Increasing Cellular Uptake and Permeation of Curcumin Using a Novel Polymer-Surfactant Formulation.

Several therapeutically active molecules are poorly water-soluble, thereby creating a challenge for pharmaceutical scientists to develop an active solution for their oral drug delivery. This study aimed to investigate the potential for novel polymer-surfactant-based formulations (designated A and B) to improve the solubility and permeability of curcumin. A solubility study and characterization studies (FTIR, DSC and XRD) were conducted for the various formulations. The cytotoxicity of formulations and commercial comparators was tested via MTT and LDH assays, and their permeability by in vitro drug transport and cellular drug uptake was established using the Caco-2 cell model. The apparent permeability coefficients (Papp) are considered a good indicator of drug permeation. However, it can be argued that the magnitude of Papp, when used to reflect the permeability of the cells to the drug, can be influenced by the initial drug concentration (C0) in the donor chamber. Therefore, Papp (suspension) and Papp (solution) were calculated based on the different values of C0. It was clear that Papp (solution) can more accurately reflect drug permeation than Papp (suspension). Formulation A, containing Soluplus® and vitamin E TPGs, significantly increased the permeation and cellular uptake of curcumin compared to other samples, which is believed to be related to the increased aqueous solubility of the drug in this formulation.

An evaluation of the adhesion of solid oral dosage form coatings to the oesophagus.

There is a requirement for the development of oral dosage forms that are adhesive and allow extended oesophageal residence time for localised therapies, or are non-adhesive for ease of swallowing. This study provides an initial assessment of the in vitro oesophageal retention characteristics of several widely utilised pharmaceutical coating materials. To this end, a previously described apparatus has been used to measure the force required to pull a coated disc-shaped model tablet across a section of excised oesophageal tissue. Of the materials tested, the well-studied mucoadhesive polymer sodium alginate was found to be associated with significant oesophageal adhesion properties that was capable of 'self-repairing'. Hydroxypropylmethylcellulose exhibited less pronounced bioadhesive behaviour and blending this with plasticiser or with low molecular weight polymers and surfactants did not significantly affect this. Low molecular weight water soluble polymers, were found to behave similarly to the uncoated glass control disc. Polysorbates exhibited bioadhesion behaviour that was majorly influenced by the nature of the surfactant. The insoluble polymer ethylcellulose, and the relatively lipophilic surfactant sorbitan monooleate were seen to move more readily than the uncoated disc, suggesting that these may have a role as 'easy-to-swallow' coatings.

An in vitro model for the evaluation of the adhesion of solid oral dosage forms to the oesophagus.

Adhesion of solid oral dosage forms to the oesophagus can be a disadvantage when delivering drugs that may cause oesophageal damage, or can be an advantage when developing localised therapies for this region. In this study, apparatus to investigate coatings that may influence oesophageal retention was developed and evaluated. The apparatus incorporated a section of porcine oesophageal mucosa held flat by the application of a gentle vacuum and kept moist by the application of a simulated saliva solution. The resistance to the application of more physiologically relevant shear stresses was evaluated. Using a range of materials it was found that differences in oesophageal adhesion could be identified. Materials like sodium alginate were highly adhesive and had a tendency to re-adhere while paraffin waxes showed no adhesion. The rapid loss of the polymer coat from the surface for water swellable materials was identified as an issue.

Nasal and buccal drug delivery: management forum conference.

The scope of the conference (Nasal and Buccal Drug Delivery Conference, Management Forum; Chairs Franz Merkus and Julie Suman) was to consider innovations in drug delivery via the nose and oral cavity, notably for the delivery of vaccines, antimalarials and rapidly acting sedatives. Presentations from experts from academia, government agencies and commercial organisations were made over the 2 days. The advantages of both routes were ease of application, patient acceptability and no requirement to produce sterile products. These routes worked best for drugs that are water soluble--but with some lipophilicity--only require low doses, are acceptable to the patient and have low irritancy (particulary for the nasal route). Challenges relate to the effectiveness of deposition from the delivery systems and the efficient clearance mechanisms. It was concluded that for many drugs, buccal and nasal delivery could become the route of choice for their application; vaccines, in particular, appear to show promise for nasal delivery.

Chitosan microparticles for the controlled delivery of fluoride.

