of any one of clauses 7026 to 7034, wherein the therapeutic amount is administered intravenously. Clause 7036. The method of any one of clauses 7026 to 7034, wherein the therapeutic amount is administered intramuscularly.

[0333] Article 7037. The amount of treatment is about 5,500 to 5,575 h * Mean AUC in ng / mL 0-inf The method of any one of clauses 7026 to 7036, providing an in vivo plasma profile of hydrocortisone comprising:

[0334] Article 7038. The amount of treatment is approximately 5,275 to 5,375 h * Mean AUC in ng / mL 0-t t is about 0.5 to 12.5 hours.

[0335] Article 7039. The patient has a C of hydrocortisone of about 800-1600 ng / mL, about 900-1600 ng / mL, about 1000-1600 ng / mL, about 1000-1500 ng / mL, about 1100-1500 ng / mL, about 1100-1400 ng / mL, or about 1200-1300 ng / mL about 30 minutes, about 45 minutes, about 1.0 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, about 2.0 hours, about 2.25 hours, about 2.5 hours, about 2.75 hours, about 3.0 hours, about 3.25 hours, about 3.5 hours, or about 4.0 hours after a therapeutic dose is administered. max The method of any one of clauses 7026 to 7038, comprising:

[0336] Article 7040. Therapeutic doses of hydrocortisone for a median T of approximately 0.5 to 2.5 hours max The method of any one of clauses 7026 to 7039, comprising providing Article 7041. Hydrocortisone is administered to patients at a mean T of approximately 1.8 to 2.1 hours. 1 / 2 el The method according to any one of clauses 7026 to 7040, wherein the stool is excreted in the urine.

[0337] Clause 7042. The method according to any one of clauses 7026 to 7041, wherein the aqueous pharmaceutical formulation exhibits a higher exposure after administration to a patient compared to a hydrocortisone reference formulation. Clause 7043. The method according to any one of clauses 7026 to 7042, wherein the aqueous pharmaceutical formulation achieves a greater area under the curve (AUC) after administration to a patient compared to a hydrocortisone reference enumerated formulation.

[0338] Article 7044. The aqueous pharmaceutical preparation, after administration to a patient, has a higher maximum (or peak) serum concentration (C max ) The method of any one of clauses 7026 to 7043, which achieves the above.

[0339] Article 7045. The aqueous medicinal preparation, after administration to a patient, has a faster maximum (or peak) serum concentration (C max). The method of any one of clauses 7026 to 7044, which achieves the above.

[0340] Clause 7046. The method according to any one of clauses 7042 to 7045, wherein the hydrocortisone reference formulation is administered intravenously to the patient. Clause 7047. The method according to any one of clauses 7042 to 7045, wherein the hydrocortisone reference formulation is administered intramuscularly to the patient.

[0341] Clause 7048. The method according to any one of clauses 7042 to 7047, wherein the hydrocortisone reference formulation comprises hydrocortisone sodium succinate. Clause 7049. The method according to any one of clauses 7042 to 7048, wherein the hydrocortisone reference formulation does not contain an antioxidant.

[0342] Clause 7050. The method of any one of clauses 7042 to 7049, wherein the hydrocortisone reference formulation comprises an aqueous formulation comprising about 67 mg / mL hydrocortisone sodium succinate, about 4.4 mg / mL sodium phosphate dibasic, about 0.4 mg / mL sodium phosphate monobasic, and water, and about 2.0 mL is administered to the patient.

[0343] A number of patent and non-patent publications are cited herein to describe the state of the art to which this invention pertains, the entire disclosures of each of which are incorporated herein by reference. The following examples further illustrate the invention, but are provided for illustrative purposes only and should not be construed as limiting the invention in any way. EXAMPLES

[0344] Example 1 The antioxidants, chelating agents and buffering agents used in the stability studies are listed in the table below. Inactive ingredients used in formulation development

[0345] [Table 1]

[0346] Formulation preparation procedure: add approximately 90% water to container, turn on mixer, add sodium phosphate monobasic anhydrous, sodium phosphate dibasic anhydrous, disodium EDTA, antioxidant, or tertiary stabilizer, rinse using some of the water if necessary, mix for at least 15 minutes or until dissolved, weigh out hydrocortisone sodium phosphate and charge into container from previous step, mix for at least 30 minutes until dissolved, measure pH, adjust pH to approximately 8 using 0.1 N HCl or 0.1 N NaOH, qs to final volume (by weight) with water, and mix for at least 15 minutes.

[0347] A stability-indicating HPLC method suitable for monitoring hydrolysis and other degradation of hydrocortisone sodium phosphate was developed based on literature methods for hydrocortisone prodrugs and other similar products. A detailed description of the HPLC method, including information such as chromatographic conditions and sample preparation, can be found in Section 5.0 Analytical Method Development, herein.

[0348] [Table 2]

[0349] The effect of pH was evaluated for formulations F#1 through F#4 at 13.42% hydrocortisone sodium phosphate, containing disodium edetate and sodium formaldehyde at levels typically used in injectable products. The effect of drug concentration on stability was investigated for F#5, which has a concentration of 6.71% (50 mg / mL hydrocortisone) compared to 13.42% (100 mg / mL hydrocortisone) for the other formulations. Prototype formulations for evaluating pH and concentration:

[0350] [Table 3]

[0351] The second group of formulations was designed to investigate whether alternative antioxidants to sodium formaldehyde sulfoxylate, such as sodium sulfite, monothioglycerol, ascorbic acid, and methionine, could achieve better stabilization effects (F#6-9). Prototype formulations for evaluating the effects of antioxidants:

[0352] [Table 4]

[0353] As disclosed by U.S. Patent No. 2,970,944, the entirety of which is incorporated herein, the stability of aqueous steroid phosphate esters, including sodium hydrocortisone phosphate, can be increased by incorporating small amounts of nitrogen-containing compounds, such as niacinamide and creatinine.The main instability of steroid phosphate esters is the formation of precipitates during storage, which is due to the formation of free hydrocortisone, which has a much lower aqueous solubility, upon hydrolysis.Niacinamide and creatinine may increase the solubility of hydrocortisone, thus preventing its precipitation after formation by hydrolysis.

[0354] The purpose of studying formulations F#10-F#13 was to evaluate whether solubilizing agents such as niacinamide, creatinine, and hydroxypropyl beta-cyclodextrin could stabilize hydrocortisone sodium phosphate injection and maintain it as a clear solution during stability testing.

[0355] [Table 5]

[0356] The needle shield of the PFS is permeable to oxygen. Without being bound to any particular theory, it is believed that the use of a barrier packaging, such as a foil pouch, may have the potential to enhance the stability of hydrocortisone sodium phosphate injection in the PFS. The foil pouches evaluated are manufactured by Glenroy with film structure EFS 477-001. Two sets of formulations F#8 and F#15 PFS were packaged in nitrogen purged foil pouches with 1 PFS per pouch and another set was packaged in foil pouches with StabilOx oxygen absorbers with 1 PFS / 2 packs of oxygen absorbers per pouch to evaluate whether the barrier packaging provides a stabilizing effect.

[0357] [Table 6]

[0358] StabilOx, D100-H60 Oxygen Absorber Packet Details:

[0359] [Table 7]

[0360] [Table 8]

[0361] All formulations were prepared together, loaded into PFS, and placed at stable conditions. There are different sets of formulations. Each set of formulations was prepared on a different day, loaded into PFS, and zero time analysis was performed the next day. Information on the actual composition of the 15 prototype formulations is described herein.

[0362] The stability program for the stability work is defined below.

[0363] [Table 9]

[0364] (X) The decision to analyze these samples is made at 6M. The following HPLC method was developed to determine the potency of hydrocortisone sodium phosphate and the area % of hydrocortisone impurities and other unknown impurities in Hydrocortisone Sodium Phosphate Injection: This method uses High Performance Liquid Chromatography (HPLC) to determine the potency of hydrocortisone sodium phosphate and the area % of hydrocortisone impurities in Hydrocortisone Sodium Phosphate Injection.

[0365] Equipment and materials: HPLC: Waters Alliance 2695 equipped with a Waters 2998 PDA detector, data processing system equipped with Empower 2 software.

[0366] reagent: 1) Trifluoroacetic acid 2) Distilled water 3) Acetonitrile, HPLC grade 4) Hydrocortisone sodium phosphate standard (in-house) 5) Hydrocortisone impurity standard (in-house) Chromatography conditions: Column: Waters Sunfire C18, 250 x 4.6 mm, 5 μm Column temperature: ambient Mobile phase A: 0.2% v / v TFA in water Mobile phase B: 0.2% v / v TFA in ACN Diluent: Water:ACN (80:20) Pump and needle cleaning: Diluent Flow rate: 1.5mL / min Injection volume: 10μL Run Time: 45 minutes Detection wavelength: 254 nm Elution method: Gradient (linear):

[0367] [Table 10]

[0368] Preparation of hydrocortisone sodium phosphate standard solution: A 0.5 mg / mL solution of hydrocortisone sodium phosphate was prepared using diluent. The required amount of standard was weighed into a clean, empty, dry volumetric flask. Approximately 80% volume of diluent was added to the flask to dissolve the standard. Sonicate if necessary. Adjust the volume to the mark using diluent, mix well and use for analysis. Standard samples were prepared in duplicate.

[0369] Preparation of hydrocortisone impurity stock solution: For qualitative purposes, a stock solution of hydrocortisone impurity was prepared using ACN. Preparation of peak identification solution: The hydrocortisone impurity stock solution was separately spiked into one of the two hydrocortisone sodium phosphate standard solutions to prepare a peak identification solution. This solution was injected into the HPLC sequence to examine the peak shape, peak symmetry, and actual retention time of the hydrocortisone sodium phosphate and hydrocortisone impurity on the chromatogram. This solution was used for qualitative purposes only.

