Use of porous aluminosilicate pellets for drug delivery.

Three pelletized porous aluminosilicate ceramics were obtained commercially and their potential to act as extended release drug delivery systems was assessed. The pellets were drug loaded using a vacuum impregnation technique. Factors such as the concentration of the loading solution and the porosity and bulk density of the ceramic influenced the drug loading. The release of drug from the pellets was extended as the drug was entrapped within their porous interior. The rate of release was influenced by the porous microstructure of the pellets and the physicochemical properties of the drug. Extrusion-spheronization was used to prepare pellets similar to the porous ceramics. The pellet formulations contained an aluminosilicate clay mineral (kaolin or halloysite), ethylcellulose 100 cps, ethanol and varying quantities of sucrose. The latter two components acted as pore forming agents. Diltiazem HCl was loaded into the pellets and its release was extended. The release rate could be modified by changing the quantity of sucrose included in the initial formulation, as this influenced the porous microstructure of the pellets. In halloysite-based products the release was further extended due to entrapment of the drug within the halloysite microtubules. Porous kaolin-based pellets were also prepared by cryopelletization. This involved freezing droplets of an aqueous suspension containing kaolin, sodium silicate solution and sodium lauryl sulphate. The resulting pellets were freeze-dried, which removed ice from them to leave pores behind. The pellets gave extended drug release with the release rate being influenced by the porous microstructure of the pellets and their microclimate pH.

Bioadhesive, rheological, lubricant and other aspects of an oral gel formulation intended for the treatment of xerostomia.

Xerostomia is commonly known as 'dry mouth' and is characterised by a reduction or loss in salivary production. A bioadhesive gel for its localised treatment was formulated to help enhance the residence time of the product, based on the polymer Carbopol 974P. The bioadhesion of various formulations was evaluated on different mucosal substrates, as simulations of the oral mucosa of xerostomic patients. Depending on the type of model substrate used, the mechanism of bioadhesion could alter. When the rheology of various formulations was examined, changes in bioadhesion were more easily interpreted, as the presence of other excipients caused an alteration in the rheological profile, with a change from a fully expanded and partially cross-linked system to an entangled system. Improving the lubricity of the product was considered important, with optimum incorporation of vegetable oil causing a desirable lowering of the observed friction of the product. The final complex formulation developed also contained salivary levels of electrolytes to help remineralisation of teeth, fluoride to prevent caries, zinc to enhance taste sensation, triclosan as the main anti-microbial/anti-inflammatory agent and non-cariogenic sweeteners with lemon flavour to increase the palatability of the product while stimulating any residual salivary function.

Formulation and preliminary in vivo dog studies of a novel drug delivery system for the treatment of periodontitis.

A novel drug delivery system for the treatment of periodontitis was developed using two components. The first was tetracycline base loaded into the microtubular excipient halloysite, which was coated with chitosan to further retard drug release. Encapsulation efficiencies of 32.5% were achieved with the loading procedure, with tetracycline base showing in vitro release for up to 50 days in simulated gingival crevicular fluid. The second component developed was a vehicle for the drug loaded coated halloysite, which was primarily based on the thermoresponsive polymer, poloxamer 407. A concentration of 20% was chosen with the thermoresponsivity of the system modified using PEG 20,000 so that the mobile product at room temperature would gel by temperature rise following syringing into a periodontal pocket. Retention of the overall system in the pocket was further improved by the addition of octyl cyanoacrylate (OCA). The thermoresponsivity of the poloxamer 407 system proved to be sensitive to the presence of added excipients with the levels of PEG 20,000 and OCA requiring modification in the presence of the halloysite component. A final formulation was developed which consisted of 200 mg of halloysite double loaded with tetracycline base and coated with chitosan, suspended in 1 ml of poloxamer 407 20% (w/w), PEG 20,000 0.5% (w/w), OCA 1.0% (w/w), water to 100%, adjusted to pH 4. The syringeability of this formulation at various temperatures was evaluated to ensure ease of delivery to the periodontal pocket. A stability study was performed to examine the change in thermoresponsivity over time, with the final formulation found to be stable for at least 9 months when stored at room temperature (approximately 20 degrees C). This formulation offered ease of delivery to the periodontal pocket and sustained release of the antibiotic for up to 6 weeks. The formulation had preliminary in vivo testing performed in dogs to determine levels of drug release, antimicrobial activity and retentive ability of the product. A wound pocket creation model was developed for the purposes of the trial. The product was easy to deliver to the pockets with application times of less than 1 min. Results showed the product was retained in the pocket for up to 6 weeks with effective tetracycline levels released locally over this time period, which achieved good antibacterial activity.

