Guanfacine injection preparation and method

Abstract

A stable lyophilized preparation containing guanfacine, wherein guanfacine is given by the following formula: [Formula 1] The substance represented by TIFF2026518459000015.tif34139, or a pharmaceutically acceptable salt thereof. Furthermore, a method for producing and using a stable guanfacine freeze-dried preparation is provided.

Description

Technical Field

[0001] The embodiments disclosed in this specification relate to a stable lyophilized formulation containing guanfacine or a pharmaceutically acceptable salt thereof, a method for preparing the formulation, and a method for using the formulation for the prevention or treatment of patients suffering from delirium.

Background Art

[0002] The mental state of inpatients can pose a serious therapeutic challenge for medical staff. Due to underlying diseases, patients often develop serious and potentially life-threatening psychological symptoms such as delirium. Delirium is a syndrome or series of symptoms caused by impairment of normal brain function. Delirium means a rapid debilitating decline in attention, concentration, perception, and cognitive function, causing a form of altered semi-conscious state. Delirium usually presents as an acute disturbance of consciousness and cognition that fluctuates over time. Generally, the subtypes of delirium based on psychomotor behavior are: hypoactive, hyperactive, and mixed types. Delirium affects at least 1 in 10 inpatients, 1 in 2 elderly inpatients, and up to 85% of critically ill patients. Postoperative delirium significantly prolongs the intensive care unit (ICU) and hospital stay, resulting in an annual increase in medical costs of up to $1.2 billion. Compared with patients without delirium, patients in a delirious state consume the time of medical staff and precious life-sustaining resources, stay in the hospital longer, and tend to develop complications in the hospital. In addition, such patients tend to transfer to facilities and may be readmitted to the hospital.

[0003] While delirium itself is not a specific disease, patients with delirium generally have a worse prognosis than patients with the same illness but without delirium. Delirium usually occurs as a postoperative complication, and more recently it has been observed in patients with COVID-19, where it is thought to be triggered by the inflammatory response caused by COVID-19 infection. A study of 101 hospitalized COVID-19 patients reported that delirium was widespread, occurring in about a quarter of the patients (Lovell et al., Journal of Pain and Symptom Management, 2020). Therefore, the high incidence of COVID-19-related delirium is further exacerbating the already strained healthcare system.

[0004] Current clinical management of delirium in COVID-19 patients includes the off-label use of certain antipsychotics (NICE Guidelines, BMJ 2020;369:m1461). However, there is sufficient evidence that antipsychotics do not improve delirium outcomes (Neufeld et al., J Am Geriatr Soc. 2016; 64(4): 705-714; Girard et al., N Engl J Med. 2018; 379(26): 2506-2516). Therefore, improved methods for preventing or treating delirium are needed. There is also a need for stable intravenous formulations for patients who are unable to swallow or take medication orally due to changes in their mental state. [Overview of the project]

[0005] This specification discloses a sterile guanfacine injection formulation comprising a vehicle containing guanfacine or a pharmaceutically acceptable salt thereof, one or more bulking agents, one or more buffering agents, and one or more pH adjusters for selectively adjusting the pH to 3.0 to 8.0; and a pharmaceutically acceptable diluent.

[0006] Furthermore, a method for treating delirium is disclosed, which includes intravenous administration of a therapeutically effective dose of sterile guanfacine for injection to patients requiring treatment.

[0007] Furthermore, a stable, lyophilized, sterile guanfacine preparation is disclosed, comprising guanfacine or a pharmaceutically acceptable salt thereof, and a vehicle, which is reconstituted with a pharmaceutically acceptable diluent to form a sterile injectable preparation.

[0008] Furthermore, a method for preparing a stable lyophilized sterile guanfacine preparation is disclosed, comprising the steps of mixing guanfacine, or a pharmaceutically acceptable salt thereof, with a vehicle to form a sterile solution, and lyophilizing the sterile solution to form a stable lyophilized sterile guanfacine preparation.

[0009] Additional aspects and advantages of the embodiments disclosed herein are, in part, shown in the following description, in part, recognizable from the description, or can be acquired by carrying out or performing the disclosed embodiments. These aspects and advantages are realized and achieved by the elements and combinations thereof specifically described in the appended claims.

[0010] It should be understood that the general statements above and the detailed statements below are for illustrative and explanatory purposes only and do not limit the scope of the attached claims. [Modes for carrying out the invention]

[0011] It should be understood that, because various modifications are possible, this disclosure is not limited to the specific embodiments described herein. It should also be understood that the terms used herein are for the purpose of describing specific embodiments only and are not intended to limit the appended claims. The embodiments described herein, and the claimed embodiments described herein, may be successfully implemented even if they lack any of the described features, elements, or steps, whether or not they are specifically disclosed herein. For example, expressions such as “one embodiment,” “an embodiment,” and “an example embodiment” herein indicate that the described embodiments may include certain features, structures, or characteristics, but not all embodiments may necessarily include such features, structures, or characteristics. Furthermore, such expressions do not necessarily refer to the same embodiment. Also, if certain features, structures, or characteristics are described in relation to an embodiment, it is considered to be within the knowledge of those skilled in the art that such features, structures, or characteristics may be affected in relation to other embodiments, whether or not they are explicitly described.