[0370] Preparation of Hydrocortisone Sodium Phosphate Injection Test Solution: A test solution of Hydrocortisone Sodium Phosphate Injection in diluent was prepared. Into a clean, empty, dry volumetric flask, the required amount of formulation equivalent to 0.5 mg / mL Hydrocortisone Sodium Phosphate was weighed. Approximately 80% volume of diluent was added to the flask to dissolve the formulation. Sonicate if necessary. Adjust volume to mark using diluent, mix well and use for analysis. Test solutions were prepared in duplicate for time zero analysis.

[0371] System suitability criteria for analysis: 1) The response precision between the two HCP standards should be between 98% and 102%. The response precision is calculated using the following formula:

[0372]

number

[0373] 2) The relative standard deviation % of the peak areas of five replicate injections of the HCP standard sample should be less than 2%. 3) The blank (diluent) chromatogram should be free of undesired peaks or humps.

[0374] 4) Note the retention times for the zero time analysis of hydrocortisone sodium phosphate and hydrocortisone impurities. These retention times should not vary by more than a 1 minute range (i.e., ±0.5 minutes).

[0375] A typical chromatogram of HCP using the developed analytical method is shown in Figure 2. Fifteen formulations were evaluated under stability study at 40°C and 25°C in PFS to evaluate pH effect, antioxidant combinations for 6 months. Results from stability data at 40°C and 25°C: Optimal pH range of 7.5-8.5, consistent with USP monograph specifications o EDTA / monothiolglycerol, EDTA / sulfite combinations show better stability than EDTA / Rongalite combinations, which are covered by U.S. Pat. No. 10,456,355, which is incorporated herein in its entirety. The addition of a third stabilizer, creatine, significantly improves the stability of formulations containing EDTA / Rongalit. The addition of creatinine as a third stabilizing agent did not result in any significant additional stability improvement for the EDTA / monothiolglycerol and EDTA / sulfite combinations. The three lead formulations have much better stability than the formulation of U.S. Patent No. 10,456,355, with approximately 60% less degradation after 6 months at 40°C, and an extrapolated shelf life of 24 months based on current stability trends (see Figure 1). The 50 mg / mL formulation has a viscosity close to that of water, with injection times of approximately 3 seconds for a 2 mL fill. The addition of creatinine as a third stabilizer to EDTA / MTG and EDTA / sulfite did not provide a significant improvement based on 3 month data.

[0376] [Table 11]

[0377] [Table 12]

[0378] [Table 13]

[0379] To develop this method, hydrocortisone sodium phosphate API was maintained under stress conditions. These stress conditions included treatment with 0.1 N HCl, 0.1 N NaOH, and dry heat. This was performed to investigate the nature of the API and the suitability of the stress conditions. It also served to generate degradation products to evaluate the specificity of the HPLC method under development. Information on the degradation products and the conditions used to generate them was used to optimize the method for better separation of such degradation products on the chromatogram. Figures 3A-3C show the chromatograms of HCP under stress conditions.

[0380] Forced degradation of HCP under three different stress conditions resulted in the formation of another common degradant, hydrocortisone. The rate at which the degradant was formed depended on the stress conditions. The stress studies performed on the API were for qualitative purposes only.

[0381] Preparation of HCP prototype formulations. Tables 12-26 below contain the actual compositions of the HCP prototype formulations prepared for this study. Each table also has density values ​​for each formulation prepared. Density was calculated using gravimetric measurements on the flasks used to prepare the formulations.

[0382] [Table 14]

[0383] [Table 15]

[0384] [Table 16]

[0385] [Table 17]

[0386] [Table 18]

[0387] [Table 19]

[0388] [Table 20]

[0389] [Table 21]

[0390] Syringes of HCP formulation #8 were split into three sublots: HCP F#8A, HCP F#8B, and HCP F#8C. The HCP F#8A syringe was kept unpouched.

[0391] HCP F#8B syringes were nitrogen purged and pouched. HCP F#8C syringes were pouched with two oxygen scavengers (not nitrogen purged).

[0392] [Table 22]

[0393] [Table 23]

[0394] [Table 24]

[0395] [Table 25]

[0396] [Table 26]

[0397] [Table 27]

[0398] [Table 28]

[0399] Syringes of HCP formulation #15 were split into three sublots: HCP F#15A, HCP F#15B, and HCP F#15C. The HCP F#15A syringe was stored unpouched.

[0400] HCP F#15B syringes were nitrogen purged and pouched. HCP F#15C syringes were pouched with two oxygen scavengers (not nitrogen purged).

[0401] Stability data of HCP prototype formulations. Tables 27-45 below contain the stability profiles for HCP formulations 1-15 stored at 25°C and 40°C for up to 6 months. They have data on assay %, peak area % of HCP, area % of known impurity hydrocortisone, and other unknown impurities. Note that the reporting threshold for hydrocortisone impurity is maintained as 0.01% since it is the major degradant. For other impurities, they are maintained as 0.05% in the chromatogram. Once identification and qualification of these unknown impurities are completed, the appropriate identification and qualification thresholds can be used in future studies.

[0402] The stability data of the following four unknown impurities are kept in the table according to their formation. The sum of the total other unknown impurities, which are lower amounts, was taken into account when calculating the peak area % of HCP. The impurities can be calculated using the following formula:

[0403] Sum of all impurities = 100-HCP peak area % Sum of total unknown impurities = 100 - (peak % of HCP + peak % of hydrocortisone impurity) Sum of other unknown impurities = 100 - (sum of peak % of HCP, hydrocortisone and impurities 1-4) Impurity 1 in the stability data table is identified on the chromatogram as a degradation product peak eluting at 5.00 minutes. The relative retention time of this impurity is 0.26. This impurity was observed during alkaline hydrolysis of HCP using 0.1N NaOH during method development. This impurity was also prevalent early on at accelerated stability conditions (40°C) in formulations that have sodium formaldehyde sulfoxylate in their composition as an antioxidant.

[0404] Impurity 2 in the stability data table is identified on the chromatogram as a decomposition product peak eluting at 15.07 minutes. The relative retention time of this impurity is 0.79. This impurity was not observed during the forced degradation of the HCP in method development.

[0405] Impurity 3 in the stability data table is identified on the chromatogram as a decomposition product peak eluting at 17.25 minutes. The relative retention time of this impurity is 0.91. This impurity was observed during alkaline hydrolysis of HCP using 0.1N NaOH during method development.

[0406] Impurity 4 in the stability data table is identified on the chromatogram as a decomposition product peak eluting at 23.64 minutes. The relative retention time of this impurity is 1.24. This impurity was observed during pyrolysis of the HCP using dry heat during method development.

[0407] The amounts of these four unknown impurities are more in the drug product compared to the amounts of other unknown impurities. Further investigations need to be conducted on such unknown impurities to mitigate the risk of their formation in future drug products.

[0408] [Table 29]

[0409] [Table 30]

[0410]

Table 31

[0411]

Table 32

[0412]

Table 33

[0413]

Table 34

[0414]

Table 35

[0415]

Table 36

[0416]

Table 37

[0417]

Table 38

[0418]

Table 39

[0419]

Table 40

[0420] [Table 41]

[0421] [Table 42]

[0422] [Table 43]

[0423] [Table 44]

[0424] [Table 45]

[0425] [Table 46]

[0426] [Table 47]

[0427] [Table 48]

[0428] Without intending to be bound by any particular theory, after stability analysis of all HCP formulations for 6 months storage at 25° C. and 40° C., HCP F#7 appears to be the most stable formulation. Contains 0.5% w / v monothioglycerol as an antioxidant. Monothioglycerol is a liquid excipient.

[0429] [Table 49]

[0430] [Table 50]

[0431] Also shown in Figure 4 is the stability of two formulations (#3 and #7) over a six month period.

[0432] [Table 51]

[0433] [Table 52]

[0434] FIG. 5 shows the stability of two formulations (#3 and #10) over a six month period.

[0435] [Table 53]

[0436] [Table 54]

[0437] [Table 55]

[0438] Example 6 One unknown impurity peak (RRT-0.91) in the hydrocortisone-phosphate product was purified by preparative HPLC and characterized by LCMS, HPLC and NMR. Its structure was tentatively proposed as a phosphate-shift isomer of hydrocortisone phosphate.

[0439] [ka]

[0440] [Table 56]

[0441] Without intending to be bound by any particular theory, it is believed that the concentration of monothioglycerol decreases over the shelf life of the formulation. In some embodiments, the level of monothioglycerol drops to about 60% of the original level at about 6 months at room temperature. Without intending to be limited by theory, it is expected that over the course of storage (e.g., but not limited to, after 12 or 18 months), the level of monothioglycerol may settle to about 0% in some embodiments. Without intending to be bound by any particular theory, it is believed that the decrease in monothioglycerol level may cause an increase in hydrocortisone (HCT)-related impurities. Monothioglycerol is an antioxidant, and therefore, without intending to be bound by any particular theory, it is believed that as long as there is a certain amount of monothioglycerol remaining in the formulation, it will attempt to protect the HCT from oxidation. Thus, in some embodiments, the initial formulation (before storage) is formulated to contain more than 0.5% w / v monothioglycerol.

[0442] In one embodiment, the formulation of Example 7 has improved stability compared to formulations in which monothioglycerol is replaced with Rongalite, creatinine, or a combination thereof. In one embodiment, the formulation of Example 7 demonstrates about 60% less degradation after 6 months at 40° C. than a formulation containing Rongalite. In one embodiment, the formulation of Example 7 is expected to have a shelf life of about 24 months.

[0443] Example 8: Impurity Specification The following table provides the organic impurity specifications for the hydrocortisone sodium phosphate formulations disclosed herein. Without intending to be bound by any particular theory, it is believed that the impurities should remain below this level over the course of storage (either at room temperature or at elevated temperatures). In some embodiments, the impurities should remain below this level up to 24 months of storage.

