WO2008146025A2

WO2008146025A2 - Methods of treating components of a medical dispenser device

Info

Publication number: WO2008146025A2
Application number: PCT/GB2008/001875
Authority: WO
Inventors: Paul Stevenson; Darren Bromley-Davenport
Original assignee: Innovatek Medical Limited
Priority date: 2007-06-01
Filing date: 2008-06-02
Publication date: 2008-12-04
Also published as: WO2008146025A3; GB0710488D0

Abstract

This invention relates to a method of treating a component of a medicament dispenser device, the component having one or more surfaces which come into contact with the medicament during storage or use of the device, the method including the steps of: providing said component; subjecting the component to a plasma induced pre-treatment step in which at least one of said surfaces is cleaned and/or conditioned using a plasma; and subjecting the pre-treated surface or surfaces to a subsequent treatment step which inhibits surface deposition of the medicament.

Description

METHODS OF TREATING COMPONENTS OF A MEDICAL DISPENSER DEVICE

This invention relates to methods of treating components of a medical dispenser device, with particular, but by no means exclusive, reference to pressurised dispenser devices.

It is well known to administer medicaments to a patient by inhalation using pressurised dispenser devices which dispense the medicament in a carrier fluid, commonly as an aerosol. Such devices are often referred to as pressurised metered dose inhalers (pMDIs), and are very commonly used for treating asthma and chronic obstructive pulmonary disease (COPD). One problem associated with dispenser devices of this kind is absorption of the active medicament on the internal surfaces of the device. This in turn can lead to a loss of potency and/or erratic dosing during the shelf-life of the device. In some instances clustering of drug particles can occur if the active medicament is present as a suspension of particles. One approach that has been adopted in order to reduce the surface absorption of the active drug is to modify the surface properties of the device, and traditionally this has been done by spray-coating with a low energy polymer. It is known from EP0642992 and EP1066073 that various interior surfaces of pMDI devices can be provided with coatings deposited by plasma polymerisation, although only limited polymer coatings are described.

The present inventors have realised that the quality of many of the known prior art surface coatings is variable. The present inventors have conducted extensive studies into the deficiencies in the prior art techniques, and have developed novel techniques which enable improved treatments for preventing absorption of the medicament onto the internal surfaces of the device. The present invention relates to some of the investigations made by the present inventors and, in at least some of its embodiments, addresses the above- described problems, needs and desires.

According to a first aspect of the invention there is provided a method of treating a component of a medicament dispenser device, the components having one or more surfaces which come into contact with the medicament during storage or use of the device, the method including the steps of: providing said component; subjecting the component to a plasma induced pre-treatment step in which at least one of said surface is cleaned and/or conditioned using a plasma; and subjecting the pre-treated surface or surfaces to a subsequent treatment step which inhibits surface deposition of the medicament.

The present inventors have found that the condition and chemical speciation of the surfaces is important if the treatment to inhibit surface deposition of the medicament is to be accomplished successfully. The present invention provides a range of conditioning and cleaning pre-treatments which can, for example, remove surface contaminants such as oils and unreacted materials, and provide an improved substrate for the subsequent treatment to be performed upon.

In preferred embodiments, the component is earthed during the plasma induced pre-treatment step. The plasma induced pre-treatment step may cause etching of at least one of said surfaces.

The plasma induced pre-treatment may cause reactive etching of at least one of said surfaces. Advantageously, at least one of said surfaces may be cleaned using a plasma formed using oxygen, a noble gas, preferably argon, a fluorocarbon, preferably CF₄, or mixtures thereof. For the avoidance of doubt, the term "noble gas" refers to a Group VIII gas. In particularly preferred embodiments, the plasma is formed using a noble gas/oxygen or oxygen/fluorocarbon mixture. In embodiments in which at least one of said surfaces is conditioned, the conditioning step preferably includes etching using a plasma formed using oxygen, a noble gas, preferably argon, a fluorocarbon, preferably CF₄, a chlorinated etching gas, or mixtures thereof.

In some embodiments, at least one of said surfaces of the component has an oxide layer and is conditioned by removing or partially removing the oxide layer using a plasma and rebuilding an oxide layer and/or other layers.

The oxide layer may be removed by etching, and the rebuilding of a layer can be performed by exposure of the surface to oxygen or a fluorine containing plasma.

The component may be a component of a pressurised dispenser that dispenses a medicament in a carrier fluid. The dispenser device may be a pMDI device. The component may be a can body for use in the pressurised dispenser, wherein at least a portion of an interior surface of the can body is subjected to the pre-treatment step and the subsequent treatment step. The can body may be formed from a metal, such as aluminium. Aluminium can bodies are an example of a component having an oxide layer which may be conditioned by removing the oxide layer and rebuilding.

