GB2445483A

GB2445483A - Seal for a pharmaceutical dispensing device

Info

Publication number: GB2445483A
Application number: GB0802588A
Authority: GB
Inventors: Daljit S Ohbi
Original assignee: Bespak PLC
Current assignee: Consort Medical Ltd
Priority date: 2004-01-29
Filing date: 2004-01-29
Publication date: 2008-07-09
Anticipated expiration: 2024-01-29
Also published as: GB0802588D0; GB2445483B

Abstract

A seal, for a valve for a pharmaceutical dispensing device, is formed from a thermoplastic alloy comprising (a) an elastomeric component, such as one or more of ethylene/alkene copolymers, polyisoprene, nitrile rubbers, butyl rubbers, EPDM, EPR; (b) a thermoplastic component, such as one or more of styrene-ethylene-butylene terpolymer, styrene-ethylene-butadiene terpolymer, styrene-propylene-styrene terpolymer, polyether block polyamide, polyether-polyester copolymer; and (c) a sensitisor, such as one or more of trially cyanurate, ethylene glycol dimethacrylate, trimethylol propane triacrylate, high vinyl 1,2-polybutadiene. Also disclosed is a process for the preparation of the seal. The seal may further comprise additional additives such as fillers, plasticizers, antioxidants, antiozonants, lubricants and pigments.

Description

2445483

- 1 -

Seal for a Dispensing Apparatus

The present invention relates to a seal material and, in particular, to a thermoplastic alloy, and a method for 5 its production. The seal may be used for dispensing pressurised fluid in the form of an aerosol. The seal is particularly suitable for use in pressurised metered dose aerosol inhaler devices (pMDIs) and in medical check devices suitable for dispensing a pharmaceutical.

10

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, 15 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 20 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.

25

The metering valves used in dispensing devices such as pressurised metered dose inhalers are typically constructed from a mixture of metal and/or thermoplastic parts and elastomeric rubber parts. The seal itself typically 30 comprises an elastomer such as a synthetic rubber, for example, nitrile rubber.

- 2 -

It is known from WO 00/40479 to use a two-phase elastomeric alloy material for a regulating member in an aerosol valve and flow regulator assembly.

5 The benefits of using "alloyed" or "blended" materials include high elasticity and low hardness. For example, favourable values of elasticity and Shore Hardness (A) can be achieved when a softer elastomeric component is dispersed in a matrix of thermoplastic material.

10

The production of seals comprising elastomeric materials typically involves steps for the curing/cross-linking of natural and synthetic rubbers. Accelerators are compounds which reduce the time required for curing/cross-15 linking of natural and synthetic rubbers. Accelerators may also act to improve the non-permeability characteristics and other physical properties of the rubber.

Peroxides such as dicumyl peroxide can also be used to 20 cure elastomers. However, the curing reaction can be variable and this may affect the material properties; in extreme cases, the material can become brittle. Moreover the products of the reaction have to be removed as they can deteriorate elastomer properties, for example ageing. 25 Another problem is that peroxides are deactivated by antioxidants. Antioxidants are often required to enhance the ageing properties of the elastomer.

In most pharmaceutical applications it is also 30 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. Prolonged extraction

- 3 -

times have been found to result in a deterioration in material properties.

Products to be dispensed are commonly provided in 5 solution or suspension in an alcohol base, this being particularly common in the dispensing of medicinal compounds for inhalation therapy.

It is an object of the present invention to provide a 10 seal material for a dispensing apparatus which addresses at least 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

15 dispensing device, which seal is formed from a thermoplastic alloy comprising:

(a) an elastomeric component;

(b) thermoplastic component; and

(c) a sensitisor.

20

In a second aspect, the present invention provides a seal for a valve for use in a pharmaceutical dispensing device, which seal is formed from a thermoplastic alloy comprising:

25 (i) two or more thermoplastic components;

(ii) a sensitisor; and

(iii) optionally an elastomeric component.

Thus, in the present invention the seal may comprise an 30 elastomeric component, a thermoplastic component and a sensitisor, or, alternatively, two or more thermoplastics and a sensitisor and optionally an elastomer.

