Mucoadhesive Systems Research Articles

Carrageenan–gelatin mucoadhesive systems for ion-exchange based ophthalmic delivery: in vitro and preliminary in vivo studies

Lambda-carrageenan is an anionic polymer able to ionically interact with alkaline drugs. This results in a complex that releases the drug slowly, due to displacement by the counterions of the release medium. The aim of this work was to assess the possible ophthalmic employment of such a complex. As a model drug, an alkaline anti-glaucoma drug, timolol maleate, was chosen. Systems in which lambda-carrageenan interacted both with the drug and a mucoadhesive polymer such as gelatin were studied. The combination of carrageenan and gelatin in different ratios proved to be useful in modulating the drug release profiles, the rheological properties of the hydrated formulations and their mucoadhesive properties. Both films and microspheres were prepared and tested in vitro. A microsphere formulation was also tested in vivo in albino rabbits. The drug concentration and bioavailability in the aqueous humour were significantly high in comparison with commercial formulations.

Thiomers: development and in vitro evaluation of a peroral microparticulate peptide delivery system

The aim of this study was to develop a peroral mucoadhesive microparticulate delivery system for peptide drugs. Microparticles containing either the mucoadhesive polymer poly(acrylic acid)–cysteine (PAA–Cys) or unmodified PAA, 15% insulin used as model peptide drug and 0, 30, 50 and 70% Eudragit RS ® (MP-RS0, MP-RS30, MP-RS50 and MP-RS70) were prepared by the emulsification solvent evaporation technique. Particle size distribution, release of incorporated insulin, mucoadhesive and swelling properties were examined. During preparation inter- and intramolecular cross-linking occurred, which could be quantified by the amount of disulfide bonds within the resulting particles; this was determined to be 69.2% of the total amount of thiol groups. This cross-linking led to a higher stability of the particles. Microparticles were spherical displaying a rough surface. The particle diameter was in the range of 1–110 μm in the following rank order beginning with the largest: MP-RS30>MP-RS50>MP-RS70=MP-RS0. The higher the ratio of Eudragit RS ® in the microparticles, the more prolonged was the release of insulin. In the case of MP-RS70, a sustained release over a time period of at least 60 min was achieved. Mucoadhesive properties and the capacity of water uptake followed the rank order: MP-RS0>MP-RS30>MP-RS50>MP-RS70. Compared to particles comprising unmodified PAA, the mucoadhesive properties of the thiolated microparticulate systems were up to 14-fold improved. According to these results PAA–Cys–Eudragit RS ® microparticles might be a promising tool for the peroral administration of peptide drugs.

Mucoadhesive alginate matrices containing sodium carboxymethyl starch for buccal delivery: in vitro and in vivo studies

The aim of this paper was to investigate the development of buccal mucoadhesive tablets (hydrophilic matrices) intended for the local delivery of an antimicrobial drug, chlorhexidine diacetate, in the oral cavity over a prolonged period of time. Sodium alginate was selected as the mucoadhesive polymer. Sodium carboxymethyl starch was used in different weight ratios to modulate the matrix erosion/drug release. The antimicrobial activity of the drug/excipient mixtures was investigated for the minimum inhibitory concentration and minimum candidicidal concentration. Buccal tablets were prepared by direct compression and studied by in vitro drug release and in vitro mucoadhesion tests. The tablets were characterised by a prolonged in vitro drug release. Sodium alginate exhibited good mucoadhesion behaviour. After their in vivo administration, the determination of chlorhexidine in saliva showed that the formulations characterised by the presence of the highest percentage of sodium carboxymethyl starch had the capacity to give a prolonged release of chlorhexidine in the buccal cavity. This behaviour was related to the in vivo erosion of the matrices. These preliminary results indicate that these matrices can be proposed as buccal mucoadhesive systems for the intraoral prolonged delivery of drugs.

