CZ20003511A3 - Nasal spraying device with elastomeric valve - Google Patents

Abstract

The invention relates to a spray device adapted to provide multiple, unit doses of a fluid, each dose having a volume in the range from about 1 to about 100 mu lambda , the device comprising an elastomeric, self-sealing valve having a fluid side and a delivery side, the valve opening to allow passage of the fluid when pressure is applied to fluid on the fluid side and sealing when the pressure is removed. The valve achieves a clean stop-start flow of the fluid at low fluid volumes. The device is particulary suitable for low volume medical applications such as nasal spraying.

Description

The spray device (4) is adapted to provide multiple unit doses of fluid, each unit dose having a volume ranging from about 1 to 100 μΐ. The device (4) comprises an elastomeric self-closing valve (8) having a fluid side and an outlet side. Opening the valve (8) permits the passage of fluid when pressure is applied to the fluid on the fluid side and the valve (8) is closed when pressure is removed. The valve (8) ensures perfect closing and opening of the fluid flow at low fluid volumes.

• · · ·

LOAD SPRAYER WITH ELASTOMERAL VALVE

......

• · · _ 640 3,640

Technical field

The present invention relates to a spray device adapted to provide a multiple unit dose of fluid, wherein the device comprises an elastomeric, self-closing valve that ensures perfect termination and initiation of fluid flow at low fluid volumes. In particular, the invention relates to a device supplying unit volumes ranging from about 1 to about 100 μΙ.

BACKGROUND OF THE INVENTION.

The treatment of diseases affecting the area of the nose, such as hay fever or runny nose due to a cold, has long been carried out by means of a nasal spray device. Recently, it has been found that the mucous membrane of the nasal cavity can be used as a convenient application site for drugs acting on other areas of the body. For example, WO 92/11049 discloses a pen-shaped device for nasal administration of primarily insulin.

A spray form is often suitable for such treatment. Also, treatment of the eyes can suitably be accomplished with a spray device. Preferably, the dosage volumes for such use are generally low, less than 10 μΙ. Repeated dosing will generally be necessary to ensure that the treatment is effective enough. It may be difficult to achieve a perfect end and start the effluent from the spray device delivering such low volumes. Typical problems encountered are the dripping of residual fluid from the valve after application, theoretically possible backflow and blockage of the valve.

It has now been found that an elastomeric valve, particularly a slotted valve, provides a perfect stop and start of the flow without clogging, even though the atomized fluid contains finely divided solid particles.

• ·

SUMMARY OF THE INVENTION The object of the present invention is to provide a spray device which is capable of efficiently and multiply producing a unit dose with a low unit volume.

Another purpose of the present invention is to provide a fluid flow cut-off device that ensures perfect cutting off of the fluid flow is not prone to fouling.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a spray device adapted to produce one or more unit doses of fluid having or having a volume in the range of about 1 to about 100 µΙ, the device comprising an elastomeric self-closing valve having a fluid side and a discharge side; when pressure is applied to the fluid on the fluid side, the valve opens and fluid flows, and the valve closes when the pressure has passed.

Preferably, the spray device is an electrostatic spray device that generates a spray prior to entering the nostrils.

DETAILED DESCRIPTION OF THE INVENTION

Fluids

The spray device of the invention comprises a liquid reservoir comprising a pharmaceutically acceptable liquid which comprises a pharmaceutically acceptable therapeutic component selected from drugs, flavors, salts, wetting agents and mixtures thereof. The fluid may contain other excipients dissolved or dispersed therein. The fluid may be aqueous or anhydrous. Suitable aqueous fluids include water and mixtures of water with water-miscible solvents such as glycerin, propylene glycol, or alcohols such as ethyl alcohol or isopropyl alcohol. Aqueous emulsions, both water-in-oil and oil-in-water emulsions, may also be used. Preferably, the fluid is in the form of an aqueous solution, dispersion or emulsion oil-in-water. Suitable anhydrous fluids include polyethylene glycol, glycerin, propylene glycol, dimethyl isosorbide, silicone oils, ketones, ethers, and mixtures thereof. Without limiting the range of resistivity in any way, the invention advantageously utilizes low resistivity fluids, particularly those having a resistivity of 3 3,640 less than 1 x 10 ⁸ ohm.cm, preferably those having a resistivity less than 1 χ 10 ⁴ ohm cm, preferably less than 1 χ 10 ³ ohm.cm. If necessary, the fluid may include a resistance modifier, such as a pharmaceutically acceptable salt, to achieve a resistivity value within the desired range.

