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Cladribine formulations for improved oral and transmucosal delivery

A technology of transmucosal and oral agent, applied in the field of compositions containing cladribine-cyclodextrin complex, can solve the problems of high cost, low bioavailability and the like

Active Publication Date: 2006-06-14
ARES TRADING SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The cost of parenteral administration is much higher because of the need for a health care professional to administer cladribine at the health care provider's site, including all additional costs associated with that administration
Also, in some cases, therapeutic considerations, such as the need for sustained-release cladribine over a prolonged period, are practically only achievable by oral or transmucosal delivery
[0007] However, to date, oral and transmucosal delivery of cladribine has the following disadvantages: low bioavailability (see, for example, J. Liliemark et al., J. Clin. Oncol., 10 (10): 1514-1518, 1992 ), and suboptimal patient-to-patient variability (see, for example, J. Liliemark, Clin. Pharmacokinet, 32(2): 120-131, 1997)
[0013] Although Schultz et al. teach that a cladribine-cyclodextrin complex increases the aqueous solubility and acid stability of cladribine, the prior art does not suggest that the complex should be administered in a solid oral or transmucosal dosage form. , how to maximize or enhance compound benefit in terms of bioavailability and interpatient variability

Method used

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  • Cladribine formulations for improved oral and transmucosal delivery
  • Cladribine formulations for improved oral and transmucosal delivery
  • Cladribine formulations for improved oral and transmucosal delivery

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076] Embodiment 1 phase solubility research

[0077] Phase solubility studies were performed as follows. Excess cladribine was added to cyclodextrin solutions of various concentrations of γ-cyclodextrin (γCD) or hydroxypropyl-β-cyclodextrin (HPβCD) and complexed as described in Example 2 below. Additionally, in one set of experiments, the effect of hydroxypropylmethylcellulose (HPMC) on compounding was investigated. Remove excess undissolved cladribine by filtration. Data points were obtained by detecting the amount of cladribine in the complex solution. The method was repeated using different known concentrations of cyclodextrin until several data points were obtained. These data points are then plotted, each data point representing the maximum amount of cladribine that can be complexed with a particular concentration of cyclodextrin, ie each point represents a saturated cladribine-cyclodextrin complex. Points on the line generated from the data points represent HTA rat...

Embodiment 2

[0083] The preparation of embodiment 2 cladribine-cyclodextrin complex

[0084]Part A: Cladribine was complexed with HPβCD or γCD by the following general method.

[0085] An excess aqueous suspension of cladribine and a concentrated solution of cyclodextrin (about 27% for γ-cyclodextrin; about 40% for HPβCD) were mixed with stirring at room temperature for about 9 hours. This will strike a balance. Excess uncomplexed cladribine that may be present is removed by filtration. To form a solid saturated cladribine-cyclodextrin complex, the aqueous cladribine-cyclodextrin solution was lyophilized prior to incorporation into solid buccal or oral tablets. The freeze-drying method comprises: the complex solution is rapidly dropped to a temperature of about -40°C to about -80°C for about 2 to 4 hours, preferably about 3 to 4 hours of freezing stage, for example, the temperature of about -45°C is maintained for about 200 minutes , followed by a primary drying stage at about -25°C for...

Embodiment 3

[0095] Pharmacokinetic Studies

[0096] The bioavailability of cladribine when complexed with γCD or HPβCD was evaluated in the beagle retriever model. Data from this model are expected to be representative for human applications.

[0097] Saturated cladribine-cyclodextrin complexes FD02 and FD03 prepared as in Example 2, part B, were used for the preparation of oral and buccal tablets. The composite material and magnesium stearate were passed through a 18 mesh (0.9 mm) screen, mixed for 5 minutes, and compressed using a 10 mm punch. The 10 mm tablet has a slightly convex upper shape and a flat beveled lower shape. The production formula is as follows:

[0098] batch number

RDT-0418 / C

RDT-0418 / D

Element

batch number

mg / tablet

mg / tablet

cladribine / γ-CD complex

FD02

232.65 *

cladribine / 2-HPβCD complex

FD03

212.85 *

Magnesium stearate

2.35

2.15

Total

235.00

2...

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Abstract

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

Description

technical field [0001] The present invention relates to compositions comprising cladribine-cyclodextrin complexes formulated into solid oral dosage forms or transmucosal dosage forms, and to methods of enhancing the oral and transmucosal bioavailability of cladribine. Background technique [0002] Cladribine is an acid-labile drug that has the chemical structure described below: [0003] [0004] It is also known as 2-chloro-2'-deoxyadenosine or 2-CdA. [0005] Cladribine is an antimetabolite used in the treatment of lymphoproliferative disorders. It has been used in the treatment of experimental leukemias such as L1210, clinically in hairy cell leukemia and chronic lymphocytic leukemia, and in Waldenstrom's macroglobulinemia. It has also been used as an immunosuppressant and as a drug to treat a variety of autoimmune diseases, including rheumatoid arthritis, inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis) and multiple Sexual sclerosis (see eg, J...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/20A61K9/00A61K31/52A61K47/61
Inventor N·S·博多
Owner ARES TRADING SA
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