Hepatic First-pass Metabolism Research Articles

Enhancing leuprolide penetration through enterocytes via the ER-Golgi pathway using lipophilic complexation.

Oral delivery of peptide drugs remains one of the most formidable challenges in the frontier of pharmaceutical research. Peptide drugs typically suffer from exceptionally low oral bioavailability, primarily attributed to rigorous enzymatic degradation within the gastrointestinal (GI) tract, limited ability to traverse the enterocyte barrier, and significant first-pass hepatic metabolism. Absorption of peptide drugs via the lymphatic route could potentially bypass intracellular lysosome degradation and hepatic first-pass metabolism. In this study, we present a strategy to enhance the lymphatic absorption of the model peptide leuprolide (LEU) by diverting its intracellular trafficking towards the endoplasmic-reticulum (ER)-Golgi pathway. Complexes were formed between LEU and lipophilic excipient and then formulated as an oral emulsion. We observed that the penetration of LEU in the emulsion across the Caco-2 cell monolayer model was diverted from the endosome-lysosome pathway, and LEU entered the bloodstream via the mesenteric lymph nodes (MLNs). The data obtained illustrates that the lipophilic LEU complexes could improve enterocyte permeability and bypass lysosomal degradation, and the change of absorption pathway may reduce hepatic first pass metabolism.

Rizatriptan loaded Bilosomes for Nose to Brain Delivery: Fabrication, Statistical Optimization, and Biological Evaluation

Rizatriptan (RTP) is an anti-migraine drug and after oral administration, it exhibits low bioavailability (45%) due to high first-pass hepatic metabolism. Therefore, to resolve this issue, RTP-loaded bilosomes (BLSs) for brain delivery through the intranasal route were developed. RTP-BLSs were prepared by the thin-film hydration technique and optimized by the L9 Taguchi model. Bile salt (sodium glycocholate, mg), surfactant (Span 40, mg), and edge activator (Cremophor RH 40, mg) were selected as independent factors and their influence was observed on vesicle size (nm) and entrapment efficiency (%). Selected optimized RTP-BLSs (F5) have low vesicle size (204.70 ± 5.8 nm) and polydispersity index (0.260 ± 0.022), good entrapment efficiency (78.32 ± 3.1%), and high zeta potential (-27.6 ± 1.67 mV). The optimized RTP-BLSs exhibited a more sustained released profile (96.41 ± 4.48 % in 24 h) than RTP-Sol (98.65 ± 3.46 % RTP released in 4 h). The flux and apparent permeability coefficient for optimized RTP-BLSs were calculated and found to be 1.069 ± 0.026 μg.cm-2.h1 and 10.690×10-4 ± 0.262×10-4 cm.h-1) and comparatively (P<0.05) better than RTP-Sol (0.548 ± 0.148 μg.cm-2.h-1 and 5.481×10-4 ± 1.476 ×10-4 cm.h-1). The relative bioavailability of RTP formulated within the optimized RTP-BLSs administered intranasally was 2.94 ± 0.78-fold higher than the one obtained with RTP-Sol. The optimized RTP-BLSs showed 1.91 ± 0.15-fold higher absolute bioavailability as compared to intravenous administration RTP-BLSs. The optimized RTP-BLSs showed 64.18 ± 2.34% nose-to-brain drug transport, while RTP-Sol exhibited 20.72 ± 1.46% after intranasal administration. The optimized RTP-BLSs showed a significantly higher brain drug targeting efficiency (279.16 ± 6.37%) as compared to RTP-Sol (126.15 ± 4.79%) given intranasally. From our findings, it can be concluded that the developed BLSs are novel alternative RTP carriers for direct nose-to-brain delivery for the improvement of brain drug targeting.

Bioavailability Enhancement and Formulation Technologies of Oral Mucosal Dosage Forms: A Review

The oral mucosa is a versatile surface for drug administration, supporting both local and systemic therapies. Many active substances are effectively absorbed in the oral cavity, offering an alternative to enteral administration by bypassing the harsh gastrointestinal environment and hepatic first-pass metabolism. This has made oral mucosal drug delivery a growing area of research. Enhancing the bioavailability of active ingredients is a key focus in pharmaceutical technology, especially given the challenges of developing new drugs. Numerous strategies to improve bioavailability are compatible with oral mucosal delivery, with the unique anatomy of the oral cavity enabling specialized applications. A variety of dosage forms tailored for oral mucosal delivery meet therapeutic needs while addressing biopharmaceutical and patient compliance challenges. Proper formulation can achieve controlled release, improved bioavailability, and patient convenience. This review highlights the potential of oral mucosal drug delivery, focusing on bioavailability enhancement methods and the types and production technologies of dosage forms optimized for use in the oral cavity.

