disposable-dosators-intended-for-dry-powder-delivery-to-mice

Disposable Dosators Intended for Dry Powder Delivery to Mice

Dry powder inhalers offer numerous advantages for delivering drugs to the lungs, including stable solid-state drug formulations, device portability, bolus ...

RTI International

Tuberculosis (TB) remains the single most serious infectious disease attributable to a single-causative organism. A variety of drugs have been evaluated for pulmonary delivery as dry powders: capreomycin sulfate has shown efficacy and was safely delivered by inhalation at high doses to human volunteers, whereas CPZEN-45 is a new drug that has also been shown to kill resistant TB. The studies here combine these drugs-acting by different mechanisms-as components of single particles by spray-drying, yielding a new combination drug therapy. The spray-dried combination powder was prepared in an aerodynamic particle size range suitable for pulmonary delivery. Physicochemical storage stability was demonstrated for a period of 6 months. The spray-dried combination powders of capreomycin and CPZEN-45 have only moderate affinity for mucin, indicating that delivered drug will not be bound by these mucins in the lung and available for microbicidal effects. The pharmacokinetics of disposition in guinea pigs demonstrated high local concentrations of drug following direct administration to the lungs and subsequent systemic bioavailability. Further studies are required to demonstrate the in vivo efficacy of the combination to confirm the therapeutic potential of this novel combination.

A Spray-Dried Combination of Capreomycin and CPZEN-45 for Inhaled Tuberculosis Therapy.

Human tuberculosis (TB) is a global health problem that causes nearly 2 million deaths per year. Anti-TB therapy exists, but it needs to be administered as a cocktail of antibiotics for six months. This lengthy therapy results in low patient compliance and is the main reason attributable to the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis.

Development and Characterization of a Dry Powder Formulation for Anti-Tuberculosis Drug Spectinamide 1599.

Inhalable metal organic framework (MOF) aerosols have been developed via spray drying as a therapy for multi-drug resistant (MDR) tuberculosis (TB). The CuPOA (pyrazinoate acid) MOFs can be tailored to exhibit a respirable mass median aerodynamic diameter (MMAD) of 2.6 μm. This method is repeated to manufacture GdCu(POA) MOFs for inhalable theragnostics.

Designing inhalable metal organic frameworks for pulmonary tuberculosis treatment and theragnostics via spray drying.

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.

Inhaled antibodies: Quality and performance considerations.

The rise of the novel virus SARS-CoV2 which causes the disease known as COVID-19 has led to a global pandemic claiming millions of lives. With no clinically approved treatment for COVID-19, physicians initially struggled to treat the disease, and a need remains for improved antiviral therapies in this area. It is conceived early in the pandemic that an inhalable formulation of the drug remdesivir which directly targets the virus at the site of infection could improve therapeutic outcomes in COVID-19. A set of requirements are developed that would be conducive to rapid drug approval: 1) try to use GRAS reagents 2) minimize excipient concentration and 3) achieve a working concentration of 5 mg/mL remdesivir to obtain a deliverable dose which is 5-10% of the IV dose. In this work, it is discovered that Poly(2-oxazoline) block copolymers can stabilize drug nanocrystal suspensions and provide suitable formulation characteristics for aerosol delivery while maintaining antiviral efficacy. The authors believe POx block copolymers can be used as a semi-ubiquitous stabilizer for the rapid development of nanocrystal formulations for new and existing diseases.

Nanoformulated Remdesivir with Extremely Low Content of Poly(2-oxazoline)-Based Stabilizer for Aerosol Treatment of COVID-19.

Tuberculosis (TB) remains one of the most serious diseases caused by a single organism. Multiple (MDR) and extensively (XDR) drug resistant disease poses a threat to global health and requires new drugs and/or innovative approaches to treatment. A number of drugs have been proposed as inhaled therapy for TB, frequently prepared by spray drying. CPZEN-45 is a novel anti-tubercular drug that has poor oral bioavailability but has shown promise when administered via inhalation.

Optimization and Scale Up of Spray Dried CPZEN-45 Aerosol Powders for Inhaled Tuberculosis Treatment.

