WO2017037232A1

WO2017037232A1 - Anidulafungin formulations

Info

Publication number: WO2017037232A1
Application number: PCT/EP2016/070718
Authority: WO
Inventors: Ivona JASPRICA; Katarina ALILOVIC
Original assignee: Xellia Pharmaceuticals Aps
Priority date: 2015-09-02
Filing date: 2016-09-02
Publication date: 2017-03-09

Abstract

The present invention is directed to stable formulations comprising therapeutically effective amount of anidulafungin and buffering agent selected from glutamic, picolinic and benzoic acid.

Description

ANIDULAFUNGIN FORMULATIONS

Field of the invention

The present invention relates to pharmaceutical formulations of anidulafungin.

Background of the invention

Anidulafungin is semi-synthetic lipopeptide synthesized from a fermentation product of Aspergillus nidulans. Anidulafungin belongs to the echinocandin class antifungals, which act as an inhibitor of fungal cell wall biosynthesis.

Echinocandins exert their effect by the inhibition of glucan synthase activity and disruption of l,3^-D-glucan formation as an essential component of the fungal cell wall, causing destabilization of the integrity of the fungal cell wall, leading to osmotic instability and cell death.

Echinocandin class compounds are among the best tolerated and safest class of antifungals available, since they exhibit very few drug-drug interactions in combination with relatively low potential for renal or hepatic toxicity.

Despite these advantages, the pharmacokinetic (limited oral bioavailability) and stability properties (must be administered by intravenous infusion) of the approved echinocandins impose restrictions on their use. They are known for susceptibility to thermal, hydrolytic, and photodegradation (micafungin), which further impose limitations for manufacturing, storage, usage and acceptable dosage forms for this attractive drug class.

Numerous attempts have been made to stabilize different echinocandins, especially anidulafungin, in both liquid and solid preparations, and are here incorporated as a reference:

Pharmaceutical formulations described in WO0051564 comprise anidulafungin and a surfactant. Inventions according to this document can optionally contain one or more stabilizing agents, a tonicity agent and/or a buffer.

In WO03105767, parenteral pharmaceutical formulations containing an echinocandin antifungal compound and an aqueous ethanolic solvent are provided. The parenteral pharmaceutical formulation may further include one or more additives, such as a stabilizing agent, buffer or tonicity agent.

Invention described in IN3668MUM2014 discloses a micelle-forming surfactant free pharmaceutical formulation of anidulafungin, wherein solubilizing agent is selected from modified cyclodextrin derivatives and acidifying agents added are selected from organic acids such as succinic acid, acetic acid, citric acid, tartaric acid, lactic acid or inorganic acid such as hydrochloric acid.

The WO2009140162 disclosure provides a method of making a stable pharmaceutical formulation comprising adding one or more vitrifying additives to an aqueous pharmaceutical solution to raise the glass transition temperature of the aqueous pharmaceutical solution.

Chinese publication CN102488888 discloses a composition containing an echinocandin antifungal agent and trehalose as an excipient, free of additional pH adjusting agents.

Chinese publication CN102512659 discloses a composition containing an echinocandin antifungal agent, together with a pharmaceutically acceptable amount of an excipient and a pharmaceutically acceptable amount of phosphate pH adjusting agent. Summary of the invention

Even though there are many formulations of anidulafungin known in the art, all of them suffer from limited stability, particularly over extended periods of time.

Due to the above mentioned, there is an unmet need for stable anidulafungin formulations, which will provide flexibility of storage conditions, as well as flexibility of dosing.

Surprisingly, the present inventors have discovered that buffering agents selected from the group consisting of benzoic acid, picolinic acid and glutamic acid stabilize anidulafungin formulations over prolonged periods of time and present invention has been made on the basis of such findings.

