Bioadhesive Layer Research Articles

Perivascular application of sirolimus multilayer nanofibrous mat for prevention of vascular stenosis: Preparation, In vitro characterization, and In vivo efficacy evaluation

Graft stenosis, occurring after coronary artery bypass surgery (CABG), diminishes the efficacy and long-term patency of vascular interventions. Multilayer nanofibers (NFs) are developed to provide localized controlled release of sirolimus to prevent vascular stenosis, as well as limit drug exposure to other organs. NFs are composed of a mid-layer of drug and polycaprolactone (PCL), a bioadhesive layer of PCL and collagen, and a backing layer of PCL. NFs are characterized in vitro regarding morphology, mechanical strength, contact angle, water uptake, drug content, and drug release behavior. The average fiber diameter is around 300–500 nm. Sirolimus entrapment is confirmed by drug content, FTIR, and XRD. It is found that sirolimus is released from multilayer NFs in a sustained manner with about half of the payload released over one week. Sirolimus multilayer NFs are implanted in the rat carotid artery after inducing vascular injury. Histological, immunohistochemical (α-SMA, Ki-67, and CD31), and in vivo imaging analyses reveal that the administration of sirolimus multilayer NFs causes significant inhibition of intimal hyperplasia in the rat carotid injury model compared to the control groups and drug suspension. The obtained results reveal that the sirolimus multilayer nanosystem could be a promising carrier for local vascular drug delivery.

Development and Evaluation of Vaginal Suppository Containing Althaea officinalis L. Polysaccharide Extract

Intrauterine adhesions cause several gynecological problems. Althaea officinalis L. roots known as marshmallows contain polysaccharides (M.P.) which possess anti-inflammatory and anti-ulcerogenic activities also can form a bio-adhesive layer on damaged epithelial membranes prompting healing processes. Vaginal formulations of herbal origin are commonly applied to relieve cervico-uterine inflammation. Herein, we aim to develop and evaluate vaginal suppositories containing polysaccharides isolated from the A. officinalis root. Six formulations (four P.E.G.-based and two lipid-based suppositories containing 25% and 50% M.P.) met standard requirements, which were then subjected to qualitative and quantitative evaluation. All suppositories exhibited acceptable weights, hardness, content uniformity, melting point, and disintegration time, which fall within the acceptable recommended limits. Higher concentrations of M.P. in PEG-bases moderately increased the hardness (p<0.05). PEG-formulations showed content uniformity>90% of the average content while it was 75-83% for suppocire formulations. All formulations disintegrated in<30minutes. In-vitro release test revealed that M.P. release from 25%-MP formulations was higher than that of 50%-M.P. suppositories. Overall, results revealed the feasibility of preparing P.E.G.-or lipid-based suppositories containing M.P., which met the B.P. quality requirement.

An Anti‐Freezing, Ambient‐Stable and Highly Stretchable Ionic Skin with Strong Surface Adhesion for Wearable Sensing and Soft Robotics

AbstractNatural living systems such as wood frogs develop tissues composed of active hydrogels with cryoprotectants to survive in cold environments. Recently, hydrogels have been intensively studied to develop stretchable electronics for wearables and soft robots. However, regular hydrogels are inevitably frozen at the subzero temperature and easily dehydrated, and have weak surface adhesion. Herein, a novel hydrogel‐based ionic skin (iSkin) capable of strain sensing is demonstrated with high toughness, high stretchability, excellent ambient stability, superior anti‐freezing capability, and strong surface adhesion. The iSkin consists of a piece of ionically and covalently cross‐linked tough hydrogel with a thin bioadhesive layer. With the addition of biocompatible cryoprotectant and electrolyte, the iSkin shows good conductivity in wide ranges of relative humidity (15–90%) and temperature (−95–25 °C). In addition, the iSkin can adhere firmly to diverse material surfaces under different conditions, including cloth fabric, skin, and elastomers, in both dry and wet conditions, at subzero temperature, and/or with dynamic movement. The iSkin is demonstrated for applications including strain sensing on both human body and winter coat, human–machine interaction, motion/deformation sensing on a soft gripper and a soft robot at extremely cold conditions. This work provides a new paradigm for developing high‐performance artificial skins for wearable sensing and soft robotics.

A Multifunctional Origami Patch for Minimally Invasive Tissue Sealing.