[0444] [Table 57]

[0445] Example 9: Pharmacokinetic Data The pharmacokinetic (PK) data for the formulation of Example 7 demonstrate that the formulation disclosed herein is biocomparable to the hydrocortisone reference-listed drug (Solu-Cortef). Solu-Cortef is a powder formulation that contains hydrocortisone sodium succinate, sodium phosphate monobasic anhydrous, and sodium phosphate dibasic dry, but lacks antioxidants, and is reconstituted in sterile water. The formulation disclosed herein achieves a greater area under the curve (AUC) and is closer to the maximum (or peak) serum concentration (C) achieved by hydrocortisone following administration. max ) occurred earlier.

[0446] Without intending to be bound by any particular theory, in some embodiments, considering that hydrocortisone is administered to treat acute events, these results demonstrate that the present formulation is better at treating such events, especially since the data indicates that the patient is far from receiving the maximum therapeutic dose or "unsafe" concentration. Specifically, the formulation disclosed herein provides a higher dose of hydrocortisone to the patient in an acute situation. This additional amount of hydrocortisone may provide additional hydrocortisone that may be helpful during an acute event and help the patient avoid adrenal crisis compared to the reference listed drug. In one embodiment, the disclosed formulation will be used in an emergency / rescue autoinjector device for the treatment of AAI (acute adrenal insufficiency) in subjects with primary or secondary adrenal insufficiency. This treatment is indicated when oral treatment is not feasible for use including the management of PAI (primary adrenal insufficiency) or SAI (secondary adrenal insufficiency), congenital adrenal hyperplasia.

[0447] Therefore, the AUC 0-tlast and AUC 0-inf Although the 90% CI for the ratios of the formulations disclosed herein (ATRS-2001) and the reference (Solu-Cortef) for C is higher than the FDA acceptable limit of 80-125%, the disclosed formulations may be beneficial for administration to subjects suffering from acute events. max The point estimates are within the criteria (80-125) with the upper limit outside the range, demonstrating that the disclosed formulations may be preferred for treating acute events / conditions, such as acute adrenal insufficiency.

[0448] [Table 58]

[0449] [Table 59]

[0450] [Table 60]

[0451] Penalty penalty visual results The cortisol plasma concentration curves for the formulations disclosed herein and Solu-Cortef are similar, with consistently higher plasma levels of cortisol observed for the formulations disclosed herein, both averages and both time periods (Figures 12 and 13).

[0452] PK analysis Pharmacokinetic parameters for each subject and period were max , T max , T 1 / 2 , Vp, Vss, CL, AUC 0-inf、 AUC 0-tlast λ z , and other standard NCA parameters in the R packages "Ubiquity" and "PKNCA" validated against WinNonLin. A summary is appended to the report.

[0453] C max , AUC 0-inf、 AUC 0-tlast and T max The parameters were analyzed with the R package “BE” using the SAS PROC GLM method of least squares fitted to a general linear model.

[0454] AUClast Figures 14 and 15 show the AUC last The equivalent plot and box plot for are provided, respectively.

[0455] [Table 61]

[0456] [Table 62]

[0457] [Table 63]

[0458] [Table 64]

[0459] [Table 65]

[0460] AUCinf Figures 16 and 17 show the AUC inf The equivalent plot and box plot for are provided, respectively.

[0461] [Table 66]

[0462] [Table 67]

[0463] [Table 68]

[0464] [Table 69]

[0465] [Table 70]

[0466] Cmax Figures 18 and 19 show max The equivalent plot and box plot for are provided, respectively.

[0467] [Table 71]

[0468] [Table 72]

[0469] [Table 73]

[0470] [Table 74]

[0471] [Table 75]

[0472] Tmax Figures 20 and 21 show max The equivalent plot and box plot for are provided, respectively.

[0473] [Table 76]

[0474] [Table 77]

[0475] Example 10: Phase 1, randomized, two-period, single-dose crossover study comparing the pharmacokinetics and safety of ATRS-1902 and Solu-Cortef background Patients with adrenal insufficiency (AI) are at risk for acute AI (AAI) and adrenal crisis (AC). Patients with AI may experience stressful situations (e.g., illness with fever, vomiting, surgical procedures) that increase the physiological demand for cortisol. When this occurs, the Endocrine Society recommends an increase in oral hydrocortisone (HCT) dose, or, if oral treatment is not feasible, an injection of 100 mg IM HCT. Additional HCT is essential to avoid progression to severe AAI or AC. A prefilled HCT autoinjector (ATRS-1902) was developed to deliver IM HCT without reconstitution. This study was performed to evaluate the PK of ATRS-1902 compared to Solu-Cortef, as well as the relative bioavailability and bioequivalence.

[0476] method In this randomized, open-label, phase 1 study, healthy human adults received a single dose of ATRS-1902 (100 mg IM HCT sodium phosphate via a prefilled syringe) and Solu-Cortef (100 mg IM HCT sodium succinate via a needle and syringe). Patients were randomized 1:1 to one of two treatment sequences (ATRS-1902 or Solu-Cortef), with the first treatment administered in Period 1 and the second treatment administered after crossover to Period 2. Prior to dosing, patients underwent a dexamethasone suppression test for adrenal cortical suppression. Doses during treatment periods were separated by approximately 5-day washout periods. Patients were evaluated for TEAEs, as well as AUC 0-inf , AUC 0-t , remaining area, C max , K el , T 1 / 2 el , and T max PK parameters including pharmacokinetics, ... and pharmacokinetics were evaluated.

[0477] result Fifty-six patients received at least one dose of ATRS-1902 and Solu-Cortef. Patients had a median (range) age of 40 (18-59) years and 50% (28 / 56) were women. In patients who received ATRS-1902 and Solu-Cortef, the mean AUC 0-inf are 5539.62 and 4530.69h respectively. * ng / mL and mean AUC 0-t are 5320.05 and 4329.14h respectively. * ng / mL. Mean C max The median (range) T max are 1.0 (0.0-2.5) and 1.0 (0.5-2.5) h, respectively, and the average T 1 / 2 el The mean time to recovery from schizophrenia was 1.98 and 2.18 h, respectively. The mean area remaining values ​​were 2.79% and 3.14% for ATRS-1902 and Solu-Cortef, respectively. These results are summarized in a percentage chart (Figure 29) compared to the reference enumerated drug. Overall, the most commonly reported TEAEs were headache (4 patients vs. 3 patients), muscle cramps (2 patients vs. 0 patients), and nausea (0 patients vs. 2 patients) in patients receiving ATRS-1902 and Solu-Cortef, respectively. No deaths or serious AEs were reported.

[0478] conclusion In this study, ATRS-1902 exhibited slightly higher exposure compared to Solu-Cortef. ATRS-1902 and Solu-Cortef demonstrated similar safety profiles, with all AEs consistent with HCT treatment. Overall, ATRS-1902 produced acceptable safety and PK characteristics. ATRS-1902 simplifies administration of HCT in critical clinical situations. ATRS-1902 increases HCT exposure compared to the reference enumeration drug (Solu-Cortef) when patients are likely to require additional doses of HCT to avoid adrenal crisis and hospitalization. Thus, ATRS-1902 can provide the unexpected benefit of additional and essential cortisol during risky stressful situations (compared to the reference enumeration drug).

[0479] Example 11: Hydrocortisone Sodium Phosphate Injection Ingredients of the drug product Hydrocortisone Sodium Phosphate Injection Hydrocortisone Sodium Phosphate Injection is available in a drug / device combination product as a ready-to-use prefilled syringe (PFS) administered with a pressure-assisted autoinjector (AI) device for intramuscular administration. The PFS contains a single 1.0 mL dose of a colorless to yellow, clear, sterile solution, resulting in a final delivered dose equivalent to 100 mg of hydrocortisone.

[0480] The final drug / device presentation comprises a PFS filled with 1.0 mL hydrocortisone sodium phosphate at a concentration of 134.2 mg / mL (equivalent to 100 mg of hydrocortisone) in a buffered aqueous solution containing edetate disodium dihydrate as a chelating agent and monothioglycerol as an antioxidant. The single-use AI delivers the labeled dose contained in the PFS. The PFS is constructed of a USP Type I clear glass syringe barrel with a fixed stainless steel needle, needle shield, and plunger stopper.

[0481] Active pharmaceutical ingredient, hydrocortisone sodium phosphate The drug substance (DS), hydrocortisone sodium phosphate (HSP), is the sodium salt of the phosphate ester of hydrocortisone. The high aqueous solubility of HSP allows for the development of an aqueous injectable formulation. The DS meets the requirements of the USP monograph "Hydrocortisone Sodium Phosphate, USP" except that a loss on drying (LOD) specification is used to test for water content that meets the British Pharmacopoeia specifications, rather than the Karl Fischer method. This is because the crystalline form obtained through the manufacturing process is a crystalline hydrate. To meet the USP LOD specification of NMT 5%, the manufacturing process must involve a lyophilization step that causes the formation of an amorphous form of HSP. The amorphous hydrocortisone sodium phosphate drug substance is therefore highly hygroscopic, as demonstrated by the data presented in Table 47.

[0482] [Table 78]

[0483] Hydrocortisone Sodium Phosphate (HSP) Injection contains a single-use pre-filled syringe with 1 mL of non-pyrogenic, colorless to yellow, clear, sterile solution of HSP at a concentration of 134.2 mg / mL and is supplied as an autoinjector (AI) that results in a delivered dose equivalent to 100 mg of hydrocortisone via intramuscular injection.

[0484] Drug Products Formulation Development Hydrocortisone sodium phosphate (HSP) is the sodium salt of the phosphate ester of hydrocortisone. Its molecular formula is C 21 H 29 Na2O8P, whose molecular weight is 486.4 g / mol. The formulation development of HSP is based on prior knowledge of two previously FDA approved injectable formulations, namely, Hydrocortone® (approved in 1960) and Solu-Cortef®.