- 4 -

The term "thermoplastic alloy", as used herein, is intended to cover a composite product comprising (A) a blend of a thermoplastic component and an elastomeric component, 5 or (B) a blend of two or more thermoplastic components and optionally an elastomeric component. Each of the thermoplastic and elastomeric components may themselves comprise blends.

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

15 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.

Benefits of using a seal in accordance with the first 20 aspect of the present invention in a pharmaceutical dispensing device include the relatively low levels of leachables and extractables which are present.

Suitable thermoplastics include, but are not limited to 25 TPEs such as, for example, one or more of styrene-ethylene-butylene-styrene terpolymers, styrene-ethylene-butadiene terpolymers, styrene-isoprene-butadiene terpolymers, styrene-propylene-styrene terpolymers, polyether block polyamide, polyether-polyester copolymers and

- 5 -

ethylene/alkene copolymer (eg ethylene/octane copolymer), including blends of two or more thereof.

Suitable elastomeric components include, but are not 5 limited to one or more of natural rubber (polyisoprene),

synthetic polyisoprene, nitrile rubber, hydrogenated nitrile rubber, butyl rubbers (isoprene-isobutylene copolymers), halogenated butyl rubbers, ethylene-propylene-diene terpolymers (EPDM) and ethylene-propylene copolymers (EPM), 10 including blends of two or more thereof.

The weight ratio of the thermoplastic component to the elastomeric component is preferably in the range of from 80:30 to 20:80.

15

Sensitisors for use in the present invention are preferably poly-functional, poly-unsaturated organic compounds, which have the propensity of forming stable free radicals when exposed to free radicals generated either 20 chemically or by high energy radiation. Preferred sensitisors yield sufficiently long lived free radicals to enable inter-cross inking of polymeric alloy components. Suitable examples include one or more of triallyl cyanurate, ethylene glycol dimethacrylate, trimethylol propane 25 triacrylate and high vinyl 1,2-polybutadiene.

Optionally, a cross-linking agent (also known as a curing agent) may be included to provide or facilitate 30 network formation to result in a three-dimensional polymer network structure. An example is a peroxide cross-linking

- 6 -

agent. The cross-linking agent may act by a free radical mechanism.

The seal advantageously further includes a filler, preferably a mineral filler. Mineral fillers are preferable 5 to carbon black in order to minimise the formation of polynuclear aromatic hydrocarbon compounds. Suitable examples include any of magnesium silicate, aluminium silicate, silica, titanium oxide, zinc oxide, calcium carbonate, magnesium oxide magnesium carbonate, magnesium

10 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

15 with a titanium or zirconate coupling agent.

The seal preferably further includes a process aid, preferably a low molecular weight polyethylene.

20 The seal may further comprise any 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 secondary accelerator or an activator, including combinations of two or more thereof.

25 Examples of antioxidants are 2:2'-methylene-bis(6-(1-methyl-cyclohexyl)-para-creosol) and octylated diphenylamine. An advantage of the seal according to the present invention is that it can be essentially free of an antioxidant if desired.

30

In relation to the first aspect, the present invention also provides a process for the preparation of a seal for a

- 7 -

valve for use in a pharmaceutical dispensing device, the process comprising:

(i) forming a composition comprising a mixture of an elastomeric component, a thermoplastic component and a

5 sensitisor;

(ii) initiating a cross-linking reaction in the mixture to form a thermoplastic alloy comprising cross-linked components; and

(iii) either before or after step (ii), forming the 10 composition into a seal.

In relation to the second aspect, the present invention also provides a process for the preparation of a seal for a valve for use in a pharmaceutical dispensing device, the 15 process comprising:

(i) forming a composition comprising a mixture of two or more thermoplastic components, a sensitisor and optionally an elastomeric component;

(ii) initiating a cross-linking reaction in the mixture 20 to form a thermoplastic alloy comprising cross-linked components; and

(iii) either before or after step (ii), forming the composition into a seal.

25 In the above-described process the step of forming the composition into a seal may involve one or more forming techniques such as compression moulding, injection moulding and/or extrusion.

30 The initiation of the cross-linking reaction may be achieved by a thermo-chemical reaction using, for example, a peroxide. Alternatively, or in combination with the thermo-

- 8 -

chemical reaction, high energy radiation is used to effect a cross-linking reaction.

