Sverre Arne Sande

Development of pectin matrix tablets for colonic delivery of model drug ropivacaine

The objective of this work was to develop pectin-based matrix tablets for colonic delivery of the model drug ropivacaine, with the future perspective of radiolabelling the system by neutron activation technique for a gamma-scintigraphic study. The aim was to investigate some formulation factors that could reduce the release of the drug in the simulated gastric and intestinal fluids, increase the release in the simulated cecal fluid (with pectinolytic enzymes) and improve the poor compactibility of pectins. For dissolution studies, the flow-through apparatus with sequential dissolution liquids simulating the mouth-to-colon conditions was used. The effect of two pectin types, the incorporation of ethylcellulose as a dry matrix-additive and water or ethanol as granulation liquids were investigated in a study designed as a D-optimal mixture. Amidated pectin (Am.P) produced harder tablets than the calcium salt of pectin (Ca.P) and was more susceptible to enzymatic degradation. Addition of ethylcellulose increased the tablet strength and the dissolution rate. Furthermore, directly compressed Am.P tablets were produced by addition of coarse or micronised qualities of ethylcellulose. The latter improved the crushing strength markedly imposing a marginal release-reducing effect. Coating this formulation with Eudragit((R)) L 100 reduced the release in the simulated upper GI conditions without interference with the subsequent enzymatic activity.

Interactions between liposomes and chitosan II : effect of selected parameters on aggregation and leakage

The interaction between liposomes and chitosan has been described in an earlier paper. In the present work, the production of liposome-chitosan complexes (Chitosomes) was further studied using factorial designs. The parameters studied were the stirring rate, rate of addition of liposomes to polymer, ionic strength, chitosan quality, lipid/polymer ratio and pH. Particle size, polydispersity and charge were the measured parameters. Cryo-electron microscopy was used for further study of one of the combinations. It was found that the ionic strength, chitosan quality, lipid/polymer ratio and pH had a significant effect on the resulting aggregate size. The leakage of quinine from Chitosomes was compared to the leakage from liposomes using a fractional dialysis method. The leakage rates were similar, but the Chitosomes produced a higher initial release and showed less scattering of the data. Measurements of zeta potential indicated adsorption of quinine to the liposomal membrane. Chitosomes could be stored in a refrigerator for at least 6 months without significant change in particle size.

Pectinic acid, a novel excipient for production of pellets by extrusion/spheronisation: preliminary studies

A very low soluble pectin-derivative (pectinic acid, degree of methoxylation 4%) was found to be well suited as an excipient for pelletisation by extrusion/spheronisation. Formulations containing pectinic acid and lactose in the following ratios were evaluated: 99/1, 80/20, 50/50 and 20/80. The capacity as an extrusion aid was found to be high; even formulations containing only 20% pectinic acid resulted in nearly spherical pellets. All pectinic acid pellets were mechanically stable, had an aspect ratio of approximately 1.15-1.20 and released 30-60% of a low solubility model drug within 15 min both in simulated gastric acid (0.1M HCl) and intestinal fluid (phosphate buffer pH 6.8).

Disintegrating pellets from a water-insoluble pectin derivative produced by extrusion/spheronisation

Pectinic acid (PA) and microcrystalline cellulose (MCC) as extrusion aiding excipients have been compared. Three different drugs were selected as models: Riboflavin with a very low water solubility, paracetamol and theophylline as drugs with high water-solubility. The drug load was varied from 1 to 80% wt. The low-soluble pectin derivative, PA (degree of methoxylation <10%) was found to be well suited as an extrusion aiding excipient in pellet preparation by extrusion/spheronisation. The substance has a high drug loading capacity and produces disintegrating pellets that are well suited for fast delivery of drugs with a low water-solubility. The pellets are also mechanically stable. Compared to MCC, PA was found to require less water for pellet formation and was more sensitive against changes in the water content. In order to achieve optimal shape of the pellets, spheronisation was carried out at 45 degrees C. PA is more sensitive to type and amount of drug and is, consequently, not as universally applicable as the conventionally used microcrystalline cellulose. The great advantage of pectinic acid is, however, the disintegrating properties of the pellets after only a short time of exposure to liquid.

Formulation and characterisation of primaquine loaded liposomes prepared by a pH gradient using experimental design

The effect of different formulation factors (lipid type, cholesterol, charge, internal buffer capacity, drug-to-lipid incubation ratio) on the encapsulation efficiency and size of primaquine liposomes (SUVs) in response to a pH gradient was investigated by a fractional factorial screen ing design. Three of the factors (charge, internal buffer capacity, drug -to-lipid incubation ratio) were further studied in a Box--Behnken optimisation design. The lipid type was the most important parameter followed by the drug-to-lipid incubation ratio, buffer capacity, cholesterol and charge. Several of the interactions wer e important. In the optimisation design a robust region with high encapsulation efficiency (>95%) was obtained for DSPC: 33.33 mol% cholesterol-liposomes at high internal citrate concentration (200 mM) by maintaining the drug-to-lipid incubation ratio below 0.15:1 (mol:mol) and varying the charge incorporation between 2 and 10%. In order to achieve long-term stability and sterility, the liposomes were lyophilised followed by gamma irradiation. The pH gradient was maintained during this treatment with little chemical degradation of the substances. The final preparation consisted of three separate vials with lyophilised liposomes, solid state primaquine and hydration medium.