In other embodiments, the component is a component of a metering valve system for use in the pressured dispenser. In other embodiments still, the component is a seal for use in sealing the pressurised dispenser, for example in sealing the can body to a metering valve system or sealing internal components of a metering valve system. The seal may be elastomeric, and may be formed from nitrile rubber, EPDM or other rubber. The cleaning process can remove contaminants present on the surface of the seal, particularly higher molecular weight contaminants. Some of these species can react with or otherwise absorb active medicaments, and so removal of these species reduces the loss of medicament onto the surface. Contaminants may include fillers, plasticizers and unreacted monomeric species.

The component may be formed from a polymeric material, and the pre- treatment step may cause cross-linking of polymeric material at the surface and/or may cause polymerisation of unreacted monomeric material present at or near to the surface. The term "near to the surface" generally refers to a depth of about 30μm from the surface, although the invention is not limited in this regard. Elastomeric seals, particularly nitrile rubber seals are example of components which may be pre-treated in this manner. Preferably, the pre-treatment step uses an ozone producing plasma, the ozone causing the cross linking and/or polymerisation. Cross-linking of unreacted monomeric material removes monomeric material which might instead react with or otherwise absorb the medicament. The subsequent treatment step may comprise coating the pre-treated surface or surface with a polymer.

The subsequent treatment step may utilise a plasma. Advantageously, the subsequent treatment step includes a plasma polymerisation step which coats the pre-treated surface or surfaces with a polymer which inhibits surface deposition of the medicament. Alternatively, the subsequent treatment step may include surface modification of the pre-treated surface or surfaces. The surface modification may be followed by a step in which the modified surface is coated with a polymer. The surface modification may modify the chemistry of the surface so as to reduce the polar component of the surface energy.

According to a second aspect of the invention there is provided a method of manufacturing a medicament dispenser device, the method including the steps of: treating a component of the medicament dispenser device in a method according to the first aspect of the invention; providing other components of the device; and assembling the components to provide an assembled medicament dispenser device.

According to a third aspect of the invention there is provided a medicament dispenser device treated by a method according to the first aspect of the invention.

Whilst the invention has been described above, it extends to any inventive combination as set out or in the following description, drawings or claims. Embodiments of methods and components in accordance with the invention will now be described with reference to the accompanying drawings, in which:

Figure 1 is a cross sectional view of a pressurised dispenser device; and Figure 2 shows an arrangement for pre-treating a can body. Figure 1 depicts a pressurised dispenser device, shown generally at 10, which comprises a housing 12 which receives a pressurised medicament containing arrangement 14. The housing 11 comprises an open ended cylindrical portion 12a in which the pressurised medicament containing arrangement 14 is disposed, and an open ended passage 12b which serves as a mouthpiece. The housing 12 further comprises an inner wall 12c which supports a socket 12d having a passageway 12e which receives the valve stem of the pressured medicament container arrangement. The passageway 12e communicates with an opening 12f which in turn is in communication with the exit passage defined by open ended passage 12b. The inner wall 12c has a number of apertures 12g formed therein which permits air to flow from the upper area of the housing 12 into the open ended passage 12b.

The structure and operation of the pressurised medicament container arrangement 14 will now be described in more detail. The arrangement 14 comprises a can body 16 on which is crimped a ferrule 18. Mounted on the ferrule 18 is a metering valve system, shown generally at 20. The metering valve system 20 comprises a valve stem 22, a portion of which is disposed in a valve member 24. The valve stem 22 and valve member 24 are both located in a valve housing 26, and the valve stem 22 is axially reciprocable therein against the action of a spring 28 which biases the valve stem 22 into a closed position as shown in Figure 1.