The most suitable liquid is a pharmaceutically acceptable intranasal carrier. Preferably, the nasal composition is isotonic, i.e., has the same osmotic pressure as blood and tears. The desired isotonicity of the composition of the invention may be achieved by using, for example, sodium chloride present or other pharmaceutically acceptable ingredients such as dextrose, boric acid, citric acid, sodium tartrate, sodium citrate, sodium phosphate, potassium phosphate, propylene glycol or other inorganic or organic substances dissolved in solution. Sodium chloride is particularly preferred for the content of buffered sodium ions. Further examples of sodium chloride equivalents are described in Remington's Pharmaceutical Sciences, pages 1491-1497 (Alfonso Gennaro 18th ed. 1990), which is incorporated by reference. AND

Medicines

The fluid may contain a wide variety of drugs. By drug is meant a drug or other substance intended to have a therapeutic effect on the body. Suitable drug contents are from 0.001 to 20%, preferably from 0.01 to 5%, most preferably from 0.1 to 5%. The contents of particular drugs will depend on a number of factors including their efficacy, the level of safety, the solubility / ease of dispersion and the intended effect. The medicament to be used may have the intended effect at the site of administration, such as blood flow suppressants, antihistamines or anti-inflammatory drugs or may be intended for systemic absorption, such as antiviral agents, antidepressants, anti-vomiting agents, anti-fever agents or hormones and the like. The drug may be soluble in the liquid or may be insoluble, in the form of finely divided particles of the liquid, or as a solid dispersed in the liquid. Suitable antihypertensive agents include oxymetazoline, tramazoline, xylometazoline, naphazoline, tetrahydrazoline, pseudoephedrine, ephedrine, phenylephrine, pharmaceutically acceptable salts thereof such as hydrochlorides, and mixtures thereof. Preferred congestion-reducing agents are those selected from the group consisting of oxymetazoline, xylometazoline, pharmaceutically acceptable salts thereof, and mixtures thereof. Particularly preferred for this use is oxymetazoline hydrochloride, which is water soluble. Preferably, when used in the compositions of the present invention, the congestion reducing agent is in the range of from about 0.01% to about 3.0%, preferably from about 0.01% to about 1%.

Atihistamines useful in the present invention include, but are not limited to, histamine H-1 as a receptor antagonist.

Such H-1 receptor antihistamine may be selected from the following classes of antihistamines: alkylamine, ethanolamine, ethylenediamine, piperazine, phenothiazine, piperidine. Examples of preferred fast-acting antihistamines include acrivastine, carbinoxamine, diphenhydramine, chloropheniramine, brompheniramine, dexchloropheniramine, doxylamine, clemastine, promethazine, trimeprazine, methdilazine, hydroxyzine, pyrilamin, tripelennamine, meclizine, rindine, triphenolamine, triphenolamine, triphenolamine, triphenolamine, triphenolamine, mixtures thereof. Other useful antihistamines include tefrenadine, azelastine, cetirizine, astemizole, ebastine, ketotifen, lodoxamide, loratadine, levocabastine, mequitazine, oxatomide, setastine, tazifylline, temelastine or pharmaceutically acceptable salts and mixtures thereof. When an antihistarpinic is used in the compositions of the invention, it is preferably present at a concentration of from about 0.01% to about 3.0%, most preferably from about 0.01% to about 1%.

The medicament may also be an anti-inflammatory agent such as a corticosteroid. Particularly preferred formulations of this group are glucocorticoids selected from the group consisting of beclomethasone, flunisolide, fluticasone, memetasone, budesonide, pharmaceutically acceptable salts thereof, and mixtures thereof. If an anti-inflammatory component is present in the compositions of the present invention, it is preferably used at a concentration of from about 0.001% to about 0.1%, most preferably from about 0.01% to about 0.1%.

Also useful are xanthine derivatives such as caffeine, methylxanthine and the like; antiallergics; mucolytics; anticholinergics; non-opioid analgesics such as acetaminophen, acetylsalicylic acid, ibuprofen, etodolac, fenbuprofen, phenoprofen, ketorolac, flurbiprofen, indomethacin, ketoprofen, naproxen, pharmaceutically acceptable salts thereof, and mixtures thereof; opioid analgesics such as butorphanol; leukotriene receptor antagonists; mast cell stabilizers such as cromolyn sodium, nedocromil and lodoxamide; and lipoxygenase inhibition kits.

