RESUMO
Nowadays, dry powder inhalation as applied in the therapy of pulmonary diseases is known as a very effective route of drug delivery to the lungs. Here, the system of coarse carrier and fine drug particles attached to the carrier surface has successfully been applied to overcome the cohesiveness of small drug particles. Particle properties of both carrier and drug are known to affect drug dispersion as has widely been discussed for lactose monohydrate and various drugs. This study utilises particle-engineered mannitol as an alternative carrier to discover the effect of mannitol carrier particle properties like particle shape, surface roughness, flowability or particle size on aerodynamic performance during inhalation. Spray drying as a technique to accurately control those properties was chosen for the generation of carrier sizes between 50 and 80 µm and different morphologies and therefore various carrier flowabilities. A set of these carriers has then been blended with different spray dried and jet-milled qualities of salbutamol sulphate as model drug to examine the influence of carrier particle properties on aerodynamic behaviour and at the same time to cover the effect of drug particle properties on particle-particle interactions. This experimental setup allowed a general view on how drug and carrier properties affect the Fine Particle Fraction (FPF) as indicator for inhalation performance and gave the first study to distinguish between mannitol carrier particle shape and surface roughness. Further it was possible to relate carrier particle size and shape to drug accumulation and detachment mechanisms during inhalation as size and shape had the main influence on drug detachment. The addition of jet-milled mannitol fines provided an initial insight into the improving effect of ternary powder blends as has been intensively studied for lactose monohydrate but not for mannitol yet.
Assuntos
Albuterol/administração & dosagem , Portadores de Fármacos/química , Inaladores de Pó Seco , Manitol/química , Administração por Inalação , Aerossóis , Lactose , Tamanho da Partícula , PósRESUMO
A prerequisite for the formation of glassy solid solutions prepared by the melting method is the miscibility of the respective drug and the carrier in the molten state. As could be shown experimentally, all investigated drug/sugar alcohol combinations miscible in the molten state form to some extent glassy solid solutions, dependent on their tendency to recrystallize during preparation. Therefore, the present study focuses on the evaluation of factors that govern the miscibility of molten drugs and sugar alcohols as carriers. In this context, solubility parameters are discussed as a means of predicting miscibility in comparison to a new approach, using calculated interaction parameters derived from molecular dynamics (MD) studies. There is evidence that a Coulomb interaction term C(SR), comprising short-range electrostatic interactions and hydrogen bonding energy is essential for the miscibility of drug and carrier in the molten state. To relate C(SR) to the molecular volume, a non-dimensional parameter P(i) is defined. For this parameter, a limiting value for miscibility exists. Contrary, calculated solubility parameter differences between drug and sugar alcohol in the range of 8-15 MPa(1/2) are not suitable for a prediction of miscibility or immiscibility, since the mixtures deviate from regular solution behavior. In irregular mixtures of drugs and sugar alcohols, an excess entropy and the formation of hydrogen bonds between unlike molecules favor miscibility, that cannot be predicted by regular solution theory.
Assuntos
Vidro/química , Soluções Farmacêuticas/química , Álcoois Açúcares/química , Vidro/análise , Soluções Farmacêuticas/análise , Valor Preditivo dos Testes , Álcoois Açúcares/análiseRESUMO
Pulmonary drug delivery by dry powder inhalers is becoming more and more popular. Such an inhalation device must insure that during the inhalation process the drug powder is detached from the carrier due to fluid flow stresses. The goal of the project is the development of a drug powder detachment model to be used in numerical computations (CFD, computational fluid dynamics) of fluid flow and carrier particle motion through the inhaler and the resulting efficiency of drug delivery. This programme will be the basis for the optimisation of inhaler geometry and dry powder inhaler formulation. For this purpose a multi-scale approach is adopted. First the flow field through the inhaler is numerically calculated with OpenFOAM(®) and the flow stresses experienced by the carrier particles are recorded. This information is used for micro-scale simulations using the Lattice-Boltzmann method where only one carrier particle covered with drug powder is placed in cubic flow domain and exposed to the relevant flow situations, e.g. plug and shear flow with different Reynolds numbers. Therefrom the fluid forces on the drug particles are obtained. In order to allow the determination of the drug particle detachment possibility by lift-off, sliding or rolling, also measurements by AFM (atomic force microscope) were conducted for different carrier particle surface structures. The contact properties, such as van der Waals force, friction coefficient and adhesion surface energy were used to determine, from a force or moment balance (fluid forces versus contact forces), the detachment probability by the three mechanisms as a function of carrier particle Reynolds number. These results will be used for deriving the drug powder detachment model.
Assuntos
Inaladores de Pó Seco , Portadores de Fármacos/química , Hidrodinâmica , Microscopia de Força Atômica , Microscopia Eletrônica de Varredura , Modelos Teóricos , Preparações Farmacêuticas/química , PósRESUMO
Enhanced therapeutics are drug products derived from existing generic drugs that provide additional benefits to the patients and the healthcare system. Enhanced therapeutics are considered to be an important and relatively low risk source of innovation. Pulmonary drug delivery is the major delivery route to treat chronic respiratory diseases and has been proven as a potential delivery route for complex drugs that cannot be delivered orally. Development of dry powder inhalation systems targets the delivery of fine drug particles to the deep lung surface by a combination of drug formulation, primary packaging and a device, whereby each contributes to the overall performance. Various methodologies for the non-clinical and clinical performance testing of orally inhaled products have been proposed and applied with variable success. Regulatory pathways have been developed and applied since. Considerable efforts have been made during the past decade to understand and optimize pulmonary drug delivery including their efficient commercial manufacturing. Pulmonary drug delivery remains an area of future innovation in the effective treatment of pulmonary diseases as well as the systemic delivery of systemically active complex drugs.
Assuntos
Sistemas de Liberação de Medicamentos , Inaladores de Pó Seco , Administração por Inalação , Sistemas de Liberação de Medicamentos/economia , Inaladores de Pó Seco/economia , Honorários Farmacêuticos , Humanos , Preparações Farmacêuticas/administração & dosagem , Farmacocinética , Equivalência TerapêuticaRESUMO
The aim of this work was to study the performance of mannitol carrier particles of tailored surface roughness in dry powder inhaler formulations. Carrier particles of different surface roughness were prepared by spray drying of aqueous mannitol solutions at different outlet temperatures at a pilot-scale spray dryer. However, the carrier particles did not only change in surface roughness but also in shape. This is why the impact of carrier shape on the performance of carrier based dry powder inhalates was evaluated also. The highest fine particle fraction (FPF), that is the amount of active pharmaceutical substance, delivered to the deep lung, is achieved when using rough, spherical carrier particles (FPF=29.23 ± 4.73%, mean arithmetic average surface roughness (mean R(a))=140.33 ± 27.75 nm, aspect ratio=0.925). A decrease of surface roughness (mean R(a)=88.73 ± 22.25 nm) leads to lower FPFs (FPF=14.62 ± 1.18%, aspect ratio=0.918). The FPF further decreases when irregular shaped particles are used. For those particles, the micronized active accumulates within the cavities of the carrier surface during the preparation of the powder mixtures. Upon inhalation, the cavities may protect the active from being detached from the carrier.