SPRAY-DRIED BIOADHESIVE FORMULATIONS FOR PULMONARY DELIVERY

This study describes developments and in vitro characterisation of lipid microparticles prepared using spray-drying for drug delivery to the lung via dry powder inhalers. Bioadhesive formulations such as prochitosome or chitosome powders have been introduced to overcome the drawbacks of liposome instability and potentially provide significant increase in the residence time of drug in the lung. Mannitol or lactose monohydrate (LMH) aqueous solutions were spray dried at inlet temperatures of 90, 130, 170 or 210ºC. Soy phosphatidylcholine and cholestrol (1:1 mole ratio) were used in all formulations. Cholesterol was added to increase vesicle membrane rigidity. Proliposomes containing salbutamol sulphate (SS) were prepared by incorporating various lipid:carrier (mannitol or LMH; 1:2, 1:4, 1:6, 1:8 and 1:10 w/w). Prochitosomes including SS or beclomethason dipropionate (BDP) were prepared by adding various chitosan glutamate:lipid ratios of 1:10, 2:10, 3:10 and 5:10 w/w. Chitosomes, including various cryoprotectants (mannitol, LMH, trehalose or sucrose), were prepared by including chitosan glutamate to liposomes generated from ethanol-based proliposomes in the ratio of 3:10 w/w chitosan to lipid. The spray-drying parameters for generation of dry powders were optimised by using an inlet temperature of 120ºC, outlet temperature of 73 ± 3°C, aspirator rate of 100%, suspension feed rate of 11%, and spray flow rate of 600 L/h using B-290 Buchi mini spray-dryer. The production yields were 48.1±2.84%, 69.73±2.05%, 61.33±2.51% and 58.0±3.0% for mannitol and 50.66±3.51%, 68.0±2.0%, 73.66±1.52%, 59.0±2.64% for LMH at 90, 130, 170 or 210ºC, respectively. The size of the particles were smaller than 5 µm for both carriers at of 90 and 130 ºC, whilst larger than 5 µm at inlet temperatures of 170 and 210 ºC. Particles had smooth, spherical and smaller size at 90 and 130 ºC than inlet temperatures of 170 and 210 ºC. Mannitol kept its crystalline properties after spray-drying, whilst LMH changed to amorphous at all drying temperatures. Mannitol-based proliposome particles were uniform, small and spherically shaped. In contrast, LMH-based proliposome particles were irregular and large. Entrapment efficiency of SS was higher for LMH-based proliposomes, however, fine particle fraction (FPF) was higher for proliposomes containing mannitol. Higher FPF was obtained for proliposome containing lipid to mannitol ratio of 1:6 (FF= 52.6%). Vesicles size decreased with increasing carrier ratio and the zeta potential was slightly negative for all formulations studied. Prochitosomes were small, porous and spherically shaped particles. Higher FPF was achieved for prochitosome powders containing chitosan to lipid ratio of 3:10 and 5:10 for both SS (FPF = 58.12±2.86% and 70.25±2.61% respectively) and BDP (FPF = 61.89±9.04% and 61.56±3.13% respectively). Zeta potential and the fraction of mucin adsorbed on the vesicles increased upon increasing chitosan concentration. Vesicle size decreased with increasing chitosan concentration. Entrapment efficiency (EE) of the formulations containing BDP was higher than that for SS. Moreover, the drug EE was higher using chitosomes compared to liposomes. LMH and trehalose-based liposome or chitosome particles were spherical with less tendency of agglomeration compared to mannitol and sucrose-based particles. Powders containing LMH, trehalose or sucrose were amorphous, whilst mannitol-based powder was crystalline. The FPF values were 14.39±1.81%, 32.29±0.15, 48.99±2.22% and 50.79±3.19% for mannitol, sucrose, LMH and trehalose-based liposome formulations, respectively. However, FPF% values were higher for chitosomes, being 23.48±3.38%, 33.89±0.66%, 54.88±1.85% and 55.9±2.74% for mannitol, sucrose, LMH and trehalose-based chitosomes, respectively. The EE of SS was increased upon coating liposome surface with chitosan regardless of cryoprotectant type. In conclusion, the findings of this study have demonstrated the potential of lipid microparticles in pulmonary drug delivery and that prochitosomes or chitosomes may offer great potential for enhancing drug resident time in the lung

Spray-Dried Proliposome Microparticles for High-Performance Aerosol Delivery Using a Monodose Powder Inhaler

