ABSTRACT
The delivery of therapeutic agents faces significant hurdles posed by the endo-lysosomal pathway, a bottleneck that hampers clinical effectiveness. This comprehensive review addresses the urgent need to enhance cellular delivery mechanisms to overcome these obstacles. It focuses on the potential of smart nanomaterials, delving into their unique characteristics and mechanisms in detail. Special attention is given to their ability to strategically evade endosomal entrapment, thereby enhancing therapeutic efficacy. The manuscript thoroughly examines assays crucial for understanding endosomal escape and cellular uptake dynamics. By analyzing various assessment methods, we offer nuanced insights into these investigative approaches' multifaceted aspects. We meticulously analyze the use of smart nanocarriers, exploring diverse mechanisms such as pore formation, proton sponge effects, membrane destabilization, photochemical disruption, and the strategic use of endosomal escape agents. Each mechanism's effectiveness and potential application in mitigating endosomal entrapment are scrutinized. This paper provides a critical overview of the current landscape, emphasizing the need for advanced delivery systems to navigate the complexities of cellular uptake. Importantly, it underscores the transformative role of smart nanomaterials in revolutionizing cellular delivery strategies, leading to a paradigm shift towards improved therapeutic outcomes.
Subject(s)
Endosomes , Lysosomes , Lysosomes/metabolism , Humans , Endosomes/metabolism , Drug Delivery Systems , Drug Carriers/chemistry , Nanostructures/chemistry , Animals , Nanoparticles/chemistryABSTRACT
To introduce products in the US market, pharmaceutical companies must first obtain FDA clearance. Manufacturers might recall a product if it poses a risk of damage or violates FDA regulations. This study investigates the types, causes and consequences of recalls, as well as FDA participation and suitable recall strategies. We relied on the FDA website to gather recall data sets from 2012 to 2023, collecting information on the date of issuance, company and type of violation. The most frequent causes for recalls were sterility issues and inadequate compliance with current good manufacturing practices (cGMP). An examination of sterility recalls revealed two primary causes: a lack of assurance in sterility (accounting for 48% of recalls) and instances of non-sterility (making up 45% of recalls). A thorough examination of cGMP recalls revealed five primary types of violations: process control issues, inadequate storage practices, manufacturing problems, the presence of nitroso-amine impurities and concerns regarding stability. The findings demonstrate that sterility and cGMP compliance are FDA priorities. Pharmaceutical companies must, therefore, enhance quality compliance and create effective quality management systems that oversee the manufacturing process, quality control, personnel training and documentation to avoid these recalls. Companies should establish an internal compliance checklist and be prepared for the rectification process.
Subject(s)
Drug Industry , United States Food and Drug Administration , United States , Drug Industry/standards , Drug Recalls , Humans , Retrospective StudiesABSTRACT
Parkinson's disease is a chronic, progressive neurological disease that currently affects about more than 10 million population worldwide. Rasagiline is a selective, irreversible monoamine oxidase type B inhibitor used as monotherapy in early Parkinson's disease. Rasagiline tablets have been recalled from market due to the presence of unacceptable levels of nitrosamine impurity. European Medical Agency has set up very stringent limit 100ng/day of N-nitrosorasagiline (NSRG) in drug product based on its mutagenicity. The analytical methods need to be sufficiently sensitive in order to adequately detect and quantify trace levels of NSRG. A highly sensitive LC-MS/MS method for determination of NSRG in rasagiline tablet formulation was developed by effectively separating on zorbax eclipse XDB C18 column using 0.1% formic acid in mixture of water and acetonitrile (35:65 v/v) in an isocratic mode at 0.5mL/min flow rate. The measurement of NSRG was performed using triple quadrupole mass detection accompanied by electrospray ionization in the multiple reaction monitoring mode. The validation of the method was comprehensive, demonstrating strong linearity across the concentration spectrum of 2 to 200ng/mL for NSRG. The obtained correlation coefficient exceeded 0.998, signifying a robust relationship. Recoveries spanning from 80.0% to 120.0% for NSRG were deemed satisfactory. The developed method was able to detect and quantitate NSRG at a concentration level of 1 to 2ng/mL respectively (1 to 2ppm with respect to 1mg/mL of rasagiline tablet sample concentration). The developed and validated method can be employed for routine quality control testing of rasagiline tablets.
