Non-invasive Route Of Administration Research Articles

Development of a dry powder formulation for pulmonary delivery of azithromycin-loaded nanoparticles.

The COVID-19 pandemic has raised concern regarding respiratory system diseases and oral inhalation stands out as an attractive non-invasive route of administration for pulmonary diseases such as chronic bronchitis, cystic fibrosis, COVID-19 and community-acquired pneumonia. In this context, we encapsulated azithromycin in polycaprolactone nanoparticles functionalized with phospholipids rich in dipalmitoylphosphatidylcholine and further produced a fine powder formulation by spray drying with monohydrated lactose. Nanoparticles obtained by the emulsion/solvent diffusion-evaporation technique exhibited a mean hydrodynamic diameter around 195-228nm with a narrow monomodal size distribution (PdI < 0.2). Nanoparticle dispersions were spray-dried at different inlet temperatures, atomizing air-flow, aspirator air flow, and feed rate, using lactose as a drying aid, resulting in a maximal process yield of 63% and an encapsulation efficiency of 83%. Excipients and the dry powder formulations were characterized in terms of morphology, chemical structure, thermal analyses and particle size by SEM, FTIR, DSC/TGA and laser light diffraction. The results indicated spherical particles with 90% at 4.06µm or below, an adequate size for pulmonary delivery. Aerosolization performance in a NGI confirmed good aerodynamic properties. Microbiological assays showed that the formulation preserves AZM antimicrobial effect against Staphylococcus aureus and Streptococcus pneumoniae strains, with halos above 18mm. In addition, no formulation-related cytotoxicity was observed against the human cell lines BEAS-2B (lung epithelial), HUVEC (endothelial) and HFF1 (fibroblasts). Overall, the approach described here allows the production of AZM-PCL nanoparticles incorporated into inhalable microparticles, enabling more efficient pulmonary therapy of lung infections.

Transport of Non-Steroidal Anti-Inflammatory Drugs across an Oral Mucosa Epithelium In Vitro Model.

Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most prescribed drugs to treat pain or fever. However, oral administration of NSAIDs is frequently associated with adverse effects due to their inhibitory effect on the constitutively expressed cyclooxygenase enzyme 1 (COX-1) in, for instance, the gastrointestinal tract. A systemic delivery, such as a buccal delivery, of NSAIDs would be beneficial and additionally has the advantage of a non-invasive administration route, especially favourable for children or the elderly. To investigate the transport of NSAIDs across the buccal mucosa and determine their potential for buccal therapeutic usage, celecoxib, diclofenac, ibuprofen and piroxicam were tested using an established oral mucosa Transwell® model based on human cell line TR146. Carboxyfluorescein and diazepam were applied as internal paracellular and transcellular marker molecule, respectively. Calculated permeability coefficients revealed a transport ranking of ibuprofen > piroxicam > diclofenac > celecoxib. Transporter protein inhibitor verapamil increased the permeability for ibuprofen, piroxicam and celecoxib, whereas probenecid increased the permeability for all tested NSAIDs. Furthermore, influence of local inflammation of the buccal mucosa on the transport of NSAIDs was mimicked by treating cells with a cytokine mixture of TNF-α, IL-1ß and IFN-γ followed by transport studies with ibuprofen (+ probenecid). Cellular response to pro-inflammatory stimuli was confirmed by upregulation of cytokine targets at the mRNA level, increased secreted cytokine levels and a significant decrease in the paracellular barrier. Permeability of ibuprofen was increased across cell layers treated with cytokines, while addition of probenecid increased permeability of ibuprofen in controls, but not across cell layers treated with cytokines. In summary, the suitability of the in vitro oral mucosa model to measure NSAID transport rankings was demonstrated, and the involvement of transporter proteins was confirmed; an inflammation model was established, and increased NSAID transport upon inflammation was measured.

