Inhaled powder formulation

Schering-Plough has developed a once-daily nasal spray formulation of momethasone furoate for the treatment and prevention of seasonal and perennial allergic rhinitis. Inhalation formulations have also been developed. Schering-Plough has developed an inhaled powder formulation for asthma maintenance treatment. 

Liquid instillation and nebulised aerosols are the most common methods for pulmonary administration to experimental animals [22, 54, 109, 134], The use of pressurised metered dose inhaler (pMDIs) and dry powder inhaler (DPIs) in preclinical studies is limited by the need for formulation development, which often cannot be performed in early drug discovery due to short supply of test materials. A number of alternative techniques for intra-tracheal administration of coarse sprays and powder formulations have been described [9, 15, 21, 36, 71, 80, 99, 138],... 

Exubera (see also Exhibit 4.14) Exubera is an inhalable insulin for the treatment of type I and II diabetes. Each dose consists of 1 or 3 mg insulin in a powder formulation with sodium citrate (dehydrate), mannitol, glycine, and sodium hydroxide. 

Formulation of dry powders for inhalation must rely on a very short list of excipients to fulfill the customary roles of diluent, stabilizer, solubilizer, processing aid, and property modifier (e.g., flow enhancer). In the United States, only a few materials are approved for use in inhalation products, and of those (e.g., propellants, surfactants) many are of little help in dry powder formulation. 

Dry powder inhalers are generally described as breath actuated devices, because the inspiratory airstream releases the dose from the dose system and supplies the energy for the generation of fine drug particles from the powder formulation. Because the efficiency of dose release and powder disintegration increases with increasing inspiratory flow rate for most DPIs, these devices would be better described as breath controlled devices. In Section 3.9, the effect of resistance and clinical conditions on the flow curve and relevant flow parameters for DPIs are discussed. 

Powder container. Dry powder inhalers may contain the dry powder formulation in many different forms. The first DPI, the Spinhaler contained single doses in capsules. Other systems, like the Diskus or Diskhaler may contain the metered dose in blisters, whereas systems like the Turbohaler , or Novolizer , have multi-dose containers. 

In Section 3.5.3, dry powder inhalers have been referred to as breath-controlled devices. The efficacy of dry powder inhalation is a function of many factors, influencing the delivered dose of fine particles and the deposition of these particles in the respiratory tract. Figure 3.4 shows that DPI performance is influenced both directly and indirectly by the design of the inhalation system. The powder formulation, the dose (measuring) system and the powder disintegration principle have to be designed correctly for release of sufficient fine drug particles in... 

Zeng XM, Martin AP, Marriott C. Particulate Interactions in Dry Powder Formulations for Inhalation. London Taylor and Francis, 2001. 

Of 335 patients with type 1 diabetes randomized to receive preprandial inhaled insulin as a dry powder formulation via an aerosol delivery system (Exubera) plus bedtime subcutaneous Ultralente insulin, or to continue NPH and regular insulins subcutaneously, 170 received inhaled insulin (mean age 33 years) (272). Six discontinued inhaled insulin, one because of mild cough, two because of hypoglycemia, and three because of insufficient responses. The risk of hypoglycemia was slightly lower in those who used inhaled insulin, at 8.6 events per month compared with 9.0 events per month in the conventional insulin group. 

Both powdered insulin formulations and liquid inhaled insulin formulations are being developed. There have been no direct comparisons of these formulations, and it is therefore difficult to make definitive statements about whether one is superior to the other (274). 

The Easyhaler (by Orion Pharma, Finland) and the Clickhaler (by Innovata pic, United Kingdom) are available at present in some European markets. Unlike the DPIs described earlier, these two reservoir-type inhalers meter the dose when the patient presses the top of the device similar to actuation of a pressurized metered-dose inhaler. Both devices contain a dose indicator, which is standard for reservoir multidose DPIs. Recently, Innovata presented the Twinhaler for asthma combination therapy, a new development based on the Clickhaler. This device does not require the combined drugs to be formulated in one powder blend but delivers two powder formulations from two reservoirs into one airflow path. 

Srichana, T., Martin, G. P, and Marriott, C. Dry powder inhalers The influence of device resistance and powder formulation on drug and lactose deposition in vitro. Eur. J. Pharm. Sci. 1 73-80, 1998. 

Research and development for dry powder inhalers have two main focuses the optimization of the powder formulation for use in these inhalers and investigations of novel DPI device designs and technology. An enormous literature now exists in each of these areas for more extensive reviews readers should consult refs. 33,167, or 168. 

Many of these techniques involve particle formation from solution formulations that contain novel excipients. Spray drying is the most advanced of these technologies and has been used to produce the powder formulation in the Exubera inhaler [175], Various modifications of this basic technique, including co-spray drying with novel excipients, have been employed. 

Single- and Multiple-Dose DPIs Inhalation powder dose metering is one of the problems encountered by DPI formulators. The powder dose can range from 250 pg in the drug-only Pulmicort Turbuhaler formulation to 25 mg in the lactose-blended... 

Only a few materials are approved in the United States for use in inhalation products, and of those (e.g., propellants, surfactants), many are of little help in dry powder formulation. 

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