Surgery – Respiratory method or device – Means for mixing treating agent with respiratory gas
Reexamination Certificate
1999-10-14
2001-06-26
Dawson, Glenn K. (Department: 3761)
Surgery
Respiratory method or device
Means for mixing treating agent with respiratory gas
C128S203120
Reexamination Certificate
active
06250300
ABSTRACT:
This invention relates to a dry powder inhaler system for dispensing a clinically effective dose of a pharmaceutically active compound.
BACKGROUND OF THE INVENTION
Inhalable drugs are commonly used in the treatment of diseases of the airways, such as rhinitis, asthma, and chronic bronchitis. Examples of such drugs include &bgr;2-adrenoreceptor agonists such as salbutamol, terbutaline, rimiterol, fenoterol, reproterol, adrenaline, pirbuterol, isoprenaline, orciprenaline, bitolterol, salmeterol, formoterol, clenbuterol, procaterol, broxaterol, picumeterol, TA-2005, mabuterol and the like, and their pharmacologically acceptable esters and salts; anticholinergic bronchodilators such as ipratropium bromide and the like; glucocorsticosteroids such as betamethasone, fluticasone, budesonide, tipredane, dexamethasone, betamethasone, flucinolone, triamcinolone, mometasone, D-5519 and the like, and their pharmacologically acceptable esters and salts; anti-allergy drugs such as sodium cromoglycate and nedocromil sodium; expectorants; antibiotics; mucolytics; antihistamines; cyclooxygenase inhibitors; leukotriene synthesis inhibitors; leukotriene antagonists, PLA2 inhibitors, PAF antagonists and prophylactics of asthma. In addition to these, some systemically active drugs might be deliverable via inhalation.
Inhalable drugs are commonly administered using either a metered dose inhaler (MDI) or a dry powder inhaler (DPI). The MDI, in which the drug is dissolved or suspended in a liquid propellant mixture (sometimes including small amounts of a volatile organic or inorganic solvent) stored in a pressurized container, is currently the more widely used device. In using an MDI, a patient activates the device to release a dose of the drug/propellant in coordination with inhalation through the mouth.
In a DPI, the drug is in the form of a dry powder, sans propellant. This type of device dispenses drug by means of the particle cloud generated by the airflow obtained upon patient inhalation through the mouth.
The aim of both the MDI and the DPI is to deposit a clinically effective amount of active compound in the lungs of the patient. By “clinically effective amount of active compound” is meant that amount of active compound which is required in order to effect the desired clinical response.
If handled correctly, MDI's and many DPI's deliver pharmaceuticals to the active site with approximately the same efficiency; however the amount of active substance which actually reaches the lungs in each case may be only approximately 10% of the amount in the metered dose. Therefore, in order to ensure that a clinically effective amount of active compound reaches the lungs, this metered dose must necessarily contain an amount of active compound many times greater than the clinically effective amount. The active compound which does not reach the lungs is lost mainly in the apparatus itself, and in the gastrointestinal tract. This is disadvantageous, since loss of active substance in the apparatus is costly and may reduce efficiency further, by for example clogging the mouthpiece or inhalation channel. More significantly for the patient, loss in the gastrointestinal tract can trigger or accentuate side effects associated with the use of any effective pharmaceutical. In the case of bronchodilators, for example, possible side effects commonly include tremor and increased heart rate, and irritation of the hyperreactive airways of many sufferers of airway disease.
It is known that optimal deposition of powder particles in the lung occurs when the particle diameter is under 10 microns, since particles having a diameter above this range are preferentially deposited in the mouth and throat. However, such fine powder will typically tend either to cling to the sides of its container, or to clump, so that a high proportion of the powder takes the form of large, loosely structured agglomerates of a size much larger than 10 microns, and only a small percentage of the powder particles remain within the primary particle diameter range. Certain new types of dry powder inhalers, including those described in European Patent Nos. 0 237 507 and 69 715 (e.g., the TURBUHALER®), are able to facilitate the delivery of a pharmaceutical powder in which a high proportion of the dispensed particles are of diameter in the desired range. This is accomplished by means of a mechanism or structural feature which causes the particle agglomerates to disintegrate during inhalation, yielding a significantly higher proportion of the powder in particles of the primary particle diameter range below 10 microns. It has generally been thought (see, for example, Bogaard et al. in “Pharmatherapeutica”, Vol.5, No.6, 1989) that the efficiency of this new type of inhaler in delivering a clinically effective dose to the patient is comparable to the efficiency of previous dry powder inhalers (and therefore also to an MDI). Dosage levels recommended for a given pharmaceutical in the new type of inhaler have therefore been of the same order as those recommended for the same pharmaceutical in an MDI.
SUMMARY OF THE INVENTION
It has been found that administration of a pharmaceutically active compound by means of a dry powder inhaler device which delivers a large proportion of the powder in the form of particles having a diameter of less than 10 microns results in a markedly enhanced efficiency of delivery to the lungs, compared to delivery from standard pressurized metered dose inhalers (MDI's). This enhanced efficiency results from a decrease in the amount of the drug which is wasted due to adhesion to the interior of the device or to deposition in non-target areas, such as the mouth and throat of the patient, and is accompanied by a decrease in side effects attributable to such inappropriately deposited drug. Thus, the size of the nominal dose (also termed the metered dose) and the size of the dispensed dose used in the method of the invention can be substantially decreased vis a vis the minimal corresponding dose required to achieve the same clinical effect as when an MDI is used by the same patient. By “nominal dose” or “metered dose” is meant the dose which is prepackaged in a single-dose inhaler, or which in a multidose inhaler is automatically measured out of a reservoir in preparation for inhalation. It thus represents the amount of compound measured before losses attributable to retention in the device, deposition in the mouth or throat, exhalation, etc. In contrast, “dispensed dose”, as used herein, refers to the amount of compound which actually exits the inhaler. Devices useful in the method of the invention include the breath-actuated, dry powder inhalers described in EP 0 237 507, EP 69 715, WO 92/04069 and WO 93/17728, including the TURBUHALER® multidose inhaler and the MONOHALER® single-dose inhaler.
The invention thus includes a system for dispensing a clinically effective dose of a pharmaceutically active compound, which system includes a dry powder inhaler device containing a powder which includes the pharmaceutically active compound, wherein
(a) of the metered dose of the compound in the inhaler (the “metered DPI dose”), at least 40% exits the inhaler in the form of powder particles less than about 10 microns in diameter;
(b) the metered DPI dose is sufficient to produce a clinically effective result in a patient; and
(c) the amount of the compound in the metered DPI dose is not more than 70% (preferably not more than 50%) of the minimal amount of the compound which, when dispensed in a pressurized metered dose inhaler, produces an equivalent clinically effective result in the same patient (the “metered MDI dose”). Preferably, the amount of the compound which exits the inhaler of the invention upon dispensing of the metered DPI dose (the “dispensed DPI dose”) is not more than 80% (preferably not more than 60%) of the amount of the same compound which exits the MDI upon dispensing of the metered MDI dose (the “dispensed MDI dose”).
In order to dispense the pharmaceutically active compound in the form of particles of the necessar
Andersson Jan
Jägfäldt Hans
Trofast Eva
Wetterlin Kjell
AB Astra
Dawson Glenn K.
Fish & Richardson P.C.
Srivastava V.
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