Journal of Controlled Release 187 (2014) 183–197

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Review

Respirable nanocarriers as a promising strategy for antitubercular drug delivery Mohammed M. Mehanna ⁎, Salma M. Mohyeldin, Nazik A. Elgindy Department of Industrial Pharmacy, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt

a r t i c l e

i n f o

Article history: Received 20 March 2014 Accepted 20 May 2014 Available online 27 May 2014 Keywords: Inhalation therapy Tuberculosis Nanoparticles Liposomes Rifampicin

a b s t r a c t Tuberculosis is considered a fatal respiratory infectious disease that represents a global threat, which must be faced. Despite the availability of oral conventional anti-tuberculosis therapy, the disease is characterized by high progression. The leading causes are poor patient compliance and failure to adhere to the drug regimen primarily due to systemic toxicity. In this context, inhalation therapy as a non-invasive route of administration is capable of increasing local drug concentrations in lung tissues, the primary infection side, by passive targeting as well as reducing the risk of systemic toxicity and hence improving the patient compliance. Nanotechnology represents a promising strategy in the development of inhaled drug delivery systems. Nanocarriers can improve the drug effectiveness and decrease the expected side effects as consequences of their ability to target the drug to the infected area as well as sustain its release in a prolonged manner. The current review summarizes the state-ofthe-art in the development of inhaled nanotechnological carriers confined currently available anti-tuberculosis drugs (anti TB) for local and targeting drug delivery specifically, polymeric nanoparticles, solid lipid nanoparticles, nanoliposomes and nanomicelles. Moreover, complexes and ion pairs are also reported. The impact and progress of nanotechnology on the therapeutic effectiveness and patient adherence to anti TB regimen are addressed. © 2014 Elsevier B.V. All rights reserved.

Contents 1. 2. 3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Respiratory system as a port for drug delivery . . . . . . . . . . . . . . . . . . . Inhaled nanotechnological carriers used for local and targeting of anti-tuberculosis drugs 3.1. Polymeric nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1. Synthetic poly lactic-co-glycolic acid-based nanoparticles . . . . . . . 3.1.2. Natural polymer-based nanoparticles . . . . . . . . . . . . . . . . 3.2. Lipidic nanocarriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. Solid-lipid nanoparticles . . . . . . . . . . . . . . . . . . . . . . 3.2.2. Nanoliposomes . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Nanomicelles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Complexation and ion pairing . . . . . . . . . . . . . . . . . . . . . . . 4. Limitations and drawbacks of nanocarriers in inhalation therapy . . . . . . . . . . . 5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction In recent decades, nanotechnology has been considered one of the most promising drug delivery strategies [1]. According to the National ⁎ Corresponding author at: Industrial Pharmacy Department, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt. E-mail address: [email protected] (M.M. Mehanna).

http://dx.doi.org/10.1016/j.jconrel.2014.05.038 0168-3659/© 2014 Elsevier B.V. All rights reserved.

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Nanotechnology Initiative, nanotechnology is defined as the science used in creation of materials on the nanometer scale [2], while nanomedicine is the application of nanotechnology in medicine for diagnosis, treatment and prevention of diseases using molecular tools and molecular knowledge of the human body [3]. Nanotechnology opens a new avenue in drug delivery represented by the widespread utilization of nanocarriers such as polymeric nanoparticles, nanoemulsions, liposomes, solid-lipid nanoparticles, niosomes,

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nanocrystals, nanosuspensions and nanocapsules either polymeric or lipidic ones [4]. Tuberculosis (TB) is a lethal infectious respiratory disorder which was considered a disease of the past but eventually about 30% of the world populations are afflicted with TB [5]. According to WHO guideline reports, TB is considered the second leading cause of death after the human immune deficiency virus. The recent estimates in 2011 were 9 million incident cases of TB with 1.4 million TB deaths. Most of these cases are in Asia and Africa compared to European and American regions [6]. The incidence of tuberculosis may be increased in case of immunosuppressive patients [7]. Tuberculosis is caused by different strains of Mycobacteria, among them Mycobacterium tuberculosis being the most common strain which may attack any part of the body; 80% of infections are pulmonary TB [8]. Mycobacterium tuberculosis is inhaled in the form of bacilli, which may spread outside the respiratory organ causing extra-pulmonary TB [9]. Tuberculosis treatment represents a challenge requiring prolonged time which may reach several months especially in the case of immunosuppressive patients and those with multidrug-resistance tuberculosis [10]. Tuberculosis is treated by first line antituberculosis drug regimen which includes: isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA) and ethambutol (EMB) [11]. In some cases, multidrug-resistant TB has developed as a result of bacterial resistance to these drugs; treatment of such cases employs second line drugs that include aminoglycoside antibiotics, cycloserine, ethionamide and fluoroquinolones (Table 1) [12]. Using second-line agents for TB treatment is not favored as a result of their many side effects such as hypokalemia, renal toxic effects, GI disturbances, neutropenia and psychosis over the first line drugs [13]. The treatment of active TB needs multi-drug therapy since single drug therapy of TB may result in development of drug resistance [14]. According to WHO guidelines, the standard regimen for TB treatment uses a combination of rifampicin, isoniazid, pyrazinamide, and ethambutol for 2 months followed by using rifampicin and isoniazid for further 4 months [15]. The most common routes of antituberculosis drug administration are the oral and parenteral routes. Although the oral and parenteral therapies are effective in treatment of TB, several studies reported some undesirable side effects leading to treatment interruption [16, 17]. In the case of oral therapy of antituberculosis drugs, prolonged administration of high doses is needed where only small amounts of the dose reach the lung causing side effects as a result of high systemic exposure [18]. For example, rifampicin when taken orally may cause nausea, flu-like symptoms, associated with acute renal failure, hepatotoxicity, and agranulocytosis [19]. Also isoniazid orally may cause convulsive seizures, mental confusion, coma, vasculitis, polyneuritis and hepatotoxicity which result in discontinuation of treatment [20]. Furthermore, the pain and inconvenience use of parenteral route, result

in development of pulmonary drug delivery systems with the idea of increasing local drug concentration in lung and decreasing systemic side effects [21].

2. Respiratory system as a port for drug delivery The lung is the primary gate for several respiratory diseases, this leads to increased attention for treating these diseases through the same pathway of entry [22]. The lung is characterized by advantageous criteria that make it attractive for both local and systemic applications [23]. Lungs have a large surface area (N100 m2) covered with a thin epithelium layer resulting in improvement of drug absorption and efficacy [24]. It is also highly perfused by blood allowing faster absorption of inhaled drugs and onset of action [25,26]. Pulmonary drug delivery systems represent an applicable alternative to both oral and parenteral routes of administration. As this system bypasses hepatic first pass metabolism that occurs upon oral administration, thus reducing the administrated doses which are reflected in side effect reduction and drug bioavailability enhancement [27]. Furthermore, this route has a non-invasive nature ‘free of needle treatment’ and can be selfadministrated easily without any help in contrast to the parenteral delivery system [28]. For inhalation therapy, the deposition of inhaled therapeutic agents in the respiratory airways is one of the crucial prerequisites to produce either their systemic or local therapeutic effects [29]. Many parameters must be taken in consideration to ensure deep lung deposition such as aerosol particle diameter (mass median aerodynamic diameters), shape, density, hygroscopicity and the respiratory system complexity [30,31]. Particle size of pulmonary drug delivery systems plays an important role in the respiratory deposition pattern and absorption profile (Fig. 1), as larger sized particles (diameter N5 μm) are deposited in the oropharynx by impaction, while smaller particles (diameter b 1 μm) are exhaled, leaving a respirable range between 1 and 5 μm to reach the lower airways and deposit efficiently in the lung [24,32,33]. Nanotechnology possesses several merits in pulmonary drug delivery. This technology allows uniform distribution of drugs within the lung and improves their absorption leading to increased drug therapeutic index [3,34]. Moreover, the large surface area of nanocarriers enhances the solubility and the dissolution rate of poorly soluble drugs [26]. As a consequence, different drugs and macromolecules have been successfully explored for pulmonary administration for both local and systemic applications such as insulin [35], itraconazole [36], sildenafil [37], tobramycin [38], azithromycin [38], celecoxib [39], thymopentin [40], beclomethasone [41], phenethyl isothiocyanate [42], budesonide [43], heparin [44] and calcitonin [45].

