Muco-adhesive multivesicular liposomes as an effective carrier for transmucosal insulin delivery

Considering limitations of conventional insulin therapies, the present study characterizes usefulness of novel mucoadhesive multivesicular liposomes as a mucoadhesive sustained release carrier of insulin via nasal and ocular routes, thus attempts to develop non-invasive carrier system for the controlled release of bioactives. Multivesicular liposomes (MVLs) of 26–34 μm were prepared with a high protein loading (58–62%) and were coated with chitosan and carbopol. These mucoadhesive carriers were characterized by zeta potential studies, in vitro mucoadhesion test and insulin protective ability against nasal aminopeptidase. In vitro, mucoadhesive carriers released insulin for a period of 7–9 days compared to 24 h of conventional liposomes. After intranasal administration to STZ induced diabetic rats, the mucoadhesive MVLs (chitosan coated MVLs) effectively reduced plasma glucose level up to 2 days (35% reduction), compared to non-coated MVLs (32% at 12 h) and conventional liposomes (34% at 8 h). Although the differences are statistically insignificant, chitosan coated formulation has shown a better hypoglycemic profile as the effects were prolonged compared to carbopol coated formulation. When compared to ocular route, chitosan formulation after nasal administration has shown better therapeutic profile as the hypoglycemic effects were prolonged until 72 h. The effectiveness of this chitosan coated MVLs was further demonstrated by the significant quantities of ELISA detectable insulin levels after nasal (334.6 μIu/ml) and ocular (186.3 μIu/ml) administration. These results demonstrate that mucoadhesive carrier is a viable option for a sustained release transmucosal insulin carrier, and open an avenue to develop a non-invasive carrier platform for the controlled release of bioactives.     

Microemulsion based intranasal delivery system for treatment of insomnia

The aim of this investigation was to prepare and characterize microemulsions/mucoadhesive microemulsions of Diazepam (D), Lorazepam (L) and Alprazolam (A), evaluate their pharmacodynamic performances by performing comparative sleep induction studies in male albino rats to assess their role in effective management of insomnia patients. Microemulsions of Diazepam (DME), Lorazepam (LME) and Alprazolam (AME) were prepared by titration method and characterized for drug content, globule size distribution and zeta potential, nasal toxicity and sleep induction. DME, LME and AME were transparent and stable with mean globule size and zeta potential in the range of 95.6?nm to 141.7?nm and -2.205?to -0.111?mV respectively. The prepared microemulsions exhibited reversible nasal toxicity. Onset of sleep and duration of sleep were observed in the following order: Lorazepam > Alprazolam>Diazepam. Faster onset of sleep following intranasal administration of microemulsions (<20?min) compared to oral administration (29-33?min) and control group (>45?min) for all three drugs suggested selective nose-to-brain transport of drug(s). Intranasal administration of microemulsion based formulations resulted in even faster onset of sleep (<12?min) with intranasal mucoadhesive microemulsion(s) resulting in fastest onset of sleep (<9?min). Duration of sleep was longest with the intranasal mucoadhesive microemulsions. These results are suggestive of larger extent of distribution of drug(s) to brain after intranasal administration of mucoadhesive microemulsion(s). These results are further corroborated with by loss or rightening reflex and startle reflex at earlier time points (within 10?min and 15?min respectively) with mucoadhesive microemulsions. Thus, the results of this investigation indicated rapid and larger extent of drug transport to the rat brain resulting in rapid induction of sleep followed by prolonged duration of sleep in rats following intranasal administration of mucoadhesive microemulsion(s). However, the role of microemulsion based formulations developed in this investigation in clinical practice can only be established after animal studies in two different animal models followed by extensive clinical trials.     

Therapeutic Effectiveness in the Treatment of Experimental Bacterial Keratitis with Ion-activated Mucoadhesive Hydrogel

Purpose: To investigate the therapeutic effectiveness of ion-activated mucoadhesive hydrogel system in the treatment of experimental bacterial keratitis.

Materials and Methods: Mucoadhesive systems were prepared using gellan or sodium alginate alone and combined with sodium carboxymethylcellulose (NaCMC) to enhance the gel bioadhesion properties. The in vivo antimicrobial efficacy of selected mucoadhesive systems was studied in an experiment on bacterial keratitis in rabbit’s eyes and compared with that of the marketed conventional eyedrops.

Results: Ocular tolerance was studied in the eye of albino rabbits and tested formulations were non-irritant with no sign of inflammation. Better improvement in experimental bacterial keratitis in rabbit eyes was observed in animals treated with mucoadhesive hydrogel formulation (GG5 and GS5) compared with marketed drug solution.

Conclusion: The developed system is a viable alternative to conventional eyedrops of GTN due to its ability to enhance bioavailability through its longer precorneal residence time.     

Pharmaceutical strategies to extend pulmonary exposure of inhaled medicines

Pulmonary administration route has been extensively exploited for the treatment of local lung diseases such as asthma, chronic obstructive pulmonary diseases and respiratory infections, and systemic diseases such as diabetes. Most inhaled medicines could be cleared rapidly from the lungs and their therapeutic effects are transit. The inhaled medicines with extended pulmonary exposure may not only improve the patient compliance by reducing the frequency of drug administration, but also enhance the clinical benefits to the patients with improved therapeutic outcomes. This article systematically reviews the physical and chemical strategies to extend the pulmonary exposure of the inhaled medicines. It starts with an introduction of various physiological and pathophysiological barriers for designing inhaled medicines with extended lung exposure, which is followed by recent advances in various strategies to overcome these barriers. Finally, the applications of the inhaled medicines with extended lung exposure for the treatment of various diseases and the safety concerns associated to various strategies to extend the pulmonary exposure of the inhaled medicines are summarized.     

