Alternative Drug Delivery Method Research Articles

A Survey of Patient Perceptions and Preferences for Glaucoma Treatment with Intravitreal Injections

To investigate patient perceptions and preferences regarding the use of intravitreal injection (IVI) for the treatment of glaucoma. Cross-sectional study of patients seen at the University of Colorado Health Eye Center. Patients with a diagnosis of glaucoma who were receiving or previously had received topical medication drops and previously had received an IVI for a different eye condition. In this pilot study, participants were surveyed by telephone using a 10-item questionnaire. Preferences regarding glaucoma treatment methods, specifically a theoretical choice between topical and IVI treatment options, were recorded. Preferences regarding IVI compared with topical drops in 2 different hypothetical scenarios, one in which both are equally effective and another in which IVI is more effective. Secondary outcomes included preferred interval between injections. Fifty patients completed the survey. The mean age was 65 years (range, 16-95 years). Patients were using an average of 1.6 glaucoma medications per day (range, 1-4). Seventy-four percent of patients (n=37) said they would prefer topical medication if equal in efficacy to monthly IVI. In a hypothetical scenario in which a monthly IVI was more effective than topical medication, 76% (n= 38) said they would then prefer injection. Additionally, injection became more preferable as the hypothetical dosing interval changed. Assuming equivalent efficacy, 46% of patients preferred injection if required every 2 months, 62% if required every 3 months, and 82% if injection was required every 6 months. The main reasons cited for preferring topical medications were fear of pain, fear of the procedure, and the inconvenience of more frequent clinic appointments to undergo treatment. Patients are open to alternative methods of drug delivery, and their willingness to undergo more invasive treatments, like IVI, for glaucoma rises with a longer theoretical duration between treatments.

Novel methods of drug administration for the treatment and care of older patients

The number of older people globally is increasing, contributing to a growing burden of morbidity and mortality. With this shift in population demographic, comes a new challenge in terms of appropriate healthcare for the over 65 years age group. As medication is the principal therapeutic intervention, it is essential that it be fully optimised, to meet the needs of this heterogeneous population. The most common routes of drug administration are oral and injectable, which may display some limitations for older people, in cases of dysphagia or frailty for example. This review considers alternative methods of drug delivery to the norm, specifically discussing the nasal, pulmonary and transdermal routes, as well as novel orally disintegrating tablets. The changing physiology as ageing occurs must be considered in the development of novel drug delivery devices. This review considers the various aspects of ageing that will influence future drug formulation design and development.

Synthesis and Characterization of a Poly(ethylene glycol)-Poly(simvastatin) Diblock Copolymer.

Biodegradable polyesters are commonly used as drug delivery vehicles, but their role is typically passive, and encapsulation approaches have limited drug payload. An alternative drug delivery method is to polymerize the active agent or its precursor into a degradable polymer. The prodrug simvastatin contains a lactone ring that lends itself to ring-opening polymerization (ROP). Consequently, simvastatin polymerization was initiated with 5 kDa monomethyl ether poly(ethylene glycol) (mPEG) and catalyzed via stannous octoate. Melt condensation reactions produced a 9.5 kDa copolymer with a polydispersity index of 1.1 at 150 °C up to a 75 kDa copolymer with an index of 6.9 at 250 °C. Kinetic analysis revealed first-order propagation rates. Infrared spectroscopy of the copolymer showed carboxylic and methyl ether stretches unique to simvastatin and mPEG, respectively. Slow degradation was demonstrated in neutral and alkaline conditions. Lastly, simvastatin, simvastatin-incorporated molecules, and mPEG were identified as the degradation products released. The present results show the potential of using ROP to polymerize lactone-containing drugs such as simvastatin.

New Perspectives in Non-oral Drug Delivery in Parkinson’s Disease

Oral therapies, including levodopa, dopamine agonists and monoamine oxidase type B (MAO-B) inhibitors, form the mainstay of medical treatment for Parkinson’s disease (PD). However, over time, chronic treatment with multiple daily doses of oral agents is often associated with the development of motor fluctuations and dyskinesias. Alternative methods of dopaminergic drug delivery, particularly if they bypass the gastrointestinal system, may be of value for PD patients who have developed motor complications despite optimised oral therapy, in particular those with gastrointestinal absorption issues, including gastroparesis. This satellite symposium, held at the XX World Congress on Parkinson’s Disease and Related Disorders, Geneva, Switzerland, from 8–11 December 2013, was chaired by Professor Werner Poewe (Austria) and Professor Andrew Lees (UK) and discussed recent evidence regarding the benefits of using non-oral drug-delivery strategies with therapies such as subcutaneous apomorphine. Beginning with the history of apomorphine and its well-established use in PD both as an intermittent injection and a continuous infusion, the presenters set out the evidence for its efficacy in managing both motor and non-motor symptoms in PD. The significance of gastrointestinal involvement in PD and how this may influence responses to oral medications was also reviewed. Interim results from the ongoing Apokyn for Motor IMProvement of Morning AKinesia Trial (AM IMPAKT) study of the use of subcutaneous apomorphine in PD patients with morning akinesia were also presented and the continuing main role of apomorphine in the treatment of PD was discussed, including the selection of the most appropriate patients for this effective yet underused therapy.