ABSTRACT
INTRODUCTION: With the increase in the elderly population and the prevalence of multiple medical conditions, medication adherence, and efficacy have become crucial for the effective management of their health. The aging population faces unique challenges that need to be addressed through advancements in drug delivery systems and formulation technologies. AREAS COVERED: The current review highlights the recent advances in dosage form design for older individuals, with consideration of their specific physiological and cognitive changes. Various dosage forms, such as modified-release tablets/capsules, chewable tablets, and transdermal patches, can be tailored to meet the specific needs of elderly patients. Advancements in drug delivery systems, such as nanotherapeutics, additive manufacturing (three-dimensional printing), and drug-food combinations, improve drug delivery and efficacy and overcome challenges, such as dysphagia and medication adherence. EXPERT OPINION: Regulatory guidelines and considerations are crucial in ensuring the safe utilization of medications among older adults. Important factors to consider include geriatric-specific guidelines, safety considerations, labeling requirements, clinical trial considerations, and adherence and accessibility considerations.
Subject(s)
Drug Delivery Systems , Humans , Aged , Tablets , Capsules , Dosage FormsABSTRACT
Over the past several decades, there has been significant growth in the design and development of more efficient and advanced biomaterials based on non-cellulosic biological macromolecules. In this context, hydrogels based on stimuli-responsive non-cellulosic biological macromolecules have garnered significant attention because of their intrinsic physicochemical properties, biological characteristics, and sustainability. Due to their capacity to adapt to physiological pHs with rapid and reversible changes, several researchers have investigated pH-responsive-based non-cellulosic polymers from various materials. pH-responsive hydrogels release therapeutic substances in response to pH changes, providing tailored administration, fewer side effects, and improved treatment efficacy while reducing tissue damage. Because of these qualities, they have been shown to be useful in a wide variety of applications, including the administration of chemotherapeutic drugs, biological material, and natural components. The pH-sensitive biopolymers that are utilized most frequently include chitosan, alginate, hyaluronic acid, guar gum, and dextran. In this review article, the emphasis is placed on pH stimuli-responsive materials that are based on biological macromolecules for the purposes of drug administration.
ABSTRACT
Cystic fibrosis (CF), a fatal genetic condition, causes thick, sticky mucus. It also causes pancreatic dysfunction, bacterial infection, and increased salt loss. Currently available treatments can improve the patient's quality of life. Drug delivery aided by nanotechnology has been explored to alter the pharmacokinetics and toxicity of drugs. In this short review, we aim to summarize various conventional formulations and highlight advanced formulations delivered via the pulmonary route for the treatment of CF. There is considerable interest in advanced drug delivery formulations addressing the various challenges posed by CF. Despite their potential to be translated for clinical use, we anticipate that a significant amount of effort may still be required for translation to the clinic.
ABSTRACT
RATIONALE: Since June 2018, globally large numbers of pharmaceuticals have been recalled due to the unexpected presence of nitrosamines. Beginning with the class of pharmaceuticals known as sartans, subsequent lines of inquiry included antidiabetic medicines, antihistamines, and antibiotics. A critical review of the U.S. Food and Drug Administration database reveals that the highest number of products recall due to the presence of unacceptable levels of nitrosamines were losartan potassium drug products and their coformulations with other drug substances. The problem can be mainly attributed to naively adopted approval revisions and the lack of sufficient current analytical technologies to detect those contaminants in time. In this work, we developed a specific, selective, accurate, precise, and robust ultra-performance liquid chromatography-triple quadrupole-mass spectrometry (UPLC-TQ-MS/MS) method for the estimation of eight genotoxic nitrosamine impurities in losartan and hydrochlorothiazide (HCTZ) tablets, which is the only fixed-dosage combination approved by the USFDA to treat hypertension. METHODS: All the nitrosamine impurities along with the drug substances were separated using an Agilent Pursuit XRs Ultra diphenyl column (150 × 2.0 mm, 2.8 µm) with mobile phase A (0.1% formic acid in water) and mobile phase B (0.1% formic acid in methanol) at a flow rate of 0.4 ml/min using the gradient elution program. The proposed method was validated per ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) Q2 (R1) guidelines to ensure the method is suitable for its intended purpose. RESULTS: Limit of detection and limit of quantification were obtained in the range of 0.25-0.5 ng/mL, which was very low compared to levels specified by the USFDA, European Medicines Agency (EMA), and other regulatory authorities that ensure the sensitivity of the method in its entire life cycle. CONCLUSIONS: The developed method can be incorporated into an official monograph and applied for routine quality control analysis of losartan and HCTZ fixed-dose combination tablets.
