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PubMed1999

Sustained release of heparin from polymeric particles for inhibition of human vascular smooth muscle cell proliferation.

Vascular smooth muscle cell (SMC) growth plays an important role in atherosclerosis, restenosis and venous bypass graft disease. With systemic drug administration no effective therapy for restenosis and venous bypass graft disease is available. This could be due to low local concentrations of the drugs at the target site. A directed delivery of drugs to tissues with a sustained release system during percutaneous transluminal coronary angioplasty (PTCA) or during bypass surgery could provide high concentrations of drugs at the target site and avoid systemic side effects. In the present study heparin was encapsulated by spray-drying into biodegradable poly(D, L-lactic-co-glycolic acid) (PLGA) to obtain a system for prolonged drug release. SMC were cultured from saphenous vein explants obtained from patients undergoing coronary bypass surgery. Cell proliferation was measured by [(3)H]thymidine incorporation. Heparin release from PLGA 50:50 microspheres in an isoosmolar PBS buffer (pH=7.4) showed a triphasic profile with an initial burst (completed after 24 h), a dormant period and a final stage with increased release rate, which lasted about 10-14 days. Cell proliferation as measured by [(3)H]thymidine incorporation was markedly stimulated by platelet-derived growth factor-BB (PDGF-BB) (5 ng/ml) or serum (5%). Proliferation of SMC was equally reduced (50%; P<0.05; n=9-11) by native heparin or heparin released from PLGA microspheres, while PLGA microspheres without heparin loading had no effect on [(3)H]thymidine incorporation in human SMC. Similar results were also obtained when SMC were stimulated with 5% serum instead of PDGF-BB (50%; P<0.05; n=6). Thus, heparin encapsulated into PLGA microspheres was released over a prolonged period of time and thereby effectively reduced human SMC proliferation stimulated either with PDGF or serum. Biodegradable PLGA microspheres may also be used to encapsulate other antiproliferative agents and provide a new approach for local drug delivery after PTCA. This may help to prevent restenosis after PTCA or to reduce graft disease after coronary bypass graft surgery.

Anticoagulants↗
PubMed2000

Microencapsulation and characterization of tramadol-resin complexes.

Tramadol was complexed with a sulfonic acid cation-exchange resin by a column method. Microencapsulation of tramadol-resin complexes (TRC) was carried out by the spray-drying method. The effect of ethylcellulose (EC) of various viscosities, different solvent systems and addition of plasticizers on microencapsulation were investigated. The morphology of microcapsules was characterized by scanning electron microscopy (SEM). Selected solvents having similar toxicity levels while various physico-chemical properties resulted in greatly different microcapsules. Regular particle morphology and sustained-release behavior were obtained when dichloromethane or ethyl acetate was used as the solvent system, whereas ethanol produced a substantial number of coalesced microcapsules and acetone produced apparently surface-smooth monomicrocapsules with faster release behavior. Three kinds of plasticizers affected the drug release rate similarly. On the addition of plasticizer (DEP), the drug release rate from the microcapsule obtained from low viscosity-grade EC reduced, while there was no alternation for those obtained from middle viscosity-grade EC. Compared to EC with a viscosity of 100 cP, which produced multi-microcapsules and released 60% of the drug within 1 h, microcapsules prepared with 10, 20 and 45 cP viscosity-grade EC showed slower drug release and regular and smooth morphology.

Delayed-Action Preparations↗
PubMed2000

In vitro and in vivo evaluation of a somatostatin analogue released from PLGA microspheres.

The purpose of this study was to design poly(lactide-co-glycolide) (PLGA) microspheres for the continuous delivery of the somatostatin analogue, vapreotide, over 2-4 weeks. The microspheres were produced by spray-drying and the desired characteristics, i.e. high encapsulation efficiency and controlled release over 2-4 weeks, achieved through optimizing the type of polymer, processing solvent, and co-encapsulated additive. The in vitro release was tested in fetal bovine serum preserved with 0.02% of thiomersal. Furthermore, formulations were injected intramuscularly into rats to obtain pharmacokinetic profiles. Encapsulation efficiency was between 34 and 91%, depending on the particular formulation. The initial peptide release (within 6 h) was lowest, i.e. <20%, when acetic acid was used as processing solvent and highest, i.e. 57%, with dichloromethane. The various co-encapsulated additives generally lowered the encapsulation efficiency by 15-30%. The best formulation in terms of low burst and effective drug serum levels (>1 ng/ml) over 21-28 days in rats was the one made with end-group uncapped PLGA 50:50, the solvent acetic acid and the additive polyethyleneglycol. In conclusion, the optimization of formulation parameters allowed us to produce vapreotide-loaded PLGA microspheres of suitable characteristics for therapeutic use.

Animals↗
PubMed2001

Amorphous pharmaceutical solids: preparation, characterization and stabilization.

