Recent advances in mucosal delivery of vaccines: role of mucoadhesive/biodegradable polymeric carriers

Importance of the field: The mucosal delivery of vaccines provides the basis for induction of humoral, cellular and mucosal immune responses against infectious diseases. The delivery of antigens to and through mucosal barriers always remains challenging due to adverse physiological conditions (pH and enzymes) and biological barriers created by tight epithelial junctions restricting transportation of macromolecules. Mucoadhesive and biodegradable polymers offer numerous advantages in therapeutic delivery of proteins/antigens particularly through the mucosal route by protecting antigens from degradation, increasing concentration of antigen in the vicinity of mucosal tissue for better absorption, extending their residence time in the body and/or targeting them to sites of antigen uptake. Furthermore, antigen can be delivered more effectively to the antigen presenting cells by anchoring the ligand having affinity on the surface of carrier for the receptors present on the mucosal epithelial cells.

Areas covered in this review: The present review covers various polymeric carriers, which allow the possibility of modification and manipulation of their properties, thereby, enhancing the effectiveness of mucosal vaccines. This article reviews the recent literature and patents in the field of vaccine delivery using mucoadhesive polymeric carriers.

What the reader will gain: The reader will gain insights into various natural polymers, synthetic polymers and ligand derived polymeric carrier systems studied to enhance mucosal immunization.

Take home message: Biodegradable polymeric carriers represent a promising approach for mucosal delivery of vaccine.     

Development of novel bioadhesive granisetron hydrochloride spanlastic gel and insert for brain targeting and study their effects on rats

The aim of this study was to formulate granisetron hydrochloride (GH) spanlastic in mucoadhesive gels and lyophilized inserts for intranasal administration to improve GH bioavailability and brain targeting. Carpapol 934 and HPMC were incorporated in GH spanlastic in nasal gels (GHSpNGs). Gelatin and HPMC as matrix former, glycine as a collapse protecting and mannitol as an insert filler and sweeting agent were used to prepare GH spanlastic loaded in lyophilized inserts (GHSpNIs). The prepared GHSpNGs were characterized for pH measurement, drug content, rheology, and in vitro drug release. The prepared GHSpNIs were characterized for drug content, surface pH, GH release, and mucoadhesion. Biological investigations including pharmacokinetics studies and brain drug targeting efficiency dimensions were performed on rats (LC–MS/MS). The results showed thixotropic pseudoplastic gels and white insert with pH values in a physiological range, drug content (89.9–98.6%), (82.4–98.38%) for gel and insert, respectively and rapid release rate of GH. Biological studies showed that C_max and AUC_0–6?h in brain and plasma after intranasal administration of gel and insert were higher compared to IV administration of GH solution. A high brain targeting efficiency (199.3%, 230%) for gel and insert, respectively and a direct nose to brain transport (49.8%, 56.95%) for gel and insert, respectively confirmed that there is a direct nose to brain transport of GH following nasal administration of GH spanlastic loaded in nasal gel and insert. GHSpNIs can be considered as potential novel drug delivery system intended for brain targeting via the nasal rout of administration than GHSpNGs.     

Entirely S-Protected Thiolated Silicone: A Novel Hydrophobic Mucoadhesive and Skin Adhesive

The aim of this study was the synthesis and evaluation of an entirely S-protected thiolated silicone as novel hydrophobic mucoadhesive and skin adhesive. 2-[(2-Amino-2-carboxyethyl)disulfanyl]nicotinic acid was covalently attached to a poly(dimethylsiloxane)-graft-polyacrylate via amide bond formation. Adhesive properties were determined via the rotating cylinder method and tensile studies on porcine small intestinal mucosa besides on porcine abdominal skin. Rheological characteristics were evaluated on a cone-plate rheometer. The S-protected thiolated silicone exhibited 128 ± 18 μmol immobilized 2-mercaptonicotinic acid per gram of polymer and showed a 5.9-fold extended time of mucosal adhesion compared with the unmodified silicone on the rotating cylinder. With a 2.3-fold higher maximum detachment force and a 1.7-fold higher total work of adhesion tested on porcine small intestinal mucosa, the S-protected thiolated silicone is superior to the unmodified silicone. Furthermore, using porcine abdominal skin, a 2.4-fold higher maximum detachment force and a 4.4-fold higher total work of adhesion obtained for the S-protected thiolated silicone outlines the preferentially adhesion to skin. Triggered by N-acetyl-L-cysteine liberated thiol groups form interchain and intrachain disulfide bonds within the polymer (6.7% m/v) causing a 23.0-fold increase in dynamic viscosity (?). In parallel, the elastic modulus (G’) and the viscous modulus (G”) increased 39.2-fold and 8.1-fold, respectively.     