Pharmacodynamic–pharmacokinetic profiles of metformin hydrochloride from a mucoadhesive formulation of a polysaccharide with antidiabetic property in streptozotocin-induced diabetic rat models

The antidiabetic property of a formulation containing metformin hydrochloride and detarium gum has been evaluated in streptozotocin model of experimental rats. Both the gum and metformin hydrochloride possess antidiabetic properties to varying degrees. The pharmacokinetics of metformin from the mucoadhesive dosage forms indicated that for metformin alone, the area under the curve (AUC) values were 125.6 and 135.6 mg h/ml at 200 and 400 mg/kg BW, respectively. For the mucoadhesive products using the same dose levels, the AUCs were modified to 102.4 and 150.2 in detarium gum and 59.9 and 80.4 in NaCMC. The results indicate that detarium gum is a good excipient for the formulation of metformin mucoadhesive delivery systems when compared with NaCMC. The gum also showed promising antidiabetic effect and should be cautiously used as it may lead to depressed blood-glucose levels beyond the desired levels.

Enhanced mucosal and systemic immune responses following intravaginal immunization with human papillomavirus 16 L1 virus-like particle vaccine in thermosensitive mucoadhesive delivery systems.

To develop more potent and convenient mucosal human papillomavirus (HPV) vaccines, we tested the effect of thermosensitive mucoadhesive vaginal vaccine delivery systems on the local and systemic antibody responses to HPV 16 L1 virus-like particles (VLP). HPV 16 L1 VLP expressed from recombinant baculovirus-infected Sf21 insect cells were delivered in phosphate-buffered saline (PBS) or thermosensitive mucoadhesive delivery systems, composed of poloxamers (Pol) and varying amounts of polyethylene oxide (PEO). Pol/PEO-based vaginal vaccine delivery systems existed in liquid form at room temperature, but gelled at 37 degrees C. The mucoadhesiveness of Pol/PEO-based delivery systems increased with PEO, but the formulations with PEO higher than 1.0% were too viscous to be administered into the vagina. Vaccine vehicles affected the vaginal and salivary immune responses to HPV 16 L1 VLP intravaginally administered into mice. At 42 days after the first intravaginal immunization of HPV 16 L1 VLP with cholera toxin, vaginal and salivary IgA titers were the highest in the group given in Pol/PEO 1.0% vehicle followed by Pol/PEO 0.4% and PBS vehicles. Intravaginal coadministration of HPV 16 L1 VLP and cholera toxin in Pol/PEO 1.0% showed 31- and 39-fold higher titers compared to the PBS-based HPV 16 L1 VLP groups administered by intravaginal and intramuscular routes, respectively. Following intravaginal administration, Pol/PEO 1.0%, but not Pol/PEO 0.4%, showed significantly higher HPV 16 L1 VLP-specific serum IgG titers as compared to the PBS vehicle. Our results indicate that the use of in situ-gelling vaginal vaccine delivery systems with increased mucoadhesiveness would be beneficial for more effective induction of mucosal and systemic immune responses to intravaginally administered HPV 16 L1 VLP vaccines.

In vitro and in vivo evaluation of mucoadhesive microspheres consisting of dextran derivatives and cellulose acetate butyrate

The objective of this study was to evaluate mucoadhesive properties and gastrointestinal transit of microspheres made of oppositely charged dextran derivatives and cellulose acetate butyrate (CAB). The microspheres were prepared by emulsion solvent evaporation method. A reference microsphere was made of lactose instead of dextran derivatives. Microspheres with a diameter of 425–710 μm were examined for in vitro mucoadhesion by the everted sac method. The results indicated that the percentage of adherence to the rat small intestine was affected by the amount of dextran derivatives in the microspheres. After 1.5 h, the adhering percent of the reference microspheres and the microspheres containing 50% of dextran derivatives were 34 and 74%, respectively. Then gastrointestinal transit after oral administration to rats was evaluated by counting the microspheres remaining in the stomach and small intestine. The microspheres containing 40% of dextran derivatives adhered to the stomach rather than the small intestine. Mathematical analysis revealed that the time required for 50% of microspheres to leave the stomach was 1.42 h, three times longer than the reference. These findings suggest that the microsphere is a promising device as a multiple-unit mucoadhesive system.

Gastric retentive dosage forms: a review.