OBJECTIVES: To manufacture and characterise chitosan/fluoride microparticles prepared by spray drying and assess their utility as controlled release vehicles for fluoride. METHODS: Microparticles were manufactured from dispersions containing 1.0% and 2.0% (w/v) chitosan and 0.20% or 0.40% (w/v) NaF in the absence/presence of glutaraldehyde. Particle size distributions were determined using laser diffraction; fluoride loading and release were determined by ion-selective electrode. Release profiles were studied in isotonic media (pH 5.5) over 360 min; microparticles exhibiting greatest cumulative fluoride release were further evaluated at pH 4.0 and 7.0. Particle morphology was investigated using environmental scanning electron microscopy. Bioadhesion parameters were determined with a texture-probe analyser. RESULTS: Microparticles exhibited low polydispersity and volume mean diameters (VMDs) <6 µm. VMDs increased on doubling the chitosan/fluoride concentrations but were largely independent of glutaraldehyde concentration. Recovered yields were inversely proportional to dispersion viscosity due to compromised fluid atomisation; adding NaF reduced viscosity and improved yields. Best-case entrapment efficiency and NaF loading were 84.1% and 14%, respectively. Release profiles were biphasic, releasing 40-60% of the total fluoride during the first 600 s, followed by a prolonged release phase extending out to 6h. Incorporation of 0.40% NaF to the 2.0% chitosan dispersion yielded microparticles with reduced bioadhesive parameters (F(max) and WOA) versus the chitosan-only control whilst retaining significant bioadhesive potential. CONCLUSIONS: Bioadhesive chitosan/fluoride microparticles manufactured using a spray-drying protocol have been extensively characterised and further opportunity for optimisation identified. These microparticles may provide a means of increasing fluoride uptake from oral care products to provide increased protection against caries, however further work is required to demonstrate this principle in vivo. CLINICAL SIGNIFICANCE: Spray-drying is a low-cost route for the manufacture of bioadhesive chitosan/fluoride microparticles which can be exploited as controlled fluoride release agents to aid fluoride retention in the oral cavity. The potential exists to optimise release profiles to suit the delivery format thereby maximising the cariostatic benefits.

Metabolism of captopril carboxyl ester derivatives for percutaneous absorption.

OBJECTIVES: To determine the metabolism of captopril n-carboxyl derivatives and how this may impact on their use as transdermal prodrugs. The pharmacological activity of the ester derivatives was also characterised in order to compare the angiotensin converting enzyme inhibitory potency of the derivatives compared with the parent drug, captopril. METHODS: The metabolism rates of the ester derivatives were determined in vitro (using porcine liver esterase and porcine ear skin) and in silico (using molecular modelling to investigate the potential to predict metabolism). KEY FINDINGS: Relatively slow pseudo first-order metabolism of the prodrugs was observed, with the ethyl ester displaying the highest rate of metabolism. A strong relationship was established between in-vitro methods, while in-silico methods support the use of in-vitro methods and highlight the potential of in-silico techniques to predict metabolism. All the prodrugs behaved as angiotensin converting enzyme inhibitors, with the methyl ester displaying optimum inhibition. CONCLUSIONS: In-vitro porcine liver esterase metabolism rates inform in-vitro skin rates well, and in-silico interaction energies relate well to both. Thus, in-silico methods may be developed that include interaction energies to predict metabolism rates.

Azo compounds in colon-specific drug delivery.

Azo compounds have the potential to act as drug carriers that facilitate the selective release of therapeutic agents to the colon, and also to effect the oral administration of those macromolecular drugs that require colon-specific drug delivery. With some further research-driven refinements, these materials may lead to more efficient treatments for local conditions, such as colonic cancer or inflammatory bowel disease. This article provides an overview of the azo-based systems developed to date, identifies the requirements for an ideal carrier, and highlights the directions for further developments in the field of azo group-facilitated colonic delivery.

Orally administered, colon-specific mucoadhesive azopolymer particles for the treatment of inflammatory bowel disease: An in vivo study.

Radiolabeled congeners of a series of azopolymers have been synthesized and characterized. The in vivo (rat) gastrointestinal transit profile of millimeter-sized particles of these azopolymers has been determined and used to facilitate the selection of a candidate material for therapeutic applications. The efficacy of the selected material as a protective coating for the colonic mucosa has been tested in a hapten-reactivated, in vivo model of inflammatory bowel disease: 7 days after reactivation of the condition, the myeloperoxidase activity of animals that had received doses of the selected azopolymer was determined to be at the same level as that of healthy animals or that of the negative control group, highlighting the therapeutic promise of this material.

