Cladribine formulations for improved oral and transmucosal delivery

Abstract

Provided are compositions of cladribine and cyclodextrin which are especially suited for the oral and buccal administration of cladribine.

Description

FIELD OF THE INVENTION [0001] The invention relates to a composition comprising a cladribine-cyclodextrin complex formulated into a solid oral dosage form or a transmucosal dosage form and to a method for enhancing the oral and transmucosal bioavailability of cladribine. BACKGROUND OF THE INVENTION [0002] Cladribine, which is an acid-labile drug, has the chemical structure as set forth below: [0003] It is also known as 2-chloro-2′-deoxyadenosine or 2-CdA. [0004] Cladribine is an antimetabolite which has use in the treatment of lymphoproliferative disorders. It has been used to treat experimental leukemias such as L1210 and clinically for hairy cell leukemia and chronic lymphocytic leukemia as well as Waldenstrom's macroglobulinaemia. It has also been used as an immunosuppressive agent and as a modality for the treatment of a variety of autoimmune conditions including rheumatoid arthritis, inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis) and multiple sclerosis ...

AI Technical Summary

Benefits of technology

[0013] It has now been found that excess cyclodextrin inhibits the absorption of cladribine from a solid oral dosage form or a transmucosal dosage form comprising a cladribine-cyclodextrin complex, and that a solid oral or a transmucosal dosage form of a saturated cladribine-cyclodextrin complex improves oral and / or transmucosal bioavailability and / or achieves lower interpatient and / or intrapatient variation of the drug.

[0017] The invention further provides for treatment of conditions responsive to administration of cladribine in mammals by administering thereto the composition of the invention. Use of cladribine in the preparation of the pharmaceutical compositions of the invention for administration to treat symptoms of cladribine-responsive conditions and for enhancing the oral or transmucosal bioavailability of cladribine is also provided.

Problems solved by technology

The cost of parenteral administration is much higher due to the requirement that a health care professional administer the cladribine in the health care provider setting, which also includes all attendant costs associated with such administration.

However, to date the oral and transmucosal delivery of cladribine has been plagued by low bioavailability (see, e.g., J. Liliemark et al., J. Clin. Oncol., 10(10): 1514-1518, 1992), and suboptimal interpatient variation (see, e.g., J. Liliemark, Clin.

Indeed, these dosage ranges include many combinations which may be suitable as mixtures but not for complex formation.

For example, a ratio of 1 mg of cladribine to 500 mg of cyclodextrin contains too much cyclodextrin, so that the drug would not readily leave the complex and achieve its therapeutic function.

On the other hand, 15 mg of cladribine and only 100 mg of cyclodextrin would not be enough to complex that amount of cladribine.

The Schultz et al. patent does suggest improving the stability of cladribine in oral dosage forms by combining / complexing it with cyclodextrin, but does not suggest improving the drug's oral bioavailability by such means; in fact, the patent does not describe or suggest a method for enhancing or maximizing the bioavailability of cladribine from a solid oral dosage form of cladribine and cyclodextrin, or a composition specially designed to do so.

Further, Schultz et al. do not suggest cladribine / cyclodextrin combinations for transmucosal administration, that is, in a form intended for administration through the mucosa lining the nasal, oral, vaginal or rectal cavities rather than via the orogastric route, much less enhancing the bioavailability of the drug when administered via such a dosage form.

While Schultz et al. teach that a cladribine-cyclodextrin complex improves the water solubility and acid stability of cladribine, the art does not suggest how to maximize or enhance the benefits of the complexation in terms of bioavailability and interpatient variation when the complex is to be administered in a solid oral dosage form or a transmucosal dosage form.

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