Title: Artemisinins with
improved stability and bioavailability for therapeutic drug development
United States Patent: 7,084,132
Issued: August 1, 2006
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.: 11/113,546
Filed: April 25, 2005
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A stable form of artemisinin wherein an
artelinic acid or artesunic acid is complexed with cyclodextrin analogs,
preferably, .beta.-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
Description of the Invention
BACKGROUND OF THE
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;
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 re-formation 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
SUMMARY OF THE
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
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
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
Claim 1 of 15 Claims
1. A method of storing an
antimalarial composition comprising a complexed cyclodextrin formulation of
artemisinin, wherein said cyclodextrin is complexed with artelinic acid in a
2:1 molar ratio in aqueous solution, said method of storing comprising:
filtering the antimalaria composition into a vile; freeze drying the
composition in said vile to form a lyophilate, wherein said lyophilate may
be re-hydrated at a later date with an aqueous solution for injection.
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