Microspheres solvent evaporation

Recently, Tsakala et al. (90) formulated pyrimethamine systems based on several lactide/glycolide polymers. These studies were conducted with both microspheres (solvent evaporation process) and implants (melt extrusion process). In vitro studies indicated that pyrimethamine-loaded implants exhibited apparent zero-order release kinetics in aqueous buffer whereas the microspheres showed an initial high burst and considerably more rapid drug release. In vivo studies in berghi infected mice confirmed that the microspheres did not have adequate duration of release for practical application. However, the implants offer promise for future clinical work as more than 3 months protection was observed in animals. 

Eudragit RS microspheres containing chitosan hydrochloride were prepared by the solvent evaporation method using an acetone/liquid paraffin solvent system, and their properties were compared with Eudragit RS microspheres without chitosan. The content of pipemidic acid, an antibacterial, increased in larger microspheres as a consequence of cumulation of undissolved pipemidic acid particles in larger droplets. Pipemidic acid release was faster from microspheres with chitosan [212]. 

Microspheres and microcapsules of lactide/glycolide polymers have received the most attention in recent years. Generally, three microencapsulation methods have been employed to afford controlled release formulations suitable for parenteral injection (1) solvent evaporation, (2) phase separation, and (3) fluidized bed coating. Each of these processes requires lactide/glycolide polymer soluble in an organic solvent. 

In vitro release profiles on phase II and phase III clinical supplies prepared more than 2 years apart are shown in Fig. 2. SeveT al thousand doses were prepared for the phase III trial initiated in 1988. Figure 3 shows the reproducibility of six individual batches of microspheres produced by the solvent evaporation method. Other studies have been reported with similar processes (47). 

Poly(DL-lactide) was used as the excipient in microspheres of CCNU, a nitrosourea, prepared by a solvent evaporation procedure (96,97). PLA-CCNU microspheres 3.0 pm in diameter were injected i.v. and leukemia cell survival was determined by spleen colony assay. A 100-fold decrease in leukemia cell survival was observed with the microspheres in both spleen and liver compared to untreated controls. Promising results were also obtained with Lewis lung carcinoma in mice. These studies showed that 2- to 4-ym microspheres were preferentially targeted to the lungs. 

Extensive studies have been reported with cisplatin in the field of chemoembolization (59,98). Microspheres prepared by a solvent evaporation procedure were characterized in vitro and critical processing parameters in regard to drug release kinetics were identified. 

Several antiinflammatory compounds have been formulated in lactide/ glycolide polymers (107-111). Methylprednisolone microspheres based on an 85 15 DL-lactide/glycolide copolymer were developed for intra-articulate administration (111). The microspheres, prepared by a solvent evaporation procedure, are 5—20 jam in diameter and are designed to release low levels of the steroid over a extended period in the joint. Controlled experiments in rabbits with induced arthritis showed that the microspheres afforded an antiinflammatory response for up to 5 months following a single injection. 

Insulin (molecular weight 7000) has been formulated in controlled release microbeads and pellets (135,136). A solvent evaporation micro-encapsulation procedure was used to produce microspheres with up to 20% by weight insulin. Solvent-casting techniques were used to prepare pellets. The investigations demonstrated that the PLA... 

Spenlehauer, G., Vert, M., Benoit, J. P., Chabot, F., and Veillard, M., Biodegradable cisplatin microspheres prepared by the solvent evaporation method Morphology and release characteristics, J. Control. Rel., 7, 217, 1988. 

Microencapsulation with PCL using the solvent evaporation method can be experimentally difficult. For example, PCL was the only polymer of five that failed to yield spherically shaped microcapsules using this technique (82). The insecticide Abate has been incorporated into PCL (21% loading) by the solvent separation method in a comparative study, PCL afforded good-quality microspheres although poly (methyl methacrylate) microcapsules were smoother and had fewer defects (83). 

