**3. Polyurethane microparticles as carriers of drug**

PU microspheres can be prepared by interfacial polycondensation in emulsions. These techniques include polycondensation of two or more complimentary monomers at the interface of two-phase system, carefully emulsified for obtaining little drop-lets in emulsion phase. Usually, the interfacial polycondensation carried out by two steps: emulsification step (emulsion formation using a mechanical stirring during few minutes and one of the monomers is dissolved in the emulsion drops; polycondensation step (the second complementary monomer is added to the external phase of the emulsion and the polycondensation reaction takes place at the liquid-liquid emulsion interface). Interest in the PU microparticles in each day has being increased since products presents numerous advantages in biomedical, pharmaceutical and cosmetic applications.

PU microparticles could be interesting matrices for controlled drug delivery. Aliphatic PU Tecoflex was evaluated as microsphere matrix for the controlled release of theophylline (Subhaga et al., 1995). PU microspheres were prepared using solvent evaporation technique from a dichloromethane solution of the polymer containing the drug. A dilute solution of poly(vinyl alcohol) served as the dispersion medium. Microspheres of good spherical geometry having theophylline content of 35% could be prepared by the technique. The release of the drug from the microspheres was examined in simulated gastric and intestinal fluids. While a large burst effect was observed in gastric fluid, in the intestinal fluid a close to zero-order release was seen.

152 Polyurethane

rifampicin is the most potent.

extracellular concentration.

practical and affordable.

PLG nanoparticle-encapsulated econazole and moxifloxacin have been evaluated against murine tuberculosis (drug susceptible) in order to develop a more potent regimen for tuberculosis (Ahmad et al., 2008). PLG nanoparticles were prepared by the multiple emulsion and solvent evaporation technique and were administered orally to mice. A single oral dose of PLG nanoparticles resulted in therapeutic drug concentrations in plasma for up to 5 days (econazole) or 4 days (moxifloxacin), whilst in the organs (lungs, liver and spleen) it was up to 6 days. In comparison, free drugs were cleared from the same organs within 12- 24h. In *M. tuberculosis*-infected mice, eight oral doses of the formulation administered weekly were found to be equipotent to 56 doses (moxifloxacin administered daily) or 112 doses (econazole administered twice daily) of free drugs. Furthermore, the combination of moxifloxacin+econazole proved to be significantly efficacious compared with individual drugs. Addition of rifampicin to this combination resulted in total bacterial clearance from the organs of mice in 8 weeks. PLG nanoparticles appear to have the potential for intermittent therapy of tuberculosis, and combination of moxifloxacin, econazole and

Antituberculosis drugs Is, rifampicin, streptomycin and moxifloxacin have been encapsulated in poly(butyl cyanoacrylate) nanoparticles (Anisimova et al., 2000, Kisich et al, 2007). Incorporation of drugs in polymeric nanoparticles not only increased the intracellular accumulation of these drugs in the cultivated human blood monocytes but also produced enhanced antimicrobial activity of these agents against intracellular *M. tuberculosis* compared with their activity in extracellular fluid. Encapsulated moxifloxacin accumulated in macrophages approximately three-fold times more efficiently than the free drug, and was detected in the cells for at least six times longer than free moxifloxacin at the same

This brief review suggested that micro- and nanoparticles based delivery systems have a considerable potential for treatment of tuberculosis. Their major advantages, such as improvement of drug bioavailability and reduction of the dosing frequency, may create a sound basis for better management of the disease, making directly observed treatment more

PU microspheres can be prepared by interfacial polycondensation in emulsions. These techniques include polycondensation of two or more complimentary monomers at the interface of two-phase system, carefully emulsified for obtaining little drop-lets in emulsion phase. Usually, the interfacial polycondensation carried out by two steps: emulsification step (emulsion formation using a mechanical stirring during few minutes and one of the monomers is dissolved in the emulsion drops; polycondensation step (the second complementary monomer is added to the external phase of the emulsion and the polycondensation reaction takes place at the liquid-liquid emulsion interface). Interest in the PU microparticles in each day has being increased since products presents numerous

**3. Polyurethane microparticles as carriers of drug** 

advantages in biomedical, pharmaceutical and cosmetic applications.

