Bioadhesive Poly Research Articles

Novel approach for enhancing skin allograft survival by bioadhesive nanoparticles loaded with rapamycin

Skin graft rejection is a significant challenge in skin allografts for skin defects, particularly in extensive burn injury patients when autografts are insufficient. Enhancing the survival duration of allogeneic skin grafts can improve the success rate of subsequent autologous skin grafting, thereby promoting the therapeutic efficacy for wound healing. Rapamycin (Rapa), a potent immunosuppressant with favorable efficacy in organ transplantation, is limited by its systemic administration-associated toxicity and side effects. Therefore, addressing the short survival time of allogeneic skin grafts and minimizing the toxicity related to systemic application of immunosuppressive agents is an urgent requirement. Here, we present a topical formulation based on bioadhesive poly (lactic acid)-hyperbranched polyglycerol nanoparticles (BNPs) with surface-modified encapsulation of Rapamycin (Rapa/BNPs), applied for local immunosuppression in a murine model of allogeneic skin grafts. Our Rapa/BNPs significantly prolong nanoparticle retention, reduce infiltration of T lymphocytes and macrophages, decrease the level of pro-inflammatory cytokines and ultimately extend skin allograft survival with little systemic toxicity compared to free Rapa or Rapamycin-loaded non-bioadhesive nanoparticles (Rapa/NNPs) administration. In conclusion, Rapa/BNPs effectively deliver local immunosuppression and demonstrate potential for enhancing skin allograft survival while minimizing localized inflammation, thus potentially increasing patient survival rates for various types of skin defects.

Preparation of a Bioadhesive Poly(Acrylic Acid)/Polyvinylpyrrolidone Complex Gel and Its Clinical Effect on Dental Hemostasis.

Poly(acrylic acid) (PAA) is a water-soluble synthetic polymer that exhibits bioadhesive properties and has been applied in various novel medical devices, such as drug-delivery carriers and hemostatic agents. PAA forms a water-insoluble complex when mixed with polyvinylpyrrolidone (PVP). If PAA and PVP are mixed in water, they form an aggregated precipitate, which neither swells nor adheres to tissues. The formation of the hydrophobic complex was caused by hydrophobic interactions between the main chains of both polymers aligned the same as a zipper. To hinder the zipper-like alignment of the polymer main chains, hyaluronic acid (HA), a macromolecular viscous polysaccharide, was added to the PVP solution prior to complex formation. When the initial concentration of PAA was lower than 0.05%, HA effectively prevented the aggregation of PAA/PVP complexes and resulted in a slightly clouded suspension. Freeze-drying of the mixture yielded a soft white sponge, which could immediately swell in water to form a highly bioadhesive hydrogel. The PAA/PVP complex prepared with HA exhibited high hemostatic efficiency in clinical studies, even in patients on antithrombotic drugs.

Various Emerging Trends in Insulin Drug Delivery Systems

Lowering of blood glucose level in patients can be achieved by insulin therapy as it plays a key role in the control of hyperglycaemia for type 1 diabetes. Insulin delivery systems that are currently available include syringes, infusion pumps, jet injectors and pens. The tedious part for the type 1 diabetes patients is to tolerate needle after needle injections while undergoing treatment for both glucose measurement and to deliver insulin. A rigorous research effort has been undertaken worldwide to replace the authentic subcutaneous route by a more accurate and non-invasive route. The newer methods explored include the artificial pancreas with closed-loop system, transdermal insulin, and buccal, oral, pulmonary, nasal, ocular and rectal routes. The future trends include use of insulin inhalers, trandermal patches, pills, pumps etc. Some of the non-invasive delivery systems include polymeric hydrogels and insulin loaded bioadhesive poly (D,L-lactide-co-glycolide) nanoparticles for oral delivery, aerosolized liposomes with dipalmitoyl phosphatidylcholine for pulmonary delivery, β cyclodextrins for nasal delivery, microneedle arrays fabricated from hyaluronic acid and iontophoresis for trandermal delivery, chitosan-zinc-insulin complex for the controlled delivery of insulin.