Subject(s)
Losartan , Nitrosamines , Humans , Losartan/analysis , Losartan/chemistry , Hydrochlorothiazide/chemistry , Chromatography, High Pressure Liquid/methods , Tandem Mass Spectrometry/methods , Chromatography, Liquid , TabletsABSTRACT
Pomegranate seed oil with its high levels of phenolic compounds is known to exhibit neuroprotective effects. Delivering hydrophilic drugs to the brain is challenging since blood-brain barrier allows only a few lipophilic molecules into the brain, thus posing an additional barrier for drug delivery to the brain in conditions like Alzheimer's. The present study focuses on the preparation of the stable galantamine hydrobromide (GHBr) microemulsion (ME) using pomegranate seed oil (PSO) as an adjuvant. The developed ME was characterized for various physicochemical properties, cytotoxicity, and protective role against Amyloid Beta (1-42) oligomer-induced toxicity in IMR 32 cell line. GHBr and PSO ratio was optimized based on an in-vitro diffusion study and compatibility study using DSC and FTIR. The ME was prepared by the water titration method and optimized using the one variable at a time (OVAT) strategy. Globule size and PDI of GHBr PSO ME were found to be 200.36 ± 0.01 nm, and 0.219 ± 0.011 nm respectively. GHBr PSO ME showed significantly better results in terms of cell line toxicity, antioxidant activity and protective effect against Aß induced cell death. The results obtained showed the potential of using PSO as an effective synergistic agent along with the anti-Alzheimer's drug for the treatment of disease.
Subject(s)
Antioxidants , Pomegranate , Galantamine , Amyloid beta-Peptides , Emulsions/chemistry , Plant Oils/chemistryABSTRACT
PURPOSE: The aim of the present study was to investigate increase in delivery of drug upon formulation as mucoadhesive microemulsion system and further to investigate possibility of any cytotoxic effects using such formulation. MATERIAL AND METHODS: Considering hydrophilic and small molecular nature of the drug, it was attempted to be formulated as microemulsion, by using pseudo ternary phase diagram method. Thus, three types of microemulsions were prepared; oil in water, water in oil type and chitosan-coated microemulsion. These microemulsions were characterized for several physicochemical properties like size, zeta potential, Polydispersity index, and compared for in vitro cell viability and ex vivo corneal irritation study. RESULTS: All three microemulsions were quite stable, transparent and homogenous systems. They showed similar drug release pattern, but highest ex vivo goat corneal permeation was observed with Chitosan coated microemulsion when compared with ganciclovir solution. CONCLUSION: All microemulsions were found to be non-irritant in in vitro cell viability assay and ex vivo corneal irritation study, indicating the potential of using such systems for delivery of drug to eye.
Subject(s)
Chitosan , Drug Delivery Systems , Drug Delivery Systems/methods , Chitosan/toxicity , Chitosan/chemistry , WaterABSTRACT
A novel stability-indicating, reversed-phase, high-performance liquid chromatography (RP-HPLC) method was developed and validated for the determination of favipiravir in an oral suspension. The effective separation of favipiravir and its degradation products was achieved on a Zorbax Eclipse Plus C18 column (5 µm particle size, 150 mm length × 4.6 mm diameter). The mobile phase was prepared by mixing 5 mM of phosphate buffer (pH 3.5) and methanol in a 75:25 v/v ratio delivered at a 1.0 mL/min flow rate. The eluents were monitored using a photodiode array detector at a wavelength of 322 nm. The stability-indicating nature of this method was evaluated by performing force degradation studies under various stress conditions, such as acidic, alkali, oxidative, thermal, and photolytic degradation. Significant degradation was observed during the alkali stress degradation condition. The degradation products generated during various stress conditions were well separated from the favipiravir peak. In addition, the major degradation product formed under alkali stress conditions was identified using UPLC-ESI-TQ-MS/MS and NMR. Method validation was performed according to the ICH Q2 (R1) guideline requirements. The developed method is simple, accurate, robust, and reliable for routine quality control analysis of favipiravir oral suspensions.
