Effects of degree of quaternization on the preparation and characterization of insulin-loaded trimethyl chitosan polyelectrolyte complexes optimized by central composite design

The aim of the present study was to investigate the effects of varying degrees of quaternization (DQ: 22, 35 and 41%) on the preparation and characterization of insulin (INS)-loaded polyelectrolyte complexes (PECs) prepared by N-trimethyl chitosan chloride (TMC). A two factor-five level central composite design was used for the optimization. The concentrations of INS and TMC were defined as independent variables, while the entrapment efficiency (EE%) and loading efficiency (LE%) as dependent variables. The three optimized INS-TMC PECs were characterized for their size, zeta potential, EE% and LE%. The morphology and electrostatic interaction of PECs were evaluated. Then, the stability in the enzyme solution and in vitro release as well as mucoadhesive properties of the three PECs were all investigated. The results showed that the size and EE% of the optimum formulations were significantly decreased using TMC of higher DQ, while the zeta potential and LE% were slightly influenced by DQ. The stability assay exhibited partial protection of TMC PECs, and the better protective effect was observed for PECs of higher DQ. The in vitro release study presented different initial and sustained release behaviors of INS-TMC PECs and the mucin adsorption study confirmed a positive correlation between the DQ and the mucoadhesive property of PECs.     

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.     

Preparation and investigation of Ulex europaeus agglutinin I-conjugated liposomes as potential oral vaccine carriers

We prepared and optimized Ulex europaeus agglutinin I (UEAI)-modified Bovine serum albumin (BSA)-encapsulating liposomes (UEAI-LIP) as oral vaccine carriers and examined the feasibility of inducing systemic and mucosal immune responses by oral administration of UEAILIP. The prepared systems were characterized in vitro for their average size, zeta potential, encapsulation efficiency (EE%) and conjugation efficiency (CE%). In vitro release studies indicated that the presence of UEAI around the optimized liposomes was able to prevent a burst release of loaded BSA and provide sustained release of the encapsulated protein. In vivo immune-stimulating results in KM mice showed that BSA given intramuscularly generated systemic response only but both systemic and mucosal immune responses could be induced simultaneously in the groups in which BSA-loaded liposomes (LIP) and UEAI-LIP were administered intragastrically. Furthermore, the modification of UEAI on the surface of liposomes could further enhance the IgA and IgG levels obviously. In conclusion, this study demonstrated the high potential of lectin-modified liposomes containing the antigen as carriers for oral vaccine.     

N-三甲基壳聚糖包衣的盐酸阿霉素脂质体的制备

研制N-三甲基壳聚糖（TMC）包衣的盐酸阿霉素（ADM）脂质体。方法：采用硫酸铵梯度法制备ADM脂质体,以包封率为指标,筛选盐酸阿霉素脂质体最佳处方;合成不同季铵化程度的TMC,并对最佳ADM脂质体进行包衣。结果：未包衣ADM脂质体平均粒径为（378．6±5．2）nm,Zeta电位为（-62．08±2．5）mv,平均包封率为（62．27±1．75）％（n=3）。TMC包衣后,脂质体粒径增大,并随着TMC季铵化程度的增大,Zeta电位显著增大（p＜0．05）;TMC20、TMC40、TMC60包衣脂质体体外释药曲线符合Higuchi方程,分别为：Q=7．6315＋3．7863t1／2（r=0．9292）,Q=6．9647＋3．5709t1／2（r=0．9318）,Q=7．3451＋2．7665t1/2（r=0．9357）。结论：TMC包衣ADM脂质体的制备工艺可行,其表面带有较高正电性,为下一步研究其血管靶向性打下基础。     

Formulation and evaluation of stomach-specific amoxicillin-loaded carbopol-934P mucoadhesive microspheres for anti-Helicobacter pylori therapy