Examples of high energy radiation include electron beam 5 and/or Gamma radiation. Such radiation may be used to expose the polymer alloy to a radiation dose in the range of from 50kGy - 300kGy (kGy = kilo Gray), for example.

The resulting components may optionally be ethanol 10 extracted to reduce the level of leachable species that could migrate into drug mixtures. In this process, the components are loaded into a glass column and washed by refluxing ethanol.

15 The sensitisor as herein described is preferably provided in liquid form and is preferably miscible with the polymer to provide a homogeneous dispersion. It has been found that the use of such a sensitisor facilitates filler dispersion and can obviate the need for a separate 20 plasticizer. The presence of plasticisers is undesirable in that they tend to leach out of the material. In contrast, the sensitisor as herein described forms or is part of the cross-linked network and therefore does not leach out into the drug media.

25

In the seal compositions according to the present invention the sensitisor is typically substantially consumed during the cross-linking reaction. This results in a cleaner rubber and the extractables are reduced. Typically, 30 substantially no nitrosamines are generalted during the cross-linking reaction. Most or substantially all of any by

- 9 -

products resulting from the cross-linking reaction may be volatiles.

The seal according to the present invention may be used 5 in a valve for use in a dispensing device, such as, for example, a nasal, pulmonary or transdermal delivery device. Preferred uses of the seal are in a pressurised metered dose aerosol inhaler device and in a medical check device suitable for dispensing a pharmaceutical.

10

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 15 pharmaceuticals, drugs, biological and medicinal products. Examples include antiallergics, analgesics, bronchodilators, antihistamines, therapeutic proteins and peptides, antitussives, anginal preparations, antibiotics, antiinflammatory preparations, hormones, or sulfonamides, such 20 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, 25 trypsin, epinephrine, ephedrine, narcotine, codeine,

atropine, heparin, morphine, dihydromorphinone, ergotamine, scopolamine, methapyrilene, cyanocobalamin, terbutaline, rimiterol, salbutamol, flunisolide, colchicine, pirbuterol, beclomethasone, orciprenaline, fentanyl, and diamorphine, 30 streptomycin, penicillin, procaine penicillin, tetracycline, chlorotetracycline and hydroxytetracycline, adrenocorticotropic hormone and adrenocortical hormones,

- 10 -

such as cortisone, hydrocortisone, hydrocortisone acetate and prednisolone, insulin, cromolyn sodium, and mometasone, including combinations of two or more thereof.

5 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, 10 edetate, edisylate, estolate, esylate, fumarate, fluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, 15 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 20 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, 25 triethylamine, l-amino-2-propanol-amino-2-

(hydroxymethyl)propane-1,3-diol, and l-(3,4-dihydroxyphenyl)-2 isopropylaminoethanol.

The pharmaceutical will typically be one which is 30 suitable for inhalation and may be provided in any suitable form for this purpose, for example as a powder or as a

- 11 -

solution or suspension in a solvent or carrier liquid, for example ethanol.

The pharmaceutical may, for example, be one which is 5 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, 10 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 15 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.

20 According to a second aspect, the present invention also provides a pharmaceutical dispensing device having a valve as herein described. The pharmaceutical dispensing device may be, for example, a nasal, pulmonary or transdermal delivery device. Preferred devices are a 25 pharmaceutical metered dose aerosol inhaler device and a medical check device.

The present invention also provides a dispensing apparatus for dispensing pressurised fluid comprising a 30 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

- 12 -

regulate the discharge of fluid, wherein the or at least one of the seals is as herein described with reference to the first aspect of the invention.

5 Such a device may be used for dispensing medicine,

pharmaceuticals, biological agents, drugs and/or products in solution or suspension as herein described.

In a preferred embodiment, the dispensing apparatus 10 comprises 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.

15

The dispensing apparatus as herein described may comprise a pressurised dispensing container operatively connected to the valve body and containing the fluid to be dispensed and a hydrofluorocarbon propellant comprising 20 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 25 propellant 227 is: 1,1,1,2,3,3,3 heptafluoropropane CF3-CHF-CF3.

