GB2467758A - Metered dose inhaler with internal coating of siloxane and/or silazane - Google Patents

Metered dose inhaler with internal coating of siloxane and/or silazane Download PDF

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Publication number
GB2467758A
GB2467758A GB0902338A GB0902338A GB2467758A GB 2467758 A GB2467758 A GB 2467758A GB 0902338 A GB0902338 A GB 0902338A GB 0902338 A GB0902338 A GB 0902338A GB 2467758 A GB2467758 A GB 2467758A
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Patent type
Prior art keywords
container
formulation
valve
medicinal
example
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
GB0902338A
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GB0902338D0 (en )
Inventor
Richard Warby
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Consort Medical PLC
Original Assignee
Consort Medical PLC
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Filing date
Publication date

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00Inhalators
    • A61M15/009Inhalators using medicine packages with incorporated spraying means, e.g. aerosol cans
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00Inhalators
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00Inhalators
    • A61M15/0001Details of inhalators; Constructional features thereof
    • A61M15/0021Mouthpieces therefor
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B65CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65DCONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
    • B65D23/00Details of bottles or jars not otherwise provided for
    • B65D23/02Linings or internal coatings
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B65CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65DCONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
    • B65D25/00Details of other kinds or types of rigid or semi-rigid containers
    • B65D25/14Linings or internal coatings
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B65CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65DCONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
    • B65D83/00Containers or packages with special means for dispensing contents
    • B65D83/14Containers or packages with special means for dispensing contents for delivery of liquid or semi-liquid contents by internal gaseous pressure, i.e. aerosol containers comprising propellant for a product delivered by a propellant

Abstract

A pressurised metered dose inhaler 1 for dispensing a medicinal formulation consists of a container 2 filled with the medicinal formulation. The container 2 has one or more internal surfaces which are in contact with the medicinal formulation, and at least part of which are coated with a silicone-containing coating material formed from a cold-plasma polymerised siloxane and/or silazane. The coating reduces deposition on the at least part of the one or more surfaces, and therefore mitigates the problems of reduced efficiency of operation known to result from deposition of contents. The siloxane may be dimethyl-siloxane, diphenyl-siloxane, hexamethyl-disiloxane (HMDSO) and/ or tetramethyl-disiloxane (TMDSO), while the silazane may be hexamethyl-disilazane. The container 2 may include a metering valve 3 for dispensing metered doses of the medical formula. The metering valve 3 may include a metering chamber which is also coated by siloxane and/or silazane. The metering valve 3 may have a valve body for connecting the metering valve to the container with the aid of a ferrule 4. The inhaler 1 may have a mouthpiece.

Description

IMPROVEMENTS IN OR RELATING TO DISPENSING APPARATUS

The present invention relates to a pressurised metered dose inhaler for dispensing a medicinal formulation. In particular, the invention relates to a pressurised metered dose inhaler that includes a pressurised dispensing container and a valve for controlling dispensing of metered doses from the pressurised metered dose inhaler. Further, the invention relates to a layer or coating formed on one or more surfaces of the pressurised dispensing container.

It is known in the art to coat parts of aerosol containers (pressurised metered dose inhalers) with a coating to, say, reduce friction, reduce deposition of a medicinal formulation and/or provide an inert barrier between a container material and a formulation stored in the container or aerosol. Numerous coatings are known in the art for this purpose, including fluorinated coatings.

A problem with known aerosols is that deposition of the medicinal formulation, or a solid component from a suspension of a particulate product in a liquid propellant, on internal surfaces and other components of the aerosols occurs after a number of operation cycles and/or storage.

This can lead to reduced efficiency of operation of the aerosol and effectiveness of the resulting treatment, in that deposition of the active product reduces the amount of active drug available in the medicinal formulation dispensed to a user. Some prior art devices rely on the aerosol being shaken in an attempt to dislodge the deposited particles as a result of the movement of a liquid propellant and medicinal product mixture. This remedy can be somewhat effective within the container itself but, owing to the relatively large internal surface area of the container, this surface area does provide a relatively large area upon which deposition can occur and shaking may not remove all deposited particles. Therefore, those active products that have a tendency to adhere to the internal surface of the container and other parts of the valve can do this over a relatively large surface-area and may not be fully removed by shaking. In these circumstances, the level of active ingredient provided in the metered dose is reduced. This is clearly disadvantageous. As the surface area of the aerosol container cannot be reduced, other solutions are required.

Another known solution is to include an agitation device, such as a ball, in the container, which aids removal of deposited product during shaking. The disadvantage of this is that the ball is noisy and adds to leachables entering the formulation. A further solution is to use glass containers, which have good surface energy and topography attributes which reduce deposition. However, the glass containers are very expensive in comparison to the typically-used aluminium containers, they are heavier and have adverse burst pressure and safety implications.