The purpose of this research was to formulate and systemically evaluate in vitro and in vivo performances of mucoadhesive amoxicillin microspheres for the potential use in the treatment of gastric and duodenal ulcers, which were associated with Helicobacter pylori. Amoxicillin mucoadhesive microspheres containing carbopol-934P as mucoadhesive polymer and ethyl cellulose as carrier polymer were prepared by an emulsion-solvent evaporation technique. Results of preliminary trials indicate that quantity of emulsifying agent, time for stirring, drug-to-polymers ratio and speed of rotation affected the characteristics of microspheres. Microspheres were discrete, spherical, free flowing and showed a good percentage of drug entrapment efficiency. An in vitro mucoadhesive test showed that amoxicillin mucoadhesive microspheres adhered more strongly to the gastric mucous layer and could retain in the gastrointestinal tract for an extended period of time. A 3² full factorial design was employed to study the effect of independent variables, drug-to-polymer-to-polymer ratio (amoxicillin-ethyl cellulose-carbopol-934P) (X₁) and stirring speed (X₂) on dependent variables, i.e. percentage mucoadhesion, drug entrapment efficiency, particle size and t₈₀. The best batch exhibited a high drug entrapment efficiency of 56%; mucoadhesion percentage after 1 h was 80% and the particle size was 109 µm. A sustained drug release was obtained for more than 12 h. The drug-to-polymer-to-polymer ratio had a more significant effect on the dependent variables. The morphological characteristics of the mucoadhesive microspheres were studied under a scanning electron microscope. In vitro release test showed that amoxicillin released slightly faster in pH 1.2 hydrochloric acid than in pH 7.8 phosphate buffer. In vivo H. pylori clearance tests were also carried out by administering amoxicillin powder and mucoadhesive microspheres to H. pylori infectious Wistar rats under fed conditions at single dose or multiple dose(s) in oral administration. The results showed that amoxicillin mucoadhesive microspheres had a better clearance effect than amoxicillin powder. In conclusion, the prolonged gastrointestinal residence time and enhanced amoxicillin stability resulting from the mucoadhesive microspheres of amoxicillin might make a contribution to H. pylori complete eradication.     

Chitosan nanoconstructs for improved oral delivery of low molecular weight heparin: In vitro and in vivo evaluation

The aim of present study was to investigate the potential of mucoadhesive polymer chitosan (CS) and N-trimethyl chitosan (TMC) based nanoparticulate systems for oral bioavailability enhancement of low molecular weight heparin (LMWH). The TMC was synthesized by methylation of chitosan followed by characterization using infrared spectroscopy and (1)H-NMR spectroscopy. The IR and NMR spectra of TMC confirmed the presence of trimethyl groups and estimated the degree of quaternization for TMC about 46%. TMC nanoparticles were then prepared by ionic gelation method. The developed CS-NPs and TMC-NPs were characterized for various parameters including morphology, particle size, zeta potential, entrapment efficiency, in vitro release behavior and storage stability at different temperature and simulated gastrointestinal tract conditions. The fluorescent microscopy study confirmed the higher particle uptake of TMC-NPs by gastrointestinal epithelium in comparison to the CS-NPs. The concentration of LMWH in the systemic circulation followed by oral administration of formulations was estimated using FXa chromogenic assay. A significant increase (p<0.05) in the oral bioavailability of LMWH was observed with TMC-NPs than both CS-NPs as well as plain LMWH solution. These findings suggested that TMC nanoparicles hold promise for oral delivery of LMWH and clinical applicability for the treatment of vascular disorders like deep vein thrombosis and pulmonary embolism, etc.     

Sustained-release diclofenac potassium-loaded solid lipid microparticle based on solidified reverse micellar solution: in vitro and in vivo evaluation

Objective: To formulate sustained-release diclofenac potassium-loaded solid lipid microparticles (SLMs) based on solidified reverse micellar solution (SRMS) and to evaluate the in vitro and in vivo properties.

Methods: SRMS consisting of mixtures of Phospholipon® 90H and Softisan® 154 were used to formulate diclofenac potassium-loaded SLMs. Characterization based on the particle size and morphology, stability and encapsulation efficiency (EE%) were carried out on the SLMs. In vitro release was carried out in simulated intestinal fluid (pH 7.5). Anti-inflammatory and ulcerogenic properties were studied using rats.

