RESUMO
PURPOSE: To study, diffusion through mucus (3D model) of different formulations of paclitaxel loaded lipid nanocapsules (Ptx-LNCs), to interpret the results in the light of LNC behavior at air-mucus interface (2D model). METHODS: LNC surface properties were modified with chitosan or poly(ethylene glycol) (PEG) coatings of different size (PEG 2,000 to 5,000 Da) and surface charges. LNC diffusion through 446 µm pig intestinal mucus layer was studied using Transwell(®). LNCs were spread at the air-water-mucus interface then interfacial pressure and area changes were monitored and the efficiency of triglyceride (TG) inclusion was determined. RESULTS: Ptx-LNCs of surface charges ranging from -35.7 to +25.3 mV were obtained with sizes between 56.2 and 75.1 nm. The diffusion of paclitaxel in mucus was improved after encapsulation in neutral or positively charged particles (p < 0.05 vs Taxol(®)). No significative difference was observed in the 2,000-5,000 PEG length for diffusion both on the 2D or 3D models. On 2D model positive or neutral LNCs interacted less with mucus. Highest efficiency of TG inclusion was observed for particles with smallest PEG length. CONCLUSIONS: The results obtained with 2D and 3D model allowed us to select the best candidates for in vivo studies (neutral or positive LNCs with smaller PEG length).
Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Portadores de Fármacos/química , Muco/metabolismo , Nanocápsulas/química , Paclitaxel/farmacocinética , Administração Oral , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Quitosana/química , Quitosana/metabolismo , Difusão , Portadores de Fármacos/metabolismo , Modelos Biológicos , Paclitaxel/administração & dosagem , Tamanho da Partícula , Polietilenoglicóis/química , Polietilenoglicóis/metabolismo , Propriedades de Superfície , SuínosRESUMO
Aim: The present study investigated renal elimination after intravenous administration of four different formulations of lipid nanocapsules (LNCs) containing dyes adapted to Förster resonance energy transfer (FRET-LNCs). Materials & methods: FRET-LNCs of 85 or 50 nm with or without a pegylated surface were injected and collected in the blood or urine of rats at different time points. Quantitative analysis was performed to measure intact FRET-LNCs. Results & conclusion: No intact LNCs were found in urine (0 particles/ml) for all formulations. The 50-nm pegylated LNCs were eliminated faster from the blood, whereas 85-nm pegylated LNCS were eliminated slower than nonpegylated LNCs. Elimination of FRET-LNCs was mainly due to liver tissue interaction and not renal elimination.
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Pharmacy compounding, the art and science of preparing customized medications to meet individual patient needs, is on the verge of transformation. Traditional methods of compounding often involve manual and time-consuming processes, presenting challenges in terms of consistency, dosage accuracy, quality control, contamination, and scalability. However, the emergence of cutting-edge technologies has paved a way for a new era for pharmacy compounding, promising to redefine the way medications are prepared and delivered as pharmacy-tailored personalized medicines. In this multi-site study, more than 30 hospitals and community pharmacies from eight countries in Europe utilized a novel automated dosing approach inspired by 3D printing for the compounding of non-sterile propranolol hydrochloride tablets. CuraBlend® excipient base, a GMP-manufactured excipient base (pharma-ink) intended for automated compounding applications, was used. A standardized study protocol to test the automated dosing of tablets with variable weights was performed in all participating pharmacies in four different iterative phases. Integrated quality control was performed with an in-process scale and NIR spectroscopy supported by HPLC content uniformity measurements. In total, 6088 propranolol tablets were produced at different locations during this study. It was shown that the dosing accuracy of the process increased from about 90% to 100% from Phase 1 to Phase 4 by making improvements to the formulation and the hardware solutions. The results indicate that through this automated and quality controlled compounding approach, extemporaneous pharmacy manufacturing can take a giant leap forward towards automation and digital manufacture of dosage forms in hospital pharmacies and compounding pharmacies.