[0485] Hydrocortisone sodium phosphate injection, including Merck's Hydrocortone®, is no longer available in the United States. Pharmacia and Upjohn's hydrocortisone sodium succinate for injection (Solu-Cortef, NDA 009866) is the only other hydrocortisone injection product currently approved for use in the United States. The active ingredient in this formulation is the sodium succinate ester of hydrocortisone. The formulation is a lyophilized powder for injection due to its poor aqueous stability. The formulation compositions of the four available forms of Solu-Cortef are given in Table 48.

[0486] [Table 79]

[0487] Solu-Cortef was used as the reference listed drug (RLD) because it is the only other hydrocortisone ester product currently approved in the United States that is listed as both an RLD and an RS (reference drug).

[0488] Analysis of Solu-Cortef (reference listed drug) One lot of Solu-Cortef RLD was analyzed for pH, density, assay, and total withdrawable and deliverable volume. Five Solu-Cortef Act-O-Vials, 100 mg hydrocortisone in 2 mL, NDC:00009-0825-01, were prepared according to the instructions on the package insert and analyzed for pH, density, and assay. The density of the hydrocortisone drug solution was determined to be 1.02075 g / mL, and the average pH value of the Solu-Cortef Injection was observed to be 7.48. Each vial was analyzed in duplicate for the assay, and the results are provided in Table 49.

[0489] [Table 80]

[0490] The mean drug concentration in the five vials was observed to be 51.79±0.63 mg / mL (on a hydrocortisone basis). The label claim is 100 mg in 2 mL of drug solution or 50 mg per mL. Based on this, the mean assay value % was observed to be 103.58±1.27%. Three vials were weighed for withdrawable and deliverable volume and then reconstituted according to the instructions on the package insert. The solution was then diluted with 18 mL of 100 mg ... * 1 1 / 2(1.2mm * A 3 mL syringe with a 40 mm (1.5 oz) needle (pre-weighed) was used to draw the solution. The weight that could be drawn was calculated by the difference in weight of the syringe with and without the solution. The volume that could be drawn was then calculated based on the density of the solution. The delivered volume was similarly calculated by measuring the weight of the solution delivered from the syringe. The results of this study are presented in Table 50.

[0491] [Table 81]

[0492] The following Quality Target Product Profile (QTPP) (Table 51) was developed as a summary of the expected determined quality, safety, and efficacy characteristics of the drug product and forms the basis for the development of CQAs, CPPs, and control strategies.

[0493] [Table 82]

[0494] Effect of pH on the stability of HSP under accelerated storage conditions (40℃) As shown in Figure 22, the levels of the major hydrolysis impurity, i.e., hydrocortisone, increase as the pH of the formulation decreases under accelerated storage conditions at 40°C. HSP is prone to general acid catalyzed hydrolysis at pH < 7.5. pH is a critical quality attribute (CQA) that needs to be controlled within pH 7.5-8.5. Effect of concentration and solubilizers on hydrocortisone sodium phosphate. The formation of hydrocortisone was primarily dependent on the pH of the formulation. Within the pH range studied (pH 7.0-8.5), the level of hydrocortisone impurity was well below 2.0% at 6 M, and no precipitate was observed in any of the formulations, regardless of HSP concentration. Therefore, the use of a solubilizer in HSP formulations is not essential as long as the pH of the formulation (>pH 7.5) is controlled over the shelf life.

[0495] Physicochemical and biological properties In addition to the above formulation development work, characterization studies were performed on selected batches in an attempt to ascertain the overall physicochemical and biological properties of the drug product. Temperature cycling studies are described below: The objective of the study was to evaluate the effect of stress temperature cycling on the product in its final container closure configuration, mimicking high and low temperature fluctuations that may be encountered during shipping and handling. The study was conducted with final container closure configurations, i.e., hydrocortisone sodium phosphate injection solution in bare syringes (PFS) and syringes with hydrocortisone sodium phosphate injection solution assembled in autoinjectors (AI) packaged in cartons with three autoinjectors per carton. All samples were stored horizontally throughout the study.

[0496] The study was performed using a PFS from the registered batch (Y0175) and one of the autoinjectors assembled from lot I2555. Temperature cycling was preformed according to Table 52 below. Standard samples were stored at room temperature and protected from light. All samples were analyzed at the end of the three cycles.

[0497] [Table 83]

[0498] After temperature cycling, the appearance of all samples was a colorless to yellowish clear solution (Table 53). Assay and impurity results for the two batches were within specifications as well as subvisible particle measurements, pH and delivery volumes. Furthermore, no significant movement of the stopper was observed upon measurement of stopper position. It can be concluded that the product can withstand repeated (3 times) exposure to -20°C and 40°C for at least 1 day with no detectable product changes as measured by the validated test method.

[0499] [Table 84-1]

[0500] [Table 84-2]

[0501] Container Closing System Container and Closure System Components The PFS container stopper system for HSP injection assembled into an autoinjector (AAI) includes a syringe, plunger stopper, and autoinjector subassembly described in Table 54. The syringe contains a 2.25 mL syringe barrel made of siliconized USP Type I borosilicate glass and a fixed siliconized stainless steel needle protected by a rigid needle shield (RNS). <660> The corresponding syringes are required for type I glass containers for parenteral preparations. They are supplied pre-cleaned and sterilized, as described in DMF 021723, held by Nuova Ompi.Srl. The plunger stopper is made of chlorobutyl as an elastomer type, <381> The stoppers meet the requirements for Type I closure as outlined in 2010 FDA CFR 1.210.122. Pre-cleaned and sterilized stoppers as described in DMF 011648, DMF 030048, and DMF 020880 maintained by West Pharmaceutical Services, Inc. are supplied. The syringe and plunger stoppers serve as the primary packaging components that have product contact with the HSP injection.

[0502] [Table 85]

[0503] Medical Equipment HSP injections are administered using a single-use autoinjector device that is disposed of after injection and does not require cleaning, maintenance or rework. The autoinjector device provides intramuscular injection of HSP based on a spring-loaded needle. The drug product can be self-injected by either the patient or the caregiver. The device provides protection from accidental needle prick after injection. The autoinjector device does not require any preparation, such as filling, reconstitution or dose dialing, prior to injection. The delivery volume is not adjustable by the end user. The autoinjector has no fluid pathway and does not come into contact with the HSP injection solution contained in the syringe. Therefore, the autoinjector is not sterilized. APMOF manufactures the autoinjector. There is no contact between the autoinjector and the drug product. Secondary packaging for combined products – cardboard carton One commercial packaging configuration is available: a paperboard shelf carton containing three autoinjectors.

[0504] Infusible and extractable container closure systems Analytical Evaluation Threshold (AET) USP <1664> According to the "Evaluation of Leachable Drug Products Related to Pharmaceutical Packaging / Delivery Systems", the Analytical Evaluation Threshold (AET) is the threshold at or above which leachables should be characterized and reported for toxicological evaluation. Therefore, the AET must be defined prior to extractable / leachable studies. The AET can be mathematically derived from the Safety Concern Threshold (SCT) based on the administration parameters of the drug product. For organic compounds, a Safety Concern Threshold (SCT) of 5 μg / day is selected based on the following rationale: (1) The SCT for each individual irritant or sensitizer is 5 μg / day according to the Product Quality Institute (PQRI).

[0505] (2) For acute use where the duration of treatment is not expected to exceed 30 days, the SCT for individual and multiple genotoxic impurities is 120 μg / day according to ICH M7(R1). Therefore, an SCT of 5 μg / day is a lower threshold than that of ICH M7, unless more than 24 genotoxic impurities are present at at least 5 μg / day, which seems highly unlikely, even when the more stringent thresholds of all impurities are used for comparison. Based on the maximum dosing regimen (single dose / day), the SCT can be converted to AET as follows (using single dose / day and single dose / component):

[0506]

number

[0507] For elemental impurities, there are currently no universal SCTs available for metals, so the AET was set at the instrument detection limit of 1 ng / mL. Elemental metals below 1 ng / mL will be reported as not detected.

[0508] Controlled extract studies The primary packaging components evaluated in the Controlled Extractables Study (CES) included the syringe / needle assembly, needle shield, and plunger stopper. The CES is summarized in Table 55.

[0509] [Table 86]

[0510] Leachables Screening Based on Aged Drug Products An aged PFS sample (Lot HCP#28) based on the same formulation as the proposed drug product stored at 40° C. for 6 months was used for leachable screening. The aged PFS sample was tested by using the same methodology used in the CES and the results are summarized in Table 56.

[0511] [Table 87]

[0512] Leaching method development and certification A GC with flame ionization detection (FID) method (M22448) was developed to test for the potential target leachables THFM and MOSDO. As MOSDO is not commercially available, the structurally similar compound 1-oxaspiro[4.5]decan-2-one (OSDO) was used as a surrogate for method development and validation. MOSDO is monitored by its relative retention time (RRT) of 1.005 vs. OSDO. Acetophenone (ACET), tetrahydrofurfuryl methacrylate (THFMA), and diphenyl ether (DPE) are common leachables found in typical PFS systems. Although ACET, THFMA, and DPE are not found in aged samples, they are also included for stability monitoring and screening purposes. The practical quantification limit (PQL) of M22448 is 1 mg / syringe, 5 times lower than AET.

[0513] The samples aged during the leachable screening study had only one non-volatile leachable, namely dodecanoic acid (approximately 2.5 mg / syringe, Table 56). Dodecanoic acid is a major component of dietary triglycerides, e.g., coconut oil, and is a common food ingredient. Its SCT and AET are likely to be much higher than 5 mg / day and 5 mg / syringe, respectively. Therefore, a method specific to dodecanoic acid for leachable stability studies has not been developed. Instead, a generic LC-MS screening method (M22182) was developed as a precaution to monitor potential non-volatile leachables, including dodecanoic acid, for stability. The surrogate compound Irganox 245 is used to demonstrate the feasibility of the method, including reporting the limit (i.e., detection limit) of 1 mg / syringe. Dodecanoic acid is monitored with an RRT of 0.78 vs. Irganox 245. Similarly, other unknown potential volatile leachables will be monitored vs. Irganox 245, RRT.

