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PURPOSE: The trial-and-error approach is still predominantly used in pharmaceutical development of nanosuspensions. Physicochemical dispersion stability is a primary focus and therefore, various analytical bulk methods are commonly employed. Clearly less attention is directed to surface changes of nanoparticles even though such interface effects can be of pharmaceutical relevance. Such potential effects in drug nanosuspensions were to be studied for temperatures of 25 and 37°C by using complementary surface analytical methods. METHODS: Atomic force microscopy, inverse gas chromatography and UV surface dissolution imaging were used together for the first time to assess pharmaceutical nanosuspensions that were obtained by wet milling. Fenofibrate and bezafibrate were selected as model drugs in presence of sodium dodecyl sulfate and hydroxypropyl cellulose as anionic and steric stabilizer, respectively. RESULTS: It was demonstrated that in case of bezafibrate nanosuspension, a surface modification occurred at 37°C compared to 25°C, which notably affected dissolution rate. By contrast, no similar effect was observed in case of fenofibrate nanoparticles. CONCLUSIONS: The combined usage of analytical surface methods provides the basis for a better understanding of phenomena that take place on drug surfaces. Such understanding is of importance for pharmaceutical development to achieve desirable quality attributes of nanosuspensions.
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Composição de Medicamentos/métodos , Estabilidade de Medicamentos , Excipientes/química , Hipolipemiantes/química , Temperatura , Bezafibrato/química , Bezafibrato/farmacocinética , Celulose/análogos & derivados , Celulose/química , Química Farmacêutica , Liberação Controlada de Fármacos , Armazenamento de Medicamentos , Fenofibrato/química , Fenofibrato/farmacocinética , Hipolipemiantes/farmacocinética , Microscopia de Força Atômica , Nanopartículas/química , Nanopartículas/ultraestrutura , Dodecilsulfato de Sódio/química , Solubilidade , SuspensõesRESUMO
RATIONALE: Sulfur-vulcanized rubber is a three-dimensional polymer network, insoluble in all organic solvents. For this reason, vulcanization products are difficult to study and identify by conventional analytical techniques. To simplify this task, low molecular weight olefins have been used as model compounds (MCs) in place of rubber in vulcanization experiments. METHODS: In this work, the vulcanization process was investigated using squalene (SQ) as MC. By-products, intermediates and products were separated by semipreparative reversed-phase liquid chromatography (RPLC) with UV detection. Each fraction was collected, concentrated and characterized by flow injection analysis (FIA) and non-aqueous reversed-phase (NARP) LC coupled to positive atmospheric pressure chemical ionization mass spectrometry (APCI-MS). Under the latter conditions, an Information-Dependent Acquisition (IDA) was performed on a linear ion trap mass spectrometer to obtain structural information. RESULTS: Several vulcanized compounds containing up to three SQ molecules, cross-linked with chains involving up to 14 sulfur atoms overall, have been identified along with some of their oxidized products (epoxides and hydroperoxides). The FIA-MS spectra showed peak clusters, each of which included two-three subclusters; the interpretation was complicated by the occurrence of more ion species per product, by the unsaturation grade and by the characteristic isotopic distribution of sulfur. The enhanced product ion scan (EPI) spectra, acquired during the IDA experiments, supported the FIA-MS identification allowing one to count the number of sulfur atoms. CONCLUSIONS: The sensitivity of the developed analytical strategy was due to the enrichment factor achieved via semipreparative chromatography and the very good response of the APCI detection. Pattern fragmentation and chromatographic behavior simplified the identification of the cured compounds and their oxidized products, whose occurrence was related to the grade of oxidation of SQ used as reagent. Copyright © 2016 John Wiley & Sons, Ltd.
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New stimuli-responsive nanomaterials, made up of host-guest lipidic cubic phases (LCPs) are presented. These biocompatible, stable, transparent and water-insoluble LCPs are composed of monoolein (MO) as a neutral host, and small amounts of one of three judiciously designed and synthesized designer lipids as guest that preserve the structure and stability of LCPs, but render them specific functionalities. Efficient pH- and light-induced binding, release and sequestration of hydrophilic dyes are demonstrated. Significantly, these processes can be performed sequentially, thereby achieving both temporal and dosage control, opening up the possibility of using such LCPs as effective carriers to be used in drug delivery applications. Specifically, because of the inherent optical transparency and molecular isotropy of LCPs they can be envisaged as light-induced drug carriers in ophthalmology. The results presented here demonstrate the potential of molecular design in creating new functional materials with predicted operating mode.
