WO2024246786A1

WO2024246786A1 - Injectable guanfacine formulations and methods

Info

Publication number: WO2024246786A1
Application number: PCT/IB2024/055236
Authority: WO
Inventors: Leo Pavliv; Andrew Vila
Original assignee: Cumberland Pharmaceuticals Inc
Current assignee: Cumberland Pharmaceuticals Inc
Priority date: 2023-05-31
Filing date: 2024-05-30
Publication date: 2024-12-05
Anticipated expiration: 2025-11-30

Abstract

Stable freeze-dried formulations containing guanfacine, represented by the formula (I): or a pharmaceutically acceptable salt thereof. Methods of making and using stable guanfacine freeze-dried formulations are also provided.

Description

INJECTABLE GUANFACINE FORMULATIONS AND METHODS

FIELD

[0001] The embodiments disclosed herein relate to stable freeze-dried formulations comprising guanfacine, or a pharmaceutically acceptable salt thereof, methods for preparing the above formulations, and methods for employing the above formulations for use in preventing or treating patients suffering from delirium.

BACKGROUND

[0002] The mental condition of a hospitalized patient can pose serious therapeutic challenges to medical care providers. Often, due to underlying medical conditions, the patient may exhibit serious and potentially life-threatening psychological manifestations such as delirium. Delirium is a syndrome, or group of symptoms, caused by a disturbance in the normal functioning of the brain. Delirium denotes an acute and debilitating decline in attention, focus, perception, and cognition that produces an altered form of semi-consciousness. Delirium manifests as an acute disturbance of consciousness and cognition that usually fluctuates overtime. There are generally three different subtypes of delirium based on psychomotor behavior: hypoactive, hyperactive and mixed-type delirium. Delirium affects at least one in 10 hospitalized patients, 1 in 2 elderly hospitalized patients, and up to 85% of critically ill patients. Post-operative delirium substantially lengthens Intensive Care Unit (ICU) and hospital stays and increases medical care costs by as much as $ 1.2 billion annually. Compared with non-delirious patients, delirious patients are more likely to consume more hospital staff time and precious life-support resources, stay longer, and develop in-hospital complications. In addition, such patients are more likely discharged to a facility, and may be readmitted to the hospital.

[0003] While it is not a specific disease itself, patients with delirium usually fare worse than those with the same illness who do not have delirium. It usually occurs as a post-operative complication and recently has been observed in patients suffering from COVID-19 infection, which is believed to cause an inflammatory response that triggers delirium in such patients. A study of 101 hospitalized patients with COVID-19 reported that delirium was a prevalent symptom, occurring in almost a quarter of the patients. (Lovell et al., Journal of Pain and Symptom Management, 2020.) Higher rates of delirium associated with COVID- 19 will therefore exacerbate an already overwhelmed healthcare system.

[0004] Current management of delirium in COVID- 19 patients includes off-label use of certain antipsychotics. (NICE Guidelines, BMJ 2020;369:ml461.) However, substantial evidence indicates that antipsychotic drugs fail to 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.) Thus, there exists a need for improved methods for preventing or treating delirium. Also needed are stable formulations that may be administered intravenously to patients who may be unable to swallow or ingest medications due to their altered mental state.

SUMMARY

[0005] Disclosed herein are sterile guanfacine injectable formulations, which comprise guanfacine or a pharmaceutically acceptable salt thereof; a vehicle, said vehicle comprising one or more bulking agents and one or more buffering agents and optionally one or more pH adjusting agents to adjust pH from 3.0 to 8.0; and a pharmaceutically acceptable diluent. [0006] Also disclosed are methods of treating delirium, comprising intravenously administering to a patient in need of treatment a therapeutically effective amount of a sterile guanfacine injectable formulation.

[0007] Also disclosed are stable freeze-dried sterile guanfacine formulations comprising guanfacine, or a pharmaceutically acceptable salt thereof, and a vehicle, wherein the formulation upon reconstitution with a pharmaceutically acceptable diluent forms a sterile injectable formulation.

[0008] Also disclosed are methods of preparing a stable freeze-dried sterile guanfacine formulation comprising combining guanfacine, or a pharmaceutically acceptable salt thereof, and a vehicle to form a sterile solution; and freeze drying said sterile solution to form the stable freeze-dried sterile guanfacine formulation.

[0009] Additional aspects and advantages of the embodiments disclosed herein will be set forth in part in the description that follows and, in part, will be discernable from the description, or may be learned by practicing or performing the disclosed embodiments. The aspects and advantages will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.

[0010] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the scope of the claim appended hereto.

