Dale L. Munday

Relationship between swelling, erosion and drug release in hydrophillic natural gum mini-matrix formulations

The swelling, erosion and solvent front penetration properties of mini-matrices containing xanthan (X), locust bean (LB) and karaya (K) gums were examined, analysed and related to the overall in vitro release kinetics of diclofenac sodium, used as a model drug. Mini-matrices were produced with drug:gum ratios of 1:1 as well as formulations of drug and X in combinations of 2:1, 2:3 and 1:2. The rank order of decreasing swelling index (SI) in both axial and radial dimensions was X?K?LB and each gum showed almost Fickian swelling behaviour. The solvent front penetration rates were consistent with the rates of swelling. However, the order of decreasing drug release and erosion rates was LB>X>K and all formulations demonstrated anomalous (non-Fickian) drug release kinetics. Therefore Fickian drug diffusion and polymer erosion were both occurring simultaneously. The dominant mechanism depended on the nature and content of the gum, as well as the stage in the dissolution time period. There was a loss of matrix integrity in formulations containing a high drug:gum ratio.

Compressed xanthan and karaya gum matrices: hydration, erosion and drug release mechanisms

Directly compressed matrices were produced containing either xanthan gum or karaya gum as a release-controlling agent. These swellable hydrophilic natural gums were used to control the release of varying proportions of two model drugs, caffeine and diclofenac sodium, which have different solubilities in aqueous medium. Gum erosion, hydration and drug release studies were carried out using a dissolution apparatus (basket method) at two agitation speeds. Xanthan gum displayed a high degree of swelling due to water uptake and a small degree of erosion due to polymer relaxation. Neither agitation speed nor drug solubility had any significant effect on water uptake, but matrices with the lower proportion of gum produced a lesser degree of hydration. In contrast, karaya gum displayed a much lower hydration capacity and a higher rate of erosion, both markedly affected by agitation speed. Drug release from xanthan and karaya gum matrices depended on agitation speed, solubility and proportion of drug. Both xanthan and karaya gums produced near zero order drug release with the erosion mechanism playing a dominant role, especially in karaya gum matrices.

Development and evaluation of a biphasic buccal adhesive tablet for nicotine replacement therapy

Bilayer nicotine mucoadhesive tablets were prepared and evaluated to determine the suitability of the formulation as a nicotine replacement product to aid in smoking cessation. A range of formulations containing 0-50% w/w Carbopol 934 and 0-50% w/w hydroxypropylcellulose (HPC) were prepared and tested for adhesive properties and drug release. Mucoadhesion was assessed using bovine buccal mucosa. Peak detachment force of the tablets was found to reach a maximum at 20% w/w Carbopol 934, whilst work of adhesion continued to increase with Carbopol 934 concentration. HPC concentrations of 20-30% w/w were found to provide nicotine hydrogen tartrate (NHT) release approaching zero order kinetics over a 4 h test period. A combination of 20% w/w Carbopol 934 and 20% w/w HPC was thus found to provide suitable adhesion and controlled drug release. The formulation of a bilayer tablet containing the adhesive controlled release layer (CRL) and a fast releasing layer provided an initial burst release of NHT followed by the controlled release for a period of up to 4 h. The same biphasic type of release was identified during an in vivo assessment using human volunteers This biphasic drug release could represent an improvement over current methods of nicotine replacement.

Development and evaluation of a multiple-unit oral sustained release dosage form for S(+)-ibuprofen: preparation and release kinetics

Mini-matrix tablets containing S(+)-ibuprofen have been prepared by the wet granulation method. The hydrophilic matrix was formed with either xanthan gum, karaya gum or hydroxymethylcellulose (HPMC) together with a choice of additives from lactose, Encompress(R), Avicel(R) PH101, talc and Lubritab(R). Multiple unit dosage forms (MUDFs) were subsequently obtained by encapsulating the mini-matrix tablets into hard gelatin capsules. Preparation, in vitro release profiles and release kinetics are presented.

Release characteristics of diclofenac sodium from encapsulated natural gum mini-matrix formulations

In attempts to design an oral sustained release multiple-unit dosage form for diclofenac sodium (D), we evaluated the use of four natural hydrophilic gums as mini-matrix formulations enclosed in a hard gelatin capsule. Carrageenan (C), locust bean (LB), karaya (K) and xanthan gums (X) were used to produce mini-matrices (3, 4.5 and 5.5 mm in diameter) containing a gum and D, and also with other release-regulating excipients in different proportions, namely lactose (L), Encompress® (E), cellulose acetate phthalate (CAP) and Veegum F® (V). The release profiles from several encapsulated mini-matrices in buffered dissolution medium (pH 7.0) showed that sustained release of D up to 77% of drug content was achieved from mini-matrices containing LB, X and K, while C did not produce sufficient sustained release. The calculated release exponents (n values) indicated that release behaviour was anomalous (non-Fickian). Polymer swelling and relaxation were both involved in the release process. For X, the drug release rate declined linearly with progressive increase in gum content but without changing the release behaviour. Maximum release from individual mini-matrices was > 90% and approaching zero-order release kinetics (n → 1). This was due to the larger surface area to volume ratio which provided an optimum balance between the diffusion and dissolution mechanisms. Solubility differences between the excipients did not affect the release rate, but increasing proportions of each excipient produced a faster release rate with the release mechanism changing from anomalous to Case II and then to Super Case II transport. The amount of gum present appeared to play the dominant role in determining the drug release rate.

