In Situ Forming, Enzyme-Responsive Peptoid-Peptide Hydrogels: An Advanced Long-Acting Injectable Drug Delivery System.

Long-acting drug delivery systems are promising platforms to improve patient adherence to medication by delivering drugs over sustained periods and removing the need for patients to comply with oral regimens. This research paper provides a proof-of-concept for the development of a new optimized in situ forming injectable depot based on a tetrabenzylamine-tetraglycine-d-lysine-O-phospho-d-tyrosine peptoid-D-peptide formulation ((NPhe)4GGGGk(AZT)y(p)-OH). The chemical versatility of the peptoid-peptide motif allows low-molecular-weight drugs to be precisely and covalently conjugated. After subcutaneous injection, a hydrogel depot forms from the solubilized peptoid-peptide-drug formulation in response to phosphatase enzymes present within the skin space. This system is able to deliver clinically relevant concentrations of a model drug, the antiretroviral zidovudine (AZT), for 35 days in Sprague-Dawley rats. Oscillatory rheology demonstrated that hydrogel formation began within ∼30 s, an important characteristic of in situ systems for reducing initial drug bursts. Gel formation continued for up to ∼90 min. Small-angle neutron scattering data reveal narrow-radius fibers (∼0.78-1.8 nm) that closely fit formation via a flexible cylinder elliptical model. The inclusion of non-native peptoid monomers and D-variant amino acids confers protease resistance, enabling enhanced biostability to be demonstrated in vitro. Drug release proceeds via hydrolysis of an ester linkage under physiological conditions, releasing the drug in an unmodified form and further reducing the initial drug burst. Subcutaneous administration of (NPhe)4GGGGk(AZT)y(p)-OH to Sprague-Dawley rats resulted in zidovudine blood plasma concentrations within the 90% maximal inhibitory concentration (IC90) range (30-130 ng mL-1) for 35 days.

Cancer Nanovaccines: Nanomaterials and Clinical Perspectives.

Cancer nanovaccines represent a promising frontier in cancer immunotherapy, utilizing nanotechnology to augment traditional vaccine efficacy. This review comprehensively examines the current state-of-the-art in cancer nanovaccine development, elucidating innovative strategies and technologies employed in their design. It explores both preclinical and clinical advancements, emphasizing key studies demonstrating their potential to elicit robust anti-tumor immune responses. The study encompasses various facets, including integrating biomaterial-based nanocarriers for antigen delivery, adjuvant selection, and the impact of nanoscale properties on vaccine performance. Detailed insights into the complex interplay between the tumor microenvironment and nanovaccine responses are provided, highlighting challenges and opportunities in optimizing therapeutic outcomes. Additionally, the study presents a thorough analysis of ongoing clinical trials, presenting a snapshot of the current clinical landscape. By curating the latest scientific findings and clinical developments, this study aims to serve as a comprehensive resource for researchers and clinicians engaged in advancing cancer immunotherapy. Integrating nanotechnology into vaccine design holds immense promise for revolutionizing cancer treatment paradigms, and this review provides a timely update on the evolving landscape of cancer nanovaccines.

Calcipotriol Nanosuspension-Loaded Trilayer Dissolving Microneedle Patches for the Treatment of Psoriasis: In Vitro Delivery and In Vivo Antipsoriatic Activity Studies.

Psoriasis, affecting 2-3% of the global population, is a chronic inflammatory skin condition without a definitive cure. Current treatments focus on managing symptoms. Recognizing the need for innovative drug delivery methods to enhance patient adherence, this study explores a new approach using calcipotriol monohydrate (CPM), a primary topical treatment for psoriasis. Despite its effectiveness, CPM's therapeutic potential is often limited by factors like the greasiness of topical applications, poor skin permeability, low skin retention, and lack of controlled delivery. To overcome these challenges, the study introduces CPM in the form of nanosuspensions (NSs), characterized by an average particle size of 211 ± 2 nm. These CPM NSs are then incorporated into a trilayer dissolving microneedle patch (MAP) made from poly(vinylpyrrolidone) and w poly(vinyl alcohol) as needle arrays and prefrom 3D printed polylactic acid backing layer. This MAP features rapidly dissolving tips and exhibits good mechanical properties and insertion capability with delivery efficiency compared to the conventional Daivonex ointment. The effectiveness of this novel MAP was tested on Sprague-Dawley rats with imiquimod-induced psoriasis, demonstrating efficacy comparable to the marketed ointment. This innovative trilayer dissolving MAP represents a promising new local delivery system for calcipotriol, potentially revolutionizing psoriasis treatment by enhancing drug delivery and patient compliance.