Proliposome formulations containing salbutamol sulphate (SS) were developed using spray drying, and the effects of carrier type (lactose monohydrate (LMH) or mannitol) and lipid to carrier ratio were evaluated. The lipid phase comprised soy phosphatidylcholine (SPC) and cholesterol (1:1), and the ratios of lipid to carrier were 1:2, 1:4, 1:6, 1:8 or 1:10 w/w. X-ray powder diffraction (XRPD) revealed an interaction between the components of the proliposome particles, and scanning electron microscopy (SEM) showed that mannitol-based proliposomes were uniformly sized and spherical, whilst LMH-based proliposomes were irregular and relatively large. Using a two-stage impinger (TSI), fine particle fraction (FPF) values of the proliposomes were higher for mannitol-based formulations, reaching 52.6%, which was attributed to the better flow properties when mannitol was used as carrier. Following hydration of proliposomes, transmission electron microscopy (TEM) demonstrated that vesicles generated from mannitol-based formulations were oligolamellar, whilst LMH-based proliposomes generated 'worm-like' structures and vesicle clusters. Vesicle size decreased upon increasing carrier to lipid ratio, and the zeta potential values were negative. Drug entrapment efficiency (EE) was higher for liposomes generated from LMH-based proliposomes, reaching 37.76% when 1:2 lipid to carrier ratio was used. The in vitro drug release profile was similar for both carriers when 1:6 lipid to carrier ratio was used. This study showed that spray drying can produce inhalable proliposome microparticles that can generate liposomes upon contact with an aqueous phase, and the FPF of proliposomes and the EE offered by liposomes were formulation-dependent

Comparison between the next generation impactor and the twin glass impinge as model pulmonary drug delivery devices

Background and objective: The British Pharmacopoeia contains four apparatus for testing inhalers. Two of these are the next generation impactor, and the twin glass impinge which differs in their use. The next generation impactor apparatus should ideally have at least five stages; even though the twin glass impinge has only two stages, it is still listed in the British Pharmacopoeia. The next generation impactor is more accurate, reliable and sophisticated than the twin glass impinger. This study gives a detailed comparison of the two pieces of equipment. Methods: Carriers including mannitol, lactose monohydrate, trehalose and sucrose with active pharmaceutical ingredient; salbutamol sulphate were delivered by dry powder inhaler using the next generation impactor and twin glass impinger at a constant flow rate of 60L/min. Results: The twin glass impinge respirable fractions of the powders were higher than the next generation impactor for each carrier. As expected, mannitol powder had the lowest percentage remaining in the capsule compared to lactose monohydrate, trehalose and sucrose had the greatest percentage remaining for both inhaler devices. Conclusion: Even though both apparatus are important for in-vitro studies of drug delivery into the lungs using inhaler devices, the next generation impactor is better suited when a specific size range is required. The twin glass impinger is useful for simple inhaler testing, and the inclusion within the British Pharmacopoeia is justified

Spray-Dried Alginate Microparticles for Potential Intranasal Delivery of Ropinirole Hydrochloride: Development, Characterization and Histopathological Evaluation

Ropinirole hydrochloride (RH) is an anti-Parkinson drug with relativity low oral bioavailability owing to its extensive hepatic first pass metabolism. Spray-dried mucoadhesive alginate microspheres of RH were developed and characterized followed by histopathological evaluation using nasal tissue isolated from sheep. Spherical microparticles having high product yield (around 70%) were obtained when the inlet temperature of spray drying was 140 °C. Fourier Transform Infrared (FTIR) studies revealed the compatibility of the drug with the polymer, and scanning electron microscopy (SEM) showed that drug-loaded microparticles were spherical, and the apparent surface roughness was inversely related to the ratio of polymer to drug. Furthermore, size of the spray-dried particles were in the range of 2.5 - 4.37 µm, depending on formulation. All formulations had high drug encapsulation efficiencies (101 - 106%). Drug loaded into the polymeric particles was in the amorphous state and drug molecules were molecularly dispersed in the polymeric matrix of the microparticles which were revealed by X-ray diffraction and differential scanning calorimetry (DSC), respectively. The in vitro drug release was influenced by polymer concentration. Histopathological study demonstrated that RH-loaded sodium alginate microparticles was safe to nasal epithelium. In conclusion, spray drying of RH using sodium alginate polymer has produced microparticles of suitable characteristics for potential intranasal administration

Studies of the Precipitation Pattern of Paclitaxel in Intravenous Infusions and Rat Plasma Using Laser Nephelometry

Cremophor EL (CrEL) is commonly used to solubilize paclitaxel (Ptx); a widely established anticancer agent used against many types of cancer. Using laser-based microplate nephelometry, in this work we assessed the precipitation kinetics of Ptx in CrEL-containing formulations upon dilutions with different infusion media or upon introduction into rat plasma. The precipitation profile of Ptx was assessed for a Taxol-like formulation and compared with a preparation with reduced CrEL content. These two formulations were diluted at various ratios in compatible infusion media and with or without rat plasma. The percentages of Ptx precipitated in dilution media and protein-binding in plasma were quantified using HPLC. The findings of turbidity measurements were in good agreement with HPLC. Despite the presence of albumin, it was possible to assess turbidity within infusion solutions and predict Ptx precipitation. Upon addition to plasma, no precipitation in Taxol-like formulation occurred after 2 h. In contrast, precipitation occurred immediately in CrEL-reduced formulation. It is possible that the high percentage of protein-bound Ptx in plasma (98.5–99.2%) has inhibited drug precipitation. Turbidity measurements using laser nephelometry can provide a rapid screening tool when developing intravenous formulations for poorly soluble drugs, such as Ptx and assess its stability upon dilution in animal plasma

