GB2445483A - Seal for a pharmaceutical dispensing device - Google Patents

Seal for a pharmaceutical dispensing device Download PDF

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Publication number
GB2445483A
GB2445483A GB0802588A GB0802588A GB2445483A GB 2445483 A GB2445483 A GB 2445483A GB 0802588 A GB0802588 A GB 0802588A GB 0802588 A GB0802588 A GB 0802588A GB 2445483 A GB2445483 A GB 2445483A
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GB
United Kingdom
Prior art keywords
seal
valve
thermoplastic
styrene
dispensing
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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.)
Granted
Application number
GB0802588A
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GB2445483B (en
GB0802588D0 (en
Inventor
Daljit S Ohbi
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Consort Medical Ltd
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Bespak PLC
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Priority to GB0802588A priority Critical patent/GB2445483B/en
Priority claimed from GB0401962A external-priority patent/GB2410500B/en
Publication of GB0802588D0 publication Critical patent/GB0802588D0/en
Publication of GB2445483A publication Critical patent/GB2445483A/en
Application granted granted Critical
Publication of GB2445483B publication Critical patent/GB2445483B/en
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    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08LCOMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L23/00Compositions of homopolymers or copolymers of unsaturated aliphatic hydrocarbons having only one carbon-to-carbon double bond; Compositions of derivatives of such polymers
    • C08L23/26Compositions of homopolymers or copolymers of unsaturated aliphatic hydrocarbons having only one carbon-to-carbon double bond; Compositions of derivatives of such polymers modified by chemical after-treatment
    • 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
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08CTREATMENT OR CHEMICAL MODIFICATION OF RUBBERS
    • C08C19/00Chemical modification of rubber
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08FMACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F299/00Macromolecular compounds obtained by interreacting polymers involving only carbon-to-carbon unsaturated bond reactions, in the absence of non-macromolecular monomers
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08FMACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F8/00Chemical modification by after-treatment
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08JWORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00Processes of treating or compounding macromolecular substances
    • C08J3/24Crosslinking, e.g. vulcanising, of macromolecules
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08JWORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00Processes of treating or compounding macromolecular substances
    • C08J3/28Treatment by wave energy or particle radiation
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08JWORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J5/00Manufacture of articles or shaped materials containing macromolecular substances
    • C08J5/20Manufacture of shaped structures of ion-exchange resins
    • C08J5/22Films, membranes or diaphragms
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08KUse of inorganic or non-macromolecular organic substances as compounding ingredients
    • C08K5/00Use of organic ingredients
    • C08K5/0008Organic ingredients according to more than one of the "one dot" groups of C08K5/01 - C08K5/59
    • C08K5/0025Crosslinking or vulcanising agents; including accelerators
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08LCOMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L21/00Compositions of unspecified rubbers
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08LCOMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L23/00Compositions of homopolymers or copolymers of unsaturated aliphatic hydrocarbons having only one carbon-to-carbon double bond; Compositions of derivatives of such polymers
    • C08L23/02Compositions of homopolymers or copolymers of unsaturated aliphatic hydrocarbons having only one carbon-to-carbon double bond; Compositions of derivatives of such polymers not modified by chemical after-treatment
    • C08L23/16Elastomeric ethene-propene or ethene-propene-diene copolymers, e.g. EPR and EPDM rubbers
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08LCOMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L23/00Compositions of homopolymers or copolymers of unsaturated aliphatic hydrocarbons having only one carbon-to-carbon double bond; Compositions of derivatives of such polymers
    • C08L23/02Compositions of homopolymers or copolymers of unsaturated aliphatic hydrocarbons having only one carbon-to-carbon double bond; Compositions of derivatives of such polymers not modified by chemical after-treatment
    • C08L23/18Homopolymers or copolymers of hydrocarbons having four or more carbon atoms
    • C08L23/20Homopolymers or copolymers of hydrocarbons having four or more carbon atoms having four to nine carbon atoms
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08LCOMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L53/00Compositions of block copolymers containing at least one sequence of a polymer obtained by reactions only involving carbon-to-carbon unsaturated bonds; Compositions of derivatives of such polymers
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08LCOMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L53/00Compositions of block copolymers containing at least one sequence of a polymer obtained by reactions only involving carbon-to-carbon unsaturated bonds; Compositions of derivatives of such polymers
    • C08L53/02Compositions of block copolymers containing at least one sequence of a polymer obtained by reactions only involving carbon-to-carbon unsaturated bonds; Compositions of derivatives of such polymers of vinyl-aromatic monomers and conjugated dienes
    • C08L53/025Compositions of block copolymers containing at least one sequence of a polymer obtained by reactions only involving carbon-to-carbon unsaturated bonds; Compositions of derivatives of such polymers of vinyl-aromatic monomers and conjugated dienes modified
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08KUse of inorganic or non-macromolecular organic substances as compounding ingredients
    • C08K3/00Use of inorganic substances as compounding ingredients
    • C08K3/01Use of inorganic substances as compounding ingredients characterized by their specific function
    • C08K3/013Fillers, pigments or reinforcing additives
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08LCOMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L15/00Compositions of rubber derivatives
    • C08L15/005Hydrogenated nitrile rubber
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08LCOMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L23/00Compositions of homopolymers or copolymers of unsaturated aliphatic hydrocarbons having only one carbon-to-carbon double bond; Compositions of derivatives of such polymers
    • C08L23/02Compositions of homopolymers or copolymers of unsaturated aliphatic hydrocarbons having only one carbon-to-carbon double bond; Compositions of derivatives of such polymers not modified by chemical after-treatment
    • C08L23/04Homopolymers or copolymers of ethene
    • C08L23/08Copolymers of ethene
    • C08L23/0846Copolymers of ethene with unsaturated hydrocarbons containing other atoms than carbon or hydrogen atoms
    • C08L23/0892Copolymers of ethene with unsaturated hydrocarbons containing other atoms than carbon or hydrogen atoms containing monomers with other atoms than carbon, hydrogen or oxygen atoms
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08LCOMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L9/00Compositions of homopolymers or copolymers of conjugated diene hydrocarbons