Phytoestrogens: Chemistry, potential health benefits, and their medicinal importance.

Phytoestrogens, also known as xenoestrogens, are secondary metabolites derived from plants that have similar structures and biological effects as human estrogens. These compounds do not directly affect biological functions but can act as agonists or antagonists depending on the level of endogenous estrogen in the body. Phytoestrogens may have an epigenetic mechanism of action independent of estrogen receptors. These compounds are found in more than 300 plant species and are synthesized through the phenylpropanoid pathway, with specific enzymes leading to various chemical structures. Phytoestrogens, primarily phenolic compounds, include isoflavonoids, flavonoids, stilbenes, and lignans. Extensive research in animals and humans has demonstrated the protective effects of phytoestrogens on estrogen-dependent diseases. Clinical trials have also shown their potential benefits in conditions such as osteoporosis, Parkinson's disease, and certain types of cancer. This review provides a concise overview of phytoestrogen classification, chemical diversity, and biosynthesis and discusses the potential therapeutic effects of phytoestrogens, as well as their preclinical and clinical development.

The cubosome-based nanoplatforms in cancer therapy: Seeking new paradigms for cancer theranostics.

Lyotropic liquid crystals are self-assembled, non-lamellar, and mesophase nanostructured materials that have garnered significant attention as drug carriers. Cubosomes, a subtype of lyotropic liquid crystalline nanoparticles, possess three-dimensional structures that display bicontinuous cubic liquid-crystalline patterns. These patterns are formed through the self-organization of unsaturated monoglycerides (amphphilic lipids such as glyceryl monooleate or phytantriol), followed by stabilization using steric polymers (poloxamers). Owing to their bicontinuous structure and steric polymer-based stabilization, cubosomes have been demonstrated to possess greater entrapment efficiency for hydrophobic drugs compared to liposomes, while also exhibiting high stability. In the past decade, there has been significant interest in cubosomes due to their ability to deliver therapeutic and contrast agents for cancer treatment and imaging with minimal side effects, establishing them as a safe and effective approach. Concerning these advantages, the present review elaborates on the general aspects, composition, and preparation techniques of cubosomes, followed by explanations of their mechanisms of drug loading and release patterns. Furthermore, the review provides meticulous discussions on the use of cubosomes in the treatment and imaging of various types of cancer, culminating in the enumeration of patents related to cubosome-based drug delivery systems.

Delivery of gene editing therapeutics.

For the past decades, gene editing demonstrated the potential to attenuate each of the root causes of genetic, infectious, immune, cancerous, and degenerative disorders. More recently, Clustered Regularly Interspaced Short Palindromic Repeats-CRISPR-associated protein 9 (CRISPR-Cas9) editing proved effective for editing genomic, cancerous, or microbial DNA to limit disease onset or spread. However, the strategies to deliver CRISPR-Cas9 cargos and elicit protective immune responses requires safe delivery to disease targeted cells and tissues. While viral vector-based systems and viral particles demonstrate high efficiency and stable transgene expression, each are limited in their packaging capacities and secondary untoward immune responses. In contrast, the nonviral vector lipid nanoparticles were successfully used for as vaccine and therapeutic deliverables. Herein, we highlight each available gene delivery systems for treating and preventing a broad range of infectious, inflammatory, genetic, and degenerative diseases. STATEMENT OF SIGNIFICANCE: CRISPR-Cas9 gene editing for disease treatment and prevention is an emerging field that can change the outcome of many chronic debilitating disorders.

Nanofibrous Microspheres: A Biomimetic Platform for Bone Tissue Regeneration.

