Dihydropyridine derivatives, also known as calcium channel blockers, are slightly water-soluble drugs, and poorly absorbed in the digestive tract. In order to improve absorption, addition of an absorbefacient (agents that improve absorption), improvement of dosage form designs etc. are necessary. The general means to overcome poor absorption are: pulverization of crystals, addition of surfactants, emulsification, cyclodextrin inclusion, dissolution in polyethylene glycol, vegetable oil etc. However, these approaches may not guarantee sufficient absorption from digestive tract. Dihydropyridine derivatives are also unstable to light exposure and are prepared into light resistant preparations or stored in light-resistant containers.

In this newsletter, we refer to a patent published by the European patent office in 1991 (Publication no. 0448091A2) where the authors provide a solution to the above problem by formulating the dihydropyridine derivatives into a non-micelle composition by adding a fatty acid monoglyceride and/or a polyoxyethylenesorbitan fatty acid ester and absorbing further on to a porous inorganic carrier like Neusilin®.

 

Formulation summary

 

 

Component

Example 1

Example 2

Example 3

Amount (g)

Amount (g)

Amount (g)

Dihydropyridine derivative

20.1

20.1

20.1

Unsaturated fatty acid monoglyceride, Excel O-95R (palmitoleic/oleic/linoleic/linolenic acid)

650

-

325

Polyoxyethylenesorbitan monooleate, TO-10M (non-ionic surfactant)

-

650

325

Neusilin® US2

370

370

370

Croscarmellose sodium, Type A

30

30

30

Purified water

250

250

250


Dihydropyridine derivatives were mixed with the fatty acid and non-ionic surfactant either alone or in the ratio 1:1 to prepare a non-micelle solution by stirring at 40°C. Neusilin® was added to this mixture in a stirring granulator. To this, croscarmellose sodium, Type A and purified water was added before preparing the granules. The granules were dried at 40°C for 17 hours with a forced air drier and passed through a sieve of 42-200 mesh to give fine granules for capsules.

Bioavailability studies

 

Bioavailability (BA) of the pharmaceutical composition was conducted as follows. A composition from examples was administered to beagle dogs weighing about 10 kg after fasting for 20 hours before administration at a dose of 3 mg/0.1 ml/kg. Blood samples were drawn at given time intervals up to 24 hours after the administration. The plasma of the blood sample was centrifuged, deproteinized with acetonitrile and determined by high performance liquid chromatography (HPLC). The BA% was estimated on the basis of blood concentration.

 

Additives used

Absorption (BA%)

Example 1

Excel O-95R/Neusilin® (fatty acid/Neusilin®)

23.0

Example 3

Excel O-95R + TO-10M (1:1)/Neusilin® (Fatty acid+ non ionic surfactant/Neusilin®)

29.4

Control

No additive

0.3

 

Stability tests

 

The dihydropyridine preparations with Neusilin® were subjected to stability tests at 60°C for 4 weeks. The content of analogous substance and appearance was recorded.

Additives used

Stability (60°C, 4 weeks)

Content of analogous substance* (%)

Appearance

Excel O-95R/Neusilin®

2.9

Colored

TO-10M/Neusilin®

1.2

No change

Excel O-95R + TO-10M/Neusilin®

1.6

No change

*Dihydropyridine degradation products

 

 

Conclusions

 

Dihydropyridine derivatives prepared by adding a fatty acid monoglyceride and/or polyoxyethylenesorbitan fatty acid ester and absorbing on to Neusilin® markedly improved the bioavailability and stability of these pharmaceutical compositions. In addition, this preparation facilitated the production of hard capsules.

 

To obtain Neusilin® sample or to find your local distributor, please contact us. For more technical information, please visit www.fujichemical.co.jp/english/neusilin.html

 

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The information found in this publication is presented in good faith with no guarantee or obligation as to accuracy and no assumption of liability. Users should make their own tests to determine the suitability of these products for their own particular purposes. However, because of numerous factors affecting results, Fuji Chemical Industry makes no warranty of any kind, express or implied, including those of merchantability and fitness for particular purpose other than the material conforms to its applicable current standard specifications. Statements concerning the use of the products or formulations described herein are not to be construed as recommending the infringement of any patent and seller assumes no liability for the infringement arising out of such use.


F-MELT, Fujicalin and Neusilin are trademarks or registered trademarks of Fuji Chemical Industry Co., Ltd. in Japan, United States of America, Europe and/or other countries.
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