Further examples of suitable drugs can be found in WO97 / 46243, EP-A-780127, US-A-5,124,315, US-A-5,622,724, US-A-5,656,255 and US-A-5,705,490 .

640

Flavors

Various seasoning and / or fragrance components (e.g., aldehydes and esters) may be used in the fluids of the invention. These include, for example, menthol, camphor, eucalyptus oil, benzaldehyde (cherries, almonds); citral (lemon, lime); neral; decanal (orange, lemon); aldehyde C-8, aldehyde C-9 and aldehyde C-12 (citrus fruit); tolyl aldehyde (cherries, almonds); 2,6-dimethyl-octanal (green fruit); 2-dodecenal (citrus, mandarin); and herbal ingredients such as thyme, rosemary and sage oil. Other aromatic ingredients suitable for use in the present invention are described in U.S. Pat. U.S. Patent 4,136,163 to Watson et al. No. 4,459,425 to Amano et al. U.S. Patent 4,230,688 to Rowsell et al; which are referred to. Mixtures of these flavoring agents may also be used.

Detergents I

The fluid may also contain one or more pharmaceutically acceptable detergents. Such a detergent may be useful for dispersing or emulsifying medicaments or flavors, for increasing absorption through the nasal membrane, or as a therapeutic component in its own meaning, for example, for dissolving earwax. The detergents may be anionic, nonionic, cationic or amphoteric, preferably nonionic detergents are useful. Typical preferred nonionic detergents include: polyoxyethylene sorbitan anhydride ester derivatives such as polysorbate 80; polyoxyethylene fatty acid derivatives such as polyoxyethylene 50 stearate as well as oxyethylate tertiary octylphenol formaldehyde polymer (manufactured by Sterling Organics under the name Tyloxapol) or mixtures thereof. Typical concentrations of these materials are from 0.1% to 3% by weight.

Salts

The fluid may also contain one or more pharmaceutically acceptable salts. These may be mineral salts such as sodium chloride, or organic acid salts such as sodium citrate.

Í3 640

Other excipients

The fluid may further comprise other additives such as thickeners, wetting agents, suspending agents, thickeners, chelating agents, and antioxidants.

The viscosity of the compositions can be maintained at a selected level using a pharmaceutically acceptable thickener. A suitable thickener is, for example, xanthine resin, methyl cellulose, microcrystalline cellulose, carboxymethyl cellulose, chitosan, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, carboxyvinyl polymer, carbomer, and the like, or pharmaceutically acceptable salts thereof. Mixtures of these thickeners may also be used. The preferred density of the thickener will depend upon which agent is selected. It is important to use an amount which achieves the selected viscosity. Viscous compositions are generally prepared from solutions by the addition of such thickeners.

The fluids of the present invention may also advantageously also contain from about 0.01% to about 5% of a mucosal preventing and drying agent. Any pharmaceutically acceptable surfactant may be used, including, for example, sorbitol, propenglycol, polyethylene glycol, glycerin or mixtures thereof. As in the case of a thickener, the density will vary depending on the substance selected, but the presence or absence of these compositions or their concentration is not a feature of the present invention.

A pharmaceutically acceptable antioxidant is generally used to extend the shelf life of the composition of the invention. Various antioxidants may be used, such as, for example, benzyl alcohol, parabens, phenylethyl alcohol, thimerosal, chlorobutanol, chlorhexidyl gluconate, or benzalkonium chloride. The most preferred antioxidant for use in the present invention comprises a combination of benzalkonium chloride, chlorhexidine gluconate and disodium EDTA as a chelating agent. A suitable concentration of antioxidant is in the range of 0.001% to 2% based on the total weight, although, depending on the agent selected, the content may vary widely.

Spraying equipment and parameters of spraying.

The spray device generally comprises means for controlling the dosage of the applied fluid. The dispenser may be a simple switch that allows the user to control the dispensing according to his or her needs. The spray device is adapted for • ·

delivering one or more unit fluid doses, preferably multiple fluid doses, each having a volume in the range of about 1 to about 100 microns, preferably about 1 to about 20 microns, most preferably about 5 to about 15 microns.

