**5. Polyurethane foams as carriers of antituberculosis drugs**

The use of soft PU foams as carriers of antituberculosis drugs is of considerable interest. In such systems pharmaceutical agents are dispersed or dissolved in the PU carrier and the

kinetics of drug release are generally controlled by diffusion phenomena through the polymer. Such systems are being used for treatment of tuberculosis-infected cavities (wounds, pleural empyema, bronchial fistula). It is the purpose of this chapter to show the possibility of using polyurethane foams as carriers of some antituberculosis agents for tuberculosis treatment.

Polyurethane as Carriers of Antituberculosis Drugs 163

All the release data show the typical pattern for a matrix-controlled mechanism. The cumulative amount of drugs released from the PU was linearly related to the square root of time and the release rate decreased with time. The process is controlled by the dissolution of the drug and by its diffusion through the polymer. The release is described by Fick's law and proceeds by first-order kinetics (Philip & Peppas, 1987). The structure of the drugs and their solubility influences the rate of release: the total amount of Is is released in 3-4 days, Eth in 5-6 days (Fig.10), Fl and Rfp in 14-16 days (Fig.11). The release time for 50% of Is is 22- 26 h, for Eth 28-30 h, for Fl and Rfp 72-76 h, respectively. The rapid release of Is and Eth in comparison with Fl and Rfp is due to the higher solubility of these drugs in the dissolution medium. Increasing the drug loading from 100 to 300 mg/g resulted in an increase in the

> **0 2 4 6 8 10 12 14 16 20** Time,days

**Figure 11.** Release of Fl from PU foam into Ringer-Locke solution at 37oC. Drug loadings (mg/g PU):

released has no significant effect upon the diffusion coefficient.

Table 1 presents the values of the diffusion coefficients for drug release into different media, calculated for the initial release stage by a modified Higuchi equation (Higuchi, 1963). With increase of drug loading, the diffusion coefficient is not significantly decreased. This is connected with the plasticizing action of the drug, resulting in the deterioration of the mechanical properties of the polymeric matrix. The medium into which the drugs are

The release results show that the use of PU as a carrier of antituberculosis drugs provides a controlled release of drugs suitable for use in practical medicine, i.e. it allows prolonged

The tuberculostatic activity of drugs released from the PU was determined by diffusion into dense Levenshtein-Iensen nutrient medium compared with a museum strain of *M.* 

It has been shown that drugs introduced into a polymeric matrix have tuberculostatic activity on the level of free drugs. Is formed a microorganism growth delay zone of 41 mm,

release rate.

**0**

**50**

**100**

Florimicine released,mg

100(), 200(), 300().

action of drugs over some days.

Eth 35 mm and Fl 29 mm.

*tuberculosis*.

**150**

**200**

PU foams were synthesized by reaction of pre-polymer with isocyanate terminal groups with a small amount of branching agent and water. Other ingredients, such as catalyst and chain extenders, were not used in order to preserve medical purity. The scheme of synthesis is presented below in Fig.9.


**Figure 9.** Scheme of PU foams synthesis.

Antituberculosis drugs Is, ethionamide (Eth), florimicin (Fl) and rifampicin (Rfp) were incorporated as fine crystals in the polymeric matrix at the stage of PU synthesis. The PU contained 100-300 mg of heterogeneously dispersed antituberculosis drugs.

The release of drugs from PU was examined by immersing polymeric samples in a model biological medium (physiological solution, phosphate buffer pH 7.4 and Ringer-Locke solution) at 37°C. The amount of drug released was determined UV-spectrophotometrically by measuring the absorbance maximum characteristic for each drug.

**Figure 10.** Release of Eth from polyurethane foam into Ringer-Locke solution at 37oC. Drug loadings (mg/g PU): 100(), 200(), 300().

All the release data show the typical pattern for a matrix-controlled mechanism. The cumulative amount of drugs released from the PU was linearly related to the square root of time and the release rate decreased with time. The process is controlled by the dissolution of the drug and by its diffusion through the polymer. The release is described by Fick's law and proceeds by first-order kinetics (Philip & Peppas, 1987). The structure of the drugs and their solubility influences the rate of release: the total amount of Is is released in 3-4 days, Eth in 5-6 days (Fig.10), Fl and Rfp in 14-16 days (Fig.11). The release time for 50% of Is is 22- 26 h, for Eth 28-30 h, for Fl and Rfp 72-76 h, respectively. The rapid release of Is and Eth in comparison with Fl and Rfp is due to the higher solubility of these drugs in the dissolution medium. Increasing the drug loading from 100 to 300 mg/g resulted in an increase in the release rate.

