Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2000-04-21
2002-10-08
Hartley, Michael G. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C424S009200, C424S045000
Reexamination Certificate
active
06462090
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to improved formulations for use in detecting asthma, a method of preparing the new formulations and a method of detecting asthma using the formulations. Preferably the formulations contain methacholine or histamine as the active ingredient.
BACKGROUND OF THE INVENTION
Asthma is a common respiratory disease affecting 5-10% of the population. It is characterized by shortness of breath, cough, airway inflammation and hyper-responsiveness to many stimuli. The diagnosis of asthma is based on the clinical history, physical examination and a number of laboratory tests. A key lab test to diagnose non-specific bronchial hyper-responsiveness is the methacholine challenge.
The methacholine challenge (MC) is the principal test that is used to measure bronchial hyper-responsiveness and hence is a key laboratory test used in the diagnosis of asthma. Methacholine is a bronchoconstrictor which causes a greater degree of airway narrowing in patients with asthma compared to non-asthmatics. The patient's pulmonary function (e.g. FEV1) is measured after each dose until the drop in pulmonary function exceeds a certain degree (e.g. 20% drop in FEV1), or a maximal dose of MC has been given. However, the widespread use of the MC is limited for a number of reasons including:
1. MC is technically difficult to perform: (a) The test is performed by having the subject inhale up to about 10 different concentrations of methacholine (usually doubling doses) via a nebulizer. The methacholine is in solution and a technician has to prepare the different concentrations. This is time consuming, is prone to error and is thus costly. (b) The equipment required is relatively cumbersome, for example, the nebulizer requires a compressor or a compressed gas tank. Furthermore, this equipment is not disposable and thus it has to be cleaned and sterilized after each use. In addition, the output of the nebulizer has to be checked on a regular basis. (c) To deliver the correct amount of methacholine that is inhaled requires some device attached to the nebulizer (e.g. a dosimeter). All of these issues makes the performance of a MC relatively difficult, such that the test is usually performed in a fully equipped laboratory and not in a physician's office. In addition, because of the equipment required, it is not suitable for mass screening of patients.
2. Quality control: Because of the need to prepare various solutions of methacholine, there is the possibility of errors in preparation of the solutions, and errors in the order of administration of the correct doses.
3. Safety: Because of the possibility of errors in preparation of the solutions, a patient may receive too high a dose and this may lead to severe bronchoconstriction.
In view of the foregoing, there is a need in the art for a method for detecting asthma which overcomes the difficulties described above.
SUMMARY OF THE INVENTION
The present invention provides improved formulations for use in detecting asthma. The novel formulations provide methacholine or histamine in ready to use powder formulations which can be inhaled directly through an inhaler in order to test for air narrowing which is diagnostic of asthma. The test can be performed at varying concentrations by varying the dose released from the inhaler. This overcomes the drawbacks of the methacholine challenge test of the prior art where several different solutions of methacholine at varying concentrations must be prepared. The prior art method is thus time consuming, prone to error and costly. In contrast, the method of the present invention can be self-administered or administered with very little supervision.
In one aspect, the present invention provides a formulation for use in detecting asthma comprising methacholine or histamine in a dry particulate form. The formulation is a composite material comprising discrete particles which are a mixture of methacholine or histamine and a carrier. In the preferred embodiment of the invention, the particles of the formulation are methacholine or histamine/sugar composite particles (where sugar is the carrier). In a preferred embodiment, the methacholine or histamine is combined with a pharmaceutically acceptable sugar, preferably of a pharmaceutical grade. Preferably the sugar is a regular grade and pharmaceutical grade sugar.
The methacholine or histamine are combined with the carrier in such a way that it will be delivered to the alveoli and lower airways of a person with the carrier. The composite particles of the formulation are formed in such a way that they have a median particle size to enable the methacholine to be conveyed on inhalation to the alveoli and lower airways of a person. Preferably the size of the particles in the formulation are from 0.1 &mgr;m to 10 &mgr;m, more preferably from 2 &mgr;m to 8 &mgr;m and most preferably from 2 &mgr;m to 5 &mgr;m.
In another aspect, the present invention provides a method of preparing a methacholine or histamine formulation for use in detecting asthma comprising:
(a) combining methacholine or histamine, a pharmaceutical grade sugar and a liquid carrier to produce a flowable mixture; and,
(b) drying the flowable mixture at conditions to produce a composite material containing methacholine or histamine/sugar composite particles suitable for delivery to the alveoli and lower airways of a person.
In one embodiment the liquid carrier is water.
The flowable mixture is preferably dried by spray drying. In one embodiment the flowable mixture is atomized prior to being dried. The conditions under which the flowable mixture is spray dried is controlled to produce the desired particle size. In one embodiment the flowable mixture is preferably dried at conditions to form substantially spherical particles. More preferably, the flowable mixture is dried at conditions to from spherical particles which have a dimpled surface.
In a further aspect, the present invention provides a method for detecting asthma in a person comprising (a) having the person inhale an effective amount of a methacholine or histamine formulation in dry particulate form of the invention containing particles of respirable size and (b) measuring airway narrowing, wherein a narrowing of the airways is diagnostic of asthma.
An advantage of the instant invention is that the particles produced by the method disclosed herein are well adapted for delivery to the alveoli and small airways of the lungs with minimal or no impact upon the throat or upper airways of the person, thus preferably resulting in no irritation.
Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples while indicating preferred embodiments of the invention are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
DETAILED DESCRIPTION OF THE INVENTION
Methacholine Formulation
As hereinbefore mentioned, the present invention provides a methacholine formulation comprising methacholine in a dry particulate form for use in detecting asthma. The methacholine formulation is a composite material comprising discrete particles which are a mixture of methacholine or histamine and a carrier in a form suitable for inhalation by a user. In the preferred embodiment of the invention, the particles of the formulation are methacholine or histamine/sugar composite particles (where sugar is the carrier). Preferably, the sugar is lactose. In particular, the formulation comprises solid discreet flowable particles which may be entrained in the air inhaled by a person so as to travel to the alveoli and smaller airways of the lungs.
The particle size of the methacholine formulation is of a “respirable particle size” which is a size sufficient to enable the methacholine to be conveyed on inhalation to the alveoli and lower airways of a person. Preferabl
Slutsky Arthur
Wulffhart Harold
Zamel Noe
Bereskin & Parr
Hartley Michael G.
Nador Anita
Ontario Inc.
Willis Michael A.
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