[0514] Irganox 245 is used as a surrogate standard in M22182 because it is detected in all three detection channels including UV, electrospray ionization (ESI)(-) and ESI(+) and shows similar response in at least one of the three detection channels compared to common leachable / extractable compounds, making it an ideal surrogate standard for quantification when reliable standards are not available for general screening purposes: · Irganox 245 contains the same phenolic moiety as typical stopper extractables such as butylated hydroxytoluene (BHT) and Irganox 1010. Therefore, Irganox 245, BHT and Irganox 1010 exhibit similar UV chromophores and UV responses.

[0515] The response of Irganox 245 in negative ESI mode is comparable to that of long-chain fatty acids in a typical extract containing dodecanoic acid. Only one volatile leachable, isopropanol (2-propanol), was found in the aged samples. However, the level of isopropanol found in the aged samples (0.04 mg / syringe or 0.04 ppm, Table 56) was 10% below the 5000 ppm limit according to ICH Q3C(R6). 5 The toxicity of isopropanol is 1 / 100 of that of isopropanol, a Class 3 residual solvent with low toxicity. Therefore, isopropanol was not selected as a potential leachable to be monitored in the leachable stability study.

[0516] Summary of leachable stability results Leachable stability results are summarized in Table 57. Three primary stability batches were manufactured in August-September 2021. Stability samples were stored at ambient before commencing leachable stability in April 2022 (approximately 8 months). No detectable (i.e., <1 mg / syringe) leachables were observed up to 14 months (including 8 months at ambient and 6 months at 25°C / 60% RH in a stability chamber). Leachable stability studies will continue up to 36 months.

[0517] [Table 88]

[0518] Excipient Specifications The excipients used in the manufacture of Hydrocortisone Sodium Phosphate Injection are tested and released in accordance with the specifications and test methods set out in the referenced Pharmacopoeias in Table 58.

[0519] [Table 89]

[0520] Additional testing for bacterial endotoxin (BET) and microbial limits (TAMC and TYMC) beyond that described in the USP monographs was performed on the following excipients as shown in Table 59. BET and microbial limits testing with sodium hydroxide was not required as it is a strong base.

[0521] [Table 90]

[0522] Justification of excipient specifications In addition to the tests specified in the United States Pharmacopeia-National Formulary (USP-NF), all excipients, except sodium hydroxide, which is a strong base, are also tested in accordance with the USP <85> The bacterial endotoxin (BET) was tested by 100 mg / kg / day to ensure proper control of BET for parenteral products. In theory, the maximum acceptable BET limit per dose for all excipients (BET 賦形剤 ) can be estimated as follows: The BET limit for a drug product (DP) is the total limit of BET per daily dose (BET DP ) 125 EU, which is 1.25 EU / mg of hydrocortisone.

[0523] The BET limit for the drug substance (DS) is 0.75 EU / mg hydrocortisone, with a maximum total limit of BET per daily dose (BETDS ) is 75 EU. BET Limits for Syringes (BET シリンジ ) and the BET limit for the stopper (BET ストッパー ) are 0.25EU / syringe and 1EU / stopper, respectively.

[0524] The maximum BET limit per dose for all excipients can be calculated as follows: BET 賦形剤 =BET DP -(BET DS +BET シリンジ +BET ストッパー )=48.75EU / dose.

[0525] Based on the BET specification limits, the maximum total BET contribution from all excipients is 8.6 EU / dose, which is much lower than the 73.75 EU / dose allowed by the DP acceptance criteria calculated above. Therefore, acceptance criteria for all excipients are justified and are shown in Table 60.

[0526] [Table 91]

[0527] Additionally, microbial limit testing was performed to ensure adequate control of microorganisms in the excipients for the parenteral product. The maximum combined microbial contribution from all excipients is 826 CFU / 100 mL (Table 61).

[0528] During the manufacture of DP, a bulk solution containing DS and other excipients was made and then filtered through a 0.22 μm bioburden reduction filter. Theoretically, DS is the main source of microorganisms since its maximum microbial contribution (11,000 CFU / 100 mL) is higher than the maximum microbial contribution from all excipients combined (i.e., 826 CFU / 100 mL). The maximum total microbial contribution of approximately 12,000 CFU / 100 mL can be easily removed / reduced by a typical sterile bioburden reduction filter to meet the in-process control (IPC) bioburden specification limit of not more than 10 CFU / 100 mL. The IPC bioburden results for all three registered batches were 0 CFU / 100 mL after bioburden reduction filtration.

[0529] [Table 92]

[0530] HSP injection specifications Testing on the proposed single-use final (drug / device) combination product was performed on both the pre-filled syringe (PFS) and the assembled autoinjector (AAI). The PFS was tested for drug product identity and for attributes related to potency, purity, and safety. The specifications of the PFS are shown in Table 62. The AAI was tested for attributes related to device performance for drug product delivery, and the results are shown in Table 63.

[0531] [Table 93]

[0532] [Table 94]

[0533] Batch Analysis The results of the batch analysis for the three enrolled batches of Hydrocortisone Sodium Phosphate Injection Prefilled Syringes (PFS) are summarized in Table 64. The release testing of the AAI functional attributes is summarized in Table 65.

[0534] [Table 95-1]

[0535] [Table 95-2]

[0536] [Table 96]

[0537] Justification for the specification of HSP injection combination products The hydrocortisone sodium phosphate (HSP) injection combination product was tested in two stages. Pre-filled syringes (PFS) containing sterile HSP injection were tested for identification (ID) and for attributes related to efficacy and patient safety. Assembled autoinjectors (AAI) were tested for attributes related to delivery device performance for drug delivery.

[0538] Testing of physicochemical and microbiological (PCM) critical quality attributes (CQAs) for HSP Injectable Drug Products (DP) is conducted in accordance with ICH Q6A, USP <1> and is designed to meet the requirements set forth in the HSP Injection USP monograph. All PCM studies will be performed on the HSP Injection PFS for the following reasons: · The autoinjector (AI) does not come into direct contact with the HSP DP solution contained in the PFS. As a result, the AI ​​does not alter the PCM properties as further described in Table 66. Comparison of the release results of the three primary stability batches confirmed that assembly of the PFS in the autoinjector did not alter the PCM properties. · AIs are not a barrier to temperature, humidity, and oxygen. When stored in a stability chamber, HSP DPs in PFS with or without AIs are subjected to the same environmental conditions, including exposure to temperature, humidity, and oxygen. AIs have no effect on product stability, and in fact AIs may provide better light protection.

[0539] [Table 97]

[0540] As shown in Table 66, the AAI was not tested for stability. There is no need for testing the AAI on stability since the materials that compose it do not change over time. The AI ​​components are made of plastics and metals. Once tested and verified for release, the functionality of the AI ​​should not change over time unless the AI ​​components that are relevant to its function deform. The rate of deformation is known to depend on the material properties, applied structural stress, exposure time, and exposure temperature. Deformation is most significant at temperatures close to the melting point of the material, but is minimal at temperatures much lower than the melting point. The melting points of the plastics and metals used in autoinjectors are significantly higher than room temperature.

[0541] Therefore, these AI components are not expected to deform within the relatively short time of 2 years (i.e., the proposed shelf life) when stored at ambient temperature. As a result, all functional attributes are not expected to change over time at long-term conditions. Testing was completed on AI units exposed to accelerated aging per ASTM F1980-21 for a representative shelf life of 2 years. This data supports that the functional attributes of the AI ​​do not change over the shelf life of the product. This justification is further supported by the stability results from the registration batches, which show that all functional attributes, including delivery volume, extrusion time, exposed needle length, trigger action, and cap removal torque, remained nearly constant at long-term conditions. Therefore, the functional attributes of the AI ​​were tested only for release and not stability in post-approval commercial batches.

[0542] exterior Acceptance Criteria (PFS): Colorless to yellowish clear solution in a 2.25 mL glass syringe with a gray stopper.

[0543] Acceptability criteria (AAI): Colorless to yellowish clear solution in a single-dose prefilled autoinjector. The objective of this study was to evaluate the appearance of the DP. Dissolution of the HSP drug substance (DS) in aqueous solution resulted in a colorless to yellowish clear colored solution.

[0544] Solution color Acceptance Criteria: Report Results The European Pharmacopoeia (EP) method, Ph.Eur.2.2.2., Method 1, is used to assess the color of the solution against a set of standard colors; the solution should be colorless.

[0545] Identification by HPLC Acceptance criteria: UV: The UV spectrum of the hydrocortisone sodium phosphate peak in the chromatogram of the sample preparation corresponds to that of the standard preparation.

[0546] HPLC retention time: The retention time of the hydrocortisone sodium phosphate peak in the chromatogram of the sample preparation corresponds to that of the standard preparation. The purpose of this RP-HPLC study was to confirm the identity (ID) of the HSPs in the DP based on both HPLC retention time and UV spectrum. For a correct ID, both of the acceptance criteria cited above must be met.

[0547] The HPLC retention time requirements were based on the intrinsic hydrophobic behavior of the HSP under defined chromatographic conditions and compared to that of the authentic standard. Identification was confirmed by HPLC using the sample preparation and chromatographic conditions described in the QE-499 method, which is also used for the HSP assay and the analysis of organic impurities. Specificity studies show that there is no diluent peak and no interference from HSP degradation products that elute at the retention time of the HSP under the chromatographic conditions of the method. The retention time of the HSP peak in the DP is specific to the DS and therefore suitable for identification.