162 Polyurethane

culosis treatment.

is presented below in Fig.9.

**Figure 9.** Scheme of PU foams synthesis.

(mg/g PU): 100(), 200(), 300().

Ethionamide released, %**.**

kinetics of drug release are generally controlled by diffusion phenomena through the polymer. Such systems are being used for treatment of tuberculosis-infected cavities (wounds, pleural empyema, bronchial fistula). It is the purpose of this chapter to show the possibility of using polyurethane foams as carriers of some antituberculosis agents for tuber-

PU foams were synthesized by reaction of pre-polymer with isocyanate terminal groups with a small amount of branching agent and water. Other ingredients, such as catalyst and chain extenders, were not used in order to preserve medical purity. The scheme of synthesis




diisocyanate macrodiol prepolymer (R\*)

Antituberculosis drugs Is, ethionamide (Eth), florimicin (Fl) and rifampicin (Rfp) were incorporated as fine crystals in the polymeric matrix at the stage of PU synthesis. The PU

The release of drugs from PU was examined by immersing polymeric samples in a model biological medium (physiological solution, phosphate buffer pH 7.4 and Ringer-Locke solution) at 37°C. The amount of drug released was determined UV-spectrophotometrically

> 01 234 56 Time, days

**Figure 10.** Release of Eth from polyurethane foam into Ringer-Locke solution at 37oC. Drug loadings

contained 100-300 mg of heterogeneously dispersed antituberculosis drugs.

by measuring the absorbance maximum characteristic for each drug.

**Figure 11.** Release of Fl from PU foam into Ringer-Locke solution at 37oC. Drug loadings (mg/g PU): 100(), 200(), 300().

Table 1 presents the values of the diffusion coefficients for drug release into different media, calculated for the initial release stage by a modified Higuchi equation (Higuchi, 1963). With increase of drug loading, the diffusion coefficient is not significantly decreased. This is connected with the plasticizing action of the drug, resulting in the deterioration of the mechanical properties of the polymeric matrix. The medium into which the drugs are released has no significant effect upon the diffusion coefficient.

The release results show that the use of PU as a carrier of antituberculosis drugs provides a controlled release of drugs suitable for use in practical medicine, i.e. it allows prolonged action of drugs over some days.

The tuberculostatic activity of drugs released from the PU was determined by diffusion into dense Levenshtein-Iensen nutrient medium compared with a museum strain of *M. tuberculosis*.

It has been shown that drugs introduced into a polymeric matrix have tuberculostatic activity on the level of free drugs. Is formed a microorganism growth delay zone of 41 mm, Eth 35 mm and Fl 29 mm.


Polyurethane as Carriers of Antituberculosis Drugs 165

6%) and had small ulcers in the place of

2 mm) (Batyrbekov et al., 1997)

8 mm (Eth); 11.

4% and

The experimental observations show that the treatment of tuberculosis in the animals by the polymeric systems gave the same therapeutic effect as daily treatment with single doses of the drugs. The most effective action was displayed by PU containing Is. This is related to its greater tuberculostatic activity in comparison with Eth and Fl. The animals of the PU-Is and Is groups had the dissemination nidi in their inner organs practically cured: guinea pigs lost

The values of weight loss and ulcer dimensions in the place of infection in animals of the

polymeric systems was analogous to daily treatment with free drugs. The use of a PU carrier provides a stable bacteriostatic concentration of chemotherapeutic agents for 5-7 days. Clinical observations have shown the efficiency of PU drug delivery systems for treatment

The results obtained in the present work have shown the possibility of using PU foams as a matrix for drug delivery systems for prolonging the action of chemotherapeutic agents in