Bissery, M. C., Puisieux, F., and Thies, C., A study of the parameters in the making of microspheres by the solvent evaporation procedure. Expo. Congr. Int. Technol. Pharm. 3rd. 

Yuksel N, Turkoglu M, Baykara T. Modelling of the solvent evaporation method for the preparation of controlled release acrylic microspheres using neural networks. J Microencapsulation 2000 17 541-51. 

J Herrmann, R Bodmeier. Biodegradable somatostatin acetate containing microspheres prepared by various aqueous and non-aqueous solvent evaporation method. Eur J Pharm Biopharm 45(l) 75-82, 1998. 

O Donnell PB, McGinity JW (1997) Preparation of microspheres by the solvent evaporation technique. Adv Drug Deliv Rev 28 25-42... 

Using two different procedures, based, respectively, on slow solvent evaporation[14] and on coprecipitation, a new proprietary method was developed during the fulfillment of a research project funded by the European Community (EC) under the Brite-EuramProgram[15,16], were tested for the preparation of microspheres. 

The number average diameter of microspheres obtained from polymers synthesized, by emulsification of polymer solutions followed by solvent extraction and/or solvent evaporation methods, can be controlled by choosing the appropriate conditions at which particles are produced. However, by this method particles with 15 p,m and with D D > 1.9 are produced. Spray drying did not provide poly(L-Lc) particles with regular spherical shape. Direct synthesis of poly(L-Lc) microspheres by ring-opening polymerization with stepwise monomer addition can be used as a method of choice for the production of microspheres with diameters controlled to ca. 6 p.m and with diameter polydispersity parameter < 1.20. 

PVA acted as a protective polymer by being absorbed at the oil-water interface of the droplets to produce a steric barrier which prevented the coalescence of the droplets. Therefore PVA formed a stable emulsion of methylene chloride in water, even when nifedipine was dissolved in the methylene chloride phase. However, nifedipine tended to crystallize spontaneously in the aqueous phase of the emulsion or on the surface of the microspheres when solvent evaporation approached completion. This nifedipine crystal formation was detected even at a low drug payload of 5%... 

In the preparation of microspheres by solvent evaporation from oil-in-water emulsions, the presence of base (NaOH) was found to enhance the release of thioridazine from polylactide micro-spheres. The amount of drug release as a function of time was dependent on the amount of base added to the aqueous phase of the emulsion. Scanning electron micrographs indicate that this increased drug release may be due to modification of the internal structure of the microspheres by sodium hydroxide during fabrication. 

The preparation of biodegradable microspheres by a solvent evaporation process using sodium oleate as the emulsifier was described in previous publications (1.21. A number of process parameters (such as drug loading, polymer molecular weight, polymer composition and initial polymer solution concentration) were studied to determine their effects on the release of drugs from biodegradable microspheres. 

The solvent evaporation microencapsulation process using sodium oleate as the emulsifier produced microspheres in high yields (75-95%), essentially free of agglomeration (1). Drugs with low solubility in water (0.02 mg/ml or less) e.g. thioridazine, were incorporated with 80-99% efficiency. Core loadings up to 60% were attained along with prolonged in vitro release. 

To recapitulate, thioridazine release from microspheres was enhanced when NaOH was added to the emulsion prior to the solvent evaporation step. This was observed for both poly(DL-lactide) and poly(L-lactide) and also for two emulsifier systems, sodium oleate and polyvinyl alcohol. It should be pointed out that NaOH is added only to the aqueous phase of the emulsion. It is not incorporated into the microspheres by this process. 

In the second experiment, the drug-loaded microspheres were posttreated with NaOH. The purpose of this experiment was to determine whether the surface of the microspheres can be altered by NaOH. Any such modification of the polymeric surface would increase its permeability. This would then account for the enhanced drug release effect. For this experiment, a sample of drug-loaded microspheres was prepared without NaOH in the usual manner. It was then posttreated with 0.14 mole NaOH/mole lactic acid. The conditions for the posttreatment were the same as for the solvent evaporation step. 

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