DEVELOPMENT OF NASAL PHARMACEUTICAL PRODUCTS FOR SYSTEMIC EXPOSURE: USE OF PERMEATION ENHANCERS TO ACHIEVE TARGET PRODUCT PROFILE

In recent years, special attention has been paid to non-invasive parenteral routes of administration, which are an alternative to injectable drugs, as well as other dosage forms whose effectiveness and safety may be compromised by the administration route. At the same time, there is a paradigm shift in relation to nasal dosage forms: they are no longer considered as primarily drugs exhibiting local effects, and an increasing number of nasal medici-nal products with systemic action are appearing on the market. There is a growing interest to the nasal delivery due to the possibility of maximizing the therapeutic potential of active substances that have proven themselves in clinical practice, for example, by quick targeted action to the site of the pathological process, increased bioavailability of the drug and reduced possible side effects. The nasal cavity as a site for systemic drug absorption has anatomical and physiological features that include a relatively large surface area, a porous endothelial basement membrane, a highly vascularized epithelial layer, high total blood flow, lack of first-pass metabolism, and easy access. Therefore, the development of a convenient (nasal) dosage form of the drug with a rapid onset of action is a promising approach. When developing a new pharmaceutical product, the factors that determine bioavaila-bility should be taken into account and addressed by appropriate formulation and delivery techniques: the use of mucoadhesive components or sub-stances that modulate mucociliary clearance, variation of the viscosity or osmolarity, or selection of an appropriate dosing device. Improving intrana-sal absorption is a promising direction for obtaining drugs with improved consumer properties. In addition to the functional properties of the formula-tions, safety aspects must also be taken into account. The article provides an analysis of the limiting factors for nasal preparations, strategies for in-creasing bioavailability, permeation enhancement mechanisms, and provides examples of the application of permeation enhancers used in developed and commercially available drugs. This review gives an idea on possible to use in nasal formulations permeation enhancers which have different mode of actions.

Non-invasive peptides delivery using chitosan nanoparticles assembled via scalable microfluidic technology

The delivery of peptides via non-invasive administration routes remains a challenge to be addressed. In this regard, chitosan nanoparticles (CS NPs) have shown promise. However, their current batch preparation methods (ionotropic gelation, polyelectrolyte complexing, emulsification solvent diffusion or micro emulsification) have proven difficult to scale up. Here, we established a microfluidic-assisted ionotropic gelation method for the manufacturing of CS NPs, ionically crosslinked with sodium tripolyphosphate (TPP), and loaded with a model peptide, Argireline. The microfluidic process was optimized through a design of experiments approach. CS concentration and pH have the greatest effect on particle size, while CS and TPP concentrations and pH on PDI. The optimum formulation was successfully loaded with the peptide (90 % EE) and characterized by a size of 186.0 ± 1.0 nm and a PDI of 0.440 ± 0.002. Subsequently, Argireline-loaded CS-TPP NPs suspension was converted into a gel for a potential topical application, considering the non-toxic, biocompatible, and biodegradable properties of the components used in the formulation. The NPs gel demonstrated appropriate mechanical properties for Argireline transdermal delivery, along with improved control over its release and enhanced skin permeation for up to 48 h, compared to NPs suspension and free drug solution. Hence, this study demonstrated that the microfluidic-assisted ionotropic gelation method could be an easy-scalable platform for the manufacturing of peptide-loaded CS-TPP NPs which could be potentially applied for the transdermal delivery of biologics.

Buccal Patch: A New Avenue for Better Patient Compliance in Management of Diabetes Mellitus

Diabetes is a persistent metabolic condition that affects many individuals globally. To manage diabetes, patients need totake medication regularly, and the buccal patch has become a promising drug delivery option for this purpose. This review articlehighlights the potential of buccal patches as a novel approach to enhance patient compliance in treating diabetes mellitus. Byexploring the advantages of buccal patches as a non-invasive drug delivery system, this article emphasizes their potential to improvemedication adherence, thereby contributing to better management of diabetes mellitus. This article aims to evaluate the role ofbuccal patches in improving patient compliance in the treatment of diabetes mellitus. With the increasing global burden of diabetes,ensuring patient adherence to medication regimens is crucial for achieving optimal therapeutic outcomes. Traditional treatmentmethods often require frequent injections or oral administrations, which may lead to poor compliance due to various factors suchas fear of injections, inconvenience, or forgetfulness. Reviewing the literature on buccal patches as an alternative drug deliverysystem, this article explores their advantages in enhancing patient compliance. Buccal patches adhere to the inner lining of thecheek, providing a convenient and non-invasive route of drug administration. This approach eliminates the need for injections andreduces the frequency of oral medication intake, improving patient acceptance and adherence to treatment regimens. Furthermore,this article highlights the potential of buccal patches in delivering medications directly into the systemic circulation through thehighly vascularized oral mucosa. By bypassing first-pass metabolism in the liver, buccal patches can achieve higher drugconcentrations and improve therapeutic effects. Presenting the benefits of buccal patches for diabetes treatment encourages furtherresearch and development. So, the conclusion of this article is to promote awareness among healthcare professionals and patientsabout the potential of buccal patches as a patient-friendly approach to enhance compliance in the management of diabetes mellitus.

