GB2559991A

GB2559991A - Diffusion test system

Info

Publication number: GB2559991A
Application number: GB1702956.2A
Authority: GB
Inventors: Nurumbetov Gabit; Haddleton David; Tombs Emma; Nikolaou Vasiliki
Original assignee: Medherant Ltd
Current assignee: Medherant Ltd
Priority date: 2017-02-23
Filing date: 2017-02-23
Publication date: 2018-08-29
Also published as: WO2018154306A1; GB201702956D0

Abstract

A diffusion test system comprises a base plate having a plurality of wells 14, each well having a blind end 51. An elongate hollow plug 42 defines a cavity to receive a magnetic agitator 43 and is configured to be removably securely insertable into a respective well. A product 35 is placed in the bottom of the well and a membrane 41 is placed on top. The bottom of the plug 42 abuts the membrane 41 when inserted. A receptor solution 37 is then added to the plug. An optional lid or cap 44 is provided. The magnetic agitator is arranged to reciprocate axially in the plug and may include a plunger (71, Figure 15) and two disc magnets (73, 74, Figure 15) connected by a rod. The magnetic agitator may be held within the plug by means or an internal rib or shelf (68, Figure 13) formed on the inner wall of the plug.

Description

(54) Title of the Invention: Diffusion test system

Abstract Title: Diffusion test system with a magnetic agitator disposed in a plug (57) A diffusion test system comprises a base plate having a plurality of wells 14, each well having a blind end 51. An elongate hollow plug 42 defines a cavity to receive a magnetic agitator 43 and is configured to be removably securely insertable into a respective well. A product 35 is placed in the bottom of the well and a membrane 41 is placed on top. The bottom of the plug 42 abuts the membrane 41 when inserted. A receptor solution 37 is then added to the plug. An optional lid or cap 44 is provided. The magnetic agitator is arranged to reciprocate axially in the plug and may include a plunger (71, Figure 15) and two disc magnets (73, 74, Figure 15) connected by a rod. The magnetic agitator may be held within the plug by means or an internal rib or shelf (68, Figure 13) formed on the inner wall of the plug.

~ 2 to 5 cm

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Provide product 35 in the bottom 51 of the welt 14

S1

Provide membrane 41 in weii 14

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Insert plug 42 in well 14

S3

Provide agitator 43 in plug 42 1 34

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Application No. GB1702956.2

RTM

Date :27 December 2017

Intellectual

Property

Office

The following terms are registered trade marks and should be read as such wherever they occur in this document:

Merck Millipore p.n Transcutol p.12

Intellectual Property Office is an operating name of the Patent Office www.gov.uk/ipo

Diffusion test system

Field of the Invention

The present invention relates to a diffusion test system and to a method of performing a 5 diffusion test.

Background

A Franz cell can be used to perform in vitro skin permeation studies and other forms of diffusion tests.

A Franz cell includes upper and lower compartments separated by a membrane (for example, in the form of a strip of human skin) having an upper face and an underside.

A fixed amount of test product (which can take the form of, for instance, a solid, liquid, gel or patch) containing an active ingredient is arranged in contact with the upper face of the membrane. The lower compartment is filled with a receptor solution. The compartment is filled with sufficient receptor solution that the level of the receptor solution reaches the underside of the membrane so as to be in contact with the membrane. Thus, active ingredient can diffuse from the test product, across the membrane, and into the receptor solution. The lower chamber is provided with a sampling port which can be used to extract a sample of the receptor solution so as to determine the concentration of the active ingredient in the receptor solution, and to replenish the compartment with fresh solution.

Referring to Figure 1, a Franz cell 1 typically includes an upper cap 2 and a lower glass body 3 containing the lower compartment 4 which is provided with the sampling port 5 and a space 6 surrounding the lower compartment which is provided with input and output ports 7, 8 and through which water can be circulated to provide a water jacket.

These types of Franz cells tend to suffer one or more disadvantages. For example, they are usually hand-made and, thus, expensive to purchase and differ in nature in accurate size and shape. Moreover, glass Franz cells are fragile and are liable to break which can increase costs further. Furthermore, air bubbles can be inadvertently introduced between the membrane and the receptor solution when filling or re-filling thereby varying the contact area and leading to measurement errors. It can be complex and costly to conduct multiplex tests. In addition, there is a significant amount of the lower compartment which is not in contact with the temperature regulated surface which can affect performance.

-3Summary

According to a first aspect of the present invention there is provided a diffusion test system. The diffusion test system comprises a plurality of wells, each well having an open end and a blind end, at least one elongate hollow plug, each plug comprising a wall running between first and second open ends and defining a cavity therein, each plug configured to be removably securely-insertable into a respective well, each plug having a length between the ends greater than the depth of the well. The diffusion test system may comprise at least one magnetic agitator, each magnetic agitator configured to be receivable in a respective cavity.

Each plug may include a shelf inwardly-projecting from the wall of the plug into the cavity for supporting the magnetic agitator.

The system may comprise at least one cap, each cap configured to close the open end of a respective well.

