Pharmaceutical Manufacturing Handbook: Production and

400 BIODEGRADABLE POLYMER-BASED MICROSPHERES
Drug
(a)
Polymer
FIGURE 1 Polymeric delivery systems: (a) reservoir systems (microcapsules); (b) matrix
systems (microspheres).
dispersion is in suspension, the product obtained is reservoir type, that is, a distinct
polymeric envelope/shell encirculating a liquid core of dissolved active ingredient
(defi ned as microcapsules). Recombinant human erythropoietin [48] and bromocriptine
mesylate, Parlodel Depot [49] , are examples of microspheres (matrix type)
obtained by the spray drying technique.
5.2.2.4 New Trends in Production Methods
Several issues such as reducing cost, reducing scale - up diffi culties, improving protein
stability, allowing for terminal sterilization, and eliminating the need for organic
solvents during addition of the peptide/protein motivate the development of new
methods to manufacture microspheres. Moreover conventional microencapsulation
methods involve relatively harsh conditions that are not generally tolerated by
peptide/protein molecules without stabilization. Therefore, new and improved processes
shielding the peptide/protein from deleterious conditions have been proposed
and evaluated.
Modifi ed Conventional Methods The w/o/w solvent evaporation or extraction is
probably one of the most widely used methods for peptide and protein microencapsulation
[44] , despite its many drawbacks. Improvements and alternatives have
therefore been proposed such as oil in water (o/w), * o/w (the asterisk including
cosolvent) and oil in oil (o/o) [50] .
Utilising a modifi ed w/o/w method, the rhIGF - 1 was encapsulated into PLGA
microspheres after increasing the pH of the protein solution from 4.5 to 5.5 – 6.0,
where rhIGF - 1 formed a viscous gel [51] . High entrapment effi ciency of fully bioactive
protein was achieved, and 92 – 100% of pure, monomeric, and bioactive rhIGF - 1
was released in vitro over 21 days. The lowering of the rhIGF - 1 solubility at pH
5.5 – 6.0 probably restricted its conformational fl exibility and changes upon exposure
to the polymer solvent. Without pH adjustment, approximately 10 – 32% of rhIGF - 1
was lost upon solvent exposure, due to degradation and aggregation. Elsewhere, a
w/o 1 /o 2 system was investigated for encapsulating different proteins and peptides,
with the o 1 and o 2 phases consisting of acetonitrile/dichloromethane and liquid
paraffi n/Span 80, respectively [52] . The acetonitrile mediated the partial mixing of
the w and o 1 phases and subsequent protein/peptide precipitation, which was a
Drug
(b)
Polymer