WO2005011574A2 - Microporous membrane nebulizers - Google Patents

Abstract

Methods are provided for disaggregating aggregated particles of a suspension formulation of nebulizable drug and effectively delivering a suspension formulation with aggregated particles of a nebulizable drug to a patient using a microporous membrane nebulizer.

Description

USE OF MICROPOROUS MEMBRANE NEBULIZERS TO DISAGGREGATE SUSPENSION FORMULATIONS OF NEBULIZABLE DRUGS

Background of the Invention Many drugs that are clinically useful for administration by inhalation, are water insoluble solids under ambient or physiologic conditions of temperature and pressure. Examples are the topically acting inhaled steroids used to treat asthma. These drugs are presently administered as suspensions or solutions in hydrofluoroalkane propellants (depending on their solubility) in metered dose inhalers, alone or with carrier substances in dry powder inhalers, or suspended in aqueous diluent . The simplest technique for formulation of a water- insoluble solid drug for inhalation via nebulizer is to mill or precipitate it into small particles, suspend unit doses in individual ampules in a pharmaceutically acceptable diluent, and gently shake or swirl to mix before emptying into a nebulizer for administration. This is referred to herein as a "first generation suspension technology" . A problem with suspensions of this type, however, is that the small particles of solid phase drug tend to aggregate, over time, into progressively fewer numbers of progressively larger particles. Under otherwise identical conditions of inhalation, larger particles impact more proximally in the airway than smaller ones. For topically acting asthma steroids and many other drugs for which inhalation is a potentially desirable route of delivery, larger particle size results in deposition of more of the drug in a different location from where it can have the greatest beneficial effect on the disease for which it is prescribed, and often with a quantitatively or sometimes qualitatively different profile and ratio of adverse effects to beneficial effects. The nebulizers with which these "first generation suspension technology" products were studied, and for which they are generally prescribed, are compressor-driven jet nebulizers, in which the energy imparted to the nebulizer fill by the jet of air coming from the compressor is sufficient to disperse the suspended particles so that they are aerosolized in direct proportion to the aerosolized volume of diluent. The energy imparted to the nebulizer fill by these aerosol generation devices is insufficient to disaggregate drug particles that were originally of highly respirable size but have clumped together, since being mixed with diluent, into aggregates for which delivery to the desired target tissues is much less efficient. A number of "second generation technologies" have been proposed to overcome the problem of aggregation of "first generation suspensions" . For example, attempts have been made to coat the drug particles with a thin, biologically inert film that makes the particles repel each other by reducing the energy of aggregation. An example is budesonide nanocrystal or nanoparticle suspensions. In this application, microparticles of budesonide, a topically acting asthma steroid, are coated with a thin film of a polymer which is hydrophobic inside so that it adheres to the budesonide and hydrophillic outside to prevent the particles from aggregating in aqueous diluent. Attempts have also been made to chemically attach long hydrophilic tails to molecular configurations on the outside of the particles, or to molecules of macromolecular drugs prior to precipitation of particles, to achieve the same end result of altering the boundary layer energy balance to disfavor aggregation. An example is pegylation wherein drug particles are coated with or bound at chemical residues that are not critical for activity of the drugs to long tails of polyethylene glycol . Nebulizing water-insoluble drugs as two phase liquid- liquid suspensions was also described in PCT/US00/34304. However, these and other second generation technologies generally have the liabilities of being costly to develop, and of involving inhalation of foreign materials not present in the first generation suspensions they are designed to replace. Thus, these technologies may require extensive testing for safety and toxicity, and involve uncertainties about ultimately being able to achieve regulatory approval. As nebulized drugs are typically less convenient to use than dry powder inhalers, metered dose inhalers and other single puff devices, they are unlikely to appeal ^"to potential users who are also able to use single puff dosage forms of the same drug classes, unless they can be brought to market at a lower price than their non-nebulizer competitors. Bringing nebulizer dosage forms to the market at lower cost than their single puff non-nebulizer equivalents would also benefit society, in general, since it offers a means for large populations of users to reduce their medical care costs. Second generation nebulizer technologies are less likely to achieve these goals, because of the high development costs, named above, that drug development companies will have to amortize .

Summary of the Invention An object of the present invention is to provide a method for disaggregating aggregated particles of a suspension formulation of nebulizable drug upon administration to a patient, which comprises administering the suspension formulation to the patient using a microporous membrane nebulizer. Another object of the present invention is to provide a method for effectively delivering a suspension formulation of a nebulizable drug with aggregated particles, which comprises administering the suspension formulation to a patient by microporous membrane nebulizer so that aggregated particles of the suspension formulation of nebulizable drug are disaggregated and delivered efficiently to targeted tissues in the lungs of the patient .