DETAILED DESCRIPTION OF EXAMPLE EMBODIMENTS

[0011] It is to be understood that this disclosure is not limited to any particular embodiment(s) described herein, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the appended claims. The example embodiments described herein and claimed hereafter may be suitably practiced in the absence of any recited feature, element or step that is, or is not, specifically disclosed herein. For instance, references in this written description to “one embodiment,” “an embodiment,” “an example embodiment,” and the like, indicate that the embodiment described can include a particular feature, structure, or characteristic, but every embodiment may not necessarily include the particular feature, structure, or characteristic. Moreover, such phrases are not necessarily referring to the same embodiment. Further, when a particular feature, structure, or characteristic is described in connection with an embodiment, it is submitted that it is within the knowledge of one of ordinary skill in the art to affect such feature, structure, or characteristic in connection with other embodiments whether or not explicitly described.

[0012] The terms “comprising,” “including,” and “containing” are non-limiting. Other nonrecited elements may be present in embodiments claimed by these transitional phrases.

Where “comprising,” “containing,” or “including” are used as transitional phrases other elements may be included and still form an embodiment within the scope of the claim. The open-ended transitional phrase “comprising” encompasses the intermediate transitional phrase “consisting essentially of’ and the close-ended phrase “consisting of.” The freeze- dried or injectable guanfacine formulations disclosed herein may consist essentially of guanfacine or a pharmaceutically acceptable salt thereof. “Consists essentially of’ means that the guanfacine, or a pharmaceutically acceptable salt thereof, is the only active ingredient in the formulation, e.g., the only ingredient that is therapeutically effective, while other inactive ingredients may be present as, for instance, vehicles or mediums for administration or stabilization such as water and/or a pH-adjusting agent.

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

[0014] A “therapeutically effective amount” or “effective amount” is that amount of guanfacine to achieve a pharmacological effect that treats delirium in a patient. The term “therapeutically effective amount” includes, for example, a prophylactically effective amount, that is an amount effective to significantly reduce the probability of occurrence of delirium in a patient. An “effective amount” is an amount needed to achieve a desired pharmacologic effect or therapeutic improvement without undue adverse side effects. The effective amount will be selected by those skilled in the art depending on the particular patient. It is understood that “an effective amount” or “a therapeutically effective amount” can vary from patient to patient, due to variation in metabolism of guanfacine, age, weight, general condition of the subject, the severity of the condition being treated, and the judgment of the prescribing physician.

[0015] The terms “treat”, “treating”, and “treatment”, etc., as used herein, refer to any action providing a benefit to a patient for which the disclosed injectable formulations may be administered, including the treatment of any physiological state or mental condition (e.g., delirium) that is modulated or otherwise susceptible to modulation by the injectable formulations.

[0016] Recitation of ranges of values are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. Where a range of values is provided, it is to be understood that each intervening value, to the tenth of the unit of the lower limit, unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The endpoints of all ranges are included within the range and independently combinable. The upper and lower limits of these smaller ranges that may independently be included in the smaller ranges are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included. [0017] All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”), is intended merely for illustration and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0018] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed embodiments belong. Any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the disclosed embodiments described herein. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.

[0019] It must be noted that as used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise. [0020] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.

[0021] As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present invention. [0022] Guanfacine is a central alpha-2 adrenergic receptor agonist indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) as monotherapy and as adjunctive therapy to stimulant medications. It is also indicated in the management of hypertension, either alone or in combination with other antihypertensive agents, especially thiazide-type diuretics. The chemical name of guanfacine hydrochloride is N-amidino-2-(2,6- dichlorophenyl) acetamide monohydrochloride. U.S. Patent Number 3,632,645 discloses guanfacine and its pharmaceutically acceptable acid addition salts specifically.

[0023] The freeze-dried and injectable formulations disclosed herein comprise guanfacine or a pharmaceutically acceptable salt thereof. The chemical structure of guanfacine is:

[0024] The guanfacine useful in the formulations disclosed herein may be formulated with a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids, where applicable. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium, magnesium and ammonium salts, among numerous other acids and bases well known in the pharmaceutical art. Examples of salts include salts of inorganic or organic acids such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, benzoate, tartrate, bitartrate, succinate, maleate, formate, fumarate, gluconate, saccharate, benzoate, sulfamate, methane sulfonate, ethanesulfonate, benzenesulfonate, mesylate, p-toluenesulfonate, pamoate [i.e., 1,1’- methylene-bis-(2 -hydroxy-3 naphthoate)], camsylate, isethionate, edisylate, closylate salts, and the like. In one embodiment, the guanfacine formulations comprise guanfacine hydrochloride.

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

[0026] The guanfacine injectable formulations may contain from 0.01 to 50.0 mg/mL guanfacine. In one embodiment, the guanfacine injectable formulation contains from 0.05 to 29.0 mg/mL, from 0.10 to 10.0 mg/mL, from 0.20 to 5.00 mg/mL, or from 0.50 to 1.50 mg/mL guanfacine. In another embodiment, the guanfacine injectable formulation 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 guanfacine.