Results: Maximum EE% of 95%, 94% and 93% were obtained for SLMs formulated with SRMS 1:1, 2:1 and 1:2, respectively. In vitro release showed about 85–90% drug release at 13?h. Diclofenac potassium-loaded SLMs showed good anti-inflammatory and gastro-protective properties.

Conclusion: Diclofenac potassium-loaded SLMs based on SRMS could be used orally or parenterally under controlled conditions, for once daily administration.     

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.     

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.     

Formulation optimization and <Emphasis Type="Italic">in vivo</Emphasis> evaluation of mucoadhesive xyloglucan microspheres

Mucoadhesive microspheres of the novel polymer, xyloglucan, have been formulated and their performance characteristics have been systematically evaluated in vitro and in vivo. The mucoadhesive microspheres were obtained by incorporating glipizide as model drug in xyloglucan as a mucoadhesive polymer and sodium alginate as a gel-forming polymer by the orifice-ionic gelation method. A3² factorial design was employed to study the effect of independent variables, xyloglucan concentration (X ₁ ) and calcium chloride (CaCl₂) concentration (X ₂ ), on the dependent variables including drug entrapment efficiency, release time (t ₈₀), and percentage mucoadhesion in 1h. The best batch exhibited high drug entrapment efficiency (92.98%) and percentage mucoadhesion (78% after 1h). The drug release was also controlled for more than 8 hours. In vivo testing of the mucoadhesive microspheres revealed significant hypoglycemic effect of glipizide.     

Formulation and evaluation of novel solid lipid microparticles as a sustained release system for the delivery of metformin hydrochloride

Abstract

The low encapsulation efficiency of conventional solid lipid microparticles (SLMs) especially for hydrophilic drugs has remained a challenge to drug formulation experts. This work seeks to address the issue of inefficient delivery of metformin hydrochloride (MTH), a potent hydrophilic oral antihyperglycemic agent, using novel SLMs based on solidified reverse micellar solutions (SRMS) prepared by melt-emulsification using a lipid derived from Capra hircus and Phospholipon® 90H. Characterization based on size, morphology, zeta potential, polydispersity index, encapsulation efficiency (EE%), loading capacity (LC) and time-resolved stability were carried out on the SLMs. The in vitro release of MTH from the SLMs was performed in phosphate buffer (pH 7.4) while the in vivo antidiabetic properties were investigated in alloxan-induced diabetic rats. Stable, spherical and smooth SLMs were obtained. Loading of MTH into the SLMs had no effect on the surface charge of the particles. The SLMs with 1.0%w/w PEG 4000 resulted in significantly (p?<?0.05) higher EE% while those with 2.0%w/w gave the least. The LC values ranged from 20.3 to 29.1 and 14.6 to 24.1 for SLMs containing 500?mg and 250?mg of MTH, respectively. The in vitro release studies revealed significant release of MTH from the SLMs whereas the in vivo antidiabetic studies indicated that novel SLMs containing 500?mg of MTH gave significantly (p?<?0.05) higher glucose reduction than glucophage®. This research has shown that SLMs based on SRMS offer a new and better approach of delivering MTH, thus encouraging further development of this formulation.     

Preparation and characterization of amoxicillin mucoadhesive microparticles using solution-enhanced dispersion by supercritical CO2