Another disadvantage of the prior art is that those known coatings can be stripped by the medicinal formulation over time, making them less effective and providing cross-contaminants. Accordingly, there is a need to develop coatings for containers which are chemically-stable with medicinal formulations over prolonged periods of storage and It is an object of the present invention to provide pressurised metered dose inhalers in general in which deposition of the medicinal formulation and active product is minimised.

According to the present invention, there is provided a pressurised metered dose inhaler, for dispensing a medicinal formulation, comprising a container, for receiving said medicinal formulation, the container comprising one or more internal surfaces which are contactable with said medicinal formulation, at least part of which one or more surfaces comprise a silicone-containing coating material formed from cold-plasma polymerised siloxane and/or silazane, in order to reduce deposition on the at least part of the one or more surfaces.

Advantageously, by coating the one or more internal surfaces of the container with a silicone-containing coating material formed by cold-plasma polymerised siloxane and/or silazane, active ingredient deposition within the container is minimised, which has the effect of improving the reliability of each metered dose of medicinal formulation containing the same amount of active ingredient every time.

Advantageously, it is believed that the deposition rate of silicone-containing coating materials is faster than the rate for fluorinated coatings and, therefore, the cost of coating containers would be reduced.

Preferably, the container comprises a pressurised medicinal formulation contained in the container. The pressurised formulation is maintained at a pressure of from 15 to 200 psig or, most preferably, is maintained at a pressure of approximately 60 psig at a room temperature of approximately 20 degrees Celsius.

Preferably, the pressurised formulation comprises a volatile propellant, such as, one or more of HFA134a or HFA227, with or without ethanol being present at a level of from about 1 to about 30%. Most preferably, the pressurised medicinal formulation contains a pharmacologically active product. The formulation may also contain other materials that can act as co-solvents or lubricants.

The pressurised metered dose inhaler may be for use in a pharmaceutical dispensing device, such as, for example, a pulmonary, nasal, or sub-lingual delivery device. A preferred use of the apparatus of the present invention is in a pharmaceutical metered dose aerosol inhaler device.

The term pharmaceutical as used herein is intended to encompass any pharmaceutical, compound, composition, medicament, agent or product which can be delivered or administered to a human being or animal, for example pharmaceuticals, drugs, biological and medicinal products.

Examples include antiallergics, analgesics, antibodies, vaccines, bronchodilators, antihistamines, therapeutic proteins and peptides, antitussives, anginal preparations, antibiotics, anti-inflammatory preparations, hormones, or sulfonamides, such as, for example, a vasoconstrictive amine, an enzyme, an alkaloid, or a steroid, including combinations of two or more thereof. In particular, examples include isoproterenol [alpha-(isopropylaminornethyl) protocatechuyl alcohol], phenylephrine, phenylpropanolamine, glucagon, insulin, DNAse, adrenochrome, trypsin, epinephrine, ephedrine, narcotine, codeine, atropine, heparin, morphine, dihydromorphinone, ergotamine, scopolamine, methapyrilene, cyanocobalamin, terbutaline, rimiterol, salbutamol, flunisolide, colchicine, pirbuterol, beclomethasone, orciprenaline, fentanyl, and diamorphine, streptomycin, penicillin, procaine penicillin, tetracycline, chlorotetracycline and hydroxytetracycline, adrenocorticotropic hormone and adrenocortical hormones, such as cortisone, hydrocortisone, hydrocortisone acetate arid prednisolone, insulin, cromolyn sodium, and mornetasone, including combinations of two or more thereof.

The pharmaceutical may be used as either the free base or as one or more salts conventional in the art, such as, for example, acetate, benzenesulphonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochioride, edetate, edisylate, estolate, esylate, fumarate, fluceptate, gluconate, glutamate, glycollylarsanulate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsuiphate, mucate, napsylate, nitrate, pamoate, (embonate), pantothenate, phosphate, diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulphate, tannate, tartrate, and triethiodide, including combinations of two or more thereof. Cationic salts may also be used, for example the alkali metals, e.g. Na and K, and amrnonium salts and salts of amines known in the art to be pharmaceutically acceptable, for example glycine, ethylene diamine, choline, diethanolamine, triethanolamine, octadecylamine, diethylamine, triethylamine, l-amino--2-propanol-amino-2- (hydroxymethyl)propane-l, 3-diol, and 1-(3, 4-dihydroxyphenyl) -2 isopropylaminoethanol.

