GB2406096A

GB2406096A - Elastomeric seal material for an inhaler

Info

Publication number: GB2406096A
Application number: GB0321720A
Authority: GB
Inventors: Sally Beken
Original assignee: Bespak PLC
Current assignee: Consort Medical Ltd
Priority date: 2003-09-16
Filing date: 2003-09-16
Publication date: 2005-03-23
Anticipated expiration: 2023-09-16
Also published as: GB2406096B; GB0321720D0

Abstract

A seal for a valve for use in a pharmaceutical metered dose aerosol inhaler device, which seal is formed from 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 ENB (ethylidene-norbornene) in an amount of up to 5 wt.%. Also disclosed is a process for preparing the seal and an inhaler device comprising the seal.

Description

Seal Material for a Dispensing Apparatus The present invention relates to

a seal material and, in particular, to an elastomeric seal material for use in a dispensing apparatus for dispensing pressurized fluid in the form of an aerosol. Such an apparatus may be used for dispensing medicine or products in solution or suspension in an alcohol base.

It is known from GB-1201918 to provide a dispensing apparatus in which pressurized fluid from a pressurized dispensing container is released by a valve in a substantially controlled manner, the valve including elastomeric seals which are annular and which co-operate with a sliding valve stem to open and close fluid ports.

Known rubber compounds for sealing pharmaceutical metered dose aerosol inhalers are based on the traditional technology of vulcanising a synthetic or natural rubber polymer.

The required material properties necessary for good seal performance include: chemical compatibility (swell), tensile strength, permanent compression set, stress relaxation and elastic modulus.

Products to be dispensed are commonly provided in solution or suspension in an alcohol base, this being particularly common in the dispensing of medicinal compounds for inhalation therapy.

A typical apparatus includes a CFC 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 nitrite rubber.

Recent trends in the production of aerosol dispensers have moved away from CFC propellants because of their environmental hazards and HFC propellants are now being introduced. A problem with such propellants is that alcohol is less soluble in the liquid phase of such propellants and tends to separate within the container thereby exposing the valve seals to a much greater concentration of alcohol than was formerly the case. Seal materials such as nitrite rubber allow alcohol vapour to escape by permeation over extended storage periods so that the remaining quantity of alcohol is significantly depleted.

It is an object of the present invention to provide a seal material for a dispensing apparatus which addresses at least some of the problems

associated with the prior art.

Accordingly, the present invention provides a seal for a valve for use in a pharmaceutical metered dose aerosol inhaler device, which seal is formed from 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 < 5 wt.% diene.

The term seal as used herein is intended to encompass any sealing member or portion thereof present in a metered does inhaler, including, but not limited to, gaskets and seals whether static or dynamic.

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

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.

The terpolymer is preferably substantially free of any catalyst residuals.

The terpolymer typically 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.

The terpolymer typically has a narrow to broad molecular weight distribution.

The terpolymer typically has a specific gravity of from 0.85 to 0.89, more typically approximately 0.87.

The terpolymer typically has an ash content of < 0.1 wt.%, and a total volatiles content of < 0.4 wt.%. 4 -

The material for the seal preferably further includes a filler, more preferably a mineral filler.

Mineral fillers are preferable to carbon black in order to minimise the formation of polyouclear aromatic hydrocarbon compounds. Suitable examples include any of magnesium silicate, aluminium silicate, silica, 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, calcified clay, and/or kaolin.

15The material for the seal will typically further include a process aid, such as, for example, stearic acid.

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, dicumyl 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 material for the seal may further include an antioxidant, such as, for example, ocLylated diphenylamine.

The material for the seal may further include one or more of a reinforcement agent, a plasticizer, a binder, a stabilizer, a lubricant and a pigment.

The present invention also provides a valve for use in a pharmaceutical metered dose aerosol inhaler device having a seal as herein described.

The present invention also provides a pharmaceutical metered dose aerosol inhaler device having a valve as herein described.

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.

