Second-line injectable induced ototoxicity in drug resistant tuberculosis: A systematic review of Indian studies.

Second-line injectables (SLIs) form an essential class of agents in the treatment of drug resistant (DR) tuberculosis (TB). However, their use is sometimes limited due to serious adverse events like ototoxicity and hearing loss, leading to permanent hearing loss if SLIs are continued. Globally as well as in India a wide variation in incidence of ototoxicity/hearing loss has been reported in patients with DR-TB. In this systematic analysis, we attempt to ascertain the ototoxicity of SLIs in Indian patients with multidrug resistant tuberculosis (MDR-TB) wherein ototoxicity onset was assessed using audiometry performed at both pre- and post-SLI treatment initiation. Twenty two studies were identified based on the inclusion criteria. Ototoxicity was observed in 10.12% [349/3447] patients within 3.8 ± 2.6 months of treatment initiation when the ototoxicity was assessed either with or without audiometry assessment. Only five studies reported ototoxicity assessment with PTA at both pre- and post-SLI initiation and ototoxicity was observed in 27.01% (121/448) patients in these five studies. Sensorineural loss was observed in three studies (high frequency loss: capreomycin, 25.0% [1/4 patients]; amikacin, 19.7% [12/61]; kanamycin, 13.3% [22/166]; streptomycin, 11.8% [2/17]; flat loss: amikacin, 8.2% [5/61]; streptomycin, 5.9% [1/17]; kanamycin 4.8% [8/166]). Most of the patients experiencing ototoxicity were managed by discontinuing (49.6% [120/242]) or replacing SLI treatment (40.8% [49/120]). The study identified high prevalence of ototoxicity in Indian patients with DR-TB treated with SLI when ototoxicity was monitored regularly using PTA (27.01%), warranting a need to develop unified guidelines for monitoring ototoxicity, improving physician awareness and educating patients/caregivers for reporting symptoms of hearing loss.

Risk of Nephrotoxicity in Patients With Drug-Resistant Tuberculosis Treated With Kanamycin/Capreomycin With or Without Concomitant Use of Tenofovir-Containing Antiretroviral Therapy.

BACKGROUND: The intersection of HIV and drug-resistant (DR) tuberculosis (TB) presents the challenge of managing convergent drug toxicities. METHODS: We conducted a retrospective study of adult patients with DR-TB treated with a kanamycin/capreomycin-based (KM) regimen, with or without concomitant antiretroviral therapy (ART). We estimated the incidence of nephrotoxicity (defined as an increase in serum creatinine greater than 26.5 µmol, or an increase in serum creatinine to 1.5 times the baseline value, or a decline in glomerular filtration rate to less than 60 mL/min/1.73 m), and evaluated the association between reported drug use and nephrotoxicity using Kaplan-Meier plots. RESULTS: A total of 215 patients with DR-TB were treated with a kanamycin/capreomycin-based regimen, with or without concomitant ART. The incidence rate of nephrotoxicity was 3.6 [95% confidence interval (CI): 1.4 to 7.3], 6.9 (95% CI: 5.2 to 9.0), and 12 (95% CI: 3.3 to 30.9) cases per 100 person-months of follow-up in the KM only group (n = 42), the KM + TDF (tenofovir disoproxil fumarate) group (n = 163), and the KM + Other ART group (n = 10), respectively. Using the KM only group as a reference, the hazard ratio was 2.06 (95% CI: 0.92 to 4.63) in the KM + TDF group, and 4.09 (95% CI: 1.17 to 14.25) in the KM + Other ART group. Advancing age was an independent predictor of nephrotoxicity (adjusted hazard ratio 1.29, 95% CI: 1.14 to 1.46). CONCLUSIONS: Our findings provide evidence of a significant risk of nephrotoxicity during treatment with a kanamycin/capreomycin-based DR-TB regimen, with or without concurrent treatment with ART. This study lends further support to calls for the substitution of TDF during the intensive phase of DR-TB treatment and for close monitoring of renal function during DR-TB treatment, especially in settings where the use of kanamycin/capreomycin is unavoidable.

Differences in VigiBase® reporting of aminoglycoside and capreomycin-suspected ototoxicity during tuberculosis treatment.