For decades, bioadhesive materials have garnered great attention due to their potential to replace sutures and staples for sealing tissues during minimally invasive surgical procedures. However, the complexities of delivering bioadhesives through narrow spaces and achieving strong adhesion in fluid-rich physiological environments continue to present substantial limitations to the surgical translation of existing sealants. In this work, a new strategy for minimally invasive tissue sealing based on a multilayer bioadhesive patch, which is designed to repel body fluids, to form fast, pressure-triggered adhesion with wet tissues, and to resist biofouling and inflammation is introduced. The multifunctional patch is realized by a synergistic combination of three distinct functional layers: i) a microtextured bioadhesive layer, ii) a dynamic, blood-repellent hydrophobic fluid layer, and iii) an antifouling zwitterionic nonadhesive layer. The patch is capable of forming robust adhesion to tissue surfaces in the presence of blood, and exhibits superior resistance to bacterial adhesion, fibrinogen adsorption, and in vivo fibrous capsule formation. By adopting origami-based fabrication strategies, it is demonstrated that the patch can be readily integrated with a variety of minimally invasive end effectors to provide facile tissue sealing in ex vivo porcine models, offering new opportunities for minimally invasive tissue sealing in diverse clinical scenarios.

Ondansetron Hydrochloride in Treating Patients with Cancer and Chronic Nausea Vomiting

The objective of this study was to develop effective bioadhesive buccal bilayered tablets comprising of drug containing bioadhesive layer and drug free backing layer, expected to release the drug in unidirection for extended period of time. Tablets of ondansetron HCl were prepared by direct compression method using bioadhesive polymers like Carbopol 934P, Methocel K4M, Methocel K15M and Hydroxy propyl cellulose in different combinations and concentrations with backing layer of ethyl cellulose. Buccal tablets were evaluated by different parameters such as thickness, hardness, weight uniformity, content uniformity, swelling index, surface pH, ex vivo bioadhesive strength, ex vivo residence time, in vitro drug release, ex vivo drug permeation, stability studies in human saliva, in vivo mucoadhesive performance studies and FTIR studies. The modified in vitro assembly was used to measure the bioadhesive strength of tablets with fresh porcine buccal mucosa as model tissue. Bioadhesion strength was increased with increase in the concentration of carbopol. The tablets were evaluated for in vitro release in pH 6.6 phosphate buffer for 8 hr in standard dissolution apparatus. In order to improve the permeation of the drug, tauroglycholate (permeation enhancer) added in the optimized formulation at 10mM concentration. In order to determine the mode of release, the data was subjected to Korsmeyer and Peppas diffusion model. The optimized formula followed non-fickian release mechanism with zero order kinetics. Carbopol 934P and HPC in the ratio of 3:1 could be used to design effective and stable buccoadhesive tablets of ondansetron HCl. The present study concludes that buccal delivery of ondansetron HCl tablets can be good way to bypass the first pass metabolism.

Implant compositions for the unidirectional delivery of drugs to the brain

The overall objective of this study was to design and characterize the properties of a bioadhesive trilayer sustained-release implant device for the unidirectional local delivery of anticancer compounds to the brain following the removal of glioblastoma multiforme tumors. Using acetaminophen as a model drug compound, we compressed trilayer wafers that contained (i) a bioadhesive layer, (ii) a drug layer that contained a lipid and a pore-forming hydrophilic polymer, and (iii) a third layer comprising a lipid substance. To maintain a unidirectional pathway of drug release from these trilayer wafers, the edges and the surface lipophilic layer were coated with molten wax followed by cooling of the wafer. These wafers were subsequently heat cured to promote interlayer adhesion in the device. Polyethylene oxide was utilized both as the bioadhesive layer and the pore-forming hydrophilic polymer. Glyceryl behenate was employed as the lipid. The drug release properties of the trilayer wafer were a function of (i) the molecular weight and concentration of polyethylene oxide in the drug-containing lipid layer, (ii) the presence of the bioadhesive layer on the wafer, and (iii) the lipid coating applied to the top and sides of the delivery system. The unidirectional release of the drug occurred from the device through the bioadhesive layer, and zero-order release kinetics resulted over a 10-day period after a 3-day lag time. During this period, <10% of the drug had been released from the wafer. All of the drug was released by 21 days.