Microencapsulation of theophylline in PU was developed with 4, 4'-methylenediphenylisocyanate, castor oil and ethylene diamine as chain extender (Rafienia et al., 2006). PU microspheres were prepared in two steps pre-polymer preparation and microspheres formation. Particle size investigation with optical microscopy revealed size distribution of 27–128 μm. Controlled release experiment of theophylline was performed in phosphate buffered saline at pH 7.4 with UV-spectrometer at 274 nm. Drug release profiles showed initial release of 2–40% and further release for more than 10 days.

The effect of chain-extending agent on the porosity and release behavior of biologically active agent diazinon from PU microspheres were studied (Jabbari & Khakpour, 2000). Microsphere was prepared using a two-step suspension polycondensation method with methylene diphenyl diisocyanate, polyethylene glycol 400 and 1,4-butanediol as the chainextending agent. Chain-extending agent was used to increase the ratio of hard to soft segments of the PU network, and its effect on microsphere morphology was studied with SEM. According to the results, porosity was significantly affected by the amount of chainextending agent. The pore size decreased as the concentration of chain-extending agent increased from zero to 50 mole%. With further increase of chain-extending agent to 60 and 67%, PU chains became stiffer and formation of pores was inhibited. Therefore, pore morphology was significantly affected by variations in the amount of chain-extending agent. The release behavior of microspheres was investigated with diazinon as the active agent. After an initial burst, corresponding to 3% of the incorporated amount of active agent, the release rate was zero order.

PU polymers and poly(ether urethane) copolymers were chosen as drug carriers for alphatocopherol (Bouchemal et al., 2004). This active ingredient is widely used as a strong antioxidant in many medical and cosmetic applications, but is rapidly degraded, because of its light, heat and oxygen sensitivity. PU and poly(ether urethane)-based nanocapsules were synthesized by interfacial reaction between two monomers. Interfacial polycondensation combined with spontaneous emulsification is a new technique for nanoparticles formation. Nanocapsules were characterized by studying particle size (150-500 nm), pH, yield of encapsulation and morphologies. Polyurethanes were obtained from the condensation of isophorone diisocyanate and 1,2-ethanediol, 1,4-butanediol , 1,6-hexanediol. Poly(ether urethane) copolymers were obtained by replacing diols by polyethylene glycol oligomers Mw 200, 300, 400 and 600. Mw of di- and polyols have a considerable influence on

nanocapsules characteristics cited above. The increase of Mw of polyols tends to increase the mean size of nanocapsules from 232±3 nm using ethanediol to 615± 39 nm using PEG 600, and led to the agglomeration of particles. We also noted that the yield of encapsulation increases with the increase of polyol length. After 6 months of storage, polyurethanes nanocapsules possess good stability against aggregation at 4 and 25o C. Comparing results obtained using different monomers, it reveals that the PU based on hexanediol offers good protection of alpha-tocopherol against damaging caused by the temperature and UV irradiation (Bouchemal et al., 2006).

Polyurethane as Carriers of Antituberculosis Drugs 155

and nature of steric stabilizer on the release of MCR from PU microcapsules have been

Poly(urea-urethane) microcapsules containing oil-soluble dye dioctyl phthalate as core material were prepared by the interfacial polymerization with using mixtures of tri- and diisocyanate monomers as wall forming materials (Chang et al., 2003, 2005). The time course of the dye release in dispersing tetrahydrofuran was measured as a function of the weight fraction of tri-isocyanate monomer in the total monomer weight and the core/wall materialweight ratio. The dye release curves were well represented by an exponential function C=Ceq(1-e-t/tau), where C is the concentration of the dye in the dispersing medium, Ceq that at equilibrium state, t the elution time and tau is a time constant. tau increased linearly against weight at high contentration, suggesting controllability of the release rate of

microcapsules by varying tri-isocyanate/di-isocyanate ratio

(Batyrbekov et al., 2009; Iskakov et al., 2004).

growing polymer with urea segments formation.