PURPOSE: To evaluate the association between the use of streptomycin, amikacin, kanamycin and capreomycin in tuberculosis (TB) treatment and the pharmacovigilance reporting of ototoxicity (deafness or hearing loss, tinnitus and vertigo). Second, to analyze patient demographic and geographic factors that influence the reporting of ototoxicity in TB treatment. METHODS: A case/non-case disproportionality analysis of the VigiBase® individual case safety reports (ICSRs) of patients treated for TB using multidrug regimens that contain either of streptomycin, amikacin, kanamycin or capreomycin. Cases were reports of ototoxicity; non-cases were other adverse drug reactions (ADRs). The unit of analysis was the drug-ADR pair. We calculated reporting odds ratios (RORs) and their 95% confidence intervals (CI). The referent drug was streptomycin. RESULTS: By June 2014, there were 3361 drug-ADR pairs in VigiBase® (1693 ICSRs) where the parenteral administration of the four drugs for TB treatment was suspected of causing the reported ADRs. Deafness, tinnitus and vertigo were reported in 576 drug-ADR pairs (cases), the rest being other ADRs (non-cases). Reporting of deafness was most disproportionately associated with amikacin use (ROR 9.3; 95%CI 3.8-23.0), followed by kanamycin use (ROR 4.3; 95%CI 1.3-14.2). Reporting of vertigo was inversely associated with capreomycin use (ROR 0.1; 95%CI 0.01-0.4). Geographic region affected the reporting of ototoxicity while age and sex did not. CONCLUSION: Spontaneous reporting of deafness cases within VigiBase® was most disproportionately associated with amikacin use, followed by kanamycin. There were regional variations in the global reporting of ototoxicity. These findings should be verified through a follow up study. Copyright © 2016 John Wiley & Sons, Ltd.

The safety and tolerability of the second-line injectable antituberculosis drugs in children.

INTRODUCTION: A growing number of children globally are being treated for multidrug-resistant tuberculosis (MDR-TB). The second-line injectable antituberculosis medications amikacin, kanamycin and capreomycin, traditionally a mainstay of MDR-TB treatment, cause important adverse effects including permanent sensorineural hearing loss, nephrotoxicity, electrolyte abnormalities, injection pain and local injection site complications. Areas covered: To characterize the safety and tolerability of the second-line injectables in children treated for MDR-TB, we reviewed data on the mechanism of injectable associated adverse effects, risk factors for their development, and the incidence of injectable-associated adverse effects in adults and children treated for MDR-TB. Expert opinion: Despite a substantial evidence base in adults demonstrating the frequent and potentially serious adverse effects of second-line injectables, important knowledge gaps remain. Improved characterization of the incidence of injectable-associated adverse effects will inform rational guidance on monitoring children with TB on injectables. Eliminating the need for injectables in MDR-TB treatment regimens is a high priority, and will rely on the use of novel antituberculosis TB drugs. Strategies to reduce the risk of adverse effects of injectables, if used, deserve evaluation. This includes evaluation of potentially otoprotective medications N-acetylcysteine or aspirin, high frequency hearing screening for earlier detection of ototoxicity and therapeutic drug monitoring.

Early culture conversion and cure for extensively drug-resistant tuberculosis is possible with appropriate treatment: lessons learnt from a case study in South Africa.

Despite the relevance of extensively drug-resistant tuberculosis (XDR-TB) to global TB control efforts, case reports on patients achieving cure are scarce. The case of a patient who was treated for more than 3 years as a multidrug-resistant TB (MDR-TB) case, and who was diagnosed retrospectively with XDR-TB, is presented herein. Soon after the initiation of a capreomycin and para-aminosalicylic acid-based regimen, the patient converted and treatment was completed successfully.

Capreomycin oleate microparticles for intramuscular administration: Preparation, in vitro release and preliminary in vivo evaluation.

Capreomycin sulfate (CS) is a second-line drug used for the treatment of multidrug-resistant tuberculosis (MDR-TB). The adverse effects profile and uncomfortable administration scheme of CS has led to the development of formulations based on liposomes and polymeric microparticles. However, as CS is a water-soluble peptide that does not encapsulate properly into hydrophobic particulate matrices, it was necessary to reduce its aqueous solubility by forming the pharmacologically active capreomycin oleate (CO) ion pair. The aim of this research was to develop a new formulation of CO for intramuscular injection, based on biodegradable microparticles that encapsulate CO in order to provide a controlled release of the drug with reduced local and systemic adverse effects. The CO-loaded microparticles prepared by spray drying or solvent emulsion-evaporation were characterized in their morphology, encapsulation efficiency, in vitro/in vivo kinetics and tissue tolerance. Through scanning electron microscopy it was confirmed that the microparticles were monodisperse and spherical, with an optimal size for intramuscular administration. The interaction between CO and the components of the microparticle matrix was confirmed on both formulations by X-ray powder diffraction and differential scanning calorimetry analyses. The encapsulation efficiencies for the spray-dried and emulsion-evaporation microparticles were 92% and 56%, respectively. The in vitro kinetics performed on both formulations demonstrated a controlled and continuous release of CO from the microparticles, which was successfully reproduced on an in vivo rodent model. The results of the histological analysis demonstrated that none of the formulations produced significant tissue damage on the site of injection. Therefore, the results suggest that injectable CO microparticles obtained by spray drying and solvent emulsion-evaporation could represent an interesting therapeutic alternative for the treatment of MDR-TB.

