Biomedical subjects

Thomas Rades

Publications and source records attributed to Thomas Rades.

At least 37 records · Page 2Linked to original sources

PubMed2005

The influence of thermal and mechanical preparative techniques on the amorphous state of four poorly soluble compounds.

A number of studies in the literature have reported on the use of different preparative techniques to convert crystalline pharmaceutical compounds into the amorphous form. However, very few direct comparisons of different preparative techniques using the same drugs are available. The purpose of this study was to determine the influence of two techniques: quench cooling and ball milling on four structurally diverse pharmaceutical drugs. Dipyridamole, carbamazepine, glibenclamide, and indomethacin were converted to the amorphous form by (a) quench cooling of the drug melt and (b) ball milling. The chemical purity and physical form of the products was determined using diffractometric, spectroscopic, and thermal analytical techniques. Products were analysed immediately post preparation and after storage under different stability conditions. Quench cooling of the melt resulted in amorphous conversion of all four compounds. However with glibenclamide, quench cooling resulted in unacceptable chemical degradation whereas ball milling of glibenclamide resulted in a change in the keto-enol tautomerism at the aryl amide moiety of this drug. Ball milling resulted in predominantly amorphous products for all compounds except carbamazepine. Ball milling of carbamazepine resulted in a polymorphic transition of the starting material to form III. Physical stability studies showed that irrespective of preparative technique and storage conditions all samples showed at least partial reversion to the crystalline state after storage. Quench cooling of drug melts may be of use as a preparative technique however it can result in chemical degradation. Ball milling may also be of use as a preparative technique however its effectiveness is dependent on the unit cell structure of the compound.

Carbamazepine↗

PubMed2005

Characterisation of indomethacin and nifedipine using variable-temperature solid-state NMR.

We have characterised the stable polymorphic forms of two drug molecules, indomethacin (1) and nifedipine (2) by 13C CPMAS NMR and the resonances have been assigned. The signal for the C-Cl carbon of indomethacin has been studied as a function of applied magnetic field, and the observed bandshapes have been simulated. Variable-temperature 1H relaxation measurements of static samples have revealed a T1rho minimum for indomethacin at 17.8 degrees C. The associated activation energy is 38 kJ mol(-1). The relevant motion is probably an internal rotation and it is suggested that this involves the C-OCH3 group. Since the two drug compounds are potential candidates for formulation in the amorphous state, we have examined quench-cooled melts in detail by variable-temperature 13C and 1H NMR. There is a change in slope for T1H and T1rhoH at the glass transition temperature (Tg) for indomethacin, but this occurs a few degrees below Tg for nifedipine, which is perhaps relevant to the lower real-time stability of the amorphous form for the latter compound. Comparison of relaxation time data for the crystalline and amorphous forms of each compound reveals a greater difference for nifedipine than for indomethacin, which again probably relates to real-time stabilities. Recrystallisation of the two drugs has been followed by proton bandshape measurements at higher temperatures. It is shown that, under the conditions of the experiments, recrystallisation of nifedipine can be detected already at 70 degrees C, whereas this does not occur until 110 degrees C for indomethacin. The effect of crushing the amorphous samples has been studied by 13C NMR; nifedipine recrystallises but indomethacin does not. The results were supported by DSC, powder XRD, FTIR and solution-state NMR measurements.

Carbon Isotopes↗

PubMed2005

Lipid based particulate formulations for the delivery of antigen.

Particulate adjuvant systems are largely classified according to their functional characteristics, such as the nature of the typical immune response they induce, or their perceived mode of action. From a formulation science perspective, it is practical to classify antigen delivery systems according to the physical nature of the formulations. This article discusses lipid based particulate systems, grouped according to the nature of their predominant lipid constituent.

Adjuvants, Immunologic↗

PubMed2005

Thermotropic liquid crystalline drugs.

