RESUMO
Freeze-dried beads made of α-cyclodextrin and soybean oil were reported previously as an efficient system for the oral delivery of lipophilic drugs. In the present study, oven-drying was evaluated as another method for drying beads. Oven-drying was optimised and the properties of the resulting beads were assessed. The behavior of oven-dried beads and the release of indomethacin from these beads were evaluated in vitro in simulated gastrointestinal fluids and compared with those of freeze-dried beads. The stability of freeze-dried and oven-dried unloaded beads stored at 25°C for 12 months and at 40°C for 6 months in closed and open vials was also studied by different techniques. An oven-drying time of 6 hours at 25°C was chosen as optimal conditions. Oven-dried beads exhibited a sticky texture making them difficult to handle. They were harder, less fragile and smaller than the freeze-dried ones. The characteristics of oven-dried beads make them more resistant in vitro even in media containing bile salt. The rate of indomethacin release from oven-dried beads was much slower than that from the freeze-dried ones. Whatever the drying method, beads must be stored at room temperature protected from humidity. However, no products of oil degradation were detected with both kinds of beads. This work clearly emphasized that the drying method of the beads had a strong influence on their properties, behavior in simulated gastrointestinal fluids and drug release.
Assuntos
Anti-Inflamatórios não Esteroides/química , Portadores de Fármacos/química , Indometacina/química , Óleo de Soja/química , alfa-Ciclodextrinas/química , Administração Oral , Anti-Inflamatórios não Esteroides/administração & dosagem , Fenômenos Químicos , Portadores de Fármacos/administração & dosagem , Composição de Medicamentos , Embalagem de Medicamentos , Estabilidade de Medicamentos , Ácidos Graxos não Esterificados/análise , Liofilização , Suco Gástrico/química , Conteúdo Gastrointestinal/química , Temperatura Alta/efeitos adversos , Humanos , Indometacina/administração & dosagem , Cinética , Peróxidos Lipídicos/análise , Suco Pancreático/química , SolubilidadeRESUMO
Intravitreal administration has been widely used since 20 years and has been shown to improve the treatment of diseases of the posterior segment of the eye with infectious origin or in edematous maculopathies. This route of administration allows to achieve high concentration of drug in the vitreous and avoids the problems resulting from systemic administration. However, two basic problems limit the use of intravitreal therapy. Many drugs are rapidly cleared from the vitreous humor; therefore, to reach and to maintain effective therapy repeated injections are necessary. Repeated intravitreal injections increase the risk of endophthalmitis, damage to lens, retinal detachment. Moreover, some drugs provoke a local toxicity at their effective dose inducing side-effects and possible retinal lesions. In this context, the development and the use of new drug delivery systems for intravitreal administration are necessary to treat chronic ocular diseases. Among them, particulate systems such as liposomes have been widely studied. Liposomes are easily injectable and permit to reduce the toxicity and to increase the residence time of several drugs in the eye. They are also able to protect in vivo poorly-stable molecules from degradation such as peptides and nucleic acids. Some promising results have been obtained for the treatment of retinitis induced by cytomegalovirus in human and more recently for the treatment of uveitis in animal. Finally, the fate of liposomes in ocular tissues and fluids after their injection into the vitreous and their elimination routes begin to be more known.
Assuntos
Portadores de Fármacos , Oftalmopatias/tratamento farmacológico , Lipossomos , Preparações Farmacêuticas/administração & dosagem , Corpo Vítreo/fisiologia , Portadores de Fármacos/farmacocinética , Sistemas de Liberação de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Olho/metabolismo , Humanos , Injeções Intravítreas , Lipossomos/farmacocinéticaRESUMO
Natural cyclodextrins are cyclic oligosaccharides which can be modified to obtain more water soluble or insoluble derivatives. The main interest of cyclodextrins results from their ability to form an inclusion complex with hydrophobic molecules. Inclusion constitutes a true molecular encapsulation. This property is employed in pharmaceutical industry to facilitate the formulation of poorly water soluble and/or fragile drugs. A more recent application of cyclodextrins consists in their use in the preparation of dispersed systems such as micro- and nanoparticles or even liposomes. When incorporated in dispersed systems, cyclodextrin can enhance drug solubility, drug stability and drug loading. Interestingly, cyclodextrins themselves can also be employed to form or stabilise dispersed systems (material or emulsifying agent). For example, the interactions between cyclodextrins with components of the vegetable oils (more especially with triglycerides) allow to stabilise simple or multiple emulsions but also to form particles called "beads". Very rich in oil, this novel lipid carrier presents an important potential for the encapsulation of highly lipophilic compounds and their delivery by topical and oral routes. These two applications are more particularly developed in the present paper.