Primary Capreomycin Resistance Is Common and Associated With Early Mortality in Patients With Extensively Drug-Resistant Tuberculosis in KwaZulu-Natal, South Africa.

BACKGROUND: Capreomycin is a key antimycobacterial drug in treatment of extensively drug-resistant tuberculosis (XDR-TB). Drug-susceptibility testing (DST) for capreomycin is not routinely performed in newly diagnosed XDR-TB in South Africa. We performed this study to assess the prevalence, clinical significance, and molecular epidemiology of capreomycin resistance in newly diagnosed patients with XDR-TB in KwaZulu-Natal, South Africa. METHODS: Retrospective cohort study of consecutive patients with XDR-TB admitted to a TB referral hospital without previous XDR-TB treatment. A subset of isolates had extended DST (including capreomycin), mutational analysis, and IS6110 restriction fragment length polymorphism assays. RESULTS: A total of 216 eligible patients with XDR-TB were identified. The majority were treated with capreomycin (72%), were young (median age: 35.5 years), and were female (56%). One hundred five (76%) were HIV+, and 109 (66%) were on antiretroviral therapy. A subset of 52 patients had full DST. A total of 47/52 (90.4%) patients with XDR-TB were capreomycin resistant. Capreomycin-resistant patients experienced worse mortality and culture conversion than capreomycin susceptible, although this difference was not statistically significant. The A1401G mutation in the rrs gene was associated with capreomycin resistance. The majority of capreomycin-resistant strains were F15/LAM4/KZN lineage (80%), and clustering was common in these isolates (92.5%). CONCLUSIONS: Capreomycin resistance is common in patients with XDR-TB in KwaZulu-Natal, is predominantly because of ongoing province-wide transmission of a highly resistant strain, and is associated with high mortality. Capreomycin should be included in routine DST in all patients with XDR-TB. New drug regimens that do not include injectable agents should be operationally tested as empiric treatment in XDR-TB.

The influence of feedstock and process variables on the encapsulation of drug suspensions by spray-drying in fast drying regime: the case of novel antitubercular drug­palladium complex containing polymeric microparticles.

The purpose of this study was to address the effect of feedstock properties and process variables on the characteristics of antitubercular drug­palladium (Pd) containing poly(lactic) acid (PLA) microparticles (MP) obtained by spray-drying of noncolloidal particle dispersions in fast drying regime. Two different systems were compared: capreomycin­Pd (C­Pd) and ofloxacin­Pd (Ofx­Pd) dispersions in acetonitrile PLA solution. Particle size, dynamic light scattering, differential scanning calorimetry, SEM­energy dispersive X-ray, and spectrophotometric methods were used for MP characterization. C­Pd-loaded MP were optimized preliminarily by experimental design and compared with Ofx­Pd-loaded MP investigated in our previous work. Morphology of feedstock particles had a dominant role in determining MP morphology. The Charlesworth and Marshall theory was used to explain such behavior. The smaller and homogeneous C­Pd microparticulates favored MP inflation and buckling by forming a thick and nonporous shell. A percolation effect was proposed for the larger and irregular Ofx­Pd particles that produced smaller MP with a more porous shell. Increasing feedstock concentration led to higher particle loss. A tentative descriptive scheme of MP formation according to feedstock particle arrangement was proposed. This work suggested that spray-drying of drug dispersions should carefully consider the morphology of feedstock particles as a major parameter influencing final MP properties.

Capreomycin inhalable powders prepared with an innovative spray-drying technique.