Design and evaluation of an innovative floating and bioadhesive multiparticulate drug delivery system based on hollow structure

In this study a gastric-retentive delivery system was prepared by a novel method which is reported here for the first time. An innovative floating and bioadhesive drug delivery system with a hollow structure was designed and prepared. The floating and bioadhesive drug delivery system was composed of a hollow spherical shell, a waterproof layer (Stearic acid), a drug layer (Ofloxacin), a release retarding film (the novel blended coating materials) and a bioadhesive layer (Carbomer 934P) prepared by using a liquid multi-layering process. A novel blended coating material was designed and investigated to solve the problem of the initial burst release of the formulation and the release mechanism of the novel material was analyzed in this study. The optimized formulation provided the sustained release characteristic and was able to float for 24h. The SEM cross-section images showed that the particulates were hollow with a spherical shell. X-ray images and pharmacokinetic studies (Frel=124.1±28.9%) in vivo showed that the gastric-retentive delivery system can be retained in the stomach for more than 6h. The floating and bioadhesive particulate drug delivery system based on a hollow structure with a dual function presented here is a viable alternative to other for gastroretentive drug delivery system.

Development and Characterization of Buccal Bilayer Tablets containing Microparticles with Ibuprofen

The aim of this study was to develop and characterize buccal bilayer tablets containing ibuprofen microparticles, prepared through emulsion/chilling method, to obtain a sustained release. In this way, three formulations of bilayer tablets containing three bioadhesive polymers, namely Noveon® AA-1 Polycarbophil USP, Carbopol® 974 and Carbopol® 980 were prepared. Weight uniformity, friability, hardness and in vitro drug release studies, by two different methods, were evaluated in the manufactured tablets. The calculation of similarity factor (f2) was also carried out. In addition, three gels (0.5%, w/w) with the same polymers were prepared and textural analysis (firmness and adhesiveness) were assessed in comparison with the bioadhesive layer of tablets. Buccal bilayer tablets with suitable physical properties (weight uniformity, hardness and friability) were produced. In vitro dissolution tests, performed during 8 hours, have demonstrated a sustained release of ibuprofen (maximum drug released: 30.0 - 45.1%). According to f2, both dissolution methods and the three studied polymers showed similar dissolution profiles (f2 > 50). Tablets containing Carbopol® 974 showed higher values of firmness and adhesiveness after 6 h of hydration in phosphate buffer pH 7.4. On the other hand, it was not possible to verify a relationship between the textural parameters of the gels and the bioadhesive layer of tablets containing the same polymers.

Glyceryl monooleate-coated bioadhesive hollow microspheres of riboflavin for improved gastroretentivity: optimization and pharmacokinetics.

The bioadhesive hollow microspheres of riboflavin were developed as a site-specific gastroretentive system to prolong the residence time of drug in the stomach and, consequently, to enhance the bioavailability. Hollow microspheres (M1-M9) prepared by the emulsion solvent diffusion method using ethyl cellulose and Eudragit E100 as shell-forming polymers were designed using 3(2) full factorial design. The optimized formulation (M5) with 93.23 ± 0.6% entrapment efficiency and 75.39 ± 3.4% cumulative drug release at 8h was subjected to coating with a bioadhesive layer of glyceryl monooleate (GMO) to obtain BM5. It exhibited excellent in vitro buoyancy for 12h (100%), in vitro bioadhesion (88.33 ± 2.35%), and presented micromeritic properties amenable to processing steps. Scanning electron microscopy depicted a spherical shape and hollow cavity of microspheres and evidenced smooth surface coating of GMO. The compatibility of drug and excipients and the absence of interaction were determined using differential scanning calorimetry and diffuse reflectance spectroscopy, respectively. The in vitro release from BM5 (novel release apparatus) demonstrated that drug release was not hindered by the bioadhesive coating layer of GMO. The pharmacokinetic study provided convincing evidence for the increased absorption of riboflavin and bioavailability (Fr = 178.47%) from bioadhesive hollow microspheres. Conclusively, the study demonstrated the superiority of the synergistic approach of floating and bioadhesive system over either floating or bioadhesive system for the prolongation of gastric residence time of riboflavin to improve its absorption.

Facile Preparation of Robust Microcapsules by Manipulating Metal-Coordination Interaction between Biomineral Layer and Bioadhesive Layer

