Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 12 de 12
Filter
1.
PLoS One ; 17(8): e0272034, 2022.
Article in English | MEDLINE | ID: covidwho-2079709

ABSTRACT

RATIONALE: Inhaled antimicrobials enable high local concentrations where needed and, compared to orally administration, greatly reduce the potential for systemic side effects. In SARS-CoV-2 infections, hydroxychloroquine sulphate (HCQ) administered as dry powder via inhalation could be safer than oral HCQ allowing higher and therefore more effective pulmonary concentrations without dose limiting toxic effects. OBJECTIVES: To assess the local tolerability, safety and pharmacokinetic parameters of HCQ inhalations in single ascending doses of 5, 10 and 20 mg using the Cyclops dry powder inhaler. METHODS: Twelve healthy volunteers were included in the study. Local tolerability and safety were assessed by pulmonary function tests, electrocardiogram and recording adverse events. To estimate systemic exposure, serum samples were collected before and 0.5, 2 and 3.5 h after inhalation. RESULTS AND DISCUSSION: Dry powder HCQ inhalations were well tolerated by the participants, except for transient bitter taste in all participants and minor coughing irritation. There was no significant change in QTc-interval or drop in FEV1 post inhalation. The serum HCQ concentration remained below 10 µg/L in all samples. CONCLUSION: Single doses of inhaled dry powder HCQ up to 20 mg are safe and well tolerated. Our data support that further studies with inhaled HCQ dry powder to evaluate pulmonary pharmacokinetics and efficacy are warranted.


Subject(s)
COVID-19 , Hydroxychloroquine , Administration, Inhalation , COVID-19/drug therapy , Dry Powder Inhalers , Healthy Volunteers , Humans , Hydroxychloroquine/adverse effects , Powders , SARS-CoV-2
2.
J Aerosol Med Pulm Drug Deliv ; 35(5): 239-251, 2022 10.
Article in English | MEDLINE | ID: covidwho-2062819

ABSTRACT

Background: Ivermectin has received worldwide attention as a potential COVID-19 treatment after showing antiviral activity against SARS-CoV-2 in vitro. However, the pharmacokinetic limitations associated with oral administration have been postulated as limiting factors to its bioavailability and efficacy. These limitations can be overcome by targeted delivery to the lungs. In this study, inhalable dry powders of ivermectin and lactose crystals were prepared and characterized for the potential treatment of COVID-19. Methods: Ivermectin was co-spray dried with lactose monohydrate crystals and conditioned by storage at two different relative humidity points (43% and 58% RH) for a week. The in vitro dispersion performance of the stored powders was examined using a medium-high resistance Osmohaler connecting to a next-generation impactor at 60 L/min flow rate. The solid-state characteristics including particle size distribution and morphology, crystallinity, and moisture sorption profiles of raw and spray-dried ivermectin samples were assessed by laser diffraction, scanning electron microscopy, Raman spectroscopy, X-ray powder diffraction, thermogravimetric analysis, differential scanning calorimetry, and dynamic vapor sorption. Results: All the freshly spray-dried formulation (T0) and the conditioned samples could achieve the anticipated therapeutic dose with fine particle dose of 300 µg, FPFrecovered of 70%, and FPFemitted of 83%. In addition, the formulations showed a similar volume median diameter of 4.3 µm and span of 1.9. The spray-dried formulations were stable even after conditioning and exposing to different RH points as ivermectin remained amorphous with predominantly crystalline lactose. Conclusion: An inhalable and stable dry powder of ivermectin and lactose crystals was successfully formulated. This powder inhaler ivermectin candidate therapy appears to be able to deliver doses that could be safe and effective to treat the SARS-COV-2 infection. Further development of this therapy is warranted.


