Drug microsphere

Nobuhiko Yui, Jun Nihira, Teruo Okano, and Yasuhisa Sakurai. Regulated release of drug microspheres from inflammation responsive degradable matrices of crosslinked hyaluronic acid. J. Contr. Rel. 25 133-143, 1993. 

Scheme 27 (Adapted from H. Ozay and O. Ozay, Synthesis and characterization of drug microspheres containing phosphazene for biomedical applications, Colloids Surf. A, 450, 99-105. Copyright (2014) with permission from Elsevier).

An example of such a product is Sterile Medroxyprogestrone Acetate Suspension used for its contraceptive property. Such an injection is designed to provide up to three months of contraceptive activity. Another such product is a depot injection of leuprolode acetate, an analogue of gonadatropin-releasing hormone (see Drug delivery systems). In this case, the product is a sterilized powder of microspheres to be suspended upon the addition of an appropriate diluent and intended for monthly injection. 

A review of chitosan microspheres as carrier for drugs pubUshed recently by Sinha et al. provides insight into the exploitation of the various properties of chitosan to microencapsulate drugs. Various techniques used for preparing chitosan microspheres and evaluation protocols have also been reviewed, together with the factors that affect the entrapment efficiency and release ki-nefics of drugs [194]. 

Spray-drying of chitosan salt solutions provides chitosan microspheres having diameters close to 2-5 p.m and improved binding fimctionaUty. The chitosan microsphere free-flowing powder is compressible and hence most suitable as a drug carrier [ 195-204]. The following are some examples. 

The emulsion technique is convenient when the drug is particularly sensitive to certain parameters connected to the spray-drying. The emulsion technique may be associated to cross-Unking or other treatments of the microspheres. The following examples are self-explanatory. 

The ability of chitosan hydrochloride to enhance the transcorneal permeability of the drug has been demonstrated [289]. Polyethylene oxide (PEO) was used as a base material to which ofloxacin-containing chitosan microspheres prepared by spray-drying were added and powder compressed resulting in circular inserts (6 mm). 

A large variety of drug delivery systems are described in the literature, such as liposomes (Torchilin, 2006), micro and nanoparticles (Kumar, 2000), polymeric micelles (Torchilin, 2006), nanocrystals (Muller et al., 2011), among others. Microparticles are usually classified as microcapsules or microspheres (Figure 8). Microspheres are matrix spherical microparticles where the drug may be located on the surface or dissolved into the matrix. Microcapsules are characterized as spherical particles more than Ipm containing a core substance (aqueous or lipid), normally lipid, and are used to deliver poor soluble molecules... 

Ribeiro, A. J., Neufeld, R. Arnaud, P. Chaumeil, J. C. (1999). Microencapsulation of lipophilic drugs in chitosan-coated alginate microspheres. International Journal of Pharmaceutics, Vol. 187,1, (September 1999), pp. (115-123), ISSN 0378-5173 Rubinstein, A. (1995). Approaches and opportunities in colon-specific drug-delivery. Critical Reviews in Therapeutic Drug Carrier Systems, Vol 12, 2-3,1995), pp. (101-149), ISSN 0743-4863... 

The earlier work of Miller (35), Outright (37), and Brady (5) on nonmedicated implants provided an excellent basis for further studies on specific controlled release formulations such as the determination of the biodegradation rates of lactide/glycolide drug-loaded microspheres (38). Those studies were done with l c-iabeled polymers produced from DL-lactic acid and glycolide. The final formulations tested in rats were microspheres loaded with H-labeled steroid and polymer as the matrix. The microspheres were administered intramuscularly and animals were serially sacrificed over a period of about a year. 

Spenlehauer (59) reported that in the case of cisplatin-loaded microspheres, irradiation only changes the processing considerations and does not influence drug release. This observation is in conflict with other literature reports showing increases in drug release rates (60,61). 

The effects of microsphere size distribution, drug/polymer ratio, and microsphere quality can be easily demonstrated in this laboratory model. Furthermore, as animal data and human clinical trial results are available the model becomes quite useful as a quality control method (46). 

The rate and duration of steroid release is affected by (1) polymer composition, (2) drug/polymer ratio (3) microsphere size distribution, and (4) microsphere quality (75). The ratio of glycolide to lactide in the copolymer has been found to be more dominant than the polymer molecular weight in the design of controlled release formulations. Microspheres of smaller size provide in vivo drug profiles of higher levels and shorter durations because of greater surface area. 

A testosterone microsphere system for treatment of hypogonadol males has been developed and clinically evaluated (61,78). This formulation is based on a glycolide/DL-lactide copolymer and natural testosterone (Fig. 6). Because testosterone is not a very potent compound, about 600 mg of the drug is needed in adult males over a 90-day period. The performance of the testosterone system in baboons is shown in Fig. 7. Similar formulations have also been used in the control of the wild horse population of the western United States. Stallions were injected with a testosterone microsphere formulation designed to inhibit sperm production over a 6-month period (79). 

The steroid microsphere systems are probably the most successful drug delivery formulations thus far ba.sed on lactide/glycolide polymers. Several of these products appear to be on track for human and animal applications in the 1990s. The success of these formulations is due to the known safety of the polymer, the reproducibility of the microencapsulation process, reliability in the treatment procedure, and in vivo drug release performance (80). 

FIGURE 5 Scanning electron micrograph of 90-day norethisterone microspheres 45-90 pm in diameter and containing 47% by weight drug. 

The investigators studied various blends of the three polymers in order to control the rate of chain scission and thus influence the induction period and onset of drug release. None of the blends provided the desired 1-week zero-order kinetics. However, blends of different microsphere types did show promise in vitro (88). 

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. 

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. 

Lactic acid oligomer microspheres containing aclarubicin have been studied for selective lymphatic delivery. Low (less than 10,000 molecular weight oligomers were used to produce microspheres designed to release drug over a 30-day period (99). Additives have been used to alter the release rate of aclarubicin-loaded poly(lactide) microspheres (100). Mitomycin C was incorporated into poly(lactic... 

Muramyl dipeptide derivatives have also been microencapsulated in lactide/glycolide copolymers for use alone as an immuno potentiator. L-lactide/glycolide copolymers were used to deliver MDP-B30, a lipophilic compound, from very small microspheres (less than 5 pm in diameter). The amount of MDP-B30 required for tumor growth inhibitory activity of mouse peritoneal macrophages was 2000 times less for the controlled release MDP-B30 microspheres than for the unen-capsulated drug (134). 

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