**4. Polyurethane microparticle as carrier of antituberculosis drug** 

New polyurethane microcapsules incorporated with antituberculosis drug Is have been synthesized by interfacial polyaddition between toluene-2,4-diisocyanate (TDI) and various poly(ethylene glycol)s (PEG). Drug Is is hydrophilic water-soluble compound, and it is insoluble in toluene. Thus Is could be capsulated by interfacial polycondensation technique using water-in-toluene emulsion, which prevents transferring of Is to the external phase. And drug encapsulation is possible during the process of the polymer wall formation

Isocyanate groups react with hydroxyl groups of PEG to form polyurethane chains according to the Scheme (Fig.1 a). TDI can also reacts with molecules of water at the border of reaction to form unstable NH-COOH group, which dissociates into amine and carbon dioxide (Fig.1 b). Chains with amine end-group reacts with the isocyanate groups of

Polycondensation was carried out in a 1 L double-neck flask fitted with a stirrer. Polyethylene glycol with 4 various molecular weights 400, 600, 1000 and 1450 (Sigma, USA) - PEG 400, PEG 600, PEG 1000 and PEG 1450 respectively were used as diol monomers. TDI (Sigma, USA) was applied as a bifunctional monomer for the polycondensation. Three solutions were prepared separately. Solution A: 10 mg surfactant Tween 40 was dissolved in 100 ml of toluene; solution B: *x* mmol diol and Is were added in *y* ml of water; amount of Is was 10, 20, and 30 mol % from PEG; solution C: 2.5 *x* mmol TDI was dissolved in 10 ml of solution A. Water/oil ratio was 1:10 vol.%. Solution B was poured into the reaction flask, contaning 90 ml of solution A under the stirring at 1000 rpm during 15 minutes. After the formation of microemulsion, solution C was added dropwise. After 180 min the polymerization was stopped. Microparticles were filtered, carefully washed with distillated water and dried at ambient conditions. Yield of polymers was estimated from the total amount of introduced monomers compared to the weight of polycondensation products.

studied.

Ovalbumin (OVA)-containing PU microcapsules were successfully prepared by a reaction between toluene diisocyanate and different polyols such as glycerol, ethane diol, and propylene glycol (Hong & Park, 2000). The structural and thermal properties of the resultant microcapsules and the release profile of the OVA from the wall membranes were studied. In conclusion, the microcapsules from the glycerol showed the highest thermal stability, with the formation of many hydrogen bonds. From the data of release profiles, it was confirmed that the particle size distribution and morphologies of microcapsules determined the release profiles of the OVA from the wall membranes.

Bi-soft segmented poly(ester urethane urea) microparticles were prepared and characterized aiming biomedical application (Campos et al., 2011). Two different formulations were developed, using poly(propylene glycol), tolylene 2,4-diisocyanate terminated pre-polymer and poly(propylene oxide)-based tri-isocyanated terminated pre-polymer (TI). A second soft segment was included due to poly(ε-caprolactone) diol. Infrared spectroscopy, used to study the polymeric structure, namely its H-bonding properties, revealed a slightly higher degree of phase separation in TDI-microparticles. TI-microparticles presented slower rate of hydrolytic degradation, and, accordingly, fairly low toxic effect against macrophages. These new formulations are good candidates as non-biodegradable biomedical systems.

The synthesis of PU microsphere-gold nanoparticle "core-shell" structures and their use in the immobilization of the enzyme endoglucanase are described (Phadtare et al., 2004). Assembly of gold nanoparticles on the surface of polymer microspheres occurs through interaction of the nitrogens in the polymer with the nanoparticles, thereby precluding the need for modifying the polymer microspheres to enable such nanoparticle binding. Endoglucanase could thereafter be bound to the gold nanoparticles decorating the PU microspheres, leading to a highly stable biocatalyst with excellent reuse characteristics. The immobilized enzyme retains its biocatalytic activity and exhibits improved thermal stability relative to free enzyme in solution.

Microencapsulation of the water soluble pesticide monocrotophos (MCR), using PU as the carrier polymer, has been developed using two types of steric stabilizers polymethyllauril acrylate (PLMA) macrodiol and PLMA-g-PEO graft copolymer (Shukla et al., 2002). The microencapsulation process is carried out in non-aqueous medium and at a moderate temperature to avoid any chemical degradation of monocrotophos during the encapsulation process. Microcapsules were characterized by optical microscopy and SEM for particle size and morphology, respectively. The effects of loading of MCR, crosslinking density of PU, and nature of steric stabilizer on the release of MCR from PU microcapsules have been studied.