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Lipídeos/química , Nanoestruturas/química , Sistemas de Liberação de Medicamentos , Estrutura MolecularRESUMO
Here, we present the design and assembly of a new light-responsive functional lyotropic liquid crystal system using host-guest lipidic mesophases (LMPs). Light as an external stimulus has many advantages in comparison to other stimuli: it is milder than acids or bases, and variation of intensity and duration can provide a high level of pharmacological control. The LMPs are composed of monoolein (MO) and oleic acid (OA) as host lipids and a small amount of a judiciously synthesized lipid bearing an azobenzene photoactive unit as a guest. While preserving the structure and stability of the host lipidic aggregates, the guest lipids render them specific functionalities. Single-step and sequential light-triggered release and retention of the embedded dye molecules are demonstrated, thereby achieving exquisite temporal, spatial, and dosage control of the release, opening up the possibility of using such lipidic biomaterials as effective matrices in therapy, when a continuous release of active drugs might be toxic.
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Cristais Líquidos/química , Raios Ultravioleta , Compostos Azo/química , Cloretos/química , Glicerídeos/química , Modelos Moleculares , Conformação Molecular , Ácido Oleico/química , Compostos de Zinco/químicaRESUMO
The functionalization of cubosomes with biotin is reported here as an alternative method for the preparation of drug delivery systems capable of active targeting specific receptors that are (over)expressed by cancer cells. We describe the design, synthesis, assembly, and characterization of these novel cubosome nanoparticles by small-angle X-ray scattering (SAXS) and dynamic laser light scattering (DLS) and show their application to human adenocarcinoma cell line HeLa. These cubosomes are stabilized and functionalized with a novel, designed biotin-based block copolymer and are able to simultaneously transport paclitaxel, a potent anticancer drug, and a hydrophobic fluorescent dye in the active targeting of cancer cells. Such biotinylated cubosomes are potentially applicable in diagnosis, drug delivery, and monitoring of the therapeutic response for active targeting versus cancer cells.
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Biotina/química , Portadores de Fármacos/química , Fluoresceína/química , Corantes Fluorescentes/química , Lipídeos/química , Nanopartículas/química , Paclitaxel/química , Transporte Biológico , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos/metabolismo , Células HeLa , Humanos , Cristais Líquidos/química , Modelos Moleculares , Conformação Molecular , Paclitaxel/farmacologiaRESUMO
The interaction of neutral and anionic phospholipid liposomes, used as cell models, with cationic liposomes formulated with 1,2-dimyristoyl-sn-glicero-3-phosphocholine and stereomeric cationic gemini surfactants was investigated by differential scanning calorimetry, fluorescence experiments and dynamic laser light scattering. This study was aimed at rationalizing the different biological features shown by liposomes based on different gemini stereoisomers observed in previous investigations. In fact, to correlate the observed biological activity of liposomes with the molecular structure of their components is critical for a rational and systematic approach to the design of new carriers for drug delivery. The obtained results show that the different stereochemistry of the gemini surfactant controls the interaction and the extent of fusion with different cell models.