Assuntos
Ciclodextrinas/química , Sistemas de Liberação de Medicamentos , Triglicerídeos/química , Química Farmacêutica , Indústria Farmacêutica , Emulsões , Excipientes , SolubilidadeRESUMO
A continuous external shaking for 2.5 days of a mixture composed of alpha-cyclodextrin (6%), soybean oil (19.6%) and water (74.4%) resulted in a calibrated lipid carrier namely bead with a high fabrication yield. The purpose of this work was to explore the possibility to substitute alpha-cyclodextrin by other natural cyclodextrins, i.e. beta- and gamma-cyclodextrin and then soybean oil by mineral (Primol) 352 and Marcol 82) or synthetic (Silicon 200) fluid 10, 50 or 100cSt) oils. Beads can be successfully prepared using Marcol 82 with alpha-cyclodextrin and Silicon 50 or 100cSt with gamma-cyclodextrin. The area inside oil/cyclodextrin/water ternary diagram corresponding to bead occurrence was superior for the Marcol 82/alpha-cyclodextrin couple compared to that observed with soybean oil/alpha-cyclodextrin couple. Only a few ratios of Silicon 50 and 100cSt/gamma-cyclodextrin/water led to beads. The combinations which did not induce bead occurrence gave either emulsions, two non-miscible liquids or a solid mixture. Whatever the materials used, beads exhibited similarities: presence of a crystalline organisation and viscoelastic properties. Manufacturing process of paraffin- and silicon-based beads need further optimisation to increase fabrication yield and later on, to take advantages from the high stability of both oils for the formulation of drugs with beads.
Assuntos
Portadores de Fármacos/química , Óleos/química , Reologia , Química Farmacêutica , Cristalização , Formas de Dosagem , Estabilidade de Medicamentos , Elasticidade , Emulsões , Tamanho da Partícula , Transição de Fase , Viscosidade , alfa-Ciclodextrinas/química , beta-Ciclodextrinas/química , gama-Ciclodextrinas/químicaRESUMO
The use of liposomes as carriers for the delivery of biologically active molecules into the eye is of major interest. Indeed, encapsulation of biologically active molecules in liposomes may increase their bioavailability and may induce a sustained release, thus avoiding repeated intraocular injections and reducing side effects. We describe here the fate of rhodamine-conjugated liposomes (Rh-Lip) injected into the vitreous of normal Lewis rats. Twenty-four hours after intravitreal injection fluorescent liposomes were detected in the vitreous, the inner layer of the retina and to a lesser extent in the anterior segment of the eye. In addition, numerous Rh-Lip were also observed in the episclera and conjunctival stroma, in conjunctival lymphatic vessels and cervical lymph nodes (LN) draining the conjunctiva and the eye. In the LN, Rh-Lip were taken up by resident macrophages adjacent to CD4+ and CD8+ T cells. Thus, intravitreal injection of anti-inflammatory drugs loaded in liposomes could modulate the ocular immune microenvironment. In addition the passage of drugs into the cervical LN could alter the immune status of these LN and contribute to the regulation of intraocular inflammation. Our results suggest that this phenomenon should be taken into account to design new therapies based on intraocular drug administration.
