Showing papers in "Expert Opinion on Drug Delivery in 2004"

Ultrasonic Drug Delivery – A General Review

Abstract: Ultrasound (US) has an ever-increasing role in the delivery of therapeutic agents including genetic material, proteins, and chemotherapeutic agents. Cavitating gas bodies such as microbubbles are the mediators through which the energy of relatively non-interactive pressure waves is concentrated to produce forces that permeabilize cell membranes and disrupt the vesicles that carry drugs. Thus the presence of microbubbles enormously enhances delivery of genetic material, proteins and smaller chemical agents. Delivery of genetic material is greatly enhanced by ultrasound in the presence of microbubbles. Attaching the DNA directly to the microbubbles or to gas-containing liposomes enhances gene uptake even further. US-enhanced gene delivery has been studied in various tissues including cardiac, vascular, skeletal muscle, tumor and even fetal tissue. US-enhanced delivery of proteins has found most application in transdermal delivery of insulin. Cavitation events reversibly disrupt the structure of the stratus corneum to allow transport of these large molecules. Other hormones and small proteins could also be delivered transdermally. Small chemotherapeutic molecules are delivered in research settings from micelles and liposomes exposed to ultrasound. Cavitation appears to play two roles: it disrupts the structure of the carrier vesicle and releases the drug; it also makes the cell membranes and capillaries more permeable to drugs. There remains a need to better understand the physics of cavitation of microbubbles and the impact that such cavitation has upon cells and drug-carrying vesicles.

Dry powder inhalers for pulmonary drug delivery

Abstract: The pulmonary route is an interesting route for drug administration, both for effective local therapy (asthma, chronic obstructive pulmonary disease or cystic fibrosis) and for the systemic administration of drugs (e.g., peptides and proteins). Well-designed dry powder inhalers are highly efficient systems for pulmonary drug delivery. However, they are also complicated systems, the the performance of which relies on many aspects, including the design of the inhaler (e.g., resistance to air flow and the used de-agglomeration principle to generate the inhalation aerosol), the powder formulation and the air flow generated by the patient. The technical background of these aspects, and how they may be tuned in order to obtain desired performance profiles, is reviewed. In light of the technical background, new developments and possibilities for further improvements are discussed.

Periocular routes for retinal drug delivery.

Abstract: Despite numerous scientific efforts, delivery of therapeutic amounts of a drug to the retina remains a challenge. This challenge is compounded if chronic therapy is desired. The inability or inefficiency of topical and systemic routes for retinal delivery of existing drugs is now widely accepted. Although the intravitreal route offers high local concentrations in the vitreous and, hence, retina, these advantages are offset by side effects, such as cataracts, endophthalmitis and retinal detachment, following repeated intravitreal injections, or intravitreal placement of sustained-release implants. As discussed in this review, periocular routes, including subconjunctival, sub-tenon, retrobulbar, peribulbar and posterior juxtascleral routes, potentially offer a more promising alternative for enhanced drug delivery to the retina compared with topical and systemic routes. Periocular routes exploit the permeability of sclera for retinal drug delivery, and they are particularly useful for administering sustained-release systems of potent drugs. This review discusses the various periocular routes with respect to their anatomical location, pharmacokinetics, safety and mechanisms of drug delivery. In the coming years, several innovations in absorption enhancement, drug delivery systems and drug administration devices are anticipated for improving retinal drug delivery via periocular routes.

Carbon nanotubes for the delivery of therapeutic molecules

Abstract: Functionalised carbon nanotubes (f-CNTs) are emerging as new tools in the field of nanobiotechnology and nanomedicine. This is because they can be easily manipulated and modified by encapsulation with biopolymers or by covalent linking of solubilising groups to the external walls and tips. The possibility of incorporating f-CNTs into biological systems has opened the way to the exploration of their potential applications in biology and medicinal chemistry. Within the different fields of applications (i.e., biosensors, composite materials, molecular electronics), one use of CNTs is as new carrier systems for the delivery of therapeutic molecules. Research discussed in this review is focused on recent advances in the development of CNT technology for the delivery of drugs, antigens and genes.

Particle uptake by Peyer's patches: a pathway for drug and vaccine delivery.

Abstract: Particle uptake by Peyer's patches offers the possibility of tailoring vaccines that can be delivered orally. However, particle uptake by the follicle-associated epithelium in the gastrointestinal tract depends on several different factors that are the physicochemical properties of the particles, the physiopathological state of the animal, the analytical method used to evaluate the uptake and finally the experimental model. These parameters do not allow a clear idea about the optimal conditions to target the Peyer's patches. The goal of this review is to clarify the role of each factor in this uptake.