[0012] The terms “comprising,” “including,” and “containing” are non-limiting. Embodiments claimed by these transitional clauses may include other elements not described. When “comprising,” “containing,” and “including” are used as transitional clauses, embodiments within the scope of the claims may be formed even if other elements are included. The open transitional clause “comprising” encompasses the intermediate transitional clause “consisting essentially of” and the closed transitional clause “consisting of.” The lyophilized or injectable guanfacine formulations disclosed herein may consist essentially of guanfacine or a pharmaceutically acceptable salt thereof. “Consisting essentially of” means that guanfacine or a pharmaceutically acceptable salt thereof is the sole active ingredient in the formulation (e.g., the sole ingredient having a therapeutic effect), and other non-active ingredients may be present as vehicles or media for administration or stabilization, such as water and / or pH adjusters.

[0013] Disclosed is a method for preventing or treating delirium in a subject or patient (e.g., an animal such as a human), comprising administering to a subject or patient in need of prevention or treatment of delirium an injectable formulation comprising an effective amount, for example, a therapeutically effective amount, of guanfacine as described herein or in a salt form thereof, and a vehicle, which is effective in preventing or treating delirium or symptoms of delirium in the subject or patient.

[0014] The term "therapeutically effective dose" or "effective dose" refers to the amount of guanfacine needed to achieve the pharmacological effect of treating delirium in a patient. The term "therapeutically effective dose" includes, for example, a prophylactic effective dose, i.e., an effective dose that significantly reduces the probability of delirium occurring in a patient. "Effective dose" refers to the amount needed to achieve the desired pharmacological effect or therapeutic improvement without excessive and harmful side effects. The effective dose is selected by a person skilled in the art on a case-by-case basis for the specific patient. It should be understood that the "effective dose" or "therapeutically effective dose" may vary from patient to patient due to differences in guanfacine metabolism, age, weight, the patient's overall health, the severity of the condition being treated, and the prescribing physician's judgment.

[0015] As used herein, terms such as “treat,” “treating,” and “treatment” refer to any action that benefits a patient who may be administered the disclosed injectable formulation, including the treatment of any physiological or mental condition (e.g., delirium) that is regulated or easily regulated by the injectable formulation.

[0016] The description of numerical ranges is intended simply as a concise way of individually referring to the individual values ​​within that range unless otherwise specified, and each individual value is incorporated into the specification as it is individually described herein. Where a range of values ​​is defined, unless the context clearly indicates otherwise, all individual values ​​between the upper and lower limits of that range, up to one-tenth of a unit of the lower limit, and any other values ​​or values ​​between them that are explicitly stated within that range should be understood to be included in the invention. All endpoints of a range are included within the range and can be combined independently. The upper and lower limits of any subranges that may be independently included within these subranges are also included in the invention unless there are limits specifically excluded within the described range. Where a described range includes one or both limit values, it also includes ranges that do not include one or both of those limit values.

[0017] All methods described herein may be performed in an appropriate order unless otherwise specifically stated herein or unless it is clearly inconsistent with the context. All examples or illustrative expressions (e.g., "such as") are for illustrative purposes only and do not limit the scope of the invention unless specifically requested. No expression in the specification should be construed as indicating that any element not described in the claims is essential for carrying out the invention.

[0018] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art in the field to which the disclosed embodiments belong. Similar or equivalent methods and materials described herein may also be used in carrying out or experimenting with the disclosed embodiments described herein. All references referred herein are incorporated herein by reference to disclose and explain methods and / or materials relating to the references cited herein.

[0019] Please note that the singular forms "a," "an," and "the" used in this specification and the appended claims include the plural form unless otherwise clearly specified in the context.

[0020] The documents referenced herein are provided solely for the purpose of disclosure prior to the filing date of this application. The contents of this specification should not be construed as acknowledging that the present invention does not precede the publication of such documents by prior art. Furthermore, the publication dates mentioned may differ from the actual publication dates and may require further verification.

[0021] As will be apparent to those skilled in the art who read this specification, each individual embodiment described and illustrated herein has independent components and features, and these can be readily separated from or combined with features of several other embodiments without departing from the scope or intent of the present invention.

[0022] Guanfacine is a central alpha-2 adrenergic receptor agonist and is indicated as monotherapy and adjunctive therapy for attention deficit hyperactivity disorder (ADHD). It is also indicated for the management of hypertension, either alone or in combination with other antihypertensive agents, particularly thiazide diuretics. The chemical name of guanfacine hydrochloride is N-amidino-2-(2,6-dichlorophenyl)acetamide hydrochloride. U.S. Patent No. 3,632,645 discloses guanfacine and its pharmaceutically acceptable acid addition salts in particular.

[0023] The lyophilized and injectable formulations disclosed herein contain guanfacine or a pharmaceutically acceptable salt thereof. The chemical structure of guanfacine is as follows: [ka]

[0024] Guanfacine useful in the formulations disclosed herein may be formulated using pharmaceutically acceptable salts. Pharmaceutically acceptable salts include, where applicable, those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium and magnesium, ammonium salts, and many other acids and bases widely known in the pharmaceutical field. Examples of salts include salts of inorganic or organic acids, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, benzoate, tartrate, bisulfate, succinate, maleate, formate, fumarate, gluconate, saccharinate, benzoate, sulfamate, methanesulfonate, ethanesulfonate, benzenesulfonate, mesylate, p-toluenesulfonate, pamoate [i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)], cansylate, isethionate, edisylate, and crosylate. In one embodiment, the guanfacine preparation contains guanfacine hydrochloride.