Assuntos
Túnica Conjuntiva/metabolismo , Corantes Fluorescentes/metabolismo , Linfonodos/metabolismo , Sistema Linfático/fisiologia , Rodaminas/metabolismo , Corpo Vítreo/metabolismo , Animais , Imuno-Histoquímica , Injeções , Lipossomos , Masculino , Microscopia Confocal , Pescoço , Ratos , Ratos Endogâmicos Lew , Retina/metabolismoRESUMO
PURPOSE: Local delivery of therapeutic molecules encapsulated within liposomes is a promising method to treat ocular inflammation. The purpose of the present study was to define the biodistribution of rhodamine-conjugated liposomes loaded with vasoactive intestinal peptide (VIP), an immunosuppressive neuropeptide, following their intravitreal (IVT) injection in normal rats. METHODS: Healthy seven- to eight-week-old Lewis male rats were injected into the vitreous with empty rhodamine-conjugated liposomes (Rh-Lip) or with VIP-loaded Rh-Lip (VIP-Rh-Lip; 50 mM of lipids with an encapsulation efficiency of 3.0+/-0.4 mmol VIP/mol lipids). Twenty-four h after IVT injection, the eyes, the cervical, mesenteric, and inguinal lymph nodes (LN), and spleen were collected. The phenotype and distribution of cells internalizing Rh-Lip and VIP-Rh-Lip were studied. Determination of VIP expression in ocular tissues and lymphoid organs and interactions with T cells in cervical LN was performed on whole mounted tissues and frozen tissue sections by immunofluorescence and confocal microscopy. RESULTS: In the eye, 24 h following IVT injection, fluorescent liposomes (Rh-Lip and VIP-Rh-Lip) were detected mainly in the posterior segment of the eye (vitreous, inner layer of the retina) and to a lesser extent at the level of the iris root and ciliary body. Liposomes were internalized by activated retinal Müller glial cells, ocular tissue resident macrophages, and rare infiltrating activated macrophages. In addition, fluorescent liposomes were found in the episclera and conjunctiva where free VIP expression was also detected. In lymphoid organs, Rh-Lip and VIP-Rh-Lip were distributed almost exclusively in the cervical lymph nodes (LN) with only a few Rh-Lip-positive cells detected in the spleen and mesenteric LN and none in the inguinal LN. In the cervical LN, Rh-Lip were internalized by resident ED3-positive macrophages adjacent to CD4 and CD8-positive T lymphocytes. Some of these T lymphocytes in close contact with macrophages containing VIP-Rh-Lip expressed VIP. CONCLUSIONS: Liposomes are specifically internalized by retinal Müller glial cells and resident macrophages in the eye. A limited passage of fluorescent liposomes from the vitreous to the spleen via the conventional outflow pathway and the venous circulation was detected. The majority of fluorescent liposomes deposited in the conjunctiva following IVT injection reached the subcapsular sinus of the cervical LN via conjuntival lymphatics. In the cervical LN, Rh-Lip were internalized by resident subcapsular sinus macrophages adjacent to T lymphocytes. Detection of VIP in both macrophages and T cells in cervical LN suggests that IVT injection of VIP-Rh-Lip may increase ocular immune privilege by modulating the loco-regional immune environment. In conclusion, our observations suggest that IVT injection of VIP-loaded liposomes is a promising therapeutic strategy to dampen ocular inflammation by modulating macrophage and T cell activation mainly in the loco-regional immune system.
