الفهرس 
Formulation and characterization of Ketotifen/Hyaluronic Acid Microparticles for Pulmonary DeliveryOnly 14 pages are availabe for public view
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Abstract
Purpose: the main and first objective of this thesis was to develop passive lung targeted systems for the controlled delivery of ketotifen hydrogen fumarate (KT). The second targets of this study were the achievement of high deep lung deposition and the evasion of the lung defense mechanisms while allowing a controlled KT delivery. The prepared systems will eventually offer the advantage of using lower doses of KT, thus minimizing its side effects.
Methods: Two different KT loaded systems were prepared and evaluated: swellable spray dried microparticles comprising KT-loaded hyaluronic acid (HA)/chitosan (CS) MPs and spray dried ketotifen/dextran sulfate (KT/DS) nanocomplexes-in-microparticles (NCs-in-MPs).
In chapter I, KT loaded HA spray dried microparticles (MPs) were developed. Different polymer to drug /ratios (P/D) were used to prepare the MPs and test the ability of the selected polymer to mask the drug bitter taste. To sustain the drug release from the spray dried MPs, chitosan was used as a matrix cross-linker. The formulation parameters namely: CS concentration (mg/mL), HA/KT (polymer to drug mass ratio) and KT placement either in HA (anion loading) or in CS (cation loading) were set as independent factors affecting entrapment efficiency percent (EE%), percent release at 0.5h (%R0.5h) and time at which 80% of KT was released. The selected formulae were characterized by evaluating in-vitro swelling behaviour, in-vitro pulmonary deposition using twin stage impinger (TSI) as well as in-vitro drug release. The surface morphology and shape were examined using scanning electron microscope (SEM). The matrix formed was further evaluated by DSC, FT-IR and X-ray diffraction analysis.
In chapter II, generation of novel core shell nanocomplexes (NCs) via electrolyte complexation of dextran sulfate (DS) and KT was attempted. The effect of different fabrication parameters viz volume of DS solution, KT and DS solutions pH values, concentration of both KT and DS solution at constant volumes as well as type and concentration of surfactant were investigated. Particle size, polydispersity index and zeta potential were the measured responses. Physico-chemical characterization of the formed matrix was performed via FT-IR, DSC and X-ray powder diffraction studies. Morphological examination was performed using transmission electron microscope (TEM) on freshly prepared NC as well as SDP after reconstitution. Stability before and following freeze drying was followed as well. selected NCs formulae were allowed to form MPs by spray drying in suitable carriers. Powder flow properties, drug association efficiency as well as mass median aerodynamic diameter (MMAD) were determined. The surface morphology and shape were examined using scanning electron microscope (SEM). A twin stage impinger was used to evaluate in-vitro pulmonary deposition from which the inhalation indices were derived.
In chapter III, in-vivo evaluation of KT inhalable SDP formulae including lung deposition and localization of selected KT-loaded HA/CS MPs was tested. A pharmacokinetic study on albino rats was performed on selected KT-loaded HA/CS MPs and KT/DS NCs-in-MPs and a limited pharmacodynamic study was conducted on selected KT/DS NCs-in-MPs to evaluate the prophylactic effect of KT on asthmatic rats. Asthma was induced using a chemical method.
Results: Results of chapter I showed that upon increasing HA concentration, there was a significant increase in yield, flow properties with efficient masking of KT bitter taste but unfortunately there was rapid release of KT within 10-15 min. To achieve sustained drug release, two concentrations of CS, 0.1 and 0.3 mg/mL, were added to the prepared drug polymer solutions before spray drying. Dispersions, with no detectable aggregations, were obtained and were then spray dried using the same operating conditions. High drug EE% reaching 94.25±2.78% was achieved at KT cation loading. Formulae selection was based on the criteria of attaining maximum EE% with low %R0.5h and high T80%. The highest swelling index was achieved using highest concentration of HA. DSC and X-ray powder diffraction showed complete amorphization of KT within polymers’ matrix. The KT and polymers interactions were evidenced by FT-IR.
In chapter II, the electrostatic ionic interaction and hydrogen bonding between KT and DS were evidenced by FT-IR results. The particle size of the prepared NCs ranged between 120 and 500 nm with negative zeta potential values at KT/DS (w/w) ratio of 1:0.34 to 1:1.5. A drug complexation efficiency exceeding 90% was achieved. The best inhalation indices were obtained with the carrier leucine and the spray dried MPs showed a MMAD ranging from 1.11±0.45 to 1.96±0.65 µm and respirable particle percent (RP%) reaching 67.41±2.6%. The drug release from the SDP lasted 7 hours. Storage for 6 months had insignificant effect on the physico-chemical stability of the SDP.
Selected swellable HA/CS SDP showed efficient lung deposition, long residence time attributed to their swelling following administration to male albino rats using the dry powder inhaler. The pharmacokinetic study showed that there was a statistically significant increase in Cmax and AUC0-t in lung homogenate following pulmonary administration of the selected formulae compared to i.v. or oral route. KT/DS inhalable SDP formula was able to reduce the inflammatory responses following provocation using toluene di-isocyanate in sensitized rats.
Conclusion: Swellable KT-loaded HA/CS SDP and KT/DS NCs-in-MPs are promising delivery carriers for controlled and targeted pulmonary delivery of KT. A pulmonary deposition with prolonged lung residence of swellable KT-loaded HA/CS SDP was proved. The superiority of all pharmacokinetic data after pulmonary administration of selected formulae over i.v. or oral solution suggests their effectiveness in decreasing dose and hence drug systemic side effects.
Keywords: pulmonary delivery, spray drying, ketotifen, chitosan, hyaluronic acid, microparticles, dextran sulphate, sustained release, nanocomplexes.