The dose volume is preferably preset, but can also be adjusted by the user. Suitably, the device comprises a fluid storage container and dispensing means for selectively delivering a unit dose from the container to the spray generator. The dosing means may be, for example, a metering valve or a pump syringe.

The device is adapted to form a spray forming a fluid stream, which stream extends from one end of the nose piece to the delivery end where it passes into a conical opening stream. By the end of the nose piece is meant the point at which the plane (hereinafter the nose piece plane) perpendicular to the axis of flow and touching the outer surface of the nose piece intersects the center of the fluid stream. The fluid stream preferably has a length of from about 1 to about 20 mm, preferably from about 1 to about 10 mm, and most preferably from about 2 to about 8 mm, and in particular from about 3 to about 6 mm from the extension end to the delivery end. .

In a preferred embodiment, the spray cone has an apex angle of from about 10 to about 90 °, preferably from 20 to about 50 °, most preferably from about 30 to about 40 °. In electrostatic devices, the length of the fluid stream and the angle of the spray cone can be adjusted by varying the viscosity or surface tension of the fluid, changing the fluid flow rate or output velocity, or changing the electric field intensity due to the applied voltage, potential gradient, or utilization of the boost electrode field.

The total length of the fluid stream may be, and preferably is, longer than the length from the end of the nose piece to the delivery end. The fluid stream preferably comes from a location on the side of the device on the surface of the nose piece, for example from an elastomeric self-sealing valve as used in this case, and passes through an opening in the nose piece. Preferably, the distance from the point of origin of the fluid stream to the plane of the nose piece is in the range of about 2 mm to about 15 mm, preferably about 3 to about 10 mm, and most preferably about 5 to about 9 mm. In this way, the nose piece can be used as a field amplifier to help control the length of the fluid stream. For this purpose, the nose piece is preferably of a non-conductive material, in particular plastic, which may be, for example, polypropylene, but a plasticized thermoplastic elastomer that provides greater comfort when held in front of the nose is preferable. The elastomers described herein for use on self-healing valves are also suitable for nasal extensions.

Electrostatic devices suitable for generating a spray fluid stream are described in WO 96/40441, EP-A-501 725 and PCT / GB97 / 02746. Preferably, the present device is constructed according to the construction described in EP-A-501 725 or PCT / GB97 / 02746, in which the current is generated by mechanical means and the high voltage applied to the fluid leads the fluid stream or its bundle to spread into a conical shape. The current can be generated, for example, by a pump syringe. Suitable flow rates are from about 0.5 to about 8, preferably from about 1 to about 3 m / s. A suitable high voltage is in the range of about 1 kV to about 10 kV, preferably from 2 kV to about 7 kV, and most preferably from 2 kV to about 5 kV.

Voltage can be applied to the fluid without problems from a small handheld device, from a low voltage (1.5V is sufficient) battery coupled to the boost transformer. The battery is preferably a long-life type and can be rechargeable. If a metal pump syringe is used, the tension may be applied to the fluid by means of a pump which is preferably enclosed in an insulating plastic housing. Alternatively, the fluid may be charged by an electrode inserted into the fluid. The generator can be activated by the user via an external switch which can also be used to mechanically drive the pump. Preferably, the switch comprises a metal portion through which the user closes the grounding branch of the high voltage circuit. A suitable arrangement of the overall design of the apparatus is described in PCT / GB97 / 02746. Also other arrangements using AC voltage can be used to form a dose.

The device is activated to deliver the spray. The atomized fluid stream passes through the orifice of the nostril into the inlet space, preferably from a short distance from the orifice, before opening into the shape of a cone beam. The device may be designed to prepare two fluid streams directed simultaneously to each of the two nostrils. Two fluid streams can be generated in two separate dispensing devices or can be obtained from a single source using an tvaru shaped valve that divides a single fluid stream into two.

In order to achieve a clean separation of low-volume doses, the device preferably comprises an elastomeric self-closing outlet valve having a fluid side and an outlet side.