The aim of the work was to produce inhalable capreomycin powders using a novel spray-drying technology. A 2(3) factorial design was used to individuate the best working conditions. The maximum desirability was identified at the smallest mean volume diameter (dv) and span, and the highest yield. Powders were characterized for size, morphology, flowability and aerodynamic properties. Mathematical models showed a good predictivity with biases lower than 20%. The maximum conformity with desirability criteria was obtained spraying a 10mg/mL bacitracin solution at 111 °C with the 4 µm pore size membrane. By processing capreomycin sulfate with the parameters optimized for bacitracin, an inhalable powder was obtained (i.e., yield of 82%, dv of 3.83 µm, and span of 1.04). By further optimization, capreomycin sulfate powder characteristics were improved (i.e., yield, ∼71%; dv, 3.25 µm; span, 0.95). After formulation with lactose, emitted dose and respirable fraction of 87% and ∼27% were obtained, respectively. Two capreomycin sulfate powders with suitable properties for inhalation were produced using the nano spray-dryer B-90.

Phase I, single-dose, dose-escalating study of inhaled dry powder capreomycin: a new approach to therapy of drug-resistant tuberculosis.

Multidrug-resistant tuberculosis (MDR-TB) threatens global TB control. The lengthy treatment includes one of the injectable drugs kanamycin, amikacin, and capreomycin, usually for the first 6 months. These drugs have potentially serious toxicities, and when given as intramuscular injections, dosing can be painful. Advances in particulate drug delivery have led to the formulation of capreomycin as the first antituberculosis drug available as a microparticle dry powder for inhalation and clinical study. Delivery by aerosol may result in successful treatment with lower doses. Here we report a phase I, single-dose, dose-escalating study aimed at demonstrating safety and tolerability in healthy subjects and measuring pharmacokinetic (PK) parameters. Twenty healthy adults (n = 5 per group) were recruited to self-administer a single dose of inhaled dry powder capreomycin (25-mg, 75-mg, 150-mg, or 300-mg nominal dose) using a simple, handheld delivery device. Inhalations were well tolerated by all subjects. The most common adverse event was mild to moderate transient cough, in five subjects. There were no changes in lung function, audiometry, or laboratory parameters. Capreomycin was rapidly absorbed after inhalation. Systemic concentrations were detected in each dose group within 20 min. Peak and mean plasma concentrations of capreomycin were dose proportional. Serum concentrations exceeded 2 µg/ml (MIC for Mycobacterium tuberculosis) following the highest dose; the half-life (t1/2) was 4.8 ± 1.0 h. A novel inhaled microparticle dry powder formulation of capreomycin was well tolerated. A single 300-mg dose rapidly achieved serum drug concentrations above the MIC for Mycobacterium tuberculosis, suggesting the potential of inhaled therapy as part of an MDR-TB treatment regimen.

A physiologically based pharmacokinetic model for capreomycin.

The emergence of multidrug-resistant tuberculosis (MDR-TB) has led to a renewed interest in the use of second-line antibiotic agents. Unfortunately, there are currently dearths of information, data, and computational models that can be used to help design rational regimens for administration of these drugs. To help fill this knowledge gap, an exploratory physiologically based pharmacokinetic (PBPK) model, supported by targeted experimental data, was developed to predict the absorption, distribution, metabolism, and excretion (ADME) of the second-line agent capreomycin, a cyclic peptide antibiotic often grouped with the aminoglycoside antibiotics. To account for interindividual variability, Bayesian inference and Monte Carlo methods were used for model calibration, validation, and testing. Along with the predictive PBPK model, the first for an antituberculosis agent, this study provides estimates of various key pharmacokinetic parameter distributions and supports a hypothesized mechanism for capreomycin transport into the kidney.

Activity of drug combinations against dormant Mycobacterium tuberculosis.

Aerobic (5-day-old cultures) and nonreplicating (dormant) Mycobacterium tuberculosis (5-, 12-, and 19-day-old cultures) bacteria were treated with rifampin (R), moxifloxacin (MX), metronidazole (MZ), amikacin (AK), or capreomycin (CP) for 7, 14, and 21 days. R-MX-MZ-AK and R-MX-MZ-CP killed both aerobic and dormant bacilli in 21 days, as shown by lack of regrowth in solid and liquid media. R-MX-MZ-AK and R-MX-MZ-CP also caused a strong decrease of nonreplicating bacilli in 7 days in a cell-based dormancy model.

Simple and scalable method for peptide inhalable powder production.