A novel approach combining biomimetic mineralization and bioadhesion is proposed to prepare robust and versatile organic-inorganic hybrid microcapsules. More specifically, these microcapsules are fabricated by sequential deposition of inorganic layer and organic layer on the surface of CaCO(3) microparticles, followed by the dissolution of CaCO(3) microparticles using EDTA. During the preparation process, protamine induces the hydrolysis and condensation of titania or silica precursor to form the inorganic layer or the biomineral layer. The organic layer or bioadhesive layer was formed through the rapid, spontaneous oxidative polymerization of dopamine into polydopamine (PDA) on the surface of the biomineral layer. There exist multiple interactions between the inorganic layer and the organic layer. Thus, the as-prepared organic-inorganic hybrid microcapsules acquire much higher mechanical stability and surface reactivity than pure titania or pure silica microcapsules. Furthermore, protamine/titania/polydopamine hybrid microcapsules display superior mechanical stability to protamine/silica/polydopamine hybrid microcapsules because of the formation of Ti(IV)-catechol coordination complex between the biomineral layer and the bioadhesive layer. As an example of application, three enzymes are respectively immobilized through physical encapsulation in the lumen, in situ entrapment within the wall and chemical attachment on the out surface of the hybrid microcapsules. The as-constructed multienzyme system displays higher catalytic activity and operational stability. Hopefully, the approach developed in this study will evolve as a generic platform for facile and controllable preparation of organic-inorganic hybrid materials with different compositions and shapes for a variety of applications in catalysis, sensor, drug/gene delivery.

Preparation of Multiparticulate Vaginal Tablet Using Glyceryl Monooleate for Sustained Progesterone Delivery

Most of the sustained release vaginal formulations are in the form of bioadhesive gels and tablets. Though proved efficient, their presence in the vagina for a longer time as a bulk produces discomfort and interference with body functioning including sexual activities. Hence, they lack complete patient compliance. In this study, multiparticulate vaginal tablets were prepared by utilizing progesterone (PRO) loaded dry powder precursor of cubic phase (DPPCP) of glyceryl monooleate (GMO). DPPCP were obtained by spray drying GMO with magnesium trisilicate (MTS) and have presented PRO sustained release in simulated vaginal fluid (SVF) for 14 hours. The effect of hydrophilic and hydrophobic tableting excipients on compression, phase, bioadhesion and drug release properties of prepared tablets was evaluated. The effervescent hydrophilic tablet (EHT) prepared with hydrophilic excipients showed rapid disintegration but, diminished sustaining ability owing to transformation into lamellar phase whereas the multiparticulate hydrophobic tablet (MHT) obtained from hydrophobic excipients presented both rapid disintegration and sustained release in SVF by virtue of cubic phase retention. During bioadhesivity testing, fast disintegration of MHT with formation of uniform and viscous bioadhesive layer on cow mucosa was observed even with a small volume of SVF. As MHT may not produce discomfort and interference, it will be preferred over bioadhesive gel or tablet.

Studies on buccoadhesive tablets of terbutaline sulphate

An attempt has been made to develop buccoadhesive bilayered tablets comprising of drug containing bioadhesive layer and drug free backing layer to release the drug for extended period of time with reduction in dosing frequency. Tablets of terbutaline sulphate were prepared by direct compression method using bioadhesive polymers like Carbopol 934P, Methocel K4M, Methocel K15M and sodium carboxy methyl cellulose either alone or in combinations with backing layer of ethyl cellulose. The physical characteristics, swelling index, surface pH, in vitro bioadhesion strength, and in vitro release of formulated tablets were shown to be dependent on characteristics and composition of bioadhesive materials used. The modified in vitro assembly was used to measure and compare the bioadhesive strength of tablets with fresh porcine buccal mucosa as a model tissue. The maximum bioadhesive strength was observed in tablets formulated with Carbopol 934P alone and strength decreases with decrease in its content. The tablets were evaluated for in vitro release in pH 6.8 phosphate buffer for 10 h using a standardized dissolution apparatus. In order to determine the mode of release, the data was subjected to Korsmeyer and Peppas diffusion model. All the formulations followed non-Fickian release mechanism. Carbopol 934P and Methocel K4M in the ratio of 1:1 could be used to design effective and stable buccoadhesive tablets of terbutaline sulphate.

Properties of a new, long-lasting vaginal delivery system (LASRS) for contraceptive and antimicrobial agents.