Design, synthesis and characterization of captopril prodrugs for enhanced percutaneous absorption.

Most drugs are designed primarily for oral administration, but the activity and stability profiles desirable for this route often make them unsuitable for transdermal delivery. We were therefore interested in designing analogues of captopril, a model drug with poor percutaneous penetration, for which the sustained steady-state blood plasma level associated with transdermal delivery (and which is unattainable orally) would be particularly beneficial. Quantitative structure-permeability relationships (QSPRs) predicted that ester and thiol prodrug derivatives of captopril would have lower maximal transdermal flux (J(m)) than the parent drug, since the increases in permeability coefficient (k(p)) of prodrugs would be outweighed by the reductions in aqueous solubility. Therefore, the aim of this study was to synthesize a series of prodrugs of captopril and to determine if a QSPR model could be used to design therapeutically viable prodrugs. Molecules with the highest predicted k(p) values were synthesized and characterized, and J(m) measured in Franz diffusion cells from saturated aqueous donor across porcine skin (fresh and frozen). In-vitro metabolism was also measured. Captopril and the prodrugs crossed the skin relatively freely, with J(m) being highest for ethyl to butyl esters. Substantial first-order metabolism of the prodrugs was observed, suggesting that their enhanced percutaneous absorption was complemented by their metabolic performance. The results suggested that QSPR models provided excellent enhancements in drug delivery. This was not seen at higher lipophilicities, suggesting that issues of solubility need to be considered in conjunction with any such use of a QSPR model.

Buccal drug delivery.

Buccal formulations have been developed to allow prolonged localised therapy and enhanced systemic delivery. The buccal mucosa, however, while avoiding first-pass effects, is a formidable barrier to drug absorption, especially for biopharmaceutical products (proteins and oligonucleotides) arising from the recent advances in genomics and proteomics. The buccal route is typically used for extended drug delivery, so formulations that can be attached to the buccal mucosa are favoured. The bioadhesive polymers used in buccal drug delivery to retain a formulation are typically hydrophilic macro-molecules containing numerous hydrogen bonding groups. Newer second-generation bioadhesives have been developed and these include modified or new polymers that allow enhanced adhesion and/or drug delivery, in addition to site-specific ligands such as lectins. Over the last 20 years a wide range of formulations has been developed for buccal drug delivery (tablet, patch, liquids and semisolids) but comparatively few have found their way onto the market. Currently, this route is restricted to the delivery of a limited number of small lipophilic molecules that readily cross the buccal mucosa. However, this route could become a significant means for the delivery of a range of active agents in the coming years, if the barriers to buccal drug delivery are overcome. In particular, patient acceptability and the successful systemic delivery of large molecules (proteins, oligonucleotides and polysaccharides) via this route remains both a significant opportunity and challenge, and new/improved technologies may be required to address these.

The basics and underlying mechanisms of mucoadhesion.

Mucoadhesion is where two surfaces, one of which is a mucous membrane, adhere to each other. This has been of interest in the pharmaceutical sciences in order to enhance localised drug delivery, or to deliver 'difficult' molecules (proteins and oligonucleotides) into the systemic circulation. Mucoadhesive materials are hydrophilic macromolecules containing numerous hydrogen bond forming groups, the carbomers and chitosans being two well-known examples. The mechanism by which mucoadhesion takes place has been said to have two stages, the contact (wetting) stage followed by the consolidation stage (the establishment of the adhesive interactions). The relative importance of each stage will depend on the individual application. For example, adsorption is a key stage if the dosage form cannot be applied directly to the mucosa of interest, while consolidation is important if the formulation is exposed to significant dislodging stresses. Adhesive joint failure will inevitably occur as a result of overhydration of a dosage form, or as a result of epithelia or mucus turnover. New mucoadhesive materials with optimal adhesive properties are now being developed, and these should enhance the potential applications of this technology.

Mucoadhesive, triclosan-loaded polymer microspheres for application to the oral cavity: preparation and controlled release characteristics.