The metering valve system 20 further comprises a metering chamber 30 which is defined by the valve member 24 and a portion of the valve stem 22 together with inner and outer seals 32,34. The inner seal 32 acts to seal the valve member 24 against the valve housing 26, and separates the metering chamber 30 from the interior 36 of the valve housing 26. The outer seal 34 acts to seal the valve member 24 and valve housing 26 against the ferrule 18, and also seals the metering chamber 30 from the outside of the pressurised medicament container arrangement 14. Further sealing is provided by a can body seal 42 which acts to seal the can body 16 against the ferrule 18 upon crimping of same. The valve housing 26 has a plurality of slots 38 which enable the interior 36 of the valve housing 26 to communicate with the interior 40 of the can body 16. The valve stem 22 has two channels 44,46. Each channel, 44,46 comprises a longitudinal passageway and a transverse passageway. The transverse passageway of the valve stem channel 44 is disposed so that, when the pressurised medicament container arrangement 14 is in its closed position as shown in Figure 1 , the metering chamber 30 is in communication with the interior 36 of the valve housing 26 and thus is also in communication with the interior 40 of the can body 16. As explained in more detail below, the volume of the metering chamber 30 corresponds to the volume of medicament containing fluid administered in a single dose. In the closed position shown in Figure 1 , the dose is wholly contained in the metering chamber 30 and cannot escape to the outside of the pressurised medicament container arrangement 14 owing to the action of the outer seal 34.

To release a dose of medicament containing fluid, the valve stem 22 is pushed against the biasing action of the spring 28 into the interior 36 of the valve housing 26 to an extent that the valve stem channel 44 no longer communicates with the metering chamber 30. The valve stem 22 is designed so that, in this dispensing position, the valve stem channel 46 of the valve stem 22 communicates with the metering chamber 30, thereby allowing the dose of medicament containing fluid in the metering chamber 30 to be dispensed through the valve stem 22. The dose then passes through the passageway 12e, opening 12f and open ended passage 12b to exit the device.

When the valve stem 22 is subsequently released the biasing action of the spring 28 causes the valve stem 22 to move back towards the position shown in Figure 1. Thus, the valve stem channel 46 assumes a position whereby the metering chamber 30 is sealed against the outside, and the valve stem channel 44 assumes a position whereby the interior 36 of the valve housing 26 is in communication with the metering chamber 30. Owing to the pressure differential between the relatively high pressure interior 40 of the can body 16 and the relatively low pressure of the metering chamber 30, the metering chamber 30 is refilled with another dose of the medicament containing fluid.

The pressurised dispenser device 10 shown in Figure 1 is one example of such a device, and many other metering arrangements are known which differ to a greater or lesser degree in their precise mode of action. The present invention does not lay claim to the mode of action of the device shown in Figure 1 or of any other pressurised dispenser device. Rather, the present invention concerns methods for producing devices and components for same which inhibit losses of medicaments to internal surfaces of the device. The device shown in Figure 1 is provided in order to assist the reader's appreciation of how the present invention might be applied. The skilled reader will appreciate that the present invention can be applied to other designs of pressurised dispenser device than the one shown in Figure 1 , and indeed can be applied to different types of medicament dispenser devices than pressurised dispenser devices.

The present invention provides a range of pre-treatment steps prior to one or more steps which inhibit losses of the medicament to the internal surfaces of the pressurised dispensing device. In some embodiments of the invention, it is the interior surfaces of the can body which are pre-treated and subsequently coated with a polymer. However, many other components of a pressurised dispensing device may be pre-treated using the methodologies of the present invention, and this is explained in some more detail below.

Figure 2 shows an arrangement in which a can body 50 is cleaned and conditioned by plasma polymerisation. In the arrangement, the can body is maintained at earth, and the mouth of the can body is sealed with a suitable vacuum tight lid 52. The lid 52 permits entry of a gas feed inlet 54, an outlet 56 for exhausting gases using a vacuum pump 58, and an RF electrode which protrudes into the interior of the can body 50 and is disposed substantially along the longitudinal axis of the can body 50. The appropriate cleaning and conditioning gases are delivered into the can body 50 through the gas feed inlet 54 from an appropriate delivery source (not shown) which typically includes one or more mass flow controllers. Cleaning and conditioning of the interior surfaces of the can body 50 is achieved by striking and maintaining a plasma whilst the gas or gases are flowed into the can body 50. Typically 13.56 MHz RF power is applied to the RF electrode 60, and the plasma is struck using techniques well known in the art. Other RF frequencies might be used, and it is anticipated that frequencies within the range 4kHz to 20MHz might be utilised. It has been found that gas pressures in the range 5xe^"2 mbar to 1xe^'1 mbar give rise to particularly good results, although gas pressures in the range of 5xe^"2 mbar to 9xe^"1 mbar can be used. Power densities between 0.1 and 1.5 watts cm^'2 of electrode are employed.

The embodiment shown in Figure 2 is a single can treatment process in which the can acts as an earth electrode. Other configurations are possible. For example, in other single can configurations, the can may act as the RF electrode. An earth electrode may be inserted into the centre of the can body through the vacuum tight lid thereby preventing excessive heating through the so-called "hollow cathode effect". Alternatively, the RF power may be pulsed. In other configurations, the RF and earth electrodes may be discrete from the can. A plurality of cans may be coated at the same time using these configurations. In such configurations, the RF plasma electrodes may be parallel plate or barrel configuration with the cans being placed either on the RF or the earth electrode or at a floating potential between the two electrodes.