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The parameters currently used for characterization of nanoparticles, such as size and zeta potential, were not able to reflect the performance of a nanocarrier in the biological environment. Therefore, more thorough in vitro characterization is required to predict their behavior in vivo, where nanoparticles acquire a new biological identity due to interactions with biomolecules. In this present study, we performed in vitro characterization in biological fluids for lipid nanocapsules (LNCs) with varying means sizes (50 nm and 100 nm), different electrical surface charges and different Poly Ethylene Glycol (PEG) compositions. Then, different methods were applied to show the impact of the protein corona formation on LNCs. Even if all formulations attached to plasmatic proteins, a higher thickness of corona and highest protein binding was observed for certain LNC50 formulations. A better knowledge of the phenomenon of protein adsorption over NPs in the plasmatic media is a cornerstone of clinical translation. In fact, after short blood circulation time, it is not the initially designed nanoparticle but the complex nanoparticle bearing its protein corona which circulates to reach its target.
Assuntos
Nanocápsulas , Nanopartículas , Coroa de Proteína , Nanocápsulas/química , Polietilenoglicóis/química , Coroa de Proteína/química , Nanopartículas/química , Proteínas SanguíneasRESUMO
Idarubicin (IDA) is an antineoplasic drug commonly used to treat hematologic diseases. Because of its relative lipophilic properties, this anthracycline is also used in transarterial chemoembolization (TACE) as part of hepatocellular carcinoma (HCC) treatment. But TACE requires injected volume to be reduced to restrict systemic diffusion and side effects. The aim of this study was to determine the stability of a highly concentrated aqueous solution of IDA, stored in polypropylene syringes between 2 °C and 8 °C. Analyses were performed with an HPLC system combined with UV detector and mass spectrometer. Forced degradation was used to investigate potential degradation products. This study demonstrated 7 days of stability after storage in previously mentioned conditions. This conservation is long enough to anticipate drug preparation and facilitates pharmacy organization.
Assuntos
Carcinoma Hepatocelular , Quimioembolização Terapêutica , Neoplasias Hepáticas , Estabilidade de Medicamentos , Humanos , Idarubicina , Polipropilenos , SeringasRESUMO
The present study investigated the pharmacokinetics of intact lipid nanocapsules (LNCs) after intravenous administration in rats. Six different Förster resonance energy transfer LNCs (FRET-LNCs) have been studied with 2 sizes (50 and 85 nm) and 3 coating types (none, DSPE-mPEG 2000 or stearylamine). A FRET-LNCs blood extraction method was developed to retain an accurate FRET signal. Intact FRET-LNCs were specifically quantified through combination of FRET signal and Nano Tracker Analysis. Pharmacokinetic data were first described by non-compartmental analysis, then used to develop a population pharmacokinetic model. The pharmacokinetic elimination of FRET-LNCs was non-linear and dependent on size and surface modification, while the distribution was dependent on size. The LNCs 85 nm volume of distribution was lower than LNCs 50 nm. As expected, LNCs 85 nm with PEG coating displayed a lower clearance than other formulations. Surprisingly, this study highlighted a faster elimination of LNCs 50 nm with PEG compared to other formulations which could be explained by instability in blood. This first pharmacokinetic model of intact LNCs allowed a thorough understanding of the influence of size and coating on pharmacokinetic properties and paves the way for future mechanistic modeling approaches to predict the fate of LNCs in vivo.
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Nanocápsulas , Animais , Ratos , Transferência Ressonante de Energia de Fluorescência/métodos , Lipídeos , Composição de MedicamentosRESUMO
Nanomedicines have been developed for more than four decades to optimize the pharmacokinetics (PK) of drugs, especially absorption, distribution, and stability in vivo. Unfortunately, only a few drug products have reached the market. One reason among others is the lack of proper PK modeling and evaluation, which impedes the optimization of these promising drug delivery systems. In this review, we discuss the specificity of nanomedicines and propose key parameters to take into account for future accurate PK evaluation of nanomedicine. We believe that this could help these innovative drug products to reach to market and change the fate of many diseases.