The importance of amorphous pharmaceutical solids lies in their useful properties, common occurrence, and physicochemical instability relative to corresponding crystals. Some pharmaceuticals and excipients have a tendency to exist as amorphous solids, while others require deliberate prevention of crystallization to enter and remain in the amorphous state. Amorphous solids can be produced by common pharmaceutical processes, including melt quenching, freeze- and spray-drying, milling, wet granulation, and drying of solvated crystals. The characterization of amorphous solids reveals their structures, thermodynamic properties, and changes (crystallization and structural relaxation) in single- and multi-component systems. Current research in the stabilization of amorphous solids focuses on: (i) the stabilization of labile substances (e.g., proteins and peptides) during processing and storage using additives, (ii) the prevention of crystallization of the excipients that must remain amorphous for their intended functions, and (iii) the selection of appropriate storage conditions under which amorphous solids are stable.

Chemistry, Pharmaceutical↗
PubMed2001

Solid lipid nanoparticles: production, characterization and applications.

Solid lipid nanoparticles (SLN) have attracted increasing attention during recent years. This paper presents an overview about the selection of the ingredients, different ways of SLN production and SLN applications. Aspects of SLN stability and possibilities of SLN stabilization by lyophilization and spray drying are discussed. Special attention is paid to the relation between drug incorporation and the complexity of SLN dispersions, which includes the presence of alternative colloidal structures (liposomes, micelles, drug nanosuspensions, mixed micelles, liquid crystals) and the physical state of the lipid (supercooled melts, different lipid modifications). Appropriate analytical methods are needed for the characterization of SLN. The use of several analytical techniques is a necessity. Alternative structures and dynamic phenomena on the molecular level have to be considered. Aspects of SLN administration and the in vivo fate of the carrier are discussed.

Capsules↗
PubMed2000

Microencapsulated enterotoxigenic Escherichia coli and detached fimbriae for peroral vaccination of pigs.

The feasibility of peroral immunisation with microencapsulated Escherichia coli and detached fimbriae to prevent enterotoxigenic E. coli infections in pigs was examined. For this E. coli and fimbriae were microencapsulated into poly(lactide-co-glycolide) microspheres by spray-drying. Various microsphere formulations designed to deliver priming and booster doses were fed to new-born and weaned pigs. The pigs were challenged 19 days after the booster dose by peroral administration of an infective dose of the homologous E. coli. Serum IgA antibody titres and excretion of challenge E. coli, as indicators for colonisation, were determined. The data showed that no significant serum antibodies were induced, and E. coli colonisation was not reduced by the peroral administration of the various antigen-loaded microspheres. These results are in contradiction to some of the previously published experiments typically in rats or rabbits, where model antigens or unpractical immunisation procedures have frequently been used.

Administration, Oral↗
PubMed2000

Towards clinical testing of a single-administration tetanus vaccine based on PLA/PLGA microspheres.

The availability of single-administration vaccines would assist in the control of global mortality caused by infectious diseases where protection can be achieved only upon repeated immunisations with appropriate vaccines. Biodegradable microspheres of poly(lactide-co-glycolide) have been studied pre-clinically for this purpose and shown to be promising for several protein and sub-unit antigens. In view of preparing a microsphere-based tetanus vaccine for clinical trials, final candidate vaccine-formulations were pre-clinically optimised here. Specifically, the importance of particular materials and processing for the induction of neutralising antibodies in guinea pigs were examined. The most efficacious vaccines were small-sized (<5 microm), co-adjuvanted with admixed alum and fabricated from fast-degrading polymers. Interestingly, the immunogenicity was less influenced by the type of antigen-stabilising excipient, the number of microsphere populations mixed together, or the microencapsulation technology, i.e. spray-drying versus coacervation, used. On the basis of these, we plan to prepare clinical samples for safety and immunogenicity testing in man.

Animals↗
PubMed2003

Evaluation of novel aerosol formulations designed for mucosal vaccination against influenza virus.

Influenza viruses are among the most significant human pathogens, responsible for increased seasonal morbidity and mortality particularly in immunodepressed and chronically ill. Conventional vaccination with non-replicative vaccine is currently performed by injection. In the present study, we explore simple spray-dried lipid formulations containing whole inactivated virus or split-subunit vaccine that allow aerosolization and thus, mucosal vaccination of the pulmonary tract. We show that by using biocompatible excipients already approved for human use, one could engineer microparticles that induce substantial local and systemic immunity subsequent to pulmonary administration. Exposure of the bronchial-associated lymphoid tissue (BALT) to vaccine was more effective than parenteral or nasal administration in triggering specific immunity. Co-formulation of a biocompatible surfactant detergent greatly ameliorated the immune profile of microparticles containing a whole inactivated virus vaccine. In addition, mere formulation of a licensed split-subunit vaccine significantly enhanced its immunogenicity. Together, our data underline a simple strategy to convert conventional parenteral vaccination of currently available non-replicative vaccines against influenza virus, into one that is more effective and practical upon respiratory administration.

