Link:  Pharm/Biotech Resources

Title:  Artemisinins with improved stability and bioavailability for therapeutic drug development and application

United States Patent:  6,951,846

Issued:  October 4, 2005

Inventors:  Hartell; Mark G. (Laurel, MD); Bhattacharjee; Apurba K. (Silver Spring, MD); Hicks; Rickey P. (Woodbridge, VA); VanHamont; John E. (Fort Meade, MD); Milhous; Wilbur K. (Germantown, MD)

Assignee:  The United States of America as represented by the Secretary of the Army (Washington, DC)

Appl. No.:  376387

Filed:  February 27, 2003

A stable form of artemisinin wherein an artelinic acid or artesunic acid is complexed with cyclodextrin analogs, preferably, β-cyclodextrin. The complexed cyclodextrin artemisinin formulation shields the peroxide portion of the artemisinin backbone from hydrolytic decomposition rendering it stable in solution. Artelinic acid and cyclodextrin are placed into contact with one another to yield a 2:1 molecular species. Artesunic acid and cyclodextrin yield a 1:1 molecular species. The complexed cyclodextrin artemisinin formulation is effective for the treatment of malaria and is stable in solution for long periods of time.

BACKGROUND OF THE INVENTION

1. Field of the Invention

A novel form of artemisinins that are complexed with cyclodextrin for solving stability problems associated with previous forms of artemisinins.

2. Brief Description of Related Art

Artelinic acid is an effective antimalarial agent when in contact with the malarial parasite. However, artelinic acid has poor stability in solution and, thus, has limited bioavailability in vivo. Artemisinins, as a class, include such analogs as artelinic acid and artesunic acid among many others. Currently, no analog of the artemisinin class of compounds exists which can remain stable in solution. Injectable formulations of artemisinin analogs, such as artelinic acid and artesunic acid, are not FDA approved due to their instability in solution. All artemisinins contain a peroxide bridge susceptible to hydrolytic cleavage. Artemisinins have been found to yield an inferior class of antimalarials due to these severe limitations in chemical stability. Artemisinins are limited to only being packaged as solids for oral dosing, as previous patents have claimed. U.S. Pat. Nos. 6,326,023; 6,307,068; 6,306,896; 5,834,491; 5,677,331; 5,637,594; 5,486,535; 5,278,173; 5,270,037; 5,219,865; 5,021,426; 5,011,951.

Application of an antimalarial formulation must be specific to administration in hot, humid tropical regions native to the malarial parasite. Thus, chemical stability under drastic environmental conditions is essential. Attempts to produce a more stable form of artelinic acid have been accompanied by critical limitations. A soluble sodium salt of artelinic acid has been successfully formulated, but eventually degrades over time. This is presumably due to a reformation of the insoluble acid. Numerous attempts at preventing this precipitate have been unsuccessful.

The osmolality of the salt solution is significantly less than the predicted value indicating possible inter-molecular complexation that may be responsible for eventual precipitation over time. An amine-based buffer of artelinic acid has been successfully formulated, but yields a higher pH solution (>8.0) that induces significant vein irritation upon injection. Additional localized redness and swelling surrounding the injection site is a notable contraindication to a preferred intravenous formulation. Additionally, amine-based buffers have been observed to take on a strong yellow hue over time. The mechanism of color formation has not been deduced, but implies a modification of the artelinate formulation, which is not conducive to pharmaceutical preparations where a defined constant state of purity is essential.

U.S. Pat. Nos. 6,326,023; 6,307,068; 6,306,896; 5,834,491; 5,677,331; 5,637,594; 5,486,535; 5,278,173; 5,270,037; 5,219,865; 5,021,426; 5,011,951 are only directed to be packaged as solids for oral dosing.

Therefore, there is a need to provide a form of artemisinins that solve the stability problems associated with previous formulations.

It is an object of the present invention to provide a form of artemisinins, such as but not limited to artelinic acid and artesunic acid that solves the stability problems associated with previous formulations.

It is another object of the present invention to provide a stable form of artemisinins that is injectable.

It is still another object of the present invention to provide a stable form of artemisinins that does not develop a yellow hue over time.

