EP1404457A1

EP1404457A1 - Nebulizer for applying liquids on the surface of the eye or the ocular connective tissue

Info

Publication number: EP1404457A1
Application number: EP02745410A
Authority: EP
Inventors: Bernd Zierenberg; Dieter Hochrainer; Isolde Martin; Michael Diestelhorst
Original assignee: Boehringer Ingelheim Pharma GmbH and Co KG
Current assignee: Boehringer Ingelheim Pharma GmbH and Co KG
Priority date: 2001-06-29
Filing date: 2002-06-26
Publication date: 2004-04-07
Also published as: WO2003002265A1; JP2004533888A; DE10131174A1; US20040164099A1; CA2451716A1

Abstract

The invention relates to a nebulizer for applying preservative-free liquids on the cornea or the ocular connective tissue, comprising special eye adapters (25) for said nebulizer. The invention also relates to the use of nebulizers in ophthalmological applications. The inventive nebulizers are propellant-free.

Description

Nebulizer for applying liquids to the surface of the eye or that

Eye tissue

The present invention relates to nebulizers for applying preservative-free liquids to the cornea or the like

Blindfold tissue, special eye attachments for nebulizers and the use of nebulizers for ophthalmic application. The nebulizers according to the invention are propellant-free.

State of the art

For the treatment of dry eyes, for moistening the surface of the eyes in contact lens wearers, many eye diseases or examination methods on the eye, medications are usually administered in the form of eye drops in an aqueous formulation. Liquid dispensers have been developed for this application form, in which the formulation e.g. is released from a storage bottle via a spout (dropper bottles or EDO ophthiols). The aqueous formulation usually flows out of the spout opening due to manual pressure on the compressible storage bottle. A drop then first forms on this, which only tears off the spout at a certain ratio between the size of the spout opening, surface tension and weight of the droplet and then drips into the eye. Aqueous eye drops usually have a volume of approx. 0.05 ml.

This method of dropping liquids on an eye has several disadvantages. For one thing, it is not easy for all patients to find one for themselves

Apply drops of liquid to the eye. This is partly because he has to lie back (recline) and then drop the drop into the eye from above. This is particularly difficult for children and the elderly. It also happens repeatedly that a patient accidentally stabs the spout of the dropper bottle.

Another disadvantage is that the applied formulation is initially only applied to one area of the cornea of the eye, which is not only because of the local pressure on the surface of the eye is felt to be uncomfortable.

Often, the patient cannot perceive for himself whether he has successfully taken the prescribed amount of eye drops or not. As a rule, a patient only notices whether liquid has actually reached the target organ when an excess amount of the application formulation emerges from the eye and e.g. is perceived either as a taste or as a liquid on the cheeks. However, once this has happened, an overdose has already occurred, which can lead to undesirable systemic side effects.

In this context it is important that the surface of the eye is coated with a liquid film of approx. 7 microliters. Each application of an additional liquid consequently causes part of the total liquid to flow off the eye through the tear duct. Naturally, this is particularly the case when larger amounts of liquid, e.g. Eye drops of 40 microliters and more can be applied. If a pharmacologically active liquid gets into the tear duct, it can be systemically absorbed by the body, i.e. the pharmacologically active ingredients are absorbed directly by the body. This can lead to allergic or toxicological effects. In conventional applications, approx. 80% of the amount of liquid applied is displaced from the eye and thus partially reaches the tear duct.

Another disadvantage is that the patient has to consciously fight against his blink reflex when dripping. If he does not succeed, he does not drip the application formulation onto the eye but the eyelid and he has to drip again, which in turn leads to an overdose with the consequences described above and can cause undesirable systemic side effects. Another disadvantage of this method is that there is a brief irritation of the eyes at the dripping point.

The conventional application devices are also not protected against the penetration of germs into the application formulation, so that preservatives have to be added to the formulations. With long-term use or chronic use, preservatives can lead to chronic inflammation of the connective tissue of the eye or the underlying tenon. This can lead to morphological changes in these tissues, which are particularly disadvantageous during operations, since the wound healing process is hindered and / or scarring can occur.

US 5588564 discloses a pump spray which is provided with an attachment for applying a spray jet to an eye. Since the spraying time of this system is short, there is a risk that the solution will not be sprayed onto the eyelid but because of the blinking reflex. Neither the pump spray nor the attachment have devices with a germicidal effect.