Table 1 First and second-line anti-tuberculosis drugs [6,15].

First-line drugs

Second –line drugs

Drug

Route of administration

Recommended dose

Isoniazid Rifampicin Pyrazinamide Ethambutol Streptomycin Ethionamide p-Aminosalicylic acid Cycloserine Kanamycin A Amikacin Capreomycin Moxifloxacin Levofloxacin Clofazimine Linezolid Clarithromycin

Orally or I.M. or I.V. Orally or I.V. Orally Orally I.M. or I.V. Orally Orally Orally I.M. or I.V. I.M. or I.V. I.M. or I.V. Orally or I.V. Orally or I.V. Orally Orally or I.V. Orally

5 mg/kg, daily, maximum daily dose is 300 mg 10 mg/kg, daily or 3 times weekly, maximum 600 mg 25 mg/kg, daily 15 mg/kg, daily 15 mg/kg daily, or 3 times weekly; maximum daily dose is 1000 mg 15–20 mg/kg/day, once or twice/day, maximum daily dose is 1 g 4 g, 2–3 times/day, maximum daily dose is 16 g 10–15 mg/kg, daily, maximum daily dose is 1 g 15 mg/kg, daily, maximum daily dose is 1 g 15 mg/kg, daily, maximum daily dose is 1 g. 15 mg/kg, daily, maximum daily dose is 1 g 400 mg/day 500–1000 mg/day, maximum daily dose is 1 g 100 to 200 mg daily 600 mg once daily 500 mg twice daily

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Fig. 1. The number and dimensions of the airways of the adult lung and structure of the airway wall with the generations as explained by Weibel's tracheobronchial tree [24].

Several inhalable nanocarriers for TB treatment have been reported in order to introduce anti-tuberculosis drugs to the lung namely, polymeric nanoparticles, solid-lipid nanoparticles, nanoliposomes, micelles and ionpairs (Table 2). This has encouraged many research groups to manipulate the nanotechnological systems for anti-tuberculosis pulmonary delivery. Our review article is concerned with reporting the impact of nanotechnology on the local pulmonary delivery of drugs used to treat tuberculosis.

3. Inhaled nanotechnological carriers used for local and targeting of anti-tuberculosis drugs 3.1. Polymeric nanoparticles Polymeric nanoparticles (PNP) are defined as sub-micron (1 to 1000 nm) colloidal particles comprising active pharmaceutical

Table 2 Inhaled nanotechnological carriers utilized for of anti-tuberculosis drugs delivery. Nanocarrier

Polymer/lipid

Drug

Inhaled form

Assessments

References

Polymeric nanoparticles

PLGA

Rifampicin, isoniazid, pyrazinamide Rifampicin Rifampicin Clarithromycin Rifampicin isoniazid pyrazinamide Rifampicin, isoniazid, pyrazinamide Isoniazid Rifampicin, isoniazid, pyrazinamide Rifampicin, isoniazid, pyrazinamide streptomycin ethionamide Rifampicin Rifampicin Isoniazid Isoniazid Rifampicin Isoniazid Levofloxacin Pyrazinamide Rifapentine Rifampicin Rifampicin Rifampicin Capreomycin

Nebulized suspension Dry powder Dry powder Dry powder Nebulized suspension Nebulized suspension Dry powder Nebulized suspension Nebulized suspension Nebulized suspension Nebulized suspension Nebulized suspension Dry powder Dry powder Dry powder Dry powder Dry powder Dry powder Nebulized suspension Nebulized suspension Dry powder

In vitro/in vivo In vitro/in vivo In vitro In vitro In vitro/in vivo In vitro/in vivo In vitro In vitro/in vivo

[60] [63,64] [65,66] [67] [62] [71] [73] [81] [90] [91] [92] [94] [97] [98] [99] [100] [101] [102] [103] [115] [116]

Solid lipid nanoparticles Nanoliposomes

Nanomicellles Nano-complex/ion pairing

Lectin/PLGA Alginate Chitosan Stearic acid DSPC/cholesterol Phospholipon 90 PC/cholesterol DPPC SPC/cholesterol

SPC/stearyl amine Stearic acid/polyethyleneimine PEG–DSPE HPβCD RAMEB Oleate, linolenate linoleate

In vitro/in vivo In vitro/in vivo In vitro In vitro In vitro In vitro In vitro/in vivo In vitro/in vivo In vitro In vitro In vitro In vitro/in vivo

Abbreviations; PLGA: poly (lactic-co-glycolic) acid, DSPC: distearoyl phosphatidylcholine, PC: phosphatidylcholine, SPC: soybean phosphatidylcholine, DPPC: dipalmitoyl phosphatidyl choline, PEG–DSPE: poly-(ethylene oxide)-block–distearoyl phosphatidyl-ethanolamine, HPβCD: hydroxyl propyl β-cyclodextrin, RAMEB: randomly methylated β-cyclodextrin.

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ingredients encapsulated within or adsorbed to macromolecular substances (polymer) [46]. PNPs have been widely investigated for drug delivery to the lung [47–50]. These polymers can be classified according to their source whether natural or synthetic polymers [51]. Common examples of natural polymers suitable for pulmonary delivery are chitosan, alginate and gelatin. On the other hand, poly lactic-co-glycolic acid, poly lactic acid, poly anhydride and poly acrylate are examples of synthetic polymers [12]. Polymeric nanoparticles have been synthesized either by dispersion of preformed polymer or monomer polymerization [52]. PNPs have considerable advantages in the treatment of pulmonary diseases by way of providing a controlled and targeted pulmonary drug deposition resulting in enhancing drug bioavailability and improving patient compliance with a possible dose frequency reduction [53,54]. Their smaller sizes also enable the drug to be deeply deposited in the lung and bypass macrophage clearance mechanism [55]. Additionally, polymeric nanoparticles have a higher encapsulation efficiency and a superior storage stability compared to lipidic nanocarriers [56]. 3.1.1. Synthetic poly lactic-co-glycolic acid-based nanoparticles Poly (lactic-co-glycolic) acid (PLGA) is a copolymer, used as a host in Food and Drug Administration (FDA) approved therapeutic devices. Many studies have already focused on using PLGA as a carrier for anti TB drugs owing to its biodegradability and biocompatibility [57]. PLGA is also reported to have a low systemic toxicity, in producing the safest monomer lactic acid and glycolic acid upon its hydrolysis inside the body [58,59]. Pandey et al. [60] demonstrated the possibility of anti TB drug (rifampicin, isoniazid and pyrazinamide) encapsulation within PLGA nanoparticles and evaluated their suitability for pulmonary delivery. Nanoparticles with average size (186–290 nm) and drug encapsulation (57–68%) were prepared using multiple-emulsion technique. After aerodynamic characterization using the cascade impactor, about 96% of the nebulized PLGA nanoparticles were in the respirable range (b6 μm) with a mass median aerodynamic diameter of 1.88 μm, which is appropriate for bronchoalveolar deposition [61]. This outcome predicted a deep deposition of encapsulated drugs in the lung regions. The pharmacokinetic studies showed prolongation in the time needed to attain peak plasma concentration as well as enhancement of the drug bioavailability of nebulized loaded nanoparticles compared to oral administration of the parent drugs as shown in Table 3. Aerosolized drug-loaded PLGA nanoparticles administrated every 10 days, caused no hepatotoxic effect in guinea pig. According to the chemotherapeutic schedule, five doses of nebulized nanoparticles every 10 days for 6 weeks were equivalent to 46 doses of orally administrated drugs. This investigation suggested the probability of using PLGA nanoparticles as an inhalable delivery system for antitubercular drugs. A step towards further improvement of anti TB drug bioavailability using PLGA nanoparticles was performed by Sharma et al. [62], through functionalization of the nanoparticles with lectin. First line anti TB drugs (rifampicin, isoniazid and pyrazinamide) were encapsulated within poly (lactide-co-glycolide) nanoparticles grafted with wheat germ agglutinin (WGA). WGA is considered to have a mucoadhesive property