The fluid to be dispensed typically comprises a liquid or particulate product as a solution or suspension in a 30 carrier liquid. The carrier liquid preferably comprises an alcohol such as ethanol. One or more surfactants may be present.

- 13 -

Claims

CLAIMS:

1. A seal for a valve for use in a pharmaceutical dispensing device, which seal is formed from a thermoplastic

5 alloy comprising:

(a) an elastomeric component;

(b) a thermoplastic component; and

(c) a sensitisor.

2. A seal as claimed in claim 1, wherein the elastomeric component comprises one or more of ethylene/alkene copolymers, polyisoprene, nitrile rubber, hydrogenated nitrile rubber, butyl rubbers, halogenated butyl rubbers, EPDM and EPR.

3. A seal as claimed in any one of the preceding claims, wherein the thermoplastic component comprises one or more of styrene-ethylene-butylene terpolymer, styrene-ethylene-butadiene terpolymer, styrene-propylene-styrene terpolymer, polyether block polyamide and polyether-polyester copolymer.

4. A seal as claimed in any one of the preceding claims, wherein the sensitisor comprises one or more of

25 triallyl cyanurate, ethylene glycol dimethacrylate, trimethylol propane triacrylate and high vinyl 1,2-polybutadiene.

5. A seal as claimed in any one of the preceding 30 claims, wherein the seal is formed from a thermoplastic alloy which further comprises across-linking agent.

10

15

20

- 14 -

6. A seal as claimed in any one of the preceding claims, wherein the weight ratio of the thermoplastic to the elastomeric component is in the range of from 80:20 to

20:80.

5

7. A seal as claimed in any one of the preceding claims, wherein the seal further includes a mineral filler

8. A seal as claimed in claim 7, wherein the mineral 10 filler is selected from one or more of clays, calcined clays, nano particle clays, talcs and amino silane coated clay.

9. A seal as claimed in any one of the preceding 15 claims, wherein the seal further includes a process aid, preferably a low molecular weight polyethylene.

10. A seal as claimed in any one of the preceding claims, further comprising one or more of a reinforcement

20 agent, a plasticizer, a binder, a stabilizer, a retarder, a bonding agent, an antioxidant, a lubricant, a pigment, a wax, a resin, an antiozonant, a secondary accelerator or an activator.

25

11. A valve for use in a pharmaceutical dispensing device having a seal as defined in any one of claims 1 to 10.

12. A pharmaceutical dispensing device having a valve 30 as claimed in claim 11.

- 15 -

13. A pharmaceutical dispensing device as claimed in claim 12 which is a pharmaceutical metered dose aerosol inhaler device.

14. 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 defined in any one of claims 1 to 10.

15. 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 10.

16. A dispensing apparatus as claimed in claim 14 or claim 15, comprising a pressurised dispensing container operatively connected to the valve body and containing the

25 fluid to be dispensed and a hydrofluorocarbon propellant comprising propellant type 134a or 227.

17. A dispensing apparatus as claimed in any one of claims 14 to 16, wherein the fluid to be dispensed comprises

30 a liquid or particulate product as a solution or suspension in a carrier liquid comprising alcohol.

5

10

15

20

- 16 -

18. A dispensing apparatus as claimed in claim 17, wherein the alcohol comprises ethanol.

19. A process for the preparation of a seal for a 5 valve for use in a pharmaceutical dispensing device, the process comprising:

(i) forming a composition comprising a mixture of an elastomeric component, a thermoplastic component and a sensitisor;

10 (ii) initiating a cross-linking reaction in the mixture to form a thermoplastic alloy comprising cross-linked components; and

(iii) either before or after step (ii), forming the composition into a seal.

15

20. A process as claimed in claim 19, wherein a thermo-chemical reaction is used to initiate the cross-linking reaction.

20

21. A process as claimed in claim 20, wherein the thermo-chemical reaction relies on a peroxide cross-linking agent.

22. A process as claimed in claim 21, wherein the high energy radiation comprises a source of one or both of an electron beam and Gamma radiation.

22. A process as claimed in any one of claims 19 to

25 21, wherein high energy radiation is used to initiate the cross-linking reaction.