[0025] Pharmaceutically acceptable base addition salts can also be used to produce pharmaceutically acceptable salt forms. Chemical bases that can be used as reagents for preparing pharmaceutically acceptable basic salts of guanfacine, which is essentially acidic, are those that form non-toxic basic salts with such compounds. Such non-toxic basic salts include, but are not limited to, salts derived from pharmacologically acceptable cations such as benzathine, choline, diethanolamine, aluminum, alkali metal cations (e.g., potassium, lithium, sodium), and alkaline earth metal cations (e.g., calcium, zinc, magnesium), ammonium salts, or water-soluble amine addition salts such as N-methylglucamine-(meglumine), as well as lower alkanolammonium salts and basic salts of other pharmaceutically acceptable organic amines.

[0026] The guanfacine injection preparation may contain 0.01 to 50.0 mg / mL of guanfacine. In one embodiment, the guanfacine injection preparation contains 0.05 to 29.0 mg / mL, 0.10 to 10.0 mg / mL, 0.20 to 5.00 mg / mL, or 0.50 to 1.50 mg / mL of guanfacine. In another embodiment, the guanfacine injection preparation contains 0.50, 0.60, 0.70, 0.80, 0.90, 1.00, 1.10, 1.20, 1.30, 1.40, or 1.50 mg / mL of guanfacine.

[0027] The guanfacine injection preparation can be administered by any pharmaceutically effective parenteral administration route. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intramedullary, intrahepatic, intralesional, and intracranial injection or infusion methods. In one embodiment, the guanfacine injection preparation is administered by intravenous injection. The intravenous injection can be a continuous infusion or a bolus injection. Such administration can be carried out using any known device useful for parenteral injection or infusion of pharmaceutical preparations.

[0028] The sterile injection preparation of guanfacine may contain: (a) guanfacine or its pharmaceutically acceptable salt; (b) a vehicle; and (c) a pharmaceutically acceptable diluent, wherein the vehicle may contain (i) one or more bulking agents and (ii) one or more buffering agents for adjusting the pH to 3.0 to 8.0, and optionally one or more pH adjusting agents.

[0029] One or more bulking agents may be present in an amount of from 0.10 mg to 100 mg, from 1.0 mg to 100 mg, from 10 mg to 50 mg, or from 20 mg to 40 mg per milliliter of the sterile injection preparation of guanfacine. Examples of bulking agents suitable for use herein include, but are not limited to, mannitol, sucrose, lactose, glycine, trehalose, maltose, xylitol, glucose, starch, sorbitol, erythritol, maltitol, dextran, dextrose, lactitol, or combinations thereof. In one embodiment, the sterile injection preparation of guanfacine contains mannitol as the bulking agent.

[0030] To adjust the pH of the guanfacine aqueous solution between 3.0 and 9.0, one or more buffers and selectively one or more pH adjusters may be used. In some embodiments, the pH may be adjusted between 3.0 and 8.0, between 3.0 and 7.0, between 3.0 and 5.0, or between 3.0 and 4.0. In other embodiments, the pH may be 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, or 9.0. To achieve such pH levels, buffers may typically be used in amounts of 5 to 100 μmol or 5.00 mM to 100 mM per milliliter of sterile guanfacine injection preparation, depending on their type. Examples of buffers suitable for use herein include, but are not limited to, phosphate buffers (e.g., sodium phosphate, potassium phosphate), borate buffers, citrate buffers (e.g., sodium citrate dihydrate, citric acid), tricine, TRIS, acetate buffers, sodium carbonate, sodium bicarbonate, arginine, histidine, cysteine, glycine, diethanolamine, tartrate, ascorbic acid, benzoic acid, lactic acid, malic acid, maleic acid, succinic acid, or combinations thereof. In one embodiment, a sterile guanfacine injection formulation contains sodium citrate dihydrate and citric acid as buffers. In one embodiment, 0.15 to 10.6 mg of sodium citrate dihydrate, 0.62 to 17.3 mg of citric acid, or a combination thereof, is used as a buffer per milliliter of the sterile guanfacine injection formulation. In another embodiment, 0.15 to 0.53 mg of sodium citrate dihydrate, 0.62 to 0.86 mg of citric acid, or a combination thereof, is used as a buffer per milliliter of sterile guanfacine injection preparation.

[0031] In aqueous solutions of lyophilized guanfacine preparations, one or more pH adjusters may be selectively used. When it is necessary to lower the pH, acidic pH adjusters such as hydrochloric acid, citric acid, malic acid, maleic acid, succinic acid, phosphoric acid, lactic acid, ascorbic acid, sulfuric acid, methanesulfonic acid, aspartic acid, glutamic acid, or combinations thereof may be used. When it is necessary to raise the pH, basic pH adjusters such as sodium hydroxide, potassium hydroxide, calcium carbonate, citrate, malate, maleate, succinate, dibasic phosphate, tribasic phosphate, lactate, ascorbate, tromethamine, tricine, bicarbonate, carbonate, lysine, arginine, ornithine, histidine, diethanolamine, triethanolamine, ethyldiamine, ammonium hydroxide, or combinations thereof may be used. In one embodiment, a sterile guanfacine injection preparation contains hydrochloric acid, sodium hydroxide, or combinations thereof as pH adjusters.