Such a device may be used for dispensing medicine or products in solution or suspension.

The dispensing apparatus may comprise a pressurized dispensing container operatively connected to the valve body and containing the fluid to be dispensed and a hydrofluorocarbon propellant comprising propellant type 134a 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.

The fluid to be dispensed will typically comprise - 6 - a liquid or particulate product as a solution or suspension in a carrier liquid comprising an alcohol, such as, for example, ethanol.

In a preferred embodiment, the dispensing apparatus is a pressurised dispensing container having a valve body provided with two annular valve seals through which a valve member is axially slidable, the seals being disposed at inlet and outlet apertures of a valve chamber so that the valve functions as a metering valve.

It will be appreciated that the seal may be provided as a separate component or may be formed integrally with the valve.

It has been found that the present invention provides particularly favourable results when used in conjunction with a hydrofluorocarbon propellant in the aerosol device.

The seal of the present invention may be t manufactured by any of the processes conventional in t the art. For example, the seal may be manufactured by compression moulding, injection moulding or extrusion.

The present invention also provides a seal for a valve for use in a pharmaceutical metered dose aerosol inhaler device, which seal comprises a vulcanisate of a mixture comprising an ethylene-propylene-diene terpolymer, which terpolymer comprises from 50 to 60 wt.% ethylene, from 35 to 45 wt.% propylene and < 5 wt.% diene, a cross-linking agent for the terpolymer, a mineral filler and optionally a process aid. The terpolymer is preferably as herein described. - 7

The present invention also provides a process for the preparation of a seal for a valve for use in a pharmaceutical metered dose aerosol inhaler device, the process comprising: (i) forming a composition comprising a mixture of an ethylene-propylene- diene terpolymer, which terpolymer comprises from 50 to 60 wt.% ethylene, from to 45 wt.% propylene and < 5 wt.% diene, a cross- I linking agent for the terpolymer, a mineral filler and optionally a process aid; tii) 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.

Again, the terpolymer is preferably as herein described.

The step of forming the composition into a seal will typically involve one or more forming techniques selected from compression moulding, injection moulding t and extrusion.

In the process, the terpolymer is preferably manufactured using a constrained geometry catalyst system.

Nordel IP 4640 (trade name) is a preferred EPDM formulation for the seal material according to the present invention. This grade adheres to the FDA CFR listing 177.2600 rubber articles intended for repeated use and 177.1520 olefin polymers (Reference: DuPont Dow Elastomers document D10382).

Nordel IP 4640 exhibits limited chemical - 8 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 I 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.

Nordel IP 4640 also exhibits a low yellowness index and lack of a characteristic odour which is associated with some EPDM elastomers.

The present invention will now be further described with reference to the following examples:

Example 1

Ingredient Grade phr Ethylene propylene Nordel IP 4640 100 i diene monomer elastomer Filler (magnesium silicate) Magsil 2628 75 Process aid (stearic acid) 1543 1 Crosslinking agent Peroximon F4O 6 (peroxide) 9 -

Example 2

Ingredient Grade phr Ethylene propylene Nordel IP 4640 100 1 diene monomer elastomer Filler (hydrated Mlstron Vapour RP6D 70 magnesium silicate) Process aid (stearic acid) 1843 Crosslinking agent Peroximon F40 (peroxide)

Example 3

Ingredient Grade phr Ethylene propylene Nordel IP 4640 100 diene monomer elastomer Filler (calcined clay) Polestar 200R 75 Process aid (stearic acid) 1843 1 Crosslinking agent Peroximon F40 6 (peroxide) -

