The influence of surfactant on the properties of albendazole-bile salts particles designed for lung delivery

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Abstract

Albendazole is a first line drug for the treatment of several parasitic diseases in humans. Some parasites target the lungs, however lung delivery of albendazole has so far not been reported. We have developed albendazole-based powders suitable for pulmonary delivery, and studied the impact of surfactant on the formulation properties. High-pressure homogenization followed by spray drying was used to produce inhalable particles of albendazole containing the bile salts sodium taurocholate and sodium glycocholate. The process resulted in porous microparticles, that exhibited good spray drying yield (>50%), low moisture contents (<1%) and aerodynamic D90 < 5 μm. The particles showed adequate aerosolization performance either for normal conditions (respiratory fraction > 71%) or conditions that simulate decreased respiratory capacity (respiratory fraction > 49%). The powders did not disturb lung surfactant function. The comparison between both formulations has revealed that the properties of the surfactants affect mainly the particle size of the suspensions and the porosity of the powders. The higher porosity of the albendazole-sodium taurocholate powder led to an enhanced aerodynamic performance of the formulation compared to albendazole-sodium glycocholate. The developed albendazole powders may pave a way for local lung treatment of parasitic diseases.

Introduction

Hydatidosis or human cystic echinococcosis (CE) is a cosmopolitan zoonotic disease that can be found in people and livestock infected with the larval stage of the nematode Echinococcus granulosus [1]. In humans, the outcome of this infection is cyst development in different organ systems, with the liver (65%) and the lungs (25%) being the most commonly affected organs [2,3]. Since lungs have high elasticity, pulmonary cysts grow very fast [4].

Albendazole (ABZ) is the drug of choice for chemotherapeutic treatment of CE [5,6]. It is known that the success of the chemotherapeutic treatment of CE depends on the capacity of the drug to access to the hydatid cyst at adequate concentrations for sufficient periods of time [7]. Since drugs administered by the oral route, once absorbed, access to the liver through the portal vein to be metabolized, this route is useful for treatment of hepatic hydatid cysts. Treatment of pulmonary CE by local administration of ABZ through the pulmonary route has so far been an unexplored alternative. There are several advantages of delivering drugs directly to the lungs, it allows the use of lower doses than those required orally, while it reduces possible side effects and, at the same time, high local concentrations are reached at the site of action [8].

Designing suitable aerosols for inhalation is challenging. Particle size is one of the most important characteristics in dry powder inhaler formulations, together with shape, porosity, density, electrical charge and hygroscopicity [9]. In order to reach the lower respiratory tract and optimize pulmonary drug deposition, the formulations need to have aerodynamic diameters between 0.5 and 5 μm [10]. Once in the respiratory parts of the lungs, particles can interact with components of the lung surfactant (LS) film and this interaction depends on the physical properties of the particles [11].

A widely used method to produce particles for pulmonary delivery is spray drying (SD) [9]. One of the main advantages of this technique is that the characteristics of the resulting particles can be controlled by adjusting the formulation and process parameters [12,13]. This scalable technology is able to process a variety of liquids. If the water solubility of drugs is very low preparation of solutions using organic solvents or aqueous suspensions are some of the available alternatives. The main disadvantage of organic solvents is their toxicity related to the presence of residual solvents in the final product, therefore, aqueous suspensions are preferred [9].

Since suspensions are unstable heterogeneous mixtures, they must be stabilized. One way to stabilize suspensions is by using surfactants. In the literature on pulmonary delivery, bile salts, such as salts of cholate, deoxycholate, glycocholate, glycodeoxycholate, taurocholate and taurodeoxycholate are used [[14], [15], [16], [17], [18], [19], [20], [21]]. Bile salts have other important roles in drug absorption and the aerodynamic properties of powders [14]. Therefore, the selection of the surfactant is a relevant formulation factor.

During the SD process, solid drugs in suspension aggregate and form dried particles with a larger size than the starting material [9]. Hence, in order to obtain microparticles suitable for pulmonary deposition by SD, suspensions need to be previously processed to obtain particles in the nanometric range (e.g. by high-pressure homogenization, HPH).

As mentioned above, to date, no formulations targeting ABZ to the lung have been reported. Therefore, the present study has addressed the production, characterization and comparison of new dry powder formulations based on ABZ and two different bile salts, namely sodium taurocholate (STC) and sodium glycocholate (SGC), for pulmonary delivery. The novel formulations were obtained by processing ABZ-bile salts suspensions by HPH followed by SD. Both formulations were characterized and compared in terms of particle size, surface tension, morphology, powder density, porosity and aerodynamic properties. The effect of the ABZ-bile salt formulations on LS function was also evaluated.

The ABZ-bile salt formulations manufactured and characterized in the present article have the potential for filling the therapeutic niche of treating pulmonary parasitic diseases, such as CE.

Section snippets

Materials

ABZ and lactose monohydrate (both pharmaceutical grade), as well as gelatin capsules number 3 were purchased from Saporiti (Buenos Aires, Argentina). Sieved lactose (+100 ASTM mesh) with D10 = 167.8 μm, D50 = 234.9 μm and D90 = 336.4 μm was used as a carrier. STC and SGC (both analytical grade), were purchased from Sigma Aldrich (St. Luis, MO, USA). Curosurf was produced by Chiesi (Parma, Italy). The unidose RS01 high resistance inhaler (Plastiape, Milano, Italy) and the multidose Turbuhaler

Characterization of the suspensions of ABZ with bile salts

Table 1 shows information about the PSD of the raw ABZ powder and the suspensions before and after the homogenization and sonication processes. ABZ, as supplied, presented a median size of 76.31 μm. By producing a suspension of ABZ with bile salts, an important decrease in the D50 value of ABZ could be observed. Interestingly, the D50 of the initial ABZ-STC suspension was about 3 times larger than the D50 exhibited by the initial ABZ-SGC suspension, suggesting that SGC is more effective as

Conclusions

In the present work, two formulations containing the hydrophobic drug ABZ and the bile salts STC and SGC, for local delivery of ABZ through the pulmonary route, were developed and compared. Both products were obtained by processing aqueous suspensions using simple and scalable techniques, such as high-pressure homogenization and spray drying. Thereby, the use of organic solvents was avoided.

Our results demonstrate that although SGC is a better suspension stabilizer than STC, the formulation

Conflicts of interest

The authors report no conflicts of interest.

Acknowledgments

Secretaría General de Ciencia y Tecnología, Universidad Nacional del Sur (PGI 24/B252), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET, PIP 11220150100704CO), and Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT, PICT-2016-0976.) support this study. Dr. Natalini and Razuc thank CONICET for their postdoctoral fellowships. The authors thank BSC Pharm. W. Starkloff (UNS), Dr. M. Piqueras, Lic. F. Cabrera (PLAPIQUI) and BSC Pharm. R. Pereyra (UNS) for their

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