Nanosuspension Innovations: Expanding Horizons in Drug Delivery Techniques.

Nanosuspensions (NS), with their submicron particle sizes and unique physicochemical properties, provide a versatile solution for enhancing the administration of medications that are not highly soluble in water or lipids. This review highlights recent advancements, future prospects, and challenges in NS-based drug delivery, particularly for oral, ocular, transdermal, pulmonary, and parenteral routes. The conversion of oral NS into powders, pellets, granules, tablets, and capsules, and their incorporation into film dosage forms to address stability concerns is thoroughly reviewed. This article summarizes key stabilizers, polymers, surfactants, and excipients used in NS formulations, along with ongoing clinical trials and recent patents. Furthermore, a comprehensive analysis of various methods for NS preparation is provided. This article also explores various in vitro and in vivo characterization techniques, as well as scale-down technologies and bottom-up methods for NS preparation. Selected examples of commercial NS drug products are discussed. Rapid advances in the field of NS could resolve issues related to permeability-limited absorption and hepatic first-pass metabolism, offering promise for medications based on proteins and peptides. The evolution of novel stabilizers is essential to overcome the current limitations in NS formulations, enhancing their stability, bioavailability, targeting ability, and safety profile, which ultimately accelerates their clinical application and commercialization.

Advancements in Transdermal Drug Delivery Systems: Harnessing the Potential of Macromolecular Assisted Permeation Enhancement and Novel Techniques.

Transdermal drug delivery (TDD) represents a transformative paradigm in drug administration, offering advantages such as controlled drug release, enhanced patient adherence, and circumvention of hepatic first-pass metabolism. Despite these benefits, the inherent barrier function of the skin, primarily attributed to the stratum corneum, remains a significant impediment to the efficient permeation of therapeutic agents. Recent advancements have focused on macromolecular-assisted permeation enhancers, including carbohydrates, lipids, amino acids, nucleic acids, and cell-penetrating peptides, which modulate skin permeability by transiently altering its structural integrity. Concurrently, innovative methodologies such as iontophoresis, electroporation, microneedles, ultrasound, and sonophoresis have emerged as potent tools to enhance drug transport by creating transient microchannels or altering the skin's microenvironment. Among the novel approaches, the development of nanocarriers such as Liposome, niosomes, and transethosomes etc. has garnered substantial attention. These elastic vesicular systems, comprising lipids and edge activators, exhibit superior skin penetration owing to their deformability and enhanced payload delivery capabilities. Furthermore, the integration of nanocarriers with physical enhancement techniques demonstrates a synergistic potential, effectively addressing the limitations of conventional TDD systems. This comprehensive convergence of macromolecular-assisted enhancers, advanced physical techniques, and next-generation nanocarriers underscores the evolution of TDD, paving the way for optimized therapeutic outcomes.

Angelica gigas Nakai (Korean Dang-gui) Root Alcoholic Extracts in Health Promotion and Disease Therapy – active Phytochemicals and In Vivo Molecular Targets

Angelica gigas Nakai (AGN) root is a medicinal herbal widely used in traditional medicine in Korea. AGN root ethanolic extracts have been marketed as dietary supplements in the United States for memory health and pain management. We have recently reviewed the pharmacokinetics (PK) and first-pass hepatic metabolism of ingested AGN supplements in humans for the signature pyranocoumarins decursin (D, Cmax 1x), decursinol angelate (DA, Cmax ~ 10x) and their common botanical precursor and hepatic metabolite decursinol (DOH, Cmax ~ 1000x). Here we update in vivo medicinal activities of AGN and/or its pyranocoumarins and furanocoumarin nodakenin in cancer, pain, memory loss, cerebral ischemia reperfusion stroke, metabolic syndrome and vascular endothelial dysfunctions, anxiety, sleep disorder, epilepsy, inflammatory bowel disease, osteoporosis and osteoarthritis. Given their polypharmacology nature, the pertinent mechanisms of action are likely misrepresented by many cell culture studies that did not consider the drug metabolism knowledge. We report here Rho-associated protein kinases (ROCK1/2) as novel targets for DA and DOH. Combining with published inhibitory activity of DOH on acetylcholinesterase, agonist activity of DOH and antagonist/degrader activity of DA/D on androgen and estrogen receptors, D/DA promoting activity for glutamic acid decarboxylase (GAD)- gamma-aminobutyric acid (GABA) inhibitory axis and inhibition of glutamate dehydrogenase (GDH), monoamine oxidase-A (MAO-A) and transient receptor potential vanilloid 1 (TRPV1), we postulate their contributions to neuro-cognitive, metabolic, oncologic, vascular and other beneficial bioactivities of AGN extracts. A clinical trial is being planned for an AGN extract to manage side effects of androgen deprivation therapy in prostate cancer patients.