Bone, a fundamental constituent of the human body, is a vital scaffold for support, protection, and locomotion, underscoring its pivotal role in maintaining skeletal integrity and overall functionality. However, factors such as trauma, disease, or aging can compromise bone structure, necessitating effective strategies for regeneration. Traditional approaches often lack biomimetic environments conducive to efficient tissue repair. Nanofibrous microspheres (NFMS) present a promising biomimetic platform for bone regeneration by mimicking the native extracellular matrix architecture. Through optimized fabrication techniques and the incorporation of active biomolecular components, NFMS can precisely replicate the nanostructure and biochemical cues essential for osteogenesis promotion. Furthermore, NFMS exhibit versatile properties, including tunable morphology, mechanical strength, and controlled release kinetics, augmenting their suitability for tailored bone tissue engineering applications. NFMS enhance cell recruitment, attachment, and proliferation, while promoting osteogenic differentiation and mineralization, thereby accelerating bone healing. This review highlights the pivotal role of NFMS in bone tissue engineering, elucidating their design principles and key attributes. By examining recent preclinical applications, we assess their current clinical status and discuss critical considerations for potential clinical translation. This review offers crucial insights for researchers at the intersection of biomaterials and tissue engineering, highlighting developments in this expanding field.

Exosome-mediated delivery and regulation in neurological disease progression.

Exosomes (EXOs), membranous structures originating from diverse biological sources, have recently seized the attention of researchers due to their theranostic potential for neurological diseases. Released actively by various cells, including stem cells, adipose tissue, and immune cells, EXOs wield substantial regulatory influence over the intricate landscape of neurological complications, exhibiting both positive and negative modulatory effects. In AD, EXOs play a pivotal role in disseminating and breaking down amyloid-ß protein. Moreover, EXOs derived from mesenchymal stem cells showcase a remarkable capacity to mitigate pro-inflammatory phenotypes by regulating miRNAs in neurodegenerative diseases. These vesicles possess the unique ability to traverse the blood-brain barrier, governing the aggregation of mutant huntingtin protein. Understanding the exosomal functions within the CNS holds significant promise for enhancing treatment efficacy in neurological diseases. This review intricately examines the regulatory mechanisms involving EXOs in neurological disease development, highlighting therapeutic prospects and exploring their utility in exosome-based nanomedicine for various neurological complications. Additionally, the review highlights the challenges associated with drug delivery to the brain, emphasizing the complexities inherent in this critical aspect of neurotherapeutics.

Block copolymer micelles as ocular drug delivery systems.

Block copolymer micelles, formed by the self-assembly of amphiphilic polymers, address formulation challenges, such as poor drug solubility and permeability. These micelles offer advantages including a smaller size, easier preparation, sterilization, and superior solubilization, compared with other nanocarriers. Preclinical studies have shown promising results, advancing them toward clinical trials. Their mucoadhesive properties enhance and prolong contact with the ocular surface, and their small size allows deeper penetration through tissues such as the cornea. Additionally, copolymeric micelles improve the solubility and stability of hydrophobic drugs, sustain drug release, and allow for surface modifications to enhance biocompatibility. Despite these benefits, long-term stability remains a challenge. In this review, we highlight their preclinical performance, structural frameworks, preparation techniques, physicochemical properties, current developments, and prospects as ocular drug delivery systems.

Fostering the unleashing potential of nanocarriers-mediated delivery of ocular therapeutics.

Ocular delivery is the most challenging aspect in the field of pharmaceutical research. The major hurdle for the controlled delivery of drugs to the eye includes the physiological static barriers such as the complex layers of the cornea, sclera and retina which restrict the drug from permeating into the anterior and posterior segments of the eye. Recent years have witnessed inventions in the field of conventional and nanocarrier drug delivery which have shown considerable enhancement in delivering small to large molecules across the eye. The dynamic challenges associated with conventional systems include limited drug contact time and inadequate ocular bioavailability resulting from solution drainage, tear turnover, and dilution or lacrimation. To this end, various bioactive-based nanosized carriers including liposomes, ethosomes, niosomes, dendrimer, nanogel, nanofibers, contact lenses, nanoprobes, selenium nanobells, nanosponge, polymeric micelles, silver nanoparticles, and gold nanoparticles among others have been developed to circumvent the limitations associated with the conventional dosage forms. These nanocarriers have been shown to achieve enhanced drug permeation or retention and prolong drug release in the ocular tissue due to their better tissue adherence. The surface charge and the size of nanocarriers (10-1000 nm) are the important key factors to overcome ocular barriers. Various nanocarriers have been shown to deliver active therapeutic molecules including timolol maleate, ampicillin, natamycin, voriconazole, cyclosporine A, dexamethasone, moxifloxacin, and fluconazole among others for the treatment of anterior and posterior eye diseases. Taken together, in a nutshell, this extensive review provides a comprehensive perspective on the numerous facets of ocular drug delivery with a special focus on bioactive nanocarrier-based approaches, including the difficulties and constraints involved in the fabrication of nanocarriers. This also provides the detailed invention, applications, biodistribution and safety-toxicity of nanocarriers-based therapeutcis for the ophthalmic delivery.

