The present invention relates to a seal material and, in particular, to a seal material comprising an elastomer. The seal may be used for dispensing pressurised fluid in the form of an aerosol. The seal is particularly suitable for use in pharmaceutical dispensing devices such as pressurised metered dose aerosol inhaler devices (pMDIs) and in medical check devices suitable for dispensing a pharmaceutical.

It is known from GB 1201918 for example to provide dispensing apparatus in which pressurised fluid from a pressurised dispensing container is released by a valve in a controlled manner, the valve including elastomeric seals which are annular and which cooperate with a sliding valve stem to open and close fluid ports. FR-A-2,549,568,

WO95/02651 and GB 2,148,912 and PCT/GB96/01551 each disclose further examples of such dispensing apparatus.

The required material properties necessary for good seal performance for pharmaceutical applications include: chemical compatibility (swell), tensile strength, permanent

compression set, stress relaxation, elastic modulus, regulatory compliance, low

permeability to fluids and gases, low levels of extractables and leachables, and stable properties after extraction.

Accordingly, as well as the requirement for good engineering properties, there is a requirement for sanitary properties, including low levels of extractables and leachables, which might otherwise increase impurities of drug products to unacceptable levels, as well as potentially reacting with the drug product, vehicle or excipients. In this connection, products to be dispensed from a pMDI are commonly provided in solution or suspension in a propellant base, this being particularly common in the dispensing of medicinal compounds for inhalation therapy. The metering valves used in dispensing devices such as pMDIs are typically constructed from a mixture of metal and/or thermoplastic parts and elastomeric rubber parts.

Known rubber compounds for sealing pharmaceutical metered dose aerosol inhalers include those based on the traditional technology of vulcanising a synthetic or natural rubber polymer. Products to be dispensed are commonly provided in solution or suspension in an alcohol or non-alcohol base, this being particularly common in the dispensing of medicinal compounds for inhalation therapy.

A typical apparatus includes a hydrofluoroalkane (HFA) volatile propellant having a liquid phase in which the product together with the alcohol carrier is readily soluble within the container. A typical material for the - 2 - valve seal is a synthetic rubber such as nitrile or chloroprene rubber.

It is an object of the present invention to provide an ethylene propylene diene terpolymer (EPDM) seal material for a dispensing apparatus which mitigates or at least addresses some of the problems associated with the prior art. Accordingly, in a first aspect, the present invention provides a seal for a valve for use in a pharmaceutical dispensing device, which seal comprises:

(a) a first elastomer based on an ethylene-propylene-diene terpolymer, which terpolymer comprises from 45 to 55 wt.% ethylene, from 40 to 50 wt.% propylene, and ENB (ethylidenenorbornene) in an amount of 0.5 to 6 wt.%, wherein the terpolymer has a Mooney Viscosity (ML 1 + 4, 125°C) of from 10 to 30; and

(b) a second elastomer based on an ethylene-propylene-diene terpolymer, which terpolymer comprises from 45 to 55 wt.% ethylene, from 40 to 50 wt.% propylene, and ENB (ethylidenenorbornene) in an amount of 0.5 to 6 wt.%, wherein the terpolymer has a Mooney Viscosity (ML 1 + 4, 125°C) of from 60 to 80.

The terpolymer of the first elastomer and/or the second elastomer preferably comprises from 48 to 52 wt.% ethylene, from 43 to 47 wt.% propylene, and from 2 to 5 wt.% ENB. More preferably, the terpolymer of the first elastomer and/or the second elastomer comprises approximately 50 wt.% ethylene, approximately 45 wt.% propylene, and approximately 5 wt.% ENB.

The ethylene content may be determined by ASTM D3900. The propylene content may be determined by ASTM D3900. The ENB content may be determined by ASTM D6047. Preferably, the terpolymer of the first elastomer and/or the second elastomer has a residual transition metal content of < 20 ppm, more preferably < 10 ppm.

Preferably, the terpolymer of the first elastomer and/or the second elastomer is

manufactured using a constrained geometry catalyst system. For example, a metallocene constrained geometry catalyst system, such as one based on titanium

monocyclopentadienyl, preferably with a silane group incorporated therein.