[0027] The guanfacine injectable formulations may be administered by any pharmaceutically effective parenteral route. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In one embodiment, the guanfacine injectable formulations are administered as an intravenous injection. The intravenous injection may be continuous or a bolus injection. Any known device useful for parenteral injection or infusion of drug formulations can be used to effect such administration. [0028] The sterile guanfacine injectable formulations may comprise: (a) guanfacine or a pharmaceutically acceptable salt thereof; (b) a vehicle; and (c) a pharmaceutically acceptable diluent, wherein the vehicle may comprise (i) one or more bulking agents and (ii) one or more buffering agents and optionally one or more pH adjusting agents to adjust pH from 3.0 to 8.0.

[0029] The one or more bulking agents may be present in an amount 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 one milliliter of the sterile guanfacine injectable formulation. Examples of bulking agents suitable for use herein include, but are not limited to, mannitol, sucrose, lactose, glycine, trehalose, maltose, xylitol, glucose, starches, sorbitol, erythritol, maltitol, dextran, dextrose, lactitol, or a combination thereof. In one embodiment, the sterile guanfacine injectable formulations comprise mannitol as the bulking agent.

[0030] One or more buffering agents and optionally one or more pH adjusting agents may be employed in an amount to adjust pH of an aqueous solution of the guanfacine formulation from 3.0 to 9.0. In some embodiments, the pH may be adjusted to from 3.0 to 8.0, from 3.0 to less than 7.0, from 3.0 to 5.0, or from 3.0 to 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, usually the buffer, depending on type, may be employed in an amount from 5 to 100 pmol per one milliliter of the sterile guanfacine injectable formulation or from 5.00 mM to 100 mM. 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, ascorbate, benzoate, lactate, malate, maleate, succinate, or a combination thereof. In one embodiment, the sterile guanfacine injectable formulations comprise sodium citrate dihydrate and citric acid as buffering agents. In one embodiment, from 0.15 to 10.6 mg of sodium citrate dihydrate, from 0.62 to 17.3 mg of citric acid, or a combination thereof are used as buffers per milliliter of the sterile guanfacine injectable formulation. In another embodiment, from 0.15 to 0.53 mg of sodium citrate dihydrate, from 0.62 to 0.86 mg of citric acid, or a combination thereof are used as buffers per milliliter of the sterile guanfacine injectable formulation.

[0031] Optional one or more pH adjusting agents may also be employed in the aqueous solution of the freeze-dried guanfacine formulation. Where the pH needs to be lowered, an acidic pH adjusting agent such as hydrochloric acid, citric acid, malic acid, maleic acid, succinic acid, phosphoric acid, lactic acid, ascorbic acid, sulfuric acid, methane sulfonic acid, aspartic acid, glutamic acid, or a combination thereof may be employed. When the pH needs to be raised, a basic pH adjusting agent may be employed 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, ethyl diamine, ammonium hydroxide, or a combination thereof. In one embodiment, the sterile guanfacine injectable formulation comprises hydrochloric acid, sodium hydroxide, or a combination thereof as the pH-adjusting agent.

[0032] Guanfacine formulations disclosed herein may optionally further comprise a pharmaceutical excipient, such as a solvent, preservative, antioxidant, solubilizer, or a combination thereof. Examples of the solvent include isotonic saline, 5% dextrose, alcohol, propylene glycol, macrogol, glycerin, and the like. Examples of the preservative include a parahydroxybenzoate, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, sorbic acid, methyl paraben, propyl paraben, phenol, thiomersal, and the like. Examples of the antioxidant include a sulfite, ascorbic acid, a-tocopherol, a reductant such as cysteine, glutathione, and N-acetyl cysteine, a metal ion chelator such as ethylene diaminetetraacetic acid, and the like. Examples of the solubilizer include a complexing agent such as a cyclodextrin (e.g., hydropropylbetacyclodextrin, sulfobutyl ether cyclodextrin), a surfactant (e.g., a polysorbate, a chremophor, solutol, D-a-tocopheryl polethylene glycol succinate (vitamin E TPGS), lecithin, a phospholipid, a negatively charged phospholipid), a hydrotropic agent (e.g., niacinamide, salicylate, urea, propyl paraben, methyl paraben), and the like.

[0033] Exemplary guanfacine formulations may be prepared using the following components:

[0034] Guanfacine, or a pharmaceutically acceptable salt thereof, may also be formulated with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as an anesthetically-effective compound. Examples of anesthetics include articaine, bupivacaine, levobupivacaine, ropivacaine, butanilicaine, carticaine, cinchocaine (dibucaine), etidocaine, lidocaine, mepivacaine, prilocaine, trimecaine, and combinations thereof. In one embodiment, the guanfacine formulations comprise guanfacine and ropivacaine as active materials. In another embodiment, the guanfacine formulations comprise guanfacine and lidocaine as active materials.