Aerosols↗
PubMed2001

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.

Calorimetry, Differential Scanning↗
PubMed2001

Quantitative determination of the specific heat and the glass transition of moist samples by temperature modulated differential scanning calorimetry.

In differential scanning calorimetry (DSC), remnant moisture loss in samples often overlaps and distorts other thermal events, e.g. glass transitions. To separate such overlapping processes, temperature modulated DSC (TMDSC) has been widely used. In this contribution we discuss the quantitative determination of the heat capacity of a moist sample from TMDSC measurements. The sample was a spray-dried pharmaceutical compound run in different pans (hermetically-sealed pan, pierced lid pan [50 microm] and open pan). The apparent heat capacity was corrected for the remaining amount of moisture. Using this procedure we could clearly identify the glass transition of the dry and the moist sample. We found that a moisture content of about 6.2% shifts the glass transition by about 50 degrees C.

Calorimetry, Differential Scanning↗
PubMed2001

Bioavailability of cyclosporin A dispersed in sodium lauryl sulfate-dextrin based solid microspheres.

The purpose of this work was to develop a solid dispersion system containing cyclosporin A (CsA) in order to improve the bioavailability of poorly water-soluble CsA. Solid dispersion systems that are spherical in shape (CsA-microspheres) were prepared with varying ratios of CsA/sodium lauryl sulfate/dextrin using a spray-drying technique. The effects of sodium lauryl sulfate (SLS) and dextrin on the dissolution of CsA dispersed in SLS-dextrin based solid microspheres were investigated. The bioavailability of CsA-microspheres was compared with CsA powder alone and commercial Sandimmun in dogs. SLS significantly enhanced the dissolution of CsA from microspheres, while dextrin did not affect this. The CsA-microspheres at the CsA/SLS/dextrin ratio of 1/3/1, which gave the highest dissolution rate of CsA among the formula treated, was selected as an optimal formula for oral delivery. This formula gave significantly higher blood levels, area under the drug concentration-time curve (AUC) and maximum blood concentration of drug (Cmax) of CsA in dogs compared with the CsA powder alone. The AUC, Cmax and time to reach maximum blood concentration (Tmax) of CsA with CsA-microspheres was not significantly different from those after oral administration of Sandimmun, suggesting the similar bioavailability to Sandimmun in dogs. Our study demonstrates that the CsA-microspheres prepared with SLS and dextrin, with improved bioavailability of CsA, would be useful to deliver a poorly water-soluble CsA and could be applicable to other poorly water-soluble drugs.

Animals↗
PubMed2001

An oral controlled release matrix pellet formulation containing nanocrystalline ketoprofen.

A controlled release pellet formulation using a NanoCrystal colloidal dispersion of ketoprofen was developed. In order to be able to process the aqueous NanoCrystal colloidal dispersion into a hydrophobic solid dosage form a spray drying procedure was used. The in vitro dissolution profiles of wax based pellets loaded with nanocrystalline ketoprofen are compared with the profiles of wax based pellets loaded with microcrystalline ketoprofen and of a commercial sustained release ketoprofen formulation. Pellets were produced using a melt pelletisation technique. All pellet formulations were composed of a mixture of microcrystalline wax and starch derivatives. The starch derivatives used were waxy maltodextrin and drum dried corn starch. Varying the concentration of drum dried corn starch increased the release rate of ketoprofen but the ketoprofen recovery remained problematic. To increase the dissolution yield surfactants were utilised. The surfactants were either added during the production process of the NanoCrystal colloidal dispersion (sodium laurylsulphate) or during the pellet manufacturing process (Cremophor RH 40). Both methods resulted in a sustained but complete release of nanocrystalline ketoprofen from the matrix pellet formulations.

Administration, Oral↗
PubMed2001

Water sorption/desorption--near IR and calorimetric study of crystalline and amorphous raffinose.

Mass loss at elevated RH is an established method for determining the occurrence of crystallisation of an amorphous material. Through the combination of near infrared spectroscopy and gravimetric vapour sorption, it has been possible to show the transition of raffinose from its spray-dried amorphous form to a crystalline form without this characteristic mass loss. It has also been possible to observe changes in the crystalline material for a period of 30 h subsequent to exposure to elevated relative humidity by near infrared spectroscopy that are not associated with changes in mass, but are related to repacking of hydrate molecules. Drying of the crystalline pentahydrate in the DVS-NIR was seen to show changes in the NIR peak related to -OH. From this, NIR peaks were tentatively ascribed as relating to a penta-, tetra-, tri- and a di-hydrate form, but the sample returned to the amorphous response by the time the water content fell to the equivalent of the monohydrate, indicating that crystallinity had been lost. These observations would be compatible with the hypothesis that lower hydrates of raffinose exist. Due to the absence of mass loss in association with crystallisation, it was found that the enthalpy of crystallisation of amorphous raffinose, as determined by isothermal microcalorimetry, is similar to the enthalpy of fusion determined by differential scanning calorimetry. Finally, it was observed that the early part of the response in the isothermal microcalorimeter was related to mobility of molecules when Tg was above T. This mobility was able to give the bulk morphology of a crystal before the sample developed long range order and crystalline properties.

