Ian G. Tucker

Mechanisms by which cyclodextrins modify drug release from polymeric drug delivery systems

For many drug candidates a modified in vivo drug release is desired to improve efficacy, sustain effect or minimise toxicity. Polymeric delivery systems, such as microspheres, nanospheres and polymeric films, have been extensively researched in an attempt to achieve modified drug release. Cyclodextrins offer an alternative approach. These cyclic oligosaccharides have the ability to form non-covalent complexes with a number of drugs and in so doing alter their physicochemical properties. In addition, the primary and secondary hydroxyl groups of the native (alpha, beta, gamma-) cyclodextrins are potential sites for chemical modification. It follows that the incorporation of these agents into polymeric drug delivery systems, as physical mixtures, covalently bound conjugates or cross-linking agents, frequently permits a greater degree of control of drug release. This paper reviews the incorporation of various cyclodextrins into polymeric formulations. The mechanisms by which cyclodextrin/polymer formulations act to modify drug release are considered.

The oral cavity as a site for systemic drug delivery

Abstract Currently there is a high level of interest in the use of the oral cavity as a portal for drug entry to the systemic circulation. As a site for drug delivery the oral cavity offers advantages over the conventional gastrointestinal route and the parenteral and other alternative routes of drug administration. It provides direct entry into the systemic circulation thereby avoiding the hepatic first pass effect, ease of administration and the ability to terminate delivery when required. In addition the membranes that line the oral cavity are readily accessible and exhibit robustness and fast cellular recovery following local stress or damage. The oral cavity appears therefore to be a potential site for the delivery of drugs to the systemic circulation. However, this site is associated with limitations that restrict its use as a route for the systemic delivery of drugs. The low permeability of the membranes that line the oral cavity results in a low flux of drug; there appears to be the need to develop strategies which enhance drug penetration to improve bioavailability. The environment of the oral cavity and the continual secretion and swallowing of saliva are unique problems which need to be considered pre-formulation to ensure successful delivery of a drug via this route. This review highlights the advantages of systemically delivering drugs via the oral mucosa and discusses the membrane, drug, dosage form and environmental issues which limit its use as a site for systemic drug delivery.

Preparation of biodegradable insulin nanocapsules from biocompatible microemulsions

AbstractPurpose. To prepare poly(ethyl 2-cyanoacrylate) nanocapsulescontaining insulin by interfacial polymerization of spontaneously forming,biocompatible microemulsions. Methods. A pseudo-ternary phase diagram of a mixture of mediumchain glycerides (caprylic/capric triglycerides and mono-/diglycerides),a mixture of surfactants (polysorbate 80 and sorbitan mono-oleate) andwater was constructed. Polarizing light microscopy was used to identifycombinations forming microemulsions. Microemulsions werecharacterized by conductivity and viscosity to select systems suitable for thepreparation of poly(ethyl 2-cyanoacrylate) nanocapsules by interfacialpolymerization. Nanocapsules were prepared by addition of 100 mgof ethyl 2-cyanoacrylate to a stirred water-in-oil microemulsioncontaining 1 g of water, 7.6 g of oil, and 1.4 g of surfactant. Thenanocapsules formed were characterized by photon correlation spectroscopy,freeze fracture transmission and scanning electron microscopy. Insulinnanocapsules were prepared by using an aqueous solution of insulin(100 units/ml) as the dispersed phase of the microemulsion. Theentrapment and the release of insulin from the nanocapsules were determined. Results. Three regions were identified in the pseudo-ternary phasediagram; a microemulsion region, a region in which liquid crystallinestructures were present and a coarse emulsion region. All systems inthe microemulsion region were water-in-oil dispersions.Poly(ethyl 2-cyanoacrylate) nanocapsules having a mean particle size of 150.9 nmwere formed upon interfacial polymerization of the microemulsion.Nanocapsules were found to have a central cavity surrounded by apolymer wall. In excess of 80;pc of the insulin present in themicroemulsion was encapsulated upon interfacial polymerization. Conclusions. Interfacial polymerization of spontaneously formingwater-in-oil microemulsions represents a convenient method for thepreparation of poly(alkylcyanoacrylate) nanocapsules suitable for theentrapment of bioactive peptides.