Crystalline solids are characterized by long-range positional and orientational order in three dimensions, whereas amorphous liquids lack long-range order in any dimension. Liquid crystals (mesophases) show structural, mechanical and optical properties intermediate to those of crystalline solids and the amorphous, liquid state of matter. There are two principle types of liquid crystals: thermotropic liquid crystals (TLCs) and lyotropic liquid crystals (LLCs). TLCs can be formed by heating a crystalline solid or by cooling an isotropic melt of a TLC-forming molecule (mesogen). In the first part of this review the types of liquid crystals are defined and classified and the structural properties of mesogens are explained. In the second part, ten case studies of thermotropic mesomorphous drugs and pharmaceutically relevant molecules (arsphenamine, nafoxidine hydrochloride, L-660711, palmitoyl propranolol hydrochloride, penbutolol sulfate, itraconazole hydrochloride, fenoprofen sodium, fenoprofen calcium, ciclosporin and cholesteryl esters) are presented and their thermotropic mesomorphism is described. The review closes with a brief discussion of the unusual properties of drug mesophases and a potential use of drugs and excipients in this fourth state of matter.

Crystallization↗

PubMed2005

Immuno-stimulating complexes prepared by ethanol injection.

This study describes the formulation of immuno-stimulating complexes (ISCOMs) utilising the ethanol injection technique. Cholesterol and phosphatidylcholine were dissolved in ethanol and the resulting solution was rapidly injected into a stirred, aqueous solution of the triterpene-saponin mixture Quil-A. The reversed experiment was also carried out by adding the aqueous Quil-A solution to a solution of cholesterol/phosphatidylcholine dissolved in ethanol. This was done by either rapid injection or dropwise addition of the aqueous Quil-A solution. The colloidal dispersions obtained by ethanol injection and reversed addition were compared with formulations obtained by the dialysis and lipid-film hydration methods. In a further experiment, the preparation of ISCOMs from liposomes as precursor structures was investigated. Transmission electron microscopy was used to analyse the resulting colloidal dispersions. Samples were also compared with respect to homogeneity of obtained particle species. The ethanol injection technique led to formation of ISCOMs in high numbers within 2 h post formulation. The reversed rapid injection resulted in a similar colloidal dispersion, differing from the former mainly due to the presence of some helical micellar structures. The reversed, dropwise addition led to the formation of helices as the predominant colloidal structure. Of the three previously established methods, only dialysis led to the formation of ISCOMs within 48 h. The lipid-film hydration method and the approach using liposomes as precursor structures did not produce ISCOMs under the conditions and within the time periods investigated. However, it is known that dispersions prepared by the hydration method equilibrate towards ISCOMs after longer storage. Ethanol injection and reversed rapid injection are simple, cost-effective and quick methods to produce ISCOMs.

Chemistry, Pharmaceutical↗

PubMed2004

Incorporation of ovalbumin into ISCOMs and related colloidal particles prepared by the lipid film hydration method.

The aim of this study was to investigate the incorporation of a model antigen, fluorescently labelled ovalbumin (FITC-OVA), into various colloidal particles including immune stimulating complexes (ISCOMs), liposomes, ring and worm-like micelles, lamellae and lipidic/layered structures that are formed from various combinations of the triterpene saponin Quil A, cholesterol and phosphatidylethanolamine (PE) following hydration of PE/cholesterol lipid films with aqueous solutions of Quil A. Colloidal dispersions of these three components were also prepared by the dialysis method for comparison. FITC-OVA was conjugated with palmitic acid (P) and PE to produce P-FITC-OVA and PE-FITC-OVA, respectively. Both P-FITC-OVA and PE-FITC-OVA could be incorporated in all colloidal structures whereas FITC-OVA was incorporated only into liposomes. The incorporation of PE-FITC-OVA into all colloidal structures was significantly higher than P-FITC-OVA (P < 0.05). The degree of incorporation of protein was in the order: ring and worm-like micelles < liposomes and lipidic/layered structures < ISCOMs and lamellae. The incorporation of protein into the various particles prepared by the lipid film hydration method was similar to those for colloidal particles prepared by the dialysis method (provided both methods lead to the formation of the same colloidal structures). In the case of different colloidal structures arising due to the preparation method, differences in encapsulation efficiency were found (P < 0.05) for formulations with the same polar lipid composition. This study demonstrates that the various colloidal particles formed as a result of hydrating PE/cholesterol lipid films with different amounts of Quil A are capable of incorporating antigen, provided it is amphipathic. Some of these colloidal particles may be used as effective vaccine delivery systems.

