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International Journal of Pharmaceutics Aug 2023Pulmonary delivery is an alternative route of administration with numerous advantages over conventional routes of administration. It provides low enzymatic exposure,... (Review)
Review
Pulmonary delivery is an alternative route of administration with numerous advantages over conventional routes of administration. It provides low enzymatic exposure, fewer systemic side effects, no first-pass metabolism, and concentrated drug amounts at the site of the disease, making it an ideal route for the treatment of pulmonary diseases. Owing to the thin alveolar-capillary barrier, and large surface area that facilitates rapid absorption to the bloodstream in the lung, systemic delivery can be achieved as well. Administration of multiple drugs at one time became urgent to control chronic pulmonary diseases such as asthma and COPD, thus, development of drug combinations was proposed. Administration of medications with variable dosages from different inhalers leads to overburdening the patient and may cause low therapeutic intervention. Therefore, products that contain combined drugs to be delivered via a single inhaler have been developed to improve patient compliance, reduce different dose regimens, achieve higher disease control, and boost therapeutic effectiveness in some cases. This comprehensive review aimed to highlight the growth of drug combinations by inhalation over time, obstacles and challenges, and the possible progress to broaden the current options or to cover new indications in the future. Moreover, various pharmaceutical technologies in terms of formulation and device in correlation with inhaled combinations were discussed in this review. Hence, inhaled combination therapy is driven by the need to maintain and improve the quality of life for patients with chronic respiratory diseases; promoting drug combinations by inhalation to a higher level is a necessity.
Topics: Humans; Quality of Life; Respiratory Aerosols and Droplets; Administration, Inhalation; Asthma; Nebulizers and Vaporizers; Drug Combinations; Pharmaceutical Preparations; Patient Compliance; Pulmonary Disease, Chronic Obstructive
PubMed: 37230369
DOI: 10.1016/j.ijpharm.2023.123070 -
Small (Weinheim An Der Bergstrasse,... Jun 2024Microneedles (MNs) have maintained their popularity in therapeutic and diagnostic medical applications throughout the past decade. MNs are originally designed to gently... (Review)
Review
Microneedles (MNs) have maintained their popularity in therapeutic and diagnostic medical applications throughout the past decade. MNs are originally designed to gently puncture the stratum corneum layer of the skin and have lately evolved into intelligent devices with functions including bodily fluid extraction, biosensing, and drug administration. MNs offer limited invasiveness, ease of application, and minimal discomfort. Initially manufactured solely from metals, MNs are now available in polymer-based varieties. MNs can be used to create systems that deliver drugs and chemicals uniformly, collect bodily fluids, and are stimulus-sensitive. Although these advancements are favorable in terms of biocompatibility and production costs, they are insufficient for the therapeutic use of MNs. This is the first comprehensive review that discusses individual MN functions toward the evolution and development of smart and multifunctional MNs for a variety of novel and impactful future applications. The study examines fabrication techniques, application purposes, and experimental details of MN constructs that perform multiple functions concurrently, including sensing, drug-molecule release, sampling, and remote communication capabilities. It is highly likely that in the near future, MN-based smart devices will be a useful and important component of standard medical practice for different applications.
Topics: Needles; Humans; Drug Delivery Systems; Animals; Theranostic Nanomedicine; Microinjections
PubMed: 38385813
DOI: 10.1002/smll.202308479 -
Journal of Controlled Release :... Aug 2023Oral administration of pharmaceuticals is the most preferred route of administration for patients, but it is challenging to effectively deliver active ingredients (APIs)... (Review)
Review
Oral administration of pharmaceuticals is the most preferred route of administration for patients, but it is challenging to effectively deliver active ingredients (APIs) that i) have extremely high or low solubility in intestinal fluids, ii) are large in size, iii) are subject to digestive and/or metabolic enzymes present in the gastrointestinal tract (GIT), brush border, and liver, and iv) are P-glycoprotein substrates. Over the past decades, efforts to increase the oral bioavailability of APIs have led to the development of nanoparticles (NPs) with non-specific uptake pathways (M cells, mucosal, and tight junctions) and target-specific uptake pathways (FcRn, vitamin B12, and bile acids). However, voluminous findings from preclinical models of different species rarely meet practical standards when translated to humans, and API concentrations in NPs are not within the adequate therapeutic window. Various NP oral delivery approaches studied so far show varying bioavailability impacted by a range of factors, such as species, GIT physiology, age, and disease state. This may cause difficulty in obtaining similar oral delivery efficacy when research results in animal models are translated into humans. This review describes the selection of parameters to be considered for translational potential when designing and developing oral NPs.
