An adaptable model for growth and/or shrinkage of droplets in the respiratory tract during inhalation of aqueous particles

AbstractThe site of deposition of pulmonary delivered aerosols is dependent on the aerosol׳s droplet size distribution, which may change during inhalation. The aim of this study was to develop a freely accessible and adaptable model that describes the growth (due to condensation) and shrinkage (due to evaporation) of inhaled droplets as a function of the distance from the airway wall during various inhalation conditions, for a laminar flow scenario. This was achieved by developing a model with which the evaporation of water from a droplet surface or condensation of water onto the droplet surface can be calculated. This model was then applied to a second model that describes the heat and mass transfer from the airway wall to the inhaled aerosol. The latter was based on the Weibel model. It was found that the growth and shrinkage of inhaled droplets markedly differs, depending on the distance from the airway wall. Droplets near the wall start to grow immediately due to fast water vapor transfer from the wall to the cold inhaled air. This growth continues until the air reaches body temperature and is fully saturated. However, droplets in the center of the airway first evaporate partly, due to a delay in water vapor transfer from the airway wall, before they start to grow. Depending on the conditions during inhalation, the droplet size distribution can widen considerably, which may affect the lung deposition and thereby the efficacy of the inhalation therapy. In conclusion, the model was able to show the effect of the conditions in the respiratory tract on the growth and shrinkage of inhaled droplets during standard inhalation conditions. Future developments can be aimed at expanding the model to include turbulent flow and hygroscopic growth, to improve the accuracy of the model and make it applicable to both droplets of solutions and dry particles

Natural and bioinspired excipients for dry powder inhalation formulations

Pulmonary drug delivery can have several advantages over other administration routes, in particular when using dry powder formulations. Such dry powder inhalation formulations generally include natural and bio-inspired excipients, which, among other purposes, are used to improve dosing reproducibility and aerosolization performance. Amino acids can enhance powder dispersibility and provide protection against moisture uptake. Sugars are used as drug-carrying diluents, stabilizers for biopharmaceuticals, and surface enrichers. Lipids and lipid-like excipients can reduce interparticle adhesive forces and are also used as constituents of liposomal drug delivery systems. Finally, biodegradable polymers are used to facilitate sustained release and targeted drug delivery. Despite their promise, pulmonary toxicity of many of the discussed excipients remains largely unknown and requires attention in future research

An overview of the production methods for core-shell microspheres for parenteral controlled drug delivery

Core-shell microspheres hold great promise as a drug delivery system because they offer several benefits over monolithic microspheres in terms of release kinetics, for instance a reduced initial burst release, the possibility of delayed (pulsatile) release, and the possibility of dual-drug release. Also, the encapsulation efficiency can significantly be improved. Various methods have proven to be successful in producing these core-shell microspheres, both the conventional bulk emulsion solvent evaporation method and methods in which the microspheres are produced drop by drop. The latter have become increasingly popular because they provide improved control over the particle characteristics. This review assesses various production methods for core-shell microspheres and summarizes the characteristics of formulations prepared by the different methods, with a focus on their release kinetics

Gene therapy strategies for idiopathic pulmonary fibrosis:recent advances, current challenges, and future directions

Idiopathic pulmonary fibrosis (IPF) is a chronic disease in which the lungs become irreversibly scarred, leading to declining lung function. As currently available drugs do not cure IPF, there remains a great medical need for more effective treatments. Perhaps this need could be addressed by gene therapies, which offer powerful and versatile ways to attenuate a wide range of processes involved in fibrosis. Despite the potential benefits of gene therapy, no one has reviewed the current state of knowledge regarding its application for treating IPF. We therefore analyzed publications that reported the use of gene therapies to treat pulmonary fibrosis in animals, as clinical studies have not been published yet. In this review, we first provide an introduction on the pathophysiology of IPF and the most well-established gene therapy approaches. We then present a comprehensive evaluation of published animal studies, after which we provide recommendations for future research to address challenges with respect to the selection and use of animal models as well as the development of delivery vectors and dosage forms. Addressing these considerations will bring gene therapies one step closer to clinical testing and thus closer to patients

Microfluidic Production of Polymeric Core-Shell Microspheres for the Delayed Pulsatile Release of Bovine Serum Albumin as a Model Antigen