Review on Buccal Drug Delivery Systems

Buccal drug delivery systems represent a promising frontier in pharmaceutical technology, offering a non-invasive route for drug administration that bypasses the gastrointestinal tract and hepatic first-pass metabolism. This method leverages the buccal mucosa’s rich vascularization and permeability to enhance drug bioavailability. Recent advancements have focused on developing mucoadhesive films, tablets, and patches that ensure prolonged contact with the mucosal surface, improving drug absorption and patient compliance. Future innovations are expected to incorporate nanotechnology and bioadhesive polymers to further optimize drug release profiles and therapeutic efficacy. Additionally, the integration of smart drug delivery systems, capable of responding to physiological conditions, holds significant potential for personalized medicine. As research progresses, buccal drug delivery systems are poised to become a cornerstone in the administration of biologics and other complex therapeutics, addressing challenges such as enzymatic degradation and poor solubility.

Advanced transdermal drug delivery system: A comprehensive review of microneedle technologies, novel designs, diverse applications, and critical challenges.

Transdermal drug delivery presents numerous advantages over conventional administration routes, including non-invasiveness, enhanced patient adherence, circumvention of hepatic first-pass metabolism, self-administration capabilities, controlled release, and increased bioavailability. Nevertheless, the barrier function of stratum corneum limits this strategy to molecules possessing requisite physicochemical attributes. To expand the field of transdermal delivery, researchers have pioneered physical enhancement techniques, with micron-sized needles emerging as a particularly promising platform for the transdermal and intradermal delivery of therapeutic agents across a spectrum of molecular sizes. Microneedles function by disrupting the skin's integrity, generating microchannels that facilitate efficient drug permeation. This innovative technology boasts a captivating profile characterized by non-invasive drug delivery, enhanced efficacy and onset time, improved patient acceptability, self-administration possibilities, and precise dosing capabilities. Consequently, both academic institutions and industry have invested substantial resources in the development of microneedle systems for pharmaceutical delivery. This comprehensive review elucidates the multifaceted aspects of microneedle technology, encompassing its historical evolution, diverse materials, innovative designs, fabrication methodologies, and characterization techniques. The review extends to various microneedle types, including solid, hollow, coated, dissolving, swelling, and porous microneedles, as well as cutting-edge designs such as stimulus-responsive, iontophoresis-assisted, and bionic microneedles. Furthermore, we explore microneedle applications in vaccination, targeted delivery, and the administration of biologics, long-acting therapeutic agents, and cosmetics. Critical challenges in microneedle development, including dimensional considerations, safety concerns, acceptability factors, production scalability, regulatory hurdles, and sustainability issues, are thoroughly addressed, alongside a presentation of future prospects in this rapidly evolving field.

Exploring peptide dendrimers for intestinal lymphatic targeting: formulation and evaluation of peptide dendrimer conjugated liposomes for enhancing the oral bioavailability of Asenapine maleate

Asenapine maleate (ASPM) is a second-generation atypical antipsychotic that is approved for treating acute schizophrenia and bipolar disorder in adults by the US FDA. The major downside of ASPM therapy is rapid, extensive first-pass hepatic metabolism following its oral administration with a very low oral bioavailability of < 2%. In this work, we developed ASPM nanoformulations conjugated with ligands such as arginine-glycine-aspartic acid (RGD) and peptide dendrimers (PDs) with the intention of improving the oral bioavailability of the drug by targeting it to the intestinal lymphatic system (ILS). Peptide dendrimers (PDs), both lipidated and nonlipidated, were synthesized by Fmoc solid phase peptide synthesis (SPPS). Reverse phase high performance chromatography (RP-HPLC) was used to purify the synthesized PDs, and the PDs were characterized by differential scanning calorimetry (DSC) electrospray ionization mass spectroscopy (ESI+-MS), Nuclear magnetic resonance (NMR) and Fourier transform infrared (FTIR) spectroscopy. The thin film hydration method was used to prepare liposomes, and the process variables affecting the liposome parameters were optimized using the Box‒Behnken design (BBD).Liposomes were PEGylated using DSPE-PEG-COOH2000 and further conjugated with ligands (RGD, PD-1 and PD-2) using EDC-NHS chemistry. The formulation was characterized using different spectroscopic techniques. In vitro, cell line studies, such as cytotoxicity, cell uptake, uptake mechanism, and receptor saturation studies, were performed on both Caco2 and Raji-B cells. The pharmacokinetic parameters of the developed liposomal formulation were evaluated using pharmacokinetic studies on Sprague- Dawley (SD) rats. The psychostimulant-induced hyperactivity model was used to evaluate the pharmacodynamic performance of the developed formulations by measuring the reversal of hyperlocomotor activity induced by levodopa-carbidopa.