Detailed Description of the Invention In recent years, innovations in nebulizer technology, specifically the development of microporous membrane nebulizers, have significantly reduced inconveniences of nebulizer administration of inhaled medications compared to use of single breath dosing devices. In two microporous membrane nebulizers, the Pari eFlow (Pari Respiratory

Equipment, Germany) and the Aerogen Aeroneb (Aerogen, Inc. Mountainview, CA) , a piezoelectric oscillator is placed circumferentially around the microporous membrane and ultrasonic vibrations shake precisely sized droplets of the nebulizer content through the membrane, to form a respirable mist of medication on the other side. In a third microporous membrane nebulizer, the Omron Micro- air (Omron, Japan) , the piezoelectric oscillator is positioned proximal to the microporous membrane instead of circumferentially around it, pushing rather than shaking droplets of droplets of nebulizer content through the pores in the membrane with a similar result. It has now been found that the low energy, low amplitude ultrasonic vibrations capable of driving droplets of a liquid nebulizer fill through the microporous membranes of these nebulizers can disaggregate granules of first generation nebulizer suspension products that have agglomerated in the course of storage, -when membranes of appropriate pore sizes and piezoelectric oscillators providing appropriate power levels are used. Studies to confirm the ability of these nebulizers to disaggregate granules of first generation suspension and to optimize system parameters for delivery of disaggregated drug are extremely inexpensive. Thus, this new use for microporous membrane nebulizers provides drug developers who elect to use microporous membrane nebulizers to disaggregate first generation nebulizer suspension products a tremendous competitive advantage, enabling them to deliver old, generic medications as efficiently and effectively as newer competitive products but without having to amortize the development costs of the newer, brand name only products. As risk of aggregation is a factor limiting the post- manufacture shelf life of aggregation-prone first generation nebulizer products, redeveloping them for administration with nebulizers that restore original particle size should allow longer shelf life, further reducing both costs of manufacture and society's costs of health care. This invention is particularly applicable to the treatment of the two classes of asthma patients who collectively consume the most asthma medications, namely patients with mild persistent asthma and moderate persistent asthma. Current guidelines of the National Asthma Education and Prevention Program of the National Heart Lung and Blood Institute, and its international counterpart, the Global Initiative for Asthma, recommend low dose inhaled topically acting steroids as the preferred first controller drug to use for patients with mild persistent asthma of any age. The least expensive drug of this class is a bulk reservoir dry powder inhaler formulation of budesonide inhaled from a device that regulators have asked the manufacturer to replace for reasons of unpredictably and uncertain stability of the drug under certain conditions of use. It is expected that the cost per inhalation of the same dose of drug will increase by almost 2-fold with the new inhalation device. Competing drugs of the same class are already at least two-fold higher in price for a comparable dose . Presently, first generation nebulizer suspension formulations of budesonide are more costly than bulk reservoir dry powder inhaler formulations. In addition, the risk of aggregation has resulted in these formulations being labeled with a short shelf life. The inconvenience of dosing with the jet nebulizers for which these formulations were developed and the low efficiency of target tissue drug delivery achieved with these devices, has further limited their use to small numbers of young children and other patients unable to use other inhalation devices . The present invention, wherein a first generation nebulizer suspension such as a budesonide formulation is administered via a microporous membrane nebulizer to disaggregate any aggregated particles particles is expected to overcome issues relating to short shelf life and low efficiency of target tissue delivery, thereby providing a low cost alternative treatment for many asthmatic patients. While dosing with a microporous membrane nebulizer is moderately more inconvenient than dosing with a single inhalation metered dose inhaler or dry powder inhaler, the lower costs achievable with volume production of an old nebulizer formulation of an old drug on which all chemical entity and manufacturing patents have expired, will provide incentive for users with mild persistent asthma to decide that the inconvenience is worth the savings . Use of a microporous membrane nebulizer to disaggregate suspension formulations of nebulizable drugs is also expected to be useful in treating patients with moderate persistent asthma. Regardless of patient age, the preferred treatment for moderate persistent asthma is a low dose of an inhaled, topically acting steroid plus an inhaled long acting beta-2 adrenergic. The most popular combination product is provided as a single inhalation dry powder inhaler. While the steroid and long acting beta adrenergic components can be taken separately, the least expensive separate formulation of a long acting beta adrenergic requires refrigerated storage except for a short term supply that the patient expects to use up within a few weeks. An exemplary generic long acting beta adrenergic, which can be used in the present invention is formoterol. Formoterol requires a different technology for the manufacture and use of a stable nebulizer formulation. Formoterol can be stored at high concentrations at acid pH and mixed as a one step operation with a buffered diluent that can also contain a first generation suspension of budesonide. The development costs of this technology are also very low, so that nebulizer combinations of the two drugs, formulated to treat the same spread of patients (i.e., covering the same dose range) could be manufactured and distributed at a net user cost per dose approximately 2 -fold less than current costs for administration via an inhaler. With microporous nebulizers being so much more convenient to use than compressor-driven jet nebulizers, it is believed that combination asthma therapy using microporous membrane nebulizer disaggregation of a first generation generic budesonide suspension, formulated to be compatible with efficient co-administration of a stable, inexpensive nebulizer formulation of the generic long acting beta-2 adrenergic, formoterol, would be preferred by pharmaceutical benefits programs because of its significant potential for cost savings.

Claims

What is Claimed is; 1. A method for disaggregating aggregated particles of a suspension formulation of nebulizable drug upon administration to a patient comprising administering the suspension formulation to the patient via a microporous membrane nebulizer.

2. A method for effectively delivering a suspension formulation with aggregated particles of a nebulizable drug to a patient comprising administering the suspension formulation to a patient by means of a microporous membrane nebulizer, so that aggregated particles of the suspension formulation of nebulizable drug are disaggregated and delivered efficiently to targeted tissues in the lungs of the patient .