Immunoadjuvant capacity of flagellin and mannosamine-coated poly(anhydride) nanoparticles in oral vaccination

Bioadhesive poly(anhydride) nanoparticles coated with mannose (M-NP) or Salmonella Enteritidis derived flagellin (F-NP) were designed to be applied in oral vaccination strategies using ovalbumin (OVA) as antigen model. Nanoparticles formulations (OVA-M-NP, OVA-F-NP and control OVA-NP) were characterized and evaluated in BALB/c mice. OVA-M-NP and OVA-F-NP displayed a size of about 300–400nm and were efficiently coated with the respective ligand, Systemic and mucosal immune responses reported after S.C. and oral administration, indicated that a single dose of OVA-M-NP and OVA-F-NP, elicited higher and balanced systemic specific antibody responses [IgG1 (Th2-response) and IgG2a (Th1-response)] compared to non-coated ones. In addition, oral immunization using OVA-M-NP or OVAF-NP was able to elicit a higher levels of intestinal secretory IgA compared to S.C. In summary, oral immunization by bioadhesive mannosylated or flagellin nanoparticles demonstrated strong long lasting systemic and mucosal immune responses than the respective non-conjugated vectors.

Gels and liposomes in optimized ocular drug delivery: Studies on ciprofloxacin formulations

Ciprofloxacin (CPFX) containing therapeutic systems were developed using gel- and liposome-based formulations to minimize tear-driven dilution in the conjunctival sac, a long-pursued objective in ophthalmology. Physicochemical properties (pH, osmolarity, viscosity, expansivity, membrane fluidity and in vitro CPFX release rate) of the preparations were studied by the appropriate methods. For gel preparation, the bio-adhesive poly(vinyl alcohol) and polymethacrylic acid derivatives were applied in various concentrations. In our liposome-supported carrier systems, multilamellar vesicles from lecithin and α- l-dipalmithoyl-phosphatidylcholine provided the encapsulating agent. Electron paramagnetic resonance (EPR) spectroscopy was applied to study the molecular interactions in the ophthalmic formulations. The polymer hydrogels used in our preparations ensured a steady and prolonged active ingredient release. In addition, encapsulation of the CPFX into liposomes prolonged the in vitro release of the antibacterial agent depending on the lipid composition of the vesicles.

Bioadhesive poly(methyl methacrylate) microdevices for controlled drug delivery

Oral delivery is the preferred route of drug administration. However, the breakdown of molecules and low levels of absorption in the gastrointestinal system render the oral delivery of proteins and peptides ineffective. Bioadhesive delivery devices can be used to circumvent these problems by protecting the drug from gastrointestinal denaturation, localizing and prolonging a drug at a specific target site, and maintaining direct contact with the intestinal cells, thereby increasing the drug concentration gradient. Microfabrication technology may offer some potential advantages over conventional delivery technologies. The benefits of microfabrication include the ability to tailor the size, shape, reservoir volume, and surface characteristics of the drug delivery vehicle. In this study, bioadhesive properties were introduced to microfabricated poly(methyl methacrylate) (PMMA) microdevices by attachment of lectins, a group of proteins capable of specifically targeting cells in the gastrointestinal tract. In this process, the PMMA microdevices were chemically modified by aminolysis to yield amine-terminated surfaces. Avidin molecules were covalently bound to the surface of the particles using a hydroxysuccinimide catalyzed carbodiimide reagent and then incubated in an aqueous solution of biotinylated lectin. The lectin-modified microdevices were examined in vitro in terms of their bioadhesive characteristics.

Facilitated intranasal induction of mucosal and systemic immunity to mutans streptococcal glucosyltransferase peptide vaccines.