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Membrana Celular/metabolismo , Lipossomos/química , 1,2-Dipalmitoilfosfatidilcolina/química , Transporte Biológico , Varredura Diferencial de Calorimetria/métodos , Cátions , Dimiristoilfosfatidilcolina/química , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Luz , Bicamadas Lipídicas/química , Microdomínios da Membrana/química , Modelos Químicos , Fosfatidilgliceróis/química , Espalhamento de Radiação , Espectrometria de Fluorescência/métodos , Propriedades de Superfície , Tensoativos/química , TemperaturaRESUMO
Due to its chronic nature and complex pathophysiology, inflammatory bowel disease (IBD) poses significant challenges for treatment. The long-term therapies for patients, often diagnosed between the ages of 20 and 40, call for innovative strategies to target inflammation, minimize systemic drug exposure, and improve patients' therapeutic outcomes. Among the plethora of strategies currently pursued, bioinspired and bioderived nano-based formulations have garnered interest for their safety and versatility in the management of IBD. Bioinspired nanomedicine can host and deliver not only small drug molecules but also biotherapeutics, be made gastroresistant and mucoadhesive or mucopenetrating and, for these reasons, are largely investigated for oral administration, while surprisingly less for rectal delivery, recommended first-line treatment approach for several IBD patients. The use of bioderived nanocarriers, mostly extracellular vesicles (EVs), endowed with unique homing abilities, is still in its infancy with respect to the arsenal of nanomedicine under investigation for IBD treatment. An emerging source of EVs suited for oral administration is ingesta, that is, plants or milk, thanks to their remarkable ability to resist the harsh environment of the upper gastrointestinal tract. Inspired by the unparalleled properties of natural biomaterials, sophisticated avenues for enhancing therapeutic efficacy and advancing precision medicine approaches in IBD care are taking shape, although bottlenecks arising either from the complexity of the nanomedicine designed or from the lack of a clear regulatory pathway still hinder a smooth and efficient translation to the clinics. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology.
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Doenças Inflamatórias Intestinais , Nanomedicina , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Animais , Vesículas Extracelulares/metabolismo , Sistemas de Liberação de Medicamentos , CamundongosRESUMO
In this study, we explored the use of lipid mesophases (LMPs) as a biocompatible and biodegradable material for sustained drug delivery. Our hypothesis centered on leveraging the high surface-to-volume ratio of LMP-based beads to enhance strength, stability, and surface interaction compared to the LMP bulk gel. To modulate drug release, we introduced antioxidant vitamin E into the beads, influencing mesophase topologies and controlling drug diffusion coefficients. Four drugs with distinct chemical properties and intended for three different pathologies and administration routes were successfully loaded into the beads with a drug entrapment efficiency exceeding 80 %. Notably, our findings revealed sustained drug release, irrespective of the drugs' chemical properties, culminating in the development of an injectable formulation. This formulation allows direct administration into the target site, minimizing systemic exposure, and thereby mitigating adverse effects. Our approach demonstrates the potential of LMP-based beads for tailored drug delivery systems with broad applications in diverse therapeutic scenarios.
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Antioxidantes , Sistemas de Liberação de Medicamentos , Sistemas de Liberação de Medicamentos/métodos , Preparações Farmacêuticas , Liberação Controlada de Fármacos , LipídeosRESUMO
Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. More effective and less toxic therapies are urgently needed for high-risk patients. Peptide-guided targeted drug delivery can increase the therapeutic index of encapsulated drugs and improve patients' well-being. To apply this strategy to RMS, we identified the peptide F3 in a screening for peptides binding to RMS cells surface. F3 binds to nucleolin, which is present on the surface of RMS cells and is abundantly expressed at the mRNA level in RMS patients' biopsies compared to healthy tissues. We developed a rapid microfluidic formulation of F3-decorated PEGylated liposomes and remote loading of the chemotherapeutic drug vincristine. Size, surface charge, drug loading and retention of targeted and control liposomes were studied. Enhanced cellular binding and uptake were observed in three different nucleolin-positive RMS cell lines. Importantly, F3-functionalized liposomes loaded with vincristine were up to 11 times more cytotoxic than non-targeted liposomes for RMS cell lines. These results demonstrate that F3-functionalized liposomes are promising for targeted drug delivery to RMS and warrant further in vivo investigations.