[0548] The UV spectrum of the HSPs was also specific and unique. The ID was confirmed when compared to authentic standards. The combination of UV spectrum and HPLC retention time provides two orthogonal methods to confirm identity. The ID test is performed on the release only.

[0549] Hydrocortisone sodium phosphate assay Acceptable standards for hydrocortisone equivalents Shelf life: 90.0% to 110.0% of the label Release: 95.0% to 105.0% of label claim pH Acceptance criteria: pH 7.5~8.5 particulate matter Acceptance criteria: ≧10μm: Max 6000 particles / syringe ≧25μm: Max 600 particles / syringe The purpose of this test is to comply with USP 101001, which specifies test procedures and acceptance criteria for evaluating particulate matter. <1> The objective of the study was to ensure compliance with ICH Guideline Q6A for parenteral and parenteral products. <788> Due to particulate matter in the injections, Method I (light obscuration particle counting method) was selected for aqueous-based hydrocortisone sodium phosphate injection. The USP recommended acceptance criteria shown above were adopted.

[0550] Monothioglycerol Acceptance criteria: 3.5-5.5mg / mL (release only) Monothioglycerol (MTG) was used as the antioxidant. The nominal concentration of MTG is 5 mg / mL. At the end of the shelf life (i.e., 24 months), MTG results were not available for the three primary stability batches, and the aged development batches (i.e., Formulations 7A through 7F) and batch Y0011 were tested for MTG.

[0551] In formulations 7A and 7D with a starting MTG level of 2.5 mg / mL, MTG was not detectable at 27 months. Therefore, in these two batches, MTG levels would likely be close to zero at 24 months. It was noted that the nominal concentration of HSP in development batches 7A to 7F was 67 mg / mL, which is 50% of the HSP concentration in the proposed formulation. The oxygen concentration in the PFS should be the same regardless of the HSP concentration. Obviously, at lower HSP concentrations, the ratio of oxygen to HSP is higher. Thus, the formulation with 67 mg / mL HSP represents the worst scenario in terms of oxidation compared to 134 mg / mL HSP.

[0552] For formulations 7B and 7C (starting MTG level 5 mg / mL), MTG levels were approximately 30% at 27 months, suggesting that MTG levels were likely to be ≥ 30% at 24 months. For batch Y0011 (starting MTG level 5 mg / mL), MTG levels were 48% at 22 months.

[0553] For formulations with a starting MTG level of 10 mg / mL, it was suggested that MTG levels were >60% at 27 months and that MTG levels were likely to be ≥60% at 24 months. In summary, when the MTG starting level ranged from 2.5 mg / mL to 5 mg / mL, oxidation was effectively inhibited, although at the end of the proposed shelf life (i.e., 24 months), MTG levels could range from near zero to approximately 30%. The upper limit of MTG (5.5 mg / mL or 110%) was due to potential manufacturing variability, while the lower limit (3.5 mg / mL or 70%) was due to both potential manufacturing variability and potential loss of MTG acting as an antioxidant during manufacturing.

[0554] Ethylenediaminetetraacetic acid Acceptable limit: 0.10-0.22 mg / mL (emission only) Ethylenediaminetetraacetic acid (EDTA) is a chlorine-based ionizer that is used to treat catalysts or transition metal ions (e.g., Fe) that may be present in the manufacturing process. 3+、 Cu 2+、 and Ni 2+ EDTA is a chelating agent that scavenges EDTA and thus prevents potential catalytic oxidation of the drug product. However, after production, any potential catalytic metal ions from the manufacturing equipment or starting materials should be completely scavenged by EDTA and there will be no free catalytic metal ions in the drug product for the following two reasons: (1) There is no mechanism by which any catalytic metal ion can be generated from any drug substance.

[0555] (2) There are no known leachable metals from the primary container closure in typical aqueous prefilled syringe systems, and this is no exception for the HSP injectable PFS. No leachable metals were found in the aged PFS batches after 6 months of storage at 40°C.

[0556] Since there are no catalytic metal ions in the drug product after manufacture, the presence (or absence) of EDTA should not affect the stability, safety and efficacy of the drug product. Therefore, only release acceptance criteria are presented. The upper limit (0.22 mg / mL or 110%) is due to potential manufacturing variability, while the lower limit (0.10 mg / mL or 50%) is due to reduced EDTA levels due to chelation with metal ions that may be present in the manufacturing process.

[0557] Bacterial endotoxins Acceptable limit: 1.25 EU / mg hydrocortisone The purpose of this study was to ensure compliance with the ICH Guideline Q6A for Parenteral Products, which specifies the inclusion of test procedures and acceptance criteria for endotoxins. <85> A bacterial endotoxin turbidimetric method was used to perform this test and was validated and qualified as suitable for use in release and stability testing of Hydrocortisone Sodium Phosphate Injection. The NMT 1.25EU / mg hydrocortisone limit was adopted as per the USP monograph. This limit is based on the patient pyrogenic response threshold (NMT 5EU / kg / hr) and a body weight of 70Kg, as specified in the USP <85> This is nearly three times the 3.5 EU / mg hydrocortisone limit recommended by the FDA.

[0558] sterility Acceptance Criteria: Media must not exhibit growth The purpose of this test is to comply with USP stipulations that include test procedures and acceptance criteria to evaluate sterility. <1> The objective of the study was to ensure compliance with ICH guideline Q6A for oral, injectable, and parenteral products. <71> A validated method based on the FDA Certification Standard was used. This validation was done to ensure that any bacteriostatic and fungistatic activity inherent in the test solution would not affect the reliability of the test and that the procedure used was suitable for its intended use.

[0559] Uniformity of Dosage Unit – Release Test Only Acceptance criteria: The acceptance value (AV) of 10 dosage units is ≦15.0. If the AV is >15.0, the next 20 units are tested, and the AV of 30 dosage units is ≦15.0. No individual dosage unit has a content less than [0.75M] or more than [1.25M]. The objective of this study was to ensure compliance with the ICH Guideline Q6A for Parenteral Products, which specifies the inclusion of test procedures and acceptance criteria for evaluating uniformity of dosage units. <905> The HSP DP is a solution in a unit dose container, so weight variations are consistent with USP <905> This study was performed at release for both PFS and AAI.

[0560] Volume in container (delivery volume) Acceptance criteria: 1.00-1.20 mL for the final combined product of the prefilled syringe (PFS) and assembled autoinjector (AAI).

[0561] The purpose of this test is to <1> The objective of the study was to verify the delivery volume of parenteral preparations by the USP 1.00 mL. The lower limit (1.00 mL) was to ensure that the delivery volume was not less than the labeled volume (i.e., 1 mL). <1> The upper limit (1.20 mL) is based on the requirement by the FDA. The upper limit (1.20 mL) is based on the maximum target fill volume (1.11 mL) and potential manufacturing variability. The volume in the container was tested at release only to ensure that the appropriate volume was filled into the PFS.

[0562] Residual Solvent HSP DP is USP <467> General chapter on residual solvents according to option 1 - corresponds to the cumulative approach with control of raw materials. Therefore, no additional testing on residual solvents is required in the HSP DP.

[0563] Elemental Impurities Elemental impurities (EI) in the HSP DP were determined by using an inductively coupled plasma mass spectrometry (ICP-MS) method for two potential EI sources (manufacturing and container closure components) as per ICH Q3D. For DS and excipients, elemental impurity statements / risk assessments from the respective vendors were considered to calculate the maximum daily exposure of EI.

[0564] The EI test results (usually at concentrations, e.g., μg / mL or μg / g) were converted to daily exposure (μg / day) based on a maximum dose of 134.2 mg / day or a maximum dose volume of 1 mL / day, and the maximum daily exposure results are shown in Table 70. The results for any given EI were not greater than 0.1 μg / day (NMT) for any one of the four potential sources, with an NMT of 0.2 μg / day for all four potential sources (Table 70). The risk of EI is assessed based on the Margin of Exposure (MOE), which is the ratio of the Permitted Daily Exposure (PDE) to the Maximum Total Daily Exposure per ICH Q3D. As shown in Table 67, the MOEs ranged from 222 to 75,000, indicating that there was no risk of EI in the drug product, and therefore testing for elemental impurities was eliminated from the completed drug product testing.

[0565] [Table 98]

[0566] Nitrosamines A risk assessment for the presence of nitrosamines in drug products was conducted based on nitrosamine disclosures from excipient and container closure component vendors and a risk assessment was also conducted by the DS manufacturer and DP manufacturing facility. The risk assessment considered the following factors: 1. Use of any nitrosating agent in the presence of any secondary / tertiary amine 2. Introduction of nitrosamines during the manufacturing process 3. Use of voluntary salvaged / recycled materials 4. Potential for cross-contamination 5. Primary packaging materials.

[0567] There is no risk of the presence of nitrosamines in hydrocortisone sodium phosphate injection, according to the following summary: 1. The drug substance, excipients, water for injection, and components (syringe barrel, stopper, and needle shield) are free of amines, nitrites, nitrates, or nitrosamines. 2. Nitrosamine formation (e.g., from nitrite sales and amines) requiring acidic conditions is minimal - HSP DP formulation, pH 8.0 base 3. There is no risk of potential contamination with or formation of nitrosamines in the drug product manufacturing process or from the drug product manufacturing equipment.

[0568] Therefore, testing for nitrosamines is not included as part of the HSP DP testing. Delivery volume (dose accuracy) Acceptance criteria: Not less than 1.00 mL, not more than 1.20 mL The autoinjector must deliver the labeled volume of drug product in order to deliver the drug to the target injection site.

[0569] Extrusion (injection) time Acceptance criteria: <10.0 seconds Drug delivery times of less than 10 seconds, which is within the range of existing products currently on the market.