The pharmaceutical will typically be one which is suitable for inhalation and may be provided in any suitable form for this purpose, for example as a solution or powder suspension in a solvent or carrier liquid, for example ethanol, or isopropyl alcohol. Typical propellants are HFA134a or I-1FA227 (HFC134a / HFC227) and/or isomers thereof.

The pharmaceutical may be, for example, one which is suitable for the treatment of asthma. Examples include salbutamol, beclomethasone, salmeterol, fluticasone, formoterol, terbutaline, sodium chromoglycate, budesonide and flunisolide, ipratropium bromide and salbutamol, and physiologically acceptable salts (for example salbutamol sulphate, salmeterol xinafoate, fluticasone propionate, beclomethasone dipropionate, and terbutaline sulphate), solvates and esters, including combinations of two or more thereof. Individual isomers such as, for example, R-salbutamol, may also be used. As will be appreciated, the pharmaceutical may comprise of one or more active ingredients, an example of which is flutiforin, and may optionally be provided together with a suitable carrier, for example a liquid carrier. One or more surfactants may be included if desired.

The seals and gaskets of the valve may be formed from any suitable material having acceptable performance characteristics. Preferred examples include nitrile, EPDM and other thermoplastic elastorners, butyl and neoprene.

Other rigid components of the valve, such as the valve body, chamber body and valve stem may be formed, for example, from polyester, nylon, acetal or similar.

Alternative materials for the rigid components of the valve include stainless steel, ceramics and glass. These rigid components can be termed as non-sealing components', although it will be understood that the inner seal, outer seal or gasket may form a seal when abutting the so-called non-sealing components. Further, the container may be formed from stainless steel, ceramics, glass, polyester, nylon, acetal and/or similar.

In order that the invention may be fully disclosed, embodiments will now be described in detail, by way of example only, with reference to the accompanying drawing and example, in which drawing Figure 1 is a side elevation of a pressurised metered dose inhaler according to the present invention.

A pressurised metering dose inhaler according to the present invention is shown in Figure 1, and is indicated in general by reference 1. The inhaler 1 comprises a pressurised dispensing container 2 and a metering valve 3.

The metering valve 3 includes a valve stem 5, for actuating the metering valve and, therefore, the metered dose inhaler 1, and the metering valve 3 is secured to the container 2 with a ferrule 4.

The container 2 is provided with one or more internal surfaces 10, shown by way of example by stippled lines, that are coated with a silicone-containing coating material formed from cold-plasma polymerised siloxane.

According to the present invention, it is desired to reduce deposition of the medicinal formulation on the container 2 and, potentially, any parts of a valve which control release of the medicinal formulation. In the present example, this is done by coating at least the container. Although, it will be understood that a metering chamber, a valve stem, a valve body, a gasket, an inner seal, and/or an outer seal of the metering valve may also be coated with a silicone-containing coating material, that reduces friction, reduces deposition and/or produces less adhesion between those respective surfaces and the medicinal formulation. Further, a valve stem receiving block or mouthpiece of a housing apparatus, for receiving the metered

-B-

dose inhaler, may also be coated. Accuracy of the pressurised metered dose inhaler of the present invention is, therefore, improved as there is less deposition of the medicinal formulation on the container and/or the more critical components of the metering valve or housing apparatus.

In an alternative, the coated surfaces described in relation to Figure 1 may be coated with a silicone-containing coating material formed by plasma polymerisation of silazane, with or without siloxane.

In a further alternative, the plasma polymerisatton may take place under normal conditions, for example, aluminium containers may be coated by a polymerisation process that is not achieved under cold-plasma conditions.

Siloxanes, such as, 100CP polydimethyl-siloxane and 2000p polydimethyl-siloxane, have also been shown to provide a coating on containers.

A range of parameters were investigated to monitor their influence on the surface composition of the coating, these being power, mass flow rate, pressure, time and power densities. The parameter were as follows: * 20W to 400W represent the RE' powers used for the depositions.

* Typical deposition times varied between 1 minute to 60 minutes.

* Deposition pressures used were in a range from about 9x102 mbar to 5x101 mbar.

* Flow rates of 5 to 150 sccm.

Example

Two sets of containers were used, container 1 and container 2, both made from polyester injected moulded plastics but of different blends. The method is also applicable to containers made from other materials specified herein.

The processing equipment used was a 155mm diameter, 140mm deep gas plasma reactor, designed as a scalable version of IML ST400 production kit, adapted to fit to existing production control systems.

The Containers used were treated in batches of 60, and were static, as they were laid flat upon a mesh plate within the reactor. An oxygen pre-treatment was provided -to initially clean the containers -which consisted of 50 sccm at 3.5x10' mbar, at a power of 150 W for 1 minute.