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Lipossomos , Rabdomiossarcoma , Criança , Humanos , Lipossomos/metabolismo , Nucleolina , Vincristina/uso terapêutico , Linhagem Celular Tumoral , Peptídeos/metabolismo , Rabdomiossarcoma/tratamento farmacológico , Rabdomiossarcoma/metabolismoRESUMO
Introduction: The standard treatment for preventing rejection in vascularized composite allotransplantation (VCA) currently relies on systemic immunosuppression, which exposes the host to well-known side effects. Locally administered immunosuppression strategies have shown promising results to bypass this hurdle. Nevertheless, their progress has been slow, partially attributed to a limited understanding of the essential mechanisms underlying graft rejection. Recent discoveries highlight the crucial involvement of innate immune components, such as neutrophil extracellular traps (NETs), in organ transplantation. Here we aimed to prolong graft survival through a tacrolimus-based drug delivery system and to understand the role of NETs in VCA graft rejection. Methods: To prevent off-target toxicity and promote graft survival, we tested a locally administered tacrolimus-loaded on-demand drug delivery system (TGMS-TAC) in a multiple MHC-mismatched porcine VCA model. Off-target toxicity was assessed in tissue and blood. Graft rejection was evaluated macroscopically while the complement system, T cells, neutrophils and NETs were analyzed in graft tissues by immunofluorescence and/or western blot. Plasmatic levels of inflammatory cytokines were measured using a Luminex magnetic-bead porcine panel, and NETs were measured in plasma and tissue using DNA-MPO ELISA. Lastly, to evaluate the effect of tacrolimus on NET formation, NETs were induced in-vitro in porcine and human peripheral neutrophils following incubation with tacrolimus. Results: Repeated intra-graft administrations of TGMS-TAC minimized systemic toxicity and prolonged graft survival. Nevertheless, signs of rejection were observed at endpoint. Systemically, there were no increases in cytokine levels, complement anaphylatoxins, T-cell subpopulations, or neutrophils during rejection. Yet, tissue analysis showed local infiltration of T cells and neutrophils, together with neutrophil extracellular traps (NETs) in rejected grafts. Interestingly, intra-graft administration of tacrolimus contributed to a reduction in both T-cellular infiltration and NETs. In fact, in-vitro NETosis assessment showed a 62-84% reduction in NETs after stimulated neutrophils were treated with tacrolimus. Conclusion: Our data indicate that the proposed local delivery of immunosuppression avoids off-target toxicity while prolonging graft survival in a multiple MHC-mismatch VCA model. Furthermore, NETs are found to play a role in graft rejection and could therefore be a potential innovative therapeutic target.
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Sistemas de Liberação de Medicamentos , Armadilhas Extracelulares , Rejeição de Enxerto , Sobrevivência de Enxerto , Neutrófilos , Tacrolimo , Alotransplante de Tecidos Compostos Vascularizados , Armadilhas Extracelulares/imunologia , Armadilhas Extracelulares/efeitos dos fármacos , Animais , Sobrevivência de Enxerto/efeitos dos fármacos , Suínos , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Tacrolimo/administração & dosagem , Neutrófilos/imunologia , Neutrófilos/efeitos dos fármacos , Alotransplante de Tecidos Compostos Vascularizados/métodos , Imunossupressores/administração & dosagem , Linfócitos T/imunologia , Humanos , Aloenxertos Compostos/imunologia , FemininoRESUMO
The peritoneal cavity offers an attractive administration route for challenging-to-treat diseases, such as peritoneal carcinomatosis, post-surgical adhesions, and peritoneal fibrosis. Achieving a uniform and prolonged drug distribution throughout the entire peritoneal space, though, is difficult due to high clearance rates, among others. To address such an unmet clinical need, alternative drug delivery approaches providing sustained drug release, reduced clearance rates, and a patient-centric strategy are required. Here, we describe the development of a 3D-printed composite platform for the sustained release of the tyrosine kinase inhibitor gefitinib (GEF), a small molecule drug with therapeutic applications for peritoneal metastasis and post-surgical adhesions. We present a robust method for the production of biodegradable liposome-loaded hydrogel microbeads that can overcome the pharmacokinetic limitations of small molecules with fast clearance rates, a current bottleneck for the intraperitoneal (IP) administration of these therapeutics. By means of an electromagnetic droplet printhead, we 3D printed microbeads employing an alginate-based ink loaded with GEF-containing multilamellar vesicles (MLVs). The sustained release of GEF from microbeads was demonstrated. In vitro studies on an immortalized human hepatic cancer cell line (Huh-7) proved concentration-dependent cell death. These findings demonstrate the potential of 3D-printed alginate microbeads containing liposomes for delivering small drug compounds into the peritoneum, overcoming previous limitations of IP drug delivery.