The aim of this study was to develop mucoadhesive microspheres that can be utilised for the controlled release of triclosan in oral-care formulations, specifically dental pastes. Using a double-emulsion solvent evaporation technique, triclosan was incorporated into microspheres that were prepared from Gantreztrade mark MS-955, Carbopol 974P, polycarbophil or chitosan and the profiles for its release were established under simulated 'in use' conditions. Triclosan was rapidly released into a sodium lauryl sulphate containing buffer from all but the chitosan microspheres. The release of triclosan from microspheres suspended in a non-aqueous paste, was found to be sustained over considerable time-periods, which were influenced strongly by the nature of the polymeric carrier. For microspheres that were fabricated from Gantrez, Carbopol or polycarbophil, the release appeared to obey zero-order kinetics whereas in the case of chitosan-derived vehicles, the release profile fitted the Baker and Lonsdale model. The work has demonstrated that these polymeric microspheres, particularly those of chitosan, are promising candidates for the sustained release of triclosan in the oral cavity.

In situ evaluation of drug-loaded microspheres on a mucosal surface under dynamic test conditions.

The ability of polymeric microspheres fabricated from Carbopol, polycarbophil, chitosan or Gantrez to retain a model hydrophilic drug (sodium fluorescein) was evaluated in situ, using a dynamic test system and image analysis. This technique used oesophageal tissues and simulated the physiological conditions within the oral cavity in terms of temperature, humidity and saliva flow. The point of sample application was observed over a 2h period by means of a digital camera. No significant differences in fluorescein colour intensity was obtained for the Gantrez and chitosan particles over 100min, indicate that these two polymers provide the possibility of prolonged action. Carbopol and polycarbophil particles became rapidly swollen and released the sodium fluorescein completely within 20min. It was concluded that the test system allowed the evaluation of the in situ behaviour of test particles, in terms of their ability to retain a water-soluble, coloured marker in 'dynamic' test conditions, and that chitosan and Gantrez were promising candidates for the production of mucoadhesive, sustained-release microspheres for water-soluble materials.

Lectin-mediated drug delivery in the oral cavity.

The delivery of therapeutic agents to, or via, the oral cavity is limited by the efficient removal mechanisms that exist in this area. Lectins are proteins or glycoproteins that bind to specific sugar residues, and can, therefore, interact with the glycoconjugates present on cell surfaces or salivary mucins. Endogenous lectins could also be used as points of attachment for carbohydrate-containing delivery systems. This review considers the possibility of using lectins as targeting agents within the oral cavity and reports on some of the limited number of studies completed to date. As lectins are multifunctional molecules, the possibility of using them as both targeting and therapeutic agents is considered. Lectin-containing delivery systems are a potential innovation for targeted and prolonged therapy within the oral cavity, but considerations such as toxicity and cost will need to be addressed before their routine use becomes a reality.

Recent developments in the use of bioadhesive systems for delivery of drugs to the oral cavity.

The delivery of therapeutic agents to, or via, the oral cavity is limited by the efficient removal mechanisms that exist in this area. Bioadhesive formulations have been developed to allow prolonged localized therapy and enhanced systemic delivery. The oral mucosa however, while avoiding first-pass effects, is a formidable barrier to drug absorption, especially for "biopharmaceutical" products arising from the recent innovations in genomics and proteomics. Bioadhesive polymers are typically hydrophilic macromolecules containing numerous hydrogen-bonding groups. Second-generation bioadhesives include modified or new polymers that allow enhanced adhesion and/or drug delivery, along with site-specific ligands such as lectins. Over the last 20 years, a range of bioadhesive formulations have been developed for the oral cavity, but only comparatively few have found their way onto the market. This review will consider some recent developments in the use of bioadhesive buccal systems, notably the development of new polymers, advanced delivery systems, and the exploitation of the multifunctional properties of some bioadhesives.

The retention of 14C-labelled poly(acrylic acids) on gastric and oesophageal mucosa: an in vitro study.

Polymers that bind from solution onto gastric mucosa can be used either as a means of facilitating localised drug delivery, or can act as therapeutic agents in their own right (e.g. by forming a protective layer or by inhibiting enzymes). In our previous study [Int. J. Pharm. 236 (2002) 87], the binding and retention of labelled poly(acrylic acid)s on sections of gastric mucosa from pigs was evaluated using 'dynamic flow' conditions and a high molecular weight poly(acrylic acid) was found to bind most avidly. In the current study, 3% solutions of 'low', 'high' and 'ultra high' molecular weight polymers were evaluated in the 'dynamic flow' model for their ability to bind to tissues from the fundic and pyloric regions of the stomach and the oesophagus of pigs. All the polymers tested were retained on each mucosa for extended periods; the high and ultra high molecular weight polymers showed the greatest retention. Examination of the kinetics of polymer elution suggested that two fractions exist, 'bound' and 'unbound' polymer, showing differing retention profiles. The high molecular weight polymer showed the greatest retention on pyloric tissue, particularly on the upper sections. The retention of the ultra high and high molecular weight polymer was similar on the fundic and oesophageal mucosa, and the distribution was even across the tissue. It was concluded that poly(acrylic acid) binding from solution presents a therapeutic opportunity, and the differences in binding and retention of the polymers on the different mucosae could present an opportunity for targeting.