[0032] The guanfacine formulations disclosed herein may further contain pharmaceutically active ingredients such as solvents, preservatives, antioxidants, solubilizers, or combinations thereof. Examples of solvents include isotonic saline, 5% glucose solution, alcohol, propylene glycol, macrogol, and glycerin. Examples of preservatives include parahydroxybenzoic acid, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, sorbic acid, methylparaben, propylparaben, phenol, and thiomersal. Examples of antioxidants include sulfites, ascorbic acid, α-tocopherol, reducing agents (e.g., cysteine, glutathione, and N-acetylcysteine), and metal ion chelating agents (e.g., ethylenediaminetetraacetic acid). Examples of solubilizers include complexing agents such as cyclodextrins (e.g., hydropropyl beta-cyclodextrin, sulfobutyl ether cyclodextrin), surfactants (e.g., polysorbate, cremofor, sorbitol, D-α-tocopheryl polyethylene glycol succinic acid (vitamin E TPGS), lecithin, phospholipids, negatively charged phospholipids), and hydration promoters (e.g., niacinamide, salicylic acid, urea, propylparaben, methylparaben).

[0033] An example guanfacine preparation may be formulated from the following ingredients: [Table 1]

[0034] Guanfacine, or a pharmaceutically acceptable salt thereof, may be compounded with other active ingredients that do not impair the desired effect, or with ingredients that complement the desired effect, such as compounds having anesthetic effects. Examples of anesthetics include articaine, bupivacaine, levobupivacaine, ropivacaine, butanilicaine, calticaine, cincocaine (dibucaine), etidocaine, lidocaine, mepivacaine, prilocaine, trimecaine, and combinations thereof. In one embodiment, the guanfacine formulation contains guanfacine and ropivacaine as active ingredients. In another embodiment, the guanfacine formulation contains guanfacine and lidocaine as active ingredients.

[0035] In carrying out a method for preparing a stable lyophilized sterile guanfacine preparation, guanfacine, or a pharmaceutically acceptable salt thereof, is mixed with a vehicle to form a solution, and the solution is lyophilized to form a lyophilized powder or cake. The components of the stable lyophilized sterile guanfacine preparation can be mixed in any order. In one embodiment, one or more buffers may be added to water for injection to form a solution. Guanfacine, or a pharmaceutically acceptable salt thereof, may be added to the solution. Then, one or more fillers may be added to the solution. Alternatively, one or more buffers may be added to water for injection, then one or more fillers may be added to the solution, and then guanfacine, or a pharmaceutically acceptable salt thereof, may be added to the solution. pH adjustment may be performed using one or more pH adjusters before and / or after the addition of guanfacine or a pharmaceutically acceptable salt thereof, before and / or after the addition of one or more buffers, and / or before and / or after the addition of one or more fillers. In either method, after mixing the other components of the solution, there may be a final pH adjustment step using one or more pH adjusters. Furthermore, before adding guanfacine or a pharmaceutically acceptable salt thereof to the solution, pH adjustment using one or more pH adjusters may be performed, and / or antioxidants, preservatives, or both may be added before and / or after the addition.

[0036] During and / or after mixing guanfacine or a pharmaceutically acceptable salt thereof with the vehicle, the solution may be sterilized, for example, by filtration, autoclaving, and / or radiation sterilization. The resulting final solution is aseptically filled into sterile containers and aseptically loaded into a sterile freeze-dryer. Once the final solution is aseptically filled into the sterile containers, the containers may be rapidly frozen.

[0037] Lyophilization can be carried out by any suitable process. For example, the lyophilization cycle can be carried out by cooling the sterile final solution to about -45°C at a suitable cooling rate. Drying can be carried out at a temperature of about 40°C or lower, with a suitable vacuum and time to form a stable lyophilized sterile guanfacine formulation. In another embodiment, the lyophilization step is carried out in at least three stages: (1) a freezing stage in which the sterile final solution is cooled to about -45°C at a suitable cooling rate, (2) a primary drying stage carried out at about -45°C or higher, with a suitable vacuum and time, and (3) a secondary drying stage carried out at about -20°C or higher, with a suitable vacuum and time to form a stable lyophilized sterile guanfacine formulation. The secondary drying stage can be carried out up to 40°C.

[0038] The containers containing the resulting stable, lyophilized, sterile guanfacine formulation can be aseptically stoppered and sealed under atmospheric pressure or partial vacuum. In one embodiment, the headspace of the container may be replaced with an inert headspace gas (e.g., nitrogen or argon) immediately before stoppering. The formulation may be provided in single-dose or multi-dose containers, such as vials, disposable syringes, pen-type syringes, IV bags, or multi-dose vials made of glass or plastic.

