A Novel Preparation Method for Microspheres of Water Soluble Polymers Using Polypropyleneglycol as the Dispersion Medium

Abstract

Microspheres (MS) are useful as drug carriers to improve the performance of therapeutic systems. For example, stable release by a valve and guaranteed delivery to the lung by a metered dose inhaler or dry powder inhaler formulations can be achieved using size-controlled spherical MS, 1) and the therapeutic drugs entrapped in MS and, when injected vascularly, can distribute to specific organs or tissues depending on their size. 2,3) The choice of the matrix material and size control of the MS are the most important factors in designing any therapeutic system. Lipophilic polymer esters such as poly(lactic-co-glycolic acid) are popular materials and exhibit prolonged drug release. On the other hand, hydrophilic polymers can be used for controlled release over shorter periods and may be better at entrapping MS for water-soluble drugs compared with lipophilic polymers. 4)MS consisting of hydrophilic polymers, such as proteins and polysaccharides, can be prepared by emulsion-evaporation and spray-drying. [5][6][7] Water is a good solvent for such polymers during the preparation processes. In most cases, cross-linking agents are used to ensure particle generation. 8)However, heating to evaporate water and addition of crosslinking agents may not be good for the stability of therapeutic drugs in MS.9,10) Although gelatin MS can be prepared in cooling processes to promote gel formation, cross-linking agents such as glutaraldehyde are needed to control drug release from the resulting MS.11) A novel preparation method for MS consisting of water soluble polymers, which can be applied to various types of polymers and does not require heating and cross-linking reactions during the preparation process, will be useful for the preparation of MS containing sensitive materials, such as protein drugs.In the present study, polypropyleneglycol (PPG) was used as a dispersion medium for the preparation of MS consisting of water-soluble polymers. PPG is hydrophobic at high temperatures but hydrophilic and freely soluble in water at low temperatures. Therefore, the PPG-water system forms two liquid phases like an emulsion at a high temperature and the system changes to a liquid phase on cooling. This temperature-dependent property of PPG can be used to remove water from aqueous polymer solutions dispersed in PPG to form solid polymer particles. Soluble starch is used mainly as the model water-soluble polymer. Gelatin, whey protein and dextran have also been used for MS preparation. ExperimentalMaterials Polypropyleneglycol (diol type 700, PPG) and soluble starch were purchased from Wako Pure Chemical (Osaka). Whey protein isolate (WPI) was kindly supplied by Snow Brand Milk Products (Tokyo). Dextran T70 and gelatin were purchased from Pharmacia Biotech (Uppsala, Sweden) and Nitta Gelatin (Osaka), respectively. All other chemicals were of reagent grade and used as received.Procedure for Microsphere Preparation Water soluble polymers (starch, gelatin, WPI or dextran T70) were initially dissolved in water (5-10%) at 60°C for the aqueous phas...

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