For each siloxane pre-cursor, a series of experiments was carried out to give a wide ranging matrix of power, mass flow rates, pressure and time (and power densities) Experiments were concentrated upon HMDSO and TMDSO coatings. In particular, it is the level of the polar component of total surface energy that is indicative of a good performance, in terms of low drug adhesion. As this approaches zero, performance is improved. Surface analysis of the coatings of the containers was carried out using a Kratos Amicus X-ray Photoelectron Spectrometer, focussing on the silicon (Si 2p) functionality in the binding region 102 to 103 eV.

A series of etches (using an argon plasma) were carried out, the relative concentration of the species measured with time. By measuring the time taken for the Si 2p peak to diminish and the underlying C is peak to increase gives an indication of the coating thickness on the inner container wall.

-10 -A coating thickness of approx llOnm was measured for the HMDSO deposited by the parameters stated below.

PARANETER SET POINT

POWER (WATTS) 50 PRESSURE (rnBar) 1 x 10 -FLOW RATE (sccm) 15 TINE (minutes) 60 A coating thickness of approx l7Onm was measured for the TMDSO deposited by the parameters stated below.

PARANETER SET POINT

POWER (WATTS) 50 PRESSURE (rnBar) 1 x 10 -1 FLOW RATE (sccm( 15 TIME (minutes) 30 For both siloxane coatings (HMDSO / TNDSO) the polar component is very similar: 0.078, 0.01 [HMDSO] verses 0.005 and 0.02 [TMDSO], for containers 1 and 2, respectively. In terms of processing, TMDSO has a faster deposition rate than HMDSO, giving a thicker coating in a shorter period of time (l7Qrim after 30 minutes verses llOnm after 60 minutes)

GB0902338A 2009-02-12 2009-02-12 Improvements in or relating to dispensing apparatus Withdrawn GB0902338D0 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
GB0902338A GB0902338D0 (en) 2009-02-12 2009-02-12 Improvements in or relating to dispensing apparatus

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB0902338A GB0902338D0 (en) 2009-02-12 2009-02-12 Improvements in or relating to dispensing apparatus

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GB0902338D0 GB0902338D0 (en) 2009-04-01
GB2467758A true true GB2467758A (en) 2010-08-18

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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4238050A (en) * 1979-07-30 1980-12-09 Dow Corning Corporation Metal containers with interior surfaces coated with an organosiloxane composition
GB2207368A (en) * 1987-08-01 1989-02-01 Harcostar Ltd A method of treating containers
US6131566A (en) * 1995-04-14 2000-10-17 Glaxo Wellcome Inc. Metered dose inhaler for albuterol
GB2355252A (en) * 1999-10-14 2001-04-18 Bespak Plc Dispensing apparatus coated with a cold plasma polymerised silazane, siloxane or alkoxysilane
GB2417479A (en) * 2004-08-26 2006-03-01 Bespak Plc Metering valves for pressurised dispensing containers
WO2008090318A1 (en) * 2007-01-22 2008-07-31 Consort Medical Plc Metering valve
GB2451833A (en) * 2007-08-13 2009-02-18 Bespak Plc Electrically actuated dose counter for dispensing apparatus
EP2028132A1 (en) * 2007-08-21 2009-02-25 Consort Medical plc (Formerly Bespak plc) Improvements in or relating to dispensing apparatus

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4238050A (en) * 1979-07-30 1980-12-09 Dow Corning Corporation Metal containers with interior surfaces coated with an organosiloxane composition
GB2207368A (en) * 1987-08-01 1989-02-01 Harcostar Ltd A method of treating containers
US6131566A (en) * 1995-04-14 2000-10-17 Glaxo Wellcome Inc. Metered dose inhaler for albuterol
GB2355252A (en) * 1999-10-14 2001-04-18 Bespak Plc Dispensing apparatus coated with a cold plasma polymerised silazane, siloxane or alkoxysilane
GB2417479A (en) * 2004-08-26 2006-03-01 Bespak Plc Metering valves for pressurised dispensing containers
WO2008090318A1 (en) * 2007-01-22 2008-07-31 Consort Medical Plc Metering valve
GB2451833A (en) * 2007-08-13 2009-02-18 Bespak Plc Electrically actuated dose counter for dispensing apparatus
EP2028132A1 (en) * 2007-08-21 2009-02-25 Consort Medical plc (Formerly Bespak plc) Improvements in or relating to dispensing apparatus

Also Published As

Publication number Publication date Type
GB0902338D0 (en) 2009-04-01 grant

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