Assuntos
Rodaminas/administração & dosagem , Rodaminas/farmacocinética , Peptídeo Intestinal Vasoativo/administração & dosagem , Peptídeo Intestinal Vasoativo/farmacocinética , Corpo Vítreo/metabolismo , Animais , Corpo Ciliar/citologia , Corpo Ciliar/efeitos dos fármacos , Corpo Ciliar/metabolismo , Túnica Conjuntiva/citologia , Túnica Conjuntiva/efeitos dos fármacos , Túnica Conjuntiva/metabolismo , Endocitose/efeitos dos fármacos , Injeções , Iris/citologia , Iris/efeitos dos fármacos , Iris/metabolismo , Lipossomos , Linfonodos/citologia , Linfonodos/efeitos dos fármacos , Linfonodos/metabolismo , Tecido Linfoide/citologia , Tecido Linfoide/efeitos dos fármacos , Tecido Linfoide/metabolismo , Masculino , Fagócitos/efeitos dos fármacos , Fagócitos/metabolismo , Fenótipo , Ratos , Ratos Endogâmicos Lew , Rodaminas/farmacologia , Distribuição Tecidual/efeitos dos fármacos , Peptídeo Intestinal Vasoativo/farmacologia , Corpo Vítreo/citologia , Corpo Vítreo/efeitos dos fármacosRESUMO
Local fungal infections with Candida, Fusarium, Curvularia and Aspergillus can lead to serious ulceration of the cornea and must be treated rapidly. The current treatment consists of 0.15% (w/v) amphotericin B eye drops prepared from Fungizone, containing deoxycholate, irritant for the cornea, which reduces patient compliance. Eye drops based on liposomal amphotericin B (AmBisome would be a convenient alternative; however, according to the manufacturer's instructions, AmBisome can only be kept refrigerated for 1 week after reconstitution. A longer shelf-life at ambient temperature would be preferable for a preparation made in a hospital pharmacy and delivered to patients. Thus, the possibility of storing an ophthalmic preparation of 0.5% (w/v) liposomal amphotericin B after reconstitution was investigated. After 6 months at room temperature or at +2-8 degrees C, the hydrodynamic diameter measured by quasi-elastic light scattering remained constant at 108 +/- 30 nm with a polydispersity index lower than 0.15. Amphotericin B content, checked by a validated HPLC method, was maintained between 94 and 107%. Amphotericin B and soy phosphatidylcholine proportions remained constant, indicating that the liposomes remained intact and retained the drug. These results show the feasibility of an ophthalmic preparation based on liposomal amphotericin B developed in hospital pharmacies.
Assuntos
Anfotericina B/química , Antifúngicos/química , Administração Tópica , Anfotericina B/administração & dosagem , Antifúngicos/administração & dosagem , Cromatografia Líquida de Alta Pressão , Úlcera da Córnea/tratamento farmacológico , Composição de Medicamentos , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Infecções Oculares Fúngicas/tratamento farmacológico , Humanos , Luz , Soluções Oftálmicas , Espalhamento de Radiação , TemperaturaRESUMO
The aim of this work was to characterise a new type of particulate system, named beads, prepared by a straightforward technique starting from a mixture of alpha-cyclodextrin aqueous solution and soybean oil without the use of any organic solvent or surface-active agent. Mechanisms involved in bead formation were also investigated. Optimal ratio between alpha-cyclodextrin (6%, w/w), soybean oil (19.6%, w/w) and water (74.4%, w/w) led to homogeneous bead size (1.6 mm) with a fabrication yield superior to 80% after a continuous external shaking during 2.5 days. After freeze-drying, oil and alpha-cyclodextrin contents were estimated at 80% (w/w) and 20% (w/w), respectively. X-ray diffraction studies revealed that beads presented a crystalline organisation and microscopic techniques showed that their inner structure was constituted by a matrix containing oily compartments. Beads offer interesting prospects for the microencapsulation of lipophilic and poorly stable molecules. Due to their semi-solid consistency and their ability to be freeze-dried, these beads have great potentialities for pharmaceutical (oral and topical routes) and cosmetic applications.
Assuntos
Sistemas de Liberação de Medicamentos , Óleo de Soja/química , alfa-Ciclodextrinas/química , Viscosidade , Difração de Raios XRESUMO
An overview of ocular implants with therapeutic application potentials is provided. Various types of implants can be used as slow release devices delivering locally the needed drug for an extended period of time. Thus, multiple periocular or intraocular injections of the drug can be circumvented and secondary complications minimized. The various compositions of polymers fulfilling specific delivery goals are described. Several of these implants are undergoing clinical trials while a few are already commercialized. Despite the paramount progress in design, safety and efficacy, the place of these implants in our clinical therapeutic arsenal remains limited. Miniaturization of the implants allowing for their direct injection without the need for a complicated surgery is a necessary development avenue. Particulate systems which can be engineered to target specifically certain cells or tissues are another promising alternative. For ocular diseases affecting the choroid and outer retina, transscleral or intrasscleral implants are gaining momentum.