[0570] Exposed needle length Acceptance criteria: 23+ / -3mm. For a patient to receive a sufficient dose of HSP, the needle must pass completely through the tissue above the muscle and through the target muscle. A needle length of 20-26 mm will accomplish this task in most patients. In the United States, the average adult (age >18 years) is often divided into one of three categories: healthy weight, overweight, and obese, with very few patients falling into the categories of underweight and morbid obesity. Each of these categories will affect the thickness of the subcutaneous fat layer causing variations in the thickness of the tissue above the muscle layer of the thigh. Furthermore, differences in the thickness of the tissue above the muscle layer may vary depending on whether the patient is male or female. This is present under all body mass and gender conditions based on available literature, with the thickness of the tissue above the muscle (skin + fat) often ranging from 2.25 mm to 21.75 mm in men and 4.0 mm to 28.3 mm in women. As can be expected, the thickness is highly dependent on BMI status.

[0571] There is a small subset of patients with the highest BMI where this may occur and the HSP product may not be able to completely pass through the muscle and deliver an intramuscular dose. Patients with a BMI>40 (morbidly obese) are encouraged to consult with their physician to see if their skin and subcutaneous tissue is thicker than the 20-26mm needle length included with the HSP product.

[0572] Trigger Force Tolerance: ≦8.5lbF (force-pounds) Based on DTI studies of strength data, 8.5 lbf is achievable with one handed pressure by adolescents with an average age of 6-10 years. Therefore, the specifications set should be achievable by the intended patient population (patients and caregivers, ages <18 years). This actuation force specification is similar to other products on the market.

[0573] Safety Cap Removal Torque Tolerance: ≦11in-lbs (inch-pounds) Like other autoinjectors on the market, strength data is based on DTI studies. 11 in-lbs is achievable by an adolescent female, average age 6-10, with one hand twisting the knob or removing the lid of a similar sized jar. Therefore, the specifications that are set should be achievable by the intended patient population (patients and caregivers, age <18 years).

[0574] Feature Functionality Qualification testing included verifying the needle was covered prior to injection, the viewing window was clear, the assembled autoinjector (AAI) was ready for injection, the needle shield was uncapped, the AAI was triggered, the AAI delivered the drug, and the viewing window was closed at the end of the injection, ensuring passive protection from sharps injury.

[0575] Acceptance Criteria: Report Results Each of these functions must occur to allow the AI ​​to deliver the dose to the target injection site. Closing the window at the end of the injection triggers the device, providing a visual cue to the user that a sufficient dose has been delivered. Activation of the passive sharps protection mechanism is a safety mechanism designed to prevent accidental needle sticks with the needle being used.

[0576] Container Closing System The proposed drug product (DP) is supplied as a single-use prefilled syringe (PFS) containing a fixed volume of 1.0 mL of sterile hydrocortisone sodium phosphate (HSP) solution for intramuscular administration, resulting in a final delivered dose of 100 mg hydrocortisone (equivalent to 132.4 mg hydrocortisone sodium phosphate). The prefilled syringe containing the final DP is then assembled into an autoinjector, which is the final proposed product.

[0577] Primary container closure The hydrocortisone sodium phosphate (HSP) drug product (DP) solution in a primary container closure system contains standard packaging components for injectable drug products. The HSP DP was aseptically filled into USP clear Type I borosilicate glass, siliconized 2.25 mL syringe barrels fitted with siliconized fixed stainless steel needles protected by a latex-free rigid needle shield. The syringes were supplied by the manufacturer Nuova Ompi Srl (Ompi) and were pre-cleaned, sterilized, and siliconized. The closures were supplied by the manufacturer West Pharmaceutical Services, Inc. and consisted of pre-cleaned, siliconized, sterile, latex-free gray chlorobutyl elastomer plunger stoppers. A detailed summary of the primary container closure system and manufacturer information is included in the Table.

[0578] [Table 99]

[0579] Syringe barrel with needle and needle shield The syringes were supplied as single units consisting of a glass barrel, a fixed stainless steel needle, and a rigid needle shield. The borosilicate glass conforms to the USP for Type I glass containers for parenteral preparations. <660> The requirements of the 2.25 mL sterile glass syringe barrels were supplied by Nuova OMPI Srl (Figure 23). Plunger Stopper Siliconized gray chlorobutyl elastomer plunger stoppers meet USP <381> The requirements for Type I closure as outlined in (Table 69) were met.

[0580] [Table 100]

[0581] Autoinjector The Vai™ autoinjector (VAI) is an automated drug delivery device for intramuscular administration of hydrocortisone sodium phosphate (1 ml via a prefilled syringe). It is a preassembled, prefilled, single-dose, spring-loaded, disposable drug delivery device that can be used by subjects, their partners / spouses, immediate family members, and third parties, such as school nurses or other healthcare professionals.

[0582] Features include the ability to deliver 1 mL (100 mg) of drug product intramuscularly to the anterior lateral thigh muscle tissue in less than 10 seconds. A display window allows visualization of the contained drug product. A visual indicator notifies the user that the drug has been delivered. The AI ​​device is designed to allow injection through clothing, if required and includes several safety mechanisms to avoid accidental triggering of the device. The device has no fluid pathways and does not come into contact with the drug contained in the prefilled syringe.

[0583] It utilizes a primary container closure of a 2.25 ml glass syringe with a 25 gauge, 25.4 mm (1") staked needle and a rigid needle shield. Injection is accomplished by holding the needle guard against the injection site and pushing the device against the injection site. Following injection, the device is removed from the injection site and the needle guard automatically extends over the needle, locking out and preventing further exposure of the needle. The delivery volume is fixed by the syringe fill volume and is not adjustable by the end user.

[0584] The Vai™ autoinjector does not require preparation, such as filling, reconstitution, or dose dialing, prior to injection. The device is designed for a single dose and is discarded after injection, requiring no cleaning, maintenance, or reprocessing. The autoinjector and its components are described in International Patent Application No. PCT / US2019 / 036178 (WO 2019 / 237082), filed December 19, 2019, and U.S. Patent Application No. 16 / 435,450 (U.S. Publication No. 2019 / 0374717), filed June 7, 2019, each of which is incorporated herein by reference in its entirety.

[0585] The front subassembly, rear subassembly, needle shield remover, and syringe holder components were assembled into an autoinjector for testing and ejection of the subassembly. A representative autoinjector assembly is provided in Figures 24 and 25. Drawings of the subassemblies are included in Figures 26 and 27.

[0586] [Table 101]

[0587] Stability Summary and Conclusions Stability studies Description of Registration Batches. Table 71 lists the information for the primary stability batches of both Hydrocortisone Sodium Phosphate (HSP) Injection Prefilled Syringe (PFS) and HSP Injection Assembled Autoinjector (AAI). The batch size of the PFS registration batch is identical to the proposed product PFS batch size of 30 liters (L), which is based on approximately 85% yield and typically results in approximately 23,000-25,000 units of PFS'. The maximum AAI product batch size is approximately 23,000 units, based on approximately 90% assembly yield, when a total of 30L PFS batches are assembled into the AAI. Thus, the batch size of the primary stability AAI batch represents approximately one-fifth of the AAI product batch size (see Table 71).

[0588] Stability Protocol Stability protocols, including storage conditions and testing intervals, were established according to current ICH guidelines. A summary of the stability protocol for PFS is provided in Table 72. PFS samples without additional packaging were stored in two orientations: horizontal and vertical (needle tip up). A summary of the stability protocol for AAI for physicochemical (PC) related attributes is provided in Table 73. For the AAI stability study, three units of AAI were packaged per carton and all AAI samples were stored in a horizontal position.

[0589] [Table 102]

[0590] [Table 103]

[0591] [Table 104]

[0592] Summary of stability results for physicochemical and microbiological properties The following physicochemical and microbiological (PCM) attributes were evaluated on the primary stability batches: appearance, color, assay, organic impurities, pH, particulate matter (subvisible particles), monothioglycerol (MTG), ethylenediaminetetraacetic acid (EDTA), bacterial endotoxins (BET), and sterility.

[0593] Stability results of all PCM attributes from storage up to 12 months at 25° C. / 60% RH, up to 12 months at 30° C. / 60% RH, and up to 6 months at 40° C. / 75% RH are summarized below.

[0594] The levels of hydrocortisone impurity increased as a function of time and storage temperature (Tables 74 and 75). After 12 months storage at 25°C / 60% RH the impurity level of hydrocortisone impurity was <0.1% and total impurities in the formulation was <0.6%. After 6 months storage at 40°C / 75% RH the impurity level of hydrocortisone impurity was <0.3% and total impurities in the formulation was <1.1%. The levels of the antioxidant MTG decreased as a function of time (Tables 76 and 77). The levels of EDTA decreased as a function of time and temperature (Tables 78 and 79).

[0595] Except for organic impurities, MTG, and EDTA, all other PCM attributes including appearance, color, assay, pH, particulate matter, bacterial endotoxin, and sterility did not show significant changes from the beginning, and there was no obvious stability trend throughout the stability shown in Tables 80 and 81 for the assays. It is noted that no obvious downward trend was observed in the assay over time, as the total impurities (≦1.2%) were less than the typical assay variability (approximately 2%). Sample orientation had no effect on stability.

[0596] Comparison of stability results in PFS and AAI confirmed that assembly in the autoinjector of PFS did not affect stability. However, since AAI stability began approximately 5 to 6 months after the start of PFS stability, organic impurity levels were slightly higher and MTG and EDTA levels were slightly lower in AAI compared to PFS at the same storage duration and under the same storage conditions. All PCM attributes met the proposed acceptance criteria and no significant changes were observed at accelerated conditions.