Subject(s)
COVID-19 , Administration, Inhalation , Antiviral Agents , COVID-19/drug therapy , Dry Powder Inhalers , Humans , Ivermectin , Lactose , Particle Size , Powders/chemistry , Respiratory Aerosols and Droplets , SARS-CoV-2
3.
Adv Drug Deliv Rev ; 189: 114527, 2022 Oct.
Article in English | MEDLINE | ID: covidwho-2060293

ABSTRACT

Lactose is the most commonly used excipient in carrier-based dry powder inhalation (DPI) formulations. Numerous inhalation therapies have been developed using lactose as a carrier material. Several theories have described the role of carriers in DPI formulations. Although these theories are valuable, each DPI formulation is unique and are not described by any single theory. For each new formulation, a specific development trajectory is required, and the versatility of lactose can be exploited to optimize each formulation. In this review, recent developments in lactose-based DPI formulations are discussed. The effects of varying the material properties of lactose carrier particles, such as particle size, shape, and morphology are reviewed. Owing to the complex interactions between the particles in a formulation, processing adhesive mixtures of lactose with the active ingredient is crucial. Therefore, blending and filling processes for DPI formulations are also reviewed. While the role of ternary agents, such as magnesium stearate, has increased, lactose remains the excipient of choice in carrier-based DPI formulations. Therefore, new developments in lactose-based DPI formulations are crucial in the optimization of inhalable medicine performance.


Subject(s)
Excipients , Lactose , Administration, Inhalation , Aerosols , Chemistry, Pharmaceutical , Drug Carriers , Dry Powder Inhalers , Humans , Particle Size , Powders
4.
Br J Clin Pharmacol ; 88(12): 5083-5092, 2022 12.
Article in English | MEDLINE | ID: covidwho-2001607

ABSTRACT

AIMS: Pressurised metered-dose inhalers (MDIs) have a much higher carbon footprint than dry powder inhalers (DPIs). We aimed to describe variations of inhaler options in local adult asthma prescribing guidance. METHODS: We reviewed local clinical commissioning group (CCG) adult asthma prescribing guidance for primary care in England in 2019 and recorded DPI and MDI inclusion. The relationship to prescribing data from OpenPrescribing.net was examined. RESULTS: In total, 58 unique guidance documents were analysed covering 144 out of 191 CCGs in England. Only 3% of CCG guidelines expressed an overall preference for DPIs, while 12% explicitly preferred MDIs. The inclusion of DPIs first-line was 77% for short-acting ß-agonists, 78% for low-dose inhaled corticosteroid (ICS) inhalers and 90-96% for combination long-acting ß-agonist/ICS inhalers. MDIs were included first-line in 98-100% of these classes. In 26% of CCGs, there was no first-line DPI option for at least 1 asthma management step. Ten percent of CCGs had no DPI included first-line for any of the 5 classes examined. Many CCGs recommended higher carbon footprint options; Ventolin MDI (25.6%), inhalers containing HFA227ea (57.9%) and ICS regimes recommending 2 puffs of a lower dose over 1 puff of higher dose (94.2%). MDIs were prescribed more in CCGs that recommended them. CONCLUSION: Before the COVID pandemic, there was substantial variation between CCGs in adult asthma prescribing guidance regarding higher and lower carbon footprint options. There may still be scope to amend local guidance to improve clinical and environmental outcomes. This study provides a method and baseline for further investigation of this.


Subject(s)
Asthma , COVID-19 , Humans , Adult , Carbon Footprint , Administration, Inhalation , Pandemics , COVID-19/drug therapy , COVID-19/epidemiology , Metered Dose Inhalers , Asthma/drug therapy , Dry Powder Inhalers , Adrenal Cortex Hormones , Primary Health Care
5.
Pharm Dev Technol ; 27(6): 635-645, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1915404

ABSTRACT

Remdesivir is one of the effective drugs proposed for the treatment of coronavirus disease 2019 (COVID-19). However, the study on inhalable regimen is currently limited though COVID-19 is respiratory diseases and infects lung area. This work aims to prepare inhalable remdesivir formulations and verify their effectiveness through in vitro evaluations. Formulations containing different ratios of jet-milled inhalable remdesivir (5, 10, 20,40, and 70%) with excipients were produced and characterized in terms of the particle size distribution, particle morphology, flowability, water content, crystallinity, the water sorption and desorption capabilities, and the aerodynamic performance. Results indicating that drug loading are a vital factor in facilitating the dispersion of remdesivir dry powder, and the ternary excipient plays a negligible role in improving aerosol performance. Besides, the 70% remdesivir with lactose carrier (70% RD-Lac) was physically stable and retain high aerosol performance after conditioned at 40 °C and 75% RH for a month. Therefore, formulation 70% RD-Lac might be recommended as a candidate product for the potential treatment of COVID-19.