The plasma cleaning step ensures that the condition and chemical speciation at the substrate surface is adequate for a subsequent polymerisation process to proceed. In particular, oils and other contaminants can be removed by the cleaning process. The plasma can be formed using a noble gas such as argon, oxygen, a fluorocarbon (especially CF4) or a mixture of these gasses. Preferred mixtures include argon/oxygen, and oxygen/fluorocarbon. Cleaning can be achieved by etching or reactive etching. Additionally, with components such as aluminium can bodies, it can be advantageous to condition the surface by removing or partially removing and then rebuilding the oxide top surface layer. Etching of the aluminium to remove the existing oxide layer can be achieved using a noble gas such as argon, oxygen, fluorocarbon (especially CF4), chlorinated gases as used in the semiconductor industry, or mixtures of these gases. The rebuilding of the oxide top layer is performed using oxygen only.

The apparatus shown in Figure 2 can be used to perform a subsequent plasma polymerisation step, and similar pressure and power densities to those employed during the pre-treatment process can be utilised. It is preferred that a pure monomer plasma is used, by which is meant that the gaseous atmosphere in which the plasma is struck and maintained consists entirely of the monomer or monomers. However, it is in principle possible to form a plasma in a gaseous atmosphere which includes one or more diluent gases. In the context of the plasma generation, the term 'gases' is understood to include volatile species which are evaporated from a solid or liquid source in a heat vaporisation system prior to introduction into the plasma. Preferred examples of monomers are CF₄, C₂F₆, C3F₆, C₄Fs, CF3CHFCF3, CF₃CH2F, C5F10H2, CβFi2, CεFu, CδFiβ, CH₄, C₂H₆, and C₂H₄. These monomers may be used singly, to form a homopolymer, or as part of a blend of monomers to produce a co-polymer. Particularly preferred blends of monomers are CF₄ZC₄F₈ and CF₄/C₂H₄. Other preferred blends of monomers are CF₄ZCH₄, CF₄ZC₂H₆, C₄F₈ZCH₄, C₄F₈ZC₂H₆, CF₄ZCF₃CHFCF₃ andZor CF₃CH₂F, C₄F₈ZCF₃CHFCF₃ andZor CF₃CH₂F.

The present invention can also be used to pre-treat other components of a pressurised dispenser device. For example, various interior surfaces of the metering valve system and the housing for the pressurised medicament container arrangement might be pre-treated. Referring to Figure 1 , the housing 12, valve member 24, valve housing 26, spring 28, valve stem 22, and the seals 42,44,46 can be usefully pre-treated using the present invention. It can be desirable to stabilise the surfaces of seals using one or more pre-treatment steps prior to one or more further steps. Such pre-treatment steps are important with seals formed from elastomeric material, particularly nitrile materials, since the outer layer of the rubber is semi-porous, and typically contains material such as fillers, plasticisers, and unreacted monomers. These materials can react with or absorb the medicament andZor dissociate a subsequent polymer coating. Other forms of elastomeric seals, such as those formed from EPDM, can also be usefully pre-treated prior to surface modification. The pre-treatment can comprise a heat treatment, a plasma treatment, or a combination of the two. The heat treatment drives off some of the lower molecular weight volatile contaminants andZor promote additional cross-linking. A further advantage of the heating step is that the seals are relatively hot at the commencement of a further step, which results in better efficiency and fluorination during the surface modification step. The heat treatment is advantageously performed at greater than 9O⁰C, most preferably in the range 90-120⁰C. A plasma pre-treatment can sputter away any residual surface contaminants and can cause cross-linking of monomers present on the surface. The plasma cleaning/cross-linking step can be performed using similar gas pressures and power densities to those used in the polymerisation process described above. The plasma pre-treatment step may be performed using an argon, oxygen, or argon/oxygen plasma. Oxygen can containing plasmas have the advantage of producing ozone which enables the cross-linking of unreacted material to take place.

It has been found to be advantageous to modify the surface of the elastomeric seals by subjecting the seals to a CF₄ plasma. Pure CF₄ gas is introduced into a chamber containing the seals and a plasma is struck. Similar gas pressures and power densities to those used in the polymerisation process described above can be employed. Without wishing to be limited by any particular theory, it is believed that the plasma that dissociates the CF₄ to form reactive F^" ions which react with the surfaces of the seals to form a highly hydrophobic species. The process is not a coating process, but rather is a surface modification wherein hydrocarbon moieties on the surfaces of the seals are converted into hydrophobic fluorocarbon moieties.