For many vaccines, multiple injections are required to confer protective immunity against targeted pathogens. These injections often consist of a primer administration followed by a booster administration of the vaccine a few weeks or months later. A single-injection vaccine formulation that provides for both administrations could greatly improve the convenience and vaccinee’s compliance. In this study, we developed parenterally injectable core-shell microspheres with a delayed pulsatile release profile that could serve as the booster in such a vaccine formulation. These microspheres contained bovine serum albumin (BSA) as the model antigen and poly(DL-lactide-co-glycolide) (PLGA) with various DL-lactide:glycolide monomer ratios as the shell material. Highly monodisperse particles with different particle characteristics were obtained using a microfluidic setup. All formulations exhibited a pulsatile in vitro release of BSA after an adjustable lag time. This lag time increased with the increasing lactide content of the polymer and ranged from 3 to 7 weeks. Shell thickness and bovine serum albumin loading had no effect on the release behavior, which could be ascribed to the degradation mechanism of the polymer, with bulk degradation being the main pathway. Co-injection of the core-shell microspheres together with a solution of the antigen that serves as the primer would allow for the desired biphasic release profile. Altogether, these findings show that injectable core-shell microspheres combined with a primer are a promising alternative for the current multiple-injection vaccines

Validasi Metode Kromatografi Lapis Tipis untuk Penentuan Konsentrasi Kurkumin dalam Sampel Disolusi yang Mengandung Ektrak Curcuma longa

Curcumin is a lipophilic compound which suffers from the poor bioavailability after oral administration. Increasing its dissolution rate can be a successful strategy to improve the bioavailability. Along with the formulation developments, a rapid and simple analytical method to determine curcumin concentrations in the dissolution medium is required. The aim of this study was to develop and to validate an analytical method based on thin layer chromatography (TLC) to determine curcumin concentrations in a dissolution medium containing 0.5% w/v sodium lauryl sulfate (SLS) and 20 mM sodium phosphate buffer. A polyvinylpyrrolidone K30 based solid dispersion of Curcuma longa extract and its corresponding physical mixture were dissolved in a medium containing 0.5% w/v SLS and 20 mM sodium phosphate buffer (pH 6.0). Dissolution samples were spotted on a normal TLC plate and eluents of various compositions were evaluated. The retardation factor (Rf), resolution (Rs), and asymmetry factor (As0.05) of the optimized method were determined. Using the optimized eluent, proper separation of curcumin peak was achieved with an Rf of 0.50, Rs of 2.62 and As 0.05of 0.87. Linearity (5-30 μg/mL) was demonstrated by r value of 0.9965. The TLC method provided precision with RSD ≤3.50 and accuracy with recovery value of 94-105%.Kurkumin merupakan senyawa lipofilik dengan permasalahan bioavailabilitas setelah pemberian oral. Meningkatkan laju disolusi menjadi strategi utama untuk meningkatkan bioavailabilitas kurkumin. Seiring dengan perkembangan formulasi, metode analisis yang cepat dan sederhana diperlukan untuk menentukan konsentrasi kurkumin dalam medium disolusi. Tujuan dari penelitian ini adalah untuk mengembangkan dan memvalidasi metode kromatografi lapis tipis (KLT) untuk analisis kurkumin dalam medium disolusi yang mengandung 0,5% b/v sodium lauryl sulfate (SLS) dalam 20 mM dapar fosfat. Formulasi dispersi padat ekstrak Curcuma longa dalam matriks polyvinylpyrrolidone K30 dan campuran fisiknya dilarutkan dalam media yang mengandung 0,5% b/v SLS dalam 20 mM buffer fosfat (pH 6,0). Sampel disolusi yang telah ditotolkan pada lempeng KLT dikembangkan dalam beberapa komposisi eluen. Faktor retardasi (Rf), resolusi (Rs), dan faktor asimetri (As0.05) dievaluasi.Komposisi eluen yang optimal dari kloroform, etanol, dan 2% asam asetat memberikan pemisahan sempurna puncak kurkumin dari puncak senyawa derivat kurkumin dengan Rf 0,50, Rs 2,62 dan As0,05of 0,87. Linearitas diperoleh pada 5-30 μg/ mL yang ditunjukkan oleh nilai r 0,9965. Metode KLT ini memberikan presisi dan akurasi sesuai dengan regulasi dengan RSD ≤ 3,50 dan perolehan kembali 94-105%