The aim of this work was to produce capreomycin dry powder and capreomycin loaded PLGA microparticles intended for tuberculosis inhalation therapy, using simple and scalable methods. Capreomycin physico-chemical characteristics have been modified by hydrophobic ion pairing with oleate. The powder suspension was processed by high pressure homogenization and spray-dried. Spray-drying was also used to prepare capreomycin oleate (CO) loaded PLGA microparticles. CO powder was suspended in the organic phase containing PLGA and the suspension was spray-dried. Particle dimensions were determined using photon correlation spectroscopy and Accusizer C770. Morphology was investigated by scanning electron microscopy (SEM) and capreomycin content by spectrophotometry. Capreomycin properties were modified to increase polymeric microparticle content and obtain respirable CO powder. High pressure homogenization allowed to reduce CO particle dimensions obtaining a population in the micrometric (6.18 microm) and one in the nanometric (approximately 317 nm) range. SEM pictures showed not perfectly spherical particles with a wrinkled surface, generally suitable for inhalation. PLGA particles were characterized by a high encapsulation efficiency (about 90%) and dimensions (approximately 6.69 microm) suitable for inhalation. Concluding, two different formulations were successfully developed for capreomycin pulmonary delivery. The hydrophobic ion pair strategy led to a noticeable drug content increase.

Preparation and in vivo evaluation of a dry powder for inhalation of capreomycin.

PURPOSE: To develop an aerosol system for efficient local lung delivery of a tuberculostatic drug. METHODS: The antibiotic, capreomycin sulfate, was spray dried to form a dry powder aerosol. The chemical content and physical properties of resulting particles were assessed under various storage conditions. Plasma concentrations of capreomycin after insufflation into guinea pigs were evaluated at three doses, and compared to IV and IM administration of a capreomycin solution. RESULTS: Dry powder aerosols containing capreomycin were formulated to enable efficient delivery of large drug masses to the lungs of guinea pigs. Aerosols loaded with 73% CS were shown to possess good aerosolization properties and physical-chemical stability for up to 3 months at room temperature. Upon insufflation into guinea pigs, the amount of CS reaching the bloodstream was significantly lower compared to IV or IM administration, but resulted in a significantly longer drug half-life. CONCLUSIONS: The results indicate that large doses of capreomycin in dry powder form can be efficiently delivered to the lungs of guinea pigs, which may result in high local drug exposure but significantly reduced systemic exposure as suggested by plasma concentrations in the present studies. These systems have considerable potential to provide more effective therapy for MDR-TB.

Inhaled large porous particles of capreomycin for treatment of tuberculosis in a guinea pig model.

Capreomycin is used for the treatment of multidrug-resistant tuberculosis (MDR-TB), but it is limited therapeutically by its severe side effects. The objectives of the present studies were (i) to design low-density porous capreomycin sulfate particles for efficient pulmonary delivery to improve local and systemic drug bioavailability and capacity to reduce the bacillary load in the lungs in a manner similar to that achieved with intramuscular injections; (ii) to determine pharmacokinetic parameters after pulmonary administration of these capreomycin particles; and (iii) to evaluate the efficacy of these particles in treating animals in a small-aerosol-inoculum guinea pig model of TB. Capreomycin particles were manufactured by spray drying and characterized in terms of size and drug content. Pharmacokinetic parameters were determined by noncompartmental methods with healthy guinea pigs after administration of capreomycin particles by insufflation. The efficacy of the particles was evaluated by histopathological analysis and in terms of wet organ weight and bacterial burden in TB-infected animals. Lungs of animals receiving a 14.5-mg/kg dose of capreomycin particles showed significantly lower wet weights and smaller bacterial burdens than those of animals receiving any other treatment. These results were supported by histopathological analysis. The feasibility of inhaling capreomycin in a novel powder form, with the ultimate objective of the treatment of MDR-TB, is demonstrated by pharmacokinetic and pharmacodynamic studies with guinea pigs. If applied to humans with MDR-TB, such a therapeutic approach might simplify drug delivery by eliminating injections and might reduce adverse effects through lowering the dose.

Preparation of large porous biodegradable microspheres by using a simple double-emulsion method for capreomycin sulfate pulmonary delivery.

The aim of this work was to evaluate if a simple double-emulsion method could be used for developing a new formulation of large porous microspheres (MS) potentially useful for capreomycin sulfate (CS) pulmonary delivery. Poly(DL-lactide-co-glycolide) was used for MS preparation. A simple W/O/W double-emulsion/solvent evaporation preparation method was employed and MS were characterized by UV spectrophotometry, particle size, and scanning electron microscopy. A computer-generated response surface method (RSM) was employed to evaluate % drug content, volume mean diameter (VMD), and span upon variation of two numeric and two categorical factors. MS size distribution was found to be strongly affected by the homogenization method and the type of emulsifier employed. Mean diameters ranged from 1 to 20 microm. The MS presented a proper morphology, with a highly porous interior and a rough surface. Peptide content ranged between 1 and 20%. The region of optimality was referred to as a low VMD and span values, and a high drug content. The best results were found when using a 20% loading, 19.8-3.2 dichloromethane/acetone ratio, ultraturrax mixing, and HPMC as emulsifier. The double-emulsion method allowed the preparation of CS loaded large porous MS having suitable characteristics to match respirability requirements. The use of RSM helped to establish the conditions to obtain formulations potentially useful for a possible CS pulmonary delivery, by using a simple preparation method with a consistent time, cost, and material saving.

