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PURPOSE: The design development of a small, hand held, battery operated, breath actuated inhaler as a drug/device platform for inhaled insulin posed a number of technical challenges. Our goal was to optimize lung deposition and distribution with aerosol generators producing 3-6 µm particle size distribution. METHODS: In silico modeling with computational fluid dynamics (CFD) and in vitro testing of device components were assessed using an Alberta idealized adult airway (Copley, UK) to optimize mouthpiece and aerosol path design for dose delivered distal to the trachea. Human factors use testing was designed to determine the ability to perform inspiratory manuevers with LED guidance within target flow limits. In vivo testing with healthy normal subjects of radiolabeled aerosol compared 2 breathing patterns for lung deposition efficiency, distribution, and subject preference. RESULTS: CFD demonstrated that flows ≤5 L/min and ≥15 L/min reduced the delivery efficiencg. Prototypes tested with inspiratory flow of 10 L/min provided up to 70% of dose delivered distal to the model throat with aerosols of 3 to 6 µm. Users guided by LED were able to inhale for 8-24 s with 5 s breath hold. Lung dose >70% with peripheral to central ratios >2.0 were achieved, with subject preference for the longer inspiratory time with breath hold. CONCLUSION: The device design phase integration led to a novel design and inspiratory pattern with greater levels of peripheral deposition than previously reported with commercial inhalers. The rationale and process of the application of these methods are described with implications for use in future device development.
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Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Administração por Inalação , Adulto , Aerossóis/administração & dosagem , Aerossóis/química , Aerossóis/farmacocinética , Idoso , Simulação por Computador , Estudos Cross-Over , Desenho de Equipamento , Feminino , Humanos , Hidrodinâmica , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Insulina/química , Insulina/farmacocinética , Pulmão/metabolismo , Masculino , Pessoa de Meia-Idade , Nebulizadores e Vaporizadores , Tamanho da Partícula , Adulto JovemRESUMO
We are in the business of research. We are in the business of developing new drug delivery systems. And we are in the business of manufacturing products that help patients, patients who must contend with diseases that diminishes or shortens their lives. At all stages from basic research to final manufacturing, teams are the best way to advance efficiently. Whether it be in academia, where the fundamental science and engineering insights are discovered and elucidated, or in the world of highly structured pharmaceutical development, where a new product must be scrupulously tested and proven to work in patients, our teams have a mission: to make lives better. A team is a group of people who perform interdependent tasks to work toward accomplishing a common mission or specific objective. In this article, we share some strategies for fostering successful teams in drug delivery. We focus here on drug delivery as the field we know the best; but we think many of the points are relevant in many fields. While it is likely in some instances you may be a team leader; it is more likely you will be a member of a team. And so we start with a focus on being a team player.
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Sistemas de Liberação de Medicamentos , HumanosRESUMO
A table-top microdevice was introduced in this work to produce ultrasmall particles for drug delivery via inhalation. The design and operation are similar to that of spray-drying equipment used in industry, but the device itself is much smaller and more portable in size, simpler to operate and more economical. More importantly, the device enables more accurate control over particle size. Using Flavopiridol, an anti-inflammation medication, formulations have been developed to produce inhalable particles for pulmonary delivery. A solution containing the desired components forms droplets by passing through an array of micro-apertures that vibrate via a piezo-electrical driver. High-purity nitrogen gas was introduced and flew through the designed path, which included the funnel collection and cyclone chamber, and finally was pumped away. The gas carried and dried the micronized liquid droplets along the pathway, leading to the precipitation of dry solid microparticles. The formation of the cyclone was essential to assure the sufficient travel path length of the liquid droplets to allow drying. Synthesis parameters were optimized to produce microparticles, whose morphology, size, physio-chemical properties, and release profiles met the criteria for inhalation. Bioactivity assays have revealed a high degree of anti-inflammation. The above-mentioned approach enabled the production of inhalable particles in research laboratories in general, using the simple table-top microdevice. The microparticles enable the inhalable delivery of anti-inflammation medicine to the lungs, thus providing treatment for diseases such as pulmonary fibrosis and COVID-19.
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Remarkably, with the exception of anaesthetic gases, the ancient human practice of inhaling substances into the lungs for systemic effect has only just begun to be adopted by modern medicine. Treatment of asthma by inhaled drugs began in earnest in the 1950s, and now such 'topical' or targeted treatment with inhaled drugs is considered for treating many other lung diseases. More recently, major advances have led to increasing interest in systemic delivery of drugs by inhalation. Small molecules can be delivered with very rapid action, low metabolism and high bioavailability; and macromolecules can be delivered without injections, as highlighted by the recent approval of the first inhaled insulin product. Here, we review these advances, and discuss aspects of lung physiology and formulation composition that influence the systemic delivery of inhaled therapeutics.