Aspartate buffer and divalent metal ions affect the oxytocin conformation in aqueous solution and protect it from degradation

In Press, Accepted Manuscript — Note to user

Dermal substitutes for full‐thickness wounds in a one‐stage grafting model

We tested different biodegradable matrix materials as dermal substitutes in a porcine wound model. Matrixes were covered with a split-skin mesh graft and protected with a microporous, semipermeable membrane, which prevents blister formation, wound infection and provides ultimate healing conditions. Evaluation parameters were as follows: epithelization, dermal reconstitution, wound contraction, and cosmetic and functional aspect. A microfibrillar matrix of nondenatured collagen gave the best result, with immediate fibroblast ingrowth and epidermal outgrowth. Slight inflammatory reaction and minimal wound contraction were observed. Application of a split-skin mesh graft, in combination with this collagen matrix, generated a thicker dermal layer than did a split-skin mesh graft directly applied on a wound bed. However, the histologic dermal architecture was less optimal than one obtained with a full-thickness punch graft method. Other matrixes caused inflammatory reactions, interfering with epithelization and dermal reconstitution. We conclude that a nondenatured collagen matrix, in combination with a split-skin mesh graft, can provide a substitute dermis in a full-thickness wound. This combination is preferable to a split-skin mesh graft directly applied on the wound bed. With our microporous semipermeable membrane, the combined use of a dermal substitute and a split-skin mesh graft can be applied in a single-stage operatio

Formulation and in vitro evaluation of pellets containing sulfasalazine and caffeine to verify ileo-colonic drug delivery

The ColoPulse coating is a pH-dependent coating that can be used to target drug release to the ileo-colonic region. ColoPulse coated tablets and capsules have demonstrated their targeting capabilities in vivo in more than 100 volunteers and patients. However, so far the ColoPulse coating has not been used for multi-particulate pellet formulations. The sulfasalazine–caffeine method can be used to confirm ileo-colonic drug delivery in vivo. Caffeine serves as a release marker in this method, while sulfasalazine serves as a marker for colonic arrival. In this study, extrusion–spheronization was used to produce microcrystalline cellulose based pellets containing both caffeine and sulfasalazine. Dissolution tests revealed that a superdisintegrant, i.e., croscarmellose sodium or sodium starch glycolate, should be incorporated in the formulation to achieve acceptable release profiles for both sulfasalazine and caffeine. However, acceptable release profiles were only obtained when the pelletizing liquid consisted of ethanol/water 1/1 (v/v) but not with pure water. This phenomenon was ascribed to the differences in the degree of swelling of the superdisintegrant in the pelletizing liquid during the granulation process. The pellets were coated with the ColoPulse coating and showed the desired pH-dependent pulsatile release profile in vitro. In future clinical studies, ileo-colonic targeting should be verified

Development of orodispersible films with selected Indonesian medicinal plant extracts

This study focused on the incorporation into orodispersible films (ODFs) of the dried extracts of five selected Indonesian medicinal plants: Lagerstroemia speciosa (L.) Pers. (LS), Phyllanthus niruri L. (PN), Cinnamomum burmanii Blume (CB), Zingiber officinale Roscoe (ZO) and Phaleria macrocarpa (Scheff.) Boerl (PM). Suitable formulae for solvent casting were developed to produce extract containing films with either a combination of hypromellose (HPMC) with carbomer 974P or only hydroxypropyl cellulose (HPC) as film forming agent. Each extract and dose in a formulation rendered different ODF characteristics. Extracts of ZO and CB and a low dose of PM extract (5 mg) could be formulated into an ODF containing HPMC with carbomer 974P. For extracts of LS, PN and high doses of PM extract HPC were the most suitable film forming agents. For each extract a different maximum load in a film was found, up to maximum 30 mg for extracts of LS and PN. Good products were obtained with 5 mg and 10 mg of each extract. The quality of the produced ODFs was tested organoleptically, and characterized by determination of uniformity of weight, thickness, disintegration time, surface pH, crystallinity, mechanical properties, water content, residual ethanol, dynamic vapour sorption, physical stability and control of the qualitative profiling of extract composition in the film. Thin layer chromatography indicated that all five extracts remained chemically unaffected during ODF production. In conclusion, ODFs are a suitable novel dosage form for herbal extracts, provided that tailor-made formulations are developed for each extract and each dose