Topics: Animals; Humans; Pharmaceutical Preparations; Nanoparticles; Administration, Oral; Biological Availability; Biological Transport; Intestinal Absorption; Drug Carriers
PubMed: 37348679
DOI: 10.1016/j.jconrel.2023.06.024 -
Medicine Sep 2023A systematic review and network meta-analysis (NMA) were conducted to explore the optimal administration route of nimodipine for treatment subarachnoid hemorrhage. (Meta-Analysis)
Meta-Analysis
BACKGROUND
A systematic review and network meta-analysis (NMA) were conducted to explore the optimal administration route of nimodipine for treatment subarachnoid hemorrhage.
METHODS
Electronic databases (Pubmed, Embase, Web of Science and Cochrane databases) were systematically searched to identify randomized controlled trials evaluating different administration route of nimodipine (intravenous and enteral) versus placebo for treatment subarachnoid hemorrhage. Outcomes included case fatality at 3 months, poor outcome measured at 3 months (defined as death, vegetative state, or severe disability), incidence of delayed cerebral ischemia (DCI), delayed ischemic neurological deficit. A random-effect Bayesian NMA was conducted for outcomes of interest, and results were presented as odds ratios (ORs) and 95% credible intervals. The NMA was performed using R Software with a GeMTC package. A Bayesian NMA was performed and relative ranking of agents was assessed using surface under the cumulative ranking (SUCRA) probabilities.
RESULTS
Nine randomized controlled trials met criteria for inclusion and finally included in this NMA. There was no statistically significant between intravenous and enteral in terms of case fatality, the occurrence of DCI, delayed ischemic neurologic deficit and poor outcomes (P > .05). Both intravenous and enteral could reduce case fatality, the occurrence of DCI, delayed ischemic neurologic deficit and poor outcomes (P < .05). The SUCRA shows that enteral ranked first, intravenous ranked second and placebo ranked the last for case fatality, the occurrence of DCI and poor outcomes. The SUCRA shows that intravenous ranked first, enteral ranked second and placebo ranked the last for delayed ischemic neurologic deficit.
CONCLUSIONS
It is possible that both enteral and intravenous nimodipine have comparable effectiveness in preventing poor outcomes, DCI, and delayed ischemic neurological deficits. However, further investigation may be necessary to determine the exact role of intravenous nimodipine in current clinical practice.
Topics: Humans; Nimodipine; Subarachnoid Hemorrhage; Network Meta-Analysis; Bayes Theorem; Administration, Intravenous; Brain Ischemia; Cerebral Infarction
PubMed: 37773855
DOI: 10.1097/MD.0000000000034789 -
Journal of Pharmaceutical Sciences Jul 2024Oligonucleotide drug products commercially approved in the US and the EU are reviewed. A total of 20 products that includes 1 aptamer, 12 antisense oligonucleotides... (Review)
Review
Oligonucleotide drug products commercially approved in the US and the EU are reviewed. A total of 20 products that includes 1 aptamer, 12 antisense oligonucleotides (ASOs), 6 small interfering ribonucleic acids (siRNAs), and 1 mixture of single-stranded and double-stranded polydeoxyribonucleotides have been identified. A typical oligonucleotide formulation is composed of an oligonucleotide with buffering agent(s), pH adjusting agents, and a tonicity adjusting agent. All the products are presented as 2.1 - 200 mg/mL solutions at pH between 6 and 8.7. Majority of the products are approved for intravenous (IV) and subcutaneous (SC) routes, with two for intravitreal (IVT), two for intrathecal (IT), and one for intramuscular (IM) routes. The primary packaging includes vials and prefilled syringes (PFS). Products approved for IV and IT administration routes and requiring >1.5 mL dose volumes are supplied in vials, while those approved for SC, IM, and IVT and requiring ≤1.5 mL dose volume are supplied in PFS. Based on the compiled dataset, we propose a generalized starting point for an oligonucleotide formulation during early phase development for IV, SC, and IT administration routes. Overall, we believe this harmonized evaluation and understanding of various oligonucleotide drug product attributes will help derive platform generalizations and allows for accelerated early phase development for first-in-human studies.
Topics: Humans; Oligonucleotides; Oligonucleotides, Antisense; Drug Approval; RNA, Small Interfering; United States; Drug Packaging; Chemistry, Pharmaceutical
PubMed: 38679232
DOI: 10.1016/j.xphs.2024.04.021 -
Pharmaceutical Research Aug 2023Iontophoresis is a noninvasive method that enhances drug delivery using an electric field. This method can improve drug delivery to the tissues in the oral cavity. The...