Use of coated microtubular halloysite for the sustained release of diltiazem hydrochloride and propranolol hydrochloride.

Halloysite is a naturally occurring microtubular aluminosilicate mineral. The highly water soluble cationic drug, diltiazem HCl, was shown to bind to the polyanionic surfaces of the material to achieve a slight sustained release effect on dissolution testing due to reversible chemisorption and/or hindered release from the drug loaded lumen. A greater sustained release effect was more apparent when the less water soluble cationic drug, propranolol HCl, was examined. Attempts to further delay drug release by loading diltiazem HCl from a polyvinylpyrrolidone solution into the halloysite had little effect. However, a range of cationic polymers, including chitosan cross-linked with glutaraldehyde, was shown to bind to halloysite and was used to achieve significant delayed drug release. Coating with adequate polyethyleneimine was particularly effective at delaying drug release, being dependent on the architecture of the interaction between the polycation and the mineral. When a range of alkyl-2-cyanoacrylate monomers applied from a non-aqueous solvent by an in situ polymerisation procedure was examined, diltiazem HCl loaded halloysite dispersed in poly-iso-butyl cyanoacrylate was found to be the most effective at reducing the burst effect noted with aqueous coating systems.

Use of commercial porous ceramic particles for sustained drug delivery.

Three commercially available microparticulate porous ceramics, N-light N3, Starlight SLK1000 and Carbolite 16/20, were characterised using a range of techniques. Starlight SLK1000 and Carbolite 16/20 were principally composed of mullite, while N-light N3 was principally composed of quartz. Each porous ceramic was partly open-cell with varying porosities and pore size distributions. Using a novel vacuum loading technique, N-light N3 was loaded with benzoic acid, sodium benzoate and diltiazem HCl, while Starlight SLK1000 and Carbolite 16/20 were loaded with diltiazem HCl. The drug loading was influenced by the solution concentration and by the porosity and bulk density of the ceramic. In vitro dissolution testing of the loaded porous microparticles showed an initial burst release of each drug followed by sustained release. The release was influenced by the surface pore size distribution of the ceramic and by electrostatic interactions between the interior and exterior microparticle surfaces and the drug.

Characterisation of halloysite for use as a microtubular drug delivery system.

Halloysite supplied from New Zealand was shown by electron microscopy to be composed mainly of hollow microtubules having typical dimensions of 2-3 microm long and 0.3/0.1 microm outer/inner diameter. Aggregates of microtubules, double tubules and occasional split or partially unrolled tubules were observed. Energy dispersive analysis showed the mineral to be composed mainly of aluminium, oxygen and silicon, with a low content of iron. The dehydrated state of the mineral was confirmed by XRD analysis, which was partially reversible using a rehydration procedure with subsequent exchange of the intercalated water gained by glycerol, but larger molecules including the drug, diltiazem HCl, failed to exchange. The surface charge was predominantly negative over most of the physiologically relevant pH range (> 2) and the specific surface area of the material was very large (approximately 57 m(2)/g), indicating that the material has significant potential for extensive binding of cationic drugs. Removal of allophanc present by a hot alkali treatment had little effect on luminal porosity, which prior to treatment was estimated to be approximately 0.25 ml/g by a mercury intrusion technique and consequently should be the major site for drug loading. Halloysite also extruded and spheronised well to form smooth round pellets as an aid to further formulation development, which rapidly disintegrated in water unless prevented by sintering at 200 degrees C.

Pharmaceutical applications of size reduced grades of surfactant co-processed microcrystalline cellulose.

New grades of ultra-fine microcrystalline cellulose (MCC), without (grade X) or with variable percentage sodium lauryl sulphate (SLS; grades Y), were prepared by an ultrasonic homogenisation process from Avicel PH-101 (grade C), prior to recovery by spray-drying. Both new grade types were found to be inferior compared with grade C in a tableting application for paracetamol, resulting largely from poor flow of the feed material. However, both new grades proved superior to grade C in an aqueous extrusion/spheronisation application for the preparation of indomethacin pellets, producing smoother pellets in greater yield. Grade Y was particularly effective at delaying drug dissolution, due mainly to decreased porosity in the pellets formed and retardation of their break-up.