Cholesterol↗

PubMed2004

Effects of intraduodenal fatty acids on appetite, antropyloroduodenal motility, and plasma CCK and GLP-1 in humans vary with their chain length.

The gastrointestinal effects of intraluminal fats may be critically dependent on the chain length of fatty acids released during lipolysis. We postulated that intraduodenal administration of lauric acid (12 carbon atoms; C12) would suppress appetite, modulate antropyloroduodenal pressure waves (PWs), and stimulate the release of cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1) more than an identical dose of decanoic acid (10 carbon atoms; C10). Eight healthy males (19-47 yr old) were studied on three occasions in a double-blind, randomized fashion. Appetite perceptions, antropyloroduodenal PWs, and plasma CCK and GLP-1 concentrations were measured during a 90-min intraduodenal infusion of 1) C12, 2) C10, or 3) control (rate: 2 ml/min, 0.375 kcal/min for C12/C10). Energy intake at a buffet meal, immediately after completion of the infusion, was also quantified. C12, but not C10, suppressed appetite perceptions (P < 0.001) and energy intake (control: 4,604 +/- 464 kJ, C10: 4,109 +/- 588 kJ, and C12: 1,747 +/- 632 kJ; P < 0.001, C12 vs. control/C10). C12, but not C10, also induced nausea (P < 0.001). C12 stimulated basal pyloric pressures and isolated pyloric PWs and suppressed antral and duodenal PWs compared with control (P < 0.05 for all). C10 transiently stimulated isolated pyloric PWs (P = 0.001) and had no effect on antral PWs but markedly stimulated duodenal PWs (P = 0.004). C12 and C10 increased plasma CCK (P < 0.001), but the effect of C12 was substantially greater (P = 0.001); C12 stimulated GLP-1 (P < 0.05), whereas C10 did not. In conclusion, there are major differences in the effects of intraduodenal C12 and C10, administered at 0.375 kcal/min, on appetite, energy intake, antropyloroduodenal PWs, and gut hormone release in humans.

Adult↗

PubMed2004

Pseudo-ternary phase diagrams of aqueous mixtures of Quil A, cholesterol and phospholipid prepared by the lipid-film hydration method.

Pseudo-ternary phase diagrams of the polar lipids Quil A, cholesterol (Chol) and phosphatidylcholine (PC) in aqueous mixtures prepared by the lipid film hydration method (where dried lipid film of phospholipids and cholesterol are hydrated by an aqueous solution of Quil A) were investigated in terms of the types of particulate structures formed therein. Negative staining transmission electron microscopy and polarized light microscopy were used to characterize the colloidal and coarse dispersed particles present in the systems. Pseudo-ternary phase diagrams were established for lipid mixtures hydrated in water and in Tris buffer (pH 7.4). The effect of equilibration time was also studied with respect to systems hydrated in water where the samples were stored for 2 months at 4 degrees C. Depending on the mass ratio of Quil A, Chol and PC in the systems, various colloidal particles including ISCOM matrices, liposomes, ring-like micelles and worm-like micelles were observed. Other colloidal particles were also observed as minor structures in the presence of these predominant colloids including helices, layered structures and lamellae (hexagonal pattern of ring-like micelles). In terms of the conditions which appeared to promote the formation of ISCOM matrices, the area of the phase diagrams associated with systems containing these structures increased in the order: hydrated in water/short equilibration period<hydrated in buffer/short equilibration period<hydrated in water/prolonged equilibration period. ISCOM matrices appeared to form over time from samples, which initially contained a high concentration of ring-like micelles suggesting that these colloidal structures may be precursors to ISCOM matrix formation. Helices were also frequently found in samples containing ISCOM matrices as a minor colloidal structure. Equilibration time and presence of buffer salts also promoted the formation of liposomes in systems not containing Quil A. These parameters however, did not appear to significantly affect the occurrence and predominance of other structures present in the pseudo-binary systems containing Quil A. Pseudo-ternary phase diagrams of PC, Chol and Quil A are important to identify combinations which will produce different colloidal structures, particularly ISCOM matrices, by the method of lipid film hydration. Colloidal structures comprising these three components are readily prepared by hydration of dried lipid films and may have application in vaccine delivery where the functionality of ISCOMs has clearly been demonstrated.