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Gynaecological health is a neglected field of research that includes conditions such as endometriosis, uterine fibroids, infertility, viral and bacterial infections, and cancers. There is a clinical need to develop dosage forms for gynecological diseases that increase efficacy and reduce side effects and explore new materials with properties tailored to the vaginal mucosa and milieu. Here, we developed a 3D printed semisolid vaginal ovule containing pirfenidone, a repurposed drug candidate for endometriosis. Vaginal drug delivery allows direct targeting of the reproductive organs via the first uterine pass effect, but vaginal dosage forms can be challenging to self-administer and retain in situ for periods of more than 1-3 h. We show that a semisoft alginate-based vaginal suppository manufactured using semisolid extrusion additive manufacturing is superior to vaginal ovules made using standard excipients. The 3D-printed ovule showed a controlled release profile of pirfenidone in vitro in standard and biorelevant release tests, as well as better mucoadhesive properties ex vivo. An exposure time of 24 h of pirfenidone to a monolayer culture of an endometriotic epithelial cell line, 12Z, is necessary to reduce the cells' metabolic activity, which demonstrates the need for a sustained release formulation of pirfenidone. 3D printing allowed us to formulate mucoadhesive polymers into a semisolid ovule with controlled release of pirfenidone. This work enables further preclinical and clinical studies into vaginally administered pirfenidone to assess its efficacy as a repurposed endometriosis treatment.
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Endometriose , Doenças Uterinas , Feminino , Humanos , Endometriose/tratamento farmacológico , Óvulo Vegetal , Preparações de Ação Retardada , Vagina , Impressão Tridimensional , Liberação Controlada de Fármacos , ComprimidosRESUMO
Ulcerative colitis is a chronic inflammatory bowel disease that strongly affects patient quality of life. Side effects of current therapies necessitate new treatment strategies that maximise the drug concentration at the site of inflammation, while minimizing systemic exposure. Capitalizing on the biocompatible and biodegradable structure of lipid mesophases, we present a temperature-triggered in situ forming lipid gel for topical treatment of colitis. We show that the gel is versatile and can host and release drugs of different polarities, including tofacitinib and tacrolimus, in a sustained manner. Further, we demonstrate its adherence to the colonic wall for at least 6 h, thus preventing leakage and improving drug bioavailability. Importantly, we find that loading known colitis treatment drugs into the temperature-triggered gel improves animal health in two mouse models of acute colitis. Overall, our temperature-triggered gel may prove beneficial in ameliorating colitis and decreasing adverse effects associated with systemic application of immunosuppressive treatments.
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Colite Ulcerativa , Colite , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Animais , Camundongos , Colite Ulcerativa/tratamento farmacológico , Qualidade de Vida , Temperatura , Colite/induzido quimicamente , Colite/tratamento farmacológico , LipídeosRESUMO
Liver fibrosis is a condition characterized by the accumulation of extracellular matrix (ECM) arising from the myofibroblastic transdifferentiation of hepatic stellate cells (HSCs) occurring as the natural response to liver damage. To date, no pharmacological treatments have been specifically approved for liver fibrosis. We recently reported a beneficial effect of polyenylphosphatidylcholines (PPCs)-rich formulations in reverting fibrogenic features of HSCs. However, unsaturated phospholipids' properties pose a constant challenge to the development of tablets as preferred patient-centric dosage form. Profiting from the advantageous physical properties of the PPCs-rich Soluthin® S 80 M, we developed a tablet formulation incorporating 70% w/w of this bioactive lipid. Tablets were characterized via X-ray powder diffraction, thermogravimetry, and Raman confocal imaging, and passed the major compendial requirements. To mimic physiological absorption after oral intake, phospholipids extracted from tablets were reconstituted as protein-free chylomicron (PFC)-like emulsions and tested on the fibrogenic human HSC line LX-2 and on primary cirrhotic rat hepatic stellate cells (PRHSC). Lipids extracted from tablets and reconstituted in buffer or as PFC-like emulsions exerted the same antifibrotic effect on both activated LX-2 and PRHSCs as observed with plain S 80 M liposomes, showing that the manufacturing process did not interfere with the bioactivity of PPCs.