Synthetic peptide vaccines which are derived from functional domains of Streptococcus mutans glucosyltransferases (GTF) have been shown to induce protective immunity in Sprague-Dawley rats after subcutaneous injection in the salivary gland region. Since mucosal induction of salivary immunity would be preferable in humans, we explored methods to induce mucosal antibody in the rat to the GTF peptide vaccines HDS and HDS-GLU after intranasal administration. Several methods of facilitation of the immune response were studied: the incorporation of peptides in bioadhesive poly(D,L-lactide-coglycolide) (PLGA) microparticles, the use of monoepitopic (HDS) or diepitopic (HDS-GLU) peptide constructs, or the use of mucosal adjuvants. Salivary immunoglobulin A (IgA) responses were not detected after intranasal administration of diepitopic HDS-GLU peptide constructs in alum or after incorporation into PLGA microparticles. However, significant primary and secondary salivary IgA and serum IgG antibody responses to HDS were induced in all rats when cholera holotoxin (CT) or a detoxified mutant Escherichia coli heat-labile enterotoxin (R192G LT) were intranasally administered with HDS peptide constructs in PLGA. Coadministration of LT with HDS resulted in predominantly IgG2a responses in the serum, while coadministration with CT resulted in significant IgG1 and IgG2a responses to HDS. Serum IgG antibody, which was induced to the HDS peptide construct by coadministration with these adjuvants, also bound intact mutans streptococcal GTF in an enzyme-linked immunosorbent assay and inhibited its enzymatic activity. Thus, immune responses which are potentially protective for dental caries can be induced to peptide-based GTF vaccines after mucosal administration if combined with the CT or LT R192G mucosal adjuvant.

Induction of secretory immunity with bioadhesive poly (D,L-lactide-co-glycolide) microparticles containing Streptococcus sobrinus glucosyltransferase.

The effect of mucosal delivery of Streptococcus sobrinus glucosyltransferase (GTF) in bioadhesive poly (D,L-lactide-co-glycolide) (PLGA) microparticles on induction of salivary IgA and serum IgG antibody responses was measured in Sprague-Dawley rats. Preparations of GTF/PLGA/gelatin microparticles, or PLGA/gelatin microparticles or GTF in alum, were administered four times at weekly intervals by intranasal or intragastric routes. Two subcutaneous injections of GTF in PLGA/gelatin microparticles or in alum were given to separate groups of rats. Significant elevations in salivary IgA antibody levels to S. sobrinus GTF were observed only in the groups immunized intranasally 28 days after immunizations were begun. Five of six rats given the GTF microparticles intranasally had positive salivary IgA antibody responses to GTF, and the mean salivary IgA antibody level of this group was 30-fold higher than any other mucosally or systemically immunized group. Salivary IgA responses in the GTF-microparticle group remained significantly higher than all other mucosally immunized groups for at least 10 weeks after the primary immunization. All rats in this group demonstrated aspects of anamnesis following a more limited secondary course of intranasal administration. Intranasal administration of GTF in microparticles also induced a serum IgG response to GTF in some rats. After secondary intranasal GTF microparticle administration, several rats had sustained serum IgG antibody levels that were within the range of sera from rats subcutaneously injected with GTF in microparticles or in alum. Thus intranasal delivery of GTF-containing bioadhesive microparticles induced the highest and longest lasting salivary immune response of any mucosal or systemic route or vehicle tested and could be expected to be a useful method for induction of mucosal immunity.

Drug release from a porous ion-exchange membrane in vitro.

The effect of environmental ionic strength on the rate of drug release from a cation exchange membrane was evaluated. Cationic propranolol-HCl, timolol, sotalol-HCl, atenolol and dexmedetomidine-HCl and neutral diazepam were adsorbed onto a porous poly(vinylidene fluoride) (PVDF) membrane that was grafted with bioadhesive poly(acrylic acid) chains (PAA-PVDF). Despite its porosity, the PAA-PVDF membrane acted as a cation exchange membrane. The release of adsorbed drug from the PAA-PVDF membrane was investigated by using a USP rotating basket apparatus. Adsorption of cationic drugs onto the PAA-PVDF membrane tended to increase with increasing lipophilicity of the drug. A decrease in the ionic strength of the adsorption medium increased the amount of the cationic drugs adsorbed onto the membrane, but had no effect on diazepam adsorption. The release of cationic drugs from the PAA-PVDF membrane was greatly affected by the ionic strength of both the adsorption medium and the dissolution medium, while ionic strengths did not affect diazepam release. Our results suggest that the ionic strength of both the adsorption and dissolution media substantially affects the release rate of a drug that has been adsorbed onto the ion exchange membrane, primarily via electrostatic interactions, while ionic strength has no effect on the release of a drug which has been adsorbed onto the membrane via non-electrostatic forces.

