WO2021033145A1

WO2021033145A1 - Novel injectable formulations of artesunate

Info

Publication number: WO2021033145A1
Application number: PCT/IB2020/057792
Authority: WO
Inventors: Chandrashekhar Kocherlakota; Nagaraju Banda; Santhosh Kumar MANKALA; Suresh Pachaiyappan
Original assignee: Leiutis Pharmaceuticals Pvt Ltd
Priority date: 2019-08-19
Filing date: 2020-08-19
Publication date: 2021-02-25

Abstract

The present invention relates to pharmaceutical formulations of artesunate for parenteral administration. The present invention also relates to manufacturing of stable and effective formulations with improved convenience of administration to treat Malaria. Artesunate formulation comprising an artesunate concentrate and a diluent, wherein the artesunate concentrate comprises artesunate dissolved in a non-aqueous solvent, selected from the group comprising n-methyl pyrrolidone, polyethylene glycol, dimethyl acetamide, dimethylsulfoxide and ethanol.

Description

NOVEL INJECTABLE FORMULATIONS OF ARTESUNATE

FIELD OF THE INVENTION

The present invention relates to pharmaceutical formulations of artesunate for parenteral administration. The present invention also relates to manufacturing of stable and effective formulations with improved convenience of administration to treat Malaria.

BACKGROUND OF THE INVENTION

Artesunate is recommended by WHO as first-line treatment for the treatment of severe malaria, under the brand name Artesun®. Further artesunate is not approved by FDA for use in the United States but is available from the Centers for Disease Control.

Commercially available Artesun® dosage form is available in a vial containing artesunate powder, a solvent ampoule containing sodium bicarbonate and water for injection; a diluent ampoule containing sodium chloride and water for injection. Artesun®, when dissolved in sodium bicarbonate often leads to cloudy solutions due to the undissolved particles getting trapped in the bubbles formed due to carbondioxide. Vigorous shaking is required to dissolve the undissolved particles.

U.S Patent 7,956,086 to Ellis et al., relates to a method for the production of an artesunic acid product. The process involves gas sterilization of artesunic acid for one hour followed by ethylene oxide sterilization for four hours. The sterilized dry powder is filled into vials which has to be reconstituted with phosphate buffer before administration.

PCT Application WO 2007/028413 to Dafra et al., discloses pharmaceutical compositions suitable for the treatment of malaria within a day. The application also relates to combination with one or more drugs, usually anti- malarial agents. The preferable formulation is a tablet for oral administration.

PCT Application WO 2011/ 009956A1 to Dafra et al., discloses pharmaceutical compositions comprising an anti-malarial agent. Further, the invention relates to a unit dose comprising of pharmaceutical compositions for the treatment of malaria.

The formulations known in the prior art require specific techniques or long manufacturing process time to improve the solubility of the preparations and present clear and stable solutions. The present invention overcomes the disadvantages of prior art and provides artesunate with improved convenience for administration.

SUMMARY OF THE INVENTION

One aspect of the present invention is to prepare stable parenteral formulations of artesunate. These formulations remain free of undissolved particles even after 2 hours after mixing with the diluent.

Another aspect of the present invention is to provide artesunate formulations, wherein the total impurities are less than 3% when stored for 2 hours at room temperature.

Yet another aspect of the invention is to provide an artesunate composition supplied in the form of a kit wherein the first ampoule comprises artesunate dissolved in a non-aqueous solvent and the second ampoule comprises a diluent.

Yet another aspect of the invention is to provide artesunate compositions with a pH less than 7.5 throughout shelf life when stored at recommended storage conditions. DETAILED DESCRIPTION OF THE INVENTION

The term “artesunate” described in the present invention refers to pharmaceutically acceptable salts, solvates, hydrates, acids, anhydrous and free base forms thereof, preferably artesunate.

The term “diluent” herein refers to mixture of ingredients in a solution that is used to dilute the concentrate and to prepare a specific concentration based on the dosage administration regimen and further which helps in attaining a desired pH.

The term “stabilizer” refers to an agent which helps in making the formulation stable.

The term “buffer” means a compound or mixture of compounds that by their presence in the solution resist changes in the pH upon the addition of small quantities of acid or base.

The term “parenteral formulations” refers to stable formulations of artesunate intended for parenteral administration.

The term “stable” herein means the formulations which remain stable, during the entire shelf-life of the composition and are intended to cover formulations with an assay of 90 to 110 percent of the original assay value when stored at recommended storage conditions.