The purpose of this research was to formulate and systemically evaluate in vitro and in vivo performances of mucoadhesive amoxicillin microparticles for the potential use in the treatment of gastric and duodenal ulcers, which were associated with Helicobacter pylori. The chitosan/amoxicillin microparticles were successfully prepared in a process of solution-enhanced dispersion by supercritical CO₂ (SEDS). The morphological characteristics of the mucoadhesive microparticles were studied under scanning electron microscope. The resulted microparticles with mean sizes ranged from 1.0 and 2.5?µm had good mucoadhesive properties. In vitro and in vivo mucoadhesive tests showed that chitosan/amoxicillin mucoadhesive microparticles adhered more strongly to gastric mucous layer and could retain in gastrointestinal tract for an extended period of time. The X-Ray Powder Diffractometry and Differential Scanning Calorimetry analysis demonstrated that the SEDS process was a typical physical coating process to produce drug-polymer composite microparticles, which is favourable for drugs since there is no changes in chemistry. In vitro release test showed that amoxicillin released faster in pH 1.0 hydrochloric acid (HCl) than in pH 7.8 phosphate buffer. In vivo H. pylori clearance tests were also carried out by administering amoxicillin powder and mucoadhesive microparticles to H. pylori infectious Wistar rats under fed conditions at single dose or multiple dose(s) in oral administration. The results showed that amoxicillin mucoadhesive microparticles had a better clearance effect than amoxicillin powder. In conclusion, the prolonged gastrointestinal residence time and enhanced amoxicillin stability resulting from the mucoadhesive microparticles of amoxicillin might make a contribution to H. pylori complete eradication.     

Bioavailability Enhancement of Polymyxin B With Novel Drug Delivery: Development and Optimization Using Quality-by-Design Approach

Polymyxin-B (Poly-B) is an effective antibiotic used to treat infections mainly caused due to sensitive gram-negative bacteria. They belong to the group of cyclic peptide antibiotics and are minimally absorbed from the gastrointestinal tract. This arises the need for bioavailability enhancement and is achieved in the present case using niosomes as carrier system. The Poly-B niosomes had been developed using Span 60 and cholesterol while optimization is achieved with quality-by-design (QBD) approach. In this QBD approach, 3 independent variables (Span 60:cholesterol, volume of phosphate-buffered saline [%], and amount of drug [mg]) each at 3 levels were studied. A total of 17 runs were suggested by the model which was further analyzed by optimizing 3 different responses (particle size, zeta potential, and entrapment efficiency [EE%]). The results had clearly shown that the optimum formulation selected by QBD was based on the criteria of attaining the maximum value of EE% and low value of size and zeta potential. Poly-B niosomes were further examined by in vitro antifungal, rat creatinine, and cytotoxicity assay. The pharmacokinetics and scintigraphy studies were also performed for in vivo behavior of Poly-B.     

Design and characterization of chitosan-alginate microspheres for ocular delivery of azelastine

Abstract

The use of mucoadhesive biopolymers is one of the best approaches to prolong the drug residence inside the cul-de-sac, consequently increasing the bioavailability. Thus, the focus of this work was to develop mucoadhesive microspheres to overcome the limitations of ocular drug delivery. The chitosan-sodium alginate microspheres of azelastine hydrochloride were fabricated using modified ionotropic gelation technique. The particle size, zeta potential, entrapment efficiency and drug release kinetics were evaluated and characterized by SEM, FT-IR, DSC, in vitro mucoadhesion and in vivo study. The microspheres had average particle size in the range of 3.55 to 6.70?µm and zeta potential +24.55 to +49.56?mV. The fabricated microspheres possess maximum drug entrapment of 73.05% with 65% mucin binding efficiency and revealed a controlled release over the 8-h period following a non-Fickian diffusion. SEM showed that microspheres were distinct solid with irregular shape. FT-IR and DSC results concluded the drug entrapment into microspheres. In vivo studies on ocular rat model revealed that azelastine microspheres had better efficacy. Chitosan sodium alginate microspheres prepared were in particle size range suitable for ocular purpose. In vitro release and in vivo efficacy studies revealed that the microspheres were effective in prolonging the drug’s presence in cul de sac with improved therapeutic efficacy.     

Formulation of ciprofloxacin hydrochloride loaded biodegradable nanoparticles: optimization of technique and process variables

Abstract

Poly lactic-co-glycolic acid (PLGA 502 H) nanoparticles incorporating ciprofloxacin HCl (CP) were prepared by double emulsion solvent diffusion technique.