Subject(s)
Alkalies , Tandem Mass Spectrometry , Amides , Chromatography, High Pressure Liquid/methods , Pyrazines , Suspensions , Tandem Mass Spectrometry/methodsABSTRACT
Epidemiologically Parkinson's disease (PD) is associated with chronic ingestion or inhalation of environmental toxins leading to the development of motor symptoms. Though neurotoxin-based animal models played a major role in understanding diverse pathogenesis, they failed to identify the risk assessment due to uncommon route of toxin exposure. Towards this, the available neurotoxin-based intranasal (i.n.) PD models targeting olfactory bulb (OB) have demonstrated the dopaminergic (DAergic) neurodegeneration in both OB and substantia nigra (SN). Despite that, the studies detecting the alpha-synuclein (α-syn) accumulation in OB and its progression to other brain regions due to inhalation of environmental toxins are still lacking. Herein, we developed oil in water microemulsion of rotenone administered intranasally to the mice at a dose which is not detectable in blood, brain, and olfactory bulb by LCMS method. Our data reveals that 9 weeks of rotenone exposure did not induce olfactory and motor dysfunction. Conversely, after 16 weeks of washout period, rotenone treated mice showed both olfactory and motor impairment, along with α-syn accumulation in the OB and striatum without glial cell activation and loss of dopaminergic neurons. The results depict the progressive nature of the developed model and highlight the role of α-syn in PD like pathology or symptoms. Together, our findings suggest the adverse consequences of early exposure to the environmental toxins on the olfactory system for a shorter period with relevance to the development of synucleinopathy or Parkinson's disease in its later stage.
Subject(s)
Parkinson Disease , alpha-Synuclein , Animals , Disease Models, Animal , Dopaminergic Neurons/metabolism , Mice , Parkinson Disease/pathology , Rotenone/toxicity , Substantia Nigra/metabolism , alpha-Synuclein/metabolismABSTRACT
The present study investigates the role of fish oil (FO)- and butter oil (BO)-enriched microemulsion-based system of galantamine hydrobromide (GH), an anti-Alzheimer drug, for its potential role in brain permeation enhancement and neuroprotection against oxidative stress. Microemulsion (ME)-based system of GH was prepared using water phase titration. The prepared ME was characterized by several physicochemical parameters like particle size, polydispersity index, and ex vivo drug permeation. Cell-based oxidative stress assays and pharmacokinetic studies were performed using C6 glial cell lines, and Sprague Dawley rats, respectively. The optimized ME comprised 5.3% v/v of Capmul MCM EP (as oil),15.8% v/v of Tween-80 (as surfactant), 5.3% v/v of Transcutol P (as co-surfactant), and 73.6% v/v of water (as aqueous phase). The addition of FO and BO resulted in a slight increase in the droplet size and decrease in transparency of ME. Cell-based anti-oxidative stress assays (glutathione assay, nitrite assay, and lipid peroxidation assay) showed the efficacy of formulation in the order of ME, BO ME, and FO ME, respectively. A similar trend was also observed in in vivo animal studies, wherein GH FO ME showed a comparatively higher percentage of drug reaching the brain when administered by intranasal route than by IV route. The study concluded the potential benefits of co-administering FO- and BO-enriched microemulsion is not only enhancing the permeation of drugs across BBB but also improving efficacy against lipopolysaccharide-induced oxidative stress. Graphical abstract.