Assuntos
Sistemas de Liberação de Medicamentos , Modelos Biológicos , Nanopartículas , Animais , Desenvolvimento de Medicamentos/métodos , Estabilidade de Medicamentos , Humanos , Nanomedicina , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/metabolismo , FarmacocinéticaRESUMO
PURPOSE: Lipid nanocapsules (LNCs) are solvent-free drug nanocarriers permitting entrapment of paclitaxel and increasing its antitumoural effect in animal models after i.v. injection. The tolerance and efficacy of LNCs after repeated dose i.v. administration were assessed in mice. The maximum tolerated dose (MTD) and 50 percent lethal dose (LD50) were studied. METHODS: Paclitaxel-loaded LNC formulation was given i.v. at the dose of 12 mg/kg per day for 5 consecutive days in comparison with blank LNCs and saline. Histological examination, complete blood counts and biochemical quantification were performed after a recovery of 7 days. Growth of NCI-H460 subcutaneous xenografts in nude mice receiving one of the aforementioned schedules was assessed. MTD and LD50 were determined by Irwin test. RESULTS: No mortality was observed in repeated injections studies. Histological studies revealed no lesions and no accumulation of lipids. Blood studies were normal. The tumoural growth was significantly reduced in the group treated by paclitaxel-loaded LNCs. The MTDs/LD50s of Taxol, paclitaxel-loaded LNCs and blank LNCs were 12/19.5, 96/216 and above 288/288 mg/kg, respectively. CONCLUSIONS: This study demonstrates that a five-day i.v. injection schedule of paclitaxel-loaded LNC dispersions induces no histological or biochemical abnormalities in mice and improves paclitaxel efficacy and therapeutic index in comparison with Taxol.
Assuntos
Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/uso terapêutico , Lipídeos/química , Nanocápsulas/química , Paclitaxel/efeitos adversos , Paclitaxel/uso terapêutico , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Linhagem Celular Tumoral , Feminino , Humanos , Lipídeos/análise , Masculino , Camundongos , Camundongos Nus , Nanocápsulas/ultraestrutura , Paclitaxel/administração & dosagemRESUMO
BACKGROUND: Acute myeloid leukemia mainly affects adult patients. Complete remission for patients younger than 60 years, who are candidates for standard induction therapy, is achieved in 60%-80% of cases. However, the prognosis is still poor for older patients, who are unfit for intensive chemotherapy, and only a few therapies are available. Hypomethylating agents, such as decitabine, are approved for such patients. The current dosing regimen consists of one administration per day, for 5 days, each 4 weeks. METHODS: Here, we present the synthesis of a decitabine prodrug, combined with its encapsulation into a lipid-based nanocapsule formulation. Decitabine (C12)2 was synthetized, then loaded into nanocapsules. Its stability in phosphate buffer ans human plasma was checked. Its activity was evaluated by Cell proliferation assays and cell-cycle analysis on human erythroleukemia cells. Then its pharmacokinetics was determined on a rat model. RESULTS: Decitabine (C12)2 was obtained with a yield of 50%. Drug loading into nanocarriers of 27.45±0.05 nm was 5.8±0.5 mg/mL. The stability of decitabine was improved and its activity on leukemia cells was not altered. Finally, pharmacokinetics studies showed a prolonged mean residence time of the drug. CONCLUSION: Decitabine (C12)2 as a prodrug showed high encapsulation efficiency, a good stability in plasma with no impact on its activity on leukemia cells and improved pharmacokinetics.
Assuntos
Decitabina/administração & dosagem , Decitabina/química , Leucemia Eritroblástica Aguda/tratamento farmacológico , Lipídeos/química , Nanocápsulas/administração & dosagem , Plasma/metabolismo , Animais , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/química , Antimetabólitos Antineoplásicos/farmacocinética , Ciclo Celular , Proliferação de Células , Decitabina/farmacocinética , Estabilidade de Medicamentos , Humanos , Leucemia Eritroblástica Aguda/metabolismo , Leucemia Eritroblástica Aguda/patologia , Masculino , Ratos , Ratos Wistar , Distribuição Tecidual , Células Tumorais CultivadasRESUMO
Gemcitabine is a nucleoside analog currently used for the treatment of various solid tumors as a single agent or in combination with other chemotherapeutic drugs. Its use against highly aggressive brain tumors (glioblastoma) has been evaluated in preclinical and clinical trials leading to controversial results. Gemcitabine can inhibit DNA chain elongation, is a potent radiosensitizer and it can enhance antitumor immune activity, but it also presents some drawbacks (e.g., short half-life, side effects, chemoresistance). The aim of this review is to discuss the challenges related to the use of gemcitabine for glioblastoma and to report recent studies that suggest overcoming these obstacles opening new perspectives for its use in the field (e.g., gemcitabine derivatives and/or nanomedicines).