Methods: The influence of the application of probe sonication besides the high pressure homogenization in the preparation of the secondary emulsion and its application during the solidification step were studied. Their effect on the particle size, Zeta potential and the percent encapsulation efficiency of the drug (EE %) were investigated. The effect of the addition of polyvinyl alcohol (PVA) during the preparation of the primary emulsion was studied. Moreover, the effect of the addition of 0.1?M sodium chloride and/or adjusting the external and extracting phases to pH 7.4 were investigated. The selected formula was examined using IR, X-ray, DSC and SEM and in vitro drug release.

Results: These formulations showed an appropriate particle size ranges between 135.7–187.85?nm, a mean zeta potential ranging from ?0.839 to ?6.81?mV and a mean EE% which ranged from 35% to 69%.

Conclusion: The presented data revealed the superiority of using probe sonication besides high pressure homogenization during the formation of secondary emulsion. Moreover, the results indicated that the tested factors had a pronounced significant effect on the EE%.     

Curcumin-loaded mixed micelles: preparation,optimization, physicochemical properties and cytotoxicity in vitro

Abstract

Although curcumin (CUR) can inhibit proliferation and induce apoptosis of tumors, the poor water solubility restricted its clinical application. The aim of this study was to improve the aqueous solubility of CUR and make more favorable changes to bioactivity by preparing curcumin-loaded phospholipid-sodium deoxycholate-mixed micelles (CUR-PC-SDC-MMs). CUR-PC-SDC-MMs were prepared by the thin-film dispersion method. Based on the results of single factor exploration, the preparation technology was optimized using the central composite design-response surface methodology with drug loading and entrapment efficiency (EE%) as indicators. The images of transmission electron microscopy showed that the optimized CUR-PC-SDC-MMs were spherical and well dispersed. The average size of the mixed micelles was 66.5?nm, the zeta potential was about ?26.96?mV and critical micelle concentration was 0.0087?g/l. CUR was encapsulated in PC-SDC-MMs with loading capacity of 13.12%, EE% of 87.58%, and the solubility of CUR in water was 3.14?mg/ml. The release results in vitro showed that the mixed micelles presented sustained release behavior compared to the propylene glycol solution of CUR. The IC₅₀ values of CUR-loaded micelles and free drug in human breast carcinoma cell lines were 4.10?μg/ml and 6.93?µg/ml, respectively. It could be concluded from the above results that the CUR-PC-SDC-MMs system might serve as a promising nanocarrier to improve the solubility and bioactivity of CUR.     

Mucoadhesive polyethylenimine–dextran sulfate nanoparticles containing Punica granatum peel extract as a novel sustained-release antimicrobial

Abstract

Mucoadhesive polyethylenimine–dextran sulfate nanoparticles (PDNPs) were developed for local oral mucosa delivery. Punica granatum peel extract (PGE) was loaded into PDNPs for oral malodor reduction and caries prevention. PDNPs were constructed using the polyelectrolyte complexation technique employing oppositely charged polymers polyethylenimine (PEI) and dextran sulfate (DS), with PEG 400 as a stabilizer. Under optimal conditions, spherical particles of ～500?nm with a zeta potential of ～+28?mV were produced. Up to 98%, drug entrapment efficiency was observed. The mass ratio of PEI:DS played a significant role in controlling particle size and entrapment efficacy. PDNPs shown to be a good mucoadhesive drug delivery system as confirmed by ex vivo wash off test. In vitro dissolution studies revealed that PGE-loaded PDNPs manifested a prolong release characteristic with a burst release within 5?min. In addition, they remained effectively against oral bacteria.     