Assuntos
Sistemas de Liberação de Medicamentos , Implantes de Medicamento , Oftalmopatias/tratamento farmacológico , Preparações Farmacêuticas/administração & dosagem , Animais , Humanos , Polímeros/químicaRESUMO
Anti-mRNA and particularly antisense oligonucleotides are molecules able to inhibit gene expression after intracellular penetration being potentially very interesting for the treatment of ocular diseases where growth factors are involved such as ocular scarring diseases or for the inhibition of viral multiplication. In most cases, the site of action of oligonucleotides has shown to be the posterior segment of the eye and these molecules are injected mainly by the intravitreal route. However, oligonucleotides are poorly stable in biological fluids, have a low intracellular penetration and are quickly eliminated form the vitreous. These issues request repeated administration of oligonucleotides which are able to induce severe damages to the retina. This is the reason why drug delivery systems were developed to improve the stability and intracellular penetration of oligonucleotides and, by sustained release, to increase their long term activity in the treatment of ocular diseases.
Assuntos
Sistemas de Liberação de Medicamentos/métodos , Oftalmopatias/tratamento farmacológico , Oligonucleotídeos Antissenso/administração & dosagem , Animais , Oftalmopatias/metabolismo , Humanos , Oligonucleotídeos Antissenso/química , Oligonucleotídeos Antissenso/metabolismoRESUMO
Antisense oligonucleotides are short synthetic fragments of genes that are able to inhibit gene expression after being internalized by cells. They can therefore be used as antiviral compounds particularly, for the treatment of ocular viral infections (i.e. Herpes simplex virus or Cytomegalovirus, CMV). Antisense oligonucleotides are however poorly stable in biological fluids and their intracellular penetration is limited. Although oligonucleotides are now currently used in therapeutics for the treatment of CMV by intravitreal injection (Vitravene) their main drawbacks impose to repeat the number of administrations which can be very harmful and damaging. A system that is able to permit a protection of oligonucleotides against degradation and their slow delivery into the vitreous would be more favorable for improving patient compliance. The use of liposomes for intravitreal administration can be very promising since these lipid vesicles are able to protect oligonucleotides against degradation by nucleases and they allow to increase the retention time of many drugs in the vitreous. In this review, the potentialities of liposomes for the intravitreal delivery of oligonucleotides will be discussed.
Assuntos
Infecções Oculares Virais/tratamento farmacológico , Lipossomos/farmacocinética , Oligonucleotídeos Antissenso/administração & dosagem , Corpo Vítreo , Administração Tópica , Animais , Ensaios Clínicos como Assunto , Preparações de Ação Retardada/farmacocinética , Sistemas de Liberação de Medicamentos , Humanos , Oligonucleotídeos Antissenso/toxicidade , Tamanho da Partícula , Cooperação do PacienteRESUMO
This study was performed to design a new ocular drug delivery system based on poly-epsilon-caprolactone (PCL) biodegradable nanospheres (NS) coated with a bioadhesive polymer, hyaluronic acid (HA), in order to combine ophthalmic prolonged action with the ease of application. The aim of this work was to investigate three strategies to attach HA on NS surface: (1) coating the core by chain entanglement with HA; (2) coating NS by HA adsorption; (3) coating NS by electrostatic interactions between negatively charged HA and a cationic surfactant (stearylamine, SA, or benzalkonium chloride, BKC). A radioimmunoassay technique, usually used for HA quantification in serum, was transposed to determine the amount of HA on the NS. The results show that HA is strongly attached on NS positively charged by cationic surfactant. This system is stable and not influenced by dilution. These results show the possibility of using cationic surfactants to obtain a HA coating by electrostatic interactions. BKC, approved for ophthalmic administration, was retained because it was more firmly anchored within the PCL matrix and the amount of HA attached was high (41.6 microg HA/mg PCL). Moreover, the yield of fixation reached 50%. Therefore, by using a simple preparation method, it was possible to obtain stable HA and intact HA-coated NS.