PU microparticles containing antituberculosis drugs were prepared by interfacial reaction between PEG and TDI in water in toluene emulsion. Two products of polycondensation were detected: the main product is spherical microparticles with size about 5-10 μm and the second product is fibrils of linear PU, which precipitate in toluene. The increase of PEG content in water phase results in increased amount of the secondary product, and as the PEG content in water phase reaches 60 vol.%, maximum of the secondary product was observed (about 40%). Decreasing PEG concentration in water phase leads to increased yield of PU microparticles. Maximum of yield was reached at PEG concentration 22 - 27 vol.% and in that conditions whole oligomer reacted at surface of emulsion drops with microparticles

The release behavior of drugs from microparticles was carried out and different conditions of synthesis such as water/PEG ratio, molecular weight of PEG and drug concentration was investigated. The increase PEG content in water phase of reaction, results in decreasing drug diffusion, due to formation of PU microparticles with densere polymer wall. Increasing molecular weight of soft segments (PEG) results in the increase of diffusion rate of drug into solution. This phenomenon can be attributed to increasing molecular weight of PEG which leads to accelerating diffusion of water-soluble drug through hydrophilic PEG chains. It was shown that microparticles with higher drug loading demonstrate faster release rate of the drug due to increased gradient of concentrations between the external solution and core of

The tuberculostatic activity of drugs released from the PU show that drugs introduced into PU have antimicrobial activity identical of low molecular drugs. The efficiency of the

4 mm (PU-Eth); 9.0% and 4.

0 mm (Fl). The treatment of experimental tuberculosis by the

2%, cf. untreated 30.

6% and 4.

of tuberculosis-infected cavities (wounds,pleural empyema, bronchial fistula).

2 mm in diameter, cf. untreated 11.

weight slightly (4.

infection (3.

5.

6% and 1.

0 mm and 3.

another groups are following: 8.

2 mm (PU-F1); 11.0% and 5.

tuberculosis treatment.

**6. Conclusion** 

formation.

microparticles.

**Table 1.** Diffusion coefficient (D) values for drug release from polyurethane foams into different media at 37oC for initial stage of release.

The efficiency of tuberculosis treatment by PU containing drugs was studied in experiments on guinea pigs (Batyrbekov et al., 1998). Several groups of animals, consisting of 20-25 guinea pigs, were infected with a 6-week culture of a laboratory strain of *M. tuberculosis.*  Treatment was started 2 weeks after infection. Animals were treated by weekly administration of PU containing 5-day doses of the drugs (PU-Is, PU-Eth or PU-Fl), or by daily administration of a day's dose of Is, Eth or Fl. Animals of the control group were not treated (C). The weights of the guinea pigs and the dimensions of ulcers at the site of infection were periodically determined during the experiment. All untreated animals died 1.5-2 months after infection. The animals of the other groups were killed with 2.5 months after the beginning of the treatment. Guinea pigs were dissected and damage to lungs, livers, spleens and lymphatic ganglions was determined. The efficiency of the applied therapy is presented in Table 2.


**Table 2.** Macroscopic evaluation of damage to inner organs of guinea pigs.

The experimental observations show that the treatment of tuberculosis in the animals by the polymeric systems gave the same therapeutic effect as daily treatment with single doses of the drugs. The most effective action was displayed by PU containing Is. This is related to its greater tuberculostatic activity in comparison with Eth and Fl. The animals of the PU-Is and Is groups had the dissemination nidi in their inner organs practically cured: guinea pigs lost weight slightly (4. 6% and 1. 2%, cf. untreated 30. 6%) and had small ulcers in the place of infection (3. 0 mm and 3. 2 mm in diameter, cf. untreated 11. 2 mm) (Batyrbekov et al., 1997)

The values of weight loss and ulcer dimensions in the place of infection in animals of the another groups are following: 8. 6% and 4. 4 mm (PU-Eth); 9.0% and 4. 8 mm (Eth); 11. 4% and 5. 2 mm (PU-F1); 11.0% and 5. 0 mm (Fl). The treatment of experimental tuberculosis by the polymeric systems was analogous to daily treatment with free drugs. The use of a PU carrier provides a stable bacteriostatic concentration of chemotherapeutic agents for 5-7 days. Clinical observations have shown the efficiency of PU drug delivery systems for treatment of tuberculosis-infected cavities (wounds,pleural empyema, bronchial fistula).

The results obtained in the present work have shown the possibility of using PU foams as a matrix for drug delivery systems for prolonging the action of chemotherapeutic agents in tuberculosis treatment.