Mucin/poly(acrylic acid) interactions: a spectroscopic investigation of mucoadhesion.

Studies using infrared, (1)H and (13)C nuclear magnetic resonance, and X-ray photoelectron spectroscopies and differential scanning calorimetry support the hypothesis that hydrogen bonds, formed between the carboxylic acid functionality of the mucoadhesive material poly(acrylic acid) and the glycoprotein component of mucus, play a significant role in the process of mucoadhesion. There are fewer H-bonded interactions between the components than within the bulk of the pure mucoadhesive agent. The pH of the medium influences the structures of both the poly(acrylic acid) and the mucus, which, in turn, determine the nature and the extent of mucoadhesive interactions.

Polymeric microspheres for drug delivery to the oral cavity: an in vitro evaluation of mucoadhesive potential.

Polymeric microparticles were fabricated from Carbopol, polycarbophil, chitosan, or Gantrez using a "water-in-oil emulsification" solvent evaporation method. Mean particle sizes, as determined by laser diffraction, were in the range 23-38 microm. Electron microscopy revealed that all microparticles were spherical and of smooth surface morphology. In pH 7.0 phosphate buffered saline, the microspheres exhibited significantly increased swelling ratios and longer half-times of swelling than the corresponding powdered polymers. The relative merits of the potential usefulness of these microspheres as formulation tools for the enhanced retention of a therapeutic entity within the oral mucosa were evaluated by in vitro mucoadhesion tests. Tensile tests showed that all microspheres under consideration were capable of adhering to porcine esophageal mucosa, with particles prepared from the poly(acrylic acid)s exhibiting greater mucoadhesive strength than those constructed from chitosan or Gantrez. However, in elution experiments involving a challenge with artificial saliva, particles of chitosan or Gantrez were retained onto mucosal tissue for longer time periods than those assembled from the poly(acrylic acid)s.

Adsorbed pluronics on the skin of human volunteers: effects on bacterial adhesion.

An amphiphilic copolymer, Pluronic F127, has been deposited, by adsorption, to the skin of human volunteers and the ability of the coated skin to resist bacterial colonisation has been evaluated. In parallel, the ability of the same copolymer to act as a bacterial release agent has been evaluated. In both cases, F127 proved to be of little added value in formulations designed to suppress the bacterial colonisation of human skin.

Adsorbed poly(ethyleneoxide)-poly(propyleneoxide) copolymers on synthetic surfaces: spectroscopy and microscopy of polymer structures and effects on adhesion of skin-borne bacteria.

Poly(ethyleneoxide)-copoly(propyleneoxide) (PEO-PPO) polymer coatings were evaluated for their resistance to the attachment of the marker organism Serratia marcescens and the skin-borne bacteria Staphylococcus epidermidis. The copolymers were adsorbed onto poly(styrene) films-chosen as simplified physicochemical models of skin surfaces-and their surface characteristics probed by contact angle goniometry, attenuated total reflectance-Fourier transform infrared (ATR-FTIR), atomic force microscopy (AFM), and X-ray photoelectron spectroscopy (XPS). These functional surfaces were then presented to microbial cultures, bacterial attachment was assessed by fluorescence microscopy and AFM, and the structures of the polymer films examined again spectroscopically. Surface characterization data suggest that the adsorbed copolymer was partially retained at the surface and resisted bacterial attachment for 24 h. Quantitative evaluation of cell attachment was carried out by scintillation counting of (14)C-labeled microorganisms in conjunction with plate counts. The results show that a densely packed layer of PEO-PPO copolymer can reduce attachment of skin commensals by an order of magnitude, even when the coating is applied by a simple adsorptive process. The work supports the hypothesis that adhesion of microorganisms to biological substrates can be reduced if a pretreatment with an appropriate copolymer can be effected in vivo.