Assuntos
Caproatos/síntese química , Sistemas de Liberação de Medicamentos/métodos , Olho , Ácido Hialurônico/síntese química , Lactonas/síntese química , Nanotecnologia/métodos , Adesivos/administração & dosagem , Adesivos/síntese química , Caproatos/administração & dosagem , Caproatos/química , Desenho de Fármacos , Olho/efeitos dos fármacos , Olho/metabolismo , Ácido Hialurônico/administração & dosagem , Lactonas/administração & dosagem , Lactonas/químicaRESUMO
The distribution of a model 16-mer oligothymidylate (pdT16) in several ocular tissues (cornea, conjunctiva, sclera, iris, lens, aqueous and vitreous humors) was determined after instillation in the eye of various dosage forms in a rabbit model. Radiolabelled pdT16 was applied as a simple solution, a 27% poloxamer 407 gel, a suspension of liposomes or liposomes dispersed within a 27% poloxamer 407 gel. pdT16 concentrations were measured in the tissues and fluids by radioactivity counting at time intervals of 10 min, 2 h and 24 h. When the pdT 16 solution was used, the highest concentrations were observed in the conjunctiva and the cornea, while a substantial amount of drug was also present in the sclera. Low concentrations were measured in the iris. Using the same treatment protocol, the two liposomal formulations (liposomes suspension or liposomes dispersed within the poloxamer gel) delivered low amounts of pdT16 to all ocular tissues, and particularly to the conjunctiva and the cornea. The poloxamer gel provided higher tissue concentrations of pdT16 than liposomes but lower than those observed with the solution except 10 min after administration in the iris where the amounts of pdT16 were higher when administered under the gel form. These findings indicate that liposomal forms may not be considered useful delivery systems for topical administration of oligonucleotides in superficial ocular diseases.
Assuntos
Olho/metabolismo , Oligonucleotídeos/farmacocinética , Absorção , Administração Tópica , Animais , Portadores de Fármacos , Lipossomos , Modelos Biológicos , Oligonucleotídeos/administração & dosagem , Soluções Oftálmicas , Coelhos , Distribuição TecidualRESUMO
In order to achieve a sustained pharmacological activity of oligonucleotides (ODNs) and avoid repeated administrations, we have developed a new concept of delivery system that combine sustained release and improved intracellular penetration. These systems are designed for the intravitreal delivery of antisense ODNs. The first concept consisted in using liposomes dispersed in a thermosensitive gel (poloxamer 407). After intravitreal administration in a rabbit model, liposomes and liposomes-gel formulations provided, 1-day postinjection, significantly higher drug levels than the control solution of the oligothymidilate pdT16. In addition, there was no significant difference in the amounts of pdT16 found in the vitreous humor between the liposomes and liposomes-gel. Nevertheless, because of their better stability in the absence of poloxamer, liposomes alone allowed to a larger extent to control the delivery of ODNs as compared to liposome-gel formulations since 37% of the ODNs were still found in the vitreous 15 days after administration. In addition, the ODNs found in the vitreous humor were protected against degradation by their encapsulation within liposomes. The second approach consisted in designing microspheres allowing to release in a controlled fashion pdT16. The ODN was encapsulated within poly(lactide-co-glycolide) microspheres alone or associated with polyethylenimine (PEI) at different nitrogen/phosphate (N/P) ratios. The introduction of PEI in the internal aqueous phase resulted in a strong increase of the ODN encapsulation efficiency. PEI affected microsphere morphology inducing the formation of very porous particles yielding to an accelerated release of pdT16. Porosity and controlled delivery was prevented by introducing sodium chloride in the external preparation medium. When incubated with HeLa cells, microspheres encapsulating pdT16/PEI complexes allowed an improvement of the intracellular penetration of the released ODN. Both liposomes and microspheres are suitable for local delivery of ODNs.