Preferably, the terpolymer of the first elastomer and/or the second elastomer is

substantially free of any catalyst residuals.

Preferably, the weight ratio of the first elastomer to the second elastomer in the seal is from 1 :10 to 10:1 , preferably 1 :3 to 3:1 , more preferably 1 :2 to 2:1 , still more preferably approximately 1 :1 .

The terpolymer of the first elastomer has a Mooney Viscosity (ML 1 + 4, 125°C) of from 10 to 30, preferably from 12 to 28, more preferably from 15 to 25, still more preferably from 18 to 22. The Mooney Viscosity may be determined by ASTM D1646. The unit for mooney viscosity is mooney units, MU.

The terpolymer of the second elastomer has a Mooney Viscosity (ML 1 + 4, 125°C) of from 60 to 80, preferably from 62 to 78, more preferably from 65 to 75, still more preferably from 68 to 72. Again, the Mooney Viscosity may be determined by ASTM D1646, and the unit for mooney viscosity is mooney units, MU.

Preferably, the terpolymer of the first elastomer and/or the second elastomer has a density of from 0.84 to 0.90 g/cm ³ , more typically from 0.85 to 0.87 g/cm ³ , more typically approximately 0.86 g/cm ³ . The density may be determined by ASTM D297. Preferably, the terpolymer of the first elastomer and/or the second elastomer has an ash content of < 0.1 wt.%, and a total volatiles content of < 0.4 wt.%.

Preferably, the terpolymer of the first elastomer and/or the second elastomer has a medium molecular weight distribution. Nordel IP 4520 (trade name) is a preferred EPDM terpolymer for use as the first elastomer. Nordel IP 4520 exhibits limited chemical interaction with drug and other component parts. Nordel IP 4520 is polymerized by a constrained geometry catalyst. This delivers precise control of, for example, Mooney viscosity, ethylene content and ENB content for highly predictable rheology and cure rates. The production process also ensures precise control of the molecular weight distribution.

Nordel IP 4570 (trade name) is a preferred EPDM terpolymer for use as the second elastomer. Nordel IP 4570 exhibits limited chemical interaction with drug and other component parts. Nordel IP 4570 is polymerized by a constrained geometry catalyst. This delivers precise control of, for example, Mooney viscosity, ethylene content and ENB content for highly predictable rheology and cure rates. The production process also ensures precise control of the molecular weight distribution. The combination of the first and second elastomers in a blend for a seal has been found particularly effective in terms of precise control of Mooney viscosity, ethylene content and ENB content for highly predictable rheology and cure rates that can enhance valve performance in a dispensing apparatus. In a second aspect, the present invention provides a seal for a valve for use in a pharmaceutical dispensing device, which seal comprises an elastomer based on an ethylene-propylene-diene terpolymer, which terpolymer comprises from 53 to 63 wt.% ethylene, from 32 to 42 wt.% propylene, and ENB (ethylidenenorbornene) in an amount of 0.5 to 6 wt.%, wherein the terpolymer has a Mooney Viscosity (ML 1 + 4, 125°C) of from 10 to 30.

In the second aspect, the terpolymer preferably comprises from 56 to 60 wt.% ethylene, from 35 to 40 wt.% propylene, and from 2 to 5 wt.% ENB. More preferably, the terpolymer comprises approximately 58 wt.% ethylene, approximately 37.5 wt.% propylene, and approximately 4.5 wt.% ENB.

In the second aspect, the terpolymer has a Mooney Viscosity (ML 1 + 4, 125°C) of from 10 to 30, preferably from 12 to 28, more preferably from 15 to 25, still more preferably from 18 to 22. Again, the Mooney Viscosity may be determined by ASTM D1646, and the unit for mooney viscosity is mooney units, MU. JSR EP123 (trade name) is a preferred EPDM terpolymer for use as the elastomer in the second aspect of the present invention. As with the first aspect, the elastomer used in the seal of second aspect of the present invention has been found particularly effective in terms of precise control of Mooney viscosity, ethylene content and ENB content for highly predictable rheology and cure rates that can enhance valve performance in a dispensing apparatus. In a third aspect, the present invention provides a seal for a valve for use in a

pharmaceutical dispensing device, which seal comprises an elastomer based on an ethylene-propylene-diene terpolymer, which terpolymer comprises from 50 to 60 wt.% ethylene, from 35 to 45 wt. % propylene and up to 5 wt.% ethylidene-norbornene (ENB), wherein the terpolymer has a Mooney Viscosity (ML 1 + 4, 125°C) of from 20 to 80.

