Self-emulsifying pellets prepared by wet granulation in high-shear mixer: influence of formulation variables and preliminary study on the in vitro absorption

doi:10.1016/j.ijpharm.2004.07.046

International Journal of Pharmaceutics

Volume 291, Issues 1–2, 3 March 2005, Pages 87-97

https://doi.org/10.1016/j.ijpharm.2004.07.046 Get rights and content

Abstract

A method of producing self-emulsifying pellets by wet granulation of powder mixture composed of microcrystalline cellulose, lactose and nimesulide as model drug with a mixture containing mono- and di-glycerides, polisorbate 80 and water, in a 10-l high shear mixer has been investigated.

The effects of the formulation variables on pellets characteristics were evaluated by mixtures experimental design and by a polynomial model, in order to describe the phenomenon, to verify eventual interactions among components of the mixture and to investigate the feasibility of scaling-up. After determination of size distribution, the pellets were characterised by scanning electron microscopy, dissolution and disintegration tests, and by in vitro absorption test

Such an approach, applied to the development of a self-emulsifying system for nimesulide as poorly water-soluble model drug, resulted in different formulations with improved drug solubility and permeability characteristics. The data demonstrate that pellets composed of oil to surfactant ratio of 1:4 (w/w) presented improvement in performance in permeation experiments.

Introduction

Self-emulsifying drug delivery systems are known to be useful for the improvement of oral bioavailability of poorly water soluble drugs (Constantinides, 1995, Humberstone and Charman, 1997). In particular, they are able to self-emulsify rapidly in the gastro-intestinal fluids, forming, under the gentle agitation given by gastro-intestinal motion, fine O/W emulsions. In such a system, the lipophilic drug is present in solution, in small droplets of oil. The large interfacial area generated by these small droplets, promotes drug diffusion into intestinal fluids (Pouton, 2000, O’Driscoll, 2002). Moreover, the emulsion droplets lead to a faster and more uniform distribution of the drug in the gastrointestinal tract, minimizing the irritation due to the contact between the drug and the gut wall (Charman et al., 1992, Shah et al., 1994, Khoo et al., 1998). In addition to the effects described above, the improved drug bioavailability could be partly ascribed to the effect of the monoglyceride components of such self-emulsifying systems, which are supposed to increase membrane permeability (Chicco et al., 1999)

Such systems are normally prepared as liquid dosage forms that can be administrated in soft gelatine capsules, which have some disadvantages especially in the manufacturing process (in-process controls), with consequent high production costs. An alternative method which is currently investigated by several authors, is the incorporation of liquid self-emulsifying ingredients (oil/surfactant/water mixture) into a powder in order to create a solid dosage form (tablets, capsules). Examples of such solid systems are pellets produced by extrusion/spheronisation, which can finally be incorporated into hard gelatine capsules (Newton et al., 2001) or the inclusion in microporous or cross-linked polymeric carriers (Chiellini et al., 2003).

The purpose of the present work was to investigate the feasibility to incorporate a mixture of mono- and di-glycerides, polysorbate 80 and water into a powder mixture of microcrystalline cellulose, lactose and nimesulide as water-insoluble model drug, in order to obtain self-emulsifying pellets using the 10-l Roto-J Zanchetta high shear mixer.

Formulations with different component ratios were investigated by mixture experimental design. The results were statistically analysed in order to evaluate the effects of formulation components on the granulometric characteristics of the pellets and to investigate the feasibility of scaling-up.

Section snippets

Materials

Microcrystalline cellulose (Microcel 101^®, Faravelli, Milano, Italy); lactose monohydrate (Granulac 200^®, Meggle, Wasserburg, Germany); mono- and di-glycerides (Cithrol GMO^®, Croda, Singaphore); polysorbate 80 (Montanox 80 VG PHA^®, Seppic, Castris, France) and nimesulide reagent-grade (Prodotti Gianni, Milano, Italy) were used as starting materials.

Experimental design and statistical analysis

Some experimental analyses were carried out with Roto-J, in order to value the feasibility of the wet granulation for the production of solid

Results and discussion

The 21 experimental runs (16 design points plus 5 check points) were carried out in a completely random order according to the experimental design (see Table 2); the observed responses are listed in Table 3.

The results showed that the process of wet granulation, using the 10 l Roto-J granulator, allowed to obtain pellets with relatively small size, a low dispersion, and high percentage in modal fraction, with fast disintegration time. The median diameter (Y₁) and the percentage in modal

Conclusions

This study showed that the experimental design approach can be useful for the optimisation of processes and products in the industrial pharmaceutical field. This approach applied to the study of solid pharmaceutical dosage forms, such as the self-emulsifying pellets produced by wet granulation, led to a mathematical model describing the effects of formulation components on the product characteristics. Therefore, by such mathematical equations, the response behaviour can be predicted over the

Acknowledgements

The authors would like to thank Prof. J.M. Newton (The School of Pharmacy, University of London), Dr. E.E. Chiellini and B. Bellich (Remedia SrL, Italy) for their helpful contributions.

References (19)

B. Campisi et al.
Experimental design for a pharmaceutical formulation: optimisation and robustness
J. Pharm. Biomed. Anal.
(1998)
D. Chicco et al.
Correlation of in vitro and in vivo paracetamol availability from layered excipient suppositories
Int. J. Pharm.
(1999)
M. Grassi et al.
Theoretical considerations on the in vivo intestinal permeability determination by means of the single pass and recirculating techniques
Int. J. Pharm.
(2001)
S.M. Khoo et al.
Formulation design and bioavailability assessment of lipidic self-emulsifying formulations of halofantrine
Int. J. Pharm.
(1998)
F. Meriani et al.
In vitro nimesulide absorption from different formulations
J. Pharm. Sci.
(2004)
M. Newton et al.
The influence of formulation variables on the properties of pellets containing a self-emulsifying mixture
J. Pharm. Sci.
(2001)
C.M. O’Driscoll
Lipid-based formulations for intestinal lymphatic delivery
Eur. J. Pharm. Sci.
(2002)
R.J. Schilling et al.
Intestinal mucosal transport of insulin
Int. J. Pharm.
(1990)
N.H. Shah et al.
Self-emulsifying drug delivery systems (SEDDS) with polyglycolized glycerides for improving in vitro dissolution and oral absorption of lipophilic drugs
Int. J. Pharm.
(1994)

There are more references available in the full text version of this article.

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Self-emulsifying pellets prepared by wet granulation in high-shear mixer: influence of formulation variables and preliminary study on the in vitro absorption

Abstract

Introduction

Section snippets

Materials

Experimental design and statistical analysis

Results and discussion

Conclusions

Acknowledgements

J. Pharm. Biomed. Anal.

Int. J. Pharm.

Int. J. Pharm.

Int. J. Pharm.

J. Pharm. Sci.

J. Pharm. Sci.

Eur. J. Pharm. Sci.

Int. J. Pharm.

Int. J. Pharm.