The currently available Artesun® formulation contains dry artesunate powder filled in a vial and supplied together with a reconstitution solution of sodium bicarbonate and diluent solution of sodium chloride. This formulation is prepared just before administration, after vigorous reconstitution of powdered drug with sodium bicarbonate in water for injection. A further dilution with sodium chloride is required until the dissolution of drug, to avoid a cloudy solution.

In one embodiment, the formulations of the present invention remain free of undissolved particles even two hours after mixing with the diluent solution. The formulations known in the prior art are recommended to be prepared just before administration. This becomes very inconvenient for the practitioners particularly when treating cases of malaria where the number of patients to be treated may be more. There are an estimated 219 million cases of malaria worldwide and 435,000 deaths caused in 2017. Treating an epidemic with such huge number of patients puts a lot of challenges on the health care practitioners. The solutions of the present invention remain clear and free of undissolved particles even two hours after mixing with the diluent. Comparative data with the currently available market formulation is tabulated in table 1 and table 2.

In another embodiment, the artesunate formulations of the present invention have improved chemical stability when compared to the currently marketed formulations. The inventors have surprisingly achieved a two component system that has superior chemical stability when compared to the multi component formulations of the prior art. The invention formulations are supplied as a kit comprising two ampoules comprising: (i) a first ampoule filled with artesunate concentrate solution and (ii) a second ampoule comprising the diluent solution.

These formulations are tested for comparative stability and the results are included in table 1 and table 2 below. Table 1 : Stability data of present invention formulation of Artesunate in comparison to Artesun® (10 mg/mL dilution)

Table 2: Stability data of present invention formulation of Artesunate in comparison to Artesun® (20 mg/mL Dilution)

From the above data it can be seen that the invention formulation shows the following advantages/ significant improvements over Artesun®:

(i) Artesun® formulations turned hazy after 1 hour on standing. On the contrary, the formulations of the present invention remained clear and free of undissolved particles even two hours after dilution.

(ii) The total impurities in the formulations of the present invention remained much below 3%, whereas the impurities in Artesun ® formulations are much higher.

(iii) There is a negligible change in the pH of the invention formulation whereas significant change was observed in Artesun® formulations within 2 hours.

Yet another aspect of the invention is to provide an artesunate composition in the form of a kit wherein the first ampoule comprises artesunate dissolved in a non- aqueous solvent(s) and the second ampoule comprises a diluent.

The first ampoule comprises artesunate dissolved in one or more solvents. These solvents can be selected from the group comprising NMP (n-methyl pyrrolidone), PEG 400 (polyethylene glycol), PEG 300 (Polyethylene glycol), DMA (Dimethyl acetamide), DMSO (dimethylsulfoxide) and ethanol. The formulation may also comprise solubilizing agents and stabilizers. Polyoxyl 15 Hydroxy stearate (Kolliphore HS 15) is one such example. The second ampoule comprises a diluent solution comprising, but not limited to buffering agents, pH adjusting agents selected from transcutol HP, tris buffer, succinic acid buffer, phosphate buffer, sodium hydroxide, boric acid, aspartic acid, potassium chloride, and solvents selected from but not limited to ethanol, glycofurol, DMSO (dimethylsulfoxide), and thereof and water for injection.

The concentration of artesunate in the first ampoule ranges from 60 mg/ml. After dilution and just before administration it is in the range from lOmg/ml, 20mg/ml, or 30mg/ml, based on the dosage regimen to be administered. The recommended dose of Artesun for treating malaria is based on the total body weight calculations. For example, an adult with 75kg body weight, the dosage to be administered will be 180 mg (that is: 75kg x 2.4= 180mg). This requires administration of 18 ampoules initially followed by maintenance doses based on the requirement. The number of ampoules to be administered is much lesser when compared to Artesun® formulation, which requires 27 ampoules to administer 180mg of drug to a 75kg bodyweight person. This is another advantage of the present invention.

The pharmaceutical compositions of the present invention may also contain monothioglycerol, DOT A and thereof.

The pharmaceutical compositions of the present invention may also contain other pharmaceutically acceptable excipients but not limited to, anti-oxidants, preservatives, tonicity modifiers, complexing agents and thereof.

Another aspect of the invention is to provide artesunate compositions having pH in the range 4-7.5. More preferably pH of the formulation is between 5 and 6. This target range of pH helps to overcome irritation during administration.

Preferred embodiment of the pharmaceutical parenteral formulations of the present invention relates to artesunate concentrate, a diluent, admixture of artesunate concentrate and diluent, and pharmaceutical acceptable excipients thereof.

Further the pharmaceutical acceptable excipients of the present invention include diluent mix components, which comprise buffer(s) and pH adjusting agent(s) to maintain the pH of the formulation, thereby increasing the solubility of the particles and reducing irritation during administration.