Development of novel mucoadhesive pellets of metformin hydrochloride

Mucoadhesive polymer-coated pellets containing metformin hydrochloride were prepared by the powder-layering technique using a centrifugal fluidizing (CF)-granulator. Four high-viscosity polymers were applied to make the pellets: 1) hydroxymethylcellulose (HPMC), 2) sodium alginate (Na-Alg), 3) HPMC/Carbopol, and 4) sodium carboxylmethylcellulose (Na-CMC). The physical crushing test, mucoadhesive test, zeta-potential test, in vitro release study and observation of gastroretention state of the dosage form were performed to investigate the pellets. The strong adhesive interaction between the Na-CMC-coated pellets and the mucin disc was obtained by mucoadhesive test. Na-Alg was most effective among the polymers used in changing the value of zeta potential of the mucin solution by the interaction between a polymer and a mucin particle. Results from drug dissolution study showed that over 95% of the drug from all the four pellets was released before 2 h, while Na-CMC- and Na-Alg-coated pellets showed a moderate sustained-release in SGF (simulated gastric fluid) and SIF (simulated intestine fluid), respectively. In conclusion, Na-CMC and Na-Alg seem to be promising candidates for mucoadhesive formulation and further studies to improve the sustained-release property are underway for achieving the ultimate goal of once-a-day formulation of metformin hydrochloride.     

Formulation and evaluation of mucoadhesive buccal films impregnated with carvedilol nanosuspension: a potential approach for delivery of drugs having high first-pass metabolism

Abstract

Context: Mucoadhesive buccal films containing three layers (mucoadhesive layer, nanosuspension containing layer and backing membrane) were incorporated with carvedilol nanosuspension.

Objective: Formulation and evaluation of nanosuspension incorporated mucoadhesive buccal films of carvedilol for bioavailability enhancement by avoiding first-pass metabolism.

Methods: Carvedilol-loaded nanosuspension was prepared by a precipitation–ultrasonication method with varying concentrations of the polymer. The formulation was analyzed for size, size distribution, surface charge and morphology. Optimized nanosuspension was incorporated into drug gel layer which was sandwiched between a mucoadhesive layer and a backing layer to form tri-layered buccal films. They were evaluated for their physical, mechanical and bioadhesive parameters followed by in vitro and in vivo studies.

Results and discussion: Nanosuspension showed a negative zeta potential (?17.21?mV) with a diameter of around 495 nm and a polydispersity index of 0.203. Nanosuspension incorporated drug gel layer (62.4% drug loading) was optimized to contain 3% HPMC and 50?mg Carbopol 934P. The mucoadhesive layer and the backing layer were optimized to contain 3% HPMC and 1% ethyl cellulose, respectively. In vitro drug release was 69% and 62.4% in 9?h across synthetic membrane and porcine buccal mucosa, respectively. In vivo studies conducted in rabbit model showed 916% increase in the relative bioavailability in comparison to marketed oral tablet formulation. The C_max and T_max of the prepared formulation increased due to increased surface area of drug and also by-passing hepatic metabolism.

Conclusion: The drug delivery system has been designed as a novel platform for potential buccal delivery of drugs having high first-pass metabolism.     

A novel tri-layered buccal mucoadhesive patch for drug delivery: assessment of nicotine delivery

Objectives The aim of this study was to assess the potential of a novel delivery device for administering drugs that suffer from a high degree of first‐pass metabolism. Methods A tri‐layered buccal mucoadhesive patch, comprising a medicated dry tablet adhered to a mucoadhesive film, was prepared and characterized by its physicochemical properties and mucoadhesive strength. Nicotine was used as a model drug for the characterization of drug release and drug permeation. The influence of different adsorbents on the release of nicotine base from the patches was evaluated in vitro. Different molecular forms of nicotine (base and complex salt) were evaluated for their effect on release performance and permeation in vitro. Key findings Results demonstrated acceptable physicochemical and mucoadhesive properties for the tri‐layered patch. Rapid release of nicotine was observed when nicotine base was incorporated with calcium sulfate dihydrate as the adsorbent. Patches incorporating nicotine base showed distinct advantages over those containing nicotine polacrilex, in terms of drug release (complete drug release achieved at 30 vs 60 min) and transmucosal permeation (37.28 ± 4.25 vs 2.87 ± 0.26% of the dose permeating through mucosa within 120 min). Conclusions The novel tri‐layered patch can effectively adhere to, and deliver an active ingredient through the buccal mucosa, confirming its potential for buccal mucoadhesive drug delivery.