Studies on surfactants, cosurfactants, and oils for prospective use in formulation of ketorolac tromethamine ophthalmic nanoemulsions

Nanoemulsions (NE) are isotropic, dispersions of oil, water, surfactant(s) and cosurfactant(s). A range of components (11 surfactants, nine cosurfactants, and five oils) were investigated as potential excipients for preparation of ketorolac tromethamine (KT) ocular nanoemulsion. Diol cosurfactants were investigated for the effect of their carbon chain length and dielectric constant (DEC), Log P, and HLB on saturation solubility of KT. Hen’s Egg Test—ChorioAllantoic Membrane (HET-CAM) assay was used to evaluate conjunctival irritation of selected excipients. Of the investigated surfactants, Tween 60 achieved the highest KT solubility (9.89 ± 0.17 mg/mL), followed by Cremophor RH 40 (9.00 ± 0.21 mg/mL); amongst cosurfactants of interest ethylene glycol yielded the highest KT solubility (36.84 ± 0.40 mg/mL), followed by propylene glycol (26.23 ± 0.82 mg/mL). The solubility of KT in cosurfactants was affected by four molecular descriptors: carbon chain length, DEC, log P and HLB. KT solubility was directly proportional to DEC and the HLB yet, inversely proportional to carbon chain length and log P. All surfactants, except Labrasol ALF, were non-irritant. The majority of cosurfactants were slightly irritant, butylene glycol was a moderate irritant, pentylene and hexylene glycols were strong irritants. These findings will inform experiments aimed at developing NE formulations for ocular administration of KT

Advances in nasal drug delivery systems

Nasal drug delivery has been around for centuries and employed both leisure and recreations and also for the treatment of various conditions such as migraine, decongestion, sinusitis, rhinitis, and in emergency. The route is convenient and popular. It has numerous advantages such as direct delivery to the (central nervous system) CNS, high bioavailability, large surface area, needles are not used, and no special skills are required to deliver the drug. The method is non-invasive and provides direct drug transfer from nose to brain via olfactory nerve, hence it bypasses the blood-brain barrier for CNS effect and first pass effect while drug absorbed via nasal mucosa for systemic effect. It is also suitable for drugs that are unstable in an acid environment. The two main mechanisms in nasal drug delivery are discussed along with various factors involved such as physicochemical properties of the drug, formulations factors, and the physiological and anatomical characteristics. Various barriers effecting nasal drug delivery are also discussed. The delivery of microspheres and liposome formations using various nasal devices is also discussed

Investigation of hydrogen production potential from different natural water sources in Turkey

Hydrogen production from the electrolysis of water by sea or lake waters used as electrolyte plays a crucial role in providing sustainable hydrogen production. Production of hydrogen from these natural sources is highly utilized from small scale to complex applications due to water resources' inconsumable potential. In this study, the hydrogen production potential of Turkey's different regions such as the Black Sea, Aegean Sea, Marmara Sea, Mediterranean Sea, Lake Van, Agcas, ar Dam, Yes, ilirmak, and Kizilirmak rivers are investigated. Solar energy potential values are used as the current sources for simulating their renewable energy hydrogen production values. According to the results, higher hydrogen production rates are obtained from the Marmara and Lake Van regions. It is concluded that the hydrogen production potential is highly dependent on the pH values of the water source and the salinity rate of seawater that is descending from the Mediterranean Sea to the Black Sea region. Besides, solar radiation, sunshine duration, and water temperature are the other essential factors. Moreover, Mediterranean Sea water (Icomma el-Anamur) has about 23% higher hydrogen production than Lake Van and has the most increased hydrogen production by 80 L m-2 in May and June. (c) 2021 Hydrogen Energy Publications LLC. Published by Elsevier Ltd. All rights reserved

A facile approach to manufacturing non-ionic surfactant nanodipsersions using proniosome technology and high-pressure homogenization

In this study, a niosome nanodispersion was manufactured using high-pressure homogenization following the hydration of proniosomes. Using beclometasone dipropionate (BDP) as a model drug, the characteristics of the homogenized niosomes were compared with vesicles prepared via the conventional approach of probe-sonication. Particle size, zeta potential, and the drug entrapment efficiency were similar for both size reduction mechanisms. However, high-pressure homogenization was much more efficient than sonication in terms of homogenization output rate, avoidance of sample contamination, offering a greater potential for a large-scale manufacturing of noisome nanodispersions. For example, high-pressure homogenization was capable of producing small size niosomes (209 nm) using a short single-step of size reduction (6 min) as compared with the time-consuming process of sonication (237 nm in >18 min) and the BDP entrapment efficiency was 29.65% ± 4.04 and 36.4% ± 2.8. In addition, for homogenization, the output rate of the high-pressure homogenization was 10 ml/min compared with 0.83 ml/min using the sonication protocol. In conclusion, a facile, applicable, and highly efficient approach for preparing niosome nanodispersions has been established using proniosome technology and high-pressure homogenization