as a result of its structure that could be recognized by both intestinal and lung tissues. Thus, this property potentiated its action as an oral/ aerosol drug delivery system. In vivo assessments after administration of WGA-coated nanoparticles with average size 350–400 nm and drug entrapment of 54%–66% through oral and aerosol route in guinea pigs showed extended plasma half-life for different anti TB drugs ranging between 6 and 14 days (Fig. 2). Further, it was proved through some chemotherapeutic studies that when WGA coated nanoparticles were administrated to infected guinea pigs (one dose every 15 days) a complete bacterial clearance in lung, liver and spleen was achieved. These results indicated that three nebulized doses of anti TB-loaded lectin-PLGA nanoparticles were therapeutically equivalent to 45 oral conventional doses of anti TB drugs. The authors explained that potentiation and prolongation of anti TB-loaded nebulized nanoparticles by the binding capacity of WGA to the alveolar epithelium maintained drug levels above MIC in the lung enabling the application of the fortnightly schedule of chemotherapy. The previously mentioned studies [60,62] demonstrated the effectiveness of nebulized anti TB-loaded PLGA nanoparticles in pharmacological management enhancement to treat experimentally induced tuberculosis. Sung et al. [63] examined the encapsulation of rifampicin within PLGA nanoparticles formulated using a solvent evaporation method. Porous nanoparticle-aggregate particles (PNAPs) were produced via spray drying of the preformed nanoparticles (Fig. 3). Lung deposition studies showed that these aggregated particles were superior to unaggregated form of the nanoparticles as the latter form was exhaled from the lung due to their small diameter. Animal pharmacokinetic assessment using intratracheal insufflation to guinea pigs was agree with the in vitro release studies, both illustrated that rifampicin was released and maintained its level in lung tissues and cells over 8 h while the free drug was cleared rapidly. This investigation provides evidence that insufflation of PNAPs enabled rapid systemic exposure with extended release of rifampicin with a high local lung concentration. This is attributed to the geometry of the particles being large and porous making them less susceptible to aggregation and vulnerable to de-aggregation under shear force. Although this study lacks in vivo chemotherapeutic testing, it represents an opportunity to use aggregated porous particles for anti TB therapy. RIF loaded PLGA nanoparticles encapsulated in mannitol microsphere in only one step for inhalation therapy of tuberculosis was produced through a four-fluid nozzle spray dryer [64]. The prepared microspheres were compared to RIF-PLGA microspheres that were produced by a traditional two-fluid spray drier. Both RIF-PLGA and RIF-PLGA containing mannitol microspheres were spherical with a mean diameter of 2.1 and 3.2 μm with RIF loading of 100.4 ± 1.0% and 104.0 ± 2.8%, respectively. In vitro aerosol performance of both microspheres was investigated via a cascade impactor. The results revealed that RIF-PLGA containing mannitol microspheres have seven fold higher fine particle deposition in stages 6–7 compared to RIF-PLGA microspheres which indicated the possibility of delivering the drug to the deepest part of the lung. An in vitro uptake study using coumarin 6 as

Table 3 Salient pharmacokinetic parameters following the nebulization of drug loaded PLGA-NP compared to the parent drugs administered orally/IV to guinea pigs [60]. Rifampicin

Cmax (mg/L) Tmax (h) Kel t1-2 (h) MRT (h) AUC0−∞(mgh/L) Relative bioavailability Absolute bioavailability

Isoniazid

Pyrazinamide

Oral

Intravenous

Nebulized PLG-NP

Oral

Intravenous

Nebulized PLG-NP

Oral

Intravenous

Nebulized PLG-NP

1.22 ± 0.30 2.00 ± 0.00 −0.16 ± 0.03 4.30 ± 0.70 6.20 ± 1.00 8.40 ± 1.10 1.00

25.40 ± 4.10 0.02 ± 0.00 −0.39 ± 0.05 1.80 ± 0.30 2.51 ± 0.60 16.50 ± 3.00 –

1.29 ± 0.20 24.00 ± 0.00 −0.01 ± 0.00 69.30 ± 4.00 60.30 ± 4.30 107.00 ± 8.20 12.70

1.71 ± 0.30 2.00 ± 0.00 −0.20 ± 0.00 3.50 ± 0.70 5.50 ± 1.10 10.90 ± 1.80 1.00

28.50 ± 3.10 0.02 ± 0.00 −0.41 ± 0.06 1.69 ± 0.30 2.41 ± 0.70 18.80 ± 2.90 –

5.06 ± 0.80 96.00 ± 0.00 −0.03 ± 0.00 23.10 ± 2.00 98.60 ± 10.20 359.00 ± 22.00 32.80

23.80 ± 2.10 2.00 ± 0.00 −0.13 ± 0.02 5.30 ± 0.60 6.60 ± 1.00 185.00 ± 6.50 1.00

71.10 ± 4.00 0.17 ± 0.00 −0.14 ± 0.02 4.95 ± 0.70 3.86 ± 0,73 202.00 ± 8.10 –

25.60 ± 2.80 96.00 ± 0.00 -0.01 ± 0.00 69.00 ± 4.80 101.20 ± 6.20 2715.00 ± 133,00 14.70

0.51

1.00

6.50

0.58

1.00

19.10

0.92

1.00

13.40

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Fig. 2. Plasma drug levels following single administration of oral/aerosol drug-loaded WGA-conjugated PLG-NPs and free drugs to guinea pigs [62].

a marker showed that the uptake percentage by alveolar macrophage cells of the coumarin/PLGA microspheres and the coumarin/PLGA nanoparticles were 47.1% and 13.5%, respectively. Meanwhile, the in vivo uptake assessment using intratracheal insufflation to rats indicated that encapsulation of RIF-PLGA nanoparticles into mannitol microspheres enhanced the uptake of RFP by alveolar macrophages compared to that of both RIF-PLGA and RIF/MAN microspheres. Using in vivo fluorescent images, the authors noticed that RIF-PLGA nanoparticles were more dispersed for longer period in the lungs of rats than PLGA microspheres (Fig. 4). The in vivo results can be correlated to the presence of mannitol which is a highly water soluble monosaccharide that could be dissolved quickly in the lung fluids releasing RIF-PLGA nanoparticles. These nanoparticles resist clearance by mucociliary mechanism which has made it more available for macrophage recognition and uptake. This investigation provided a convenient technique to produce efficient dry powder system for tuberculosis treatment targeting

alveolar macrophages through a facile technique involving only one step. Trehalose, another saccharide was used to formulate inhalable nanocomposite particles by Tomoda et al. [65] aiming at deep lung deposition followed by decomposition into nanoparticles to overcome the disadvantages of nanoparticle aerosolization performance. The nanocomposite particles were made up with RIF-loaded PLGA nanoparticle additive complex. Initially, the primary RIF-PLGA nanoparticles were prepared by solvent evaporation method then the preformed nanoparticles were added to trehalose solution to construct the nanocomposite particles via spray drying technique. The study of the effect of size, weight ratio of primary nanoparticles and spray dryer inlet temperature on nanocomposite properties revealed that the desired nanocomposite characteristics required an optimum inlet spray dryer temperature that depends on the size of primary PLGA nanoparticles. Nanocompositebased PLGA nanoparticles with a larger size (400 nm) showed complete

Fig. 3. Scanning electron micrographs of spray dried rifampicin porous particle containing 80% nanoparticles by weight [63].