The opening of the valve is ensured by the fluid passing through when the pressure is exerted on the fluid side and closes when the pressure is not applied. By the outlet valve, it is meant that the elastomeric. .:. The .13 64Ο valve is an end-to-end metering valve and that no other device elements are used that mechanically restrict or alter the fluid flow at the outlet side of the valve. In a preferred embodiment, the valve is slotted. The valve may comprise a single slot or two or more intersecting slits arranged, for example, in the shape of a cross. Preferably, however, the valve comprises a single slot. Although the valve may be flat, it is preferably dome-like, meaning a non-planar valve having a recess with, for example, a hemispherical or frustoconical vault. In a preferred embodiment, the valve is substantially in the form of a hemispherical dome having a flange along its periphery so that the sleeve can hold the valve in the device. The diameter of the valve, including the flange, is generally from about 2 to about 6 mm and the dome portion has a diameter of from about 1 to about 4 mm, typically about 2.5 mm, and a thickness within from about 0.5 to about 1.5 mm, preferably about 1 mm.

The valve need not always have the same thickness. In a preferred embodiment, the outer surface of the valve dome is hemispherical, while the inner surface is formed with a small area at the upper end of the dome at the location where the groove is formed. A suitable groove width is in the range of about 50 to about 400 microns, preferably from about 150 to about 250 microns. Obviously, the width of the slot is meant at the location of the largest dimension of the slot at the time of its formation. By elastomeric is meant herein a material that is both elastically compressible and elastically extensible. For the purposes of the present invention, a wide range of elastomers can be used, including but not limited to polyurethanes; chloroprene, butyl, butadiene and styrene-butadiene rubbers, and silicone elastomers as two-component RTV silicones. Two-component RVT silicones are most suitable for use herein. Suitable RTVS silicones are sold under the trademark NuSil and have a hardness of from about 30 to about 80 Shore A, preferably from about 40 to about 70 Shore A. The elastomers may be admixed with a suitable plasticizer or foaming agent to provide greater compressibility. The elastomers may also contain dispersed materials therein to adjust their properties, such as their conductivity. If elastomers of low tear strength are used, the slit width may increase if the slit is open for a long time. The slit valve may be formed by punching the elastomeric seal produced by injection molding, at the same dimensions and shape as the valve used, the punching being performed by a needle having a sharpened tip. The width of the slot is roughly appropriate to the width of the needle. The needle may be a flat blade or the needles may have a polygonal or circular cross-section. Preferably, the needles have a polygonal or most preferably circular cross-section. It has been found that a needle made by a sharp-pointed needle works better than a pinhole when used as a valve. This may cause the fluid flow to be non-direct, or 18,640 ··· ··········· · «Even two or more jets may be formed, which may cause unreliable or unpredictable atomisation. Suitable needle diameters are from about 100 to 350, preferably from 150 to 250 µm. When using silicone elastomers, it is advisable to remove the punch needle quickly after the slit has been formed to avoid undesirable enlargement of the slit. Furthermore, it has been found that the geometry of the elastomeric seal and the punching methods have an important effect on the efficiency and repeatability of the slit formation. Thus, a more reliable slot formation is provided if the seal is pierced from the interior of the dome, not from the outside. The valve opens when the fluid side pressure is applied to the fluid and closes when the pressure has passed. As mentioned previously, pressure can be applied to the fluid by a dosing device such as a pump syringe. The pressure is suitably in the range of about 200 to about 5000 mbar (20 to 500 kPa), preferably about 500 to about 3000 mbar (50 to 300 kPa). The flow through the valve is generally proportional to the applied pressure and is suitably in the range of about 5 to about 50, preferably about 5 to about 30 µl / sec. At such pressures and with the type of valve described and the dimensions of the gap dimensions, a straight fluid flow f is obtained at an outlet velocity of from about 0.5 to about 8, preferably from about 1 to about 3 m / s.

The diameter of the outflow is partially determined by the flow rate and is generally smaller than the width of the valve slot. Depending on the flow rate, fluid flow diameters of less than 50 µm can be achieved, even when a valve having a slot width of 200 µm is used. The diameter of the fluid stream has a major effect on the particle size of the stream after it has been distributed into a conical stream, the particle size being very similar to the diameter of the fluid stream. A distinctive feature of the fluid stream in the electrostatic spray generation mode is that it is possible to obtain a precisely distributed, almost monodisperse fluid stream. Thus, a mean droplet size of from about 20 to about 80, preferably from about 30 to about 70 microns, and most preferably from about 40 to about 60 microns can be achieved, with a standard particle distribution of less than 5, typically less than 2 and preferably less than 1 pm. It is known that for nasal sprays, the particle size should be 10 µm or less so that the particles do not enter the lungs. This is much less likely because the electrostatic charge of the fluid jet particles tends behind the nose to carry them relatively quickly to the grounded surface.