Adjuvants, Immunologic↗

PubMed2004

Partial characterization of different mixtures of solids by measuring the optical nonlinear response.

We report on the theoretical basis and first experimental results of a new method based on optical nonlinearity, for characterising crystallinity and polymorphism of pharmaceuticals in the solid state. Once the theoretical basis of optical nonlinearity of crystalline structures is established, a new and rapid method based on this physical theory can be developed to quantitatively determine polymorphism or crystallinity. An apparatus was set up to measure the second harmonic response of powdered samples when irradiated with a pulsed laser source. The response of quartz-glass, enalapril maleate forms I-II and enalapril maleate form II-PVP mixtures were measured and modeled. It was found that the quartz-glass system showed high sensitivity to the presence of quartz and was well predicted by our theoretical model. The response of enalapril maleate polymorph mixtures was also sensitive to changes in the polymorph ratio. The theoretical predictions of the polymorph mixtures agreed quantitatively with the experimental results. The response of enalapril maleate form II-PVP mixtures agreed quantitatively with the physical model and showed extremely low noise and high sensitivity, giving very promising limits of detection (LOD) and quantification (LOQ) of 0.12 and 0.41%, respectively. This rapid, novel technique has potential for industrial monitoring of pharmaceutical manufacturing processes.

Electrochemistry↗

PubMed2004

Effect of incorporation of the adjuvant Quil A on structure and immune stimulatory capacity of liposomes.

Liposomes have been widely used as drug delivery systems for many years. However, they are of limited use as delivery systems for subunit vaccines due to their low immunogenicity. Here we examine the effect of incorporating the adjuvant Quil A into liposomes on the type of particles produced, on the ability of the different particles to incorporate antigen and on the ability of the different particles to stimulate murine bone-marrow-derived dendritic cells (DC) and lymphocytes. The incorporation of increasing amounts of Quil A, from 20% to 70% of the total lipid into liposomes, reduces the size of the particles that form in aqueous dispersion and decreases antigen incorporation and uptake by DC. Interestingly, the particles with 20% Quil A were more toxic to cells in culture than the particles containing 70% Quil A, and the 20% particles were also more immunostimulatory.

Adjuvants, Immunologic↗

PubMed2003

Liposomal delivery of antigen to human dendritic cells.

This study investigated whether formulation of antigen in mannosylated liposomes enhanced uptake and activation of dendritic cells (DC) and increased the ability of DC to induce primed T cell proliferation compared to formulation of antigen in unmodified liposomes or in solution. Immature human DC were generated from peripheral blood monocytes cultured with GM-CSF and IL-4. Uptake of antigen by DC and the degree of expression of the cell surface markers MHC class II, CD80, CD86 and the DC maturation marker CD83, was investigated by flow cytometry following incubation with liposomes or solution containing FITC-conjugated antigen. Exposure to liposomes containing FITC-ovalbumin resulted in enhanced expression of cell surface markers when compared to exposure to antigen in solution. Expression was highest following exposure to mannosylated liposomes. Mannosylated liposomes containing tetanus toxoid (TT) stimulated primed T cell proliferation more effectively than TT-neutral liposomes or TT-solution. This work suggests that mannosylated liposomes provide a versatile delivery vehicle for initiating enhanced immune responses to encapsulated peptide or protein vaccines.

Antigen Presentation↗

PubMed2003

Physical stability and enthalpy relaxation of drug-hydroxypropyl methylcellulose phthalate solvent change co-precipitates.