Subject(s)
Fish Oils/administration & dosage , Galantamine/administration & dosage , Ghee , Neuroprotective Agents/administration & dosage , Administration, Intranasal , Administration, Intravenous , Animals , Brain/metabolism , Cell Line, Tumor , Cell Survival/drug effects , Emulsions , Fish Oils/chemistry , Fish Oils/pharmacokinetics , Galantamine/blood , Galantamine/chemistry , Galantamine/pharmacokinetics , Glutathione/metabolism , Goats , Lipopolysaccharides , Malondialdehyde/metabolism , Neuroprotective Agents/blood , Neuroprotective Agents/chemistry , Neuroprotective Agents/pharmacokinetics , Oxidative Stress/drug effects , Rats, Sprague-DawleyABSTRACT
In order to investigate the possible role of butter oil (BO) and omega-3 fatty acids-rich fish oil (O3FO) in the delivery of donepezil hydrochloride microemulsion (DH-ME) to the brain via intranasal route, the present study was conducted. DH:BO and DH:O3FO binary mixtures (9:1 to 1:9) were prepared by simple physical mixing and subjected to in vitro diffusion study. Ratios of DH:BO and DH:O3FO, which showed the highest diffusion, were selected for further development of microemulsion (ME). Globule sizes of DH-BO-ME and DH-O3FO-ME were found to be 87.66 ± 5.23 nm and 88.59 ± 8.23 nm, respectively. Nasal histopathological study and in vitro cytotoxicity study revealed the safety of the formulation. Higher percentage of nasal diffusion was found with DH-BO-ME (71.22 ± 1.21%) and DH-O3FO-ME (62.16 ± 1.23%) in comparison to DH-ME (59.69 ± 1.74%) and DH solution (55.01 ± 1.19%), which was further supported by in vitro cell permeability study. After intranasal administration, %bioavailability of drug in the rat brain (Sprague-Dawley rats)(on the basis of DH-ME IV) was higher with DH-BO-ME (313.59 ± 12.98%) and DH-O3FO-ME (361.73 ± 15.15%) in comparison to DH-ME (168.62 ± 6.60%) and DH solution (8.960 ± 0.23%). The results of ex vivo diffusion study and in vivo pharmacokinetic study suggested that BO and O3FO helped in enhancing the nasal permeability and the brain uptake of drug when administered intranasally.
Subject(s)
Brain/metabolism , Donepezil/administration & dosage , Emulsions/metabolism , Fatty Acids, Omega-3/administration & dosage , Ghee , Administration, Intranasal , Animals , Biological Availability , Drug Delivery Systems , Male , Rats , Rats, Sprague-DawleyABSTRACT
Purpose: Androgenic alopecia (AGA) is a condition of progressive hair loss and involves follicular miniaturization triggered mainly due to varying levels of androgen besides environmental and genetic factors, which may also play some role. Minoxidil (MXD) has been considered as most effective therapeutic moiety to treat this disorder. Another drug Tretinoin (TRET) is known for its comedolytic activity and is reported to enhance percutaneous absorption of MXD. Presently both these drugs are being utilized for treatment of androgenic alopecia (AGA) in solution form which poses several problems in terms of poor solubility of drug, frequency of application and side effects.Materials and methods: Current work investigates liposomal hydrogel system for simultaneous delivery of MXD and TRET to overcome the limitations of existing formulation. Successful development of liposomes was commenced by thin film hydration method and various parameters affecting desired characteristics like size, morphology, entrapment efficiency; stability and ex vivo permeation were optimized. The formulated liposomes were further characterized for various physicochemical properties and evaluated for in vivo irritancy study in animals.Results and discussion: Results suggested prepared liposomes to be stable, homogenous and capable to hold both the drugs within. Association with hydrogel enhanced the permeation of MXD through skin ex vivo but TRET retained on the skin. Liposome loaded hydrogel was found to be non-irritant to skin.Conclusion: Overall developed system showed potential for effective and simultaneous delivery of both the drugs.
Subject(s)
Hydrogels , Liposomes , Minoxidil/chemistry , Minoxidil/pharmacology , Tretinoin/chemistry , Tretinoin/pharmacokinetics , Administration, Topical , Alopecia/drug therapy , Animals , Biological Transport , Drug Therapy, Combination , Keratolytic Agents/administration & dosage , Keratolytic Agents/chemistry , Keratolytic Agents/pharmacology , Male , Minoxidil/administration & dosage , Minoxidil/adverse effects , Rats , Rats, Sprague-Dawley , Skin/drug effects , Skin Diseases/chemically induced , Tretinoin/administration & dosage , Tretinoin/adverse effects , Vasodilator Agents/administration & dosage , Vasodilator Agents/chemistry , Vasodilator Agents/pharmacologyABSTRACT
Since the discovery of fatty acids, a niche has been carved for their vital role as adjuvants in drug delivery and as treatment for various diseases. The literature has repeatedly described the essential role of various fatty acids in treating a wide range of diseases and disorders, from central nervous system diseases to wound healing. The use of fatty acids has expanded to many horizons and in recent decades they have gained importance as drug delivery adjuvants in addition to their auxiliary benefits in treating various diseases. Although fatty acids aid in solving both formulation-based and therapeutic challenges to our knowledge, they have never been viewed as dual agents in modern scientific literature. The aim of this review was to provide this perspective and combine the very discreet literature about fatty acids, which includes their role as therapeutic adjuvants and drug delivery agents. It gives insights on the use of fatty acids in treating the diseases of the eye, skin, central nervous system, viral diseases, and so on. The review further discusses how the structure of fatty acids plays an important role in therapeutic activity and affects formulation stability.