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Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Desoxicitidina/análogos & derivados , Glioblastoma/tratamento farmacológico , Animais , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Humanos , Nanomedicina/métodos , Radiossensibilizantes/farmacologia , Radiossensibilizantes/uso terapêutico , GencitabinaRESUMO
Acute myeloid leukemia (AML) is the most common cause of leukemia-related mortality. The combination of cytarabine and anthracycline has been the gold standard of treatment over the past 40 years, but the distribution of the drugs in the body leads to severe adverse effects. Poor prognosis of older patients with AML is the consequence not only of comorbidities, but also of chemoresistance resulting from frequent secondary AML. Numerous strategies using nanotechnologies are in development to improve drug targeting, pharmacokinetics, administration route, chemoresistance, and adverse effects generally observed. Among the four new drugs approved for AML by the US Food and Drug Administration (FDA) in 2017, Vyxeos® is a novel liposomal formulation of historical AML drugs. Here, we review current AML treatments and discuss how the development of new formulations will change the therapeutic armamentarium.
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Leucemia Mieloide Aguda/tratamento farmacológico , Preparações Farmacêuticas/administração & dosagem , Animais , Antraciclinas/efeitos adversos , Antraciclinas/uso terapêutico , Citarabina/efeitos adversos , Citarabina/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , HumanosRESUMO
AIM: Anticancer drug-loaded hydrogels are a promising strategy for the local treatment of incurable brain tumors such as glioblastoma (GBM). Recently, we demonstrated the efficacy of lauroyl-gemcitabine lipid nanocapsule hydrogel (GemC12-LNC) in a U-87 MG xenograft orthotopic mouse model. In this study, we developed a reliable and reproducible surgical procedure to resect orthotopic GBM tumors in rats. GemC12-LNC hydrogel integrity was tested after brain administration in rats and its anti-tumor efficacy was tested on a 9L syngeneic orthotopic model. RESULTS: We demonstrated that LNC integrity is maintained at least for one week after local administration of GemC12-LNC. GemC12-LNC was able to delay the formation of recurrences in 9L tumor-bearing resected rats, demonstrating the efficacy of this nanomedicine hydrogel in this preclinical model. CONCLUSION: Our results confirm that GemC12-LNC, a hydrogel uniquely formed by a nanocarrier and a cytotoxic drug, could be a promising and safe delivery tool for the local treatment of operable GBM tumors.
Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Desoxicitidina/análogos & derivados , Glioblastoma/tratamento farmacológico , Hidrogéis/química , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Desoxicitidina/administração & dosagem , Desoxicitidina/química , Desoxicitidina/uso terapêutico , Feminino , Imageamento por Ressonância Magnética , Nanomedicina/métodos , Ratos , Ratos Sprague-Dawley , GencitabinaRESUMO
The small intestine is a complex organ with movements, flora, mucus and flows. Despite this, the most widely used absorption models consider the organ a cylindrical monoepithelial tube. This review presents the recent evolution of models to take into consideration the complex nature of gut physiology. The most commonly encountered issues are ethical (in vivo models) and differences in drug transport as a result of a modified expression of drug transporters or metabolic enzymes compared with human (in vitro and in vivo models). Finally, this review discusses the way forward to reach an ideal equilibrium between reproducibility, predictability and efficiency for predicting permeability. The features of an ideal model are listed as a guideline for future development.
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Absorção Intestinal , Intestino Delgado/metabolismo , Modelos Biológicos , Preparações Farmacêuticas/metabolismo , Animais , HumanosRESUMO
Decitabine is a hydrophilic drug that acts by hypomethylating DNA. Decitabine is used in Europe for the treatment of acute myeloid leukemia (AML) in patients aged ≥65 years. However, it can only be administered intravenously due to very low oral bioavailability and a large distribution volume. Oral administration would allow outpatient treatment, improving quality of life and reducing treatment costs. The present study proposes to develop lipid nanocapsules (LNCs), originally designed for lipophilic drugs, to encapsulate decitabine. Two different formulations of LNCs were designed: LNCs based on a high proportion of Transcutol® HP (THP-LNCs) and LNCs associated with a mixture of Transcutol® HP and Tween® 80 (THP-T80-LNCs). The second formulation had a diameter of 26.5±0.5 nm, high encapsulation efficiency (>85%), and a drug payload of 472±64 µg/mL. Decitabine-loaded THP-T80-LNC cytotoxicity was evaluated on two AML cell lines depending on their decitabine resistance: HEL (not resistant) and HL-60 (resistant). The permeability of decitabine-loaded THP-T80-LNCs was also evaluated on Caco-2 cell monolayers. Decitabine cytotoxicity against HEL and HL-60 was higher when decitabine was loaded in THP-T80-LNCs than when free. Apparent permeability on Caco-2 cell monolayers was also increased, suggesting a potentially useful formulation to increase the oral bioavailability of decitabine.