In the third aspect, the terpolymer preferably comprises from 52 to 58 wt.% ethylene, from 37 to 43 wt.% propylene and from 0.5 to 5 wt.% ethylidene-norbornene (ENB). Still more preferably, the terpolymer comprises approximately 55 wt.% ethylene, approximately 40 wt.% propylene and approximately 5 wt. % ENB. The ethylene content may be determined by ASTM D3900. The propylene content may be determined by ASTM D3900. The ENB content may be determined by ASTM D6047.

In the third aspect, the terpolymer has a Mooney Viscosity (ML 1 + 4, 125°C) of from 20 to 80, preferably from 30 to 70, more preferably from 35 to 60, still more preferably from 35 to 45. Again, the Mooney Viscosity may be determined by ASTM D1646, and the unit for mooney viscosity is mooney units, MU.

In the third aspect, the terpolymer preferably has a residual transition metal content of < 20 ppm, more preferably < 10 ppm.

In the third aspect, the terpolymer is preferably manufactured using a constrained geometry catalyst system, preferably a metallocene constrained geometry catalyst system. For example, one based on titanium monocyclopentadienyl, preferably with a silane group incorporated therein. In the third aspect, the terpolymer is preferably substantially free of any catalyst residuals.

In the third aspect, the terpolymer typically has a narrow to broad molecular weight distribution.

In the third aspect, the terpolymer typically has a specific gravity of from 0.85 to 0.89, more typically approximately 0.87. The density may be determined by ASTM D297.

In the third aspect, the terpolymer typically has an ash content of < 0.1 wt.%, and a total volatiles content of < 0.4 wt.%.

Nordel IP 4640 (trade name) is a preferred EPDM formulation for use as the elastomer in the third aspect of the present invention. Nordel IP 4640 exhibits limited chemical interaction with drug and other component parts. Nordel IP 4640 is polymerized by a constrained geometry catalyst. This delivers precise control of, for example, Mooney viscosity, ethylene content and ENB content for highly predictable rheology and cure rates that can enhance valve performance in a dispensing apparatus. The production process also ensures precise control of the molecular weight distribution. Because of the high efficiency of the constrained geometry catalyst, Nordel IP 4640 is a relatively clean and uniform EPDM elastomer, with substantially no catalyst residuals and reduced metal content compared with conventional Ziegler-Natta catalysed EPDM elastomers.

The following description is applicable to the first, second and third aspects of the present invention.

The term seal as used herein is intended to encompass any sealing member or portion thereof present in a pharmaceutical dispensing device (eg a metered dose inhaler), including, but not limited to, gaskets and seals whether static or dynamic. It will be appreciated that the seal may be provided as a separate component or may be formed integrally with the valve, i.e. be co-moulded.

The seal according to the present invention is formed from an elastomeric composition. The seal will preferably further comprise a mineral and/or inorganic filler. Mineral fillers are preferable to carbon black in order to minimise the formation of polynuclear aromatic hydrocarbon compounds. Suitable examples include any of magnesium silicate, aluminium silicate, titanium oxide, zinc oxide, calcium carbonate, magnesium oxide magnesium carbonate, magnesium aluminium silicate, aluminium hydroxide, talc, kaolin and clay, including combinations of two or more thereof. Preferably, the filler is or comprises one or more of magnesium silicate, talc, calcined clay, nano particle clays, kaolin and/or amino silane coated clay or clay coated with a titanium or zirconate coupling agent. The filler is typically present in the seal material in an amount of from 1 to 70 wt.%, preferably from 2 to 60 wt.%, more preferably from 5 to 50 wt.%, still more preferably from 10 to 40 wt.%. The seal may comprise, for example, 35-50 wt.% of the filler and 45-60 wt.% terpolymer.

