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Improving dissolution rate of formulations of Apremilast by particle size reduction

IP.com Disclosure Number: IPCOM000228600D
Publication Date: 2013-Jun-21
Document File: 4 page(s) / 39K

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Abstract

Apremilast is described as a very slightly soluble drug. A tablet formulation with API of particle size of d90 of approx. 90 µm completely dissolves after 60 minutes. For an immediate release formulation a shorter dissolution time is sensible. One of the first choices of people known in the art is to use particle-size reduction techniques for micronisation or nanoisation of the API. A reduction in particle size increases surface area dramatically and is known to improve dissolution rate and bioavailability for a broad selection of APIs. Increase of dissolution rate is significantly quicker when using micronized material of a particle size of d90 of 5.5 microns. Bioavailability can be improved.

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Improving dissolution rate of formulations of Apremilast by particle size reduction

Abstract

Apremilast is described as a very slightly soluble drug. A tablet formulation with API of particle size of d90 of approx. 90 µm completely dissolves after 60 minutes. For an immediate release formulation a shorter dissolution time is sensible. One of the first choices of people known in the art is to use particle-size reduction techniques for micronisation or nanoisation of the API. A reduction in particle size increases surface area dramatically and is known to improve dissolution rate and bioavailability for a broad selection of APIs. Increase of dissolution rate is significantly quicker when using micronized material of a particle size of d90

of 5.5 microns. Bioavailability can be improved.

Introduction

Poor dissolution rate and poor solubility have been a problem in development of pharmaceutical products for decades. Various approaches are proposed and established for lots of products.

A direct proportionality between dissolution rate and surface area is established for over a century and well-known to everyone skilled in the art. Noyes and Whitney [1] described in 1897 the proportionality in the equation named after both researchers:

[1]

m resembles the mass of the solid, t is the time, D stands for diffusion coefficient, A for surface area, h for thickness of diffusion layer, cs for saturation solubility, c for concentration in solution, k is the dissolution coefficient.

Particle-size reduction of active pharmaceutical ingredients has often been used for a long time. Relatively coarse particles were transferred into smaller particles with higher surface area (A in the Noyes-Whitney equation). Commonly micronised material has a d90 between 1 and 20 µm [2], nanonised material a d90 below 1 micron. For example Jounela et al compared in 1975 Digoxin with a particle size of d90 of 102 µm to milled particles of a size of d90 of 7 respectively 13 µm [3]. Digoxin is a good example as it is a practically insoluble substance (solubility of 65 mg/l) with a low standard dose of 0.25 mg. Therefore it can be classified within the Biopharmaceutics Classification System (BCS) as "highly soluble", but it still shows problems with bioavailability and dissolution rate. Dissolution rate and bioavailability of digoxin improved by micronisation of the API. Other researchers like Hargrove et al. [4] investigated the influence of particle size on absorption of other drugs (in this case Hargrove et al. [4] used progesterone) and also proved particle-size reduction as technique to overcome the mentioned problems. Nanosized material improved bioavailability of danazol which has been shown by Liversidge et al [5].

Apremilast is the first oral inhibitor of phosphodiesterase 4 (PDE4). It is currently in clinical testing for patients with psoriasis and psoriatic arthritis [6]. Its solubility is described as 0.69 mg/ml [7]. Using the classification of the Euro...