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Excipientes , Fígado , Humanos , Ratos , Animais , Excipientes/farmacologia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/patologia , Comprimidos/farmacologia , Células Estreladas do FígadoRESUMO
Liposomes show promise as biolubricants for damaged cartilage, but their small size results in low joint and cartilage retention. We developed a zinc ion-based liposomal drug delivery system for local osteoarthritis therapy, focusing on sustained release and tribological protection from phospholipid lubrication properties. Our strategy involved inducing aggregation of negatively charged liposomes with zinc ions to extend rapamycin (RAPA) release and improve cartilage lubrication. Liposomal aggregation occurred within 10 min and was irreversible, facilitating excess cation removal. The aggregates extended RAPA release beyond free liposomes and displayed irregular morphology influenced by RAPA. At nearly 100 µm, the aggregates were large enough to exceed the previously reported size threshold for increased joint retention. Tribological assessment on silicon surfaces and ex vivo porcine cartilage revealed the system's excellent protective ability against friction at both nano- and macro-scales. Moreover, RAPA was shown to attenuate the fibrotic response in human OA synovial fibroblasts. Our findings suggest the zinc ion-based liposomal drug delivery system has potential to enhance OA therapy through extended release and cartilage tribological protection, while also illustrating the impact of a hydrophobic drug like RAPA on liposome aggregation and morphology.
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Cartilagem Articular , Osteoartrite , Humanos , Lipossomos/química , Fricção , Sirolimo/farmacologia , Fosfolipídeos , Osteoartrite/tratamento farmacológico , LubrificaçãoRESUMO
BACKGROUND: Routes along the olfactory nerves crossing the cribriform plate that extend to lymphatic vessels within the nasal cavity have been identified as a critical cerebrospinal fluid (CSF) outflow pathway. However, it is still unclear how the efflux pathways along the nerves connect to lymphatic vessels or if any functional barriers are present at this site. The aim of this study was to anatomically define the connections between the subarachnoid space and the lymphatic system at the cribriform plate in mice. METHODS: PEGylated fluorescent microbeads were infused into the CSF space in Prox1-GFP reporter mice and decalcification histology was utilized to investigate the anatomical connections between the subarachnoid space and the lymphatic vessels in the nasal submucosa. A fluorescently-labelled antibody marking vascular endothelium was injected into the cisterna magna to demonstrate the functionality of the lymphatic vessels in the olfactory region. Finally, we performed immunostaining to study the distribution of the arachnoid barrier at the cribriform plate region. FINDINGS: We identified that there are open and direct connections from the subarachnoid space to lymphatic vessels enwrapping the olfactory nerves as they cross the cribriform plate towards the nasal submucosa. Furthermore, lymphatic vessels adjacent to the olfactory bulbs form a continuous network that is functionally connected to lymphatics in the nasal submucosa. Immunostainings revealed a discontinuous distribution of the arachnoid barrier at the olfactory region of the mouse. INTERPRETATION: Our data supports a direct bulk flow mechanism through the cribriform plate allowing CSF drainage into nasal submucosal lymphatics in mice. FUNDING: This study was supported by the Swiss National Science Foundation (310030_189226), Dementia Research Switzerland-Synapsis Foundation, the Heidi Seiler Stiftung and the Fondation Dr. Corinne Schuler.
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Vasos Linfáticos , Nervo Olfatório , Animais , Camundongos , Osso Etmoide , Sistema Linfático/metabolismo , Espaço Subaracnóideo/metabolismoRESUMO
Lipid mesophases are able to incorporate and release a plethora of molecules, spanning from hydrophobic drugs to small hydrophilic proteins and therefore they have been widely used as drug delivery systems. However, their 3-5 nm water channels do not allow the release of large hydrophilic molecules such as monoclonal antibodies and therapeutic proteins. To overcome this major geometrical constraint, we designed a gel by mixing monoacylglycerol lipids, generally recognized as safe for human and/or animal use by FDA, and phospholipids, to obtain a material with swollen water channels suitable to host and further release macromolecules. Apoferritin, a 12 nm nanocage protein with intrinsic tumor-targeting properties able to incorporate several molecules, was selected here as the hydrophilic model protein to be embedded in the biocompatible gel. When immersed completely in the release media, mesophases with a swollen water channel of 22 nm, composed of monoolein and doped with 5 mole% of DOPS and 10 mole% of Chol allowed us to achieve a protein release of 60%, which is 120 times higher with respect to that obtained by employing non swollen-LMPs composed only of monoolein. Thus, the formulation can be administered locally to the rectal or vaginal mucosa, reducing the drawbacks often associated with the parenteral administration of bio-therapeutics. This approach would pave the way for the local application of other biomacromolecules (including human ferritin, monoclonal antibodies and antibody drug-conjugates) in those diseases easily reachable by a local application such as rectal or vaginal cancer.