Advances in Transdermal Drug Delivery: The Development of Microneedle Technology for Improved Therapeutic Outcomes

Transdermal Drug Delivery Systems (TDDS) represent a significant advancement in therapeutic administration by allowing drugs to bypass the gastrointestinal system and first-pass hepatic metabolism, enhancing patient compliance, and enabling sustained drug release. However, traditional TDDS face limitations, including resistance from the skin's natural barrier and limited efficacy in delivering large or hydrophilic molecules. Microneedle (MN) technology offers a breakthrough solution, using minimally invasive micron-sized needles to bypass the stratum corneum, facilitating efficient drug delivery without significant pain or discomfort. This review explores the evolution and recent advancements in microneedle technology, highlighting its role in overcoming the limitations of conventional TDDS. Microneedles have been shown to enhance drug bioavailability, reduce side effects, and expand the range of deliverable therapeutics, including vaccines, insulin, and genetic materials. The development of bioinspired 4D microneedles further extends their application to diagnostics and cosmetic treatments, positioning MNs as a versatile tool in modern medicine. Key sections of the review focus on the types of microneedles—solid, coated, dissolving, hollow, and hydrogel-forming—and their respective fabrication methods, materials, and drug delivery mechanisms. The review also discusses the challenges related to scaling up production, ensuring consistent quality, and regulatory hurdles in achieving clinical approval. Future directions include the integration of microneedles with nanotechnology, combination therapies, and sustainable design, particularly in developing regions where biodegradable materials may address environmental and disposal concerns. The potential for microneedle technology to revolutionize transdermal drug delivery, diagnostics, and therapeutic monitoring is significant, with ongoing research paving the way for multifunctional applications that can reshape patient care and treatment modalities.

Microneedle: Shaping the Future of Research with Novel Solutions

Background: The application of microfabrication to produce arrays of microscale needles, known as microneedle technology, has greatly improved transdermal drug delivery. This analysis focuses on different types and advances of microneedles to emphasize their tremendous potential in healthcare. Transdermal medication delivery is a common method used in modern medicine to treat a variety of illnesses. By avoiding the hepatic first-pass metabolism, the use of microneedles improves medication penetration via the skin and increases bioavailability. Method: Using databases like PubMed and Google Scholar, a thorough literature study was carried out to look at the most recent peer-reviewed papers and patents on microneedle technology. Based on factors like size, shape, material, and drug delivery techniques, comparative analysis assessed the safety and effectiveness of several microneedles. Skin physiology was examined to comprehend how permeability enhancers and microneedles affect medication penetration. Results: Microneedle technology has made significant strides that show it can completely transform medication delivery systems. A large number of patents suggests that research and development are expanding quickly. The market for microneedles is reflecting the increased need for less intrusive medical treatments, highlighting the significance of this method in medical research. Conclusion: Medical science could be revolutionized by microneedles, especially in the area of drug administration. Researchers and physicians can benefit greatly from this review, which guides the investigation of sophisticated microneedle applications for transdermal treatment of acute or chronic illnesses. Future Recommendation: Subsequent investigations ought to focus on refining microneedle designs for particular uses, enhancing the biocompatibility of materials, and investigating integration with alternative drug delivery methods. To confirm the safety and effectiveness of microneedle technology in practical medical settings, clinical trials are required.

To Explore Nasal-Brain Lymphatic System for Brain-Targeted Drug Delivery and to Treat Neurodegenerative Diseases.

Brain-related Neurodegenerative Disorders (NDD) are the leading cause of low life expectancy globally. Brain-targeted drug delivery is required for treating most the NDD via bypassing the blood-brain barrier, and hepatic first-pass metabolism. The nasal-brain drug delivery route has the advantage of locally enhancing drug delivery to the brain, mainly through the olfactory route rather than systemic circulation. To overcome the limitations of nasal-brain drug delivery, a nanocarrier approach and mucoadhesive polymers are needed. Notwithstanding these constraints, various nanotechnology techniques have been created, including polymeric micelles, liposomes, polymeric nanoparticles, solid lipid nanoparticles, & nano-emulsions. This review aims to explore the intranasal pathway for drug delivery through the nasal-brain lymphatic systems, considering brain anatomy and physiology along with a drug formulation design approach.

Transdermal Drug Delivery Systems: Different Generations and Dermatokinetic Assessment of Drug Concentration in Skin.