It is still another object of the invention to promote bioavailability and membrane permeability while decreasing the likelihood of localized inflammation at the route of entry, thus increasing its therapeutic activity.

SUMMARY OF THE INVENTION

The present invention is directed to cyclodextrin complexed with artelinic acid or artesunic acid to form complexed cyclodextrin-artemisinin formulations in a 2:1 ratio of cyclodextrin per artelinic acid molecule or in a 1:1 ratio of cyclodextrin per artesunic acid molecule. The formulation is stable in solution, bioavailable, membrane permeable and does not cause inflammation upon injection.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a novel form of artemisinins that remain stable over time in solution. The artemisinins may be, but are not limited to artelinic acid and artesunic acid. This novel form of artemisinins uses a unique complexed form of the therapeutic agent with cyclodextrin analogs, such as but not limited to alpha-, beta-, and gamma-cyclodextrin analogs and their derivatives.

The present invention is directed to cyclodextrin complexed with artelinic acid in a 2:1 ratio which is a form of artemisinin that alters the electron cloud surrounding the artemisinin molecule in such a way as to stabilize this agent to promote bioavailability and membrane permeability while decreasing the likelihood of localized inflammation at the route of entry. Thus, this form of artemisinin increases its therapeutic activity. Artesunic acid was complexed with cyclodextrin, but in a unique 1:1 ratio in such a way as to stabilize the agent yield similar increases in its therapeutic activity.

The stability of the artemisinins is achieved by changing the physiocochemical properties such as but not limited to electron density, electrostatic potential and charge transfer mediated complexation.

The complexed cyclodextrin formulation of the artemisinins described deliberately shields the peroxide bridge of the artemisinin backbone from hydrolytic decomposition. Additionally, the aromatic benzoic acid portion of the artelinate molecule is also complexed with a second cyclodextrin molecule. This unique 2:1 complexation with cyclodextrin is not intuitively obvious because artelinic acid alone is unstable in aqueous solution. Simply placing cyclodextrin in solution with artelinic acid would not achieve these results, as the artelinic acid would not be in contact with the cyclodextrin to form complexation. Futher, cyclodextrin is know to form complexes with itself and thus may not be readily available in solution to interact efficiently and effectively with the artelinic acid. The inventors have placed artelinic acid and cyclodextrin into contact with one another and have complexed them in such a manner as to yield a stable 2:1 molecular species. The inventors have also placed artesunic acid and cyclodextrin into contact with one another and have complexed them in such a manner as to yield a stable 1:1 molecular species.

Injectable Formulation:

The stable form of artemisinin, the cyclodextrin complexed with artenilate in a 2:1 ratio, may be dissolved in saline, phosphate buffered saline (PBS), deionized water or any other suitable aqueous carrier for injection. The pH is preferably about 7.4. Generally, 40 milligrams of artelinate complexed with cyclodextrin per milliliter of solution is suitable. A dose of about 4-6 mg of artelinic acid (in complex) per kilogram of weight for a human is an appropriate dose. An injection of 10 ml of complex in solution or less is appropriate for treatment.

The formulation of the cyclodextrin complexed with artelinate in solution can be prepared and pumped through a filter into an injection vile, freeze dried for storage and later rehydrated with sterile water or saline or PBS for injection. The cyclodextrin complexed with artelinate in solution can also be administered orally, sublingually, or in the form of a suppository.

Toxicity:

Cyclodextrins and artemisinins are both non-toxic to humans. However, large doses of cyclodextrins are not implicated in cases where kidneys are not fully functional.

Advantages

The complexed cyclodextrin-artemisinins formulation does not precipitate or degrade over time. Formulations of artemisinins and cyclodextrin have been observed to remain completely soluble for up to seven weeks at elevated physiological temperatures (40 degrees C.) without any degradation and up to 6 months at room temperature. The complexed cyclodextrin formulation of the artemisinins does not change color over time. Formulations of artemisinins and cyclodextrin have been observed to remain colorless for several weeks at elevated physiological temperatures of 40 degrees C.
 

Claim 1 of 27 Claims

1. A composition comprising: cyclodextrin complexed with artelinic acid in a 2:1 molar ratio.

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