The present invention provides a stable pharmaceutical composition comprising anidulafungin; buffering agent selected from the group consisting of benzoic, picolinic and glutamic acid and one or more pharmaceutically acceptable excipients. In one specific embodiment, a pharmaceutical composition comprising anidulafungin; buffering agent selected from the group consisting of benzoic acid, picolinic acid and glutamic acid and pharmaceutically acceptable excipients selected from surfactants and/or bulking agents and/or stabilizing agents is provided.

In one aspect of the aforementioned specific embodiment, a pharmaceutical composition comprising anidulafungin; glutamic acid as a buffering agent and pharmaceutically acceptable excipients selected from surfactants and/or bulking agents and/or stabilizing agents is provided.

In second aspect of the aforementioned specific embodiment, a pharmaceutical composition comprising anidulafungin; picolinic acid as a buffering agent and pharmaceutically acceptable excipients selected from surfactants and/or bulking agents and/or stabilizing agents is provided.

In third aspect of the aforementioned specific embodiment, a pharmaceutical composition comprising anidulafungin; benzoic acid as a buffering agent and pharmaceutically acceptable excipients selected from surfactants and/or bulking agents and/or stabilizing agents is provided.

In specific embodiments of all of the aforementioned aspects, liquid and lyophilized formulations are provided.

The present invention further provides a stable pharmaceutical composition comprising anidulafungin, polysorbate 80, fructose, mannitol and a buffering agent selected from glutamic, picolinic and benzoic acid in aqueous solution wherein pH of said composition is from 3-5.

Concentrations of individual components, according to the present invention range from about 5 mg/mL to about 15 mg/mL for anidulafungin; about 25 to about 75 mg/mL for mannitol, about 12.5 to about 37.5 mg/mL for polysorbate 80, about 5 to about 15 mg/mL for fructose and for acid selected from glutamic, picolinic and benzoic acid concentration ranges from about 0.56 to about 1.68 mg/mL.

In one specific embodiment of the above mentioned invention, formulation comprises anidulafungin at a concentration of about 10 mg/mL, mannitol at a concentration of about 50 mg/mL, polysorbate 80 at a concentration of about 25 mg/mL, fructose at a concentration of about 10 mg/mL, acid selected from glutamic, picolinic and benzoic acid at a concentration of about 1.12 mg/mL, NaOH used for pH adjustment to target pH, and water.

The present invention also provides stable pharmaceutical compositions comprising anidulafungin, polysorbate 80, fructose, mannitol and a buffering agent selected from glutamic, picolinic and benzoic acid wherein when reconstituted from solid state or diluted from liquid state, with aqueous solvents or diluents affords a solution having a pH from 3-5.

The present invention further provides a stable lyophilized pharmaceutical composition comprising anidulafungin, polysorbate 80, fructose, mannitol and a buffering agent selected from glutamic, picolinic and benzoic acid wherein when reconstituted and optionally further diluted with aqueous solvents or diluents affords a solution having a pH from 3-5.

In one specific embodiment of the above mentioned invention, preferred formulation comprises anidulafungin at a concentration of about 10 mg/mL, mannitol at a concentration of about 50 mg/mL, polysorbate 80 at a concentration of about 25 mg/mL, fructose at a concentration of about 10 mg/mL, acid selected from glutamic, picolinic and benzoic acid at a concentration of about 1.12 mg/mL and NaOH used for pH adjustment.

The present invention further relates to a process of preparing a stable formulation comprising therapeutically effective amount of anidulafungin and one or more pharmaceutically acceptable excipients and buffering agent selected from glutamic, picolinic and benzoic acid, wherein the pH of the composition is from 3-5, wherein the composition is stable over the shelf life of not less than 24 months at storage temperature of 2-8°C.

Other objects, features and advantages of the present invention will become apparent from the following detailed description.

Detailed description of the invention

The chemical name for anidulafungin is 1-[(4R, 5R)-4,5-dihydroxy-N(2)-[[4"- (pentyloxy)[l,l':4',l"-terphenyl]-4-yl]carbonyl]-L-ornithine]echinocandin B {Formula I.). Anidulafungin appears to have several advantages over existing antifungals. It is unique because it slowly degrades in humans, undergoing a process of biotransformation rather than being metabolized. It has a potent in vitro activity against Aspergillus and Candida species, including those resistant to fluconazole or amphotericin B.