Synthesis and Evaluation of Boronated Chitosan as a Mucoadhesive Polymer for Intravesical Drug Delivery

This work reports the synthesis of boronated chitosan by reacting it with 4-carboxyphenylboronic acid to improve its mucoadhesive properties. Three products with differing extent of boronate conjugation were synthesized and characterized using ¹H NMR, FT-IR, and UV-Vis spectroscopy, and the potential of these polymers to extend the residence time of loaded model drug in the bladder was investigated. ¹H NMR and ninhydrin test were used to evaluate the extent of chitosan modification. Mucoadhesive properties were evaluated using ex vivo flow-through technique on porcine bladder mucosal tissue combined with fluorescent microscopy, where fluorescein sodium was used as a model drug. The mucoadhesive properties of these polymers on porcine bladder mucosa were also studied using tensile test. There was good correlation in the mucoadhesive profiles of the polymers using the flow through and tensile techniques. The degree of chitosan modification had a remarkable influence on their mucoadhesive behavior, and greater mucoadhesion was observed with increased degree of boronation. These chitosan derivatives have the potential as intravesical drug delivery systems to improve bladder therapy.     

芬太尼双层缓释贴膜的研制及性质评价

 目的制备芬太尼双层口腔贴膜,并对其进行性能评价。方法以保护层和生物黏附层制备芬太尼双层口腔贴膜,并以贴膜的体外黏附力、体内黏附时间、释药行为及离体颊膜渗透能力等为指标,对贴膜的处方进行筛选。结果海藻酸钠与羧甲基纤维素钠及聚乙烯醇以2:1:2的比例制成的膜剂为最佳处方,其体外黏附力为(203±21)g·cm^-2,口腔黏附时间为120 min,体外释药行为符合Higuchi方程。芬太尼的平均渗透速率为10.527μg·cm^-2·h^-1,其渗透过程属于零级动力学过程。加入甘草甜素前后,药膜的黏附力稍有下降,体外溶出速度与颊膜渗透速度均增加。结论芬太尼双层口腔贴膜有望成为芬太尼的新型透颊膜给药制剂。     

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.     

复方维锌口腔贴膜的制备及质量控制

目的:制备复方维锌口腔贴膜,并建立其质量控制方法。方法:用聚乙烯醇为成膜材料,以维生素E、硫酸锌、醋酸地塞米松、盐酸土霉素等为主药制备膜剂;采用高效液相色谱法测定其中主药维生素E的含量。结果:所制制剂鉴别、检查等符合《中国药典》2005年版相关规定;维生素E检测量线性范围为1.0～16.0μg(r=0.9999),平均回收率为(99.28±1.15)%,RSD<0.52%。结论:复方维锌口腔贴膜处方及制备工艺合理可行,质量控制方法快速、简便,准确性好,灵敏度高。     

Improved Oral Delivery of Desmopressin via a Novel Vehicle: Mucoadhesive Submicron Emulsion

Purpose. Desmopressin acetate (DDAVP) is used parenterally and intranasally in the control of several diseases. Oral administration of DDAVP, while most desirable, is not practical presently due to low bioavailability. The objective of the present study was to explore the feasibility for employing oil-in-water MucoAdhesive SubMicron Emulsion (MA-SME), a novel mucoadhesive vehicle with polymer-coated droplets, for enhanced oral delivery of DDAVP. Methods. We used a modified pharmacopeal method, based on measurement of the antidiuretic activity, for the assessment of oral delivery of DDAVP in rats. DDAVP formulated in two MA-SME preparations, in non-mucoadhesive SME (plain-SME), in saline and in other control solutions was administered orally to rats via a stomach tube at a dose of 0.5 units/kg. At various times following DDAVP administration, water was given via a stomach tube. Excretion times for 30% and 60% of the total water load were measured. Results. Excretion times for DDAVP in MA-SME formulations were always longer (up to 2-fold) than those following DDAVP in saline. By contrast, excretion times for DDAVP in plain-SME and in non-SME Carbopol (a Mucoadhesive polymer) solution were virtually identical to those for DDAVP in saline. Conclusions. Formulations of MA-SME were shown to generate substantial enhancement (up to 12-fold) of the rat oral bioavailability of DDAVP with regard to simple saline solution of the drug. From the results it is also evident that MA-SME, but not plain-SME or non-SME Carbopol solution, is responsible for the enhancement of oral delivery of DDAVP in rats.     

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.