Another preferred embodiment of the pharmaceutical parenteral formulations of the present invention relates to artesunate, pH adjusting agent(s), buffer(s), stabilizing agent(s), solubilizing agent(s) and pharmaceutical acceptable excipients thereof. The compositions of the present invention can be administered through Intramuscular, Intravenous, Subcutaneous, Intraperitonial and Intrathecal routes of administration.

Dosing of the present invention is done by calculating the amount of the drug to be administered based on the total body weight.

The following Examples are intended to illustrate the present invention and are not to be considered as limiting the scope of the invention.

Example 1

Composition of proposed Artesunate Injection 60 mg/mL Concentrate

Note: QS: Quantity sufficient

Manufacturing Process

1. 80% of PEG 400 was added to n-methyl pyrrolidone in a manufacturing vessel and mixed until a clear solution was obtained.

2. To the above solution artesunate was added and stirred at 500 rpm for 1 hour, until a clear solution was obtained.

3. The final volume was adjusted with remaining quantity of PEG 400 and stirred for 15 minutes at 500 rpm to obtain a homogenous solution.

4. The prepared bulk solution was filled in glass ampules and were sealed hermetically. Composition of diluent for proposed Artesunate Injection

Manufacturing Process

1. Potassium phosphate was added to required quantity of water for injection in a manufacturing vessel and stirred at 500 rpm for 15minutes until a clear solution is obtained.

2. Sodium hydroxide was added to the above solution and stirred followed by addition of spiking Tris base to adjust the pH to 9.4.

3. To the above solution measured quantity of succinic acid was added and stirred.

4. Final volume was adjusted with remaining quantity of water for injection, ensuring the pH in target range (6.0 to 12.0).

5. Final solution was filtered from 0.22 micron PVDF filter and filled in glass or polymer ampoules and were sealed hermetically.

Example 2

Composition of Artesunate Injection 60 mg/mL

Note: QS: Quantity sufficient

Manufacturing Process

1. Required quantity of kolliphore HS 15 was added to ethanol in a compounding vessel, and mixed under continuous stirring till a clear solution was obtained.

2. 90% of required quantity of PEG 400 was added to above solution and stirred.

3. To the above solution required quantity of API was added and stirred until a clear solution was obtained.

4. Final volume was adjusted to required volume, by adding remaining quantity of PEG 400 and stirred well.

5. Online filtration of the bulk solution was performed through two 0.2 micron (PVDF) Filters arranged in series.

6. The prepared 1ml of bulk solution was filled into 5ml Depyrogenated USP type-I Glass ampoule and were sealed. Composition of Diluent for Artesunate Injection

Note: QS: Quantity sufficient Manufacturing Process

1. Required quantity of potassium phosphate was added to 95% of required quantity of water for injection taken in a compounding vessel and stirred.

2. To the above solution required quantity of sodium hydroxide was added and stirred, followed by addition of required quantity of Tris base and stirred until a clear solution is obtained.

3. pH of the above solution was adjusted to 8.0 ± 0.1 using sufficient quantity of Succinic acid.

4. Final volume of solution was adjusted using remaining quantity of water for injection followed by 15 more minutes of stirring.

5. Bulk solution was submitted for online filtration through two 0.2 micron (PVDF) filters arranged in series.

6. 2ml of above bulk solution was filled into 5 mL Depyrogenated USP type- I Glass ampoule and were sealed aseptically. The formulation manufactured with the above mentioned composition was tested for stability:

Table 3: Stability data

Table 4: Stability data of Diluted Artesunate Injection at Room Temperature

From the above data, it is clear that the formulations have excellent stability and the impurity DHA-a is only 0.61% after storing for two hours. The total impurities are only 0.98%.

Claims

We claim

Claim 1: An Artesunate formulation comprising an artesunate concentrate and a diluent, wherein the total impurities are less than 3%, when stored up to 2 hours at room temperature after reconstitution.

Claim 2: The formulation of claim 1, wherein the solution remains clear and colourless, when stored upto 2 hours at room temperature after reconstitution.

Claim 3: The formulation of claim 1, wherein the pH is in from 5.0 to 7.0.

Claim 4: The formulation of claim 1, wherein the artesunate concentrate comprises artesunate dissolved in a non-aqueous solvent.

Claim 5: An Artesunate formulation comprising an artesunate concentrate and a diluent, wherein the artesunate concentrate comprises artesunate dissolved in a non- aqueous solvent.

Claim 6: The formulation of claim 5, wherein the non-aqueous solvent is selected from the group comprising n-methyl pyrrolidone, polyethylene glycol, dimethyl acetamide, dimethylsulfoxide and ethanol.