Subject(s)
COVID-19 , Excipients , Adenosine Monophosphate/analogs & derivatives , Administration, Inhalation , Alanine/analogs & derivatives , COVID-19/drug therapy , Dry Powder Inhalers/methods , Humans , Lactose , Particle Size , Powders , Respiratory Aerosols and Droplets , Water
6.
Int J Chron Obstruct Pulmon Dis ; 17: 559-568, 2022.
Article in English | MEDLINE | ID: covidwho-1902770

ABSTRACT

Purpose: A suboptimal peak inspiratory flow (PIF) against a dry powder inhaler (DPI) may result in ineffective inhalation of medications, which may affect outcomes. The primary objective of this study was to examine the association between PIF status and COPD exacerbations among outpatients with moderate to very severe COPD. Patients and Methods: This was a prospective, observational study of patients from 7 US outpatient centers. PIF was measured using an inspiratory flow meter (In-Check™ DIAL G16) set to medium low resistance. Patients were classified by suboptimal (<60 L/min) or optimal PIF (≥60 L/min). The primary outcome was the proportion of patients with moderate/severe COPD exacerbations collected by medical record review over 12 months. Secondary outcomes were time to first exacerbation and mortality. Results: Of 474 patients screened, 38.8% had suboptimal PIF, and 71 patients with optimal PIF were excluded from the study. The enrolled sample included 184 and 219 patients with suboptimal and optimal PIF, respectively. Suboptimal PIF was associated with shorter stature (66.6±4.1 vs 67.8±3.8 inches, P = 0.002), female sex (45.1 vs 34.7%, P = 0.033), Black race (27.2 vs 11.0%, P < 0.001), and greater symptom burden (CAT: 22.3±7.7 vs 19.0±7.0, P < 0.001; mMRC: 2.0±1.1 vs 1.7±1.1, P = 0.003). The proportion of patients with COPD exacerbations at 12 months was not significantly different (29.3 vs 27.9%, P = 0.751). Suboptimal PIF was associated with shorter time to first COPD exacerbation (3.8±2.7 vs 4.9±3.0 months, P = 0.048). The mortality rate at 12 months was higher in the suboptimal cohort but not significantly different (6.5 vs 2.8%, P = 0.073). Conclusion: Over one-third of outpatients with stable moderate to very severe COPD had a suboptimal PIF against a medium low resistance DPI. The phenotype of suboptimal PIF was short stature, female, and Black. Suboptimal PIF status was associated with shorter time to moderate/severe COPD exacerbations compared with optimal PIF.


Subject(s)
Pulmonary Disease, Chronic Obstructive , Administration, Inhalation , Dry Powder Inhalers , Female , Humans , Outpatients , Powders/therapeutic use , Pulmonary Disease, Chronic Obstructive/diagnosis , Pulmonary Disease, Chronic Obstructive/drug therapy
7.
Int J Pharm ; 619: 121704, 2022 May 10.
Article in English | MEDLINE | ID: covidwho-1763774

ABSTRACT

Unpredictable outbreaks due to respiratory viral infections emphasize the need for new drug delivery strategies to the entire respiratory tract. As viral attack is not limited to a specific anatomic region, antiviral therapy that targets both the upper and lower respiratory tract would be most effective. This study aimed to formulate tamibarotene, a retinoid derivative previously reported to display broad-spectrum antiviral activity against influenza and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), as a novel dual particle size powder formulation that targets both the nasal cavity and the lung by a single route of intranasal administration. Spray freeze drying (SFD) and spray drying (SD) techniques were employed to prepare tamibarotene powder formulations, and cyclodextrin was used as the sole excipient to enhance drug solubility. With the employment of appropriate atomizing nozzles, particles of size above 10 µm and below 5 µm could be produced for nasal and lung deposition, respectively. The aerosol performance of the powder was evaluated using Next Generation Impactor (NGI) coupled with a glass expansion chamber and the powder was dispersed with a nasal powder device. By blending powder of two different particle sizes, a single powder formulation with dual aerosol deposition characteristic in both the nasal and pulmonary regions was produced. The aerosol deposition fractions in the nasal cavity and pulmonary region could be modulated by varying the powder mixing ratio. All dry powder formulations exhibited spherical structures, amorphous characteristics and improved dissolution profile as compared to the unformulated tamibarotene. Overall, a novel dual targeting powder formulation of tamibarotene exhibiting customizable aerosol deposition profile was developed. This exceptional formulation strategy can be adopted to deliver other antimicrobial agents to the upper and lower airways for the prevention and treatment of human respiratory infections.