The poorly water-soluble drug GWX was co-precipitated with hydroxypropyl methylcellulose phthalate (HPMCP) using a solvent change method. The two co-precipitate formulations made, with drug-HPMCP ratios of 2:8 and 5:5, were analysed using modulated temperature differential scanning calorimetry. They were found to consist of completely amorphous solid solution and a mixture of amorphous solid solution, crystalline drug and amorphous drug, respectively. Stability with respect to crystallization of the two co-precipitates and pure amorphous drug made by quench cooling was compared by storing preparations at 25 degrees C and 40 degrees C, under vacuum over P(2)O(5), and at 75% relative humidity (r.h.). Humidity (75% r.h. compared with dry) had a larger influence on crystallization of the amorphous drug than temperature (25 degrees C compared with 40 degrees C). The solid solution phase in co-precipitates had a relatively higher stability than amorphous drug alone, with respect to crystallization, in presence of the plasticizer water, and crystalline drug. These findings were partly explained by evidence of decreased molecular mobility in the amorphous solid solution with respect to amorphous drug alone, using enthalpy relaxation measurements. At an ageing temperature of 65 degrees C, the calculated half-life for enthalpy relaxation of the 2:8 drug-HPMCP ratio coprecipitate was about 6 orders of magnitude greater than that of amorphous drug alone, indicating a large difference in relative molecular mobility.

Chemical Phenomena↗

PubMed2002

Physical stability and solubility of the thermotropic mesophase of fenoprofen calcium as pure drug and in a tablet formulation.

The aim of this study was to investigate and compare the physical stability and solubility of the liquid crystalline form of fenoprofen calcium as pure drug and in a proprietary tablet formulation (Nalfon), and to investigate if a simple heat treatment of a proprietary tablet containing fenoprofen calcium may lead to a physically stable formulation with enhanced dissolution rate and apparent solubility. The liquid crystalline form of fenoprofen calcium (thermotropic mesophase) was prepared by heating the crystalline drug to 125 degrees C to remove the water of crystallisation. Differential scanning calorimetry investigation revealed an endothermic peak at 89 degrees C upon heating (liquid crystal formation) attributable to water loss from the crystalline dihydrate. The liquid crystalline order was maintained upon cooling. No interference of tablet excipients with the thermal behaviour of the drug in the tablet formulation was observed. The crystalline dihydrate and liquid crystalline forms of fenoprofen calcium could be differentiated by diffuse reflectance infra-red spectroscopy and X-ray powder diffraction, both as pure drug and in tablet formulation. The supercooled liquid crystal (thermotropic reversed hexagonal phase) alone and in preheated and ground tablets was physically stable when stored in a dry environment or at 33% relative humidities (RH) at both 20 and 40 degrees C for 2 months. At 40 degrees C and 75% RH the supercooled mesophase extensively converted to the crystalline dihydrate within 6 days. Liquid crystalline fenoprofen calcium stored at 20 degrees C and 75% RH showed only partial dihydrate conversion after 2 months of storage. The solubility of the crystalline dihydrate alone and from the tablet formulation was 2.8+/-0.2 mg/ml and 3.0+/-0.2 mg/ml (mean+/-s.d.), respectively, (not significantly different), whereas the maximum solubility of the liquid crystal was 5.0+/-0.3 mg/ml (mean+/-s.d.) and 6.9+/-0.6 mg/ml (mean+/-s.d.), respectively (significantly different). The difference in maximum solubility between the crystalline dihydrate form of fenoprofen calcium and the fenoprofen calcium mesophase was highly significant, for both the pure drugs and the tablet formulations. The dissolution rate of the liquid crystalline fenoprofen calcium in preheated, intact tablets was significantly lower than that of the crystalline form in non-preheated tablets. Gross visual changes and scanning electron microscopy indicated that the disintegration properties of the tablet may be detrimentally effected by heating the tablet to 125 degrees C, diminishing the beneficial effect of improved solubility of the liquid crystal. The study has shown that conversion of the crystalline form of fenoprofen calcium to the liquid crystal can enhance the apparent solubility of the pure drug and the drug in presence of tablet excipients, but that the conversion should be performed before tablet formulation in order to increase dissolution of this poorly water-soluble drug.

Chemistry, Pharmaceutical↗

PubMed2002

Factors affecting incorporation of drug into solid solution with HPMCP during solvent change co-precipitation.