Tympanotomy with sealing of the round window as surgical salvage option in sudden idiopathic sensorineural hearing loss

Conclusion: Tympanotomy with sealing of the round window is a promising surgical alternative as a salvage strategy in younger patients with acute idiopathic sensorineural hearing loss (SNHL) and may be considered as an alternative drug delivery method to the round window. Objectives: To analyze the potential benefit of the sealing of the round window with special emphasis on the age of treated patients and the influence of time elapsed between symptom onset and surgery. Methods: This was a retrospective cohort study of 25 patients (13 males,12 females) with an average age of 55 years (range 31–75 years) with sudden SNHL, who underwent an enaural tympanotomy with sealing of the round niche using triamcinolone-soaked fascia. Pre- and postoperative bone conduction thresholds were compared for each frequency and for the pure-tone average (PTA) measured at 500 Hz, 1 kHz, 2 kHz, and 3 kHZ. The time (days) between primary symptom onset and surgery as well as age was scrutinized. Hearing improvement was described as ‘no improvement' (0–9 dB), ‘moderate recovery' (10–29 dB), or ‘marked recovery' (≥30 dB). The difference in age of patients who improved was compared to those who did not. Results: A statistically significant improvement in PTA values (mean change 20.4 dB) was noted (p = 0.0002). In all, 13/25 (52%) patients exhibited improved bone conduction postoperatively regardless of age and time of treatment. A marked recovery (≥30 dB) could be seen in eight patients (median time to surgery, 9 days; average age, 48.5 years); recovery between 10 and 30 dB in five patients (median time to surgery, 10 days; average age, 46.6 years). Twelve significantly older patients showed no improvement (average time to surgery, 19 days; average age, 61.8 years; p = 0.004). No patient over the age of 65 years showed improvement in bone conduction.

Extemporaneous Compounding of Oral Liquid Dosage Formulations and Alternative Drug Delivery Methods for Anticancer Drugs

Oncology pharmacists face a constant challenge with patients who cannot swallow oral anticancer drugs, making extemporaneous oral liquid preparation a requirement. Improper extemporaneous preparation of these agents, especially with the traditional chemotherapy with a narrow therapeutic index, may increase the risk of over- or underdosing. In community pharmacies, multiple barriers exist that prevent these pharmacies from preparing extemporaneous oral anticancer drug formulations for a patient's use at home. In a home setting, patients or caregivers without proper counseling and education on how to safely handle chemotherapy are at increased risk for exposure to these drugs. Based on a review of the literature, compounding recipes are available for 46% of oral anticancer agents. A paucity of data exists on dose uniformity, bioequivalence, and stability of extemporaneous oral liquid formulations of anticancer drugs. Pharmacists must have an understanding of the basic scientific principles that are an essential foundation for the proper preparation of extemporaneous oral anticancer liquid formulations. The collaborative effort of a multidisciplinary team can also help identify different barriers in the community setting, especially in areas where community pharmacies may lack resources for the extemporaneous compounding of oral chemotherapy, and to find ways to coordinate better pharmaceutical care. There are great opportunities for oncology pharmacists, as well as community pharmacists, as a resource for educating and monitoring patients receiving oral chemotherapy to ensure dosing accuracy, safe administration, and proper disposal of hazardous drugs. Development of national guidelines to promote standards of practice in the community and/or home setting is urgently needed to help improve the safety of dispensing and handling oral chemotherapeutic agents, including extemporaneously compounded oral liquid formulations of these drugs.