Design, development, and technical considerations for dry powder inhaler devices.

The dry powder inhaler (DPI) stands out as a highly patient-friendly and effective pulmonary formulation, surpassing traditional and other pulmonary dosage forms in certain disease conditions. The development of DPI products, however, presents more complexities than that of other dosage forms, particularly in device design and the integration of the drug formulation. This review focuses on the capabilities of DPI devices in pulmonary drug delivery, with a special emphasis on device design and formulation development. It also discusses into the principles of deep lung particle deposition and device engineering, and provides a current overview of the market for DPI devices. Furthermore, the review highlights the use of computational fluid dynamics (CFD) in DPI product design and discusses the regulatory environment surrounding these devices.

Antitoxin nanoparticles: design considerations, functional mechanisms, and applications in toxin neutralization.

The application of nanotechnology has significantly advanced the development of novel platforms that enhance disease treatment and diagnosis. A key innovation in this field is the creation of antitoxin nanoparticles (ATNs), designed to address toxin exposure. These precision-engineered nanosystems have unique physicochemical properties and selective binding capabilities, allowing them to effectively capture and neutralize toxins from various biological, chemical, and environmental sources. In this review, we thoroughly examine their therapeutic and diagnostic potential for managing toxin-related challenges. We also explore recent advancements and offer critical insights into the design and clinical implementation of ATNs.

Poly(acrylic acid)/Poly(vinyl alcohol) Microarray Patches for Continuous Transdermal Delivery of Levodopa and Carbidopa: In Vitro and In Vivo Studies.

Levodopa (LD) has been the most efficacious medication and the gold standard therapy for Parkinson's disease (PD) for decades. However, its long-term administration is usually associated with motor complications, which are believed to be the result of the fluctuating pharmacokinetics of LD following oral administration. Duodopa® is the current option to offer a continuous delivery of LD and its decarboxylase inhibitor carbidopa (CD); however, its administration involves invasive surgical procedures, which could potentially lead to lifelong complications, such as infection. Recently, dissolving microarray patches (MAPs) have come to the fore as an alternative that can bypass the oral administration route in a minimally invasive way. This work explored the potential of using dissolving MAPs to deliver LD and CD across the skin. An acidic polymer poly(acrylic acid) (PAA) was used in the MAP fabrication to prevent the potential oxidation of LD at neutral pH. The drug contents of LD and CD in the formulated dissolving MAPs were 1.82 ± 0.24 and 0.47 ± 0.04 mg/patch, respectively. The in vivo pharmacokinetic study using female Sprague-Dawley® rats (Envigo RMS Holding Corp, Bicester, UK) demonstrated a simultaneous delivery of LD and CD and comparable AUC values between the dissolving MAPs and the oral LD/CD suspension. The relative bioavailability for the dissolving MAPs was calculated to be approximately 37.22%. Accordingly, this work highlights the use of dissolving MAPs as a minimally invasive approach which could potentially bypass the gastrointestinal pathway and deliver both drugs continuously without surgery.

Hollow microneedles for ocular drug delivery.

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.

Dissolving microarray patches loaded with a rotigotine nanosuspension: A potential alternative to Neupro® patch.