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Fig. 4. (a) In vivo uptake of RIF by alveolar macrophages in lungs of rats after administration of RIF/MAN, RIF/PLGA, and (RIF/PLGA)/MAN microspheres. (b) In vivo fluorescent images of lungs of rats after administration of ICG/PLGA and (ICG/PLGA)/MAN microspheres [64].

decomposition at different inlet spray dryer temperatures (70, 80, and 90 °C) while those based on nanoparticles with smaller size (200 nm) completely decomposed only at 70 °C. Regardless of the weight ratio of primary nanoparticles to trehalose, the optimum inlet temperature for nanocomposites containing larger nanoparticles (400 nm) and those containing smaller nanoparticles (200 nm) were 80 °C and 70 °C, respectively. Furthermore, fine particle fractions and aerodynamic diameter of both nanocomposites prepared (2 μm) predicted deep lung deposition suitable for pulmonary drug delivery. Further investigation was performed by the same group, addressing the technical aspects of the influence of different kinds of binders (lactose and trehalose) used in preparing nanocomposites and the inlet temperature of the spray dryer on the aerodynamic diameter and fine particle fractions of these particles. Results showed that the inlet temperature of the spray dryer affects the decomposition properties of nanocomposites into primary nanoparticles in water. The prepared nanocomposites at 80 °C are considered to have better redispersion efficiency in water after the dissolution of the sugar moiety (trehalose or lactose) than those prepared at a temperature above 100 °C. At higher inlet temperature, the aggregation of primary nanoparticles was observed since the melting point of PLGA particles was lower than that of trehalose or lactose [66]. The difference in performance between lactose and trehalose was not fully discussed. The results of this study are technically favorable but they lack in vivo evaluation as the observed in vitro decomposition may be hindered in the lung or takes place in the trachea or even in the mouth. Clarithromycin, a second line drug, was loaded into PLGA nanoparticles for respiratory drug delivery. Nanoparticles were prepared by emulsification solvent-evaporation technique using polyvinyl alcohol (PVA) as a stabilizing agent [67]. The prepared nanoparticles were

co-spray dried with different sugar-based carries for improving their inhalation performance. PLGA nanoparticles were 78–347 nm in size with 0.08%–7.44% drug loading as a result of using various PVA concentrations and drug/polymer ratios (Fig. 5). In vitro release studies showed that 50% of the loaded drug was released into phosphate buffer (pH 6) at 37 °C during the first 4 h followed by a gradual decline in drug release that remained constant after 2 days. The yield parameter after using mannitol and lactose as inert carriers for PLGA nanoparticles was 22.50 and 32.87%, respectively. An increase in the yield of the spray drying process upon incorporation of L-leucine as a third component to prevent the stickiness behavior was observed. The in-vitro aerosolization of the co-spray dried powders showed that the presence of leucine increased the fine particle fractions from 19.88 to 52.38%. This was explained as a result of decreasing particle surface cohesiveness and particle interactions. It was apparent that the nano-microcarrier system could provide a sustained pulmonary drug delivery. 3.1.2. Natural polymer-based nanoparticles Among the naturally occurring polymers, numerous studies reported that alginates and chitosan are the most popular polymers used in pulmonary drug delivery systems. Chitosan and alginate polymers possess attractive features, namely biocompatibility, low toxicity, biodegradability, and being approved by the FDA for oral use [68,69]. Additionally, as a result of chitosan cationic nature, it has mucoadhesive properties and considered to be a permeation enhancer [70]. Microencapsulation of chitosan nanoparticles has been widely used for pulmonary drug delivery [71]. Pourshahab et al. [72] prepared isoniazid loaded chitosan/tri-poly phosphate (TPP) nanoparticles via ionic gelation method. The resulting nanoparticles with chitosan/TPP 3:1

Fig. 5. Scanning electron micrographs of clarithromycin loaded polymeric NPs: (a) Large agglomerates were produced upon using 0.25% w/w PVA; (b) large particles were obtained when the amount of polymer increased and (c) small particles were seen when doubling the concentration of PVA (0.5% w/w) [67].

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ratio were 248 nm in size with a polydispersity index of 0.191, a zeta potential of 37.7 mV and encapsulation efficiency of 13%. By increasing chitosan/TPP weight ratio to 6:1, particle size and drug encapsulation were raised to 449 nm and 17%, respectively. These nanoparticles were encapsulated by a spray dryer into carbohydrate carriers (mannitol, lactose and maltodextrin) with or without leucine. The addition of leucine before spray drying improved the process yield from 33.5% to 52.5, 23.1% to 35.3% and 19.7% to 29.8% when using lactose, mannitol and maltodextrin carriers, respectively. The incorporation of leucine was found to decrease the particle size of inhalable powder and cause some modification in the particle shape (Fig. 6). The release profile of isoniazid in phosphate buffer saline (pH 7.4) at 37 °C from produced nanoparticles was characterized by an initial burst effect up to 4 h followed by a sustained release for 6 days. In vitro aerosol performance of inhalable isoniazid-loaded nanoparticles demonstrated that fine particle fraction when using lactose (45%) was higher than that of mannitol (24.5%) and maltodextrin (16.23%) making it suitable for aerosol delivery to the lung. Despite these technical results, the study lacked in vivo and chemotherapeutic evaluations. Zahoor and his co-workers [73] produced an inhalable drug delivery system made of sodium alginate in order to reduce the toxicity related to other delivery systems. Alginate nanoparticles encapsulating RIF, INH and PZA were formulated using the cation-induced controlled gelification technique, which is a solvent-free, simple and inexpensive method. The study showed that the prepared nanoparticles were 235.5 nm in size with polydispersity index of 0.439. Drug encapsulation within alginate nanoparticles ranged between 80 and 90% for RIF and 70–90% for INH and PZA. In vitro aerosol performance of nebulized alginate nanoparticles showed that 80.5% had an aerodynamic diameter of 0.4–2 μm making them suitable for pulmonary drug delivery. In vivo pharmacokinetic and pharmacodynamic studies proved that the respirable alginate nanoparticles had higher relative bioavailability compared to oral free drug. Following the aerosol administration, the encapsulated drugs were maintained in the plasma for 14, 10 and 14 days for INH, RIF and PZA, respectively and in the tissues (lung, liver and spleen) for 15 days whereas free drugs were cleared from the circulation within 12–24 h. Chemotherapeutic efficacy of three doses for 15 days of nebulized alginate nanoparticles against experimental tuberculosis in guinea pigs indicated no detectable Mycobacterium colony forming units (CFUs) compared to untreated controls with no observed hepatotoxic effect. Thus, the authors suggested that alginate-based nanoparticles encapsulating antitubercular drugs could