Drug-hydroxypropyl methylcellulose phthalate (HPMCP) mixtures were completely dissolved in acetone, and the resulting solution was added drop-wise into HCl(aq). Resulting co-precipitates were filtered, and then dried under vacuum at 45 degrees C, -800 mbar for 24 h. Modulated differential scanning calorimetry, thermogravimetric analysis, X-ray powder diffraction and HPLC were used to detect and quantify different phases present in co-precipitates. A 1/8 factorial study followed by a circumscribed central composite (CCC) study of significant factors, were used to detect and quantify respectively, the effects that processing factors had on the percentage of drug present in co-precipitates which was incorporated into solid solution (the response). Robustness of the model obtained from the CCC study was tested. Statistically significant factors were found to be the percentage of drug added into solvent, stirrer speed, and antisolvent pH. The statistically significant mathematical model obtained from the CCC study predicted that the dominant factor influencing the response is the percentage of drug added into solvent. The effect of stirrer speed on the response includes a local maximum at stirrer speed approximately 700 rpm. Both stirrer speed and antisolvent pH showed interactions with the percentage of drug added into solvent. The model obtained from this study indicated the possibility of two opposing phenomena influencing the response: crystallization inhibition by HPMCP, and solvent-antisolvent plasticization. Testing of this model using eight experimentally determined points showed reasonable robustness, with six out of eight points lying inside 95% prediction intervals.

Acetone↗

PubMed2002

A method for the incorporation of ovalbumin into immune stimulating complexes prepared by the hydration method.

This study describes the development of a method for the incorporation of fluorescently labelled ovalbumin (FITC-OVA) into immune stimulating complexes (ISCOMs) prepared by the hydration method. Conjugation of palmitic acid was performed to fluorescently labelled OVA (pFITC-OVA) or to non-labelled OVA, with subsequent conjugation of FITC to the resulting palmitified OVA (FITC-pOVA). Both pFITC-OVA and FITC-pOVA, but not FITC-OVA, could be incorporated into ISCOMs and other non-liposomal colloidal structures. The degree of incorporation of pFITC-OVA or FITC-pOVA in non-liposomal colloidal particles reaches a maximum, if ISCOMs are the predominant colloids in the system.

Adjuvants, Immunologic↗

PubMed2002

Factors influencing the entrapment of hydrophilic compounds in nanocapsules prepared by interfacial polymerisation of water-in-oil microemulsions.

This study demonstrates the effect of drug properties and method of loading (sorption and encapsulation) on entrapment within poly(alkyl cyanoacrylate) nanocapsules prepared by interfacial polymerisation of biocompatible water-in-oil microemulsions. For small molecular weight compounds (<1000 Da), entrapment efficiency is more dependent on charge of the compound than on the method used for entrapment. Entrapment efficiency within the negatively charged nanocapsules (zeta potential approximately -30 mV) was in the order cationic compound > neutral compound > anionic compound. Only minimal differences for entrapment efficiency were noted between sorption (addition of the compound 4 h after initiation of the polymerisation) and encapsulation (addition of the compound to microemulsion prior to polymerisation). For high molecular weight compounds, the method used for entrapment however, is very important. For hydrophilic macromolecules such as proteins, high entrapment efficiencies can only be achieved by encapsulation. Entrapment of such compounds seems to be independent of the net charge of the compound being encapsulated but depended on the molecular weight. For nanocapsules prepared by interfacial polymerisation of water-in-oil microemulsions, these findings are useful as a foundation in the development of nanocapsules with desired properties.

Biocompatible Materials↗

PubMed2002

Quantitative analysis of polymorphic mixtures of ranitidine hydrochloride by Raman spectroscopy and principal components analysis.

Ranitidine hydrochloride exists as two polymorphs, forms I and II, both of which are used to manufacture commercial tablets. Raman spectroscopy can be used to differentiate the two forms but univariate methods of quantitative analysis of one polymorph as an impurity in the other lack sensitivity. We have applied principal components analysis (PCA) of Raman spectra to binary mixtures of the two polymorphs and to binary mixtures prepared by adding one polymorph to powdered tablets of the other. Based on absorption measurements of seven spectral regions, it was found that >97% of the spectral variation was accounted for by three principal components. Quantitative calibration models generated by multiple linear regression predicted a detection limit and quantitation limit for either forms I or II in mixtures of the two of 0.6 and 1.8%, respectively. This study demonstrates that PCA of Raman spectroscopic data provides a sensitive method for the quantitative analysis of polymorphic impurities of drugs in commercial tablets with a quantitation limit of less than 2%.

Drug Evaluation, Preclinical↗

PubMed2002

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.

Administration, Oral↗