Gastric retentive dosage forms have been investigated to provide controlled release therapy for drugs with reduced absorption in the lower gastrointestinal (GI) tract or for local treatment of diseases of the stomach or upper GI tract. Gastric retentive dosage forms rely on either natural GI physiology, such as floating or large tablets that depend on delayed emptying from the fed stomach, or those dosage forms that are designed to fight the physiology and avoid emptying in the fasted state through dosage forms of even larger sizes with or without flotation or bioadhesion. To understand the behavior of the dosage forms, an introduction to GI motility and its measurement is provided. Because the fed mode underlies the successful development of dosage forms that rely on size or flotation, the emptying of these dosage forms in the fed mode and identification of the key factors influencing the variability of gastric retention are discussed. The design and limitations of size or density-based fed mode, and mucoadhesive and expandable fasting-state gastric retentive systems are presented.

Enhanced mucosal and systemic immune responses to a vaginal vaccine coadministered with RANTES-expressing plasmid DNA using in situ-gelling mucoadhesive delivery system

To develop more potent and convenient mucosal vaccines, we investigated the effect of an in situ-gelling mucoadhesive vaginal vaccine delivery system and a genetic chemokine adjuvant on the local and systemic immune responses. The in situ-gelling mucoadhesive delivery system of hepatitis B surface antigen (HBsAg), composed of poloxamers and polycarbophil, showed the prolonged retention at the vaginal tissues. Following intravaginal administration to mice, HBsAg-specific IgA was induced in the vagina and saliva, and IgG was produced in the serum. RANTES-expressing plasmid (pRANTES) intravaginally coadministered with HBsAg showed the expression at the vaginal tissues, and more effectively induced the vaginal IgA and serum IgG immune responses than did cholera toxin (CT). The intramuscular coadministration of pRANTES with HBsAg also increased both serum IgG levels and mucosal IgA levels. Regardless of the adjuvants, the in situ-gelling mucoadhesive HBsAg delivery system enhanced the mucosal and systemic immune responses. At 42 days after the first immunization, the highest vaginal IgA levels were induced after intravaginal immunization of HBsAg plus pRANTES using the in situ-gelling mucoadhesive delivery system, showing 182- and 1035-fold higher titer compared to the groups receiving HBsAg alone in PBS by intravaginal and intramuscular routes, respectively. Our results indicate that the use of in situ-gelling mucoadhesive delivery systems with the genetic chemokine adjuvant pRANTES would be advantageous for more effective induction of mucosal and systemic immune responses to intravaginally administered vaccines.

Mucoadhesive vaginal tablets as veterinary delivery system for the controlled release of an antimicrobial drug, acriflavine.

The aim of the study was the development of mucoadhesive vaginal tablets designed for the local controlled release of acriflavine, an antimicrobial drug used as a model. The tablets were prepared using drug-loaded chitosan microspheres and additional excipients (methylcellulose, sodium alginate, sodium carboxymethylcellulose, or Carbopol 974). The microspheres were prepared by a spray-drying method, using the drug to polymer weight ratios 1:1 and 1:2 and were characterized in terms of morphology, encapsulation efficiency, and in vitro release behavior, as MIC (Minimum Inhibitory Concentration), MBC (Minimum Bacterial Concentration), and killing time (KT). The tablets were prepared by direct compression, characterized by in vitro drug release and in vitro mucoadhesive tests. The microparticles have sizes of 4 to 12 microm; the mean encapsulation yields are about 90%. Acriflavine, encapsulated into the polymer, maintains its antibacterial activity; killing time of the encapsulated drug is similar to that of the free drug. In vitro release profiles of tablets show differences depending on the excipient used. In particular Carbopol 974, which is highly cross-linked, is able to determine a drug-controlled release from the matrix tablets for more than 8 hours. The in vitro adhesion tests, carried out on the same formulation, show a good adhesive behavior. The formulation containing microspheres with drug to polymer weight ratios of 1:1 and Carbopol 974 is characterized by the best release behavior and shows good mucoadhesive properties. These preliminary data indicate that this formulation can be proposed as a mucoadhesive vaginal delivery system for the controlled release of acriflavine.