154 Polyurethane

irradiation (Bouchemal et al., 2006).

relative to free enzyme in solution.

profiles of the OVA from the wall membranes.

nanocapsules characteristics cited above. The increase of Mw of polyols tends to increase the mean size of nanocapsules from 232±3 nm using ethanediol to 615± 39 nm using PEG 600, and led to the agglomeration of particles. We also noted that the yield of encapsulation increases with the increase of polyol length. After 6 months of storage, polyurethanes nanocapsules possess good stability against aggregation at 4 and 25o C. Comparing results obtained using different monomers, it reveals that the PU based on hexanediol offers good protection of alpha-tocopherol against damaging caused by the temperature and UV

Ovalbumin (OVA)-containing PU microcapsules were successfully prepared by a reaction between toluene diisocyanate and different polyols such as glycerol, ethane diol, and propylene glycol (Hong & Park, 2000). The structural and thermal properties of the resultant microcapsules and the release profile of the OVA from the wall membranes were studied. In conclusion, the microcapsules from the glycerol showed the highest thermal stability, with the formation of many hydrogen bonds. From the data of release profiles, it was confirmed that the particle size distribution and morphologies of microcapsules determined the release

Bi-soft segmented poly(ester urethane urea) microparticles were prepared and characterized aiming biomedical application (Campos et al., 2011). Two different formulations were developed, using poly(propylene glycol), tolylene 2,4-diisocyanate terminated pre-polymer and poly(propylene oxide)-based tri-isocyanated terminated pre-polymer (TI). A second soft segment was included due to poly(ε-caprolactone) diol. Infrared spectroscopy, used to study the polymeric structure, namely its H-bonding properties, revealed a slightly higher degree of phase separation in TDI-microparticles. TI-microparticles presented slower rate of hydrolytic degradation, and, accordingly, fairly low toxic effect against macrophages. These

The synthesis of PU microsphere-gold nanoparticle "core-shell" structures and their use in the immobilization of the enzyme endoglucanase are described (Phadtare et al., 2004). Assembly of gold nanoparticles on the surface of polymer microspheres occurs through interaction of the nitrogens in the polymer with the nanoparticles, thereby precluding the need for modifying the polymer microspheres to enable such nanoparticle binding. Endoglucanase could thereafter be bound to the gold nanoparticles decorating the PU microspheres, leading to a highly stable biocatalyst with excellent reuse characteristics. The immobilized enzyme retains its biocatalytic activity and exhibits improved thermal stability

Microencapsulation of the water soluble pesticide monocrotophos (MCR), using PU as the carrier polymer, has been developed using two types of steric stabilizers polymethyllauril acrylate (PLMA) macrodiol and PLMA-g-PEO graft copolymer (Shukla et al., 2002). The microencapsulation process is carried out in non-aqueous medium and at a moderate temperature to avoid any chemical degradation of monocrotophos during the encapsulation process. Microcapsules were characterized by optical microscopy and SEM for particle size and morphology, respectively. The effects of loading of MCR, crosslinking density of PU,

new formulations are good candidates as non-biodegradable biomedical systems.

Poly(urea-urethane) microcapsules containing oil-soluble dye dioctyl phthalate as core material were prepared by the interfacial polymerization with using mixtures of tri- and diisocyanate monomers as wall forming materials (Chang et al., 2003, 2005). The time course of the dye release in dispersing tetrahydrofuran was measured as a function of the weight fraction of tri-isocyanate monomer in the total monomer weight and the core/wall materialweight ratio. The dye release curves were well represented by an exponential function C=Ceq(1-e-t/tau), where C is the concentration of the dye in the dispersing medium, Ceq that at equilibrium state, t the elution time and tau is a time constant. tau increased linearly against weight at high contentration, suggesting controllability of the release rate of microcapsules by varying tri-isocyanate/di-isocyanate ratio