Parkinson's disease (PD), affecting about ten million people globally, presents a significant health challenge. Rotigotine (RTG), a dopamine agonist, is currently administered as a transdermal patch (Neupro®) for PD treatment, but the daily application can be burdensome and cause skin irritation. This study introduces a combinatorial approach of dissolving microarray patch (MAP) and nanosuspension (NS) for the transdermal delivery of RTG, offering an alternative to Neupro®. The RTG-NS was formulated using a miniaturized media milling method, resulting in a nano-formulation with a mean particle size of 274.09 ± 7.43 nm, a PDI of 0.17 ± 0.04 and a zeta potential of -15.24 ± 2.86 mV. The in vitro dissolution study revealed an enhanced dissolution rate of the RTG-NS in comparison to the coarse RTG powder, under sink condition. The RTG-NS MAPs, containing a drug layer and a 'drug-free' supporting baseplate, have a drug content of 3.06 ± 0.15 mg/0.5 cm2 and demonstrated greater amount of drug delivered per unit area (∼0.52 mg/0.5 cm2) than Neupro® (∼0.20 mg/1 cm2) in an ex vivo Franz cell study using full-thickness neonatal porcine skin. The in vivo pharmacokinetic studies demonstrated that RTG-NS MAPs, though smaller (2 cm2 for dissolving MAPs and 6 cm2 for Neupro®), delivered drug levels comparable to Neupro®, indicating higher efficiency per unit area. This could potentially avoid unnecessarily high plasma levels after the next dose at 24 h, highlighting the benefits of dissolving MAPs over conventional transdermal patches in PD treatment.

Novel nano-in-micro fabrication technique of diclofenac nanoparticles loaded microneedle patches for localised and systemic drug delivery.

Diclofenac, a nonsteroidal anti-inflammatory drug, is commonly prescribed for managing osteoarthritis, rheumatoid arthritis, and post-surgical pain. However, oral administration of diclofenac often leads to adverse effects. This study introduces an innovative nano-in-micro approach to create diclofenac nanoparticle-loaded microneedle patches aimed at localised, sustained pain relief, circumventing the drawbacks of oral delivery. The nanoparticles were produced via wet-milling, achieving an average size of 200 nm, and then incorporated into microneedle patches. These patches showed improved skin penetration in ex vivo tests using Franz-cell setups compared to traditional diclofenac formulations. In vivo tests on rats revealed that the nanoparticle-loaded microneedle patches allowed for quick drug uptake and prolonged release, maintaining drug levels in tissues for up to 72 h. With a systemic bioavailability of 57 %, these patches prove to be an effective means of transdermal drug delivery. This study highlights the potential of this novel microneedle delivery system in enhancing the treatment of chronic pain with reduced systemic side effects.

Essential oils for clinical aromatherapy: A comprehensive review.

ETHNOPHARMACOLOGICAL RELEVANCE: Aromatherapy, a holistic healing practice utilizing the aromatic essences of plant-derived essential oils, has gained significant attention for its therapeutic potential in promoting overall well-being. Use of phytoconstituent based essential oil has played a significant role in the evolving therapeutic avenue of aromatherapy as a complementary system of medicine. AIM OF THE STUDY: This comprehensive review article aims to explore the usage of essential oils for aromatherapy, shedding light on their diverse applications, scientific evidence, and safety considerations. Furthermore, the growing interest in using essential oils as complementary therapies in conjunction with conventional medicine is explored, underscoring the significance of collaborative healthcare approaches. MATERIALS AND METHODS: Literature search was performed from databases like PubMed, ScienceDirect, Scopus, and Bentham using keywords like Aromatherapy, Aromatic Plants, Essential oils, Phytotherapy, and complementary medicine. The keywords were used to identify literature with therapeutic and mechanistic details of herbal agents with desired action. RESULTS: The integration of traditional knowledge with modern scientific research has led to a renewed interest in essential oils as valuable tools in contemporary healthcare. Various extraction methods used to obtain essential oils are presented, emphasizing their impact on the oil's chemical composition and therapeutic properties. Additionally, the article scrutinizes the factors influencing the quality and purity of essential oils, elucidating the significance of standardization and certification for safe usage. A comprehensive assessment of the therapeutic effects of essential oils is provided, encompassing their potential as antimicrobial, analgesic, anxiolytic, and anti-inflammatory agents, among others. Clinical trials and preclinical studies are discussed to consolidate the existing evidence on their efficacy in treating diverse health conditions, both physical and psychological. Safety considerations are of paramount importance when employing essential oils, and this review addresses potential adverse effects, contraindications, and best practices to ensure responsible usage. CONCLUSIONS: This comprehensive review provides valuable insights into the exploration of essential oils for aromatherapy, emphasizing their potential as natural and potent remedies for a wide range of ailments. By amalgamating traditional wisdom and modern research, this article aims to encourage further investigation into the therapeutic benefits of essential oils while advocating for their responsible and evidence-based incorporation into healthcare practices.