[0035] In carrying out the method for preparing the stable freeze-dried sterile guanfacine formulation, the guanfacine, or a pharmaceutically acceptable salt thereof, and a vehicle are combined to form a solution and the solution is freeze-dried in a manner to form a freeze- dried powder or cake. The components of the stable freeze-dried sterile guanfacine formulation may be combined in any order. In one embodiment, the one or more buffering agents may be added to water for injection, forming a solution. Guanfacine, or a pharmaceutically acceptable salt thereof, may be added to the solution. One or more bulking agents may then be added to the solution. Alternatively, one or more buffering agents may be added to water for injection, followed by addition of one or more bulking agents to the solution, followed by addition of guanfacine, or a pharmaceutically acceptable salt thereof to the solution. PH adjustment using one or more pH-adjusting agents may occur prior to and/or after the addition of guanfacine, or a pharmaceutically acceptable salt thereof, prior to and/or after addition of one or more buffering agents, and/or prior to and/or after addition of one or more bulking agents. In any methodology, there may be a final pH adjustment step with one or more pH-adjusting agents after the other components of the solution are combined. Further, an anti-oxidant, preservative, or both may be added before the addition of guanfacine, or a pharmaceutically acceptable salt thereof, to the solution with pH adjustment using one of more pH adjusting agents prior to and/or after addition.

[0036] During combination and/or after the guanfacine, or a pharmaceutically acceptable salt thereof, and a vehicle, are combined, the solution may be subjected to sterilization by, for instance, filtration, autoclaving, and/or radiation sterilization. The resulting final solution may be aseptically filled into sterile containers and aseptically loaded into a sterilized freeze drier. As the final solution is aseptically filled into a sterile container, the container may be flash frozen.

[0037] The freeze drying may be carried out by any suitable process. For instance, the freeze drying cycle may be carried out by cooling of the sterile final solution to about -45°C at a suitable cooling rate. The drying may be performed at a temperature below around 40°C and a suitable vacuum and duration to form the stable freeze-dried sterile guanfacine formulation. In another embodiment, the freeze drying step is carried out in at least three phases: (1) a freezing phase which includes cooling of the sterile final solution to about -45 °C at a suitable cooling rate, (2) a primary drying phase which is performed at about -45°C or higher and a suitable vacuum and duration, and (3) a secondary drying phase which is performed at about -20°C or higher and a suitable vacuum and duration, to form the stable freeze-dried sterile guanfacine formulation. The secondary drying phase may be performed up to 40°C.

[0038] The containers with the resulting stable freeze-dried sterile guanfacine formulation may be aseptically stoppered under atmospheric pressure or partial vacuum and sealed. In one embodiment, the headspace of the container may be purged with an inert headspace gas (e.g., nitrogen or argon) just prior to stoppering. The formulations may be presented in unitdose or multi-dose containers, for example vials, disposable syringes, pens, IV bags, or multiple dose vials made of glass or plastic.

[0039] The freeze-dried guanfacine formulation may be reconstituted in a pharmaceutically acceptable diluent in an amount sufficient to deliver to a patient a therapeutically effective amount. The pharmaceutically acceptable diluent may be water for injection, normal saline, half normal saline, 5% dextrose, lactated ringers, or a combination thereof. In one embodiment, the freeze-dried guanfacine formulation may be reconstituted with water for injection.

[0040] A suitable dosage of guanfacine may be from 0. 1 mg to 5.0 mg or from 0.5 to 4.0 mg per day. In one embodiment, a dosage 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 may be administered daily. The dosage may be administered as a single daily dose or in multiple doses per day. For instance, the reconstituted guanfacine formulations may be administered twice daily. In one embodiment, the dose may be 0.5, 1.0, or 2.0 mg guanfacine administered twice a day. [0041] The disclosed guanfacine formulations are useful in the prevention or treatment of delirium in a subject. Accordingly, also disclosed are methods for treating delirium, comprising intravenously administering to a patient in need of treatment a therapeutically effective amount of a guanfacine formulation. The terms “subject”, “individual” or “patient” are used interchangeably herein and refer to a vertebrate, such as a mammal. Mammals include, but are not limited to, murines, rodents, simians, humans, farm animals, sport 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, cardiac disease, pulmonary disease, diabetes, kidney disease, cancer, and combinations thereof. In yet another embodiment, the human patient is on mechanical ventilation, on non-invasive positive pressure ventilation (NIPPV), being treated for shock (e.g., with vasopressors), or a combination thereof.