I

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be used safely in treatment of tuberculosis infection through inhalation therapy. 3.2. Lipidic nanocarriers 3.2.1. Solid-lipid nanoparticles Solid-lipid nanoparticles (SLN) are colloidal lipidic nanocarriers ranging in size from 40 to 1000 nm consisting of a solid core made of biodegradable physiological lipids coated with surfactants for stabilization [74]. SLNs are obtained by two main approaches either high-pressure homogenization or micro-emulsion technique [75,76]. Recently, solid-lipid nanoparticles have been adapted as an alternative to other nanocarrier systems for pulmonary delivery [77] since it showed prolonged physical stability and high drug incorporation compared to those of liposomes [78]. Furthermore, in contrast to polymeric nanoparticles, their toxicity profile is considered safer, since among their production methods, they demand small amount of organic solvent and their core comprises physiological lipids, which exhibits lower cytotoxicity and higher tolerability [79,80]. Pandey and Khuller [81] investigated the encapsulation of the first line anti TB drugs (rifampicin, isoniazid and pyrazinamide) within solid-lipid nanoparticles prepared via emulsion solvent diffusion method and assessed their chemotherapeutic potentials in the guinea pig tuberculosis model. The entrapment efficiency was 51, 45 and 41% for RIF, INH and PZA, respectively. In vitro release studies in simulated gastric fluid during 72 h showed that about 12% was released from the drugs. This can be explained as the more lipophilic the drug was, the slower the drug was released. Aerodynamic characterization of nebulized solid-lipid nanoparticles using Anderson cascade impactor revealed that the majority were in the respirable range (b6 μm) with a lower mass median aerodynamic diameter indicating delivery of encapsulated drugs into bronchoalveolar regions. In vivo drug deposition studies showed that drug concentration in plasma was detectable after 45 min and up to 5 days after single nebulization of drug-loaded SLN into guinea pigs. Moreover, encapsulated drugs were observed in the lung, spleen and liver up to 7 days while free drugs were cleared from these organs in 24–48 h. Before the beginning of chemotherapy, the count load of colony forming units (CFUs) after infection with M. tuberculosis H37Rv was 2.8 logs. Seven doses of weekly-aerosolized drug loaded solid-lipid nanoparticles to infected guinea pigs resulted in undetectable CFU. In order to achieve the same consequences with conventional therapy, 46 doses were required. Thus, conventional

II

Fig. 6. I. Scanning electron micrographs of spray dried microparticles containing lactose (a), mannitol (b), maltodextrin (c). II. Scanning electron micrographs of spray dried microparticles containing lactose + leucine (a), mannitol + leucine (b), maltodextrin + leucine(c) [72].

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therapy may be reduced to 7 nebulized doses resulting in improved patient compliance with no hepatotoxic effects. 3.2.2. Nanoliposomes Liposomes are considered to be one of the oldest and simplest drug delivery systems for the treatment of pulmonary infections [82]. Liposomes are spherical colloidal vesicles, 0.02–10 μm in diameter, composed of phospholipid bilayer encapsulating an aqueous core [83, 84]. Phospholipids are based on natural or synthetic sources; the most popular phospholipids used are phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol and phosphatidylserine [85]. Liposomes have been prepared through many techniques including film hydration, reverse phase evaporation, solvent injection and freeze thaw extrusion methods [86,87]. According to the liposome phospholipid structure, they are capable of loading both hydrophilic and lipophilic drugs [81]. Liposomes also provide controlled and targeted drug delivery to the lung which results in increasing drug concentration, reducing dose frequency and improving patient compliance [88]. Further, liposomes are composed of phospholipids similar in structure to that of pulmonary surfactants making them safe and decreasing local irritation of the lung tissue [89]. Justo and Moraes [90], developed liposome encapsulating antitubercular drugs (isoniazid, pyrazinamide, streptomycin, rifampicin, and ethionamide) for direct delivery to the lung. Large unilamellar vesicles with a mean diameter of 360 nm and encapsulation extent of 2, 2.5 and 42% for pyrazinamide, isoniazid and ethionamide, respectively were prepared. On the other hand, both rifampicin and streptomycin didn't efficiently encapsulate within the prepared vesicles as both drugs are characterized by high molecular weight and bulky structure, which interfered with their entrapment in the liposomal structure.

After storage for 3 weeks at 5 °C, isoniazid-loaded liposomes exhibited good stability in contrast to either pyrazinamide- or ethionamideloaded liposomes as a result of difference in drug structure as well as their partition coefficients (Fig. 7). Further, liposome storage in the presence of surface active agents did not affect the integrity of the liposomes. The authors didn't scientifically discuss the observed stability of the liposomes in the presence of non-ionic surfactant solution, although they mentioned the formation of mixed micelles. In addition, neither aerodynamic characterization nor in vivo chemotherapeutic evaluation was carried out for the obtained nanoliposomes. Moreover, liposomes were used for pulmonary passive targeting by Zaru et al. [91], who planned to develop rifampicin-loaded liposomes made of phospholipon 90®, soy lecithin and cholesterol prepared via the film hydration method followed by freeze drying. The obtained liposomes appeared as multilamellar vesicles with 78% entrapment efficiency, 185 nm average size and 0.24 PDI. The reported high entrapment efficiency was attributed to the multilamellar nature of liposomes unlike the results of Justo and Moraes [90]. The authors reported that the freeze-dried samples showed a higher entrapment efficiency compared to the sonicated vesicles. This observation was initially due to the dialysis step as rifampicin diffused more rapidly from SUVs than from MLVs not merely as a result of drug location within the liposomal bilayers. Liposome stability after nebulization was studied using a modified 2-stage glass impinger. Findings showed an increase in their mean size as a result of partial liposome disruption. Additionally, calculated nebulization efficiency was more than 50% and drug content after nebulization was 65% predicting stability. In vitro performance against Mycobacterium avium revealed complete inhibition (100%) of bacterial growth with lowest liposomal drug concentration (0.05 μg/ml) whereas free rifampicin drug exhibited 80% reduction in bacterial growth.

Fig. 7. Variations in (a) the hydrodynamic diameters and (b) the final drug-to-lipid molar ratios of liposomes containing isoniazid, ethionamide, and pyrazinamide prepared at initial drugto-lipid-molar ratios of 13.3, 0.1 and 13.3, respectively, storage at 5 °C [90].