Transdermal drug delivery systems (TDDS) are a highly appealing and innovative method of administering drugs through the skin, as it enables the drugs to achieve systemic effects. A TDDS offers patient convenience, avoids first-pass hepatic metabolism, enables local targeting, and reduces the toxic effect of drug. This review details several generations of TDDS and the advancements made in their development to address the constraints associated with skin delivery systems. Transdermal delivery methods of the first generation have been consistently growing in their clinical application for administering small, lipophilic, low-dose drugs. Second-generation TDDS, utilizing chemical enhancers and iontophoresis, have led to the development of clinical products. Third-generation delivery systems employ microneedles, thermal ablation, and electroporation to specifically target the stratum corneum, which is the skin's barrier layer. Dermatokinetics is the study of the movement of drugs and formulations applied to the skin over a period of time. It provides important information regarding the rate and extent to which drugs penetrate skin layers. Several dermatokinetic techniques, including tape stripping, microdialysis, and laser scanning microscopy, have been used to study the intricate barrier properties and clearance mechanisms of the skin. This understanding is essential for developing and improving effective TDDS.

9224 Evaluation of Safety and Efficacy of Administration of Estradiol by Subcutaneous Injection in Transgender Women

Abstract Disclosure: H. Perkins: None. H. Moreau: None. J. LaBudde: None. W. Craig: None. D.I. Spratt: None. Background: Off-label use of subcutaneous (SC) estradiol (E2) by transgender women for gender-affirming hormone therapy is becoming increasingly widespread, despite a lack of published data regarding its efficacy and safety. Methods: This retrospective cohort study used manual data extraction from electronic medical records for patients ages 18-79 years, currently or previously receiving oral (PO) 17-beta E2 or SC E2 valerate therapy at Maine Medical Center Reproductive Endocrinology and Infertility and Gender Clinics between 5/30/14-5/30/23, who completed E2 dose adjustments aimed at obtaining a serum E2 of 75-250 pg/mL. SC E2 was administered weekly and PO E2 daily. Serum testosterone (T), estrone (E1), and sex hormone binding globulin (SHBG) levels were recorded if drawn within 90 days of E2 measurement on an optimized dose. In a subset of patients receiving SC E2, serum E2 levels were drawn 1-2 days post- and pre-injection. All patient-reported local or systemic reactions were recorded. Data are expressed as median (full range) or mean ± standard deviation (full range). Results: 45 patients were included with no significant differences in demographics between PO (n=20) and SC (n=25) groups. Both groups achieved therapeutic E2 levels after dose adjustment without statistical difference in mean serum E2 (pg/mL) between SC and PO groups: 148.7 ± 41.0 (78-226) vs. 151.6 ± 31.7 (97-208); p=0.79 by t-test. In patients without orchiectomy, both SC and PO groups had T (ng/dL) suppressed to normal adult female range (10-55) in 11/12 SC patients and in 17/17 PO patients; median T was 14.0 (7.7-86) for SC vs. 20.6 (3.4-42) for PO; p=0.98 by Mann-Whitney U test. Median E2 dose (mg/week) in the SC group was 3.0 (1.4-6.0) and in the PO group was 42.0 (28-84). Median serum E1 (pg/mL) was lower in the SC group than the PO group: 73.5 (29-115), n=12 vs. 907 (596-1601), n=5, p&amp;lt;0.001 by Mann-Whitney U test. E1/E2 ratio was lower in the SC group than the PO group: 0.4 ± 0.1 vs. 8.0 ± 2.9; p&amp;lt;0.001 by t-test. There was no significant difference in median serum SHBG (nmol/L) between SC and PO groups: 71.7 (19.3-146.7), n=15 vs. 73.4 (51.0-187.4), n=14; p=0.20 by Mann-Whitney U test. Mean post- and pre-dose serum E2 levels in 5 patients were 138.0 ± 24.0 and 88.0 ± 57.6, respectively. There was one transient local reaction and no systemic allergic or inflammatory reactions in the SC group with no systemic reactions in the PO group. Conclusion: These results demonstrate that SC E2 at doses of 1.4-6 mg/week can be administered safely to achieve therapeutic serum E2 levels and suppress serum T levels to within the normal female range. Our preliminary data reveal lower serum E1 levels in the SC group than in the PO group suggesting reduced hepatic first-pass metabolism with SC administration; this pattern was not seen with serum SHBG levels. Post- and pre-dose serum E2 levels revealed only a mild decline in E2 levels between injections. Presentation: 6/3/2024