Assuntos
Portadores de Fármacos/administração & dosagem , Géis/administração & dosagem , Ácidos Nucleicos/administração & dosagem , Animais , Portadores de Fármacos/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Géis/farmacocinética , Lipossomos , Ácidos Nucleicos/farmacocinética , Oligonucleotídeos/administração & dosagem , Oligonucleotídeos/farmacocinética , Coelhos , Corpo Vítreo/efeitos dos fármacos , Corpo Vítreo/metabolismoRESUMO
Liposomes are vesicular lipidic systems allowing encapsulation of drugs. This article reviews the relevant issues in liposome structure (composition and size), and their influence on intravitreal pharmacokinetics. Liposome-mediated drug delivery to the posterior segment of the eye via intravitreal administration has been addressed by several authors and remains experimental. Liposomes have been used for intravitreal delivery of antibiotics, antivirals, antifungal drugs, antimetabolites, and cyclosporin. Encapsulation of these drugs within liposomes markedly increased their intravitreal half-life, and reduced their retinal toxicity. Liposomes have also shown an attractive potential for retinal gene transfer by intravitreal delivery of plasmids or oligonucleotides.
Assuntos
Lipossomos/administração & dosagem , Corpo Vítreo/efeitos dos fármacos , Administração Tópica , Disponibilidade Biológica , Barreira Hematorretiniana , Sistemas de Liberação de Medicamentos/métodos , Técnicas de Transferência de Genes , Meia-Vida , Humanos , Lipossomos/química , Taxa de Depuração Metabólica , Corpo Vítreo/metabolismoRESUMO
The main interest of cyclodextrins results from their ability to form inclusion complexes with hydrophobic molecules. This property is employed in pharmaceutical industry to facilitate the formulation of poorly-soluble and/or fragile drugs. Cyclodextrins are also used to form or stabilise dispersed systems. An original multiparticulate system named "beads" is obtained thanks to the interactions occurring between the molecules of α cyclodextrin and the triglycerides of vegetable oils. Beads are prepared by a simple process involving the external shaking of a mixture of an aqueous solution of α cyclodextrin with soybean oil. This is done without any organic solvent or surface-active agent. Once freezedried, beads have a diameter of 1.6 mm and a high lipid content. They consist in a partially crystalline matrix of cyclodextrin surrounding microdomains of oil. The coating of beads with a layer of α cyclodextrin improves their resistance in gastro- intestinal fluids and prolongs the release of drugs. Beads can also be manufactured from mineral oils with α cyclodextrin and from silicone oils with γ cyclodextrin. Poorly-soluble drugs which do not form inclusion complexes with α cyclodextrin are encapsulated in beads with high efficiency and drug loading. In rats, the oral bioavailability of isotretinoin is twofold enhanced with uncoated beads as compared to the lipid content of a soft capsule. The relative oral bioavailability of indomethacin is improved with both coated and uncoated beads versus a commercial hard capsule. Beads demonstrate an important potential for the encapsulation of poorly-soluble and/or fragile compounds and their delivery by oral route.
Assuntos
Sistemas de Liberação de Medicamentos/métodos , Preparações Farmacêuticas/química , Óleo de Soja/química , alfa-Ciclodextrinas/química , Administração Oral , Animais , Disponibilidade Biológica , Humanos , Indometacina/administração & dosagem , Indometacina/farmacologia , Isotretinoína/administração & dosagem , Isotretinoína/farmacologia , Preparações Farmacêuticas/administração & dosagem , Ratos , Óleo de Soja/administração & dosagem , alfa-Ciclodextrinas/administração & dosagem , alfa-Ciclodextrinas/farmacologiaRESUMO
The purpose of this work was to investigate the potential of α-cyclodextrin combined to soybean oil-based formulations to modulate the release of a model drug, indomethacin. Dry emulsion, naked and coated beads were prepared from the same initial formulation using the same manufacturing process. Dry emulsion was selected to accelerate drug release while beads coated with α-cyclodextrin were designed to sustain it. Indomethacin-loaded systems were prepared, characterised and evaluated in vitro. Pharmacokinetic studies were performed in fasted and fed rats. The presence of the α-cyclodextrin coat was confirmed by confocal microscopy, and an increase of the mass and diameter of the beads. The layer of α-cyclodextrin improved their resistance in simulated gastro-intestinal fluids. In vitro, the dissolution of indomethacin was slower with coated beads than with emulsion and naked beads. Lipid-based formulations showed an increase of relative bioavailability of IND versus Indocid®. Whatever the formulation, greater and faster release of indomethacin was noticed in sodium taurocholate-rich medium and in fed rats. Compared to naked beads, an increased Cp(max) with a shorter T(max) was observed with the emulsion while T(max) and MRT were increased and Cp(max) reduced with the coated beads. Interestingly, formulations based on alpha cyclodextrin and soybean oil can modify the release of a lipophilic drug depending on the system formed.