Perfect shut-off of the valve can be further improved by reducing the pressure downstream of the valve. This is accomplished by providing a bypass to the fluid reservoir so that any residual fluid is forced to release the elastomer to return to the reservoir instead of fluid from the valve outlet.

• 9

• »·

^: .JŠ 640

If necessary, several self-closing valves in tandem can be used to achieve a higher flow volume while maintaining a preferred small spray particle size. The seals from which the valves are formed can usually be manufactured by traditional injection molding.

Methods

The spray device according to the invention is suitable for spraying liquids into the body cavity, especially into the nose, mouth or ears of a human. Due to its low volume and fine spray, the device is also suitable, for example, for eye sprays. Preferably, the device is suitable as a nasal spray device. A preferred method of dispensing fluid into the nasal cavity from the nebulizer device comprises spraying the fluid into the nasal cavity without substantially penetrating the device into the nostrils. The term without substantial penetration into the nostrils means that there is no insertion of a nozzle or the like into the nasal vestibule. When using the device, the nose piece is preferably placed in contact with the nose hole, which provides the benefit of the described field of intensifying action in conjunction with the nose piece. If pressure is applied by the user, to ensure contact or to assist in orientation, there may be some widening of the nostril or contact with the cartilage wall, but the nasal attachment will not be completely surrounded by the nostril.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will now be described by way of example, with reference to the following figures, in which:

Giant. 1 is a schematic cross-section of a human nose.

Giant. 2 is a perspective view of a spray device according to the invention.

Giant. 3 is a very simplified cross-sectional view of the spray device of FIG. 2 showing the relationship of the elastomeric nozzle to the nose piece and dispensing device;

Giant. 4 is a schematic partial cross-section showing the spray of mist coming out of the device according to the invention.

Giant. 5 is an enlarged cross-sectional view of the elastomeric outlet valve of the invention.

640

DETAILED DESCRIPTION OF THE INVENTION

According to FIG. 1, the human nose comprises a nasal cavity 1 in which the nasal shells 2 are located, spiral-like finger-shaped bodies lined with lining and which are susceptible to inflammation. The nasal cavity is connected to the outer space by two nostrils 3. Because the nasal shells are located in the distal part of the nasal cavity, it is generally difficult to spray them effectively without inserting the spray device into the nostrils.

In Figures 2 and 3, a spraying device 4 is provided with a soft elastomeric nose piece 5 which is designed to abut the edge of the user's nostril without sliding into the buttonhole.

The nose piece is provided with an aperture 6 to which a spray pump 7, the internal components of which are not shown, is connected, which is used to generate a jet of mist passing through the elastomeric outlet valve 8. The device insulation box 9 further comprises a fluid exchange container (not shown), battery, transformer and an electronic circuit supplying high voltage from the transformer to the fluid. The device is equipped with a drive mechanism 10 that mechanically drives the pump to provide a preset unit dose of fluid. The drive mechanism comprises a metal portion forming a return from the user to the high voltage circuit.

In Fig. 4, there is a spray jet comprising a spray beam 11 and a conical jet 12 forming an apex angle θ. In practice, the cone angle can be measured by spraying from a fixed distance onto the paper and then measuring the diameter of the sprayed cone beam track or by looking directly at the spray stream using a high-speed backlit image. The bundle has a delivery end 13 where the bundle opens in the shape of a cone and the extension end 14 defined as the point where the plane A-A intersects the spray bundle 11. The plane A-A is situated perpendicular to the bundle axis and touches the end face of the nose piece 5.

Giant. 5 shows an elastomeric outlet valve 8 according to the invention. The nozzle, which is circularly symmetrical, is provided with a flange 15 for fastening the nozzle in the spraying device, a domed boss 16, a recess 17 and a slot 18 extending from the recess to the crown top. The nozzle is designed as a gasket produced by spraying and is provided with a slot formed by subsequent piercing of the vault with a sharp circular cross-section needle of 200 μηi diameter from inside the recess.

-3 640

Examples.