6961 Evaluation of Safety and Efficacy of Administration of Estradiol by Subcutaneous Injection in Transgender Women

Abstract Disclosure: H. Perkins: None. H. Moreau: None. J. LaBudde: None. W. Craig: None. D.I. Spratt: None. Background: Off-label use of subcutaneous (SC) estradiol (E2) by transgender women for gender-affirming hormone therapy is becoming increasingly widespread, despite a lack of published data regarding its efficacy and safety. Methods: This retrospective cohort study used manual data extraction from electronic medical records for patients ages 18-79 years, currently or previously receiving oral (PO) 17-beta E2 or SC E2 valerate therapy at Maine Medical Center Reproductive Endocrinology and Infertility and Gender Clinics between 5/30/14-5/30/23, who completed E2 dose adjustments aimed at obtaining a serum E2 of 75-250 pg/mL. SC E2 was administered weekly and PO E2 daily. Serum testosterone (T), estrone (E1), and sex hormone binding globulin (SHBG) levels were recorded if drawn within 90 days of E2 measurement on an optimized dose. In a subset of patients receiving SC E2, serum E2 levels were drawn 1-2 days post- and pre-injection. All patient-reported local or systemic reactions were recorded. Data are expressed as median (full range) or mean ± standard deviation (full range). Results: 45 patients were included with no significant differences in demographics between PO (n=20) and SC (n=25) groups. Both groups achieved therapeutic E2 levels after dose adjustment without statistical difference in mean serum E2 (pg/mL) between SC and PO groups: 148.7 ± 41.0 (78-226) vs. 151.6 ± 31.7 (97-208); p=0.79 by t-test. In patients without orchiectomy, both SC and PO groups had T (ng/dL) suppressed to normal adult female range (10-55) in 11/12 SC patients and in 17/17 PO patients; median T was 14.0 (7.7-86) for SC vs. 20.6 (3.4-42) for PO; p=0.98 by Mann-Whitney U test. Median E2 dose (mg/week) in the SC group was 3.0 (1.4-6.0) and in the PO group was 42.0 (28-84). Median serum E1 (pg/mL) was lower in the SC group than the PO group: 73.5 (29-115), n=12 vs. 907 (596-1601), n=5, p&amp;lt;0.001 by Mann-Whitney U test. E1/E2 ratio was lower in the SC group than the PO group: 0.4 ± 0.1 vs. 8.0 ± 2.9; p&amp;lt;0.001 by t-test. There was no significant difference in median serum SHBG (nmol/L) between SC and PO groups: 71.7 (19.3-146.7), n=15 vs. 73.4 (51.0-187.4), n=14; p=0.20 by Mann-Whitney U test. Mean post- and pre-dose serum E2 levels in 5 patients were 138.0 ± 24.0 and 88.0 ± 57.6, respectively. There was one transient local reaction and no systemic allergic or inflammatory reactions in the SC group with no systemic reactions in the PO group. Conclusion: These results demonstrate that SC E2 at doses of 1.4-6 mg/week can be administered safely to achieve therapeutic serum E2 levels and suppress serum T levels to within the normal female range. Our preliminary data reveal lower serum E1 levels in the SC group than in the PO group suggesting reduced hepatic first-pass metabolism with SC administration; this pattern was not seen with serum SHBG levels. Post- and pre-dose serum E2 levels revealed only a mild decline in E2 levels between injections. Presentation: 6/3/2024

