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Molecular Therapy. Nucleic Acids Mar 2024Pharmacokinetics (PK) of antisense oligonucleotides (ASOs) is characterized by rapid distribution from plasma to tissue and slow terminal plasma elimination driven by...
Pharmacokinetics (PK) of antisense oligonucleotides (ASOs) is characterized by rapid distribution from plasma to tissue and slow terminal plasma elimination driven by re-distribution from tissue. Quantitative understanding of tissue PK and RNA knockdown for various ASO chemistries, conjugations, and administration routes is critical for successful drug discovery. Here, we report concentration-time and RNA knockdown profiles for a gapmer ASO with locked nucleic acid ribose chemistry in mouse liver, kidney, heart, and lung after subcutaneous and intratracheal administration. Additionally, the same ASO with liver targeting conjugation (galactosamine--acetyl) is evaluated for subcutaneous administration. Data indicate that exposure and knockdown differ between tissues and strongly depend on administration route and conjugation. In a second study, we show that tissue PK is similar between the three different ribose chemistries locked nucleic acid, constrained ethyl and 2'--methoxyethyl, both after subcutaneous and intratracheal administration. Further, we show that the half-life in mouse liver may vary with ASO sequence. Finally, we report less than dose-proportional increase in liver concentration in the dose range of 3-30 μmol/kg. Overall, our studies contribute pivotal data to support design and interpretation of ASO studies, thereby increasing the probability of delivering novel ASO therapies to patients.
PubMed: 38419941
DOI: 10.1016/j.omtn.2024.102133 -
Current Rheumatology Reports Dec 2023This review aims to critically evaluate the potential benefit of either oral or subcutaneous administration of methotrexate (MTX) in various immune-mediated inflammatory... (Review)
Review
PURPOSE
This review aims to critically evaluate the potential benefit of either oral or subcutaneous administration of methotrexate (MTX) in various immune-mediated inflammatory disorders (IMIDs) through analysis of efficacy, toxicity, pharmacokinetics and pharmacodynamics of both administration routes.
RECENT FINDINGS
Recent studies comparing the efficacy of oral versus subcutaneous MTX administration in IMIDs have revealed contradicting results. Some reported higher efficacy with subcutaneous administration, while others found no significant difference. Regarding toxicity, some studies have challenged the notion that subcutaneous administration is better tolerated than oral administration, while others have supported this. Pharmacokinetic studies suggest higher plasma bioavailability and increased accumulation of MTX-polyglutamates (MTX-PGs) in red blood cells (RBCs) with subcutaneous administration during the initial treatment phase. However, after several months, similar intracellular drug levels are observed with both administration routes. There is no conclusive evidence supporting the superiority of either oral or subcutaneous MTX administration in terms of efficacy and adverse events in IMIDs. Subcutaneous administration leads to higher plasma bioavailability and initial accumulation of MTX-PGs in RBCs, but the difference seems to disappear over time. Given the variable findings, the choice of administration route may be based on shared decision-making, offering patients the option of either oral or subcutaneous administration of MTX based on individual preferences and tolerability. Further research is needed to better understand the impact of MTX-PGs in various blood cells and TDM on treatment response and adherence to MTX therapy.
Topics: Humans; Methotrexate; Antirheumatic Agents; Injections, Subcutaneous; Administration, Oral; Immunomodulating Agents
PubMed: 37768405
DOI: 10.1007/s11926-023-01116-7 -
Journal of Controlled Release :... Jul 2024Microneedles (MNs) are micron-sized needles, typically <2 mm in length, arranged either as an array or as single needle. These MNs offer a minimally invasive approach... (Review)
Review
Microneedles (MNs) are micron-sized needles, typically <2 mm in length, arranged either as an array or as single needle. These MNs offer a minimally invasive approach to ocular drug delivery due to their micron size (reducing tissue damage compared to that of hypodermic needles) and overcoming significant barriers in drug administration. While various types of MNs have been extensively researched, significant progress has been made in the use of hollow MNs (HMNs) for ocular drug delivery, specifically through suprachoroidal injections. The suprachoroidal space, situated between the sclera and choroid, has been targeted using optical coherence tomography-guided injections of HMNs for the treatment of uveitis. Unlike other MNs, HMNs can deliver larger volumes of formulations to the eye. This review primarily focuses on the use of HMNs in ocular drug delivery and explores their ocular anatomy and the distribution of formulations following potential HMN administration routes. Additionally, this review focuses on the influence of formulation characteristics (e.g., solution viscosity, particle size), HMN properties (e.g., bore or lumen diameter, MN length), and routes of administration (e.g., periocular transscleral, suprachoroidal, intravitreal) on the ocular distribution of drugs. Overall, this paper highlights the distinctive properties of HMNs, which make them a promising technology for improving drug delivery efficiency, precision, and patient outcomes in the treatment of ocular diseases.