Growth factor delivery for bone tissue repair: an update

Abstract: Growth factors (GFs) are endogenous proteins capable of acting on cell-surface receptors and directing cellular activities involved in the regeneration of new bone tissue. The specific actions and ...

Tumour-selective drug delivery via folate receptor-targeted liposomes

Abstract: Tumour cell-targeted liposomal delivery has the potential to enhance the therapeutic efficacy and reduce the toxicity of anticancer agents. Folate receptor (FR) expression is frequently amplified among human malignancies. FR is, therefore, potentially useful as a tumour marker for targeted drug delivery. FR-mediated liposomal delivery has been shown to enhance the antitumour efficacy of doxorubicin both in vitro and in vivo, and to overcome P-glycoprotein-mediated multi-drug resistance. In addition, FR-targeted liposomes have shown utility as effective delivery vehicles of genes and antisense oligodeoxyribonucleotides to FR(+) tumour cells. Both solid tumours and leukaemias can potentially benefit from FR-targeted drug delivery. Multiple mechanisms might contribute to greater therapeutic efficacy for FR-targeted liposomes, such as FR-dependent cytotoxicity and antiangiogenic activity. Further investigation of this promising drug delivery strategy is clearly warranted.

Adaptive Aerosol Delivery (AAD) technology.

Abstract: Jet nebulisers have, since the 1920s, been used for delivery of inhaled drugs for the treatment of asthma, chronic-obstructive pulmonary disease and pulmonary infections. During the last two decades, recognition of the shortcomings of conventional nebulisers has led to the development of new ‘intelligent’ nebulisers such as the Adaptive Aerosol Delivery (AAD®, Profile Therapeutics, a Respironics company) systems. Diseases of the airways have traditionally been logical candidates for treatment with inhaled drugs. The introduction of the ‘intelligent’ nebulisers has, however, broadened the possibilities for inhaled treatment to include drugs targeted for systemic diseases. These nebulisers offer the possibility to deliver more precise doses of drug, maximise lung deposition, enhance adherence to treatment and compliance with the device through feedback to the patient, and last but not least, offer the possibility to reduce nebulisation times.

Thiomers for oral delivery of hydrophilic macromolecular drugs.

Abstract: In recent years thiolated polymers (thiomers) have appeared as a promising new tool in oral drug delivery. Thiomers are obtained by the immobilisation of thio-bearing ligands to mucoadhesive polymeric excipients. By the formation of disulfide bonds with mucus glycoproteins, the mucoadhesive properties of thiomers are up to 130-fold improved compared with the corresponding unmodified polymers. Owing to the formation of inter- and intramolecular disulfide bonds within the thiomer itself, matrix tablets and particulate delivery systems show strong cohesive properties, resulting in comparatively higher stability, prolonged disintegration times and a more controlled drug release. The permeation of hydrophilic macromolecular drugs through the gastrointestinal (GI) mucosa can be improved by the use of thiomers. Furthermore, some thiomers exhibit improved inhibitory properties towards GI peptidases. The efficacy of thiomers in oral drug delivery has been demonstrated by various in vivo studies. A pharmacological efficacy of 1%, for example, was achieved in rats by oral administration of calcitonin tablets comprising a thiomer. Furthermore, tablets comprising a thiomer and pegylated insulin resulted in a pharmacological efficacy of 7% after oral application to diabetic mice. Low-molecular-weight heparin embedded in thiolated polycarbophil led to an absolute bioavailability of > or = 20% after oral administration to rats. In these studies, formulations comprising the corresponding unmodified polymer had only a marginal or no effect. These results indicate drug carrier systems based on thiomers appear to be a promising tool for oral delivery of hydrophilic macromolecular drugs.

Intracellular trafficking of nucleic acids.

Abstract: Until recently, the attention of most researchers has focused on the first and last steps of gene transfer, namely delivery to the cell and transcription, in order to optimise transfection and gene therapy. However, over the past few years, researchers have realised that the intracellular trafficking of plasmids is more than just a "black box" and is actually one of the major barriers to effective gene delivery. After entering the cytoplasm, following direct delivery or endocytosis, plasmids or other vectors must travel relatively long distances through the mesh of cytoskeletal networks before reaching the nuclear envelope. Once at the nuclear envelope, the DNA must either wait until cell division, or be specifically transported through the nuclear pore complex, in order to reach the nucleoplasm where it can be transcribed. This review focuses on recent developments in the understanding of these intracellular trafficking events as they relate to gene delivery. Hopefully, by continuing to unravel the mechanisms by which plasmids and other gene delivery vectors move throughout the cell, and by understanding the cell biology of gene transfer, superior methods of transfection and gene therapy can be developed.