OR17-06 Clinical And Mechanistic Insight For The Therapeutic Potential Of Intranasal Kisspeptin Administration To Treat Reproductive Disorders In Humans

Abstract Disclosure: E.G. Mills: None. M. Swedrowska: None. V. Delli: None. K. Chachlaki: None. M. Silva: None. L. Decoster: None. G. Ternier: None. L. Thurston: None. M. Phylactou: None. B. Patel: None. L. Yang: None. S.A. Clarke: None. B. Muzi: None. E.C. Alexander: None. M. Choudhury: None. P. Bech: None. A. Abbara: None. B. Forbes: None. P. Giacobini: None. V. Prevot: None. A.N. Comninos: None. W.S. Dhillo: None. Background: Kisspeptin is a key regulator of hypothalamic GnRH neurons with emerging potential to treat reproductive, psychosexual and bone disorders. However, current therapeutic application is limited to the subcutaneous or intravenous routes, which presents significant barriers to further development. Alternative delivery routes could overcome this and capitalise on the clinical utility of kisspeptin-based therapeutics. Herein, we comprehensively examine the translational potential of intranasal kisspeptin administration for the first time using a series of human, rodent and pharmaceutical studies. Methods:Human studies: Healthy men (n=12) and a patient group of women with Hypothalamic Amenorrhoea (HA) (n=5) completed a randomised, double-blind, crossover, placebo-controlled study investigating the acute effects of intranasal kisspeptin-54 administration (doses 3.2-25.6nmol/kg [healthy men] and 12.8nmol/kg [women with HA] vs 0.9% saline placebo). Plasma kisspeptin and serum reproductive hormones were measured every 15mins for 4hrs. Thereafter, we conducted rodent studies in adult C57BL/6J male mice to elucidate the possible mechanism by which intranasal kisspeptin induces reproductive hormone release, using intranasal administration of fluorescently-tagged kisspeptin-54 and a series of c-Fos experiments. From a medicines development perspective, we undertook pharmaceutical studies to evaluate the chemical stability of kisspeptin-54 in solution for nasal delivery in real-time. Results:Human studies: in healthy men, intranasal kisspeptin dose-dependently increased plasma kisspeptin at doses 6.4-25.6nmol/kg (p&amp;lt;0.01 for all doses vs placebo), with the maximal rises achieved within 15-30 minutes. Correspondingly, intranasal kisspeptin acutely and potently increased serum LH at doses 6.4-25.6nmol/kg (p&amp;lt;0.01 all doses vs placebo) with maximal rises at 30 minutes. Likewise, in women with HA, intranasal kisspeptin acutely increased plasma kisspeptin (p=0.004 vs placebo) and serum LH (p=0.004 vs placebo). Animal studies: To provide mechanistic insight, we demonstrate in male mice that GnRH neurons located in the olfactory bulb express kisspeptin receptors and that intranasal administration of fluorescently-tagged kisspeptin-54 binds to the olfactory epithelium. Pharmaceutical studies: Kisspeptin-54 in 0.9% saline remained within pharmaceutically accepted limits for stability for up to 60 days at 4°C demonstrating realistic pharmaceutical potential. Conclusion: We identify robust clinical effects and provide mechanistic and pharmaceutical data for intranasal delivery as a novel, non-invasive, safe and effective kisspeptin administration route for the management of common reproductive disorders that would be far preferable to patients and clinicians and so transform the ongoing rapid development of kisspeptin-based therapeutics. Presentation: Saturday, June 17, 2023

The promise of RNA-based therapeutics in revolutionizing heart failure management - a narrative review of current evidence.

This review elucidates the potential of RNA-based therapeutics to revolutionize heart failure (HF) management. Through a comprehensive analysis of relevant studies, this review reveals the promising prospects of these novel interventions in personalized treatment strategies, targeted modulation of specific molecular pathways, and the attainment of synergistic effects via combination therapies. Moreover, the regenerative capacity of RNA-based therapeutics for cardiac repair and the inherent advantages associated with noninvasive routes of administration are explored. Additionally, the studies accentuate the significance of diligent monitoring of disease progression and treatment response, ensuring safety and considering long-term outcomes. While ongoing research endeavours and technological advancements persist in addressing extant challenges and limitations, the transformative potential of RNA-based therapeutics in HF management offers a beacon of hope for enhanced patient outcomes.