Claims

CLAIMS: 1. A seal for a valve for use in a pharmaceutical metered dose

aerosol inhaler device, which seal is formed from 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 ENB (ethylidenenorbornene) in an amount of up to 5 wt.%.
2. A seal as claimed in claim 1, wherein the terpolymer comprises from 52 to 58 wt.% ethylene, from 37 to 43 wt.% propylene, and from 0.5 to 5 wt.% ENB.
3. A seal as claimed in claim 2, wherein the terpolymer comprises approximately 55 wt.% ethylene, approximately 40 wt.% propylene, and approximately 5 wt.% ENB.
4. A seal as claimed in any one of the preceding claims, wherein the terpolymer has a residual transition metal content of < 20 ppm.
5. A seal as claimed in any one of the preceding claims, wherein the terpolymer is manufactured using a constrained geometry catalyst system.
6. A seal as claimed in any one of the preceding claims, wherein the terpolymer has substantially no catalyst residuals.
7. A seal as claimed in any one of the preceding claims, wherein the terpolymer has a Mooney Viscosity (ML 1 + 4, 125 C) of from 20 to 80.
8. A seal as claimed in any one of the preceding claims, wherein the seal further includes a mineral filler.
9. A seal as claimed in any one of the preceding claims, wherein the mineral filler is selected from one or more of magnesium silicate, aluminium silicate, silica, titanium oxide, zinc oxide, calcium carbonate, magnesium oxide magnesium carbonate, magnesium aluminium silicate, aluminium hydroxide, talc, kaolin and clay.
10. A seal as claimed in any one of the preceding claims, wherein the seal further includes a process aid, preferably stearic acid.
11. A seal as claimed in any one of the preceding claims, wherein the seal further includes a peroxide curing agent and/or a sulphur curing agent.
12. A seal as claimed in claim 5, wherein the curing agent is dicumyl peroxide.
13. A seal as claimed in any one of the preceding claims, further comprising one or more of a reinforcement agent, a plasticizer, a binder, a stabilizer, a retarder, a bonding agents, an antioxidant, a lubricant, a pigment, a wax, a resin, an antiozonants, a primary accelerator, a secondary accelerator or an activator.
14. A valve for use in a pharmaceutical metered dose aerosol inhaler device having a seal as defined in any one of claims 1 to 13.
15. A pharmaceutical metered dose aerosol - 12 inhaler device having a valve as claimed in claim
16. A dispensing apparatus for dispensing pressurized 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 defined in any one of claims 1 to 13.
17. 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 defined in any one of claims 1 to 13.
18. A dispensing apparatus as claimed in claim 16 or claim 17, comprising a pressurized dispensing container operatively connected to the valve body and containing the fluid to be dispensed and a hydrofluorocarbon propellant comprising propellant type 134a or 227.
19. A dispensing apparatus as claimed in any one of claims 16 to 18, wherein the fluid to be dispensed comprises a liquid or particulate product as a solution or suspension in a carrier liquid comprising alcohol.
20. A dispensing apparatus as claimed in claim 18, wherein the alcohol comprises ethanol.
21. A seal for a valve for use in a pharmaceutical metered dose aerosol inhaler device, which seal comprises a vulcanisate of a mixture comprising an ethylene-propylene-diene terpolymer, which terpolymer comprises from 50 to 60 wt.% ethylene, from 35 to 45 wt.% propylene and < 5 wt.% ENS (ethylidene-norbornene), a cross-linking agent for the terpolymer, a mineral filler and optionally a process aid.
22. A process for the preparation of a seal for a valve for use in a pharmaceutical metered dose aerosol inhaler device, the process comprising: (i) forming a composition comprising a mixture of an ethylene-propylene- diene terpolymer, which terpolymer comprises from 50 to 60 wt.% ethylene, from to 45 wt.% propylene and < 5 wt.% ENB (ethylidene norbornene, a cross-linking agent for the terpolymer, 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.
23. A process as claimed in claim 22, wherein the step of forming the composition into a seal involves one or more forming techniques selected from compression moulding, injection moulding and extrusion.
24. A process as claimed in claim 22 or claim 23, wherein the terpolymer is manufactured using a constrained geometry catalyst system.
25. A seal for a dispensing apparatus - 14 substantially as hereinbefore described with reference to any one of the Examples.