[0039] Lyophilized guanfacine preparations can be reconstituted with a pharmaceutically acceptable diluent in an amount sufficient to administer a therapeutically effective dose to a patient. Pharmaceutically acceptable diluents may be sterile water for injection, saline, semi-saline, 5% glucose solution, Ringer's lactate solution, or a combination thereof. In one embodiment, the lyophilized guanfacine preparation may be reconstituted with sterile water for injection.

[0040] Appropriate doses of guanfacine may range from 0.1 mg to 5.0 mg per day, or from 0.5 mg to 4.0 mg per day. In one embodiment, doses of 0.1, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 mg per day may be administered. These doses may be administered as a single dose once daily or as multiple doses per day. For example, a reconstituted guanfacine preparation may be administered twice daily. In one embodiment, the dose may be 0.5, 1.0, or 2.0 mg of guanfacine twice daily.

[0041] The guanfacine formulations disclosed are useful for the prevention or treatment of delirium in subjects. Accordingly, a method for treating delirium is also disclosed, comprising intravenous administration of a therapeutically effective amount of the guanfacine formulation to a patient in need of treatment. In this specification, the terms “subject,” “individual,” and “patient” are used interchangeably and refer to vertebrates such as mammals. Mammals include, but are not limited to, mice, rodents, monkeys, humans, livestock, sports animals, and pets. In one embodiment, the human patient is at least 60 years old. In another embodiment, the human patient has at least one comorbidity selected from the group consisting of hypertension, heart disease, lung disease, diabetes, kidney disease, cancer, and combinations thereof. In yet another embodiment, the human patient is on mechanical ventilation, non-invasive positive pressure ventilation (NIPPV), shock treatment (e.g., with vasopressors), or a combination thereof.

[0042] As defined herein, the term “delirium” refers to an acute cognitive disorder associated with a medical problem. Delirium can be triggered by a variety of factors, including but not limited to surgical trauma, drug or alcohol withdrawal, metabolic disorders, and / or sepsis. Symptoms of delirium may include hallucinations, delusions, psychosis, disorientation, confusion, anxiety, attention deficit, memory impairment, personality changes, depression, immobility, sleep disturbances, speech disturbances, sensory disturbances, or a combination thereof.

[0043] In one embodiment, the delirium treated or prevented by the guanfacine formulation disclosed herein is associated with severe acute respiratory syndrome (SARS) coronavirus 2 infection. In another embodiment, the delirium is associated with surgery, for example, postoperative delirium following surgery. In yet another embodiment, the delirium is associated with patients in critical condition, i.e., patients in poor health who have or are at risk of developing life-threatening injuries or diseases (for example, patients generally admitted to the intensive care unit (ICU) of a hospital).

[0044] The subject matter of the patents disclosed herein is further illustrated by the following specific but non-limiting examples. These examples may include collections of data representative of data collected at various points in the development and experimentation process related to the present invention. [Examples]

[0045] The following examples are not limiting and illustrate specific embodiments of the present invention.

[0046] [Example 1: Compatibility of mixing guanfacine and ropivacaine] The compatibility of solutions prepared by diluting 1.0 mg / mL and 0.1 mg / mL guanfacine in 30 mL of ropivacaine (USP 5 mg / mL, Hospira, lot number 48-031-DK) was tested. Solutions of 0.1 mg / mL and 1.0 mg / mL free guanfacine base were prepared in sterile water for injection (WFI). 1 mg of free guanfacine base is present per 1.148 mg of guanfacine HCl. For the 0.1 mg / mL solution, 57.4 mg of guanfacine HCl (lot number CPL-01-2013-014-033, Laxai Avanti) was dissolved in 400 mL of sterile water for injection (Hospira, 1000 mL bag, lot number 51-114-JT). After complete dissolution, the solution was transferred to a 500 mL volumetric flask and brought to a final volume. For the 1.0 mg / mL solution, 114.8 mg of guanfacine HCl was dissolved in 80 mL of WFI. After complete dissolution, the solution was transferred to a 100 mL volumetric flask and brought to a final volume.

[0047] Two glass vials were washed three times with WFI and their contents were discarded. The vials were washed three times with 5 mL each of filtered guanfacine solution. Approximately 35 mL of guanfacine solution was filtered into the vials using a Millex GV Sterile PVDF 0.22 μm syringe filter. The particle content in the filtered guanfacine solution was measured using an APSS Liquiliaz particle counter before adding it to the ropivacaine vial. 1.2 mL of filtered guanfacine solution at 0.1 or 1.0 mg / mL was injected into three separate vials containing ropivacaine (guanfacine:ropivacaine 1:25 dilution) according to concentration. The free base concentrations of guanfacine in the WFI control solution were measured by HPLC at 0.10 mg / mL and 1.05 mg / mL. Because guanfacine and ropivacaine have very similar elution times, the compatible solution could not be analyzed for guanfacine by HPLC, and only the peak for ropivacaine was observed on the chromatogram.

[0048] The appearance, pH, and particle content of one vial at each concentration were evaluated at 0, 4-6 hours, and 24 hours, and the results are shown in Table 1 below. [Table 2]

[0049] All samples were colorless and transparent from 0 to 24 hours. Furthermore, the number of particles per container was all within the USP standard for small-volume injectable preparations. <788> The limit was below the specified threshold. The particle content of the filtered guanfacine solution was measured before mixing guanfacine and ropivacaine. The results in the "Guanfacine Only" row of the table above indicate that the number of particles in those solutions is at a low level per milliliter.