In vivo intranasal delivery of coagulation factor IX: a proof-of-concept study

BackgroundHemophilia B (HB) is a bleeding disorder characterized by coagulation factor (F) IX (FIX) deficiency. The current standard-of-care for severe HB is prophylaxis with long-term repetitive intravenous (i.v.) infusions of recombinant FIX (rFIX) with standard half-life or extended half-life. Unmet needs remain regarding the development of non-invasive administration routes for coagulation factors. The aim of this study was to evaluate the effectiveness of intranasal delivery (IND) of rFIX and rFIX fused to Fc fragment (rFIX-Fc) in mice. MethodsDrops of rFIX and rFIX-Fc were deposited in the nostrils of wild-type, FcRn knock-out, FcRn humanized, and FIX knock-out mice. rFIX mucosal uptake was evaluated by measuring plasma FIX antigen and FIX activity (FIX:C) levels, and by performing histologic analysis of the nasal mucosa following IND. ResultsAfter IND, both rFIX and rFIX-Fc were equally delivered to the blood compartment, irrespective of the mouse strain studied, mostly through a passive mechanism of transportation across the mucosal barrier, independent of FcRn receptor. Both plasma FIX antigen and FIX:C activity levels increased following IND in FIX knock-out mice. ConclusionThis proof-of-concept study describes evidence supporting the nasal route as an alternative to FIX i.v. infusion for the treatment of HB.

An Integrated Approach to The Rehabilitation of Infants with Sepsis.

The results of a comparative study of two groups of children with sepsis who received combined rehabilitation therapy during the rehabilitation period, including correction of the intestinal biocenosis, neurometabolic therapy, and immunotherapy with Viferon, and children who received only the immunomodulator T-activin, showed that an integrated approach to rehabilitation was much more effective. In addition, a relatively rapid immunological effect, good tolerability of viferon, a non-invasive route of administration, and the absence of side effects with the described methods of immunorehabilitation allow us to recommend the use of this drug in infants suffering from sepsis.

Dexmedetomidine Sublingual Film: A New Treatment to Reduce Agitation in Schizophrenia and Bipolar Disorders.

The objective of this study was to review the available literature for dexmedetomidine sublingual film use in the treatment of acute agitation associated with schizophrenia and bipolar disorders. A literature search of PubMed (January 2017-March 2023) and EMBASE (January 2017-March 2023) was performed using the terms: Igalmi, dexmedetomidine, schizophrenia, bipolar disorder, and agitation. Additional information sources include ClinicalTrials.gov, scientific posters, and articles identified through review of references from clinical trials publications. Relevant English-language articles conducted in humans were considered, with a preference for phase 3 clinical trials. Trial analyses and articles discussing pharmacology, pharmacokinetics, efficacy, and safety were also evaluated. Dexmedetomidine sublingual film was evaluated for use in schizophrenia in the SERENITY 1 pivotal trial and for bipolar disorders in the SERENITY 2 pivotal trial. Both studies found treatment of mild to moderate agitation with dexmedetomidine sublingual film 180 and 120 μg to be superior to placebo in reducing the severity of agitation. Treatment effect was seen as early as 20 minutes. Somnolence was the most common adverse effect in both studies. Cardiovascular adverse effects were mild and transient in most cases. Dexmedetomidine sublingual film is a new and novel treatment for agitation and gives clinicians an alternative to antipsychotic and benzodiazepine use. It has advantageous properties including its noninvasive route of administration, fast absorption, and rapid onset of effect. Cost may limit its use. Dexmedetomidine sublingual film provides an alternative approach to treatment of acute agitation in adults with schizophrenia and bipolar disorders based on both mechanism of action and route of administration.