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Manufacturing & Machinery (AREA)
  • Anesthesiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pulmonology (AREA)
  • Materials Engineering (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Containers And Packaging Bodies Having A Special Means To Remove Contents (AREA)
  • Medicinal Preparation (AREA)
  • Medical Preparation Storing Or Oral Administration Devices (AREA)

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 (22)

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.
GB0802588A 2004-01-29 2004-01-29 Seal for a dispensing apparatus Expired - Lifetime GB2445483B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
GB0802588A GB2445483B (en) 2004-01-29 2004-01-29 Seal for a dispensing apparatus

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0401962A GB2410500B (en) 2004-01-29 2004-01-29 Seal for a dispensing apparatus
GB0802588A GB2445483B (en) 2004-01-29 2004-01-29 Seal for a dispensing apparatus

Publications (3)

Publication Number Publication Date
GB0802588D0 GB0802588D0 (en) 2008-03-19
GB2445483A true GB2445483A (en) 2008-07-09
GB2445483B GB2445483B (en) 2008-08-20

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
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Country Status (1)

Country Link
GB (1) GB2445483B (en)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2108943A (en) * 1981-10-02 1983-05-25 Terumo Corp Medical container stopper
WO1995003984A1 (en) * 1993-07-28 1995-02-09 Minnesota Mining And Manufacturing Company Seals for use in an aerosol delivery device
US5714545A (en) * 1995-07-19 1998-02-03 Yukong Limited Thermoplastic elastomeric composition and process for preparing the same

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2108943A (en) * 1981-10-02 1983-05-25 Terumo Corp Medical container stopper
WO1995003984A1 (en) * 1993-07-28 1995-02-09 Minnesota Mining And Manufacturing Company Seals for use in an aerosol delivery device
US5714545A (en) * 1995-07-19 1998-02-03 Yukong Limited Thermoplastic elastomeric composition and process for preparing the same

Also Published As

Publication number Publication date
GB2445483B (en) 2008-08-20
GB0802588D0 (en) 2008-03-19

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PE20 Patent expired after termination of 20 years

Expiry date: 20240128