9224 Evaluation of Safety and Efficacy of Administration of Estradiol by Subcutaneous Injection in Transgender Women

Abstract Disclosure: H. Perkins: None. H. Moreau: None. J. LaBudde: None. W. Craig: None. D.I. Spratt: None. Background: Off-label use of subcutaneous (SC) estradiol (E2) by transgender women for gender-affirming hormone therapy is becoming increasingly widespread, despite a lack of published data regarding its efficacy and safety. Methods: This retrospective cohort study used manual data extraction from electronic medical records for patients ages 18-79 years, currently or previously receiving oral (PO) 17-beta E2 or SC E2 valerate therapy at Maine Medical Center Reproductive Endocrinology and Infertility and Gender Clinics between 5/30/14-5/30/23, who completed E2 dose adjustments aimed at obtaining a serum E2 of 75-250 pg/mL. SC E2 was administered weekly and PO E2 daily. Serum testosterone (T), estrone (E1), and sex hormone binding globulin (SHBG) levels were recorded if drawn within 90 days of E2 measurement on an optimized dose. In a subset of patients receiving SC E2, serum E2 levels were drawn 1-2 days post- and pre-injection. All patient-reported local or systemic reactions were recorded. Data are expressed as median (full range) or mean ± standard deviation (full range). Results: 45 patients were included with no significant differences in demographics between PO (n=20) and SC (n=25) groups. Both groups achieved therapeutic E2 levels after dose adjustment without statistical difference in mean serum E2 (pg/mL) between SC and PO groups: 148.7 ± 41.0 (78-226) vs. 151.6 ± 31.7 (97-208); p=0.79 by t-test. In patients without orchiectomy, both SC and PO groups had T (ng/dL) suppressed to normal adult female range (10-55) in 11/12 SC patients and in 17/17 PO patients; median T was 14.0 (7.7-86) for SC vs. 20.6 (3.4-42) for PO; p=0.98 by Mann-Whitney U test. Median E2 dose (mg/week) in the SC group was 3.0 (1.4-6.0) and in the PO group was 42.0 (28-84). Median serum E1 (pg/mL) was lower in the SC group than the PO group: 73.5 (29-115), n=12 vs. 907 (596-1601), n=5, p&amp;lt;0.001 by Mann-Whitney U test. E1/E2 ratio was lower in the SC group than the PO group: 0.4 ± 0.1 vs. 8.0 ± 2.9; p&amp;lt;0.001 by t-test. There was no significant difference in median serum SHBG (nmol/L) between SC and PO groups: 71.7 (19.3-146.7), n=15 vs. 73.4 (51.0-187.4), n=14; p=0.20 by Mann-Whitney U test. Mean post- and pre-dose serum E2 levels in 5 patients were 138.0 ± 24.0 and 88.0 ± 57.6, respectively. There was one transient local reaction and no systemic allergic or inflammatory reactions in the SC group with no systemic reactions in the PO group. Conclusion: These results demonstrate that SC E2 at doses of 1.4-6 mg/week can be administered safely to achieve therapeutic serum E2 levels and suppress serum T levels to within the normal female range. Our preliminary data reveal lower serum E1 levels in the SC group than in the PO group suggesting reduced hepatic first-pass metabolism with SC administration; this pattern was not seen with serum SHBG levels. Post- and pre-dose serum E2 levels revealed only a mild decline in E2 levels between injections. Presentation: 6/3/2024

6961 Evaluation of Safety and Efficacy of Administration of Estradiol by Subcutaneous Injection in Transgender Women

Abstract Disclosure: H. Perkins: None. H. Moreau: None. J. LaBudde: None. W. Craig: None. D.I. Spratt: None. Background: Off-label use of subcutaneous (SC) estradiol (E2) by transgender women for gender-affirming hormone therapy is becoming increasingly widespread, despite a lack of published data regarding its efficacy and safety. Methods: This retrospective cohort study used manual data extraction from electronic medical records for patients ages 18-79 years, currently or previously receiving oral (PO) 17-beta E2 or SC E2 valerate therapy at Maine Medical Center Reproductive Endocrinology and Infertility and Gender Clinics between 5/30/14-5/30/23, who completed E2 dose adjustments aimed at obtaining a serum E2 of 75-250 pg/mL. SC E2 was administered weekly and PO E2 daily. Serum testosterone (T), estrone (E1), and sex hormone binding globulin (SHBG) levels were recorded if drawn within 90 days of E2 measurement on an optimized dose. In a subset of patients receiving SC E2, serum E2 levels were drawn 1-2 days post- and pre-injection. All patient-reported local or systemic reactions were recorded. Data are expressed as median (full range) or mean ± standard deviation (full range). Results: 45 patients were included with no significant differences in demographics between PO (n=20) and SC (n=25) groups. Both groups achieved therapeutic E2 levels after dose adjustment without statistical difference in mean serum E2 (pg/mL) between SC and PO groups: 148.7 ± 41.0 (78-226) vs. 151.6 ± 31.7 (97-208); p=0.79 by t-test. In patients without orchiectomy, both SC and PO groups had T (ng/dL) suppressed to normal adult female range (10-55) in 11/12 SC patients and in 17/17 PO patients; median T was 14.0 (7.7-86) for SC vs. 20.6 (3.4-42) for PO; p=0.98 by Mann-Whitney U test. Median E2 dose (mg/week) in the SC group was 3.0 (1.4-6.0) and in the PO group was 42.0 (28-84). Median serum E1 (pg/mL) was lower in the SC group than the PO group: 73.5 (29-115), n=12 vs. 907 (596-1601), n=5, p&amp;lt;0.001 by Mann-Whitney U test. E1/E2 ratio was lower in the SC group than the PO group: 0.4 ± 0.1 vs. 8.0 ± 2.9; p&amp;lt;0.001 by t-test. There was no significant difference in median serum SHBG (nmol/L) between SC and PO groups: 71.7 (19.3-146.7), n=15 vs. 73.4 (51.0-187.4), n=14; p=0.20 by Mann-Whitney U test. Mean post- and pre-dose serum E2 levels in 5 patients were 138.0 ± 24.0 and 88.0 ± 57.6, respectively. There was one transient local reaction and no systemic allergic or inflammatory reactions in the SC group with no systemic reactions in the PO group. Conclusion: These results demonstrate that SC E2 at doses of 1.4-6 mg/week can be administered safely to achieve therapeutic serum E2 levels and suppress serum T levels to within the normal female range. Our preliminary data reveal lower serum E1 levels in the SC group than in the PO group suggesting reduced hepatic first-pass metabolism with SC administration; this pattern was not seen with serum SHBG levels. Post- and pre-dose serum E2 levels revealed only a mild decline in E2 levels between injections. Presentation: 6/3/2024