[0050] After mixing guanfacine and ropivacaine, a slightly higher particle count was observed at time zero. This is likely due to the initial mixing of the guanfacine and ropivacaine solutions. The amount of microbubbles formed during mixing probably decreased over time, which could explain the decrease in particle count observed above.

[0051] These results indicate that 1.0 mg / mL of guanfacine in WFI is compatible with ropivacaine at a 1:25 dilution ratio of guanfacine to ropivacaine.

[0052] [Example 2: Compatibility of mixing guanfacine and lidocaine] Guanfacine HCl (Laxai Avanti, lot number CPL-01-2013-014-033) was dissolved in WFI to a final concentration of 1.14 mg / mL. 1 mL of the 1.14 mg / mL guanfacine solution was added to a 30 mL vial of 1% lidocaine (Hospira, lot number 81-434-DK) and mixed (final guanfacine concentration approximately 31 μg / mL). 6 mL of the guanfacine-lidocaine mixture was transferred to a 10 mL syringe. The mixture in the syringe was stored at room temperature overnight (maximum approximately 17 hours). The mixture was analyzed by HPLC at 1 hour, 3 hours, 5 hours, 6 hours, and overnight, based on the USP monograph for the guanfacine hydrochloride assay. To prepare a standard curve, guanfacine HCl was dissolved in WFI at a concentration of 1.0 mg / mL and gradually diluted to 0.025 mg / mL. The concentrations of the standard solutions were 1.0, 0.50, 0.05, and 0.025 (mg / mL). The main peak of guanfacine elution occurred at RT=5.9 min.

[0053] The mixture was confirmed to be physically compatible after being stored overnight at room temperature. Regarding chemical stability, guanfacine-related degradation products increased slightly after 3 hours, reaching 1.0% after overnight storage (approximately 17 hours) (see Table 2 below). 1.0% of degradation products corresponds to a maximum of 2.5 μg per single dose, which is below the identification threshold of less than 1 mg per day according to ICH guideline Q3B(R2) "Impurities in the active pharmaceutical ingredient of new active ingredients". [Table 3]

[0054] [Example 3: Effect of pH on the stability of guanfacine solution] Guanfacine HCl powder (Laxai Avanti, lot number CPL-01-2013-014-033) was dissolved in WFI at a concentration of 0.5 mg / mL. The solution was filtered through a 0.22 μm PVDF membrane in a biological safety cabinet and then packed into 20 mL glass vials (particle-free) or 150 mL polyolefin IV bags. The vials and IV bags were stored at room temperature. The pH of the guanfacine solutions in the vials and IV bags was 5.7 and 5.0, respectively. After 72 hours at room temperature, 0.23% degradation products were produced in the guanfacine solution in the vials, and 0.16% degradation products were produced in the guanfacine solution in the IV bags. [Table 4] [Table 5]

[0055] Furthermore, guanfacine HCl (Laxai Avanti, lot number CPL-01-2013-014-033) was dissolved in WFI to a final concentration of 1.14 mg / mL and pH 4.5. The solution was then filtered through a 0.22 μm PVDF membrane in a biological safety cabinet and filled into glass vials. The glass vials were stored at room temperature. After one week of storage at room temperature, the guanfacine solution formed 0.26% degradation products, which was approximately equivalent to the amount of degradation that occurred in just three days in the guanfacine solution in the vials shown in Table 3 above. [Table 6]

[0056] To investigate whether the stability of guanfacine solution could be improved by lowering its pH, additional pH stability tests were conducted. For the stability tests, 1 mg / mL guanfacine solutions were prepared in the pH range of 3.0 to 6.0. For samples with pH 3.0, 3.5, and 4.0, 5 mM citrate buffer was prepared by mixing 1 M citric acid stock solution with sodium citrate dihydrate at each pH. For pH 3.0, 900 μL of citric acid was added to 100 μL of sodium citrate dihydrate; for pH 3.5, 750 μL of citric acid was added to 250 μL of sodium citrate dihydrate; and for pH 4.0, 640 μL of citric acid was added to 360 μL of sodium citrate dihydrate. Next, 0.25 mL of each buffer stock solution was added to 40 g of WFI in a glass beaker and mixed with a magnetic stirrer until homogeneous. To each mixed buffer, 57.4 mg of guanfacine HCl, equivalent to 50 mg of free guanfacine base, was added, and the solution was mixed until the powder dissolved. Next, the pH of the solution was adjusted to 3.0, 3.5, or 4.0 using 0.1 N NaOH, and the total net weight was adjusted to 50 grams using WFI. After mixing the solution until homogeneous, it was filtered through a 0.22 μm PVDF filter, and 4 mL of the solution was filled into a 5 mL serum vial, which was then stoppered and sealed.