Abstract 4154: mRNA-based immunotherapies to treat women's cancers

Abstract With its ability to potentially code for any given protein, peptide and fragments, synthetic mRNA has landed itself a broad range of cancer immunotherapy applications, including costimulatory receptors, therapeutic antibodies, vaccines, and cytokines able to change the tumor microenvironment.We have been able to leverage our mRNA platform to generate a vaccine for HPV-associated cervical cancer (CC), as well as an immune-stimulatory cytokine for triple negative breast cancer (TNBC), both diseases that disproportionately affects minorities who do not participate in routine medical screenings and contribute to disparity in mortality beyond individual risk factors.IL-12 is a potent pro-inflammatory type 1 cytokine with potential to enter the clinical practice as immunotherapy for cancer. Its use in the form of recombinant protein and/or DNA plasmid has been hampered by issues with systemic toxicity or protein bioavailability within the tumor. To overcome these roadblocks, we developed a novel secreted single chain IL-12p70 mRNA. Intra-tumoral dosing of this mRNA induced tumor regression in a syngeneic and orthotopic mouse model of TNBC. Almost all cervical cancers are HPV (human papilloma virus) associated. We have developed a therapeutic vaccine, based on a single mRNA coding for two de-risked antigens, that is able to induce a T cell response against the oncogenic proteins E6 and E7 of the most common serotype (HPV16). When injected intramuscularly in mice bearing C3.43 masses, this vaccine suppressed tumor growth and generated immunological memory.Currently, these women’s cancers do not have a cure or an effective standard of care. With an efficacy that relies on a few injections and non-invasive routes of administration, we believe our innovative RNA-based pharmaceuticals might close some treatment gaps. Citation Format: Dan Tse. mRNA-based immunotherapies to treat women's cancers. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4154.

SNAC for Enhanced Oral Bioavailability: An Updated Review.

The delivery of proteins and peptides via an oral route poses numerous challenges to improve the oral bioavailability and patient compliance. To overcome these challenges, as well as to improve the permeation of proteins and peptides via intestinal mucosa, several chemicals have been studied such as surfactants, fatty acids, bile salts, pH modifiers, and chelating agents, amongst these medium chain fatty acid like C10 (sodium caprate) and Sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC) and its derivatives that have been well studied from a clinical perspective. This current review enumerates the challenges involved in protein and peptide delivery via the oral route, i.e., non-invasive routes of protein and peptide administration. This review also covers the chemistry behind SNAC and toxicity as well as mechanisms to enhance the oral delivery of clinically proven molecules like simaglutide and other small molecules under clinical development, as well as other permeation enhancers for efficient delivery of proteins and peptides.

Implication of Echinochrome A in the Plasticity and Damage of Intestinal Epithelium.

The diverse therapeutic feasibility of the sea urchin-derived naphthoquinone pigment, Echinochrome A (Ech A), has been studied. Simple and noninvasive administration routes should be explored, to obtain the feasibility. Although the therapeutic potential has been proven through several preclinical studies, the biosafety of orally administered Ech A and its direct influence on intestinal cells have not been evaluated. To estimate the bioavailability of Ech A as an oral administration drug, small intestinal and colonic epithelial organoids were developed from mice and humans. The morphology and cellular composition of intestinal organoids were evaluated after Ech A treatment. Ech A treatment significantly increased the expression of LGR5 (~2.38-fold change, p = 0.009) and MUC2 (~1.85-fold change, p = 0.08). Notably, in the presence of oxidative stress, Ech A attenuated oxidative stress up to 1.8-fold (p = 0.04), with a restored gene expression of LGR5 (~4.11-fold change, p = 0.0004), as well as an increased expression of Ly6a (~3.51-fold change, p = 0.005) and CLU (~2.5-fold change, p = 0.01), markers of revival stem cells. In conclusion, Ech A is harmless to intestinal tissues; rather, it promotes the maintenance and regeneration of the intestinal epithelium, suggesting possible beneficial effects on the intestine when used as an oral medication.

RF34 | PMON222 Reproductive Hormone Secretion is Increased by Intranasal Kisspeptin in Humans