[0042] The term “delirium” is defined herein as acute cognitive impairment associated with a medical problem. Delirium may be precipitated by various factors, including but not limited to, surgical trauma, withdrawal from drugs or alcohol, metabolic disturbances, and/or sepsis. Symptoms of delirium may include hallucinations, delusions, psychosis, disorientation, confusion, anxiety, attention deficit, memory impairment, personality changes, depression, immobility, sleep disturbance, language disturbance, sensory deficits, or a combination thereof.

[0043] In one embodiment, the delirium treated or prevented by the guanfacine formulations disclosed herein is associated with a severe acute respiratory syndrome (SARS) coronavirus 2 infection. In another embodiment, the delirium is associated with surgery, for instance postoperative delirium following a surgical procedure. In yet another embodiment, the delirium is associated with a critically ill patient, i.e., a patient with a state of poor health with life-threatening injuries and illnesses or at risk of developing them (e.g., those patients that would generally be admitted to an Intensive Care Unit (ICU) of a hospital).

[0044] The presently-disclosed subject matter is further illustrated by the following specific but non-limiting examples. The following examples may include compilations of data that are representative of data gathered at various times during the course of development and experimentation related to the present invention.

EXAMPLES

[0045] The following examples are not meant to be limiting and represent certain embodiments of the present invention.

Example 1 : Compatibility of Guanfacine with Ropivacaine

[0046] The compatibility of 1.0 mg/mL and 0.1 mg/mL solutions of Guanfacine diluted into 30 mb Ropivacaine (USP 5 mg/mL Hospira, Lot- 48-031-DK) was tested. A 0.1 and 1.0 mg/mL solution of Guanfacine free base in water for injection (WFI) was prepared. For every 1.148 mg of Guanfacine-HCl there is 1 mg of Guanfacine free base. For the 0.1 mg/mL solution, 57.4 mg of Guanfacine-HCl (lot # CPL-01-2013-014-033 Laxai Avanti) was dissolved in 400 mL of WFI (Hospira 1000 mL Bag, Lot 51-114-JT). Once fully dissolved, the solution was transferred to a 500 mL volumetric flask and q.s. to volume. For the 1.0 mg/mL solution, 114.8 mg of Guanfacine-HCl was dissolved in 80 mL of WFI. Once fully dissolved, the solution was transferred to a 100 mL volumetric flask and q.s. to volume.

[0047] Two glass vials were rinsed with WFI three times and emptied. The vials were rinsed with fdtered Guanfacine solution three times, 5 mLs at a time. Approximately 35 mLs of the Guanfacine solutions were fdtered into the vials using a Millex GV Sterile PVDF 0.22 pm syringe fdter. The particulate content in the fdtered Guanfacine solutions was determined prior to adding to the Ropivacaine vial using an APSS Liquiliaz particle counter. 1.2 mLs of fdtered Guanfacine solutions at 0.1 or 1.0 mg/mL were injected into three separate vials containing Ropivacaine for each concentration (1:25 dilution of Guanfacine:Ropivacaine).

The concentration of Guanfacine freebase in the WFI control was 0.10 mg/mL and 1.05 mg/mL, as determined by HPLC. The compatibility solutions were not able to be analyzed by the HPLC assay for Guanfacine because Guanfacine and Ropivacaine have very similar elution times and only the Ropivacaine peak could be seen on the chromatogram.

[0048] The appearance, pH, and particulate content for one vial at each concentration at time zero, 4 to 6 hours, and 24 hours was assessed and the results are reported in Table 1, below.

Table 1.

[0049] All of the samples appeared clear and colorless from time zero through 24 hours. In addition, the particle counts per container were all below the limits for small volume parenterals USP<788>. Prior to mixing Guanfacine with Ropivacaine, the particulate content of the filtered Guanfacine solution was assayed. The results in the above table in the “Guanfacine Only” rows show low levels of particle count for those solutions in particles per milliliter.

[0050] After Guanfacine was mixed with Ropivacaine it was noted that the time zero particle counts were slightly high. This was most likely due to the initial mixing of Guanfacine and Ropivacaine solutions. The amount of small air bubbles that formed during mixing probably decreased overtime, which could explain the decreasing particle counts seen above.

[0051] The results demonstrate that Guanfacine at 1.0 mg/mL in WFI is compatible with Ropivacaine at a 1:25 dilution of Guanfacine to Ropivacaine.

Example 2: Compatibility of Guanfacine with Lidocaine

[0052] Guanfacine HC1 (Laxai Avanti, Lot CPL-01-2013-014-033) was dissolved in WFI to a final concentration of 1. 14 mg/mL. One milliliter of the 1.14 mg/mL guanfacine solution was added to the 30 mL vial of 1% Lidocaine (Hospira Inc. Lot#81-434-DK) and mixed (final guanfacine concentration ~31 pg/mL). Six milliliters of the Guanfacine-Lidocaine mixture were removed into 10 mL syringes. The mixture in the syringes was stored at room temperature overnight (up to ~I7 hours). The mixture was analyzed using HPLC at 1, 3, 5, and 6 hour time points and after overnight according to the USP monograph for Guanfacine- Hydrochloride Assay. To make the standard curve, Guanfacine -HC1 was dissolved in WFI to a concentration of 1.0 mg/mL and then serially diluted down to 0.025 mg/mL. The concentrations for the standards in mg/mL were 1.0, 0.50, 0.05, and 0.025. The guanfacine main peak eluted at RT = 5.9 min.