[0597] [Table 105]

[0598] [Table 106]

[0599] [Table 107]

[0600] [Table 108]

[0601] [Table 109]

[0602] [Table 110]

[0603] [Table 111]

[0604] [Table 112]

[0605] impurities organic impurities The structural formulas and names of potential synthesis or degradation impurities of hydrocortisone sodium phosphate are listed in Table 82. Hydrocortisone, the starting material of the drug substance, is the only impurity in the drug substance. Additionally, hydrocortisone is a potential degradation product of the drug substance through hydrolysis. In the evaluation, it was concluded that the starting material hydrocortisone has high purity and all impurities are less than 0.05% or not detectable, therefore these impurities do not impact the impurity profile of hydrocortisone sodium phosphate.

[0606] [Table 113]

[0607] Residual Solvent Solvents used in the manufacture of hydrocoritisone sodium phosphate include: tetrahydrofuran (Class 2) as reaction solvent, ethanol (Class 3) as crystallization solvent, and methanol (Class 2) as crytallizing solvent. These three solvents were routinely tested using a validated in-house GC-Headspace method. Limits were set at less than 720 ppm for tetrahydrofuran, less than 3000 ppm for methanol, and less than 5000 ppm for ethanol based on the ICH Q3C: Impurities: Residual Solvents guideline and maintaining caution for derivation of residual solvents. Test results with the three solvents in three certified batches are provided in Table 83.

[0608] Methylene chloride is an ICH class 2 solvent present in the starting material and therefore based on guideline CPMP / QWP / 450 / 03, Annex 1, methylene chloride is not included in the drug substance specification since its content in three consecutive industrial scale batches (certified batches) has been demonstrated to be below 10% of the ICH limit for each solvent.

[0609] [Table 114]

[0610] During the manufacturing process of hydrocortisone sodium phosphate, methanol and ethanol are used as solvents. These solvents may be potential sources of the Class 1 solvent benzene. Benzene is tested in methanol and ethanol prior to synthesis of the drug substance. Nevertheless, three certified batches of hydrocortisone sodium phosphate are analyzed to demonstrate the absence of Class 1 solvents (Table 84).

[0611] [Table 115]

[0612] Inorganic Impurities Inorganic impurities including phosphate and chloride ions are controlled by using the test described in the USP monograph for hydrocortisone sodium phosphate with limits not to exceed 1.0% and 1.00%, respectively (NMT).

[0613] Genotoxic Impurities A genotoxicity assessment was performed and the following conclusions were provided: Hydrocortisone sodium phosphate is not a genotoxic product and all impurities associated with hydrocortisone sodium phosphate were identified as ICH M7-Class 5 compounds that are treated as non-mutagenic compounds as defined according to the ICH Q3A guideline.

[0614] Elemental Impurities Potential elemental impurities, which may arise from several sources, were analyzed in three production batches. The elements evaluated were class 1 (As, Cd, Hg and Pb), class 2A (Co, Ni and V) and class 3 (Li, Sb and Cu). The route of administration chosen was parenteral. All of them were demonstrated to be absent (below 30% of the limit value for option 1).

[0615] Drug Product Batch Analysis Two lots of hydrocortisone sodium phosphate drug substance (DS) were used to make three primary stability batches of drug product (DP). The results of the release studies are summarized in Table 85 based on the Certificate of Analysis.

[0616] [Table 116]

[0617] The water content test method utilizes the British Pharmacopoiea (BP) HSP monograph semi-micro water content method instead of the less specific USP HSP monograph water content Loss on Drying method. Additionally, the water content acceptance criteria utilizes the BP HSP monograph acceptance criteria of ≦10.0% based on the properties of this drug substance. This is because the crystalline form obtained through the manufacturing process is a crystalline hydrate. To meet the USPLOD specification of NMT 5%, the manufacturing process must involve a lyophilization step that causes the formation of the amorphous form of HSP. Thus, the amorphous hydrocortisone sodium phosphate drug substance is highly hygroscopic (see Figure 28) and is not as stable as compared to the crystalline form, as demonstrated by the data presented in Table 47. Therefore, the water content of the desired polymorphic form (crystalline) of the drug substance is measured through Karl Fischer titration and not through the LOD method recommended by the USP monograph.

[0618] The stability of the manufactured crystalline product is assured in terms of both purity and moisture content. For these reasons, the manufacturing process for hydrocortisone sodium phosphate (with a moisture content specification of NMT 10%) has been certified.

[0619] While specific embodiments of the present invention have been described and / or exemplified above, various other embodiments will be apparent to those skilled in the art in light of the foregoing disclosure. Accordingly, the present invention is not limited to the specific embodiments described and / or exemplified, but can be made to considerable variation and modification without departing from the scope and spirit of the appended claims.

Claims

1. For use in the treatment of diseases, conditions, or disorders that are relieved by the administration of hydrocortisone or hydrocortisone sodium phosphate, Hydrocortisone sodium phosphate at 127-141 mg / mL, 3.5–5.5 mg / mL of monothioglycerol, 0.5–2.5 mg / mL of monobasic sodium phosphate, 5-25 mg / mL of dibasic sodium phosphate, 0.1 to 1 mg / mL of EDTA disodium, and A water-based pharmaceutical composition containing water.

2. The aqueous pharmaceutical composition according to claim 1, wherein a therapeutically effective amount of 1.0 mL of the aqueous pharmaceutical composition is administered to a patient in need of treatment.

3. The therapeutically effective dose of the aqueous pharmaceutical composition is administered over approximately 5,500 to 5,575 hours. ＊ Area under the mean curve (AUC) extrapolated from administration time 0 to infinite time for ng / mL ０－ｉｎｆ The aqueous pharmaceutical composition according to claim 1, comprising ) to provide an in vivo plasma profile of hydrocortisone in a patient.

4. The aqueous pharmaceutical composition according to claim 1, wherein a therapeutically effective amount of the aqueous pharmaceutical composition is administered intravenously or intramuscularly.

5. The therapeutically effective dose of the aqueous pharmaceutical composition is administered over approximately 5,275 to 5,375 hours. ＊ The area under the mean curve (AUC) from administration time 0 to time t for ng / mL. ０－ｔ The aqueous pharmaceutical composition according to claim 1, comprising ) to produce an in vivo plasma profile of hydrocortisone in a patient, wherein t is approximately 12 hours.

6. The therapeutically effective dose of the aqueous pharmaceutical composition corresponds to the maximum serum concentration (C) in patients with a concentration of approximately 800-1600 ng / mL. ｍａｘ The aqueous pharmaceutical composition according to claim 1, which brings about ).

7. The administration of a therapeutically effective dose of the aqueous pharmaceutical composition results in a median time (T) of approximately 0.5 to 1.5 hours after administration to the peak concentration of hydrocortisone in the patient. ｍａｘ The aqueous pharmaceutical composition according to claim 1, which brings about ).

8. Hydrocortisone has an average excretion half-life of approximately 1.8 to 2.1 hours (T １／２ｅｌ The aqueous pharmaceutical composition according to claim 1, which is excreted from the patient.

9. After administration to patients, compared to hydrocortisone reference formulations, patients may experience higher exposure, a larger area under the curve (AUC), or higher maximum serum concentrations (C). ｍａｘ The aqueous pharmaceutical composition according to claim 1, wherein one or more of the following are provided, and the hydrocortisone reference preparation comprises about 67 mg / mL of hydrocortisone sodium succinate, about 4.4 mg / mL of dibasic sodium phosphate, about 0.4 mg / mL of monobasic sodium phosphate, and water, and about 2.0 mL of the hydrocortisone reference preparation is administered to the patient.

10. The aqueous pharmaceutical composition according to claim 9, which provides a larger area under the curve (AUC) after administration to a patient compared to a hydrocortisone reference formulation.

11. After administration to a patient, the aqueous pharmaceutical composition according to claim 9, which provides a higher maximum serum concentration (C ｍａｘ ), compared to a hydrocortisone reference preparation.

12. After administration to the patient, a faster peak serum concentration (C) was achieved compared to the hydrocortisone reference formulation. ｍａｘ The aqueous pharmaceutical composition according to claim 9, which provides ).

13. The aqueous pharmaceutical composition according to claim 9, wherein the hydrocortisone reference preparation is administered intravenously or intramuscularly to the patient.

14. The aqueous pharmaceutical composition according to claim 9, wherein the hydrocortisone reference preparation does not contain an antioxidant.

15. The aqueous pharmaceutical composition according to claim 9, wherein the disease, condition, or disorder is selected from adrenal insufficiency, acute adrenal insufficiency, primary adrenal insufficiency, secondary adrenal insufficiency, or adrenal crisis.

16. For use in the prevention of adrenal crisis and / or acute adrenal insufficiency in patients with adrenal insufficiency, Hydrocortisone sodium phosphate at 127-141 mg / mL, 3.5–5.5 mg / mL of monothioglycerol, 0.5–2.5 mg / mL of monobasic sodium phosphate, 5-25 mg / mL of dibasic sodium phosphate, 0.1 to 1 mg / mL of EDTA disodium, and A water-based pharmaceutical composition containing water.

17. The aqueous pharmaceutical composition according to claim 16, wherein a therapeutically effective amount of 1.0 mL of the aqueous pharmaceutical composition is administered to a patient in need of prevention.

18. The therapeutically effective dose of the aqueous pharmaceutical composition is administered over approximately 5,500 to 5,575 hours. ＊ Area under the mean curve (AUC) extrapolated from administration time 0 to infinite time for ng / mL ０－ｉｎｆ The aqueous pharmaceutical composition according to claim 16, which provides an in vivo plasma profile of hydrocortisone in a patient, comprising )

19. An effective dose of the aqueous pharmaceutical composition reaches a maximum serum concentration (C) of approximately 800–1600 ng / mL in the patient. ｍａｘ ), the median time to the peak concentration of hydrocortisone (T) is approximately 0.5 to 1.5 hours. ｍａｘ ), and / or average excretion half-life (T) of about 1.8 to 2.1 hours １／２ｅｌ The aqueous pharmaceutical composition according to claim 1, which provides one or more of the following:

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