Abstract Background Kisspeptin is a critical activator of hypothalamic gonadotrophin releasing hormone (GnRH) neurons and has significant potential to treat common reproductive disorders. To date, kisspeptin has solely been administered to humans via the intravenous or subcutaneous routes, however intranasal administration could offer a novel non-invasive delivery route, which is preferred by patients. We therefore sought to determine the effects of intranasal kisspeptin on reproductive hormone release in humans for the first time. Methods Randomised, double-blinded, placebo-controlled, cross-over study in 12 healthy men (mean±SEM age 28.3±1.7 yrs; BMI 24.5±0.7 kg/m2). After monitored self-administration of intranasal kisspeptin-54 (3.2, 6.4, 12.8 and 25.6 nmol/kg) or 0.9% saline, serum reproductive hormone levels were measured every 15 minutes for four hours. Subsequently, four women (mean age 29.8±3.7 yrs; BMI 21.2±1.1 kg/m2) with hypothalamic amenorrhoea (HA) attended for the same protocol comparing intranasal kisspeptin-54 (12.8 nmol/kg) and 0.9% saline. Mean ±SEM was presented unless otherwise stated. Time profiles of hormone levels during the four-hour study were compared using two-way ANOVA with Bonferroni's multiple comparison test. Multiple means were compared using one-way ANOVA with Bonferroni's multiple comparison test. Results In healthy men, intranasal kisspeptin dose-dependently increased mean luteinising hormone (LH) levels at doses between 3.2-12.8 nmol/kg (p=0.008 and &amp;lt;0.0001 for 6.4 and 12.8 nmol/kg vs saline, respectively), with the maximal rises occurring at 30-45 minutes post-administration. Correspondingly, the area under the curve (AUC) for the LH change was significantly elevated following all doses of kisspeptin compared to saline (saline: -25.4±70.5 h.IU/L; 3.2 nmol/kg: 172.2±64.2 h.IU/L [p=0.03]; 6.4 nmol/kg: 300.2±79.2 h.IU/L [p=0.002]; 12.8 nmol/kg: 595.7±98.3 h.IU/L [p=0.001]; 25.6 nmol/kg: 549.0±108.6 h.IU/L [p&amp;lt;0.0001]). Follicle stimulating hormone (FSH) levels followed a similar trajectory to LH in response to intranasal kisspeptin. Moreover, kisspeptin at 12.8 nmol/kg increased serum testosterone from 120 minutes onwards (p=0.02), with a maximal change from baseline of 4.9±0.7 nmol/L (p=0.03). In women with HA, intranasal kisspeptin increased mean LH (p=0.002 vs saline), with the peak levels occurring at 30-45 minutes post-administration. The AUC for the LH change was 508.4±77.5 h.IU/L (p=0.02 vs saline AUC for LH). The maximal LH change from baseline was 4.1±0.9 IU/L compared to 0.2±0.4 IU/L for saline (p=0.03). Intranasal kisspeptin increased mean FSH (p=0.01 vs saline). No significant changes in downstream serum oestradiol or progesterone were observed during the acute four-hour study. Conclusion We report the first investigation of the effects of intranasal kisspeptin delivery on reproductive hormone release in humans. Our results demonstrate that intranasal kisspeptin robustly and dose-dependently stimulates reproductive hormone release in healthy men and crucially in a patient-group of women with hypogonadism. Given the ongoing development of kisspeptin therapeutics, intranasal kisspeptin therefore offers a novel, safe, effective and non-invasive route of administration for the management of reproductive disorders. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 12:36 p.m. - 12:41 p.m.

S1566 Evaluation of the Pharmacokinetics of PGN-OB1 Following Oral Administration of an Oral Biotherapeutics Delivery System (OBDS) in Yucatan Swine

Introduction: Biologics/peptides/nucleic acids are highly effective drugs; however, oral delivery of these therapeutics has proved to be difficult due to the harsh conditions of the upper gastrointestinal tract (GIT) and the poor absorption rate in the small intestinal mucosa. We aimed to develop an oral biotherapeutic delivery system (OBDS) that protects these biomolecules from degradation in the upper GIT and increases oral bioavailability via needless injection in the submucosal space of the small intestine. We describe the development of models to assess the functional capability of the OBDS capsule. A Yucatan minipig model was chosen to better represent the pharmacokinetic properties of submucosal injection in humans and evaluate the injection efficiency of OBDS in vivo. Methods: Due to prolonged and variable gastric residence times in the swine model, the semi-autonomous OBDS capsules containing a variant of adalimumab (PGN-001), PGN-OB1, were administrated by intraduodenal endoscopic placement (ID) and released into the proximal small intestines of the female Yucatan swine. Blood samples post-ID dosing were collected to evaluate the injection efficiency of the OBDS compared with the IV control group. Results: All OBDS capsules were successfully advanced through the pyloric sphincter via endoscopic placement, without early deployment, and released in the proximal duodenum to naturally transit and deploy in vivo. Out of 13 animals dosed, 8 animals showed detectable drug levels (Figure), and an oral bioavailability average of 22% or 25% (range from 7-55%) excluding an animal showing a late deployment at 72hr post-dose. The variability in the swine model is believed to be due to physiologic variability that may not directly translate to humans including variability in small intestinal transit time, and more frequent and larger, gas and fluid pockets in the swine. Conclusion: Here we have provided proof-of-concept of a semi-autonomous OBDS device that can achieve as high as 55% bioavailability of a variant of adalimumab that is a magnitude higher than current oral protein or peptide delivery technology in the market and at levels much closer to the subcutaneous route of administration estimated in human trials. The OBDS capsules could potentially provide a better alternative for the non-invasive route of administration with better patient compliance.Figure 1.: Plasma concentration of PGN-001 treated with ID and IV over time