Subject(s)
Adjuvants, Immunologic/pharmacology , Drug Delivery Systems , Fatty Acids/pharmacology , HumansABSTRACT
PURPOSE: Presence of tight junctions in blood brain barrier (BBB) pose a major hurdle for delivery of drug and severely affects adequate therapeutic concentration to reach the brain. In present work, we have selected Rivastigmine hydrogen tartrate (RHT), a reversible cholinesterase inhibitor, which exhibits extensive first-pass metabolism, resulting in limited absolute bioavailability (36%). RHT shows extremely low aqueous solubility and poor penetration, resulting in inadequate concentration reaching the brain, thus necessitating frequent oral dosing. To overcome these problems of RHT, microemulsion (ME) and mucoadhesive microemulsion (MME) of RHT were formulated for brain targeting via intranasal delivery route and compared on the basis of in vivo pharmacokinetics. METHODS: ME and MME formulations containing RHT were developed by water titration method. Characterization of ME and MME was done for various physicochemical parameters, nasal spray pattern, and in vivo pharmacokinetics quantitatively and qualitatively (gamma scintigraphy studies). RESULTS: The developed ME and MME were transparent having globule size approximately in the range of 53-55 nm. Pharmacokinetic studies showed higher values for Cmax and DTP for intranasal RHT: CH-ME over RHT-ME, thus indicating the effect of chitosan in modulating tight junctions, thereby enhanced paracellular transport of RHT. CONCLUSION: Gamma scintigraphy and in vivo pharmacokinetic study suggested enhanced RHT concentration, upon intranasal administration of RHT:CH-ME, compare with other groups administered formulations intranasally. These findings suggested the potential of non-invasive intranasal route for brain delivery, especially for therapeutics, facing challenges in oral administration.
Subject(s)
Blood-Brain Barrier/metabolism , Brain/drug effects , Cholinesterase Inhibitors/pharmacokinetics , Emulsions/chemistry , Rivastigmine/pharmacokinetics , Administration, Intranasal/methods , Adsorption , Alzheimer Disease/drug therapy , Animals , Biological Availability , Biological Transport , Chitosan/chemistry , Cholinesterase Inhibitors/administration & dosage , Cholinesterase Inhibitors/chemistry , Cholinesterases/metabolism , Chromatography, High Pressure Liquid/methods , Drug Compounding/methods , Drug Delivery Systems/methods , Drug Liberation , Humans , Isotope Labeling/methods , Nasal Mucosa/metabolism , Rats , Rats, Sprague-Dawley , Rivastigmine/administration & dosage , Rivastigmine/chemistry , Solubility , Tissue DistributionABSTRACT
The aim of the study was to formulate a microemulsion (ME) using chitosan (CH) and the butter oil (BO) as a permeation enhancer for targeting drug to the posterior segment of the eye, via topical route. Triamcinolone acetonide (TA) was selected as the model drug since it undergoes extensive first-pass metabolism, leading to poor oral bioavailability of 23%. For optimisation of BO concentration, different ratios of TA:BO were prepared by simple physical mixing in the ratio of 1:9 to 9:1 and diffusion study was performed. MEs containing TA, TA:BO and TA CH ME were formulated by water titration method. Globule sizes of TA ME, TA:BO ME and TA CH ME were found to be 66.06 ± 0.32 nm, 78.52 ± 1.50 nm and 97.30 ± 2.50 nm, respectively. In ex vivo diffusion studies using goats eye, TA:BO ME (31.33 ± 0.46 and 33.98 ± 0.23) and TA CH ME (24.10 ± 0.41 and 27.00 ± 0.18) showed higher percentage of drug diffusion in comparison to TA ME (13.29 ± 0.41and 15.56 ± 0.34) and TA solution (8.20 ± 1.04 and 10.39 ± 0.22) in presence and in absence of vitreous humour. Fluorescence intensity of coumarin-6 (as a marker) loaded ME with BO and CH was found to be higher, confirming their role in altering membrane permeability and facilitating coumarin-6 diffusion to the posterior chamber. Overall, it was concluded that BO enhances the bioavailability of TA across the retina, thereby proving its potential as permeation enhancer in facilitating drug delivery to the posterior segment of the eye.