Formula I

Anidulafungin structure

Definitions

For the purpose of the present disclosure, the following terms have the following meanings:

The term "pharmaceutical composition" as used herein, means a composition that is made under conditions such that it is suitable for administration to a patient and contains pharmaceutically acceptable excipients, e.g. without limitation to stabilizers, bulking agents, surfactants, buffers, carriers, diluents, vehicles, solubilizers and binders.

Pharmaceutical compositions of the present invention include both lyophilized forms and solution forms. Examples of solution forms include a solution form ready for lyophilization, a solution form reconstituted after lyophilization and a solution form ready for administration to a patient.

As used herein, the terms "pharmaceutical composition", "pharmaceutical formulation", "composition" and "formulation" are used interchangeably.

Term "stable" as used herein refers to a pharmaceutical formulation containing anidulafungin having sufficient stability to have utility as a pharmaceutical product and meets defined, regulatory shelf life specifications for this product as a marketed product.

Preferably, a stable pharmaceutical composition has sufficient stability to allow storage at a convenient temperature, wherein the storage temperature is preferably from 2°C to 30°C, more preferably from 2°C to 25°C, and even more preferably from 2°C to 8°C, for a reasonable period of time, e.g. the shelf-life of the product which can be as short as one month but is typically 12 months or longer.

The language "therapeutically effective amount" of the anidulafungin compound, as used herein, refers to an amount of anidulafungin administered to a patient sufficient to produce a therapeutic response to one or more of the symptoms of the disease being treated.

The term "pharmaceutically acceptable" as used herein, means that it does not cause unacceptable loss of pharmacological activity or unacceptable adverse side effects. The term "pH" is the conventional measurement unit of hydrogen ion activity in a solution at 25°C unless other temperature is specified.

The "pH regulating agent" is an agent that can change - increase or decrease, the pH of a solution or stabilizes the pH of a solution at a given pH, e.g. an acid, a base or a buffer.

The term "buffer" refers to a pharmaceutically acceptable excipient that maintains the pH of the solution within a particular range specific to the buffering system.

The term "buffering agent" refers to a mixture of an acid and its corresponding base e.g. when the compositions comprise benzoic acid as a buffering agent, the compositions comprise benzoic acid and benzoate in a ratio that will resist pH change if dissolved in an aqueous solution.

Suitable buffering agents include glutamic, picolinic or benzoic acid. Sodium hydroxide and/or hydrochloric acid can be used to adjust the pH.

Solid state compositions can also contain a buffer in the form of salts and/or acids that have buffering capacity when dissolved in a solution.

Unless otherwise indicated, all experimental data and procedures described herein are obtained or performed at room temperature and atmospheric pressure.

The "diluent" of interest herein is one which is pharmaceutically acceptable; safe and non-toxic for administration to a human, and is useful for the preparation of a reconstituted and diluted formulation. Exemplary diluents include sterile water, bacteriostatic water for injection (BWFI), sterile saline solution, Ringer's solution or dextrose solution. Examples

The following formulations and process for producing solution forms and lyophilized forms are shown for exemplary and explanatory purpose and are not intended to limit the scope of the present invention.

In order to determine the stabilizing effect of a buffer in anidulafungin formulations, concentrations of substances present in formulations disclosed below were the following:

There were three manufacturing processes used for development and optimization of the manufacturing process for preparation of a bulk solution and ultimately for preparation of a lyophilized anidulafungin formulation.

The bulk solutions were manufactured according to the following procedures:

1^st Manufacturing Process

Buffer solution was prepared by addition of an acid in ultrapure water and buffering the solution to pH about 4.3 with 0.1 M NaOH. Polysorbate 80 was gradually added to buffered solution and stirred until complete dissolution and addition of fructose and subsequently anidulafungin followed in the same manner. After dissolution of anidulafungin, addition of mannitol followed and finally ultrapure water for solution volume make up.