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After nebulization of rifampicin-loaded liposomes into rats using noseonly exposure chamber, it showed deep deposition in lung airways in comparison with the free drug suspension. The in vivo model used was aimed at evaluation of the carrier deposition in the lung not the therapeutic effect in an infected animal model. In another approach, Pandey and his collaborators [92], developed a respirable multilamellar liposome encapsulating RIF/INH and containing phosphatidyl choline and cholesterol as bilayer lipid-forming components with a molar ratio (2:1.5). The encapsulation extent was 40–45% and 8–12% for RIF and INH, respectively. The in vitro aerosol efficacy evaluation showed that liposomes had a mass median aerodynamic diameter equal to 0.96 ± 0.06 μm and geometric standard deviation of 2.3 ± 0.4 μm indicating the suitability of the prepared liposomes for pulmonary delivery. Biodistribution studies of nebulized liposomal drugs (RIF/INH) in comparison with either nebulization or IV injection of free drug were performed on Dunkin Hartley guinea pigs. The results showed that the accumulation of anti TB drugs in the lung were 0.25 and 0.29 μg/ml for RIH and INH, respectively. In the alveolar macrophages after their isolation by bronchoalveolar lavage, their accumulation rates were 0.15 μg/105 cells and 0.1 μg/105 cells for RIH and INH, respectively, proving the ability of aerosolized liposomal drug to reach and target the alveolar macrophages which are the primary location of the bacilli. In contrast to the nebulized/IV free drugs that were unable to be detected in the lungs or macrophage beyond 48 h, nebulized liposomal drugs remained for 5 days after nebulization. Pharmacokinetic parameters indicated that absolute bioavailability of aerosolized liposomes encapsulated drug was 1.2 folds higher than that of aerosolized free drug and the same as that of IV free drug. Moreover, nebulization of liposomal drug increased both the half-life (t1/2) and the mean residence time compared to other formulas while the peak plasma concentrations were nearly the same or lower than that of nebulized/IV free drug. Finally, in contrast to free drugs, liposome encapsulated drugs showed a sustained plasma drug level after 45 min from single nebulization up to 48 h. Although the study provided positive outcomes encouraging the use of liposomes in TB inhalation therapy, it lacks stability studies and clinical evaluation of the prepared liposomes. One of the features of advanced stages of pulmonary tuberculosis is the development of atelectasis (alveolar collapse) as a result of lung surfactant deficiency [93]. Chimote and Banerjee [94] evaluated the synergistic action of isoniazid-loaded dipalmitoyl phosphatidyl choline (DPPC) based liposome as exogenous pulmonary surfactant and respirable drug delivery system for TB treatment in an attempt to solve this problem. The vesicle had a mean diameter 755.16 nm with narrow size distribution (0.2 PDI) and 36.66% entrapment efficiency. In vitro release profile revealed a slow and sustained release of isoniazid from

(a)

191

DPPC liposomes over 24 h whereas free drug exhibited a complete release after 6 h. Upon nebulization of isoniazid loaded-DPPC liposomes in glass twin impinger, 25–27% was deposited in the lower impinger chamber. These characteristics enabled the use of isoniazid-loaded DPPC liposomes for inhalation therapy. Based on lung surfactant function, isoniazid-DPPC liposomes expanded the collapsed airways allowing the drug to be deeply deposited in these airways; this property was evaluated using a capillary surfactometer. It also possessed a faster adsorption at the pulmonary air–aqueous interface with a decrease in surface tension in comparison with commercial lung surfactants. Moreover, stronger antimycobacterial activity, in vitro cytocompatibility and hemocompatibility were obvious leading to the conclusion of the suitability of using isoniazid-DPPC surfactant-based liposome as an inhaled drug therapy for treatment of late stages of TB infection. For enhancing the stability of liposomal dispersions, lyophilization and spray drying techniques were applied in order to prepare more stable dry form of liposomes that can be inhaled via powder inhalers [95, 96]. Changsan et al. [97], demonstrated rifampicin encapsulation within liposomes followed by freeze drying in the presence of cryoprotectants to develop stable dry RIF-loaded liposomes as an alternative system for pulmonary delivery. Multilamellar liposomes with an average size of 200 nm were produced with various ratios of phosphatidylcholine and cholesterol through film hydration method (Fig. 8). Encapsulation of rifampicin was raised from 33 to 52% as a result of increased lipid content ratios. Moreover, liposomes prepared with higher cholesterol contents exhibited better physical size stability because of the increased rigidity and decreased fluidity of the liposomal bilayers. The location of RIF within the prepared liposomes was mainly dependent on cholesterol concentration as revealed by solid NMR investigations. Upon using mannitol as a cryoprotectant, freeze-dried powders were crystalline in nature in contrast to using lactose or trehalose, where prepared powders were amorphous (Fig. 9). After storage for 6 weeks at 4 °C, freeze-dried liposomes revealed a good stability in comparison with both rifampicin-loaded liposomal dispersion and RIF aqueous solution. Aerosolized efficacy of freeze-dried liposomal powder using mannitol showed the lowest mass median aerodynamic (3.4 μ m) with the highest fine particle fraction (66.8%), enabling the delivery of the drug deep into the lung. This study represents a significant step towards better understanding of the interaction between liposomal bilayers and RIF and its effect on encapsulation efficiency. Despite that, further studies are required in order to shed more light on the in vivo performance of the prepared liposomes and their chemotherapeutic effects. Proliposome free-flowing dry powder denotes another strategy to overcome the stability limitations associated with ordinary liposomal dispersions [97]. Proliposomes loaded with isoniazid and levofloxacin were

(b)

Fig. 8. Cryo-transmission electron microscope image of liposome dispersion (a) and liposome vesicles reconstituted from freeze-dried liposome powder (b) [97].

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(a)

(b)

Fig. 9. (a) DSC thermograms of liposomes dried with different sugars and (b) XRD pattern of dry powders of liposomes encapsulated with RIF [97].

prepared using the spray drying method. Proliposomes, composed of isoniazid and phospholipids was adsorbed on microporous mannitol as a core carrier with different ratios were converted into liposomal dispersion after reconstitution with water. The mean sizes of vesicles ranged from 300 to 1000 nm and encapsulation efficiency was 18–30%. INH-proliposome aerosol performance was evaluated using a cascade impactor exhibiting a mass median aerodynamic diameter (b 5 μm) and fine particle fraction (15–35%). Cell culture studies showed that INH-proliposome mimics the free INH induced toxicity on respiratory epithelial cell with no observed toxicity for mannitol. The prepared proliposomes were immunologically passive as they were unable to activate the alveolar macrophages to produce inflammatory mediators. Furthermore, the encapsulation of INH in liposomes showed a better permeation resulting in higher antimycobacterial effect against Mycobacterium bovis but equivalent activity towards M. tuberculosis compared to free INH [98,99]. The same procedure was followed for the preparation of levofloxacin-loaded proliposomes and comparable results were obtained with no obvious differences [100]. A recent investigation by the same authors, Rojanarat et al. [100], evaluated the in vivo toxicity of the pulmonary delivery of pyrazinamide proliposomes in male Wistar rats; the findings showed no evidence for neither renal nor hepatic toxicity after their administration by intratracheal instillation through 28 days. Additionally, it was found that PZA proliposomes were rapidly phagocytocized by NR8383 cells within 2 min using a fluorescence microscope. These investigations suggested that proliposomes were considered a promising delivery system for tuberculosis infection treatment. The authors did not challenge the obtained results with an in vivo model which represents a weak point in their studies. Manipulation of inhalable proliposome powder preparation method was carried out by Patil-Gadhe and Pokharkar [101], who focused on implementing a new fast, single step spray drying technique. The prepared proliposomes were optimized by a systematic method known as quality by design developing a modified Ishikaw diagram. Optimized rifapentine, a novel semi-synthetic rifamycin analog, was

loaded on proliposomes with an average size of 578 nm and encapsulation efficiency of 72.08%, were developed with a drug/hydrogenated soya phosphatidylcholine ratio at 1:2 and stearylamine as a chargeinducing agent. The prepared rifapentine-loaded proliposomes were spherical with smooth surface in contrast to the lipid free spray dried rifapentine with rough surface. In vitro lung deposition study showed that 92% of prepared liposomes were in the respirable range with mass median aerodynamic diameter of 1.56 μm. In contrast to the free drug that was completely released after 4 h, optimized proliposome revealed a sustained drug release over 24 h. It was apparent in the pharmacokinetic studies that the optimized formula improved drug bioavailability (14 fold increases) and elongated the mean residence time and t1/2 (7 fold increases) compared to pure drug. This enhancement was explained on the basis of distribution pattern modification by the proliposomal preparation although the mentioned volume of distribution did not reflect this enhancement. Further mechanistic investigations are required to fully elucidate the reasons for the reported pharmacokinetic differences. 3.3. Nanomicelles Mixed micelles are kinetically stable system based on lipid-polymer mixture in order to possess the advantages of both lipidic and polymeric nanocarriers. In a recent investigation, Vadakkan and his co-workers [102] had demonstrated the possibility of using lipopolymeric nanomicelle as a carrier for anti TB drugs. Nanomicelles with average size (218 nm) and zeta potential (16.7 mv) were developed by covalent linkage between stearic acid and amino group of branched polyethyleneimine. Spray-dried RIF-loaded nanomicelles were spherical with drug load of 99% and release of 85% over 24 h. In vitro lung deposition revealed about 68% of dried nanomicelles in the inhalable range with aerodynamic diameter 2.31–2.45 μm in contrast to the free drug. Further, in vitro cytotoxicity using cell viability assay of the lipopolymer conjugation after incubation with THP-1 differentiated to

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aerosolization performance of the freeze-dried form was not carried out to be compared with that of the rehydrated micelles.