Topics: Needles; Humans; Drug Delivery Systems; Animals; Administration, Ophthalmic; Eye; Pharmaceutical Preparations; Microinjections
PubMed: 38735395
DOI: 10.1016/j.jconrel.2024.05.013 -
Pediatric Research Oct 2023
Topics: Fluid Therapy; Administration, Intravenous; Infusions, Intravenous
PubMed: 37138024
DOI: 10.1038/s41390-023-02635-w -
Journal of Drug Targeting Dec 2023Changes in the homeostasis of blood sugar levels are a hallmark of diabetes mellitus, an incurable metabolic condition, for which the first-line treatment is the... (Review)
Review
Changes in the homeostasis of blood sugar levels are a hallmark of diabetes mellitus, an incurable metabolic condition, for which the first-line treatment is the subcutaneous injection of insulin. However, this method of administration is linked to low patient compliance because of the possibility of local infection, discomfort and pain. To enable the administration of the peptide through more palatable paths without requiring an injection, like by oral routes, the use of nanoparticles as insulin carriers has been suggested. The use of nanoparticles usually improves the bioavailability and physicochemical stability of the loaded medicine. The utilisation of several forms of nanoparticles (like lipid and polymeric nanoparticles, micelles, dendrimers, liposomes, niosomes, nanoemulsions and drug nanosuspensions) is discussed in this article as a way to improve the administration of various oral hypoglycaemic medications when compared to conventional treatments.
Topics: Humans; Drug Delivery Systems; Diabetes Mellitus; Nanoparticles; Drug Carriers; Insulin; Liposomes; Administration, Oral
PubMed: 37725445
DOI: 10.1080/1061186X.2023.2261077 -
The Journal of Pharmacy and Pharmacology Aug 2023Hydrogel microneedles are emerging, and promising microneedles mainly composed of swelling polymers. This review is intended to summarize the preparation materials,... (Review)
Review
OBJECTIVES
Hydrogel microneedles are emerging, and promising microneedles mainly composed of swelling polymers. This review is intended to summarize the preparation materials, formation mechanisms, applications and existing problems of hydrogel microneedles.
METHODS
We collected the literature on the materials, preparation and application of hydrogel microneedles in recent years, and summarized their mechanism and application in drugs delivery.
KEY FINDINGS
Hydrogel microneedles have higher safety and capabilities of controlled drug release, and have been mainly used in tumour and diabetes treatment, as well as clinical monitoring. In recent years, hydrogel microneedles have shown great potential in drug delivery, and have played the role of whitening, anti-inflammatory and promoting healing.
CONCLUSIONS
As an emerging drug delivery idea, hydrogel microneedles for drug delivery has gradually become a research hotspot. This review will provide a systematic vision for the favourable development of hydrogel microneedles and their promising application in medicine, especially drug delivery.
Topics: Hydrogels; Administration, Cutaneous; Drug Delivery Systems; Drug Liberation; Polymers; Needles; Microinjections; Skin
PubMed: 37330272
DOI: 10.1093/jpp/rgad058 -
ACS Applied Bio Materials Sep 2023The vagina has been regarded as a crucial route for drug delivery. Despite the wide range of available vaginal dosage forms for vaginal infection control, poor drug... (Review)
Review
The vagina has been regarded as a crucial route for drug delivery. Despite the wide range of available vaginal dosage forms for vaginal infection control, poor drug absorptivity remains a significant challenge due to various biological barriers in the vagina, such as mucus, epithelium, immune systems, and others. To overcome these barriers, different types of vaginal drug delivery systems (VDDSs), with outstanding mucoadhesive, mucus-penetrating properties, have been designed to enhance the absorptivity of vagina-administered agents in the past decades. In this Review, we introduce a general understanding of vaginal administration, its biological barriers, the commonly used VDDSs, such as nanoparticles and hydrogels, and their applications in controlling microbe-associated vaginal infections. Additionally, further challenges and concerns regarding the design of VDDSs will be discussed.