Efficient spatially targeted gene editing using a near-infrared activatable protein-conjugated nanoparticle for brain applications

Spatial control of gene expression is critical to modulate cellular functions and deconstruct the function of individual genes in biological processes. Light-responsive gene-editing formulations have been recently developed; however, they have shown limited applicability in vivo due to poor tissue penetration, limited cellular transfection and the difficulty in evaluating the activity of the edited cells. Here, we report a formulation composed of upconversion nanoparticles conjugated with Cre recombinase enzyme through a photocleavable linker, and a lysosomotropic agent that facilitates endolysosomal escape. This formulation allows in vitro spatial control in gene editing after activation with near-infrared light. We further demonstrate the potential of this formulation in vivo through three different paradigms: (i) gene editing in neurogenic niches, (ii) gene editing in the ventral tegmental area to facilitate monitoring of edited cells by precise optogenetic control of reward and reinforcement, and (iii) gene editing in a localized brain region via a noninvasive administration route (i.e., intranasal).

Carbonic anhydrase inhibitors in the management of macular edema: A review of the literature.

Macular edema (ME) is a vision-threatening condition that commonly develops as a consequence of ocular diseases, including age-related macular degeneration, retinal vaso-occlusion of the central retinal vein and its branches, diabetic retinopathy, central serous chorioretinopathy, uveitis, retinitis pigmentosa, pseudophakia, ocular trauma, and drug toxicity. The treatment of ME remains challenging, although steroids and vascular endothelial growth factor inhibitors are available. Cost-effective therapy using a noninvasive administration route is required. This study aimed at reviewing the role of carbonic anhydrase inhibitors (CAIs) in the management of ME. A literature search was conducted using PubMed/MEDLINE and Google Scholar for studies from January 2000 to March 2022. The following keywords were used in various combinations: "macular edema", "carbonic anhydrase", "carbonic anhydrase inhibitors", "acetazolamide", "dorzolamide", and "brinzolamide". Articles with high or medium clinical relevance were selected for this review. We found that multiple studies have demonstrated the relevance and efficacy rates of CAIs in the management of ME. Most published studies focused on acetazolamide and dorzolamide, with nearly all studies reporting therapeutic responses. ME is the leading cause of vision loss and requires noninvasive and cost-effective pharmacotherapy. With progress in the understanding of ME, particularly the role of carbonic anhydrase as a key driver, CAIs are the focus of research. Further optimization of the choice of CAIs and retinal bioavailability, potentially with nanoparticle formulations, is required to enable the effective management of ME. Further research is warranted to address the therapeutic effects of CAIs in different formulations.

Formulacije bioloških lekova za alternativne puteve administracije - trenutni problemi i perspektive

Introduction: Biologics (biopharmaceuticals) present new promising therapies for many diseases such as cancers, chronical inflammatory diseases and today's biggest challenge - COVID-19. Research: Today, most biologics have been synthetized using modern methods of biotechnology, in particular DNA recombinant technology. Current pharmaceutical forms of protein/peptide biopharmaceuticals are intended for parenteral route of administration due to their instability and large size of molecules. In order to improve patient compliance, many companies are working on developing adequate forms of biopharmaceuticals for alternative, non-invasive routes of administration. The aim of this work is to review current aspirations and problems in formulation of biopharmaceuticals for alternative (non-parenteral) routes of administration and to review the attempts to overcome them. These alternative routes of administration could be promising in prevention and treatment of COVID-19, among other serious diseases. Conclusion: The emphasis is on stabilizing monoclonal antibodies into special formulations and delivery systems; their application should be safer, more comfortable and reliable. When it comes to hormones, vaccines and smaller peptides, some companies have already registered drugs intended for nasal and oral delivery.

Pharmacokinetic Characterisation and Comparison of Bioavailability of Intranasal Fentanyl, Transmucosal, and Intravenous Administration through a Three-Way Crossover Study in 24 Healthy Volunteers.