3.4. Complexation and ion pairing

Fig. 10. Rifampicin permeability measured for an initial rifampicin concentration of 0.34 mM in the presence of 0.066 M of free HPβCD or 0.076Mof free RAMEB [115].

macrophage proved their safety and biocompatibility in which 80% of cells were viable. The cellular uptake studies demonstrated an evidence for the existence of non-endocytic entry of the nanomicelles. Their cationic property can help in targeting the bacilli lodge in the phagosome of alveolar macrophage through proton sponging effect [102]. Abdulla et al. [103] demonstrated the possibility of using poly(ethylene oxide)-block–distearoyl phosphatidyl-ethanolamine (mPEG–DSPE) as a pulmonary drug delivery carrier. The resulting rifampicin loaded mPEG–DSPE nanoparticles were 162–395 nm in size, polydispersity index of less than one with an encapsulation efficiency range from 83.5% to 103.9% depending on molecular weight, the ratio of hydrophobic segment to hydrophilic segment and crystallinity of the copolymer. As a result of rifampicin entrapment in the copolymer matrix, glass transition temperature of mPEG–DSPE in the differential scanning calorimetry thermograms was shifted to a lower value due to the presence of rifampicin compared to the unloaded nanoparticles. Reference rifampicin lyophilized powder was released after 24 h, while the encapsulated rifampicin showed a slower release rate over a 3 day period following a first-order kinetic and Higuchi diffusion model. The slower release rate was the result of hydrophobic interaction between the drug and copolymer micelle. Thus by increasing polymer to drug ratio, the release rate was slower where the T50% values of polymer to drug ratio (1:10) and (1.5:10) were 16.52 and 20.88 h, respectively. To ensure deposition of these nebulized nanoparticles deeply in the lung, their aerodynamic characterization was evaluated using next generation impactor which showed 40.8% of drug deposited in stage 3 and below with mass median aerodynamic diameter of 2.6 μ m. The prepared nanostructures are micelles although the authors termed them as nanoparticles. Moreover, the prepared micelles were freeze-dried then rehydrated again for no apparent reason. The

Complexation with cyclodextrins (CDs) represented an interesting approach investigated to improve the pulmonary drug delivery [104, 105]. CDs are cyclic oligosaccharides made of 6 or more (α-1, 4)-linked α-D-glucopyranose units [106]. The molecule exists as a truncated cone where the outer surface is considered to be hydrophilic while the central cavity has a hydrophobic character [107]. This structure accommodates CDs to form inclusion complexes with many lipophilic drugs [108–111]. Complexation of drugs with CD offers many merits in the inhalation therapy; in other words, CD complexes improve the solubility of the poorly soluble drugs leading to faster onset of action. It was also obvious that this complexation had been able to reduce drug-induced lung irritation [112]. Further, size population of CD (hydrodynamic diameter b 1 nm) enables deep deposition in the lung and reduces the alveolar drug clearance [113,114]. The complexation of rifampicin with different cyclodextrin derivatives namely, hydroxyl propyl β-cyclodextrin (HPβCD) and randomly methylated β-cyclodextrin (RAMEB) and the evaluation of their suitability for use as an alternative pulmonary delivery system was investigated [115]. Solubilization process of rifampicin in the presence of 5% w/v of HPβCD or RAMEB was pH-dependent. According to phase solubility studies, a hypothesis of 1:1 RIF/CD complex was conducted only in the concentration ranges of 0–0.23 M and 0–0.066 M for RAMEB and HPβCD, respectively, whereas RIF solubility showed a linear increase within these concentration ranges. With the intention to evaluate the nebulization efficiencies of both RIF/CD derivative complexes, their aerodynamic performance was measured using a 7-stage cascade impactor. The results pointed out that 70% of the generated aerosols for both derivatives were in the respirable range (1–5 μm), RIF/HPβCD complex as well exhibited larger nebulization efficiency (64.8%) and smaller mass median aerodynamic diameter (2.36 μm) than those achieved for either RIF/RAMEB complex or free RIF suggesting deep rifampicin lung deposition. The effect of complexation on RIF bacteriostatic activity was assessed by determination of the minimum inhibitory concentration (MIC) in A. baumannii. Minimum inhibitory concentration (MIC) values for RIF/RAMEB were (17.5–35 μg/mL) showing almost the same activity as that of free RIF otherwise, RIF/HPβCD complexes showed more pronounced bacteriostatic activity with a significant decrease in MIC values to 3.75–7.5 μg/ mL. Finally, the permeation of RIF/CD through lung epithelium was estimated using a Calu-3 cell layer epithelial alveolar model (Fig. 10). Complexation with either HPβCD or RAMEB reduced rifampicin transcellular transport (1.4 times) in comparison with free rifampicin, which represents an advantage since the accumulation of RIF inside the alveoli

Table 4 Susceptibility studies on Mycobacterium tuberculosis [116]. Capreomycin (5 μg/mL)

Mycobacterial inoculum

Control-drug free (medium number of mycobacterial colonies ± st. dev./quadrant)

Treated (medium number of mycobacterial colonies ± st. dev./quadrant)

CS

10° 10−2 10−4 10° 10−2 10−4 10° 10−2 10−4 10° 10−2 10−4

+(Confluent) +(306 ± 21) +(38 ± 6) +(Confluent) +(304 ± 15) +(33 ± 2) +(Confluent) +(308 ± 27) +(39 ± 6) +(Confluent) +(307 ± 22) +(35 ± 3)

+(62 ± 4) − − +(318 ± 17) − − +(69 ± 10) − − (Confluent) +(51 ± 9) −

CO

CL

CLn

CS, capreomycin sulfate; CO, capreomycin oleate; CL, capreomycin linoleate; CLn, capreomycin liolenate.