Synthesis of bioadhesive poly(acrylic acid) nano- and microparticles using an inverse emulsion polymerization method for the entrapment of hydrophilic drug candidates

Bioadhesive latices of water-swollen poly(acrylic acid) nano-and microparticles were synthesized using an inverse (W/O) emulsion polymerization method. They are stabilized by a co-emulsifier system consisting of Span ™ 80 and Tween ™ 80 dispersed in aliphatic hydrocarbons. The initial polymerization medium contains emulsion droplets and inverse micelles which solubilize a part of the monomer solution. The polymerization is initiated by free radicals, and particle dispersions with a narrow size distribution are obtained. The particle size is dependent on the type of radical initiator used. With water-soluble initiators, for example ammonium persulfate, microparticles were obtained in the size range of 1 to 10 μm indicating that these microparticles originate from the emulsion droplets since the droplet sizes of the W/O emulsion show similar distribution. When lipophilic radical initiators, such as azobis-isobutyronitrile, are used, almost exclusively nanoparticles are generated with diameters in the range of 80 to 150 nm, due to the limited solubility of oligomeric poly(acrylic acid) chains in the lipophilic continuous phase. These poly(acrylic acid) micro- and nanoparticles yielded excellent bioadhesive properties in an in-vitro assay and may, therefore, be suitable for the encapsulation of peptides and other hydrophilic drugs.

Interactions between bioadhesive poly(acrylic acid) and calciumions

Polycarbophil (PC) is a weakly crosslinked poly(acrylic acid) used for bioadhesive delivery systems. Complexation of calcium ions by this polymer depends on the accessability of carboxylate functions in the polymer. Therefore, the calcium binding capacity increased linearly with the degree of neutralisation. Crosslinking rendered 20% of the carboxyl inaccessable to calcium whereas in water-soluble non-crosslinked poly(acrylic acid) (PAA), all carboxylate groups bound calcium. Addition of ionic substances reduced the fraction of calcium ions bound due to a dehydration of the polymer and a competition between the ions for binding. In a physiological buffer, PC chelated maximally 80% of the total calcium concentration, and water-soluble PAA bound 95%. In comparison to calcium chloride solution, the binding constant decreased from 51400 I/mol to 1800 1/mol in Tyrode's solution, moreover, the number of binding sites in the polymer was reduced. A dispersion of PC in water yielded swollen particles with a size of ca. 2.5 μm, depending on the degree of neutralisation and on the concentration of electrolytes, especially calcium ions. Addition of electrolytes caused a decrease of the particle size due to dehydration of the polymer. The reduction was more pronounced with calcium. Chelation of calcium by PC could be an explanation for the increase in bioavailability of drugs observed with bioadhesive PC delivery systems. The function and structure of epithelial tissue could be affected by chelation of extracellular calcium.

Oral availability of a poorly absorbed drug, hydrochlorothiazide, from a bioadhesive formulation in the rat

The bioavailability of certain drugs can be limited by the residence time of the formulation in the upper GI tract. The availability of a poorly-absorbed drug, hydrochlorothiazide, was determined from two formulations: a bioadhesive poly(acrylic acid) (Carbopol) formulation, which showed delayed transit to the ileocaecal junction, and a similar non-adhesive formulation. The results showed identical availabilities from the two formulations, suggesting that factors other than GI residence time were affecting drug availability from these formulations.