US 5921444 discloses a spray device with an attachment for applying a liquid to an eye. The disadvantages of this system are similar to those described above.

WO 96/00050 discloses an applicator for liquids on an eye, in which the spray device is located within a housing, one side of which is designed such that it can encompass an eye. The aerosol droplets generated by the device have a diameter of at least 20 micrometers. The spraying time of this system is less than 1/20 second (page 13), which has the disadvantages described above.

EP 0911056 discloses a nebulizer for placement on an eye with an attachment which has a diaphragm or deflection plate which is positioned in such a way that the spray jet does not strike the cornea directly. Such protection is dirty however, on the one hand very quickly and can only be cleaned poorly, on the other hand it prevents exact and reproducible dosing.

DESCRIPTION OF THE INVENTION The object of the present invention is to apply aqueous solutions or ophthalmologically active formulations to the surface of the eye in such a way that the local irritation of a site on the cornea is reduced compared to the customary application methods for eye drops.

Another task is to develop a method with which

Eye drops can be applied in a way that is more convenient for the user than is known from the prior art.

Another object is to develop a method in which the liquid to be applied can be applied evenly to the eye.

Another task is to minimize the risk of injury to the eye when applying the eye drops.

Another object is to provide an applicator for ophthalmic liquids in which the use of preservatives such as EDTA or benzalkonium chloride in the application solution can be dispensed with.

The present invention solves this problem by creating nebulizers which transfer the formulation to be applied via a nozzle into a spray cloud with small particle sizes and bring this spray cloud into contact with the surface of the eye, the nebulizers having devices for suppressing nucleation.

These nebulizers have an adapter near the nozzle from which the spray cloud emerges, which fixes the distance between the nozzle and the eye and prevents the spray cloud from being blown away by wind. Detailed description of the invention

According to the invention, nebulizers can be used as eye applicators, which are equipped with an adapter for guiding the spray cloud to the eye. Any type of nebulizer can be used for this purpose, which fulfills the above-mentioned criteria and has devices for preventing the implantation of biological germs in the application solution.

Examples of nebulizers are: nebulizers which are known from propellant-free pulmonary inhalation therapy or intranasal use, such as:

a) nebulizers, which consist of a push-on plastic bottle with a spout, b) nebulizers, consisting of glass, metal or plastic bottles with pump attachments, preferably those as are known from WO 97/18902, to which reference is hereby made in full ,

These nebulizers must have devices for preventing nucleation in the storage bottle. Such devices include microbiological filters located in the paths through which air can enter the metering chamber or storage bottle. These filters are dimensioned in such a way that they do not let biological germs through, but air. Other means include, for example, the application of germicidal or oligodynamic substances to at least part of the above-mentioned airways or to the entire airways. The latter measures are preferred. In addition to or instead of applying the germicidal coating, oligodynamically active substances can be used as the material perse. Springs, rods, etc., made of an oligodynamically effective material, can also be hung in the airways. Oligodynamic substances are taken to mean metals or metal ions with a germicidal effect. These include, for example, and preferably silver. However, the substances mentioned must be such that they do not irritate or injure the eye, even in the smallest concentration. Nebulizers and / or pump attachments equipped in this way make it possible to dispense with the use of preservatives in the formulations to be applied.

Preferred nebulizers are those mentioned under point b).

With such nebulizers, the nebulization process is triggered by manual actuation of a pump device. To equalize the pressure, air can flow into the storage container that has been sterilized beforehand. The active substance formulation is preferably under normal pressure, overpressure can be dispensed with.

Therefore, in the context of the present invention, the nebulizer should consist of a storage vessel and a pump attachment attached to it. The pump attachment preferably has the following features:

- a closure for placing on the storage container, which e.g. is designed as a snap, screw or crimp closure;

- A pump channel that can pump liquid from the reservoir into a pressure chamber;

- A valve in the pump channel, which is formed between the storage vessel and the pressure chamber; - A riser pipe leading from the pressure chamber to a nozzle;

- a pressure control valve in the riser;

- a nozzle for atomizing the liquid;

- A trigger element, via which a piston can be actuated, which builds up the pressure required for nebulization in the pressure chamber; - Air intake points outside the pump tube or the riser and

Air inlet paths from outside the pump attachment to the storage container;

- Oligodynamically active substances in and / or along the path taken by the liquid in the pump channel and / or riser pipe between the reservoir and the nozzle; Means for sterilization along the path the incoming air takes, i.e. between the air inlet openings and the storage container and

- An adapter in the form of a cavity with two opposing openings, the smaller opening at least the exit point of the aerosol surrounds the nozzle in a coherent manner and the larger opening has a contour that allows this opening to be placed over an eye.