Mucoadhesive vaginal tablets as veterinary delivery system for the controlled release of an antimicrobial drug, acriflavine

The aim of the study was the development of mucoadhesive vaginal tablets designed for the local controlled release of acriflavine, an antimicrobial drug used as a model. The tablets were prepared using drug-loaded chitosan microspheres and additional excipients (methylcellulose, sodium alginate, sodium carboxymethylcellulose, or. Carbopol 974). The microspheres were prepared by a spray-drying method, using the drug to polymer weight ratios 1∶1 and 1∶2 and were characterized in terms of morphology, encapsulation efficiency, and in vitro release behavior, as MIC (Minimum Inhibitory Concentration), MBC (Minimum Bacterial Concentration), and killing time (KT). The tablets were prepared by direct compression, characterized by in vitro drug release and in vitro mucoadhesive tests. The microparticles have sizes of 4 to 12 μm; the mean encapsulation yields are about 90%. Acriflavine, encapsulated into the polymer, maintains its antibacterial activity; killing time of the encapsulated drug is similar to that of the free drug. In vitro release profiles of tablets show differences depending on the excipient used. In particular Carbopol 974, which is highly cross-linked, is able to determine a drug-controlled release from the matrix tablets for more than 8 hours. The in vitro adhesion tests, carried out on the same formulation, show a good adhesive behavior. The formulation containing microspheres with drug to polymer weight ratios of 1∶1 and Carbopol 974 is characterized by the best release behavior and shows good mucoadhesive properties. These preliminary data indicate that this formulation can be proposed as a mucoadhesive vaginal delivery system for the controlled release of acriflavine.

Design and evaluation of a mucoadhesive therapeutic agent delivery system for postoperative chemotherapy in superficial bladder cancer

The most common treatment method is known as the transurethral resection (TUR) for the therapy of bladder cancer. Unfortunately, because of the recurrency of the tumoral tissues after TUR the chemotherapy or immunotherapy should be performed. In these kind of therapies the pharmacotherapeutics are infused intravesically into the bladder after TUR periodically (i.e. upto 6–36 weeks, each week). But these therapies are having very big problems (i.e. disturbancy to patients, adjustment of the suitable dosage, loss of active agents without using etc.). An alternative approach can be proposed as to design a pharmacotherapeutic agent delivery system, which will supply the suitable dosage of the agent for a certain time period to solve those problems. In this study; the pharmacotherapeutic agent (i.e. Mytomycin-C) delivery system was prepared by using a mucoadhesive polymer (i.e. chitosan) in the form of cylindirical geometry to facilitate the insertion of the carrier for in vivo studies. The chitosan carriers were prepared by cross-linking during the solvent evaporation technique. In the preparation of the chitosan carriers the chitosan polymers with different molecular weights, different amounts of cross-linker (i.e. glutaraldehyde) and different amounts of pharmacotherapeutic agent were used to obtain desired attachment onto the bladder wall and optimum release rate of the agent. On the other hand because of the gelous structure of the chitosan, the swelling behaviour of the polymer was evaluated by gravimetric determinations in aqueous media periodically.

Evaluation of Gastrointestinal Mucoadhesive Patch System(GI-MAPS) Containing Caffeine as a Model Drug in Human Volunteers.

Evaluation of Gastrointestinal Mucoadhesive Patch System(GI-MAPS) Containing Caffeine as a Model Drug in Human Volunteers.

Peptide Washout and Permeability from Glyceryl Monooleate Buccal Delivery Systems

ABSTRACTSimultaneous evaluation of the permeation and washout of a peptide from the mucoadhesive liquid crystalline phases of glyceryl monooleate (GMO) has been investigated using a donor compartment flow-through diffusion cell. [d-Ala2, d-Leu5]enkephalin (DADLE) was incorporated into the cubic and lamellar liquid crystalline phases of GMO and applied to excised porcine buccal mucosa mounted in the donor compartment flow-through cell. Phosphate-buffered saline pH 7.4 (PBS) was pumped across the upper surface of the liquid crystalline phases to mimic salivary flow. The steady-state fluxes of DADLE and GMO from the cubic phase were significantly greater than that from the lamellar phase (P<0.01). There was no statistical difference between the amounts of DADLE and GMO washed out from the lamellar and cubic phases (P>0.05). The donor compartment flow-through diffusion cell was found to be a useful tool to evaluate the impact of salivary washout on mucoadhesive oral mucosal delivery systems.