Polymer Delivery Systems for Long-Acting Antiretroviral Drugs.

The success of long-acting (LA) drug delivery systems (DDSs) is linked to their biocompatible polymers. These are used for extended therapeutic release. For treatment or prevention of human immune deficiency virus type one (HIV-1) infection, LA DDSs hold promise for improved regimen adherence and reduced toxicities. Current examples include Cabenuva, Apretude, and Sunlenca. Each is safe and effective. Alternative promising DDSs include implants, prodrugs, vaginal rings, and microarray patches. Each can further meet patients' needs. We posit that the physicochemical properties of the formulation chemical design can optimize drug release profiles. We posit that the strategic design of LA DDS polymers will further improve controlled drug release to simplify dosing schedules and improve regimen adherence.

Dual stimuli-responsive delivery system for self-regulated colon-targeted delivery of poorly water-soluble drugs.

Inflammatory bowel disease (IBD) are chronic inflammatory conditions which cause significant patient morbidity. Local drug delivery to the colon can improve treatment efficacy and reduce side effects associated with IBD treatment. Smart drug delivery systems are designed to regulate the release of therapeutic agents at the desired site of action. pH-responsive drug carriers have been previously utilised for improved oral drug delivery beyond stomach harsh conditions. Additionally, the colon possesses a diverse microbiome secreting bioactive molecules e.g., enzymes, that can be exploited for targeted drug delivery. We herein synthesised and characterised a 2-hydroxyethyl methacrylate and methacrylic acid copolymer, crosslinked with an azobenzyl crosslinker, that displayed pH- and enzyme-responsive properties. The swelling and drug release from hydrogel were analysed in pH 1.2, 6.5 and 7.4 buffers, and in the presence of rat caecal matter using metronidazole and mesalamine as model BCS Class I and IV drugs, respectively. Swelling studies displayed pH-responsive swelling behaviour, where swelling was maximum at pH 7.4 and minimum at pH 1.2 (69 % versus 32 %). Consequently, drug release was limited in gastric and small intestinal conditions but increased significantly when exposed to colonic conditions containing caecal matter. This system displays promising capacity for achieving colon-targeted drug delivery with enhanced dissolution of poorly water-soluble drugs for local treatment of IBD and other colon-targeted therapies.

Intradermal delivery of the antiretroviral drugs cabotegravir and rilpivirine by dissolving microarray patches: Investigation of lymphatic uptake.

The lymphatic system possesses the main viral replication sites in the body following viral infection. Unfortunately, current antiretroviral agents penetrate the lymph nodes insufficiently when administered orally and, therefore, cannot access the lymphatic system sufficiently to interrupt this viral replication. For this reason, novel drug delivery systems aimed at enhancing the lymphatic uptake of antiretroviral drugs are highly desirable. Dissolving polymeric microarray patches (MAPs) may help to target the lymph intradermally. MAPs are intradermal drug delivery systems used to deliver many types of compounds. The present work describes a novel work investigating the lymphatic uptake of two anti-HIV drugs: cabotegravir (CAB) and rilpivirine (RPV) when delivered intradermally using dissolving MAPs containing nanocrystals of both drugs. Maps were formulated using NCs obtained by solvent-free milling technique. The polymers used to prepare the NCs of both drugs were PVA 10 Kda and PVP 58 Kda. Both NCs were submitted to the lyophilization process and reconstituted with deionized water to form the first layer of drug casting. Backing layers were developed for short application times and effective skin deposition. In vivo biodistribution profiles of RPV and CAB after MAP skin application were investigated and compared with the commercial intramuscular injection using rats. After a single application of RPV MAPs, a higher concentration of RPV was delivered to the axillary lymph nodes (AL) (Cmax 2466 ng/g - Tmax 3 days) when compared with RPV IM injection (18 ng/g - Tmax 1 day), while CAB MAPs delivered slightly lower amounts of drug to the AL (5808 ng/g in 3 days) when compared with CAB IM injection (9225 ng/g in 10 days). However, CAB MAPs delivered 7726 ng/g (Tmax 7 days) to the external lumbar lymph nodes, which was statistically equivalent to IM delivery (Cmax 8282 ng/g - Tmax 7 days). This work provides strong evidence that MAPs were able to enhance the delivery of CAB and RPV to the lymphatic system compared to the IM delivery route.