[0057] Using stock solutions of acetic acid and sodium acetate, separate samples with pH 4.0 and pH 5.0 were prepared. For the pH 4.0 sample, 920 μL of acetic acid was added to 80 μL of sodium acetate, and then the final solution was prepared according to the method described above to achieve a buffer concentration of 5 mM. For the pH 5.0 sample, 700 μL of acetic acid was added to 1,300 μL of sodium acetate, and 1.0 mL of the stock buffer solution was added to achieve a final buffer concentration of 20 mM. Excluding the buffer concentration, the pH 5.0 sample solution was prepared using the method described above. Another sample solution was also prepared with 20 mM sodium acetate and pH 5.0, but to remove air from the sample, nitrogen was blown into the solvent, the headspace of the vial was replaced with nitrogen, and then the vial was immediately stoppered. For the sample with a pH of 6.0, a stock solution was prepared using 1,840 μL of 0.5 M disodium hydrogen phosphate and 160 μL of 0.5 M disodium phosphate. 1.0 mL of this solution was added to dilute the sodium phosphate concentration in the final 50-gram solution to 10 mM. The solution was then prepared using the method described above. For the pH of 7.0, it was found that 1 mg / mL of guanfacine did not dissolve completely; therefore, this solution underwent further investigation according to the procedure described in detail below.

[0058] All stability test sample solutions were analyzed by HPLC, then stored for one week under stable conditions at 25 and 40°C before analysis. As shown in Table 6, guanfacine solution was found to be more stable at lower pH values. In the pH 3.0 sample, the major degradation product accounted for approximately 1.2% of the total peak area, with an RRT of 7.21, and this was also the major degradation product at all pH values. At pH 4.0, differences were observed in the stability of guanfacine between the citrate buffer and acetate buffer samples, with the former having a purity of 98% and the latter 97.5% after one week. The pH 5.0 sample, in which the air in the solution was replaced with nitrogen, showed similar degradation to the pH 5.0 sample without nitrogen injection, suggesting that the degradation in these liquid samples proceeds by hydrolysis rather than oxidation. [Table 7]

[0059] Follow-up tests were conducted to confirm that the solubility of guanfacine was lower at pH 7.0 and 8.0 compared to other samples prepared under pH ≤ 6.0 conditions. For the pH 7.0 sample, 0.192 mL of stock 0.5 M monobasic sodium phosphate solution and 0.208 mL of stock 0.5 M dibasic sodium phosphate solution were added to a glass test tube, followed by approximately 8.0 mL of WFI and approximately 11.5 mg of guanfacine HCl. The pH was then adjusted to 7.0 with 0.2 N NaOH solution, and the volume was finalized with WFI until it reached 10 mL. For the pH 8.0 sample, 0.028 mL of stock 0.5 M monobasic sodium phosphate solution and 0.372 mL of stock 0.5 M dibasic sodium phosphate solution were added to a glass test tube, followed by approximately 8.0 mL of WFI and 11.48 mg of guanfacine HCl. Next, the pH was adjusted to 8.0 with a 0.2N NaOH solution, and the volume was reduced to 10 mL using WFI. Both samples showed turbidity and precipitate after 1 hour of sonication. After 1 hour of sonication, both samples were filtered through a 0.22 μm PVDF filter and analyzed by HPLC. The concentration of the sample with a pH of 7.0 after filtration was approximately 0.35 mg / mL, and the concentration of the sample with a pH of 8.0 after filtration was approximately 0.12 mg / mL. Therefore, the solubility of guanfacine HCl decreased at pH 7.0 and 8.0 compared to when the pH was 6.0 or lower.

[0060] [Example 4: Stability of lyophilized guanfacine formulation] Guanfacine HCl solution (1 mg / mL) was prepared under the conditions of adding 2% mannitol or sucrose, 4% mannitol or sucrose, and without the addition of a volume extender. For the solution with a pH of 3.0, 4.5 mL of 1 M citric acid solution and 0.5 mL of 1 M sodium citrate dihydrate solution were added to a glass test tube and mixed until homogeneous. 3.125 mL of the mixed buffer was added to 400 g of water, and 0.7175 g of guanfacine HCl was added. The final pH of the solution was adjusted to 3.00 ± 0.05 using 1 N NaOH, and the volume was stabilized to 500 g using WFI. 80 mL of pH-adjusted solution was added to a 300 mL beaker, and either 20 mL of 20% mannitol solution (4% mannitol), 10 mL of 20% mannitol solution (2% mannitol), 8.62 mL of 46.4% sucrose solution (4% sucrose), 4.31 mL of 46.4% sucrose solution (2% sucrose), or no additive (no bulking agent) was added. Then, the WFI was diluted to a final volume of 100 grams, and the pH was adjusted to 3.00 ± 0.05 using HCl or NaOH. The solution was then filtered through a 0.22 μm PVDF filter.

[0061] For the pH 4.0 solution, 3.20 mL of 1 M citric acid solution and 1.80 mL of 1 M sodium citrate dihydrate solution were added to a glass test tube and mixed until homogeneous. 3.125 mL of the mixed buffer was added to 400 g of water, and 0.7175 g of guanfacine HCl was added. The final pH of the solution was adjusted to 4.00 ± 0.05 using 1 N NaOH, and the volume was stabilized to 500 g using WFI. 80 mL of the pH-adjusted solution was added to a 300 mL beaker, and either 20 mL of 20% mannitol solution (4% mannitol), 10 mL of 20% mannitol solution (2% mannitol), 8.62 mL of 46.4% sucrose solution (4% sucrose), 4.31 mL of 46.4% sucrose solution (2% sucrose), or no additive (no bulking agent) was added. Subsequently, the WFI was diluted to a volume of 100 grams, and the pH was adjusted to 4.00 ± 0.05 using HCl or NaOH. The solution was filtered through a 0.22 μm PVDF filter.