Assuntos
Azacitidina/análogos & derivados , Portadores de Fármacos/química , Leucemia Mieloide Aguda/tratamento farmacológico , Nanocápsulas/administração & dosagem , Administração Oral , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/farmacocinética , Azacitidina/administração & dosagem , Azacitidina/farmacocinética , Disponibilidade Biológica , Células CACO-2 , Linhagem Celular Tumoral , Decitabina , Portadores de Fármacos/administração & dosagem , Liberação Controlada de Fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Estabilidade de Medicamentos , Etilenoglicóis/química , Humanos , Lipídeos/química , Nanocápsulas/química , Polissorbatos/químicaRESUMO
Lipid nanocapsules (LNCs) offer a promising method for the entrapment and nanovectorisation of lipophilic molecules. This new type of nanocarrier, formulated according to a solvent-free process and using only regulatory-approved components, exhibits many prerequisites for being well tolerated. Although toxicological reference values have already been obtained in mice, interaction of LNCs at the cell level needs to be elucidated. LNCs, measuring from 27.0±0.1nm (25nm LNCs) and 112.1±1.8nm (100nm LNCs) and with a zeta potential between -38.7±1.2mV and +9.18±0.4mV, were obtained by a phase inversion process followed by post-insertion of carboxy- or amino-DSPE-PEG. Trypan blue, MTS and neutral red uptake (NRU) assays were performed to evaluate the cytotoxicity of LNCs on mouse macrophage-like cells RAW264.7 after 24h of exposure. The determination of 50% lethal concentration (LC50) showed a size effect of LNCs on toxicity profiles: LC50 ranged from 1.036mg/L (MTS) and 0.477mg/mL (NRU) for 25nm LNCs, to 4.42mg/mL (MTS) and 2.18mg/mL (NRU) for 100nm LNCs. Surfactant Solutol® HS15 has been shown to be the only constituent to exhibit cytotoxicity; its LC50 reached 0.427mg/mL. Moreover, LNCs were not more toxic than their components in simple mixtures. At sublethal concentration, 100nm LNCs only were able to induce a significant production of nitric oxide (NO) by RAW264.7 cells, as assessed by the Griess reaction. Again, surfactant was the only component responsible for an increased NO release (1.8±0.2-fold). Genotoxicity assays revealed no DNA damage on human lymphocytes in both the in vitro Comet and micronucleus assays using 4-hour and 24-hour treatments, respectively.
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Portadores de Fármacos/toxicidade , Lipídeos/toxicidade , Nanocápsulas/toxicidade , Polietilenoglicóis/toxicidade , Ácidos Esteáricos/toxicidade , Tensoativos/toxicidade , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ensaio Cometa , Feminino , Humanos , Linfócitos/efeitos dos fármacos , Masculino , Camundongos , Testes para Micronúcleos , Óxido Nítrico/metabolismo , Células RAW 264.7RESUMO
Lipid nanocapsules (LNCs) are potential drug carriers for pulmonary delivery since they can be nebulized without any structural or functional changes, and the aerosols produced are highly compatible with pulmonary drug delivery in human beings. The alveolar surface tension, in vitro cytotoxicity, biodistribution and pulmonary toxicity in rats of a single endotracheal spray of LNCs or paclitaxel-loaded LNCs were studied. In vitro cytotoxicity of LNCs after a spray remained unchanged. Biodistribution study showed a homogeneous repartition in the lungs in rats with an improvement in lung retention of the radiolabeled tracer loaded in LNCs compared to the absence of LNCs with a lung half-time of 8.8±0.7 hours. Bronchoalveolar fluid analysis revealed transient 7-day alveolar inflammation, reaching a maximum between days 2 and 4, characterized by a peak of granulocytes at day 1 followed by a peak of lymphocytes at day 3. Alveolar protein levels were increased at days 3 and 7. Acute inflammation was increased with paclitaxel-loaded LNCs in comparison with blank LNCs but dropped out at day 7. No histological pulmonary lesion was observed at day 60. LNCs lowered surface tension to a greater degree than Curosurf® in a physicochemical model of the pulmonary alveolus. A single pulmonary delivery of LNCs induces a short-term alveolar inflammation with no residual lesions in rats at day 60. These data permit to start the study of LNCs in surfactant replacement therapy.