Nontuberculous mycobacterial (NTM) pulmonary infections are a global health concern and a significant contributor to lung disease. Systemic therapies of a cocktail of antibiotics administered over a long period often lead to adverse reactions and/or treatment failure. NTM pathogens, such as Mycobacterium abscessus (Mabs), are notoriously difficult to treat due to resistance to many traditional antibiotics. However, the antibiotic tigecycline has demonstrated efficacy in vitro and in vivo against Mabs strains varying in drug susceptibility. Tigecycline exhibits instability in aqueous medium, posing delivery challenges, and has caused severe adverse gastrointestinal effects following intravenous administration, requiring treatment discontinuation. To mitigate both of these concerns, inhalation therapies using dry powder aerosols are proposed as an alternative administration route and means of delivery. Tigecycline dry powder formulations were prepared, characterized, and optimized to develop a therapeutic aerosol with low moisture, high dispersibility, and a large fraction of particles in the respirable size range (1-5 μm). The addition of lactose, leucine, and phosphate buffer salts was investigated to achieve additional stability, dispersibility, and tolerability. Preliminary delivery of the dry powders to Mabs-infected mice for 30 min per day over 7 d demonstrated a 0.91-log (87.7%) decrease in lung bacterial burden.

Spray dried tigecycline dry powder aerosols for the treatment of Nontuberculous mycobacterial pulmonary infections.

 () has infected one-quarter of the world's population and led to the deaths of 1.6 million individuals in 2021 according to estimates from the World Health Organization. The rise in prevalence of multidrug-resistant and extensively drug-resistant  strains coupled with insufficient therapies to treat such strains has motivated the development of more effective treatments and/or delivery modalities. Bedaquiline, a diarylquinoline antimycobacterial agent, effectively targets mycobacterial ATP synthase but may lead to systemic complications upon oral delivery. Targeted delivery of bedaquiline to the lungs represents an alternative strategy to harness the sterilizing benefits of the drug against  while mitigating off-target side effects. Two pulmonary delivery modalities were developed herein, including dry powder inhalation and liquid instillation. Despite bedaquiline's poor water solubility, spray drying was performed in predominantly aqueous conditions (≥80%) to avoid a closed-loop, inert system. Aerosols of spray-dried bedaquiline with L-leucine excipient outperformed spray-dried bedaquiline alone, demonstrating superior fine particle fraction metrics (~89% of the emitted dose below <5 µm), suitable for inhalation therapies. Furthermore, the use of a 2-hydroxypropyl-β-cyclodextrin excipient allowed a molecular dispersion of bedaquiline in an aqueous solution for liquid instillation. Both delivery modalities were successfully administered to Hartley guinea pigs for pharmacokinetic analysis and were well-tolerated by the animals. Intrapulmonary liquid delivery of bedaquiline led to adequate serum absorption and appropriate peak serum concentrations of the drug. The liquid formulation was superior in systemic uptake compared to the powder formulation. The predominant route via which  bacilli enter the body is aerosol droplets that are deposited onto airway surfaces. For this reason, we believe that further studies should focus on inhalation or intrapulmonary therapies that target the site of entry and primary site of infection for .

Article	Year
A Spray-Dried Combination of Capreomycin and CPZEN-45 for Inhaled Tuberculosis Therapy. Journal of pharmaceutical sciences\| PubMed ID: 31152746	2019
Development and Characterization of a Dry Powder Formulation for Anti-Tuberculosis Drug Spectinamide 1599. Pharmaceutical research\| PubMed ID: 31321552	2019
Designing inhalable metal organic frameworks for pulmonary tuberculosis treatment and theragnostics via spray drying. Chemical communications (Cambridge, England)\| PubMed ID: 33025961	2020
Inhaled antibodies: Quality and performance considerations. Human vaccines & immunotherapeutics\| PubMed ID: 34191682	2022
Nanoformulated Remdesivir with Extremely Low Content of Poly(2-oxazoline)-Based Stabilizer for Aerosol Treatment of COVID-19. Macromolecular bioscience\| PubMed ID: 35526106	2022
Optimization and Scale Up of Spray Dried CPZEN-45 Aerosol Powders for Inhaled Tuberculosis Treatment. Pharmaceutical research\| PubMed ID: 36114362	2022
Spray dried tigecycline dry powder aerosols for the treatment of Nontuberculous mycobacterial pulmonary infections. Tuberculosis (Edinburgh, Scotland)\| PubMed ID: 36716525	2023
Preparation Strategies of the Anti-Mycobacterial Drug Bedaquiline for Intrapulmonary Routes of Administration. Pharmaceuticals (Basel, Switzerland)\| PubMed ID: 37242512	2023

Ian E. Stewart

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