It has been found that seals which have been surface modified in accordance with the invention can be highly resistant to deposition of the medicament, and thus may be used directly in a pressurised dispenser device. Alternatively, it may be appropriate to provide a discrete coating of a polymer on top of the modified surfaces of the seals. This is particularly useful when the surface of the seal is rough, for example having any cavities, since pores, cavities, and other features associated with surface roughness can be filled by a polymer coating. It is particularly preferred to deposit a polymer coating by plasma polymerisation. Plasma polymerisation of a coating can be effected by turning off the flow of CF₄ into the chamber whilst introducing a second, monomeric, gas to the chamber. Alternatively, it is possible to maintain a flow of

CF₄ and to bleed a second gas into the CF₄ gas flow to produce a gas blend which is used to perform the plasma polymerisation. Suitable monomeric gases include C₄F_8, C₂H₆, and CF₃CHFCF₃ but other species described earlier might be used instead. These gases can also be used to form a blend with the CF₄ for polymerisation purposes. Similar pressures and power densities to those used during the surface modification step can be used during the polymerisation step. The present invention is not limited to pressurised dispenser devices, and can be used in conjunction with delivery systems for dry powder drugs and active liquids.

Claims

1. A method of treating a component of a medicament dispenser device, the component having one or more surfaces which come into contact with the medicament during storage or use of the device, the method including the steps of: providing said component; subjecting the component to a plasma induced pre-treatment step in which at least one of said surfaces is cleaned and/or conditioned using a plasma; and subjecting the pre-treated surface or surfaces to a subsequent treatment step which inhibits surface deposition of the medicament.

2. A method according to claim 1 in which the plasma induced pre-treatment causes etching of at least one of said surfaces.

3. A method according to claim 1 in which the plasma induced pre-treatment causes reactive etching of at least one of said surfaces.

4. A method according to any one of claims 1 to 3 in which at least one of said surfaces is cleaned using a plasma formed using oxygen, a noble gas, preferably argon, a fluorocarbon, preferably CF₄, or mixtures thereof.

5. A method according to claim 4 in which the plasma is formed using a noble gas/oxygen or oxygen/fluorocarbon mixture.

6. A method according to any previous claim in which at least one of said surfaces is conditioned, and the conditioning step includes etching using a plasma formed using oxygen, a noble gas, preferably argon, a fluorocarbon, preferably CF₄, a chlorinated etching gas, or mixtures thereof.

7. A method according to any previous claim in which at least one of said surfaces of the component has an oxide layer and is conditioned by removing or partially removing the oxide layer using a plasma and rebuilding an oxide layer.

8. A method according to any previous claim in which the component is a component of a pressurised dispenser that dispenses a medicament in a carrier fluid.

9. A method according to claim 8 in which the component is a can body for use in the pressurised dispenser, and wherein at least a portion of an interior surface of the can body is subjected to the pre-treatment step and the subsequent treatment step.

10. A method according to claim 8 in which the component is a component of a metering valve system for use in the pressurised dispenser.

11. A method according to claim 8 in which the component is a seal for use in sealing components of the pressurised dispenser.

12. A method according to claim 11 in which the seal is elastomeric.

13. A method according to claim 12 in which the seal is formed from nitrile rubber.

14. A method according to any previous claim in which the component is formed from a polymeric material, and the pre-treatment step causes cross- linking of polymeric material at the surface and/or causes polymerisation of unreacted monomeric material present at or near to the surface.

15. A method according to claim 14 in which the pre-treatment step uses an ozone producing plasma, the ozone causing the cross-linking and/or polymerisation.

16. A method according to any previous claim in which the subsequent treatment step utilises a plasma.

17. A method according to claim 16 in which the subsequent treatment step includes a plasma polymerisation step which coats the pre-treated surface or surfaces with a polymer which inhibits surface deposition of the medicament.

18. A method according to claim 16 or claim 17 in which the subsequent treatment step includes surface modification of the pre-treated surface or surfaces.

19. A method according to any previous claim in which the component is earthed during the plasma induced pre-treatment step.

20. A method of manufacturing a medicament dispenser device, the method including the steps of: treating a component of the medicament dispenser device in a method according to any one of claims 1 to 19; providing other components of the device; and assembling the components to provide an assembled medicament dispenser device.

21. A component of a medicament dispenser device treated by a method according to any one of claims 1 to 19.