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Administração por Inalação , Pulmão/metabolismo , Preparações Farmacêuticas/administração & dosagem , Absorção , Química Farmacêutica , Humanos , FarmacocinéticaRESUMO
The benefits of intensive insulin therapy in the prevention of complications in patients with diabetes mellitus are now well established. However, the current methods of insulin administration fall well short of the ideal. Consequently, alternative routes of insulin administration have been investigated. The pulmonary route has received the most attention, helped by advances in inhaler devices and insulin formulation technology. As a result, several insulin inhalation systems are at varying stages of development, with one already filed for marketing approval in Europe. Knowledge of the pharmacokinetic and pharmacodynamic characteristics of the various inhaled insulin formulations will help to determine their positioning in current and evolving diabetes treatment strategies. For instance, a rapid onset and short duration of action would be desirable for use in postprandial glucose control. Pharmacokinetic studies with inhaled insulin reveal that serum insulin concentrations peak earlier and decay more rapidly following inhalation compared with subcutaneously administered regular insulin, and pharmacodynamic studies measuring glucose infusion rate under euglycaemic glucose clamp show corresponding rapid changes in glucose control. Furthermore, intrapatient variability in the pharmacokinetics and pharmacodynamics of inhaled insulin is low; variability is similar to (or perhaps less than) that seen when insulin is administered subcutaneously. Estimates of the bioavailability and bioefficacy achievable with the current inhalation systems are typically in the region of 10% of that experienced with subcutaneously administered insulin. Most of the losses are in the device, mouth and throat, with approximately 30-50% of the insulin deposited in the lungs being absorbed. Clinical experience to date indicates that inhaled insulin has the potential to be an effective treatment in patients with diabetes, and that it may have particular utility in the treatment of postprandial hyperglycaemia.
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Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Insulina , Administração por Inalação , Área Sob a Curva , Disponibilidade Biológica , Ensaios Clínicos como Assunto , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Insulina/administração & dosagem , Insulina/farmacocinética , Insulina/farmacologiaRESUMO
BACKGROUND: Pancreatic proteolytic digestive enzymes are a major extracellular barrier to the sucessful systemic delivery of biopharmaceuticals via the oral route, whereas in health in the lungs these powerful proteases are virtually absent from the extracellular fluids. Despite this, the absorption of some (but not all) natural peptides and proteins from the lungs may be poor, and one has to acknowledge that information on the activity and spatial distribution of proteolytic enzymes in the human lung is scarce. Here, we investigated expression patterns of a series of proteolytic enzymes in several human respiratory cell types on mRNA level in an attempt to better understand the fate of inhaled biopharmaceuticals. METHODS: The mRNA expression of proteolytic enzymes (i.e., carboxypeptidases: CPA1, CPA2, CPB, CPM; gamma-glutamyltransferases: GGT1, GGT2; angiotensin-converting enzymes: ACE, ACE2; aminopeptidases: APA, APB, APN, APP1, APP2, APP3; endopeptidases: 24.11 (neprilysin), 24.15 (thimet oligopeptidase), 24.18 (meprin A); enteropeptidase; trypsin 1, trypsin 2; neutrophilic elastase; dipeptidyl peptidase 4; gamma-glutamylhydrolase) was investigated by semiquantitative RT-PCR in human bronchial (hBEpC, Calu-3, 16HBE14o-) and alveolar (A549) epithelial cells, respectively. Gastrointestinal Caco-2 cells were used as comparison. RESULTS: Obvious differences were observed in proteinases' expression pattern between the investigated cell types. Although considered to be of bronchial epithelial phenotype, neither Calu-3 nor 16HBE14o- cells matched the mRNA expression pattern of hBEpC in primary culture. Of all investigated cell lines, Caco-2 expresses the highest number of proteases and peptidases. CONCLUSIONS: Although mRNA expression does not necessarily signify enzyme functionality, our results provide the first comprehensive analysis of peptidase and protease expression and distribution in human lung epithelial cells and are the basis for further investigations.
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Células Epiteliais/enzimologia , Perfilação da Expressão Gênica/métodos , Peptídeo Hidrolases/genética , Mucosa Respiratória/enzimologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células CACO-2 , Células Cultivadas , Regulação Enzimológica da Expressão Gênica , Humanos , Mucosa Intestinal/enzimologia , RNA Mensageiro/metabolismoRESUMO
Although there is a modest body of literature on the absorption of inhaled pharmaceuticals by normal lungs and some limited information from diseased lungs, there is still a surprising lack of mechanistic knowledge about the details of the processes involved. Where are molecules absorbed, what mechanisms are involved, how well are different lung regions penetrated, what are the determinants of metabolism and dissolution, and how best can one retard the clearance of molecules deposited in the lung or induce intracellular uptake by lung cells? Some general principles are evident: (1) small hydrophobic molecules are absorbed very fast (within tens of seconds) usually with little metabolism; (2) small hydrophilic molecules are absorbed fast (within tens of minutes), again with minimal metabolism; (3) very low water solubility of the drug can retard absorption; (4) peptides are rapidly absorbed but are significantly metabolized unless chemically protected against peptidases; (5) larger proteins are more slowly absorbed with variable bioavailabilities; and 6) insulin seems to be best absorbed distally in the lungs while certain antibodies appear to be preferentially absorbed in the upper airways. For local lung disease applications, and some systemic applications as well, many small molecules are absorbed much too fast for convenient and effective therapies. For systemic delivery of peptides and proteins, absorption may sometimes be too fast. Bioavailabilities are often too low for cost-effective and reliable treatments. A better understanding of the determinants of pulmonary drug dissolution, absorption, metabolism, and how to target specific regions and/or cells in the lung will enable safer and more effective inhaled medicines in the future.