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through reducing its systemic absorption leads to enhancement of RIF pharmacodynamics, as it is concentration-dependent. On the other hand, complexation increased the rifampicin concentration in bronchoalveolar epithelium lining fluid improving its antibacterial activity. This study dealt with the treatment of multidrug resistant bacteria in nosocomial infections with nebulized RIF-CD complexes but it lacks both in vivo and chemotherapeutic evaluations. Schoubben et al. [116] had demonstrated a simple strategy to produce inhalable powder suitable for pulmonary drug delivery. In this study, capreomycin hydrophobic ion pairs were prepared by combining drug and three fatty counter ions (oleate, linolenate and linoleate) in different solvent mixtures tailored to minimize their systemic absorption and intensify their intracellular concentration. These combinations were then dried using two instruments (mini spray dryer and nano spray dryer) to obtain respirable fine powders used as supergenerics. It was found that the nano spray dryer was more efficient than the mini spray dryer in the method of preparation. The nano spray dryer produced hydrophobic ion pairs with small particle sizes (35.50 nm, 145.5 nm and 82.40 nm for capreomycin oleate, capreomycin linoleate and capreomycin linolenate, respectively) and high yield processes (53.5%, 39.1% and 43.4% for capreomycin oleate, capreomycin linoleate and capreomycin linolenate, respectively). By comparing the aerodynamic diameter properties and the morphological characters of the three hydrophobic ion pairs, the authors found that capreomycin oleate provided considerable characteristics for inhalation therapy. Additionally, antimycobacterial activity was evaluated using the agar proportion susceptibility test. As opposed to capreomycin linolenate, the oleate and the linoleate exhibited the highest efficacy on M. tuberculosis inhibition (Table 4). In vivo toxicity studies using chicken chorioallantoic membrane assay exhibited that capreomycin oleate had the lowest toxic effect 48 h after treatment, 30% only of chicken embryos were died in comparison to the single component (capreomycin) that caused 50% death. It was suggested that capreomycin oleate could be used as inhalable powder for tuberculosis treatment. This promising safety profile of capreomycin ion pair should be weighed up in animal models and clinically since the drug was reported to exert nephro- and ototoxicity in humans. 4. Limitations and drawbacks of nanocarriers in inhalation therapy Recently, arguments about the pros and cons of nanocarrier usage in inhalation therapy have been elaborated [117]. Many evidences have demonstrated the hazards of inhaled nanocarriers as well as their benefits. The same attractive criteria of using nanocarriers as a pulmonary drug delivery system viz., size, surface area, shape, biodegradability, solubility, bioavailability and chemical composition could represent threatening drawbacks through promoting their potential toxicity [118–120]. Nanoparticle toxicity is controlled by its size as the smaller the size, the more toxic effects it exerts. It was found that the clearance of nanocarriers mediated by alveolar macrophages is impaired as a result of nanoparticle size. This phenomenon allowed long-term accumulation of inhaled nanocarriers in the lung, followed by deeper penetration into pulmonary tissues and interaction of particles with lung epithelial cells and macrophages, which may lead to many toxic pulmonary issues such as pulmonary inflammation, fibrosis and lung cancer [77,121]. Many studies as well have elucidated that the shape and chemical compositions of the inhaled nanocarriers influence their cytotoxicity [122]. Dailey et al. [123] reported that respirable biodegradable nanoparticles made from PLGA and amine-modified branched polyester had a lower inflammatory potential compared to to that of non-biodegradable polystyrene nanoparticles. Cellular toxicity studies of SLN in murine peritoneal macrophages showed that stearic acid-based SLN exerted a notable cytotoxicity relative to other SLNs composed of different lipid materials [124]. On top of this, nanoparticle toxicity may be linked to the excipients utilized during their formulation. For instance, it was found that

different surfactants used during inhaled nanocarrier preparation, play a substantial role in increasing their toxicity [125,126]. Additionally, inhaled nanocarrier toxicity and adverse effects may be due to translocation and delivery to the extrapulmonary organs such as liver, spleen, heart and brain after their administration [127,128]. This observed translocation can be done by cellular endocytosis, transcytosis, neuronal, epithelial and circulatory distribution [34]. It was reported that inhaled carbon nanoparticles can cross the blood brain barrier and migrate to the brain and can also reach the systemic circulation causing severe cardiovascular effects [129]. So, safety and toxicological issues of nanocarriers for pulmonary applications require full concern. More mechanistic studies are required in order to thoroughly understand the complex nature of nanocarrier influence on biological systems. 5. Conclusion Despite the fact that tuberculosis infection is a historic disease, contemporary, more than nine million patients still suffer; most of them are in the developing countries. The ubiquitous spread of various nanocarriers and their modifications resulted from their unique characteristics and ability to alter loaded-drug physicochemical properties and pharmacokinetics. Inhalation of drug-loaded nanocarriers offers a potential value in local and passive delivery of antituberculosis therapy. Nanocarriers loaded with antitubercular drugs have been found to be more effective consequently, representing an emerging platform for the potential delivery of anti TB drugs to the primary site of infection, the lung. Currently, advances and manipulation of these carriers generate more pronounced influence not only on drug effectiveness and therapeutic potential but also, on patient compliance and recurrence rate. Till today, the presence of well-established anti TB regimens did not prevent tuberculosis from occupying the first place in preventable death causes. This is due to the current therapy faults as many anti TB drugs have low solubility and instability issues resulting in low bioavailability. The authors believe that one of the gates that may help in solving this dilemma is the utilization of various nanotechnological carriers in anti TB therapy. In the near future, inhalable nanocarriers loaded with anti TB drugs will provide a key to overcome such administration limitations paving the way for successful curative anti-tuberculosis therapy. References [1] S.K. Sahoo, V. Labhasetwar, Nanotech approaches to drug delivery and imaging, Drug Discov. Today 8 (2003) 1112–1120, http://dx.doi.org/10.1016/S13596446(03)02903-9. [2] S.K. Sahoo, S. Parveen, J.J. Panda, The present and future of nanotechnology in human health care, Nanomedicine 3 (2007) 20–31, http://dx.doi.org/10.1016/j. nano.2006.11.008. [3] M.L. Forrest, G.S. Kwon, Clinical developments in drug delivery nanotechnology, Adv. Drug Deliv. Rev. 60 (2008) 861–862, http://dx.doi.org/10.1016/j.addr.2008. 02.013. [4] L. Mei, Z. Zhang, L. Zhao, L. Huang, X.-L. Yang, J. Tang, S.-S. Feng, Pharmaceutical nanotechnology for oral delivery of anticancer drugs, Adv. Drug Deliv. Rev. 65 (2013) 880–890, http://dx.doi.org/10.1016/j.addr.2012.11.005. [5] A. Sosnik, Á.M. Carcaboso, R.J. Glisoni, M.A. Moretton, D.A. Chiappetta, New old challenges in tuberculosis: potentially effective nanotechnologies in drug delivery, Adv. Drug Deliv. Rev. 62 (2010) 547–559, http://dx.doi.org/10.1016/j.addr.2009. 11.023. [6] Global tuberculosis control: surveillance, planning, financing: WHO report 2012, http://apps.who.int/iris/bitstream/10665/75938/1/9789241564502_eng.pdf 2012. [7] N. Padayatchi, G. Friedland, Decentralised management of drug-resistant tuberculosis (MDR- and XDR-TB) in South Africa: an alternative model of care, Int. J. Tuberc. Lung Dis. 12 (2008) 978–980. [8] P. Muttil, C. Wang, A.J. Hickey, Inhaled drug delivery for tuberculosis therapy, Pharm. Res. 26 (2009) 2401–2416, http://dx.doi.org/10.1007/s11095-009-9957-4. [9] D. Dube, G.P. Agrawal, S.P. Vyas, Tuberculosis: from molecular pathogenesis to effective drug carrier design, Drug Discov. Today 17 (2012) 760–773, http://dx. doi.org/10.1016/j.drudis.2012.03.012. [10] R. Shegokar, L. Al Shaal, K. Mitri, Present status of nanoparticle research for treatment of tuberculosis, J. Pharm. Pharm. Sci. 14 (2011) 100–116. [11] J.A. Caminero, G. Sotgiu, A. Zumla, G.B. Migliori, Best drug treatment for multidrugresistant and extensively drug-resistant tuberculosis, Lancet Infect. Dis. 10 (2010) 621–629, http://dx.doi.org/10.1016/s1473-3099(10)70139-0.

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Respirable nanocarriers as a promising strategy for antitubercular drug delivery.

Tuberculosis is considered a fatal respiratory infectious disease that represents a global threat, which must be faced. Despite the availability of or...
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