This type of nebulizer is in no way limiting for the present invention.

In the Vemeblem, the solution formulations are stored in a reservoir. It is necessary for the active substance formulations used to have sufficient storage stability and, at the same time, to be such that they can be applied directly to the medical purpose, if possible without further manipulation. Furthermore, they must not have any components that can interact with the nebulizer in such a way that the nebulizer or the pharmaceutical quality of the solution or the aerosol produced could be damaged.

The adapter represents a cavity surrounded by a wall with two openings. One opening surrounds the nozzle in such a way that an emerging one

Spray jet is directed exclusively into the cavity. The nozzle is preferably surrounded in the center by the opening. The spray jet leaves the cavity through the second opening, which is generally opposite the first opening, in order to meet the eye. The outer contour of the second opening is preferably designed such that it encloses the visible part of the human eye, preferably without directly touching the eye.

In order to meet this criterion, this second opening is preferably of the following shape when the adapter is connected to the nebulizer:

When viewed from above, the openings of the adapter have a round to oval shape. The opening facing the eye is shaped so that it completely surrounds the eye, i.e. part of the opening is drawn longer than the other. In cross section, the opening thus presents itself as a concave line, one of which

End has a greater distance from the nozzle than the other end. In its simplest embodiment, the adapter is a funnel-shaped tube with two opposite openings, the opening on the tapering side surrounding the nozzle of the nebulizer and thereby being encased by the adapter through the nozzle opening. The opening on the other side of the adapter is so large that it encloses the outer contours of an eye.

The adapter can be permanently connected to the nebulizer via the first opening, e.g. in which the edge of this opening is welded onto part of the nebulizer or in that the jacket of the nebulizer and the adapter represent a single element. The adapter is then an integral part of the nebulizer and this first opening is in fact only a non-open part of the nebulizer.

The adapter can also be designed as a removable element. The side of the adapter connected to the nebulizer can be designed so that it can be placed directly on the nozzle or attached to another element in the vicinity of the nozzle.

For example, the adapter can be attached to the nozzle of a conventional nebulizer.

The other end of the adapter is designed so that it can be placed on a person's face in such a way that it completely encloses the visible area of the eye lying in the face and thereby covers as little facial skin as possible. This ensures that the largest part of the spray reaches the surface of the eye without significantly moistening the facial skin. The opening of this side of the adapter is preferably oval.

On the outlet side of the adapter, openings can optionally be formed in the side wall of the adapter, through which excess spray can escape. These openings preferably have a diameter of up to 1 cm, particularly preferably of up to 0.5 cm. The adapter is also such that it cannot injure the skin of the face or the eye.

DESCRIPTION OF THE FIGURES A preferred nebulizer (1) with a pump attachment (2) is shown in FIG. The pump attachment (2) is firmly connected to the bottle neck (102) of the storage bottle (101) via the snap closure (3). This can be made of plastic, glass or metal, for example aluminum, but should be sufficiently rigid that the pump head can be moved without the bottle giving way. The inner edge of the snap closure (4) slides over the flange-shaped edge of the bottle neck (102). Between the bottle neck and pump attachment there is a seal (5), which is designed, for example, from rubber, natural rubber or synthetic rubber or preferably from polyethylene. A piston (6) with an axial pump channel (7) is located in the pressure cylinder (8). The piston (6) is held in the upper rest position by the spring (9) at a stop. The

Pressure chamber (10) is connected to the pump channel (7) and is located between the piston (6) and the ball valve (11).

The piston (6) has a smaller outside diameter than the inside diameter of the pressure cylinder (8), so that a gap (12) remains between the outside wall of the piston and the inside wall of the cylinder, which is sealed by the peripheral sealing body (13) of the piston. In the lower area of the pressure chamber (10), the pressure cylinder (8) has an area (14) with a larger inside diameter, in which the sealing body (13) has no sealing effect.

