Table 3 Synopsis of Novel Anti-TB Drug Delivery Systems
From: Tuberculosis chemotherapy: current drug delivery approaches
Drug | Delivery System and Polymer Employed | ROA | Preparatory Methods | Characterisation Studies and System Suitability | Reference |
|---|---|---|---|---|---|
INH | Porous, non-porous and hardened microparticles employing PLG | SC injection | Double emulsification solvent evaporation | Size: Mean volume diameters were: 62.11 μm, 71.95 μm and 11.75 μm for porous, non-porous and hardened microparticles, respectively. In vitrostudies: Sustained release of INH up to 6 days from non-porous microparticles. Porous microparticles released INH over 3 days. Hardened PLG microparticles sustained release of INH for up to 7 weeks In vivodisposition studies (in mice): Porous and non-porous microparticles released INH in plasma for up to 2 days. Hardened PLG microparticles sustained release of INH for up to 7 weeks. Concentrations of INH obtained were higher than the MIC of INH. | [50] |
RIF, INH, PYZ, ETB | Microparticles employing PLG | Oral, singly or in combi-nation | Double emulsification solvent evaporation | DEE: 8–10% for PZA; 10–11% for INH and 12–18% for RIF. Size: Diameters were 1.11 μm for INH, 1.40 μm for RIF and 2.20 μm for PZA microparticles. In vitrostudies: Entrapped drugs were released in a sustained manner. In the intestinal fluid drug release was obtained for up to 20 days In vivostudies: Entrapped drugs remained in circulation up to 72 h as compared to free drugs (eliminated within 24 h). Level of PLG encapsulated INH was found to be higher than its MIC value (0.1 μg/ml). Pharmacokinetic analysis (PLG encapsulated drugs and free drugs): Increased Cmax; AUCo-α; t1/2 (a) and t1/2 (e) when drug were given entrapped in PLG microparticles indicated the potential of PLG for effective treatment of TB | [52] |
RIF, INH, PYZ | Nanoparticles employing PLG | Oral | Multiple emulsion technique | Size: Majority (>80%) in the size range of 186–290 nm, polydispersity index of 0.38 ± 0.04 DEE: 56.9 ± 2.7% for RIF, 66.3 ± 5.8% for INH and 68 ± 5.6% for PZA. Drug loading: 570 to 680 mg drug per gram of polymer. In vitrostudies: drug release profile in PBS showed an initial (up to 48 h) burst release followed by a negligible release of either drug up to 6 weeks. In vivostudies (experimental infection and chemotherapy): following oral administration of drug-loaded nanoparticles to M. tuberculosis-infected mice at every 10th day – no tubercle bacilli could be detected in the tissues after 5 oral doses of treatment | [48] |
RIF, INH | Osmotically regulated capsular multi-drug oral delivery system employing HPMC and NaCMC | Oral | Phase inversion process – precipitation of membrane structure on a stainless steel mould pin | SEM: porous structure of the membranes was evident. In vitrostudies: sustained release of RIF and INH, with initial burst release, which may be sufficient to achieve MIC in blood. Thereafter, the system sustained the release of the drugs in a near zero order rate In vitrorelease kinetics: first order kinetics. Statistical analysis of release rate data – modified asymmetric system the preferred system. | [41] |
INH, RIF | Microparticles employing PLG | SC, Inhaled | Double emulsification solvent evaporation | Size: Volume mean diameters of 11.75 μm (INH-loaded) and 11.64 μm (RIF-loaded) DEE: 10–11% (INH-loaded) and 12–14% (RIF-loaded) In vivo-combination drug disposition studies and experimental infection and chemotherapy studies: single dose of PLG microparticles – sustained release of INH and RIF for up to 7 and 6 weeks, respectively. Free drugs (in combination) injected in the same doses were detectable in vivo up to 24 h only. One dose of PLG microparticles cleared bacteria more effectively from lungs and liver in experimental murine model of TB (compared with a daily administration of the free drugs) Phase I trials | [51] |
RIF | Microspheres employing PLG | Inhaled/aerosol | Solvent evaporation | Size: reported for 2 formulations – 3 to 4 μm, and distribution demonstrated a Gaussian curve. In vitrostudies: best in vitro release patterns, resulted in 21 and 12% cumulative in vitro drug release, respectively, after 6 days Release in monocytic cell lines (murine J774 and the human Mono Mac 6): Bioassay assessment of cell culture supernatants from monocyte cell lines – release of RIF during a 7-day experimental period. Treatment of M. tuberculosis H37Rv-infected monocyte cell lines with RIF-loaded microspheres resulted in a significant decrease in numbers of CFU at 7 days following initial infection | [64] |
INH, RIF | Microspheres employing PLG | Inhaled | Combination of solvent extraction and evaporation | Size: mean diameter of 6.214 μm and only 38% of the microspheres fell in the size range of 0.5–3 μm In vivostudies: Microspheres were tested for uptake by murine macrophages in culture and resultant intracellular drug concentrations. The extent of microparticle delivery in vivo was examined by flow-cytometry. Drug concentrations (blood and alveolar macrophages) estimated after oral, vascular, intratracheal, and inhalation administration. Large numbers of particles delivered to the bronchiopulmonary system through a 2 min exposure to fluidized particles. The intracellular drug concentrations resulting from vascular delivery of soluble drugs were lower than those resulting from particle inhalation. | [66] |