[0053] The mixture was found to be physically compatible after overnight storage at room temperature. For chemical stability there was a slight increase in a guanfacine-related degradation product after 3 hours, which then reached levels of 1.0% after overnight storage (~17 hours) (Table 2, below). The 1.0% degradation product would represent a maximum of 2.5 ig per injection, which is below the identification threshold for maximum daily doses < 1 mg, according to ICH guideline Q3B(R2), Impurities in New Drug Substances.

Table 2.

Example 3: Effect of pH on stability of Guanfacine Solutions

[0054] Guanfacine HC1 powder (Laxai Avanti, Lot CPL-01-2013-014-033) was dissolved in

WFI at a concentration of 0.5 mg/mL, passed through a 0.22 pm PVDF membrane in a biosafety cabinet, and then filled into 20 mb glass vials (particle free), or 150 ml polyolefin IV bags. The vials and IV bags were stored at room temperature conditions. The Guanfacine solutions in the vials and IV bags were at pH 5.7 and 5.0, respectively. After 72 hours at room temperature the Guanfacine solution in the vials formed a degradation product at 0.23% and the Guanfacine solution in the IV bags formed a degradation product at 0.16%.

Table 3 , Chemical stability of 0.5 mg/mL Guanfacine in WFI in vials, pH 5.7

Table 4, Chemical stability of 0.5 mg/mL Guanfacine in WFI in IV bags, pH 5.0

[0055] Additionally, Guanfacine HC1 (Laxai Avanti, Lot CPL-01-2013-014-033) was dissolved in WFI to a final concentration of 1. 14 mg/mL, pH 4.5, passed through a 0.22 pm

PVDF membrane in a biosafety cabinet, and then filled into glass vials. The glass vials were stored at room temperature conditions. The Guanfacine solution showed that a degradation product formed at 0.26% after one week of storage at room temperature, which was about the same amount of degradation that occurred after only three days in the Guanfacine solutions in the vials from Table 3, above.

Table 5 , Chemical stability of the 1.14 mg/mL Guanfacine-HCl solution in WFI (pH 4.5)

[0056] Additional pH stability studies were performed to determine if the stability of

Guanfacine solutions could be enhanced by lowering the pH. Solutions of 1 mg/mL Guanfacine were made at pH levels ranging from 3.0 to 6.0 for stability testing. For the pH

3.0, 3.5, and 4.0 samples, 5 mM citrate buffers were made at each pH from combinations of 1

M stock solutions of citric acid and sodium citrate dihydrate. For pH 3.0, 900 pL of citric acid was added to 100 pL of sodium citrate dihydrate, for pH 3.5, 750 pL of citric acid was added to 250 pL of sodium citrate dihydrate, and for pH 4.0, 640 pL of citric acid was added to 360 pL of sodium citrate dihydrate. Next, 0.25 mb aliquots of each buffer stock solution were added to 40 grams of WFI in a glass beaker and then mixed until uniform with a magnetic stir bar. To each buffered mixture, 57.4 mg of Guanfacine -HC1 was added, which is equivalent to 50 mg of Guanfacine free base, and the solution was mixed until the powder was dissolved. The pH of the solutions was then adjusted to 3.0, 3.5, or 4.0 using 0.1 N NaOH, the total net weight was adjusted to 50 grams with WFI, the solutions were mixed until uniform followed by fdtration through a 0.22 pm PVDF fdter, and then 4 mLs were fdled into 5 mb serum vials that were subsequently stoppered and sealed.

[0057] Stock solutions of acetic acid and sodium acetate were used for making another pH 4.0 sample and a pH 5.0 sample. Forthe pH 4.0 sample, 920 pL of acetic acid was added to 80 pL of sodium acetate and then the final solution was prepared as described above to achieve a 5 mM buffer concentration. For the pH 5.0 sample, 700 pL of acetic acid was added to 1,300 pL of sodium acetate and 1.0 mLs of that buffer stock solution was added to make a final buffer concentration of 20 mM. With the exception of the buffer concentration, the pH 5.0 sample solution was completed as described above. Another sample solution was also made at 20 mM sodium acetate, pH 5.0, except the solvent was sparged with nitrogen and the head space of the vial was purged with nitrogen just prior to stoppering in order to remove air from the sample. For the pH 6.0 sample, a stock solution with 1,840 pL of 0.5 M sodium phosphate monobasic and 160 pL of 0.5 M sodium phosphate dibasic was made that was then diluted to 10 mM sodium phosphate by adding 1.0 mb to a final of 50 grams of solution. The solution was then completed as described previously. It was found that at pH 7.0, 1 mg/mL of guanfacine did not completely dissolve and so this solution was further examined, as described in more detail below.