Assuntos
Portadores de Fármacos/farmacocinética , Indometacina/farmacocinética , Óleo de Soja/farmacocinética , alfa-Ciclodextrinas/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Emulsões , Interações Hidrofóbicas e Hidrofílicas , Indometacina/administração & dosagem , Indometacina/química , Masculino , Ratos , Ratos Wistar , Óleo de Soja/administração & dosagem , Óleo de Soja/química , alfa-Ciclodextrinas/administração & dosagem , alfa-Ciclodextrinas/químicaRESUMO
The aim of this work was to investigate the stability in vitro, in simulated gastro-intestinal fluids, of beads, made of α-cyclodextrin and soybean oil, and to study the release of progesterone, a model of lipophilic drug. This was evaluated over time by the monitoring of the proportion of intact beads, their volume and the percentage of progesterone dissolved. Their incubation in the simulated gastric fluid provoked a moderate reduction of their number (20%) and a decrease of their volume (50%) after 55 min. Whatever the intestinal medium subsequently introduced, bead number and volume decreased more until bead disintegration that appeared faster in sodium taurocholate rich-medium. In such fluid, the amount of progesterone dissolved increased rapidly between 65 and 180 min, with both beads and emulsion to be equal after 85 min. With soft capsules, the increase was more gradual. In sodium taurocholate free-medium, more progesterone was dissolved from the emulsion than from beads or soft capsules. The release of progesterone from beads resulted from the erosion of their matrix and its partition equilibrium between oily micro-droplets and aqueous phase. The original structure of beads confers to this multiparticulate system interesting properties for the oral delivery of lipophilic drugs.
Assuntos
Sistemas de Liberação de Medicamentos , Progesterona/química , Óleo de Soja/química , alfa-Ciclodextrinas/química , Portadores de Fármacos/química , Estabilidade de Medicamentos , Emulsões , Suco Gástrico/metabolismo , Progesterona/administração & dosagem , Progesterona/farmacocinética , Solubilidade , Ácido Taurocólico/metabolismo , Fatores de TempoRESUMO
A promising strategy based on the antisense oligonucleotides against the Plasmodium falciparum topoisomerase II has been considered using cationic nanoemulsion as oligonucleotide delivery system. Phosphodiester and chemically modified phosphorothioate oligonucleotides bearing negative charges were adsorbed on positively charged emulsion composed of medium chain triglycerides, egg lecithin, 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), and water, at different +/- charge ratios (positive charges from cationic lipid/negative charges from oligonucleotide): +0.5/-, +2/-, +4/- and +6/-. The physicochemical properties of the complexes were determined, as well as their stability in culture medium. Their interaction with erythrocytes through hemolysis, binding experiments and confocal microscopy were also evaluated. Finally, the in vitro evaluation of parasite growth and reinfection capacity was performed. The overall results showed that antisense oligonucleotides against P. falciparum topoisomerase II gene can be efficiently adsorbed onto a cationic nanoemulsion forming complexes. Whereas unloaded nanoemulsion displayed an hemolytic effect due to the presence of the cationic lipid, this was not the case of loaded nanoemulsion at low +/- ratios. Oligonucleotide-loaded nanoemulsions were found to be located inside the infected erythrocytes, inhibiting efficiently parasite growth (until 80%) and causing a delay in P. falciparum life cycle.