In Vitro Cytotoxicity and Pharmacokinetic Study for Bosutinib Solid Lipid Nanoparticles.

Bosutinib (BST) is a Biopharmaceutics Classification System Class II drug having very low solubility and high permeability. Low aqueous solubility and poor dissolution of BST lead to poor bioavailability, Thus, limited aqueous solubility is the bottleneck for the therapeutic outcome of BST. Animal data suggest that the absolute bioavailability of BST is about 14-34% due to an extensive first-pass effect. To overcome hepatic first-pass metabolism and to enhance oral bioavailability, lipid-based drug delivery systems such as solid lipid nanoparticles (SLNs) can be used. SLNs are submicron colloidal carriers having a size range of 50-1000 nm. These are prepared with physiological lipid and dispersed in water or aqueous surfactant solution. BST can be conveniently loaded into SLNs to improve the oral bioavailability by exploiting the intestinal lymphatic transport. An optimal system was evaluated for bioavailability study in rats compared with that of BST suspension (SUS). An in vitro cytotoxicity study was done by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay method through ATCC cell lines; the percent inhibition was more in SLN when compared with SUS. The pharmacokinetics of BST-SLNs after oral administration in male Wistar rats was studied. The bioavailability of BST was increased by 2.28 fold when compared with that of a BST SUS. The results are indicative of SLNs as suitable lipid-based carrier system for improving the oral bioavailability of BST.

Preparation of Mouth Dissolving Sublingual Film of Fixed Dose Combination of Hydrochlorothiazide and Losartan Potassium and Statistical Optimization of Film.

Fast-dissolving films (FDFs) are innovative dosage forms offering advantages such as improved patient compliance, rapid onset of action, precise dosing, and favorable taste. Particularly beneficial for patients unable to swallow or require immediate drug absorption, FDFs dissolve rapidly in the mouth, releasing medication directly into the oral cavity. The sublingual application enhances drug delivery due to the high permeability of the sublingual mucosa, bypassing hepatic first-pass metabolism. This route is advantageous for drugs like losartan potassium (LP) and hydrochlorothiazide (HCZ), which benefit from enhanced bioavailability and faster onset of action. Preformulation studies included UV spectroscopy for λmax determination (LP: 282 nm, HCZ: 250 nm), DSC for thermal analysis (LP: 289.11°C, HCZ: 104.76°C), and solubility studies confirming LP’s solubility in acidic pH and HCZ’s increased solubility in pH 6.7 buffer. Compatibility studies using FTIR and DSC validated stability with excipients. Formulation optimization with HPMC E15 resulted in films with characteristics like film weight (145.66–167.0 mg), thickness (0.246–0.326 mm), folding endurance (898.0–1274.0), pH (6.0–6.70), disintegration time (77.66–174.6 s), tensile strength (77.04–141.90 g/cm²), and drug release profiles (LP: 68.78–96.22%, HCZ: 59.49–95.43% at 21 minutes). In summary, this study successfully developed LP and HCZ FDFs with optimized characteristics, demonstrating their potential in hypertension management and improving therapeutic outcomes.

Optimizing Transdermal Patch Design: A Quality by Design Approach for Dysmenorrhea Relief.

This study explores the potential of transdermal patches as a systemic delivery system for donepezil (DPZ), aiming to circumvent hepatic first-pass metabolism and mitigate oral administration-associated side effects. DPZ, known for its poor solubility and adverse effects, is formulated into transdermal patches using a matrix-type approach with PVP K30 and HPMC K100 polymers alongside dimethyl sulfoxide as a plasticizer. Through solvent casting on a mercury surface, the patches are prepared and assessed for physical properties and drug-excipient interactions using FTIR analysis. The results demonstrate satisfactory physical characteristics, including appearance, weight variation, and tensile strength. Notably, formulations containing HPMC K100 (400 mg) and PVP K30 (300 mg) exhibit enhanced DPZ discharge, signifying their potential as an effective drug delivery system for mitigating DPZ-associated side effects.