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Apoferritinas , Sistemas de Liberação de Medicamentos , Animais , Anticorpos Monoclonais , Interações Hidrofóbicas e Hidrofílicas , Substâncias MacromolecularesRESUMO
By direct deposition of the drug at the local site of action, injectable depot formulations - intended for treatment of a local disease or for local intervention - are designed to limit the immediate exposure of the active principle at a systemic level and to reduce the frequency of administration. To overcome known drawbacks in the production of some marketed phospholipid-based depots, here we propose to manufacture drug-loaded negatively charged liposomes through conventional technologies and to control their aggregation mixing a solution of divalent cations prior to administration. We identified phosphatidylglycerol (PG) as the most suitable phospholipid for controlled aggregation of the liposomes and to modulate the release of the anesthetic bupivacaine (BUP) from liposomal depots. In vivo imaging of the fluorescently-labelled liposomes showed a significantly higher retention of the PG liposomes at the injection site with respect to zwitterionic ones. In situ mixing of PG liposomes with calcium salts significantly extended the area under the curve of BUP in plasma compared to the non-depot system. Overall, controlling the aggregation of negatively charged liposomes with divalent cations not only modulated the particle clearance from the injection site but also the release in vivo of a small amphipathic drug such as BUP.
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Bupivacaína , Fosfolipídeos , Preparações de Ação RetardadaRESUMO
OBJECTIVES: This review highlights aspects of drug hydrophobicity and lipophilicity as determinants of different oral formulation approaches with specific focus on enabling formulation technologies. An overview is provided on appropriate formulation selection by focussing on the physicochemical properties of the drug. KEY FINDINGS: Crystal lattice energy and the octanol-water partitioning behaviour of a poorly soluble drug are conventionally viewed as characteristics of hydrophobicity and lipophilicity, which matter particularly for any dissolution process during manufacturing and regarding drug release in the gastrointestinal tract. Different oral formulation strategies are discussed in the present review, including lipid-based delivery, amorphous solid dispersions, mesoporous silica, nanosuspensions and cyclodextrin formulations. SUMMARY: Current literature suggests that selection of formulation approaches in pharmaceutics is still highly dependent on the availability of technological expertise in a company or research group. Encouraging is that, recent advancements point to more structured and scientifically based development approaches. More research is still needed to better link physicochemical drug properties to pharmaceutical formulation design.
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Química Farmacêutica/métodos , Desenho de Fármacos , Preparações Farmacêuticas/administração & dosagem , Administração Oral , Sistemas de Liberação de Medicamentos , Desenvolvimento de Medicamentos/métodos , Liberação Controlada de Fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Preparações Farmacêuticas/química , SolubilidadeRESUMO
The use of lipid-based nanoparticles for the delivery of biomacromolecules has attracted considerable attention due to the current interest in protein-based therapeutics. Cubosomes protect the incorporated therapeutics, which are susceptible to degradation by enzymes, thereby improving their bioavailability, and concomitantly enhance cellular uptake. The cubosome nanoparticles presented herein were loaded with bovine serum albumin (BSA) and characterized by small-angle X-ray scattering and dynamic light scattering techniques, while the BSA encapsulation and its release were evaluated in vitro. The ability of this formulation to increase the cellular uptake of albumin by 2-fold was tested on various types of renal tubular cells and confirmed by in vivo renal uptake experiments in mice. The obtained results show that cubosomes are able to deliver BSA inside the cell through distinct uptake and intracellular routing. These data were substantiated, with evidence of a high cubosome-mediated uptake of BSA in Clcn5 knockout mice characterized by defective receptor-mediated endocytosis. The use of cubosomes as a delivery system thus represents a promising approach to overcome the low endocytic uptake in diseased epithelial cells and to treat dysfunctions of the kidney proximal tubule.