The seal will typically further comprise a process aid, preferably a low molecular weight polyethylene, stearic acid or an organic or non-organic stearate. The process aid, for example stearic acid, may be provided in the gasket seal in an amount of up to 1 wt.%.

The material for the seal will typically further include a curing or cross-linking agent. For example, the material may further include a peroxide curing agent, sulphur or a sulphur- containing compound. A peroxide curing agent such as, for example, dialkyl peroxide is, however, preferable to other curing agents such as sulphur since its use minimises the formation of extractives (e.g. 2-mercaptobenzothiazole, N-nitrosamines,

mercaptobenzothiazole disulphide) resulting from contact between the material and alcohol in use. The curing or cross-linking agent (for example a dialkyl peroxide) may be provided in the seal in an amount of up to 7 wt.%. One example of a suitable crosslinking agent is Luperox F40 (1 ,3 1.4-bis(tert-butylperoxyisopropyl)benzene).

The seal may further comprise one or more of a reinforcement agent, a plasticizer, a binder, a stabilizer, a retarder, a bonding agent, an antioxidant, a lubricant, a pigment, a wax, a resin, an antiozonants, a primary accelerator, a secondary accelerator and/or a crosslink activator. One or more of these may be provided in the seal in an amount of up to 1 wt.%. For example, an antioxidant, such as, for example, octylated diphenylamine, may be included in an amount of up to 0.7 wt.%.

In most pharmaceutical applications it is also necessary to extract or wash the cured elastomer in order to remove surface residues and by-products resulting from the cure reaction and moulding process. The seal is therefore preferably subjected to a wash and/or an extraction to reduce or eliminate extractives and/or leachables. For example, a solvent-extraction and / a supercritical fluid-extraction. An alcohol extraction is preferred. An alcohol extraction (for example an ethanol extraction) of the gasket seal is preferably performed after the seal has been manufactured and before the valve is assembled. This step reduces or eliminates extractives and/or leachables.

The present invention also provides a valve for use in a pharmaceutical dispensing device having a seal as herein described, i.e. a seal according to the first, second or third aspects. The present invention also provides a pharmaceutical dispensing device having a valve as herein described. Examples include a pharmaceutical metered dose aerosol inhaler device, a syringe, a vial stopper, a pharmaceutical pump, a peristaltic pump, an auto injector, a medical check valve and a dry powder inhaler. Preferred uses of the seal are in a pressurised pharmaceutical metered dose aerosol inhaler device and in a medical check device suitable for dispensing a pharmaceutical.

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, 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- (isopropylaminomethyl) protocatechuyl alcohol], phenylephrine, phenylpropanolamine, glucagon, 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 and prednisolone, insulin, cromolyn sodium, and mometasone, 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, bircarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, fluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride,

hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulphate, 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 ammonium salts and salts of amines known in the art to be pharmaceutically acceptable, for example glycine, ethylene diamine, choline, diethanolamine, triethanolamine, octadecylamine, diethylamine, triethylamine, 1 - amino-2-propanol-amino-2-(hydroxymethyl)propane-1 ,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 powder or as a solution or suspension in a solvent or carrier liquid, for example ethanol.

The pharmaceutical may, for example, be one which is suitable for the treatment of asthma. Examples include salbutamol, beclomethasone, salmeterol, fluticasone, formoterol, terbutaline, sodium chromoglycate, budesonide and flunisolide, 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 flutiform, and may optionally be provided together with a suitable carrier, for example a liquid carrier. One or more surfactants may be included if desired.

Further examples of formulations that include two active ingredients include:

beclomethasone and formoterol; budesonide and formoterol; salmeterol and fluticasone; salbutamol and ipratropium bromide; and formoterol and mometasone. Examples of formulations that include three active ingredients include: formoterol, glycopyrrolate and mometasone; and beclamethasone, glycopyrrolate and formoterol.

The present invention also provides a dispensing apparatus for dispensing pressurised fluid comprising a valve body defining a chamber, a valve member extending movably through the chamber and through at least one annular seal co-operating with the valve member and the body to regulate the discharge of fluid, wherein the or at least one of the seals is as herein described. The present invention also provides a dispensing apparatus which comprises a pressurised dispensing container having a valve body provided with two annular valve seals through which a valve member is axially slidable, said seals being disposed at inlet and outlet apertures of a valve chamber so that the valve functions as a metering valve, wherein at least one of the annular valve seals is as herein described.

