Surgery – Liquid medicament atomizer or sprayer – Gas stream aspirating medicament from reservoir
Reexamination Certificate
2001-06-12
2003-06-03
Doerrler, William C. (Department: 3761)
Surgery
Liquid medicament atomizer or sprayer
Gas stream aspirating medicament from reservoir
Reexamination Certificate
active
06571791
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to a device for inhaling dosed pharmaceuticals in the form of an aerosol into the lungs. Suitable pharmaceuticals include analgesics, anti-angina agents, anti-allergics, antihistamines and anti-inflammatory agents, expectorants, antitussives, bronchodilators, diuretics, anticholinergics, corticoids, xanthins, anticancer drugs and therapeutically active proteins or peptides, such as insulin or interferon.
The administration of pharmaceuticals including vitamin A is particularly useful for treating respiratory diseases, such as asthma, and for the prophylactic treatment and therapy of the mucosae of the tracheobronchial tract.
BACKGROUND OF THE INVENTION
The term “vitamin A” stands for a number of chemically similar compounds producing different effects in human and animal organisms. Vitamin A is essential for man as a vitamin deficiency appears if the vitamin is not supplied together with food. A vitamin A deficiency shows up in various modifications in the skin, mucosae and eyes. Symptoms include a cornification (keratinisation) of the mucosae of the respiratory system or the connective tissue membrane of the eye and a higher disposition for infections and blindness, where the deficiency is pronounced. The majority of the modifications resulting from the deficiency, especially in the mucosae, can be repaired by a vitamin A supply. However, the systemic administration aiming at the repair, of for instance a pavement (squamous) epithelium metaplasia, or at the prevention of a recurrence of such modifications requires high concentrations, which can sometimes produce considerable side effects (cerebral pressure symptoms, disorders of the liver cell metabolism, etc.). Moreover, the use of preparations in high doses is contraindicated in pregnancy because of the risks of fetal deformation (Bauernfeind J. C.: The Safe Use of Vitamin A, The Nutrition Foundation, Washington D.C., 1980).
Moreover, in the case of a diet-caused protein deficiency and in the case of disorders of the liver cell metabolism, such as inflammation or cirrhosis, the supply of vitamin A even in physiological concentrations is banned, because the associated disorders of protein synthesis (deficient formation of the transport proteins) of the liver do not allow the vitamin to be eliminated from the storage organs into which it is transferred after resorption (absorption).
Furthermore, after systemic administration, the vitamin can only be taken up by the peripheral target tissues, such as the respiratory epithelium, and caused to exert its function, if it is bound to this very transport protein.
EP-A-0 352 412 describes the use of a preparation of esters of retinol and retinoic acid for administration by inhalation to solve this problem. This in particular allows the active ingredient to exert a topical action on the mucosae of the tracheobronchial tract of man and animal. This facilitates the prophylactic treatment and therapy of specific diseases and functional abnormalities, for instance of specific cellular differentiation disorders, pavement (squamous) epithelium metaplasia, neoplastic modifications, reduced activity of the ciliated epithelium and dysfunction of mucosa-forming cells. Moreover, this preparation can also be used for the therapy or as an adjuvant in the therapy of inter alia bronchial carcinoma, acute and chronic bronchites and the bronchopulmonary dysplasia of newborn children. Clinical studies reveal, however, that the application of vitamin A by inhalation using conventional inhalators only allows insufficient amounts of the active ingredient to be administered to the target tissue, the ciliated epithelium of the bronchial mucosa.
DE-A-199 12 461 by the same inventors as those named for the present patent application was published on Sep. 21, 2000 and is consequently a postpublished document. It discloses a device for limiting the flow at low differential pressures, in particular for limiting the inhalation flow volume during the inhalation of therapeutic aerosols. The device has a housing which comprises an inhalation opening, an exhalation opening, and a flow channel arranged therebetween and has a flat oblong cross section and flexible large-surface walls. Depending on the differential pressure between the inhalation opening and the exhalation opening and the flexibility of the wall material, the cross section of the flow channel can be reduced in size to suit a predetermined maximum inhalation flow volume.
Essentially, the administration of pharmaceuticals in the form of an aerosol to the lung by inhalation is influenced by four factors: (i) the particle size and particle properties of the aerosol; (ii) the volume inhaled by the patient in one breath; (iii) the patient's breath flow; and (iv) the patient's morphometry and respiratory system. Although aerosols in suitable particle size ranges are produced by the conventional systems, the parameters “one breath volume” and “breath flow” (rate of breathing) are taken into account either insufficiently or not at all. This leads to an uncontrolled inhalation of the aerosol, which in turn has the result that the aerosol particles reach the lung in insufficient amounts or do not reach the areas (for instance the alveolar area) within the lung to be treated.
EP-A 0 965 355 proposes a device for the controlled application of a measured amount of pharmaceuticals into the lung by inhalation. This controlled inhalator comprises a closed container which can be filled with a predetermined aerosol volume and from which the aerosol can be withdrawn via a control means for the inhalation flow. In this known inhalator, said control means is either an adjustable valve or a critical nozzle. The use of an adjustable valve or a critical nozzle allows the breath flow to be limited.
EP-B-0 050 654 proposes an inhalation device for the administration of pulmonary medication. This device has an inflatable envelope from which an aerosol can be inhaled through a mouthpiece. This aerosol is introduced via a nebulizer into the inflatable envelope from a cartridge prior to inhalation. In order to limit the amount of air flowing through the mouthpiece during inhalation, the mouthpiece has a restriction. This restriction limits the breath flow during inhalation.
The two above-mentioned inhalation devices are distinguished by the fact that the flow is limited, i.e. during the inspiratory phase, the breath flow rises only slowly and the breath flow increase decreases steadily, leading to a steady flattening of the curve in the graph of the breath flow versus time. The result of this flow limitation is that, depending on the patient's inspiratory capacity, the breath flow increases differently (and flattens) and, in the worst case, is insufficient for the treatment required. This means that the envisaged flow limitation of the known inhalators can lead to an insufficient aerosol deposition.
SUMMARY OF THE INVENTION
In light of this, the invention addresses the problem of providing an inhalation device, which, irrespective of the patient's characteristics, provides the breath flow required for the inhalation of aerosols, in particular vitamin A. This problem is solved by an inhalation device possessing the features of the claims.
The invention starts from the basic idea of providing a control means which keeps the inhalation flow at an essentially constant level during the entire inhalation period of the aerosol. This means that according to the invention, the inhalation flow increases right at the start of the inspiratory phase to its maximum value, which is required for adequate aerosol administration, and remains at this maximum value as long as the patient produces a minimum pressure during inhalation. This minimum pressure is preferably 10 mbar at the most and preferably lies in the range between 5 and 10 mbar. According to the invention, a flow limitation is thus provided even at low differential pressures.
The inhalation device according to the invention is a combination of a self-expanding container for
Haas Friedel
Müllinger Bernhard
Roeder Sascha
Scheuch Gerhard
Sommerer Knut
Doerrler William C.
Drake Malik N.
Eugene Stephens & Associates
InAMed GmbH
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