[0062] Various filtration solutions (2 mL) were filled into 5.0 mL glass vials and partially sealed with two-legged freeze-drying stoppers. The solutions were freeze-dried using the freeze-drying cycle shown in Table 7 below. After the freeze-drying cycle was completed, the samples were subjected to stability tests at 25°C and 40°C. [Table 8]

[0063] As shown in Tables 8 and 9, all lyophilized guanfacine samples were stable at 25°C for up to 36 months. Since cakes prepared with formulations containing sucrose as an extender disintegrated after 12 months at 40°C, mannitol-containing formulations may be physically more stable than sucrose-containing formulations. [Table 9] [Table 10] [Table 11] [Table 12]

Claims

1. below: a. Guanfacine or its pharmaceutically acceptable salts b. A vehicle, which is as follows: i. One or more bulking agents, and ii. One or more buffering agents for adjusting the pH to 3.0 to 5.0, and one or more selective pH adjusting agents. Vehicles including; and c. Pharmaceutically acceptable diluents A sterile guanfacine injection preparation containing the above.

2. A sterile guanfacine injection preparation according to claim 1, wherein one or more volume extenders are mannitol.

3. A sterile guanfacine injection preparation according to claim 1, wherein the pH is between 3.0 and 4.

0.

4. a. Guanfacine or a pharmaceutically acceptable salt thereof is present in an amount of 0.10 to 10.0 mg / mL; b. One or more extenders are present in an amount of 1.0 to 100 mg / mL; and c. One or more buffering agents and one or more selective pH adjusting agents are present in amounts that adjust the pH of the formulation to 3.0 to 5.

0. A sterile guanfacine injection preparation according to claim 1.

5. below: a. Guanfacine hydrochloride; b. Mannitol; c. One or more buffering agents that adjust the pH to 3.0 to 5.0, and one or more selective pH adjusters; and d. Pharmaceutically acceptable diluents A sterile guanfacine injection preparation according to claim 1, comprising:

6. A sterile guanfacine injection preparation according to claim 5, wherein mannitol is present in an amount of 10 to 50 mg / mL.

7. A sterile guanfacine injection preparation according to claim 5, wherein the pH is between 3.0 and 4.

0.

8. A sterile guanfacine injection preparation according to claim 5, wherein guanfacine is present at a concentration of 0.5 mg / mL.

9. A method for treating delirium, comprising intravenously administering a therapeutically effective amount of a sterile guanfacine injection preparation as defined in claim 1 to a patient in need of treatment.

10. A stable lyophilized sterile guanfacine preparation comprising guanfacine or a pharmaceutically acceptable salt thereof, and a vehicle, wherein the preparation is reconstituted with a pharmaceutically acceptable diluent to form a sterile injectable preparation, and the vehicle comprises one or more buffers that adjust the pH to between 3.0 and 5.0, and one or more selective pH adjusters.

11. The stable, freeze-dried, sterile guanfacine preparation according to claim 10, wherein the guanfacine or a pharmaceutically acceptable salt thereof is guanfacine hydrochloride.

12. The stable, freeze-dried, sterile guanfacine preparation according to claim 10, wherein the vehicle further comprises one or more extenders.

13. A stable, freeze-dried, sterile guanfacine preparation according to claim 12, wherein one or more extenders are mannitol.

14. A stable, freeze-dried, sterile guanfacine preparation according to claim 12, wherein the pH is between 3.0 and 4.

0.

15. below: a. Guanfacine hydrochloride; b. Mannitol; and c. One or more buffering agents that adjust the pH to 3.0 to 5.0, and one or more selective pH adjusting agents. A stable, freeze-dried, sterile guanfacine preparation according to claim 10, comprising:

16. A stable, freeze-dried, sterile guanfacine preparation according to claim 15, wherein the pH is between 3.0 and 4.

0.

17. A stable, freeze-dried, sterile guanfacine preparation according to claim 15, wherein one or more buffering agents and one or more pH adjusting agents are selected from the group consisting of sodium citrate dihydrate, citric acid, and hydrochloric acid.

18. A method for producing a stable, freeze-dried, sterile guanfacine preparation according to claim 10, the following: a. The step of mixing guanfacine or a pharmaceutically acceptable salt thereof with a vehicle to form a sterile solution; and b. The step of freeze-drying the sterile solution to form a stable freeze-dried sterile guanfacine preparation. Methods that include...

19. The method according to claim 18, wherein the freeze-drying step is carried out by cooling the sterile final solution to about -45°C and drying the cooled sterile final solution at about 40°C or below to form freeze-dried guanfacine.

20. The method according to claim 18, wherein the freeze-drying step is carried out in at least three steps: (1) a freezing step comprising cooling the sterile final solution to about -45°C; (2) a primary drying step carried out at a temperature of about -45°C or higher; and (3) a secondary drying step carried out at a temperature of about -20°C or higher to form freeze-dried guanfacine.

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