Subject(s)
Chitosan , Cornea/metabolism , Drug Delivery Systems/methods , Ghee , Triamcinolone Acetonide , Animals , Chick Embryo , Chitosan/chemistry , Chitosan/pharmacokinetics , Chitosan/pharmacology , Emulsions , Goats , Triamcinolone Acetonide/chemistry , Triamcinolone Acetonide/pharmacokinetics , Triamcinolone Acetonide/pharmacologyABSTRACT
The objective of the present investigation was to optimize and develop quetiapine fumarate (QF) loaded chitosan nanoparticles (QF-NP) by ionic gelation method using Box-Behnken design. Three independent variables viz., X1-Concentration of chitosan, X2-Concentration of sodium tripolyphosphate and X3-Volume of sodium tripolyphosphate were taken to investigate their effect on dependent variables (Y1-Size, Y2-PDI and Y3-%EE). Optimized formula of QF-NP was selected from the design space which was further evaluated for physicochemical, morphological, solid state characterization, nasal diffusion and in-vivo distribution for brain targeting following non-invasive intranasal administration. The average particle size, PDI, %EE and nasal diffusion were found to be 131.08±7.45nm, 0.252±0.064, 89.93±3.85% and 65.24±5.26% respectively. Neither toxicity nor structural damage on nasal mucosa was observed upon histopathological examination. Significantly higher brain/blood ratio and 2 folds higher nasal bioavailability in brain with QF-NP in comparison to drug solution following intranasal administration revealed preferential nose to brain transport bypassing blood-brain barrier and prolonged retention of QF at site of action suggesting superiority of chitosan as permeability enhancer. Overall, the above finding shows promising results in the area of developing non-invasive intranasal route as an alternative to oral route for brain delivery.
Subject(s)
Antipsychotic Agents/pharmacokinetics , Brain/metabolism , Chitosan/chemistry , Drug Carriers/pharmacokinetics , Nanoparticles/chemistry , Quetiapine Fumarate/pharmacokinetics , Administration, Intranasal , Animals , Antipsychotic Agents/chemistry , Area Under Curve , Biological Availability , Drug Carriers/chemistry , Drug Compounding , Factor Analysis, Statistical , Goats , Nanoparticles/ultrastructure , Nasal Mucosa/metabolism , Particle Size , Permeability , Polyphosphates/chemistry , Quetiapine Fumarate/chemistry , Rats, Sprague-Dawley , Tissue Culture Techniques , Tissue DistributionABSTRACT
Systemic drug delivery in schizophrenia is a major challenge due to presence of obstacles like, blood-brain barrier and P-glycoprotein, which prohibit entry of drugs into the brain. Quetiapine fumarate (QF), a substrate to P-glycoprotein under goes extensive first pass metabolism leading to limited absorption thus necessitating frequent oral administration. The aim of this study was to develop QF based microemulsion (ME) with and without chitosan (CH) to investigate its potential use in improving the bioavailability and brain targeting efficiency following non-invasive intranasal administration. QF loaded ME and mucoadhesive ME (MME) showed globule size, pH and viscosity in the range of 29-47nm, 5.5-6.5 and 17-40cP respectively. CH-ME with spherical globules having mean size of 35.31±1.71nm, pH value of 5.61±0.16 showed highest ex-vivo nasal diffusion (78.26±3.29%) in 8h with no sign of structural damage upon histopathological examination. Circular plume with an ovality ratio closer to 1.3 for CH-ME depicted ideal spray pattern. Significantly higher brain/blood ratio of CH-ME in comparison to QF-ME and drug solution following intranasal administration revealed prolonged retention of QF at site of action suggesting superiority of CH as permeability enhancer. Following intranasal administration, 2.7 and 3.8 folds higher nasal bioavailability in brain with CH-ME compared to QF-ME and drug solution respectively is indicative of preferential nose to brain transport (80.51±6.46%) bypassing blood-brain barrier. Overall, the above finding shows promising results in the area of developing non-invasive intranasal route as an alternative to oral route for brain delivery.