A trigger element (15) is located on the piston (6). From there, a riser pipe (16) leads to a pressure control valve (17) in order to discharge the liquids to be atomized through the opening (18). According to the function, the axial pump channel (7) and the riser pipe (16) form a common riser pipe which connects the pressure chamber to the nozzle.

If the piston (6) is in the upper rest position, as shown in the drawing, the sealing body (13) seals the pressure chamber (10) from the opening (19) of the storage container. The plunger (20) is fixed to the piston (6) in the region (21) and has a star-shaped diameter, so that there is a space between the

pressure chamber

(10) and the pump channel (7) remains. In the rest position, the plunger (20) is far away from the ball valve (11), so that this valve is open with respect to the storage container if enough overpressure is generated in the pressure chamber (10) and the valve is closed when the pressure there is low ,

The path that the liquid takes from the reservoir through the pump attachment is shown by the arrow (22). When the ball valve (11) is open, the liquid passes this valve and enters the pump channel (7).

In the following, it also passes through the open pressure control valve (17) and reaches the nozzle (18).

In order to avoid biological contamination of the liquid in the storage container, oligodynamically active substances are formed along the path that the

Takes liquid from the pantry to the nozzle.

These substances can, for example, on the spring (9), on the wall of the

Pump channel (7), be formed in the pressure control valve (17) and / or on the nozzle (18).

To equalize the pressure in the storage container (101) after the discharge of liquids, air can flow into the device from the outside at points (23) and then penetrate into the storage container (101), as shown, for example, by arrow (22) in the Drawing is shown. Means for sterilizing the incoming air are formed along the airway. These include, for example, sterility filters, membranes that are only permeable to air, bacteria-retaining materials, oligodynamically active substances, or microbiocidal substances or combinations thereof. A sterility filter (24) is shown as an example in FIG.

As already stated, the pump attachment (2) is firmly connected to the bottle neck (102) via a snap lock (3). The adapter (25) is attached to the trigger element (15) such that the spray jet coming from the nozzle (18) is directed directly into the widened area of the adapter. The lower area of the adapter (26) is detachably connected to the trigger element (15). The other end of the adapter (27) is designed such that it can be placed on the area around the eyes like a negative.

The area (14) can pass below the ball valve (11) into a further pump channel, which is only indicated in Fig. 1 (A). This pump channel then opens into the storage vessel.

In Figure 2, the adapter (25) is shown again schematically, the lower region (26) is placed on one or more circular to oval projections in the vicinity of the nozzle or with which it is firmly connected.

The other end of the adapter, which is designed as a negative of the surroundings of the eye, is identified by (27). The concave outer contour described above is not shown, as in none of the figures.

The adapter can be designed in such a way that the momentum of particles of the spray is reduced, in particular by reducing the speed of the particles.

In the simplest case, this is achieved by increasing the distance between the two openings in the adapter.

The nebulizers described above are suitable for nebulizing the ophthalmic aerosol preparations to form an aerosol suitable for application to the eye.

All known opthalmologically active formulations are suitable as a formulation which can be applied by the nebulizers according to the invention. Formulations of this type can also differ from the prior art in that the active compounds may be present in a higher concentration. In the simplest case, the formulation is merely water (water for injections), or isotonic water or other agents that moisturize the eye. Ie there is no active ingredient.

Suitable co-solvents include ethanol, polyethylene glycols, polypropylene glycols, ethylene glycols, propylene glycols.

As active ingredients come e.g. Active substances from the group of antibiotics and anti-infectives, anticholinergics, antiglaucomas, antifungals, antiseptics, anesthetics, eye tonics, corticoids and steroids, film formers, vasoactive substances, homeopathic drugs, mydriatics, NSAIDs (anti-inflammatory drugs) and prostagens, vitamins or antioxidants, tear substitutes or viral agents ,