Background For more than 60 years, the synthetic opioid fentanyl has been widely used in anaesthesia and analgesia. While the intravenous formulation is primarily used for general anaesthesia and intensive care settings, the drug's high lipophilic properties also allow various noninvasive routes of administration. Published data suggest that intranasal administration is also attractive for use as intranasal patient-controlled analgesia (PCA). A newly developed intranasal fentanyl formulation containing 47 μg fentanyl, intravenous fentanyl, and oral transmucosal fentanyl citrate were characterised, and bioavailability was compared to assess the suitability of the intranasal formulation for an intranasal PCA product. Methods 27 healthy volunteers were enrolled in a single-centre, open-label, randomised (order of treatments), single-dose study in a three-period crossover design. The pharmacokinetics of one intranasal puff of fentanyl formulation (47 μg, 140 mL per puff), one short intravenous infusion of 50 μg fentanyl, and one lozenge with an integrated applicator (200 μg fentanyl) were studied, and bioavailability was calculated. Blood samples were collected over 12 hours, and plasma concentrations of fentanyl were determined by HPLC with MS/MS detection. Results 24 volunteers completed the study. The geometric mean of AUC0-tlast was the highest with oral transmucosal administration (1106 h ∗ pg/ml, CV% = 32.86), followed by intravenous (672 h ∗ pg/ml, CV% = 32.18) and intranasal administration (515 h ∗ pg/ml, CV% = 30.10). Cmax was 886 pg/ml (CV% = 59.38) for intravenous, 338 pg/ml (CV% = 45.61) for intranasal, and 310 pg/ml (CV% = 29.58) for oral transmucosal administration. tmax was shortest for intravenous administration (0.06 h, SD = 0.056), followed by intranasal (0.21 h, SD = 0.078) and oral transmucosal administration (1.20 h, SD = 0.763). Dose-adjusted absolute bioavailability was determined to be 74.70% for the intranasal formulation and 41.25% for the oral transmucosal product. In total, 38 adverse events (AEs) occurred. Fourteen AEs were potentially related to the investigational items. No serious AE occurred. Conclusion Pharmacokinetic parameters and bioavailability of the investigated intranasal fentanyl indicated suitability for its intended use as an intranasal PCA option.

Intranasal Administration as a Route to Deliver Drugs to the Brain (Review)

Introduction. Intranasal drug delivery from nose-to-brain is one of the promising approaches for the treatment of brain diseases including neurodegenerative diseases, stroke, brain tumors, etc.Text. Delivery of drugs through the nose has a number of advantages, including the rapid onset of a pharmacological effect, the ability to bypass the blood-brain barrier, avoidance of some side effects and fast and non-invasive route of administration. However, the significant disadvantages of this route are rapid elimination of the drug from the surface of the mucosal membrane, poor penetration of the drug through the nasal mucosa, mucociliary clearance and effects of proteolytic enzymes. Currently, to overcome the above limitations, various approaches are used, including the development of delivery systems from nose-to-brain, which are mucoadhesive, mucus-penetrating and gel-forming systems that facilitate the retention or penetration of drugs through the mucosal membranes. At the same time, high-molecular weight compounds play a significant role in the design of these systems. In particular, mucoadhesive systems can be prepared from cationic and anionic polymers. Recent studies have also shown that interpolyelectrolyte complexes also exhibit mucoadhesive properties. An improvement in mucoadhesive properties of polymers can also be achieved by conjugating various functional groups such as thiols, maleimides, acrylates, methacrylates, catechols, etc. Mucus-penetrating systems can be prepared by PEGylation of nanoparticles, as well as functionalization with some poly(2-oxazolines), polyvinyl alcohol, etc. The mucus-penetrating ability of these polymers has been shown in other mucosal membranes in the body. Finally, increased penetration can be achieved by using mucolytic agents in combination with non-ionic surfactants. Another approach to increase the efficiency of drug delivery from nose-to-brain is the use of in situ gelling systems. Initially, this type of formulation exists as a solution; then a phase transition to gel is observed in response to chemical and physical effects. Depending on the external stimulation of the phase transition, thermo-, pH-, ion-reversible and other systems are known. These systems have shown effectiveness for delivery to the brain by intranasal administration.Conclusion. Effective intranasal delivery of drugs and therapeutic agents to the brain can be achieved by using mucoadhesive, mucus-penetrating, gelling systems and/or their combinations.