PURPOSE
Iontophoresis is a noninvasive method that enhances drug delivery using an electric field. This method can improve drug delivery to the tissues in the oral cavity. The effects of iontophoresis on gingival drug delivery have not been investigated. The objectives of this study were to (a) determine the flux enhancement of model permeants across porcine and human gingiva during iontophoresis, (b) examine the transport mechanisms of gingival iontophoresis, and (c) evaluate the potential of iontophoretically enhanced delivery for three model drugs lidocaine, ketorolac, and chlorhexidine.
METHODS
Passive and iontophoretic fluxes were determined with porcine and human gingiva using a modified Franz diffusion cell and model drugs and permeants. To investigate the transport mechanisms of iontophoresis, the enhancement from the direct-field effect was determined by positively and negatively charged model permeants. The electroosmosis enhancement effect was determined with neutral permeants of different molecular weight. The alteration of the gingival barrier due to electropermeabilization was evaluated using electrical resistance measurements.
RESULTS
Significant flux enhancement was observed during gingival iontophoresis. The direct-field effect was the major mechanism governing the iontophoretic transport of the charged permeants. Electroosmosis was from anode to cathode. The effective pore radius of the iontophoretic transport pathways in the porcine gingiva was ~0.68 nm. Irreversible electropermeabilization was observed after 2 and 4 h of iontophoresis under the conditions studied.
CONCLUSION
Iontophoresis could enhance drug delivery and reduce transport lag time, showing promise for gingival drug delivery.
Topics: Humans; Animals; Swine; Iontophoresis; Gingiva; Diffusion; Electroosmosis; Drug Delivery Systems; Administration, Cutaneous
PubMed: 37258949
DOI: 10.1007/s11095-023-03535-8 -
Cannabis and Cannabinoid Research Aug 2023This systematic review aimed to assess efficacy and safety for skin-applied formulations containing CBD. Bibliographic and clinical trial registries were searched for... (Review)
Review
This systematic review aimed to assess efficacy and safety for skin-applied formulations containing CBD. Bibliographic and clinical trial registries were searched for interventional human trials using cutaneously administered CBD or reported plasma CBD concentrations (any species). Eight of 544 articles fitted the selection criteria: 3 placebo-controlled randomized and 5 single-arm trials. Eleven more studies were found in clinical trial databases but not accessible. Symptoms targeted were dermatopathologies or safety (two studies), pain (two), and behavior (one). Doses were 50-250 mg or 0.075-1.0% CBD, but coformulated with other ingredients. Risk of bias was high and reporting deficiencies further compromised data reliability. Diverse methodologies and formulations hampered syntheses for CBD dose, efficacy, and safety. Plasma CBD levels in dogs and rodents were 0.01-5 μM translating to <100 nM free, unbound CBD in humans. Adverse events were uncommon and mild, but meaningless without CBD's contribution to efficacy data. Achievable CBD plasma concentrations ∼100 nM can interact predominantly with high-affinity CBD targets, for example, TRPA1 and TRPM8 membrane channels that are abundantly expressed in pathological conditions. Even if reached, higher CBD concentrations on less susceptible targets risk complex and unsafe CBD therapy. A conceptual framework is proposed where dermal capillary loops create sinking for topical CBD demonstrating parallels between topical and transdermal CBD administration. Users risk generalizing inadequately designed trials to all CBD preparations. New clinical trials are urgently needed: they must demonstrate that outcomes are solely from CBD pharmacology, are reliable, unbiased, safe, and comparable. Measurements of sustained plasma CBD levels are mandatory, irrespective of administration route for successful translation from systems that express human molecular targets. Placebos must be appropriate. Transcutaneous and topical formulations need preliminary studies to optimize CBD skin penetration. Then, users can rationally balance efficacy against potential harms and cost-effectiveness of CBD formulations.