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Sistemas de Liberação de Medicamentos , Pulmão/metabolismo , Preparações Farmacêuticas/administração & dosagem , Administração por Inalação , Aerossóis , Animais , Disponibilidade Biológica , Humanos , Interações Hidrofóbicas e Hidrofílicas , Tamanho da Partícula , Preparações Farmacêuticas/química , Preparações Farmacêuticas/metabolismo , Fatores de Tempo , Distribuição TecidualAssuntos
Produtos Biológicos/administração & dosagem , Portadores de Fármacos , Indústria Farmacêutica , Proteínas/administração & dosagem , Tecnologia Farmacêutica/métodos , Administração por Inalação , Produtos Biológicos/química , Produtos Biológicos/metabolismo , Escolha da Profissão , Química Farmacêutica , Portadores de Fármacos/história , Composição de Medicamentos , Indústria Farmacêutica/história , Indústria Farmacêutica/legislação & jurisprudência , Indústria Farmacêutica/tendências , História do Século XX , História do Século XXI , Humanos , Legislação de Medicamentos , Proteínas/química , Proteínas/metabolismo , Tecnologia Farmacêutica/história , Tecnologia Farmacêutica/legislação & jurisprudência , Tecnologia Farmacêutica/tendênciasRESUMO
As the incidence of diabetes reaches epidemic proportions, the use of new, alternative routes of insulin delivery to manage glycaemic control is becoming an ever more active area of research. The high permeability and large surface area of the lung make it an attractive alternative to subcutaneous (SC) insulin injections. This review discusses the technical factors that influence the efficacy of pulmonary drug delivery and describes how an appreciation of these issues has enabled the design of Exubera, a novel, non-invasive, pulmonary dry-powder human insulin delivery system currently in development by Pfizer and the Sanofi-Aventis Group in collaboration with Nektar Therapeutics. While clinical trials of this novel aerosol delivery of insulin are still ongoing in patients with diabetes, the results so far suggest it is simple to use and can provide reproducible doses of insulin in therapeutic amounts with only a few inhalations per dose. In addition, it has been shown to be comparable in terms of efficacy and safety to a conventional SC insulin injection regimen. Delivering aerosolized drugs via the lungs avoids the necessity for SC injections and thereby may increase the patient's acceptability of an insulin-based therapeutic regimen.
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Diabetes Mellitus/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Administração por Inalação , Glicemia/metabolismo , Diabetes Mellitus/sangue , Humanos , Hipoglicemiantes/farmacocinética , Insulina/farmacocinética , Nebulizadores e VaporizadoresRESUMO
The lung is naturally permeable to all small-molecule drugs studied and to many therapeutic peptides and proteins. Absorption can be estimated using a simple animal test, intratracheal instillation. Inhalation offers a noninvasive route for the delivery of peptides and proteins that otherwise must be injected. Peptides that have been chemically altered to inhibit peptidase enzymes exhibit very high bioavailabilities by the pulmonary route. Natural mammalian peptides, less than about 30 amino acids, are broken down in the lung by ubiquitous peptidases and have very poor bioavailabilities. In general, proteins with molecular weights between 6,000 and 50,000 D are relatively resistant to most peptidases and have good bioavailabilities following inhalation. For larger proteins the bioavailability picture is not clear. Although the lung is rich in antiproteases, aggregation of inhaled proteins will stimulate opsonization (coating) by special proteins in the lung lining fluids, which will then mark the aggregated proteins for phagocytosis and intracellular enzymatic destruction. Small peptides and proteins are absorbed more rapidly after inhalation than after subcutaneous injection. For other small molecules, inhalation is also a fast way to get into the body because drug efflux transporters and metabolizing enzymes are present in the lung at much lower levels than the gastrointestinal tract. Lipophilic small molecules are absorbed extremely fast, t(1/2) (abs) approximately 1 to 2 minutes. Water-soluble small molecules are absorbed rapidly t(1/2) (abs) approximately 65 minutes. Small molecules can exhibit prolonged absorption if they are highly insoluble or highly cationic. Encapsulation in slow release particles such as liposomes can also be used to control absorption.