Calorimetry, Differential Scanning↗
PubMed2001

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.

Algorithms↗
PubMed2002

Quantification of low levels (<10%) of amorphous content in micronised active batches using dynamic vapour sorption and isothermal microcalorimetry.

During the processing of pharmaceutical solids (e.g. milling, spray drying, tablet compaction, wet granulation and lyophilisation), various degrees of disorder in the form of crystal defects and/or amorphous regions may be generated. Even relatively low levels of amorphous material (<10%) may have a detrimental impact on the stability, manufacturability and dissolution characteristics of the formulated drug product. In this paper an isothermal heat conduction microcalorimetry and dynamic vapour sorption technique have been evaluated for the quantification of low levels (<10%) of amorphous material within a crystalline active. Both techniques were able to detect a 0.5% amorphous content, and in each case the limit of detection may be further lowered by increasing the sample size. The impact of micronisation on the crystallinity of a batch of active was evaluated using the two methods. The isothermal microcalorimetry and dynamic vapour sorption data showed excellent agreement (+/-0.2% amorphous content) and indicated that the amount of amorphous material generated is extremely sensitive to small changes in the operating conditions of the microniser. The techniques described in this paper have been developed at a very early stage of the actives development program such that the impact of small quantities of amorphous material on the quality attributes of the formulation can be fully assessed. The methods can be applied to any active, the only criteria is that the amorphous material will recrystallise on exposure to moisture or solvent vapours, and no hydrates or solvates are formed.

Calorimetry↗
PubMed2002

Influence of different chitosan salts on the release of sodium diclofenac in colon-specific delivery.

Chitosan (CH) was dissolved in aqueous solutions containing aspartic, glutamic, hydrochloric, lactic and citric acids to obtain different chitosan salts. Chitosan salts were collected from the solutions by spray-drying and the powders obtained were mixed with Sodium Diclofenac (SD), taken as a model anti-inflammatory drug. This study evaluated in vitro the influence of acid type on the release behaviour of SD from the physical mixture during gastrointestinal transit. The physical mixture of the chitosan salts with SD provided slower drug release than the pure drug both in acidic and alkaline pHs. In addition, the interaction with beta-glucosidase at pH 7.0 enhanced the release rate. Among the CH salts used, glutamic and aspartic salts provided the best control of release.

Algorithms↗
PubMed2002

In vivo evaluation of matrix pellets containing nanocrystalline ketoprofen.

The aim of this study was to evaluate the in-vivo behaviour of matrix pellets formulated with nanocrystalline ketoprofen after oral administration to dogs. No significant differences in AUC-values were seen between pellet formulations containing nanocrystalline or microcrystalline ketoprofen and a commercial ketoprofen formulation (reference: Rofenid 200 Long Acting). C(max) of the formulations containing nano- or microcrystalline ketoprofen was significantly higher compared to reference, whereas t(max) was significantly lower. The in-vivo burst release observed for the spray dried nanocrystalline ketoprofen matrix pellets was reduced following compression of the pellets in combination with placebo wax/starch pellets. These matrix tablets sustained the ketoprofen plasma concentrations during 5.6 and 5.4 h for formulations containing nano- and microcrystalline ketoprofen, respectively.

Administration, Oral↗
PubMed2002

Preparation and in vitro evaluation of pyridostigmine bromide microparticles.

Pyridostigmine bromide (PB) is an anticholinesterase agent whose aqueous solubility is high and which has a short elimination half-life. Its dosage rate in the treatment of myastenia gravis is frequent due to the short half-life and it exhibits side effects. Microparticles designed to deliver a pharmaceutical active ingredient efficiently at the minimum dose and also to enhance stability, reduce side effects and modify drug release were prepared in this study using an acrylic polymer (Eudragit) as the vehicle by the spray-drying technique. The drug was either dissolved or dispersed in the polymeric solution and following the preparation of microparticles using different ratios of ingredients, characterization studies including the determination of shape, particle size distribution, amount loaded, release and stability of PB were performed. The results obtained were compared to those of pure PB. Drug release from microparticles could be modified and was found to depend on the shapes of the microparticles. In vitro evaluation results indicate that the frequent dosage and side effects of pure PB may be reduced with the formulation of microparticles.

Acrylic Resins↗