All pharmacologically and ophthalmically compatible pharmaceutical auxiliaries can also be added to the formulations. This includes Arufil, benzalkonium chloride, boric acid, calcium chloride, carbomer, chlorhexidine digluconate, citric acid, EDTA, editic acid salts; Glucose, glutathione disulfide, hydroxyethyl cellulose, hypromellose, potassium chloride, magnesium chloride, magnesium sulfate, magrocol, mannitol, sodium acetate, sodium chloride, sodium dihydrogen phosphate, sodium bicarbonate, sodium hydroxide, sodium monohydrogen phosphate, sodium tetraborate, sodium thiosulfate, phenylmercuryl, polypropylene, polyethylenepolyethylene, polyethylenepolyethylene, polyethylenepolyethylene, polyethylenepolyethylene, polyethylenepolymer, polyethylenepolyethylene, polyethylenepolyethylenepolyethylene, polyethylenepolyethylene, polyethylenepolymer, polyethylenepolyethylene, polyethylenepolyethylene, polyethylenepolyethylene, polyethylenepolymer, polyethylenepolymer, polyethylenepolyethylene, polyethylenepolyethylene, polyethylenepolyethylenepolyethylenepolyethylenepolyethylenepolyethylene polypropylene, polyethylenepolymer, Hydrochloric acid, sorbitol, thiomersal, tyloxapol.

As already mentioned several times, the addition of preservatives such as EDTA, benzalkonium chloride and others can and is preferably dispensed with in the nebulisers according to the invention.

The advantages of the method according to the invention are, inter alia, that the irritation of the cornea or the connective tissue is reduced in the case of formulations applied to the eye in this way; - Apply ophthalmic formulations evenly on the surface of the eye and thus improve the absorption by the cornea or the connective tissue of the eye;

- there is no need to add preservatives; - the head does not have to be reclined during application due to the active pump mechanism and the resulting moving spray cloud;

- Every spray burst is deliberately carried out by means of a pump movement, so that the patient knows how many strokes he has carried out, so that - the dosage can be reproducibly and very precisely carried out;

- the quantity applied is comparatively small;

- an overdose is avoided;

- Systemic side effects are reduced due to the small amount of application; - the supply bottle does not need to be pressed to trigger the spray jet, i.e. there is less risk of the applicator being accidentally pressed into the eye.

Claims

claims

1. Propellant-free nebulizer for the application of liquids to the cornea or the connective tissue of humans, containing: - a storage container for the liquid to be applied

- a pump attachment on the storage vessel;

- A closure on the pump attachment for placement on the storage container, which e.g. is designed as a snap, screw or crimp closure

- A valve in the pump channel, which is formed between the storage vessel and the pressure chamber;

- A riser pipe leading from the pressure chamber to a nozzle;

- a pressure control valve in the riser; - a nozzle for atomizing the liquid;

- A trigger element, via which a piston can be actuated, which builds up the pressure required for nebulization in the pressure chamber;

- Air inlet points outside the pump tube or the riser pipe and air inlet paths from outside the pump attachment to the storage container; - Oligodynamically active substances in and / or along the path that the

Takes liquid in the pump channel and / or riser pipe between the reservoir and nozzle;

- Means for sterilization along the path that the incoming air takes and an adapter according to one of the preceding claims, which is formed at the top of the pump attachment, and an adapter in the form of a wall-encased cavity with two openings, the one opening the Surrounds the nozzle in such a way that a spray jet emerging therefrom is directed exclusively into the cavity and the second opening, which lies opposite the first, has an outer contour which is such that the opening adjoins the nozzle encloses the visible part of the eye of a human or animal without touching the eye directly.

2. Nebulizer according to claim 1, characterized in that the

The outer contour of the second opening of the adapter is oval in plan view and in cross section as a concave curved line with a longer and a shorter drawn end.

3. Nebulizer according to claim 1 or 2, characterized in that the adapter is inseparably connected to the nebulizer as an integral part.

4. Nebuliser according to claim 1 or 2, characterized in that the adapter is plugged onto the nozzle.

5. Nebuliser according to one of the preceding claims, characterized in that the attachment with a nozzle is a pump system.

6. Nebulizer, according to one of the preceding claims, characterized in that the means for sterilization along the path that the inflowing air takes are filters for microbiological germs or filters with a germicidal effect.

7. Nebulizer according to one of the preceding claims, characterized in that the openings are formed in the side wall of the adapter.

8. Adapter for a nebulizer for applying liquid to the cornea or the connective tissue of humans according to one of claims 1 to 7.

9. Use of a nebulizer according to one of the preceding claims for the application of liquids to the cornea or the connective tissue of humans.