Iron oxide induced enhancement of mucoadhesive potential of Eudragit RLPO: formulation,evaluation and optimization of mucoadhesive drug delivery system

Objectives: The objective of the study was to investigate the effect of iron oxide in the development of mucoadhesive tablets of cinnarizine using Eudragit RLPO polymer. A simplex lattice design was employed for optimizing the drug delivery system.

Methods: Different concentrations of Eudragit RLPO (X₁), iron oxide (X₂) and PVP K 30 (X₃) were taken as independent variables and mucoadhesive strength, t_50%, t_90%, MDT and tablet tensile strength were the selected response variables. Contour and 3D plots were drawn to portray the relationship between independent and response variables. Ex vivo studies were performed for the determination of mucoadhesive strength of formulated tablets employing texture analyzer. ATR-FTR, DSC and zeta potential determination were conducted for drug-excipient and ionic interaction studies.

Results: Friability, hardness and tensile strength of mucoadhesive tablet formulation were found to be 0.42 ± 0.21%, 3.93 ± 1.57 kg/cm² and 0.65 ± 0.26 mN/m², respectively. Mucoadhesive strength was found to be ranging between 5.75 ± 4.41 and 42.85 ± 3.94 g. Value of release exponent (n) was found to be 0.65 ± 0.22, indicating anomalous drug release behavior from the formulations. Numerical optimization using the desirability approach was employed for developing optimized formulation by setting constraints of the dependent and independent variables. The mucoadhesive tablet formulation composition consisting of 8.58% w/w Eudragit RLPO, 7.02% w/w iron oxide and 7.26% w/w PVP K 30 fulfilled maximum requirements of an optimum formulation with better regulation of the selected constraints.

Conclusions: Eudragit RLPO and iron oxide combination showed high level potential for fabricating gastroretentive as well as mucoadhesive drug delivery systems.     

N-trimethyl chitosan-modified liposomes as carriers for oral delivery of salmon calcitonin

Therapeutic peptide and protein drugs have high specificity and activity in their functions but present challenges in their administration route, requiring development of new delivery systems to improve their bioavailability. The aim of this work was to investigate the role of N-trimethyl chitosan- (TMC-) coated liposomes in the oral administration of calcitonin. TMC with a degree of quaternization around 78% was synthesized and its mucoadhesive properties were examined in vitro using the mucin-particle method, which confirmed that TMC showed mucoadhesion comparable to that of chitosan. TMC-coated liposomes containing calcitonin were prepared and characterized as having a particle size of 262?nm, zeta potential of 35.8 mV and high entrapment efficiency (89.1%). The in vivo evaluation of mucoadhesion was carried out using confocal laser microscopy to observe the residence time and permeation extent after intragastric administration. The results showed that TMC-coated liposomes prolonged the residence time and increased the penetration effect of the liposomal system compared to non-coated liposomes. The study of pharmacological effects confirmed that TMC-coated liposomes increased the area above the blood calcium concentration-time curves (AAC) from 3.13?±?20.50 to 448.84?±?103.56 compared to the calcitonin solution. These results support the feasibility of TMC-coated liposomes as a new oral delivery system for peptide and protein drugs.     

Management of recurrent aphthous ulcers exploiting polymer-based Muco-adhesive sponges: in-vitro and in-vivo evaluation

Recurrent aphthous ulcer (RAU) is a well-known painful, inflammatory disease with uncertain etiology for which local symptomatic therapy is only available. The aim of this study was to formulate and characterize muco-adhesive sponges containing a mixture of tenoxicam and miconazole nitrate to manage pain, inflammation and avoid candida infection that may accompany RAU due to poor oral hygiene. Two polymers at different concentrations were used to prepare sponges applying simple freeze-drying. Medicated chitosan (2%) sponges (mC2) showed acceptable physical appearance, surface pH (6.3 ± 0.042), porosity (25.7% ± 1.8), swelling index (5.7 ± 0.11), in-vivo and ex-vivo muco-adhesion time (115 min.±0.813 and 155 min.±1.537, respectively), ex-vivo muco-adhesion force (0.09 N ± 0.002) and scanning electron microscope (SEM) images. For concurrent clear-cut determination of tenoxicam and miconazole nitrate from mC2, a new UPLC method was developed and validated. mC2 sponges exhibited superior in-vitro drug release profiles where ∼100% of tenoxicam released within 5 min for fast pain relief with a more prolonged miconazole nitrate release. Furthermore, in-vivo animal study revealed that mC2 caused a significant decrease in the acetic acid-induced ulcer size in rats after 6 days of treatment (p < .0001) compared to negative and positive controls. Additionally, histopathological examination showed faster healing with complete restoration of the normal oral histology in rats. The present study concludes that chitosan sponge loaded with a combination of tenoxicam and miconazole nitrate could improve healing of RAU cases.     

Brain-Targeted Nasal Clonazepam Microspheres

Gelatin-chitosan mucoadhesive microspheres of clonazepam were prepared using the emulsion cross linking method. Mirospheres were evaluated using the in vitro and ex vivo drug release patterns. In vivo CNS drug distribution studies were carried out in rats by administering the clonazepam microspheres intra-nasally and clonazepam solution intravenously. From the drug levels in plasma and CSF, drug targeting index and drug targeting efficiency were calculated. Results obtained indicated that intranasally administered clonazepam microspheres resulted in higher brain levels with a drug targeting index of 2.12. Gelatin-chitosan cross linked mucoadhesive microspheres have the potential to be developed as a brain-targeted drug delivery system for clonazepam.