Assuntos
Portadores de Fármacos/efeitos adversos , Portadores de Fármacos/farmacocinética , Pulmão/efeitos dos fármacos , Pulmão/patologia , Nanocápsulas/efeitos adversos , Aerossóis/administração & dosagem , Aerossóis/efeitos adversos , Aerossóis/química , Animais , Produtos Biológicos , Linhagem Celular , Portadores de Fármacos/administração & dosagem , Sistemas de Liberação de Medicamentos/efeitos adversos , Sistemas de Liberação de Medicamentos/métodos , Feminino , Fibrose , Humanos , Lipídeos/química , Nanocápsulas/administração & dosagem , Nanocápsulas/química , Paclitaxel/química , Paclitaxel/farmacocinética , Fosfolipídeos , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/fisiopatologia , Ratos Sprague-Dawley , Tensão Superficial/efeitos dos fármacos , Distribuição TecidualRESUMO
Lipid nanocapsules (LNCs) were designed more than 15 years ago to deliver lipophilic drugs to cells with non toxic excipients by mimicking lipoproteins. During the last 5 years these promising nanocarriers were re-designed to deliver nucleic acids to cancer cells. This short review sums up the features of LNCs and describes how DNAs or RNAs can be associated or encapsulated in these lipid carriers. The results of transfection effects on cells in vitro or in vivo are also presented. These new therapeutic strategies have been mainly proposed for glioma and melanoma treatment because these cancers are characterized by multiple acquired resistances, which can be reversed by DNA transfection or siRNA interference as it is discussed in this paper. In conclusion, LNCs are very good candidates to deliver nucleic acids to cells in the course of anti-cancer therapies.
Assuntos
DNA/administração & dosagem , Lipídeos/química , Nanocápsulas/química , RNA/administração & dosagem , Glioma/tratamento farmacológico , Humanos , Melanoma/tratamento farmacológico , Transfecção/métodosRESUMO
The oral administration of proteins is a current challenge to be faced in the field of therapeutics. There is currently much interest in nanocarriers since they can enhance oral bioavailability. For lack of a clear definition, the key characteristics of nanoparticles have been highlighted. Specific surface area is one of these characteristics and represents a huge source of energy that can be used to control the biological fate of the carrier. The review discusses nanocarrier stability, mucus interaction and absorption through the intestinal epithelium. The protein corona, which has raised interest over the last decade, is also discussed. The universal ideal surface is a myth and over-coated carriers are not a solution either. Besides, common excipients can be useful on several targets. The suitable design should rather take into account the composition, structure and behavior of unmodified nanomaterials.
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Portadores de Fármacos/química , Portadores de Fármacos/síntese química , Nanopartículas/química , Peptídeos/administração & dosagem , Peptídeos/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Humanos , Mucosa Intestinal/metabolismoRESUMO
Medicines for the treatment of rare diseases frequently do not attract the interest of the pharmaceutical industry, and hospital pharmacists are thus often requested by physicians to prepare personalized medicines. Tuberous Sclerosis Complex (TSC) is a rare disease that causes disfiguring lesions named facial angiofibromas. Various topical formulations of rapamycin (=sirolimus) have been proved effective in treating these changes in small case series. The present study provides for the first time characterization of a 0.1% rapamycin cream formulation presenting good rapamycin solubilisation. The first step of the formulation is solubilisation of rapamycin in Transcutol(®), and the second step is the incorporation of the mixture in an oil-in-water cream. A HPLC stability-indicating method was developed. Rapamycin concentration in the cream was tested by HPLC and confirmed that it remained above 95% of the initial concentration for at least 85days, without characteristic degradation peaks. The preparation met European Pharmacopoeia microbial specifications throughout storage in aluminum tubes, including when patient use was simulated. Odour, appearance and colour of the preparation were assessed and no change was evidenced during storage. The rheological properties of the cream also remained stable throughout storage. To conclude, we report preparation of a novel cream formulation presenting satisfactory rapamycin solubilisation for the treatment of TSC cutaneous manifestations, with stability data. The cream is currently being used by our patients. Efficacy and tolerance will be reported later.