A review of co-milling techniques for the production of high dose dry powder inhaler formulation.

Drug delivery by inhalation offers several advantages compared to other dosage forms, including rapid clinical onset, high bioavailability, and minimal systemic side effects. Drug delivery to the lung can be achieved as liquid suspensions or solutions in nebulizers and pressurized metered-dose inhalers (pMDI), or as dry powders in dry powder inhalers (DPIs). Compared to other delivery systems, DPIs are, in many cases, considered the most convenient as they are breath actuated and do not require the use of propellants. Currently, the delivery of low drug doses for the treatment of lung conditions such as asthma and chronic obstructive pulmonary disease are well established, with numerous commercial products available on the market. The delivery of low doses can be achieved from either standard carrier- or aggregate-based formulations, which are unsuitable in the delivery of high doses due to particle segregation associated with carrier active site saturation and the cohesiveness of micronized aggregates which have poor flow and de-agglomeration properties. High-dose delivery is required for the treatment of lung infection (i.e. antibiotics) and in the emerging application of drug delivery for the management of systemic conditions (i.e. diabetes). Therefore, there is a demand for new methods for production of high-dose dry powder formulations. This paper presents a review of co-mill processing, for the production of high-efficiency inhalation therapies, including the jet mill, mechanofusion, or ball mill methodologies. We investigate the different techniques, additives, and drugs studied, and impact on performance in DPI systems.

Investigation into the Manufacture and Properties of Inhalable High-Dose Dry Powders Produced by Comilling API and Lactose with Magnesium Stearate.

The aim of the study was to understand the impact of different concentrations of the additive material, magnesium stearate (MGST), and the active pharmaceutical ingredient (API), respectively, on the physicochemical properties and aerosol performance of comilled formulations for high-dose delivery. Initially, blends of API/lactose with different concentrations of MGST (1-7.5% w/w) were prepared and comilled by the jet-mill apparatus. The optimal concentration of MGST in comilled formulations was investigated, specifically for agglomerate structure and strength, particle size, uniformity of content, surface coverage, and aerosol performance. Secondly, comilled formulations with different API (1-40% w/w) concentrations were prepared and similarly analyzed. Comilled 5% MGST (w/w) formulation resulted in a significant improvement in in vitro aerosol performance due to the reduction in agglomerate size and strength compared to the formulation comilled without MGST. Higher concentrations of MGST (7.5% w/w) led to reduction in aerosol performance likely due to excessive surface coverage of the micronized particles by MGST, which led to failure in uniformity of content and an increase in agglomerate strength and size. Generally, comilled formulations with higher concentrations of API increased the agglomerate strength and size, which subsequently caused a reduction in aerosol performance. High-dose delivery was achieved at API concentration of >20% (w/w). The study provided a platform for the investigation of aerosol performance and physicochemical properties of other API and additive materials in comilled formulations for the emerging field of high-dose delivery by dry powder inhalation.

Formulation techniques for high dose dry powders.

Delivery of drugs to the lungs via dry powder inhaler (DPI) is a promising approach for the treatment of both local pulmonary conditions and systemic diseases. Though DPIs are widely used for the pulmonary deposition of potent bronchodilators, anticholinergics, and corticosteroids, there is growing interest in the utilization of this delivery system for the administration of high drug doses to the lungs, as made evident by recent regulatory approvals for anti-microbial, anti-viral and osmotic agents. However, the formulation of high dose DPIs carries several challenges from both a physiological and physicochemical standpoint. This review describes the various formulation techniques utilized to overcome the barriers associated with the pulmonary delivery of high dose powders.

The Delivery of High-Dose Dry Powder Antibiotics by a Low-Cost Generic Inhaler.

The routine of loading multiple capsules for delivery of high-dose antibiotics is time consuming, which may reduce patient adherence to inhaled treatment. To overcome this limitation, an investigation was carried out using four modified versions of the Aerolizer® that accommodate a size 0 capsule for delivery of high payload formulations. In some prototypes, four piercing pins of 0.6 mm each were replaced with a single centrally located 1.2-mm pin and one-third reduced air inlet of the original design. The performance of these inhalers was evaluated using spray-dried antibiotic powders with distinct morphologies: spherical particles with a highly corrugated surface (colistin and tobramycin) and needle-like particles (rifapentine). The inhalers were tested at capsule loadings of 50 mg (colistin), 30 mg (rifapentine) and 100 mg (tobramycin) using a multistage liquid impinger (MSLI) operating at 60 L/min. The device with a single pin and reduced air inlet showed a superior performance than the other prototypes in dispersing colistin and rifapentine powders, with a fine particle fraction (FPF wt% <5 µm in the aerosol) between 62 and 68%. Subsequently, an Aerolizer® with the same configuration (single pin and one-third air inlet) that accommodates a size 00 capsule was designed to increase the payload of colistin and rifapentine. The performance of the device at various inspiratory flow rates and air volumes achievable by most cystic fibrosis (CF) patients was examined at the maximum capsule loading of 100 mg. The device showed optimal performance at 45 L/min with an air volume of 1.5-2.0 L for colistin and 60 L/min with an air volume of 2.0 L for rifapentine. In conclusion, the modified size 00 Aerolizer® inhaler as a low-cost generic device demonstrated promising results for delivery of various high-dose formulations for treatment of lung infections.

How can we bring high drug doses to the lung?

In the last decades, dry powder inhalation has become a very attractive option for pulmonary drug delivery to treat lung diseases like cystic fibroses and lung infections. In contrast to the traditional pulmonary application of drugs for asthma and chronic obstructive pulmonary disease, these therapies require higher lung doses to be administered. The developments and improvements toward high dose powder pulmonary drug delivery are summarized and discussed in this chapter. These include the invention and improvement of novel inhaler devices as well as the further development of formulation principles and new powder engineering methods. The implementation of these strategies is subsequently described for some prototypes and formulations in research and development stage as well as for already marketed dry powder products. Finally, possible adverse effects that can occur after inhalation of high powder doses are shortly addressed.