Production and evaluation of size reduced grades of microcrystalline cellulose.

Size reduction of microcrystalline cellulose (MCC, Avicel PH-101) powder by ball milling was poorly effective, particularly in the presence of sodium lauryl sulphate (SLS), which tended to form a protective foam. Ultrasonic homogenisation of an aqueous suspension more readily produced ultra-fine MCC, even in the presence of the surfactant and two other de-aggregating agents, and factorial experimentation was used to optimise the process. The product was recovered by spray-drying and readily redispersed in water without re-aggregation. Two new grades of ultra-fine MCC, prepared by an optimised treatment with or without 1% SLS, were characterised by a range of techniques in comparison to the starting coarser grade, Avicel PH-101. Mercury porosimetry and scanning electron microscopy confirmed the less porous and smaller particle size of the new grades, where deposition of SLS as a coating was evident. Surface area determination confirmed that the size-reduced grades had larger specific surface areas, particularly the SLS treated material. Low temperature DSC and X-ray diffraction studies suggested that the new ultra-fine grades were more amorphous. Collectively the results indicate that the new grades should have unique functionality, possibly of benefit in pharmaceutical formulation.

Tableting of coated ketoprofen pellets.

Ketoprofen pellets were prepared by the method of extrusion-spheronization, and a film coating of guar gum and Eudragit NE was applied to drug cores using pan technology. In an attempt to design a tablet which, on peroral administration, disintegrates rapidly, releasing intact coated pellets which maintain the integrity of both the cores and their release retarding membrane, Avicel PH101, lactose DT and magnesium stearate were used as excipients to prepare tablets comprising ketoprofen pellets or microcapsules. Preliminary experiments were conducted on uncoated pellets to determine the optimum compression force required to prepare tablets of satisfactory mechanical properties and release profiles. Coated pellets containing ketoprofen were used to investigate the influence of excipients levels. In an attempt to minimize problems associated with blending and segregation of microcapsules and excipients, placebo spheres of Avicel PH101 and lactose DT were produced by the method of extrusion-spheronization. The use of placebo spheres produced tablets with improved drug content uniformity and disintegration time. The tensile strength of such compacts was enhanced by excluding magnesium stearate from the mixes without significant problems of sticking or picking. The use of placebo pellets resulted in significant damage to drug microcapsules, which was attributed to the higher hardness and density of the excipients pellets. The role of membrane coating in protecting the drug core during compression was also evaluated.

Use of hydrophilic polymers with microcrystalline cellulose to improve extrusion-spheronization.

Microcrystalline cellulose 19 parts was combined with sodium carboxymethylcellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose or polyvinylpyrrolidone one part, either by spray-drying or physical mixing. This combined excipient (20%) mixed with lactose (80%) and water was added to aid formation of pellets by the process of extrusion-spheronization. Spray-dry combined excipient produced pellets with higher yield, better sphericity and improved tolerance to minor variation in the level of water added, compared with the physical mix excipient. Physicochemical testing based on scanning electron microscopy with energy dispersive analysis, differential scanning calorimetry and X-ray diffraction analysis, indicated that the spray-drying with the hydrophilic polymer caused disintegration of the microcrystalline cellulose component into smaller crystallites, favouring its more uniform dispersion throughout the lactose during subsequent processing. The hydroxypropyl cellulose or polyvinylpyrrolidone containing excipients were the most satisfactory of the hydrophilic polymers examined, because they had the least adhesive strength favouring maximum yield of highly spherical pellets.

Comparison of two commercial brands of microcrystalline cellulose for extrusion-spheronization.

Two commercial brands of microcrystalline cellulose, the widely used Avicel PH-101 and the newly available Pharmacel 101, were compared for aqueous extrusion-spheronization of a model mix with lactose. Based on the results of multi-level experiments employing pellet size analysis by sieving and sphericity determination by image analysis, Avicel was shown to be less adversely affected by variation in added water or speed of spheronization. Physicochemical testing of powder samples from both brands was carried out using laser particle sized analysis, density determinations, differential scanning calorimetry and X-ray diffraction studies. The results indicated that the improved ease of processing with Avicel may be related to its smaller particle size with less aggregates, improved flow, lower depolymerization temperature range and absence of traces of cellulose II in its cellulose I content.