Solution without buffer was prepared by dissolving Polysorbate 80 in ultrapure water, and all other steps followed above described procedure.

2^nd Manufacturing Process

Mannitol was added in the ultrapure water. Upon its dissolution, fructose, followed by polysorbate 80, were added and mixed until complete dissolution. After addition of anidulafungin, pH of solution was adjusted with sodium hydroxide to approximately 7.0 and mixed until complete dissolution. The obtained solution was then buffered with addition of an acid and optionally NaOH to pH about 4.3 and ultrapure water was finally added for solution volume make up. 3^rd Manufacturing Process

Polysorbate 80 was slowly added in the ultrapure water and mixed until complete dissolution. Addition of fructose followed, and after its dissolution, anidulafungin was added. pH was adjusted to about 7 with sodium hydroxide and solution was mixed until anidulafungin is completely dissolved. Solution was buffered to pH about 4.3 with addition of an acid and optionally NaOH. At the end, mannitol was added, mixed and solution volume was made up with ultrapure water.

Lyophilization can be performed according to standard procedures well known to those skilled in the art, for example following the principles described in Review Design of Freeze-Drying Processes for Pharmaceuticals: Practical Advice Xiaolin (Charlie) Tang and Michael J. Pikal Pharmaceutical Research, Vol. 21, No. 2, February 2004.

Samples were divided into two groups in order to compare effect of a buffer on anidulafungin stabilization and degradation profile, both in liquid and lyophilized form, wherein first group contained formulations of anidulafungin without buffering agent present, and with tartrate, succinate, lactate, maleate, citrate and glutamate buffer, respectively, present.

Second group contained formulations of anidulafungin with picolinate, benzoate, tartrate and glutamate buffer, respectively. In both groups, compositions containing tartaric acid as a buffering agent were representing a composition similar to what is currently available on the market.

Established stress conditions for bulk solutions were 24 hours at 40°C/75% RH and for lyophilized formulations 48 hours at 40°C/75% RH.

Stress test for lyophilized formulations (48 hrs at 40°C/75% RH) can be used to predict the results of 1 month accelerated stability testing (at 25°C/60% RH). Stability testing of lyophilized formulations also includes long term stability at 2-8°C and accelerated stability at 25°C/60% RH.

Over time, anidulafungin degrades into two major degradation products named Degradation Product 1 (DPI) and Degradation Product 2 (DP2), both in solution and in lyophilized product.

Therefore, as an indicator of product stability, sum of quantities of DPI and DP2 (DPI + DP2) are shown, along with total impurities content.

In order to quantitate anidulafungin and its primary degradants, a reversed phase high-performance liquid chromatography (HPLC) method was developed and analytical operating conditions include:

Column: Zorbax SB-Phenyl; 150x2.1 mm; 1.8 μΙ

Detection: 300 nm

Flow: 0.350 ml/min

Injection: 10 μΙ

Column temperature: 40°C

Mobile phase: Mobile phase buffer

mix 500 mL of ultra-purified water, 2.3 mL of triethylamine and 1.4 mL of trifluoroacetic acid

Mobile phase A

mix 200 mL Mobile phase buffer with 300 mL of ultra-purified water

Mobile phase B

mix 200 mL Mobile phase buffer with 100 mL of methanol and 200 mL of acetonitrile Stability test results are presented in tables below.