Topics: Humans; Animals; Dogs; Cannabidiol; Reproducibility of Results; Pain; Administration, Cutaneous; Seizures
PubMed: 35605018
DOI: 10.1089/can.2021.0154 -
Carbohydrate Polymers Nov 2023Oral drug delivery is the preferred route of drug administration for patients, especially those who need long-term medication. Recently, bioinspired drug delivery... (Review)
Review
Oral drug delivery is the preferred route of drug administration for patients, especially those who need long-term medication. Recently, bioinspired drug delivery systems have emerged for the oral delivery of various therapeutics. Among them, the yeast-based β-glucan system is a novel and promising platform, for oral administration that can overcome the biological barriers of the harsh gastrointestinal environment. Remarkably, the yeast-based β-glucan system not only protects the drug through the harsh gastrointestinal environment but also achieves targeted therapeutic effects by specifically recognizing immune cells, especially macrophages. Otherwise, it exhibits immunomodulatory properties. Based on the pleasant characteristics of the yeast-based β-glucan system, they are widely used in various macrophage-related diseases for oral administration. In this review, we introduced the structure and function of yeast-based β-glucan. Subsequently, we further summarized the current preparation methods of yeast-based β-glucan carriers and the strategies for preparing yeast-based β-glucan drug delivery systems. In addition, we focus on discussing the applications of β-glucan drug delivery systems in various diseases. Finally, the current challenges and future perspectives of the β-glucan drug delivery system are introduced.
Topics: Humans; Saccharomyces cerevisiae; beta-Glucans; Drug Carriers; Drug Delivery Systems; Macrophages; Administration, Oral
PubMed: 37567689
DOI: 10.1016/j.carbpol.2023.121163 -
Journal of Controlled Release :... Dec 2023Disorders of the central nervous system (CNS), such as multiple sclerosis (MS) represent a great emotional, financial and social burden. Despite intense efforts, great... (Review)
Review
Disorders of the central nervous system (CNS), such as multiple sclerosis (MS) represent a great emotional, financial and social burden. Despite intense efforts, great unmet medical needs remain in that field. MS is an autoimmune, chronic inflammatory demyelinating disease with no curative treatment up to date. The current therapies mostly act in the periphery and seek to modulate aberrant immune responses as well as slow down the progression of the disease. Some of these therapies are associated with adverse effects related partly to their administration route and show some limitations due to their rapid clearance and inability to reach the CNS. The scientific community have recently focused their research on developing MS therapies targeting different processes within the CNS. However, delivery of therapeutics to the CNS is mainly limited by the presence of the blood-brain barrier (BBB). Therefore, there is a pressing need to develop new drug delivery strategies that ensure CNS availability to capitalize on identified therapeutic targets. Several approaches have been developed to overcome or bypass the BBB and increase delivery of therapeutics to the CNS. Among these strategies, the use of alternative routes of administration, such as the nose-to-brain (N2B) pathway, offers a promising non-invasive option in the scope of MS, as it would allow a direct transport of the drugs from the nasal cavity to the brain. Moreover, the combination of bioactive molecules within nanocarriers bring forth new opportunities for MS therapies, allowing and/or increasing their transport to the CNS. Here we will review and discuss these alternative administration routes as well as the nanocarrier approaches useful to deliver drugs for MS.
Topics: Humans; Multiple Sclerosis; Administration, Intranasal; Central Nervous System; Brain; Drug Delivery Systems; Blood-Brain Barrier; Pharmaceutical Preparations
PubMed: 37926243
DOI: 10.1016/j.jconrel.2023.10.052 -
Cannabis and Cannabinoid Research Apr 2024This review aims to provide an overview of the advancements and status of clinical studies and potential permeation-enhancing strategies in the transdermal delivery of... (Review)
Review
This review aims to provide an overview of the advancements and status of clinical studies and potential permeation-enhancing strategies in the transdermal delivery of cannabinoids. A systematic and comprehensive literature search across academic databases, search engines, and online sources to identify relevant literature on the transdermal administration of cannabinoids. Cannabinoids have proven beneficial in the treatment of wide-ranging physical and psychological disorders. A shift toward legalized cannabinoid products has increased both interests in cannabinoid research and the development of novel medicinal exploitations of cannabinoids in recent years. Oral and pulmonary delivery of cannabinoids has several limitations, including poor bioavailability, low solubility, and potential side effects. This has diverted scientific attention toward the transdermal route, successfully overcoming these hurdles by providing higher bioavailability, safety, and patient compliance. Yet, due to the barrier properties of the skin and the lipophilic nature of cannabinoids, there is a need to increase the permeation of the drugs to the underneath layers of skin to reach desired therapeutic plasma levels. Literature describing detailed clinical trials on cannabinoid transdermal delivery, either with or without permeation-enhancing strategies, is limited. The limited number of reports indicates that increased attention is needed on developing and examining efficient transdermal delivery systems for cannabinoids, including patch design and composition, drug-patch interaction, clinical effectiveness and safety , and permeation-enhancing strategies.
Topics: Humans; Cannabinoids; Administration, Cutaneous; Skin; Pharmaceutical Preparations; Biological Availability
PubMed: 37751171
DOI: 10.1089/can.2023.0130