Development and in vitro evaluation of a mucoadhesive vaginal delivery system for progesterone

The purpose of the present study was to design a novel carrier system based on a mucoadhesive polymer exhibiting improved properties concerning drug delivery to the vaginal mucosa. This was reached by the covalent attachment of l-cysteine to commercially available polyacrylic acid (Carbopol 974P). Mediated by a carbodiimide, increasing amounts of l-cysteine were covalently linked to the polymer. The resulting thiolated polyacrylic acid conjugates (NaC974P–Cys) displayed between 24.8 and 45.8 μmol thiol groups per gram of polymer. Because of the formation of intra- and/or intermolecular disulfide bonds, the viscosity of an aqueous thiolated polymer gel (3%) increased about 50% at pH 7.0 within 1 h. In oscillatory rheological measurements, it was shown that this increase in viscosity is mainly due to the increase in elasticity. Tensile studies carried out on freshly excised cow vagina demonstrated a significant ( P<0.05) increase in the total work of adhesion (TWA) compared to the unmodified polymer. An amount of 24.8 μmol thiol groups per gram of polymer resulted in a 1.45-fold increase in the TWA, whereas an amount of 45.8 μmol showed an even 2.28-fold increase. These improved mucoadhesive properties can be explained by the formation of disulfide bonds between the thiolated polymer and cysteine rich subdomaines of the mucus layer. The release rate of the model drug progesterone from tablets based on microcrystalline cellulose serving as the reference was approximately 1% per hour, whereas it was 0.58% per hour for the unmodified polymer (NaC974P) and 0.12% per hour for the thiolated polymer (NaC974P–Cys). Therefore, this thiolated polymer is a promising carrier for progesterone providing a prolonged residence time and a controlled drug release.

Gastrointestinal mucoadhesive patch system (GI-MAPS) for oral administration of G-CSF, a model protein

A new gastrointestinal mucoadhesive patch system (GI-MAPS) has been designed for the oral delivery of protein drugs. The system consists of four layered films, 3.0×3.0 mm 2, contained in an enteric capsule. The 40 μm backing layer is made of a water-insoluble polymer, ethyl cellulose (EC). The surface layer is made of an enteric pH-sensitive polymer such as hydroxypropylmethylcellulose phthalate (HP-55 ®), Eudragit ® L100 or S100 and was coated with an adhesive layer. The middle layer, drug-containing layer, made of cellulose membrane is attached to the EC backing layer by a heating press method. Both drug and pharmaceutical additives including an organic acid, citric acid, and a non-ionic surfactant, polyoxyethylated castor oil derivative (HCO-60 ®), were formulated in the middle layer. The surface layer was attached to the middle layer by an adhesive layer made of carboxyvinyl polymer (Hiviswako ® 103). Fluorescein (FL), 30 mg, was first used as a model drug for oral administration of GI-MAPS having different surface layers in beagle dogs. The plasma FL concentration vs. time profiles demonstrated that the targeting of the systems was obtained, because the T max, the time when plasma FL concentrations reaches to its maximum lelev, was 2.33±0.82 h for HP-55 system, 3.33±0.41 h for Eudragit L100 system and 5.00±0.00 h for Eudragit S100 system. The same three kinds of GI-MAPSs containing 125 μg of recombinant human granulocyte colony-stimulating factor (G-CSF) were prepared and orally administered to dogs and the increase in total white blood cell (WBC) counts were measured as the pharmacological index for G-CSF. Comparison with the total increase of WBCs after iv injection of the same amount of G-CSF (125 μg) indicated the pharmacological availabilities (PA) of G-CSF were 23%, 5.5% and 6.0% for Eudragit L100, HP-55 and Eudragit S100 systems. By decreasing the amount of HCO-60 and citric acid, the PA of G-CSF decreased. These results suggest the usefulness of GI-MAPS for the oral administration of proteins.