Evaluation of Selected Polysaccharide Excipients in Buccoadhesive Tablets for Sustained Release of Nicotine

Some naturally occurring biocompatible materials were evaluated as mucoadhesive controlled release excipients for buccal drug delivery. A range of tablets were prepared containing 0–50% w/w xanthan gum, karaya gum, guar gum, and glycol chitosan and were tested for swelling, drug release, and mucoadhesion. Guar gum was a poor mucoadhesive and lacked sufficient physical integrity for buccal delivery. Karaya gum demonstrated superior adhesion to guar gum and was able to provide zero‐order drug release, but concentrations greater than 50% w/w may be required to provide suitable sustained release. Xanthan gum showed strong adhesion to the mucosal membrane and the 50% w/w formulation produced zero‐order drug release over 4 hours, about the normal time interval between daily meals. Glycol chitosan produced the strongest adhesion, but concentrations greater than 50% w/w are required to produce a nonerodible matrix that can control drug release for over 4 hours. Swelling properties of the tablets were found to be a valuable indicator of the ability of the material to produce sustained release. Swelling studies also gave an indication of the adhesion values of the gum material where adhesion was solely dependent upon penetration of the polymer chains into the mucus layer.

Film Coated Pellets Containing Verapamil Hydrochloride: Enhanced Dissolution into Neutral Medium

Abstract Weakly basic drugs, such as verapamil hydrochloride, that are poorly soluble in neutral/alkaline medium may have poor oral bioavailability due to reduced solubility in the small intestine and colon. Film coated pellets were prepared using two strategies to enhance drug release at high pH values. Firstly, pellets were coated with Eudragit® RS/hydroxypropyl methylcellulose acetate succinate (HMAS) mixtures in proportions of 10:1 and 10:3, respectively. The enteric polymer, HMAS, would dissolve in medium at pH>6 creating pores through the insoluble Eudragit RS membrane to increase drug release. Secondly, an acidic environment was created within the core by the inclusion of fumaric acid at concentrations of 5 and 10% in order to increase drug solubility. Both strategies enhanced drug release into neutral medium in dissolution studies using the pH change method to simulate GIT transit. Dissolution profiles of samples tested in pH 1.2 for 12 hr were compared with those using the pH change method (pH 1.2 for first 1.5 hr, pH raised to 6.8 for remaining 10.5 hr) using the area under the dissolution curve (AUC), the dissolution half-life (t50%), and the amount of drug released in 3 hr (A3 hr) values. Both strategies enhanced drug release into neutral medium although the strategy using HMAS in the film was more effective. The formulation least affected by pH change was a combination of the two strategies, i.e., pellets containing 5% fumaric acid coated with Eudragit RS 12% w/w and HMAS 1.2% w/w.

In vitro-in vivo correlation studies on a novel controlled release theophylline delivery system and on Theo-Dur tablets

Abstract A good correlation should be obtained between data derived from in vitro dissolution and bioavailability studies on drug delivery systems if bioavailability parameters are to be reliably predicted from the in vitro dissolution variables. This study compares the in vivo absorption with the in vitro dissolution profiles into various dissolution media of a novel controlled release theophylline capsule (Mintab) containing mini-matrices, and also those of Theo-Dur 300 mg tablets. Mintab displayed significant pharmacokinetic advantages over Theo-Dur. However, Theo-Dur demonstrated good in vitro-in vivo correlation, whereas Mintab showed poor correlation.

Enzymatic synthesis and evaluation of new novel ω-pentadecalactone polymers for the production of biodegradable microspheres

Two novel co-polymers based on ω-pentadecalactone were enzymatically synthesized by a combination of ring-opening polymerization and polycondensation. Modified literature procedures enabled the production of the semi-crystalline materials with suitable molecular weights and melting characteristics. Microspheres were produced using an emulsion solvent evaporation method over a range of variables including manufacturing temperature, stirring speed and duration, surfactant concentration, continuous and disperse phase volume and polymer amount to establish how each variable affected the morphological characteristics of the microspheres. Results demonstrated that changes in emulsion viscosity influenced microsphere size. For polymer SH-L333, the microsphere surface was either smooth or porous depending on the manufacturing temperature used. For polymer SH-L334 the microsphere surface was rough or porous regardless of manufacturing temperature. This was possibly due to several combined factors including molecular weight and the greater hydrophilic nature of SH-L334. These new polymers have the potential for the manufacture of drug-loaded biodegradable microspheres for modified release drug delivery.

Preparation and evaluation of microspheres prepared from novel polyester-ibuprofen conjugates blended with non-conjugated ibuprofen

A novel polyester, poly(glycerol-adipate-co-ω-pentadecalactone) (PGA-co-PL), was conjugated with a model drug, ibuprofen, through the free hydroxyl groups of the former and the free carboxyl group of the latter at various levels of substitution. The conjugated material was processed into microspheres by both emulsion solvent evaporation and spray-drying methods. Samples of conjugated material were also blended with non-conjugated drug and the microspheres produced were evaluated by various methods. Morphologically, the microspheres produced were satisfactory. However, there was some initial burst drug release from all samples, probably due to the presence of non-conjugated drug. Subsequent drug release was very slow due to the relative stability of the covalent bonding of the drug–polyester conjugate. Stability tests showed that storage at high relative humidity resulted in increased burst release.