Table 1: Stability comparison of anidulafungin solution formulations containing different buffers

* High impurity profile

** Visible particles observed in solution after stress test

Group 1:

Bulk solutions

Table 2: Stress test data (24 hrs at 40°C/75% RH) for bulk solution without buffer and for bulk solutions containing tartrate, succinate, lactate, maleate, citrate and glutamate buffer

DPI + DP2 (%) Total impurities i o/o)

Used buffer 24 hrs at Δ (24 hrs- 24 hrs at Δ (24 hrs-

Start Start

40°C START) 40°C START)

Without buffer 0.73 1.70 0.97 1.13 2.24 1.11

Tartrate 0.71 1.21 0.50 1.10 1.61 0.51

Succinate 0.75 1.19 0.44 1.04 1.59 0.55

Lactate 0.73 1.26 0.53 1.12 1.63 0.51

Maleate 0.74 1.21 0.47 1.07 1.54 0.47

Citrate 0.72 1.16 0.44 1.05 1.54 0.49

Glutamate 0.60 1.15 0.55 1.07 1.48 0.41 L yophilized product:

Table 3: Results of stress test (48 hrs at 40°C/75% RH), 1 and 3 months of accelerated (25°C/60% RH) and long term (2-8°C) stability testing of lyophilized formulations containing tartrate, glutamate, maleate, citrate, succinate and lactate buffer

NA - not available

NA - not available

Group 2:

Table 4: Stress test data (24 hrs at 40°C/75% RH) for bulk solutions containing picolinate, benzoate, tartrate and glutamate buffer, respectively.

DPI + DP2 (%) Total impurities (%)

Used buffer 24 hrs at Δ 24 hrs- 24 hrs at Δ 24 hrs-

Start Start

40°C START 40°C START

Picolinate 0.26 0.62 0.36 0.32 0.81 0.49

Benzoate 0.28 0.70 0.42 0.39 0.93 0.54

Tartrate 0.23 0.64 0.41 0.35 0.82 0.47

Glutamate 0.50 0.86 0.36 0.68 1.09 0.41 Table 5: Results of stress test (48 hrs at 40°C/75% RH), 1 and 3 months of accelerated (25°C/60% RH) and long term (2-8°C) stability testing of lyophilized formulations containing picolinate, benzoate, tartrate and glutamate buffer

NA - not available

NA - not available

Claims

1. Pharmaceutical composition comprising anidulafungin and a buffering agent selected from glutamic, picolinic or benzoic acid and optionally one or more pharmaceutically acceptable excipients such as surfactants and/or bulking agents and/or stabilizing agents.

2. Pharmaceutical composition according to claim 1, wherein said surfactant is polysorbate 80, said bulking agent is mannitol, and said stabilizing agent is fructose.

3. Composition according to any of the preceding claims wherein anidulafungin is present in concentration from about 5 mg/mL to about 15 mg/mL; mannitol is present in concentration about 25 to about 75 mg/mL, polysorbate 80 is present in concentration of about 12.5 to about 37.5 mg/mL, fructose at concentration from about 5 to about 15 mg/mL and buffering agent selected from glutamic, picolinic and benzoic acid in concentration from about 0.56 to about 1.68 mg/mL.

4. Composition according to claim 3, wherein anidulafungin is present in a concentration of about 10 mg/mL, mannitol in a concentration of about 50 mg/mL, polysorbate 80 in a concentration of about 25 mg/mL, fructose in a concentration of about 10 mg/mL, and buffering agent selected from glutamic, picolinic and benzoic acid in a concentration of about 1.12 mg/mL.

5. Composition according to any of the preceding claims, wherein the composition is liquid and the pH is from 3 - 5.

6. Composition according to claims 1-4, wherein the composition is lyophilized.

7. Composition according to claim 6, wherein when reconstituted with aqueous solvents or diluents affords a solution having a pH from 3 - 5. A method for making a pharmaceutical composition cited in any one of claims 1 to 7, the method comprising the steps of:

a) preparing a solution of anidulafungin, a surfactant, a bulking agent, a stabilizing agent, and a buffer, wherein said buffer is comprised of a pH buffering agent, wherein said buffering agent is selected from glutamic, picolinic or benzoic acid; said surfactant is polysorbate 80, said bulking agent is mannitol; and said stabilizing agent is fructose, wherein the pH of the solution is from 3- 5 and;

b) optionally lyophilizing said solution.

Pharmaceutical composition according to any of the preceding claims 1-6 for use in treatment of fungal infections.