Characterizing colloidal structures of pseudoternary phase diagrams formed by oil/water/amphiphile systems

Two pseudoternary phase diagrams were constructed using ethyl oleate, water, and a surfactant blend containing poly (oxyethylene 20) sorbitan monooleate and sorbitan monolaurate with or without the cosurfactant 1-butanol. Two colloidal regions were identified in the cosurfactant-free phase diagram; a microemulsion (ME) and a region containing lamellar liquid crystals (LC). The addition of 1-butanol increased the area in which systems formed microemulsions and eliminated the formation of any liquid crystalline phases. Samples that form the colloidal regions of both systems were investigated by freeze-fracture transmission electron microscopy and by viscosity and conductivity measurements. The three techniques were compared and evaluated as characterisation tools for such colloidal systems and also to identify transitions between the colloidal systems formed. A droplet ME was present at a low water volume fraction (ϕw) in both systems (ϕw <0.15) as revealed by electron microscopy. At higher ϕw values, LC structures were observed in micrographs of samples taken from the cosurfactant-free system while the structure of samples from the cosurfactant-containing system was that of a bicontinuous ME. The viscosity of both systems increased with increasing ϕw to 0.15 and flow was Newtonian. However, formation of LC in the cosurfactant-free system resulted in a dramatic increase in viscosity that was dependent on ϕw and a change to pseudoplastic flow. In contrast, the viscosity of the bicontinuous ME was independent of ϕw. Three different methods were used to estimate the percolation threshold from the conductivity data for the cosurfactant-containing system. The use of nonlinear curve fitting was found to be most useful yielding a value close to 0.15 for the ϕw.

Effects of alcohols and diols on the phase behaviour of quaternary systems

The aim of the current study was to investigate the effect of different co-surfactants on the phase behaviour of the pseudoternary system water:ethyl oleate:nonionic surfactant blend (sorbitan monolaurate/polyoxyethylene 20 sorbitan mono-oleate). Four aliphatic alcohols (1-propanol, 1-butanol, 1-hexanol and 1-octanol) and four 1, 2-alkanediols (1,2-propanediol, 1,2-pentanediol, 1,2-hexanediol and 1,2-octanediol) were used. The co-surfactant-free system forms two different colloidal structures, a water-in-oil microemulsion (w/o ME) and lamellar liquid crystals (LC) and two coarse dispersions, water-in-oil (w/o EM) and oil-in-water (o/w EM) emulsions. Microemulsion region area (%ME), liquid crystalline region area (%LC), amount of amphiphile blend required to produce a balanced microemulsion (%AMPH) and amount of water solubilised (%W) were used as assessment criteria to evaluate the co-surfactants. Seven calculated physico-chemical descriptors were used to represent the different co-surfactants. 1-butanol, 1,2-hexanediol and 1, 2-octanediol produced balanced MEs capable of solubilising a high percentage of both oil and water. A similarity was observed between the descriptors attributed to 1-butanol and 1,2-hexanediol. The requirements of a co-surfactant molecule to produce a balanced microemulsion were: HLB value 7.0-8.0, a carbon backbone of 4-6 atoms, percentage carbon of 60-65%, percentage oxygen of 20-30%, logP value 0.2-0.9 and log 1/S (S: aqueous solubility) close to zero.

The potential of small-scale fusion experiments and the Gordon-Taylor equation to predict the suitability of drug/polymer blends for melt extrusion

The aim of this study was to investigate the use of small-scale fusion experiments and the Gordon-Taylor (GT) equation to predict whether melt extrusion of a drug with an amorphous polymer produces a stable amorphous dispersion with increased drug dissolution. Indomethacin, lacidipine, nifedipine, piroxicam, and tolbutamide were used as poorly soluble drugs. Drug/polyvinylpyrrolidone (PVP) blends were prepared at a 1:1 mass ratio. Small-scale fusion experiments were performed in a differential scanning calorimeter (DSC) and in stainless steel beakers. Extrusion was performed in a Brabender Plasti-corder. The glass transition temperatures Tg were determined by DSC. Taking an average Tg from the DSC melt, beaker melt, and GT equation accurately predicted the extrudate Tg. Physical stability of beaker melt and extrudate samples was tested by X-ray powder diffraction (XRPD) and DSC after storage at 30°C (beaker melt) or 25°C (extrudate) and less than 10%, 60%, and 75% relative humidity (RH). Beaker melts were amorphous, apart from some residual crystallinity. Extrudates were amorphous after preparation. Except for indomethacin/PVP, which remained amorphous, the crystallinity of beaker melts and extrudates increased only at 75% RH. Recrystallization occurred even when the Tg of the sample was well above the storage temperature. Chemical stability of the beaker melts and extrudates was tested by capillary electrophoresis and high-performance liquid chromatography (HPLC). Stability was slightly improved in the extrudate compared to the beaker melt. In general, the order for rate of dissolution was crystalline drug was less than the physical mixture, which was less than the drug/PVP beaker melt, which was approximately equal to the extrudate. The use of beaker melts allows a conservative estimate of the potential to melt extrude a drug. To predict physical stability, analysis of the Tg must be combined with physical stability experiments.

In-vitro release and oral bioactivity of insulin in diabetic rats using nanocapsules dispersed in biocompatible microemulsion.