Retention and transit of intestinal mucoadhesive films in rat small intestine

The retention and transit characteristics of intestinal mucoadhesive film systems have been studied after intraduodenal administration in rats. Small size four layered film preparations, 0.5×0.5 mm, were prepared, where the backing layer (45.1±2.9 μm thick) was made of a water-insoluble polymer, ethylcellulose (EC), the surface layer was made of enteric pH-sensitive polymers, Eudragit® L100, S100 or HP-55® and the middle layer was made of cellulose membrane. The surface layer was attached to the middle layer with an adhesive layer composed of carboxyvinyl polymer (Hiviswako® 103). After administration of ten films to the duodenum, the rats were sacrificed hourly and the distribution of the films in the whole small intestine was directly observed after abdominal incision. The HP-55, Eudragit L100 and S100 film systems were found to adhere to the upper, middle and lower part of the small intestine after 1, 2 and 4 h, respectively, for 2–3 h. Direct inspection study suggests that intestinal mucoadhesive film system has functions of: (1) pH-dependent intestinal adhesion site specificity; (2) adhesion to the intestinal wall; and (3) retention in the small intestinal adhesion site for at least 2 h. Intestinal mucoadhesive film system has been suggested to be a targeting system for drugs to the gastrointestinal tract.

Mucoadhesive nanoparticulate systems for peptide drug delivery

This chapter describes the preparation of and methods for evaluating mucoadhesive nanoparticulate systems, including liposomes and polymeric nanoparticles. Mucoadhesive ability is conferred on the particulate systems by coating their surface with mucoadhesive polymers such as chitosan and Carbopol. The feasibility of this surface modification was confirmed by measuring the zeta potential. Several methods of evaluating the mucoadhesive properties of particulate systems have been reported in the literature. We have also developed some novel evaluation procedures including a particle counting method using a Coulter counter for polymer-coated liposomes. The mucoadhesive properties of the polymer-coated liposomes and polymeric nanoparticles were confirmed by means of these mucoadhesion tests. In applying these mucoadhesive nanoparticles to the oral and pulmonary administration of peptide drugs, more effective and prolonged action was observed in comparison with non-coated systems, thereby confirming the usefulness of mucoadhesive nanoparticulate systems for the delivery of peptide drugs.

Atomic force microscopy of gastric mucin and chitosan mucoadhesive systems

Atomic force microscopy of gastric mucin and chitosan mucoadhesive systems

Atomic force microscopy of gastric mucin and chitosan mucoadhesive systems

Atomic force microscopy has been utilized to probe, at a molecular level, the interaction between purified pig gastric mucin (PGM) and a mucoadhesive cationic polymer, chitosan (sea cure 210+), with a low degree (approx. 11%) of acetylation. Images were produced detailing the structures of both PGM and chitosan in 0.1 M acetate buffer (pH 4.5), followed by the complex of the two structures in the same buffer. PGM in 0.1 M acetate buffer revealed long linear filamentous structures, consistent with earlier electron microscopy and scanning tunnelling micoscopy studies. The chitosan molecules also adopted a linear conformation in the same buffer, although with a smaller average length and diameter. They appeared to adopt a stiff-coil conformation consistent with earlier hydrodynamic measurements. The complexes formed after mixing PGM and chitosan together revealed large aggregates. In 0.1 M ionic strength buffer they were of the order of 0.7 microm in diameter, consistent with previous electron microscopy studies. The effect of ionic strength of the buffer on the structure of the complex was also studied and, together with molecular hydrodynamic data, demonstrates that the interaction is principally electrostatic in nature.

Molecular aspects of muco- and bioadhesion:: Tethered structures and site-specific surfaces

Mucoadhesive controlled-release devices can improve the effectiveness of a drug by maintaining the drug concentration between the effective and toxic levels, inhibiting the dilution of the drug in the body fluids, and allowing targeting and localization of a drug at a specific site. Acrylic-based hydrogels have been used extensively as mucoadhesive systems. They are well suited for bioadhesion due to their flexibility and nonabrasive characteristics in the partially swollen state, which reduce damage-causing attrition to the tissues in contact. Crosslinked polymeric devices may be rendered adhesive to the mucosa. For example, adhesive capabilities of these hydrogels can be improved by tethering of long flexible chains to their surfaces. Tethering of long poly(ethylene glycol) (PEG) chains on poly(acrylic acid) hydrogels and their copolymers can be achieved by grafting reactions, or by copolymerization in the presence of several PEG-containing acrylates. The ensuing hydrogels exhibit mucoadhesive properties due to enhanced anchoring of the chains with the mucosa. Theoretical calculations can lead to optimization of the tethered structure. Experimental results indicate that the chain interpenetration is a strong function of the PEG molecular weight, the polymer swelling ratio and the mucosa composition.