Subject(s)
COVID-19 , Dry Powder Inhalers , Administration, Inhalation , Administration, Intranasal , Aerosols , Antiviral Agents , COVID-19/drug therapy , Humans , Lung , Particle Size , Powders , SARS-CoV-2
8.
Int J Pharm ; 619: 121688, 2022 May 10.
Article in English | MEDLINE | ID: covidwho-1747894

ABSTRACT

Pharmacokinetic limitations associated with oral ivermectin may limit its success as a potential COVID-19 treatment based on in vitro experiments which demonstrate antiviral efficacy against SARS-CoV-2 at high concentrations. Targeted delivery to the lungs is a practical way to overcome these limitations and ensure the presence of a therapeutic concentration of the drug in a clinically critical site of viral pathology. In this study, the pharmacokinetics (PK) and safety of inhaled dry powders of ivermectin with lactose were investigated in healthy mice. Female BALB/c mice received ivermectin formulation by intratracheal administration at high (3.15 mg/kg) or low doses (2.04 mg/kg). Plasma, bronchoalveolar lavage fluid (BALF), lung, kidney, liver, and spleen were collected at predetermined time points up to 48 h and analyzed for PK. Histological evaluation of lungs was used to examine the safety of the formulation. Inhalation delivery of ivermectin formulation showed improved pharmacokinetic performance as it avoided protein binding encountered in systemic delivery and maintained a high exposure above the in vitro antiviral concentration in the respiratory tract for at least 24 h. The local toxicity was mild with less than 20% of the lung showing histological damage at 24 h, which resolved to 10% by 48 h.


Subject(s)
COVID-19 , Administration, Inhalation , Animals , Antiviral Agents , COVID-19/drug therapy , Dry Powder Inhalers , Female , Humans , Ivermectin , Lung/metabolism , Mice , Mice, Inbred BALB C , Powders/metabolism , SARS-CoV-2
9.
Int J Pharm ; 614: 121457, 2022 Feb 25.
Article in English | MEDLINE | ID: covidwho-1616526

ABSTRACT

Dry powder inhalation therapy has been shown to be an effective method for treating respiratory diseases like asthma, Chronic Obstructive Pulmonary Diseases and Cystic Fibrosis. It has also been widely accepted and used in clinical practices. Such success has led to great interest in inhaled therapy on treating systemic diseases in the past two decades. The current coronavirus (COVID-19) pandemic also has increased such interest and is triggering more potential applications of dry powder inhalation therapy in vaccines and antivirus drugs. Would the inhaled dry powder therapy on systemic disorders be as encouraging as expected? This paper reviews the marketed and in-development dry powder inhaler (DPI) products on the treatment of systemic diseases, their status in clinical trials, as well as the potential for COVID-19 treatment. The advancements and unmet problems on DPI systems are also summarized. With countless attempts behind and more challenges ahead, it is believed that the dry powder inhaled therapy for the treatment of systemic disorders still holds great potential and promise.