Treatment outcome of multidrug-resistant tuberculosis among Vietnamese immigrants.

OBJECTIVE: To review the outcome for MDR-TB treatment among potential migrants from Vietnam. SETTING: All cases of documented MDR-TB treated by the International Organization of Migration (IOM) in Vietnam from 1989 to 2000 were reviewed. METHODS: MDR-TB was defined as isoniazid- and rifampicin-resistant Mycobacterium tuberculosis. All cases of TB treated by the IOM and recorded in the computerised database were reviewed to identify MDR-TB cases. Demographics, chest radiograph results, drug resistance, drug use and dosage, duration of treatment, and outcome were analysed. RESULTS: Forty-four cases of MDR-TB were identified. Treatment consisted of ambulatory directly observed treatment with an 8-drug protocol: isoniazid, rifampicin, pyrazinamide, ethambutol, capreomycin, ethionamide, ofloxacin and cycloserine. This initial protocol was modified due to drug availability or drug intolerance. Patients were treated with a median of 8 drugs (range 6-12). Mean duration of treatment for MDR-TB was 23.0 (SD+/-11.4) months. Thirty-eight (86%) patients were cured and emigrated, one failed treatment (2%), three were lost to follow-up (7%) and two died (4%). CONCLUSION: Treatment for MDR-TB provided by the IOM was effective in preparing a low-income population for migration.

UV spectroscopy and reverse-phase HPLC as novel methods to determine Capreomycin of liposomal fomulations.

Capreomycin (CS) is an antitubercular drug active against several Mycobacterium strains, in particular, against M. Avium. In spite of its activity, it is considered a second line drug because it can induce severe renal and hepatic damages when administered as free drug. However, it is possible to employ drug delivery systems, such as liposomes, to reduce the toxicity of the peptide without loss of its biological activity. For this purpose, appropriately validated time and money saving analytical methods are needed for a careful capreomycin dosage. In the present paper, UV spectroscopy and a reverse-phase HPLC (RP-HPLC) were investigated as alternative methods for capreomycin quantitative analysis. These techniques were validated against the USP XXVI microbiological turbidimetric assay and the normal-phase HPLC (NP-HPLC) method reported in the British Pharmacopoeia 2003. The results obtained showed that either UV spectrophotometry or RP-HPLC are techniques having higher accuracy and reproducibility with respect to the microbiological assay. Moreover, the RP-HPLC method provided improved performances if compared to NP-HPLC. In fact, RP-HPLC showed: (i) enhanced sensitivity and (ii) increased resolution. Thus we propose RP-HPLC and UV as valid alternative methods to the conventional procedures for capreomycin quantitative analysis.

Unilamellar vesicles as potential capreomycin sulfate carriers: preparation and physicochemical characterization.

The aim of this work was to evaluate unilamellar liposomes as new potential capreomycin sulfate (CS) delivery systems for future pulmonary targeting by aerosol administration. Dipalmitoylphosphatidylcholine, hydrogenated phosphatidylcholine, and distearoylphosphatidylcholine were used for liposome preparation. Peptide-membrane interaction was investigated by differential scanning calorimetry (DSC) and attenuated total internal reflection Fourier-transform infrared spectroscopy (ATIR-FTIR). Peptide entrapment, size, and morphology were evaluated by UV spectrophotometry, photocorrelation spectroscopy, and transmission electron microscopy, respectively. Interaction between CS and the outer region of the bilayer was revealed by DSC and ATIR-FTIR. DSPC liposomes showed enhanced interdigitation when the CS molar fraction was increased. Formation of a second phase on the bilayer surface was observed. From kinetic and permeability studies, CS loaded DSPC liposomes resulted more stable if compared to DPPC and HPC over the period of time investigated. The amount of entrapped peptide oscillated between 10% and 13%. Vesicles showed a narrow size distribution, from 138 to 166 nm, and a good morphology. These systems, in particular DSPC liposomes, could represent promising carriers for this peptide.