Review: doxorubicin delivery systems based on chitosan for cancer therapy

Abstract Objectives This review sheds insight into an increasingly popular polymer that has been widely explored as a potential drug delivery system. The abundant, biodegradable and biocompatible polysaccharide chitosan, with many other favourable properties, has been favoured as a drug delivery system for the purposes of encapsulating and delivery of doxorubicin with reduced side-effects. Key findings Doxorubicin is frequently used as a frontline chemotherapeutic agent against a variety of cancers. It has largely been able to demonstrate anti-tumour effects, though there are major shortfalls of doxorubicin, which include serious side-effects such as cardiomyopathy and myelosuppression, and also an ever-present danger of extravasation during drug administration. In view of this, drug delivery systems are currently being explored as alternative methods of drug delivery in a bid to more effectively direct doxorubicin to the specific lesion site and reduce its systemic side-effects. Liposomes and dendrimers have been tested as potential carriers for doxorubicin; however they are not the focus of this review. Summary Recent advancements in doxorubicin and chitosan technology have shown some preliminary though promising results for cancer therapy.

Subretinal delivery of immunoglobulin G with gold nanoparticles in the rabbit eye

To examine the feasibility of subretinal delivery of immunoglobulin G (IgG) adsorbed onto gold nanoparticles (GNPs) and its histologic distribution in the rabbit retina after the injection. Goat IgG was adsorbed onto GNPs electrostatically. Goat IgG-adsorbed GNPs or buffer with goat IgG was injected into the subretinal space of rabbit eyes and followed up for 3 months by examination of fundus photographs, immunohistochemistry against goat IgG, and transmission electron microscopy (TEM). Human retinal pigment epithelial cells (ARPE-19 cells) were cultured, and cell proliferation with or without GNPs was assayed. At 1 week after the subretinal injection of goat IgG-adsorbed GNPs, retinal degeneration was observed in the outer retina, and goat IgG was immunolabeled in the retinal pigment epithelium (RPE) and the photoreceptor cells. TEM showed GNPs located in the outer segments and in the lysosomes in the RPE at 1 month and no apparent cytotoxicity of the RPE. There were no inhibitory effects of GNPs on proliferation of ARPE-19 cells. Goat IgG was successfully delivered into photoreceptor cells and RPE using GNPs, though retinal degeneration in the outer retina occurred in this model. This might be an alternative drug delivery method to photoreceptors and RPE.

Review: doxorubicin delivery systems based on chitosan for cancer therapy

This review sheds insight into an increasingly popular polymer that has been widely explored as a potential drug delivery system. The abundant, biodegradable and biocompatible polysaccharide chitosan, with many other favourable properties, has been favoured as a drug delivery system for the purposes of encapsulating and delivery of doxorubicin with reduced side-effects. Doxorubicin is frequently used as a frontline chemotherapeutic agent against a variety of cancers. It has largely been able to demonstrate anti-tumour effects, though there are major shortfalls of doxorubicin, which include serious side-effects such as cardiomyopathy and myelosuppression, and also an ever-present danger of extravasation during drug administration. In view of this, drug delivery systems are currently being explored as alternative methods of drug delivery in a bid to more effectively direct doxorubicin to the specific lesion site and reduce its systemic side-effects. Liposomes and dendrimers have been tested as potential carriers for doxorubicin; however they are not the focus of this review. Recent advancements in doxorubicin and chitosan technology have shown some preliminary though promising results for cancer therapy.

Evaluation of the effects of biodegradable nanoparticles on a vaccine delivery system using AFM, SEM, and TEM

Hepatitis B is a deadly disease, and is carried by 30% of the world's population. Antibodies are produced through a series of three manual vaccinations during infancy and childhood. However, the current needle vaccination not only induces pain in patients, but also can be inconvenient to administer. This is particularly true for the case of newborn babies. Intranasal vaccination is emerging as an alternative parenteral drug delivery method that facilitates drug delivery without causing pain. Chitosan, which is obtained through the deacetylation of chitin from crustacea, is a cationic polymer that is biodegradable, avirulent, and highly absorptive. In this study, ionic gelation between chitosan and TPP was conducted to synthesize chitosan nanoparticles with sizes of 200–400 nm and a surface potential of 55–60 mV, and which can be used as Hepatitis B vaccine carriers. Then, Heptatitis B antigen protein was impregnated to manufacture chitosan–recombinant gene vaccine protein (RGVP) nanoparticles. AFM, SEM, TEM, and STEM were used to analyze the manufactured nanoparticles, whose function as drug carriers and whose usefulness for intranasal vaccination were confirmed through in vivo tests with SD rats.

Pharmacologic Considerations in the Treatment of Repetitive or Prolonged Seizures

Seizure emergencies are relatively common; however, in-hospital emergency care often is delayed by a variety of factors. Home-based treatment is effective at interrupting prolonged or repetitive seizures, but this option is underused despite its wide availability. The choice of agent used to treat seizure emergencies will depend chiefly on differences among the properties of the available drugs, particularly with regard to route of administration, lipid solubility, formulation characteristics, and the relative size of the absorptive surface area. These factors also can play a part in the decision to use one route of administration over another. Intravenous administration is the fastest and most reliable method of drug delivery, but alternative methods of drug delivery include oral, intramuscular, buccal, nasal, and rectal routes.