In view of the need for improved vaginal formulations that are contraceptive, that may prevent transmission of sexually transmitted infections, or both, a new delivery system (base formulation; called Long Acting, Sustained Release of Spermicide, or LASRS) was developed that contains bioadhesive and other ingredients with a long history of safety, and was designed to provide long-lasting vaginal retention of the formulation and to minimize possible vaginal irritation caused by incorporated active ingredients. Nonoxynol-9 (N-9) was added as an active ingredient to study the vaginal irritating properties of the formulation and to assess its long-term effectiveness by postcoital spermicidal tests. In the first series of experiments, in vitro studies showed that the formulation spreads rapidly over a cellulose membrane, forming a bioadhesive layer that remained for at least 12 hours. The second series of experiments addressed the safety of the LASRS suppository in rabbits and primates. Even with a very high concentration of N-9 (20.5%), LASRS caused only mild/moderate but acceptable irritation in the rabbit. No vaginal irritation occurred in the primate at an even higher concentration (22.5%). During the third series of experiments, the long-lasting vaginal retention properties were evaluated by postcoital spermicidal tests in the primate. LASRS with N-9 was highly spermicidal even when mating was delayed for 12 hours after placement of the formulation. Spermicidal activity was also observed when 1) mating was delayed for 24 hours after insertion of the formulation, and 2) if the females were mated 2 or even 3 times without reinsertion of the suppository before collection of the vaginal contents. In the final series of tests, the postcoital spermicidal properties of menfegol, another cytotoxic spermicide, were evaluated as were several modifications in the base formulation. Menfegol produced essentially the same results as N-9. Altering the base formulation proved to be nonbeneficial because a decrease in the long-term spermicidal effectiveness was obtained. These results suggest that the LASRS suppository has good vehicle properties for the delivery of active ingredients to the vagina.

Formulation development and in vivo evaluation of a novel bioadhesive lozenge containing a synergistic combination of antifungal agents

Two novel bioadhesive antifungal lozenges were developed. Both were two-layered with an upper modified-release drug-containing layer and a lower bioadhesive layer composed of drum-dried waxy maize starch and Carbopol 980 to facilitate application to the oral mucosa. The first type of lozenge contained miconazole nitrate as a spray-dried form containing acacia and Cremophor RH40 to increase the dissolution of the poorly soluble azole, plus flavourings. The second type also contained chlorhexidine acetate in the drug layer, as both drugs had been reported to act synergistically. In vivo release of drug(s) into saliva was assessed in a group of healthy volunteers, with the lozenges located in an upper posterior site in the oral cavity. Therapeutic levels were achieved for extended periods of time with both formulations. Intra-subject variation was greater than inter-subject variation. By examining salivary drug concentrations obtained when the second formulation was applied to an upper anterior location, the release of drugs was shown not to be significantly affected by the location within the oral cavity. In comparison to a proprietary oral gel formulation, the new bioadhesive lozenges produced much more uniform and effective salivary levels of miconazole nitrate over a prolonged period.

A bioadhesive patch cervical drug delivery system for the administration of 5-fluorouracil to cervical tissue

A novel bioadhesive cervical patch drug delivery is described, containing 5-fluorouracil for the treatment of cervical intraepithelial neoplasia (CIN). The patch was of bilaminar design, with a drug-loaded bioadhesive film cast from a gel containing 2% (w/w) Carbopol® 981 plasticised with 1% (w/w) glycerin. The casting solvent was ethanol/water 30:70, chosen to give a non-fissuring film with an even particle size distribution. The film, which was mechanically stable on storage under ambient conditions, was bonded directly to a backing layer formed from thermally-cured polyvinyl chloride emulsion. Bioadhesive strength was independent of drug loading in the bioadhesive matrix over the range investigated but was influenced by both the plasticiser concentration in the casting gel and the thickness of the final film. Release of 5-fluorouracil from the bioadhesive layer into an aqueous sink was rapid but was controlled down to an undetectable level through the backing layer. The latter characteristic was desirable to prevent drug spill from the device onto vaginal epithelium in vivo. Despite the relatively hydrophilic nature of 5-fluorouracil, substantial drug release through human cervical tissue samples was observed over approximately 20 h. Drug release, which was clearly tissue rather than device dependent, may have been aided by a shunt diffusion route through aqueous pores in the tissue. The bioadhesive and drug release characteristics of the 5-fluorouracil cervical patch indicated that it would be suitable for further clinical investigation as a drug treatment for CIN.

Bioadhesive Lozenge for the improved Delivery of Cetylpyridinium Chloride

Conventional lozenges produce a high initial release of drug in the oral cavity, which rapidly declines to subtherapeutic levels, and requires multiple daily administration with associated problems of systemic toxicity and compliance. Various multilayer compacts containing cetylpyridinium chloride were evaluated in vitro using release into simulated saliva (buffer pH 6.6). The drug loading, the wax content of the active layer, and the composition of the bioadhesive layer were important variables affecting product performance. Following preliminary in vivo studies, the release of a three-layered device containing drug in a nonadhesive and flavored waxy exposed layer was studied in six humans using HPLC and was shown not to be affected by location within the mouth. In comparison with a proprietary lozenge formulation, the device produced more uniform and effective levels of drug (~20 μg.mL−1), with adequate comfort, taste, and irritancy over a period of 3h.