This study evaluated the potential of poly(iso‐butyl cyanoacrylate) (PBCA) nanocapsules dispersed in a biocompatible microemulsion to facilitate the absorption of insulin following intragastric administration to diabetic rats. Insulin‐loaded PBCA nanocapsules were prepared in‐situ in a biocompatible water‐in‐oil microemulsion by interfacial polymerisation. The microemulsion consisted of a mixture of medium‐chain mono‐, di‐ and tri‐glycerides as the oil component, polysorbate 80 and sorbitan mono‐oleate as surfactants and an aqueous solution of insulin. Resulting nanocapsules were approximately 200 nm in diameter and demonstrated a high efficiency of insulin entrapment (> 80%). In‐vitro release studies showed that PBCA nanocapsules could suppress insulin release in acidic media and that release at near neutral conditions could be manipulated by varying the amount of monomer used for polymerisation. Subcutaneous administration of insulin‐loaded nanocapsules to diabetic rats demonstrated that the bioactivity of insulin was largely retained following this method of preparing peptide‐loaded nanocapsules and that the pharmacodynamic response was dependent on the amount of monomer used for polymerisation. The intragastric administration of insulin‐loaded nanocapsules dispersed in the biocompatible microemulsion resulted in a significantly greater reduction in blood glucose levels of diabetic rats than an aqueous insulin solution or insulin formulated in the same microemulsion. This study demonstrates that the formulation of peptides within PBCA nanocapsules that are administered dispersed in a microemulsion can facilitate the oral absorption of encapsulated peptide. Such a system can be prepared in‐situ by the interfacial polymerisation of a water‐in‐oil biocompatible microemulsion.

Application of neural networks for response surface modeling in HPLC optimization

The usefulness of artificial neural networks for response surface modeling in HPLC optimization is compared with multiple regression methods. The results show that neural networks offer promising possibilities in HPLC method development. The predicted capacity factors of analytes were better to those obtained with multiple regression method.

Probiotic treatment reduces blood glucose levels and increases systemic absorption of gliclazide in diabetic rats.

SummaryThe action of gliclazide, a sulphonylurea with beneficial extrapancreatic effects in diabetes, may be enhanced by administering probiotics. The aim of this study was to investigate the influence of probiotics on gliclazide pharmacokinetics and the effect of both probiotics and gliclazide on blood glucose levels in healthy and diabetic rats. Male Wistar rats (2 to 3 months, weight 350 ± 50 g) were randomly allocated to 4 groups (n =10), two of which were treated with alloxan i.v. 30 mg/kg to induce diabetes. One group of healthy and one group of diabetic rats were then gavaged with probiotics (75 mg/kg) for three days after which a gliclazide suspension (20 mg/kg) was administered by gavage to all groups. Blood samples were collected from the tail vein at various time points for 10 hours post-administration for the determination of blood glucose and gliclazide serum concentrations. It was found that probiotic treatment had no effect on blood glucose levels in healthy rats, but it reduced them (up to 2-fold;p < 0.01) in diabetic rats. Probiotic treatment reduced gliclazide bioavailability in healthy rats (3-fold) whereas it increased gliclazide bioavailability in diabetic rats (2-fold;p < 0.01). Gliclazide had no effect on blood glucose levels in either healthy or diabetic rats despite the changes in its bioavailability. In conclusion, the probiotic treatment of diabetic rats increases gliclazide bioavailability and lowers blood glucose levels by insulin-independent mechanisms, suggesting that the administration of probiotics may be beneficial as adjunct therapy in the treatment of diabetes.

Effects of formulation variables on characteristics of poly (ethylcyanoacrylate) nanocapsules prepared from w/o microemulsions

The effect of several formulation variables on some of the physico-chemical characteristics of poly (ethyl cyanoacrylate) (PECA) nanocapsules prepared by the interfacial polymerisation of biocompatible water-in-oil microemulsions was investigated. In all cases, yields were high (>90%) and the polydispersity in size of nanocapsules was narrow. The molecular weight of the nanocapsules formed was influenced by the pH of the aqueous component of the microemulsion, increasing with increasing pH. The size of the nanocapsules formed (ranging from around 130 to 180 nm) was a function of the ratio of the mass of monomer used to the water weight fraction of the microemulsion, increasing as this ratio was increased. This is due to the formation of a thicker polymer wall resulting from the increased mass of monomer available per unit interfacial area as this ratio is increased. The rate of release of insulin from nanocapsules was also influenced by this ratio, in agreement with its effect on wall thickness. This study demonstrates that many pharmaceutically relevant physico-chemical properties of poly (alkyl cyanoacrylate) (PACA) nanocapsules prepared by interfacial polymerisation of microemulsions can readily be manipulated by changing either the pH of the aqueous component, the water weight fraction of the microemulsion or the mass of monomer used for polymerisation.