Effect of common classes of excipients on extrusion-spheronization.

Different classes of excipients with potential for use in the design of novel pelletized formulations manufactured by extrusion-spheronization were examined using factorial experiments. Among the various silicates examined in a model mix with microcrystalline cellulose and lactose wetted with water, kaolin, talc and Veegum F provided improved plasticity for the formation of spherical pellets. Weak bases such sodium bicarbonate and weak acids such as fumaric acid also aided spheronization. Whereas waxy materials such as hydrogenated castor oil and Precirol ATO5, and wetting agent such as sodium lauryl sulphate improved sphericity, these excipients reduced pellet yield by favouring agglomeration. Other materials promoting unwanted formation of over-size pellets were bentonite, citric acid and tartaric acid. The inclusion of Bentone 27, various hydroxide and carbonate bases, and fumaric acid favoured fines production. Collectively the results showed that within classes of excipients, it was not possible to predict the effect of different materials on pellet yield and sphericity. However, Carr's index and Hausner ratio calculated from density determinations correlated well with sphericity measured by image analysis.

Use of cellulose ether containing excipients with microcrystalline cellulose for the production of pellets containing metformin hydrochloride by the process of extrusion-spheronization.

The project is concerned mainly with the evaluation of two cellulose ether containing excipients, Aquacoat WG and Avicel 955 MCC for the improved extrusion-spheronization of metformin hydrochoride. Factorially designed experiments subject to statistical analyses were employed and products obtained were evaluated by sieve, packing density and image analysis, scanning electron microscopy and dissolution testing at pH 6.8. Aquacoat WG did not improve the ease of spheronization of drug mixes containing microcrystalline cellulose wetted with the optimum level of water. However, Avicel 955 MCC, which is a new experimental excipient containing 95% microcrystalline cellulose and 5% methylcellulose, did aid ease of spheronization facilitating acceptable yield of good spheres with high drug loadings (70%). Avicel 955 MCC containing drug mixes were more tolerant to minor alterations in level of hydration and yielded spheres which showed a small retardation of drug release despite the very high solubility of metformin hydrochloride.

An investigation into the transdermal delivery of nifedipine.

A systematic attempt to develop a transdermal delivery system for nifedipine is presented. Measured physicochemical properties influencing percutaneous absorption such as solubility and partition coefficient confirmed the drug's potention for such a formulation approach. However, studies involving permeation through hairless mouse skin from a range of hydrophilic and hydrophobic donor vehicles indicated inadequate penetration. Attempts to increase the drug flux through the animal skin or a range of artificial membranes alone or in parallel by use of the penetration enhancers sodium lauryl sulphate 1% and propylene glycol 20% in a sodium carboxymethylcellulose 3% gel base failed to raise the drug flux to an acceptable level. Likewise increase in the drug thermodynamic gradient across the skin by use of mixed solvents or supersaturated drug solutions was ineffective if an aqueous receiving phase was used. Collectively the results suggest that the development of a transdermal delivery system for the chemically unmodified drug in humans is unlikely to be successful.

Combined dipyridamole and aspirin pellet formulation for improved oral drug delivery. Part 1: Development pharmaceutics.

The dissolution profile of various weight fractions of dipyridamole: hydropropylmethylcellulose acetate succinate (HPMC-AS) and dipyridamole: hydroxypropylmethylcellulose phthalate co-precipitates lead to the choice of 1:2 dipyridamole: HPMC-AS as the controlled-release component. It was deposited to form two-third of the total dose as an inner layer on inert sucrose cores by air suspension coating for release mainly in the small intestine. Further examination of this material by IR spectroscopy, differential scanning calorimetry and X-ray diffraction indicated some free drug, preferentially soluble under gastric pH conditions. One-third of the total dose was applied by pan coating as an outer layer of micronized dipyridamole around the inner enteric co-precipitate layer. Aspirin-loaded cores were prepared also by pan coating for use in the final product, which contained both anti-platelet drugs.

Combined dipyridamole and aspirin pellet formulation for improved oral drug delivery. Part 2: In-vivo evaluation and stability.