Topics: Female; Humans; Vagina; Drug Delivery Systems; Administration, Intravaginal; Nanoparticles; Hydrogels
PubMed: 36932958
DOI: 10.1021/acsabm.3c00097 -
Current Medicinal Chemistry 2024Statins are HMG-CoA reductase inhibitors and decrease plasma low-density lipoprotein cholesterol (LDL-C) levels. They are well tolerated, and because of their... (Review)
Review
Statins are HMG-CoA reductase inhibitors and decrease plasma low-density lipoprotein cholesterol (LDL-C) levels. They are well tolerated, and because of their LDL-C-lowering effect, they are utilized to decrease the risk of atherosclerosis and cardiovascular disease. However, statins have pleiotropic effects, including immunomodulatory, anti-inflammatory, antioxidant, and anticancer. Currently, oral administration is the only Food and Drug Administration (FDA)-approved route of administration for statins. However, other administration routes have demonstrated promising results in different pre-clinical and clinical studies. For instance, statins also seem beneficial in dermatitis, psoriasis, vitiligo, hirsutism, uremic pruritus, and graft-versus-host disease. Topically applied statins have been studied to treat seborrhea, acne, rhinophyma, and rosacea. They also have beneficial effects in contact dermatitis and wound healing in animal studies, (HIV) infection, osseointegration, porokeratosis, and some ophthalmologic diseases. Topical and transdermal application of statins is a non-invasive drug administration method that has shown significant results in bypassing the first-pass metabolism in the liver, thereby reducing possible adverse effects. This study reviews the multifaceted molecular and cellular impacts of statins, their topical and transdermal application, novel delivery systems, such as nanosystems for topical and transdermal administration and the challenges concerning this approach.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Administration, Cutaneous; Animals; Administration, Topical
PubMed: 37157198
DOI: 10.2174/0929867330666230508141434 -
Annals of Allergy, Asthma & Immunology... Aug 2023
Topics: Humans; Epinephrine; Anaphylaxis; Injections; Injections, Intramuscular
PubMed: 37530680
DOI: 10.1016/j.anai.2023.06.016 -
Pharmaceutical Medicine Nov 2023Pharmacokinetics (PK) includes how a drug is absorbed, distributed, metabolized and eliminated. The compartment providing this information is usually the plasma. This... (Review)
Review
Pharmacokinetics (PK) includes how a drug is absorbed, distributed, metabolized and eliminated. The compartment providing this information is usually the plasma. This is as close to the tissue of interest that we can get, although biopsies may be obtained to give "tissue levels" of drugs. Ultimately, the goal of PK is to understand how long the drug is actually engaged with the target in the tissue of interest after a dose has been administered. Most drugs at some point in their development will have been administered intravenously (IV), which acts as the standard for 100% bioavailability. By comparing various routes of administration to IV, the percentage of drug delivered to the plasma, on a dose-normalized basis, can be calculated and is referred to as the "absolute bioavailability". As pharmacology has advanced and more drugs have become available, many older products have been reformulated to be given by routes other than those originally intended (often oral). As the drawbacks of oral (or IV) administration have become better appreciated, non-oral, non-IV formulations and methods of administration have become more popular. Nasal administration is one route that has historically been overlooked as an alternative to oral administration-particularly for products needing rapid and non-invasive access to the target tissue-mostly via the blood stream. But attention is now focused on nasal administration for direct access to the brain, as that has the potential to bypass the blood-brain-barrier (BBB), which not even IV administration can always achieve. Assessing PK for these drugs targeting the brain may require serial sampling of the cerebrospinal fluid (CSF), making PK assessments of CNS drugs more invasive and complex, but still possible in future product development. However, we are now seeing more drugs reformulated for nasal delivery to gain faster systemic levels than oral administration (especially in patients with known or suspected gastrointestinal dysmotility), while avoiding the use of needles. For example, in recent years several different formulations and delivery methods for an old drug, dihydroergotamine (DHE), have been developed and these show very different characteristics, suggesting that delivery to different parts of the nose may have very different PK profiles. This review summarizes the systemic PK of different nasal DHE options that have been, or are being, developed and suggests that delivery of drugs to the upper nasal space (UNS) may represent an optimal target. Further research is required to ascertain if this route could also be utilized for direct administration to the CNS (as an attractive alternative to intrathecal delivery) via the olfactory or trigeminal nerves-but already preclinical data (and some human data) suggest this is entirely possible.
Topics: Humans; Pharmaceutical Preparations; Administration, Intranasal; Brain; Blood-Brain Barrier; Central Nervous System Agents
PubMed: 37537422
DOI: 10.1007/s40290-023-00495-7