[0058] All stability sample solutions were analyzed by HPLC and then the solutions were placed on stability at 25 and 40°C and analyzed after a week of storage. As demonstrated in Table 6, it was found that guanfacine solutions were more stable at lower pH values. The major degradation product in the pH 3.0 sample was -1.2% of the total peak area and at RRT = 7.21, which was also the major degradation product across all pH values. There was a difference in guanfacine stability between the citrate and acetate buffered samples at pH 4.0 after 1 week where the former had a purity of 98% and the latter had a purity of 97.5%. The pH 5.0 sample where the air in the solution was replaced with nitrogen had similar degradation to the pH 5.0 sample that was not sparged with nitrogen, suggesting that the degradation in these liquid samples does not proceed through oxidation but rather by hydrolysis.

Table 6, HPLC Purity Analysis of Guanfacine -HC1 samples at pH 3-6

[0059] Follow up testing was done to confirm that Guanfacine solubility was lower at pH 7.0 and 8.0 compared to the other samples made at pH levels < 6.0. For the pH 7.0 sample, a stock solution of 0.192 mL of 0.5 M sodium phosphate monobasic and 0.208 mLs of 0.5 M sodium phosphate dibasic was added to a glass tube followed by ~8.0 mLs of WFI and - 11.5 mg of Guanfacine -HC1. The solution was then adjusted to pH 7.0 with a solution of 0.2 N NaOH and adjusted to a volume of 10 mLs with WFI. For the pH 8.0 sample, a stock solution of 0.028 mL of 0.5 M sodium phosphate monobasic and 0.372 mLs of 0.5 M sodium phosphate dibasic was added to a glass tube followed by -8.0 mLs of WFI and 11.48 mg of Guanfacine-HCl. The solution was then adjusted to pH 8.0 with a solution of 0.2 N NaOH and adjusted to a volume of 10 mLs with WFI. Both samples were cloudy and contained precipitate after 1 hour of sonication. After 1 hour of sonication both samples were then filtered through a 0.22 pm PVDF filter and analyzed by HPLC. The concentration of the filtered pH 7.0 sample was -0.35 mg/mL and the concentration of the filtered pH 8.0 sample was -0.12 mg/mL. Therefore Guanfacine-HCl was less soluble at pH 7.0 and 8.0 compared to pH levels of 6.0 and lower.

Example 4: Stability of Lyophilized Guanfacine Formulations

[0060] Guanfacine-HCl solutions (1 mg/ml) with 2% mannitol or sucrose, 4% mannitol or sucrose, and with no bulking agent were made. For the pH 3.0 solutions, 4.5 mL of a 1 M citric acid solution and 0.5 mL of a 1 M sodium citrate dihydrate solution were added into a glass tube and mixed until uniform. 3.125 mLs of the buffer mixture was added into 400 grams of water and 0.7175 g of Guanfacine-HCl was added. The solution was adjusted to a final pH of 3.00 ± 0.05 using IN NaOH and q.s. to 500 grams using WFI. 80 mLs of the pH- adjusted solution was added to a 300 mL beaker and either 20 mLs of a 20% mannitol solution (4% mannitol), 10 mLs of a 20% mannitol solution (2% mannitol), 8.62 mLs of a 46.4% sucrose solution (4% sucrose), 4.31 mLs of a 46.4% sucrose solution (2% sucrose), or nothing (no bulking agent) was added. Subsequently, WFI was added to q.s. to 100 grams and the pH was adjusted to 3.00 ± 0.05 with either HC1 or NaOH. The solutions were then filtered through a 0.22 pm PVDF filter.

[0061] For the pH 4.0 solutions, 3.20 mb of a 1 M citric acid solution and 1.80 mb of a 1 M sodium citrate dihydrate solution were added into a glass tube and mixed until uniform. 3.125 mLs of the buffer mixture was added into 400 grams of water and 0.7175 g of Guanfacine- HC1 was added. The solution was adjusted to a final pH of 4.00 ± 0.05 using IN NaOH and q.s. to 500 grams using WFI. 80 mLs of the pH-adjusted solution was added to a 300 mb beaker and either 20 mLs of a 20% mannitol solution (4% mannitol), 10 mLs of a 20% mannitol solution (2% mannitol), 8.62 mLs of a 46.4% sucrose solution (4% sucrose), 4.31 mLs of a 46.4% sucrose solution (2% sucrose), or nothing (no bulking agent) was added. Subsequently, WFI was added to q.s. to 100 grams and the pH was adjusted to 4.00 ± 0.05 with either HC1 or NaOH. The solutions were then filtered through a 0.22 pm PVDF filter.