Non-surgical treatment for detrusor overactivity

Urinary incontinence is a common but under-reported condition. Approximately 17% of women are affected by detrusor overactivity at some time in their lives. Pharmacological treatment of this condition used to be severely limited by the side-effects of the drugs and the associated poor patient compliance. Recently, however, the tolerability and effectiveness of pharmacotherapy have been improved by the introduction of new drugs and alternative methods of drug delivery. This review assesses the effectiveness and tolerability of these new treatments. Anticholinergic agents, botulinum toxin and neuromodulation are also discussed.

Tumor Vascular Permeability, Accumulation, and Penetration of Macromolecular Drug Carriers

Delivery of anticancer therapeutic agents to solid tumors is problematic. Macromolecular drug carriers are an attractive alternative drug delivery method because they appear to target tumors and have limited toxicity in normal tissues. We investigated how molecular weight influences the accumulation of a model macromolecular drug carrier, dextran covalently linked to a fluorophore, in tumors. We used dextrans with molecular weights from 3.3 kDa to 2 MDa. Vascular permeability, accumulation, and three-dimensional penetration of these dextrans were simultaneously measured in solid tumors via a dorsal skin fold window chamber, intravital laser-scanning confocal microscopy, and custom image analysis. Increasing the molecular weight of dextran statistically significantly reduced its vascular permeability by approximately two orders of magnitude (i.e., from 154 x 10(-7) cm/s, 95% confidence interval [CI] = 134 to 174 x 10(-7) cm/s, for 3.3-kDa dextran to 1.7 x 10(-7) cm/s, 95% CI = 0.7 to 2.6 x 10(-7) cm/s for 2-MDa dextran; P < .001, two-sided Kruskal-Wallis test) but increased its plasma half-life, which provided ample time for extravasation (i.e., to enter tumor tissue from the vasculature). Tumor accumulation was maximal for dextrans with molecular weights between 40 and 70 kDa. Dextrans of 3.3 and 10 kDa penetrated deeply (greater than 35 microm) and homogeneously into tumor tissue from the vessel wall. After a 30-minute period, a high concentration was observed only approximately 15 microm from the vessel wall for 40- to 70-kDa dextrans and only 5 microm for 2-MDa dextrans. Increasing the molecular weight of dextran statistically significantly reduced its tumor vascular permeability. Dextrans of 40 and 70 kDa had the highest accumulation in solid tumors but were largely concentrated near the vascular surface.

Fabrication of self assembled micro reservoirs for controlled drug release.

Conventional dosage means, such as oral delivery or injection, are the predominant routes for drug delivery. The main drawbacks of these types of dosages consist essentially in a limited control of the drug delivery rate and of the target area. The conventional delivery is often associated with an immediate or rapid drug release. Accordingly, the initial concentration of the drug in the body peaks above the level of toxicity and then gradually diminishes over time to an ineffective level. Besides, the drug can have undesired side-effects if distributed in all the body by the circulatory system. Our activity is aimed at the development of alternative drug delivery methods enabling a more precise control of the delivery rate and target area. A technique for microreservoirs fabrication combining conventional photolithography and self assembling is presented. The drug contained in the microreservoirs can be released by externally applied electromagnetic waves focused on the target volume.

A review of ipratropium bromide/fenoterol hydrobromide (Berodual) delivered via Respimat Soft Mist Inhaler in patients with asthma and chronic obstructive pulmonary disease.