RIF | Microparticles employing PLGA | Inhaled | Spray drying | Size: Volume median diameters (VMD) and geometric standard deviations (S.D.) were [VMD (μm)/geometric S.D.]: RIF-PLGA, 2.76/1.57; PLGA, 2.87/1.45; and RIF alone, 3.83/1.75. In vivostudies: Alveolar macrophage M. tuberculosis(H37Rv)-infected guinea pig model was used to screen for targeted delivery to the lungs by insufflation (with lactose excipient) or nebulisation RIF-PLGA microspheres. Animals treated with single and double doses of RIF-PLGA microspheres – reduced numbers of viable bacteria, inflammation and lung damage compared with RIF-only treated animals 28 days post-infection. Two doses of RIF-PLGA – reduced splenic enlargement. | [69] |
RIF | Microparticles employing PLGA | Inhaled | Solvent evaporation and spray drying | Morphology: Spray dried RIF-loaded PLGA microparticles – shriveled morphology, spherical particles produced by solvent evaporation. Size: Median diameters by volume were 3.45 μm (solvent evaporation) and 2.76 μm (spray dried) DEE: 20% (solvent evaporation) and 30% (spray dried) Particles are being evaluated in an animal model of TB. | [70] |
Ionizable prodrug of INH, INHMS | Spherical microparticles employing PLA | Inhaled | Precipitation with a compressed antisolvent process | Drug loading efficiency: 93 to 152% Size: Aerodynamic diameters ranged from 1 to 3 μm In vitrostudies: Release profiles displayed two phases of drug release that were characterised by an initial burst effect, followed by a period of slower release In vivostudies (drug accumulation in cultured rat alveolar macrophages): Liquid chromatographic tandem mass spectrometric (LC-MS/MS) assay developed detected high level of INH in NR8383 (rat AM cell line) following exposure to drug-loaded microparticles. Compared INH levels in lavaged bronchoalveolar macrophages by LC-MS/MS after Sprague-Dawley rats administered either INHMS in PLA microparticles by intra-tracheal instillation or INH solution by gavage or intra-tracheal instillation – sustained delivery of INH to alveolar macrophages. Reduction in the blood levels of acetylisoniazid (AcINH), a major and potential toxic metabolite of INH. | [68] |
INH, RIF, PZA and RIF, INH, PYZ, ETB | Nanoparticles employing alginate | Inhaled | Cation-induced gelification of alginate | Size: 235.5 ± 0 nm in size, with majority of particles (80.5%) were in the respirable range, with mass median aerodynamic diameter of 1.1 ± 0.4 μm and geometric standard deviation of 1.71 ± 0.1 μm. DEE: 70–90% for INH and PZA, 80–90% for RIF and 88–95% for ETB. In vivostudies (disposition studies and chemotherapeutic studies): The formulation was orally administered to mice at two dose levels. A comparison was made in mice receiving free drugs at equivalent doses. Relative bioavailabilities of drugs encapsulated in alginate nanoparticles significantly higher compared with oral free drugs. Drug levels were maintained at or above the MIC90 post nebulisation until Day 15 in organs (lungs, liver and spleen) after administration of encapsulated drugs, whilst free drugs stayed at or above the MIC90 up to Day 1 only irrespective of dose. Clinical trials envisaged in the future | [71,72] |
RIF, INH and PYZ | Nebulised SLNs prepared from nanocrystalline lipid suspensions in water | Inhaled | Emulsion solvent diffusion technique | Size: favourable mass median aerodynamic diameter suitable for bronchoalveolar drug delivery In vivostudies: Therapeutic experimental TB drug concentrations were maintained in the plasma for 5 days and in the organs for 7 days whereas free drugs were cleared by 1–2 days | [73] |
RIF | Aerosolised liposomes formulated using Egg PC-and Chol-based liposomes | Inhaled | Neutral liposomes were prepared by cast film method | Modification: Imparted negative charge (DCP) or by coating them with alveolar macrophage-specific ligands (MBSA and O-SAP). Size: neutral and negatively charged liposomes composed of PC:Chol:DCP had average vesicle size of 2.32 ± 0.48 μm and 2.50 ± 0.54 μm, respectively. MBSA-coated liposomes size: 3.64 ± 0.65 μm, O-SAP-coated vesicles size: 3.85 ± 0.59 μm. DEE: 47.4 ± 2.7% In vivostudies: Percent viability of Mycobacterium smegmatis inside macrophages (in vitro) after administration of drug (in vivo) was 7–11% (ligand-anchored liposomal aerosols), 45.7 and 31.6% in case of plain drug and plain neutral liposomal aerosol (based on PC:Chol)-treated macrophages. Preferential accumulation of MBSA- and O-SAP-coated formulations in alveolar macrophages. Drug was estimated in the lung in high concentration (even after 24 h). | [74] |
INH | Implant prepared from PLGA | Depot | PLGA polymer rods | In vivostudies: Rods implanted in the back of rabbits under anaesthesia. Concentrations of INH and acetylisoniazid in serum and urine determined by HPLC. Concentrations of INH ≥ 0.2 μg/ml were found both in serum and urine up to 63 days after implant. Urine specimen obtained at 6 weeks after implant inhibited the growth of M. tuberculosis in vitro measured by the radiometric (Bactec) method. | [49] |
INH, PYZ | Single implants prepared from PLGA | Depot | Depot drug preparation | In vivostudies: 3 times the daily dose of PYZ contained in single PLGA polymer implant – no burst levels of the drug evident after administration – sustained levels up to 54 days. Chemotherapeutic activity (investigated in mice) of the single PLGA polymer implants similar to standard oral treatment with the two drugs given daily for 8 weeks, determined by mortality and CFU counts of tubercle bacilli from lungs and spleen. | [75] |