[0062] The various filtered solutions (2 mLs) were filled into 5.0 mL glass vials and partially stoppered with 2-legged lyophilization stoppers. The solutions were freeze-dried using the lyophilization cycle in Table 7 below. After the freeze-drying cycle was completed the samples were placed on stability at 25 and 40°C.

Table 7, Freeze drying cycle

[0063] As demonstrated in Tables 8 and 9, all lyophilized guanfacine samples were stable for up to 36 months at 25°C. The mannitol containing formulations may be more physically stable than the sucrose containing formulations as the cakes made with the latter bulking agent collapsed after 12 months at 40°C.

Table 8, 24, 30, and 36 Month visual analysis of the samples stored at 25 and 40 °C.

Table 8 (cont). 24, 30, and 36 Month visual analysis of the samples stored at 25 and 40 °C.

Table 9, 36 Month HPLC content and purity at 25°C.

Table 9 (cont.). 36 Month HPLC content and purity at 25°C.

Claims

We Claim:

1. A sterile guanfacine injectable formulation, which comprises: a. guanfacine or a pharmaceutically acceptable salt thereof; b. a vehicle, said vehicle comprising: i. one or more bulking agents and ii. one or more buffering agents and optionally one or more pH adjusting agents to adjust pH from 3.0 to 5.0; and c. a pharmaceutically acceptable diluent.

2. The sterile guanfacine injectable formulation of claim 1, wherein the one or more bulking agents is mannitol.

3. The sterile guanfacine injectable formulation of claim 1, wherein the pH is from 3.0 to 4.0.

4. The sterile guanfacine injectable formulation of claim 1, wherein: a. the guanfacine or a pharmaceutically acceptable salt thereof is present in an amount from 0.10 to 10.0 mg/mL; b. the one or more bulking agents is present in an amount from 1.0 to 100 mg/mL; and c. the one or more buffering agents and optionally one or more pH adjusting agents is present in an amount to adjust the pH of the formulation from 3.0 to 5.0.

5. The sterile guanfacine injectable formulation of claim 1 comprising: a. guanfacine hydrochloride; b. mannitol; c. one or more buffering agents and optionally one or more pH adjusting agents to adjust pH from 3.0 to 5.0; and d. a pharmaceutically acceptable diluent.

6. The sterile guanfacine injectable formulation of claim 5, wherein the mannitol is present in an amount from 10 to 50 mg/mL.

7. The sterile guanfacine injectable formulation of claim 5, wherein the pH is from 3.0 to 4.0.

8. The sterile guanfacine injectable formulation of claim 5, wherein the guanfacine is present at a concentration of 0.5 mg/mL.

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

10. A stable freeze-dried sterile guanfacine formulation comprising guanfacine, or a pharmaceutically acceptable salt thereof, and a vehicle, wherein the formulation upon reconstitution with a pharmaceutically acceptable diluent forms a sterile injectable formulation, and wherein the vehicle comprises one or more buffering agents and optionally one or more pH adjusting agents to adjust pH from 3.0 to 5.0.

11. The stable freeze-dried sterile guanfacine formulation of claim 10, wherein the guanfacine or pharmaceutically acceptable salt thereof is guanfacine hydrochloride.

12. The stable freeze-dried sterile guanfacine formulation of claim 10, wherein the vehicle further comprises one or more bulking agents.

13. The stable freeze-dried sterile guanfacine formulation of claim 12, wherein the one or more bulking agents is mannitol.

14. The stable freeze-dried sterile guanfacine formulation of claim 12, wherein the pH is from 3.0 to 4.0.

15. The stable freeze-dried sterile guanfacine formulation of claim 10, comprising: a. guanfacine hydrochloride; b. mannitol; and c. one or more buffering agents and optionally one or more pH adjusting agents to adjust pH from 3.0 to 5.0.

16. The stable freeze-dried sterile guanfacine formulation of claim 15, wherein the pH is from 3.0 to 4.0.

17. The stable freeze-dried sterile guanfacine formulation of claim 15, wherein the one or more buffering agents and optionally one or more pH adjusting agents is selected from the group consisting of sodium citrate dihydrate, citric acid, and hydrochloric acid.

18. A method of preparing a stable freeze-dried sterile guanfacine formulation according to claim 10, comprising: a. combining guanfacine, or a pharmaceutically acceptable salt thereof, and a vehicle to form a sterile solution; and b. freeze drying said sterile solution to form the stable freeze-dried sterile guanfacine formulation.

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 said cooled sterile final solution at about 40°C or below, to form freeze-dried guanfacine.

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