Reducing the immunostimulatory activity of CpG-containing plasmid DNA vectors for non-viral gene therapy

Abstract: The mammalian innate immune system has the ability to recognise and direct a response against incoming foreign DNA. The primary signal that triggers this response is unmethylated CpG motifs present in the DNA sequence of various disease-causing pathogens. These motifs are rare in vertebrate DNA, but abundant in bacterial and some viral DNAs. Because gene therapy generally involves the delivery of DNA from either plasmids of bacterial origin or recombinant viruses, an acute inflammatory response of variable severity inevitably results. The response is most serious for non-viral gene delivery vectors composed of cationic lipid-DNA complexes, producing adverse effects at lower doses and lethality at higher doses of complex. This review examines the role of immunostimulatory CpG motifs in the acute inflammatory response to non-viral gene therapy vectors. Strategies to neutralise or eliminate CpG motifs within plasmid DNA vectors, and the existing limitations of CpG reduction on improving the safety profile of non-viral vectors, will be discussed.

The second annual symposium on nanomedicine and drug delivery: exploring recent developments and assessing major advances. 19-20 August 2004, Polytechnic University, Brooklyn, NY, USA.

Abstract: The meeting was dedicated to novel aspects of nanomedicine, including polymer drug delivery systems (DDS) and biomaterials. Self-assembled micellar DDS have been evaluated in terms of morphology, biological properties, and results of clinical trials. Important advances in the design of nanoparticles as DDS have been highlighted in various presentations. Unexpected issues of polymer-related biological effects, including gene expression, were stressed in relation to polymer DDS. Great potential of nanofabrication of biomaterials, and preliminary data on the design of polymer scaffolds were demonstrated in a number of reports. This symposium demonstrated how timely the development of nanosised DDS is, with advances in understanding the disease-related mechanisms, and outlined the major areas of application of nanomedicine technology.

Technology versus products--what's the real driving force of interest for the pharmaceutical industry?

Abstract: (2004). Technology versus products – what’s the real driving force of interest for the pharmaceutical industry? Expert Opinion on Drug Delivery: Vol. 1, No. 1, pp. 1-2.

Medical and pharmaceutical nanoengineering conference/International conference on MEMS, nano and smart systems.

Abstract: Researchers representing all the northern hemispheric continents gathered for 3 days in Banff, Canada, to hear a wide range of talks on the application of micro- and nanotechnology to drug delivery. Topics included nanotubes, nanoparticles, liposomes, micelles, novel inhaled aerosols, antibody engineering and vaccines. Also featured were talks on the application of micro- and nanotechnology to diagnostics, including microfluidics, as well as biomolecular computing. The conference showcased the first demonstration of preliminary concepts for "smart particle aerosols", in which nanofabrication methods are used to produce inhaled aerosol particles with "intelligent" features. The conference provided an excellent forum for cross-fertilisation and discussion between disciplines, with attendees covering a broad range of areas in engineering and the physical and life sciences that are not often found together at a single conference. This breadth of attendees and topics provided a highly stimulating environment. An invitation to next year's conference (24-29 July 2005, Banff, Alberta, Canada) was extended, as listed at the conference website [101].

Innovative therapeutics: from molecules to medicines. 27 June-7 July 2004, Parma, Italy.

Abstract: The Socrates Intensive Programme offers annual courses focusing on the specific aspects of innovative therapeutics. The 2004 meeting was coordinated by the University of Parma and covered various subjects in the field of advanced drug delivery and pharmaceutical technology, including sessions on biopharmaceutics, pharmacokinetics, polymers, oral delivery, colloidal vectors, peptide and protein delivery, vaccines, oligonucleotide delivery, gene delivery, non-conventional routes of administration, and a graduate student symposium. The meeting had a highly interactive character and provided a unique opportunity for young scientists to present and discuss their work in an international setting.

Delivery of biologicals: the wish list is long...

Abstract: In this editorial, a wish list is drawn up for future research and development activities regarding biologicals.