The following examples further describe and represent a solution within the scope of the present invention. The examples are for the purpose of illustration only and are not intended to limit the scope of the present invention.

Example I

The fluid of the present invention is prepared by combining the following ingredients using conventional mixing techniques similar to those described below.

Ingredient oxymetazoline hydrochloride sodium citrate dihydrate citric acid tyloxapol digluconate chlorhexidine benzalkonium chloride camphor eucalyptus oil sodium salt EDTA distilled water content (% by weight)

0.31 <

, 75

0.35

0.70

0,054

0.02

0.04

0.02

0.01

100ml

In a container of a suitable size, the above ingredients are added with stirring one after the other to the water so that each component dissolves before adding the other. After all the ingredients have been added, the starting mixture is diluted with distilled water to a suitable density. The solution has a resistivity of 120 ohm.cm. The solution is filled into a flexible laminate container and loaded with it into an electrostatic spray device of the same type as in Figure 2. The device further comprises an elastomeric valve as shown in Figure 5. The valve is held in place by a screw flange securing the flange. The nasal attachment of the device is held against the nostril and the device is oriented so that the spray stream will enter the nostril. When the device is started, the pump syringe exerts a pressure of 100 kPa (1000 mbar) under the valve, which opens the slit valve to a width of about 50 gm and emits 8 μΙ of solution during: ί 640 for about 1 second. When the fluid dose is dispensed, the valve closes completely, preventing further fluid leakage and preventing contamination of the fluid in the reservoir. The dosed fluid provides relief from the effect of reducing blood flow without causing appreciable moisture on the nose or inside the nose. The low dose volume and its gentle delivery results in no perceptible physical impact from the flowing substance by the user.

Example II

Additional fluid is prepared by combining the following components using a conventional mixing technique similar to that described in Example I.

Component

Λ content (weight%)

flunisolid 0,025 chlorpheniramine 0.350 levocabastine 0.0125 propylene glycol 2,000 polyethylene glycol 1,000 amintetraacetic acid 0.050 benzalkonium chloride 0.010 Distilled water 100ml

A nasal spray administered according to the method of Example I in an amount of about 10 μΙ of the fluid composition is prescribed to reduce the manifestation of allergies or similar symptoms.

Example III

The fluid of the present invention is prepared by combining the following components using a conventional mixing technique similar to that described in Example I.

Component content (% by weight)

Diproprionate-beclomethasone monohydrate 0.042 ··· · »··‘ £> 640

chlorfeniramine 0.500 AVICEL RC - 591 0.200 dextroza 5,100 polysorbat 80 0.050 benzalkonium chloride 0.020 phenylethyl alcohol 0,025 Distilled water 100ml

* microcrystalline cellulose and sodium carboxymethyl cellulose supplied by FMC Corporation.

A nasal spray administered in the manner of Example I in an amount of about 10 μinové of the fluid composition is used to provide relief from the effects of allergy or allergy-like symptoms. AND

.. COO-yyil

640 • · · 9

99 9 9 999

9 9 · 9

9 9 9

9 9

9

PATENT CLAIMS

Claims (8)

Spraying device, adapted to provide one or more unit doses of fluid, each having a volume in the range of about 1 to about 100 μΙ, comprising an elastomeric self-closing drain valve having a fluid side and an outlet side, wherein upon opening the valve in As a result of the pressure exerted on the fluid on the fluid side of the valve, fluid is allowed to pass through and the valve closes when the pressure has passed. The spray device of claim 1, which is adapted to provide a multiple unit dose of fluid. Spray device according to claim 1 or claim 2, wherein the valve is slotted, the slot having a width of from 50 to 400 μιτι, preferably from 150 to 250 μιτι. The spray device of any one of claims 1 to 3, wherein the valve has a dome shape. The spray device of claim 3 or claim 4, wherein the slit has been formed by a sharp circular needle. Electrostatic spray device according to any one of claims 1 to 5. The electrostatic spray device of claim 6, which is adapted to apply a voltage to the fluid in the range of 1 kV to 10kV. The spray device of any one of claims 1 to 7, wherein the device is adapted to use a fluid pressure in the range of 200 to 5000 mbar (20-500 kPa). 13 • · • · • · • · Cl idctiti rrc cucct / 0111 c oc é · · · · · · · · · · · · · · · · · · · · 2/3 FIG. 3