Hard capsules containing 150 mg dipyridamole and 100 mg aspirin containing pellets were compared in 12 humans against the equivalent dose of conventional products given twice daily. The new product gave extended and more uniform levels of dipyridamole in the steady-state, with a lower incidence of undesirable side-effects, whereas aspirin levels were similar. The new product also had acceptable long-term stability provided it was stored under cool conditions and low humidity.

Evaluation of drug-containing microcapsules.

The characterization of microcapsules containing drugs is reviewed with particular emphasis on sustained-release products produced commercially by pan or air-suspension coating and intended for oral administration. After considering aspects of the core and coating, various technologies used to assess microcapsules are discussed such as optical and spectroscopic evaluation, particle size analysis, filling into hard gelatin capsules, and disintegration, dispersion and dissolution testing. The in vivo testing of microcapsules and correlation with in vitro data is considered. Finally some miscellaneous tests applied to the formation and assessment of microcapsules are presented.

Microencapsulation studies on aminophylline involving spherical crystallization, spheronization and drug loading on to non-pareil seeds.

Aminophylline was formulated as small spherical cores for subsequent coating in an attempt to develop a competitor microencapsulated product to the commercial available sustained-release tablet, Phyllocontin. Optimum spherical crystallization conditions yielded cores of loosely adhering crystals of active, with highly irregular surface morphology and poor mechanical strength during pan coating. Aqueous spheronization yielded satisfactory cores in high yield when microcrystalline cellulose and liquid paraffin were used. However, application of large amounts of controlled-release coatings based on Eudragit RL and RS failed to produce a product with retarded drug dissolution comparable to the commercial product. Drug loaded non-pareils were easily formed, but required application of about 20 per cent Eudragit RL/RS coating to achieve adequate prolonged-release properties. Application of 10 per cent hydrogenated castor oil/ethylcellulose based coating gave acceptable in vitro release only if the microcapsules formed were tableted and annealed. All products investigated rapidly discoloured during storage and none were considered to represent a realistic alternative to tableting technology for the production of a sustained-release oral dosage form of aminophylline.

Use of hydroxypropyl methylcellulose acetate succinate in an enteric polymer matrix to design controlled-release tablets of amoxicillin trihydrate.

A controlled-release table of amoxicillin trihydrate was developed by use of a matrix formulation based on the enteric polymer hydroxypropyl methylcellulose acetate succinate (HPMCAS). Sustained drug release was shown by in vitro dissolution testing; the polymer could suppress drug release in the presence of gastric pH but could enhance drug release in the presence of small intestinal pH, compared with compacts of pure drug. Grinding or physical mixing of the drug with the polymer, an alteration in normal compaction pressure, or a substitution of other enteric polymers did not markedly affect drug release from compacts. Physicochemical testing of samples confirmed that the method of mixing did not alter powder morphology. An ethanolic granulation procedure was used in the production of final tablets (21 x 10 mm) containing amoxicillin (750 mg), HPMCAS, anhydrous directly compressible lactose, and lubricants. These large tablets showed a promising sustained-release effect in vitro when a variable-pH-shift dissolution procedure was used. However, single-dose studies with a panel of fasting subjects showed that the tablets had a relative bioavailability of only 64.4%. Other pharmacokinetic parameters confirmed a lack of therapeutic advantage of these tablets over an equivalent dose of conventional capsules.

Use of deacetylated gellan gum (Gelrite) for the production of sulphamethizole containing beads.

Deacetylated gellan gum (Gelrite) was used to produce a bead formulation containing sulphamethizole by a hot extrusion process into chilled ethylacetate. The spherical dried beads recovered had a porous surface which could be reduced in porosity by increasing the Gelrite concentration. Energy dispersive analysis showed the drug to be uniformly distributed throughout the beads. Dissolution studies confirmed that the drug was slowly released from the beads, the retardation of which could be extended by the use of increasing Gelrite concentration or by post-treatment of dried beads with either a waxy sealant or gamma irradiation. In-vivo studies in dogs confirmed that dried beads prepared by extruding a suspension of 10 per cent w/w sulphamethizole in 3 per cent aqueous Gelrite dispersion had effective sustained properties on oral dosing in comparison to a conventional capsule formulation but had a possible small loss in relative bioavailability.