The formation and permeability of drugs across free pectin and chitosan films prepared by a spraying method

This study has investigated the permeation of drugs through free films made of pectin and chitosan. The background for this study is the intended use of the films as coating material in a colon-specific drug delivery device. The factors that varied when making the films were the pectin source and grade of the pectin, degree of deacetylation of the chitosan and ratio between pectin and chitosan. The permeability of the model drug in 0.1 M HCl was low with an average drug release of 1.3 x 10(-3)%/cm. The films containing high content of chitosan showed exponential kinetics while the films containing high content of pectin showed 0-order kinetics. The release of drug in phosphate buffer pH 6.8 showed 0-order kinetics. The lowest permeability was obtained for a film consisting of a high content of pectin to chitosan, chitosan with a high degree of deacetylation and non-amidated low methoxylated citrus pectin. The permeation of paracetamol for this combination was 9.4 x 10(3)%/cm. This film combination had a combined diffusion of only 0.046%/cm after 1 h in 0.1 M HCl and 4 h in phosphate buffer pH 6.8.

Mucoadhesion and drug permeability of free mixed films of pectin and chitosan: an in vitro and ex vivo study.

The objective of this study was to identify the important factors for the drug permeability and mucoadhesion of casted free pectin/chitosan combination films. The factors varied were: the type of pectin (low and high methoxyl pectin) and the ratio pectin:chitosan (25:75, 50:50 and 75:25). The model drug used for measuring drug permeability was paracetamol. A texture analyzer was used for measuring mucoadhesion by using two different setups: (1) in vitro tensile tests measuring the detachment force of films versus a mucin dispersion and (2) ex vivo shear tests measuring the friction forces between pre-hydrated films and fresh porcine small intestine, with the system immersed in phosphate buffer, pH 6.8. The type of pectin used in the combination films did not have a significant effect on the drug permeability. The ex vivo mucoadhesion test revealed significant differences between low and high methoxyl pectin only for the 50:50 pectin:chitosan films. For that type of film, the peak and friction forces were highest for high methoxyl pectin. Both the mucoadhesion and drug permeability generally increased with decreasing amounts of pectin relative to chitosan in the films.

Pectin-based oral drug delivery to the colon

This review presents an overview of studies concerning oral formulations intended for site-specific drug delivery to the colon with pectin as the main excipient. The biological aspects covered include gastrointestinal transit and the enzymatic degradation of pectin. Scintigraphic methods demonstrating the functionality of pectin formulations are discussed. The main focus is on the various formulations reported, including matrix tablets, multiparticulate formulations as pellets and hydrogel beads, and pectin-based coatings. Also included is an evaluation of common excipients employed to improve colon specificity by crosslinking or increasing the hydrophobicity. Finally, properties of the pectin molecules that are important for successful formulations are examined. The conclusion is that the studies found in the literature provide an excellent platform for the development of pectin-based colon delivery systems.

In Vitro Measurements of Mucoadhesive Properties of Six Types of Pectin

ABSTRACT The objective of this study was to measure and compare the specific- and general mucin interaction of six pectin types from three manufacturers, differing mainly in the degree of methoxylation and degree of amidation. Mucoadhesive properties were measured using a texture analyzer. It was found that an intermediate degree of methoxylation (35 and 36%) improved the specific mucin interaction. Amidation did not increase mucin interaction. Samples from different manufacturers did not alter these conclusions. This study indicates that the general classification of pectin as a poor mucoadhesive, without differentiating between the amount and type of substituents, probably is an oversimplification.

Thermoresponsive polymers as gene and drug delivery vectors: architecture and mechanism of action

Introduction: This topic is important as it allows for improved specificity in drug delivery, providing possibilities for reduced side effects, and thereby improved pharmacotherapy. As a wealth of different polymers and mechanisms of action has been suggested, a systematic overview of the field is of current importance. Areas covered: This article presents an overview over a selection of thermoresponsive polymers suitable as excipients in systems for gene and drug delivery with particular emphasis on the influence of polymer structure, composition, molecular weight (MW) and architecture on the responsive mechanisms. Due to the immense number of reports on these increasingly popular materials, focus has been restricted to the use of micelle-forming polymers with a lower critical solution temperature, temperature-responsive hydrogels for drug delivery applications and temperature-sensitive polymers as non-viral vectors for polynucleotide delivery. Specific examples covered are poly-(N-isopropylacrylamide) (PNIPAAM), Pluronics and their derivatives. It is concluded that the studies constitute an excellent platform for development of thermoresponsive systems with improved gene and drug delivery properties. Expert opinion: A thorough knowledge of factors important for loading efficiency and drug release is necessary to be able to develop optimal nano-carriers for the future. Other issues that are not fully understood is how small the carriers need to be, and which manufacturing procedures should be used.