Asthma and chronic obstructive pulmonary disease (COPD) can be effectively treated by the use of bronchodilator therapies delivered by inhalation. Berodual is a fixed combination of the anticholinergic agent ipratropium bromide (IB) and the beta2-adrenergic agonist fenoterol hydrobromide (FEN). IB/FEN has been available for the treatment of asthma and COPD in a pressurised metered dose inhaler (MDI) [pMDI] formulation for many years. The pMDI is the most widely used device for the delivery of inhaled medications, such as IB/FEN. However, most conventional pMDIs contain chlorofluorocarbon (CFC) propellants, which are currently being withdrawn because of their detrimental effects on the environment. This has resulted in alternative methods of drug delivery being developed. Respimat Soft Mist Inhaler (SMI) is a new generation, propellant-free inhaler that generates a fine, slow-moving cloud (the Soft Mist) which can be easily inhaled. Scintigraphic studies have shown that this improves deposition of drugs in the lung and results in less oropharyngeal deposition than the CFC-MDI. A clinical development programme has been conducted to compare the efficacy and safety of IB/FEN delivered via Respimat SMI with that of IB/FEN via CFC-MDI in the treatment of patients with asthma or COPD. Five clinical studies (two phase II and three phase III) investigated dosages of IB/FEN 5/12.5 microg to 320/800 microg via Respimat SMI in single and multiple dose administration regimens. Four of the trials were conducted in patients with asthma (three in adults and one in children), while one phase III trial was conducted in patients with COPD. In phase III, 2058 patients participated, with a total of 1112 patients treated with IB/FEN via Respimat SMI. In the phase III studies, each dose from Respimat SMI was given in one actuation compared with two actuations with the CFC-MDI. In the paediatric asthma phase III study, all CFC-MDI doses were delivered via a spacer device. The results of the trials demonstrated that IB/FEN via Respimat SMI allows a reduction in the nominal dose of IB/FEN, while offering similar therapeutic efficacy and safety to a CFC-MDI. In children, Respimat SMI obviates the need for a spacer.

Pharmacoeconomics of chronic nonmalignant pain.

Pain is one of the most common reasons for patients to seek medical care. In most settings, the model of acute pain treatment, with its emphasis on pharmacological therapy, is used for acute and chronic pain alike. Persistent chronic pain, however, often leads to complex social and psychological maladaptations, as well as substantial direct and indirect costs. Thus, the proper treatment of chronic pain usually involves pharmacological, behavioural and psychological interventions. Pain is a subjective sensation, but persistent chronic pain often results in long term neurophysiological and psychological changes that might be more appropriately considered disease manifestations. Unfortunately, the subjectivity of pain has meant that the assessment of the epidemiology, pharmacotherapy and economic costs of chronic pain has been difficult. As a result, many of the techniques for chronic pain management are unfamiliar to practising physicians. Even those healthcare professionals who are familiar with the special techniques for the management of chronic pain may be unable to identify the subpopulations for which they might be most effective. The clinician must evaluate patients for the appropriateness of a number of alternative drug delivery methods, novel analgesic agents, neuromodulatory techniques and multidisciplinary behavioural and psychological treatment programmes. The most effective treatment will often involve a combination of these techniques, as determined by the unique features of the patient's pain condition as well as individual patient characteristics. The costs and outcomes of various treatment strategies vary considerably and there is a need for comparative studies. Increasing emphasis on diagnosis and treatment in the primary care setting will place more importance on knowing the relative efficacies and appropriate use of a widening array of choices for chronic pain treatment. The management of chronic pain is remarkably complex and resource-intensive, and there is clearly a need for more intensive pharmacoeconomic studies, especially those comparing the many alternative strategies for management.

Drug therapy of cardiopulmonary resuscitation in children.

In contrast to adults, cardiopulmonary arrest in infants and children is rarely an acute, primary cardiac event. Instead, it is often the terminal event in a progressive deterioration of respiratory or circulatory function. Successful resuscitation from cardiac arrest therefore is unusual in the paediatric patient and most survivors have persistent neurological impairment. Rapid vascular access and recall of drug dosages are major obstacles in treating paediatric emergencies. This paper reviews vascular access and alternative drug delivery methods. The endotracheal and intraosseous routes provide alternative sites for drug delivery, but the optimal doses and methods of drug administration via these routes are unknown. Indeed, although great progress in cardiopulmonary resuscitation (CPR) research has been made over the past 10 years, there are only limited data on paediatric arrest mechanisms and drug treatment. In this paper, recommended dosages and mechanisms of action of drugs useful during cardiopulmonary resuscitation are reviewed, highlighting recent data which suggest that changes in current drug recommendations may be needed. To avoid delays in management, precalculated tables of drugs should be readily available in emergency departments and other care areas where paediatric cases are likely to be seen. Adrenaline (epinephrine) remains the drug of choice in a cardiac arrest, but the most effective dose may be higher than currently used. Treatment of acidosis during the arrest concentrates on restoration of ventilation and blood flow and not on bicarbonate administration. In the post-arrest setting increasing data suggest bicarbonate may not be beneficial and may actually be detrimental. Calcium and atropine also have relatively minor roles in resuscitation pharmacology. Calcium is only indicated to treat hypocalcaemia, counteract the effects of hyperkalaemia or hypermagnesaemia, or reverse calcium channel blocker toxicity. Finally, the role of isoprenaline (isoproterenol), dopamine, dobutamine and adrenaline infusions to restore or maintain cardiovascular stability post-arrest is reviewed.