Subject(s)
COVID-19 , Administration, Inhalation , COVID-19/drug therapy , Dry Powder Inhalers , Humans , Powders , SARS-CoV-2
10.
Int J Pharm ; 608: 121122, 2021 Oct 25.
Article in English | MEDLINE | ID: covidwho-1433361

ABSTRACT

Herein, we demonstrated the development and characterization of a dry powder inhaler (DPI) formulation of edoxaban (EDX); and investigated the in-vitro anticoagulation effect for the management of pulmonary or cerebral coagulopathy associated with COVID-19 infection. The formulations were prepared by mixing the inhalable micronized drug with a large carrier lactose and dispersibility enhancers, leucine, and magnesium stearate. The drug-excipient interaction was studied using X-Ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) methods. The drug and excipients showed no physical inter particulate interaction. The in-vitro drug aerosolization from the developed formulation was determined by a Twin Stage Impinger (TSI) at a flow rate of 60 ± 5 L /min. The amount of drug deposition was quantified by an established HPLC-UV method. The fine particle fraction (FPF) of EDX API from drug alone formulation was 7%, whereas the formulations with excipients increased dramatically to almost 7-folds up to 47%. The developed DPI formulation of EDX showed a promising in-vitro anticoagulation effect at a very low concentration. This novel DPI formulation of EDX could be a potential and effective inhalation therapy for managing pulmonary venous thromboembolism (VTE) associated with COVID-19 infection. Further studies are warranted to investigate the toxicity and clinical application of the inhaled EDX DPI formulation.


Subject(s)
Blood Coagulation Disorders/drug therapy , COVID-19 , Dry Powder Inhalers , Pyridines/administration & dosage , Thiazoles/administration & dosage , Administration, Inhalation , Aerosols , Blood Coagulation Disorders/virology , COVID-19/complications , Humans , Particle Size , Powders
11.
Hum Vaccin Immunother ; 18(2): 1940650, 2022 04 29.
Article in English | MEDLINE | ID: covidwho-1287959

ABSTRACT

The use of antibodies in the treatment of lung diseases is of increasing interest especially as the search for COVID-19 therapies has unfolded. Historically, the use of antibody therapy was based on multiple targets including receptors involved in local hyper-reactivity in asthma, viruses and micro-organisms involved in a variety of pulmonary infectious disease. Generally, protein therapeutics pose challenges with respect to formulation and delivery to retain activity and assure therapy. The specificity of antibodies amplifies the need for attention to molecular integrity not only in formulation but also during aerosol delivery for pulmonary administration. Drug product development can be viewed from considerations of route of administration, dosage form, quality, and performance measures. Nebulizers and dry powder inhalers have been used to deliver protein therapeutics and each has its advantages that should be matched to the needs of the drug and the disease. This review offers insight into quality and performance barriers and the opportunities that arise from meeting them effectively.


Subject(s)
Asthma , COVID-19 , Administration, Inhalation , Aerosols/therapeutic use , Antibodies/therapeutic use , Drug Delivery Systems/methods , Dry Powder Inhalers , Humans
12.
Int J Pharm ; 603: 120701, 2021 Jun 15.
Article in English | MEDLINE | ID: covidwho-1225261

ABSTRACT

In this work, we have developed and tested a dry powder form of niclosamide made by thin-film freezing (TFF) and administered it by inhalation to rats and hamsters to gather data about its toxicology and pharmacokinetics. Niclosamide, a poorly water-soluble drug, is an interesting drug candidate because it was approved over 60 years ago for use as an anthelmintic medication, but recent studies demonstrated its potential as a broad-spectrum antiviral with pharmacological effect against SARS-CoV-2 infection. TFF was used to develop a niclosamide inhalation powder composition that exhibited acceptable aerosol performance with a fine particle fraction (FPF) of 86.0% and a mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) of 1.11 µm and 2.84, respectively. This formulation not only proved to be safe after an acute three-day, multi-dose tolerability and exposure study in rats as evidenced by histopathology analysis, and also was able to achieve lung concentrations above the required IC90 levels for at least 24 h after a single administration in a Syrian hamster model. To conclude, we successfully developed a niclosamide dry powder inhalation that overcomes niclosamide's limitation of poor oral bioavailability by targeting the drug directly to the primary site of infection, the lungs.


Subject(s)
COVID-19 , Niclosamide , Administration, Inhalation , Aerosols , Animals , Cricetinae , Dry Powder Inhalers , Freezing , Humans , Particle Size , Powders , Rats , SARS-CoV-2
SELECTION OF CITATIONS
SEARCH DETAIL