23. A process as claimed in claim 22, wherein the high energy radiation comprises a source of one or both of an

30 electron beam and Gamma radiation.

AMENDMENTS TO THE CLAIMS HAVE BEEN FILED AS FOLLOWS:-

<7

CLAIMS:

1. A seal for a valve for use in a pharmaceutical dispensing device, which seal is formed from a thermoplastic 5 alloy comprising:

(a) an elastomeric component,

(b) a thermoplastic component, and

(c) a sensitisor,

wherein the weight ratio of the thermoplastic to the 10 elastomeric component is in the range of from 80:20 to 20:80.

• • • • • • • •• • ••• • •

2. A seal as claimed in claim 1, wherein the elastomeric component comprises one or more of 15 ethylene/alkene copolymers, polyisoprene, nitrile rubber, hydrogenated nitrile rubber, butyl rubbers, halogenated butyl rubbers, EPDM and EPR.

• •• • • •

Ml •

• • •

• ••• • • • • • • • • • • • • • • •

3. A seal as claimed in any one of the preceding

• 20 claims, wherein the thermoplastic component comprises one or more of styrene-ethylene-butylene terpolymer, styrene-ethylene-butadiene terpolymer, styrene-propylene-styrene terpolymer, polyether block polyamide and polyether-polyester copolymer.

25

4. A seal as claimed in any one of the preceding claims, wherein the sensitisor comprises one or more of triallyl cyanurate, ethylene glycol dimethacrylate, trimethylol propane triacrylate and high vinyl 1,2-

30 polybutadiene.

I&

5. A seal as claimed in any one of the preceding claims, wherein the seal is formed from a thermoplastic alloy which further comprises a cros.s-linking agent.

5 6. A seal as claimed in any one of the preceding claims, wherein the seal further includes a mineral filler

• •• • • • • •• • ••• • #

7. A seal as claimed in claim 6, wherein the mineral filler is selected from one or more of clays, calcined

10 clays, nano particle clays, talcs and amino silane coated clay.

8. A seal as claimed in any one of the preceding claims, wherein the seal further includes a

15 process aid, preferably a low molecular weight polyethylene,

9. 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

• ft

• •• •

• 20 bonding agent, an antioxidant, a lubricant, a pigment, a wax, a resin, an antiozonant, a secondary accelerator or an activator.

• ••

• ••• » • • • • •

• • • • • • ••

10. A valve for use in a pharmaceutical dispensing

25 device having a seal as defined in any one of claims 1 to 9.

11. A pharmaceutical dispensing device having a valve as claimed in claim 10.

30

12. A pharmaceutical dispensing device as claimed in claim 11 which is a pharmaceutical metered dose aerosol inhaler device.

11

13. 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 5 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 9.

10 14. 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

15 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 9.

• •• •

♦ •

• ••

% .. 15. A dispensing apparatus as claimed in claim 13 or

• • •

4 20 claim 14, comprising a pressurised 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.

25 16. A dispensing apparatus as claimed in any one of claims 13 to 15, wherein the fluid to be dispensed comprises a liquid or particulate product as a solution or suspension in a carrier liquid comprising alcohol.

30

17. A dispensing apparatus as claimed in claim 16, wherein the alcohol comprises ethanol.

20

18. A process for the preparation of a seal for a valve for use in a pharmaceutical dispensing device, the process comprising:

(i) forming a composition comprising a mixture of an 5 elastomeric component, a thermoplastic component and a sensitisor, wherein the weight ratio of the thermoplastic to the elastomeric component is in the range of from 80:20 to 20:80;

(ii) initiating a cross-linking reaction in the mixture 10 to form a thermoplastic alloy comprising cross-linked components; and

(iii) either before or after step (ii), forming the composition into a seal.

• II

• • 4

I

• I

***•

15 19. A process as claimed in claim 18, wherein a thermo-chemical reaction is used to initiate the cross-linking reaction.

4

* •••

» • I II I

• ;

20. A process as claimed in claim 19, wherein the

K

agent,

• ••

• I I

*•# I

, 20 thermo-chemical reaction relies on a peroxide cross-linking

! 21. A process as claimed in any one of claims 18 to

20, wherein high energy radiation is used to initiate the 25 cross-linking reaction.