The present invention also provides a dispensing apparatus for dispensing pressurised fluid comprising a valve body and a gasket seal to prevent or limit leakage of fluid from the dispensing apparatus, wherein the gasket seal is as herein described. In the dispensing apparatus as described above, the apparatus may comprise a

pressurised dispensing container operatively connected to the valve body and containing the fluid to be dispensed and a hydrofluorocarbon propellant (typically a hydrofiuoroalkane, HFA) comprising propellant type 134a and/or 227. The designation of propellant types referred to in the present application is as specified in British Standard BS4580:1970 "Specification for number designations of organic refrigerants". Accordingly, propellant 134a is: 1 ,1 ,1 ,2-tetrafluoroethane CH2F-CF3 and propellant 227 is: 1 ,1 ,1 ,2,3,3,3 heptafluoropropane CF3-CHF-CF3.

In the dispensing apparatus as described above, which includes a seal as herein described, the fluid to be dispensed comprises a liquid or particulate product as a solution or suspension in a carrier liquid. The carrier liquid preferably comprises an alcohol, for example ethanol. One or both of oleic acid and/or glycerol may also be included in the carrier liquid. The present invention also provides a seal comprising a vulcanisate of a mixture comprising:

(a) a first elastomer based on an ethylene-propylene-diene terpolymer, which terpolymer comprises from 45 to 55 wt.% ethylene, from 40 to 50 wt.% propylene, and ENB (ethylidenenorbornene) in an amount of 0.5 to 6 wt.%, wherein the terpolymer has a Mooney Viscosity (ML 1 + 4, 125°C) of from 10 to 30;

(b) a second elastomer based on an ethylene-propylene-diene terpolymer, which terpolymer comprises from 45 to 55 wt.% ethylene, from 40 to 50 wt.% propylene, and ENB (ethylidenenorbornene) in an amount of 0.5 to 6 wt.%, wherein the terpolymer has a Mooney Viscosity (ML 1 + 4, 125°C) of from 60 to 80;

(c) a cross-linking agent for the terpolymer of the first and/or second elastomer;

(d) a mineral filler; and

(e) optionally a process aid. The present invention also provides a seal comprising a vulcanisate of a mixture comprising:

(a) an elastomer based on an ethylene-propylene-diene terpolymer, which terpolymer comprises from 53 to 63 wt.% ethylene, from 32 to 42 wt.% propylene, and ENB

(ethylidenenorbornene) in an amount of 0.5 to 6 wt.%, wherein the terpolymer has a Mooney Viscosity (ML 1 + 4, 125°C) of from 10 to 30;

(c) a cross-linking agent for the terpolymer of the first and/or second elastomer;

(d) a mineral filler; and

(e) optionally a process aid. The elastomer blends according to the present may be produced by conventional methods, for example mixing using an intermix twin-screw mixer extruder by injection moulding.

A process for the preparation of the seal may comprise the following steps: (i) forming a composition comprising a mixture of one or more of the elastomers as herein described, and a cross-linking agent for the terpolymer(s), a mineral filler and optionally a process aid; (ii) initiating a cross-linking reaction in the mixture to form a cross-linked elastomeric composition; and (iii) either before or after (ii) forming the composition into a seal. The step of forming the composition into a seal will typically involve one or more forming techniques selected from compression moulding, injection moulding and extrusion. The seal material according to the present invention lends itself to commonly used compression, transfer and injection moulding. Injection moulding also results in reduced process waste compared to compression/transfer processes. The seal can also be co- moulded if desired with thermoplastics such as PBT, nylon and/or polyacetal.

EPDM elastomers comprising a terpolymer of ethylene with propylene and a non- conjugated diene providing unsaturation on the side chain are especially preferred. In particular it has been found that the combination of such elastomers with the cross-linking agents described herein provide an improved seal for a dispensing device, for example, having low levels of extractable leachables. Ethylene based terpolymers manufactured using single site metallocene constrained geometery catalyst (CGC) (INSITE process and catalyst technology) are the most preferred in the present invention.