The system may comprise a base plate comprising the plurality of wells. The plurality of wells may comprise a plurality blind holes in the base plate.

Each magnetic agitator may include a magnet which is arranged to be able to reciprocate axially in the plug. Each magnetic agitator may comprise a plunger comprising the magnet disposed at an end of a rod and a frame configured to span the cavity and which is positionable between the first and second ends of the plug, the frame including an axially-aligned guide for the rod. The end of the rod is a first end of a rod having first. The plunger may include a second magnet disposed at the second end of the rod. Each magnetic agitator may comprise a disc-shaped magnet. The magnetic agitator may include an inert coating.

The well has a depth between the ends and each plug has a length between the ends of the plug which may be greater than the depth of the well. The wells and plugs may be cylindrical.

Each cavity has a transverse area which maybe equal to or greater than 0.1 cm² and equal to or less than 10 cm².

-4Each cavity has length which may be equal to or greater than 1 cm and equal to or less than to cm.

The system may comprise at least one membrane, each membrane having an area equal 5 to or greater than a transverse area of the cavity and which is interposable between the blind end of a well and the first end of a plug.

The system may further comprise a portion of test product, each portion interposable between the blind end of the well and the membrane. The system comprises, in one or io more wells, test product disposed at the blind end of a respective well, a membrane in contact with and overlying the test product and a plug, the first end of the plug abutting the membrane. The system may further comprise a respective agitator disposed in the cavity in the one or more wells. The system may further comprise receptor solution disposed in the cavity.

The test product may comprise a transdermal patch. The test product may comprise a gel or cream. The test product may comprise a solid. The test product may comprise a liquid. The test product may comprise a solution.

There may be at least three wells, at least nine wells, at least 25 wells, at least 36 wells or at least 49 wells.

The system may comprise a case for holding one or more base plates, the case comprising a main housing portion defining a space, a system for controlling the temperature of the space and one or more magnetic stirrers.

The temperature controlling system may comprise a fan heater or water/fluid controlled device.

The wells are preferably made from a chemically inert, biocompatible polymer, such as polyether ether ketone (PEEK), PTFE or similar engineering-grade polymer. The plugs are preferably made from a chemically inert, biocompatible polymer, such as PEEK, PTFE or similar engineering-grade polymer.

The system or parts of the system may be provided as a kit of parts. For example, a first supplier may provide the wells (e.g. as a base plate) and plugs, and, optionally the

-5magnetic agitators. The first supplier or a second, different supplier may provide the temperature controlling system. The first supplier, the second supplier or a third, different supplier may provide the membrane.

According to a second aspect of the present invention there is provided a magnetic agitator including a magnet which is arranged to be able to reciprocate.

According to a third aspect of the present invention there is provided a method of performing a diffusion test using the system according to the first aspect. The method comprises providing a respective portion of test product in one or more wells, providing a respective membrane over each test product portion in the one or more wells, inserting a respective plug into in the one or more wells such that the first end of the plug abuts the membrane, providing a respective magnetic agitator in the one or more wells and providing receptor solution in the one or more wells.

-6Brief Description of the Drawings

Certain embodiments of the present invention will now be described, by way of example, with reference to Figures 2 to 25 of the accompanying drawings, in which: Figure 1 is a perspective view of a glass-bodied Franz cell;

Figure 2 is a perspective view of a diffusion test system;

Figure 3 is a perspective downward view of a bay of the diffusion test shown in Figure 1 containing a base plate in which a majority of wells contain inserts;

Figure 4 is a perspective downward view of an empty bay of the diffusion test system shown in Figure 1 illustrating a rotatable magnet arrangement;

Figure 5 is a perspective view of a base plate providing an array of wells

Figure 6 is an exploded perspective view of an assembled diffusion cell;

Figure 7 is a side view of an assembled diffusion cell;

Figure 8 is a cross sectional view of a well having a first geometry;

Figure 9 is a cross sectional view of a well having a second geometry;

Figure 10 is a perspective view of an insert;

Figure 11 is a top plan view of the insert shown in Figure 10;

Figure 12 is a bottom plan view of the insert shown in Figure 10;

Figure 13 is a longitudinal cross sectional view of an insert having a first configuration; Figure 14 is a longitudinal cross sectional view of an insert having a second configuration;

Figure 15 is a perspective view of a magnetic plunger-based agitator which comprises a magnetic plunger and a holder;

Figure 16 is a plan view of the holder shown in Figure 15;

Figure 17 is a side view of the agitator shown in Figure 15;

Figure 18 is a cross sectional view of a first type of cap for an insert;

Figure 19 is a cross sectional view of a second type of cap for an insert;

Figure 20 is process flow diagram of a method of carrying out a diffusion test;

Figure 21 shows methyl salicylate permeation profiles obtained using a diffusion cell and a comparative example in the form of a Franz-type cell;

Figure 22 shows nicotine permeation profiles obtained using a diffusion cell and a comparative example in the form of a Franz-type cell;

Figure 23 shows lidocaine permeation profiles obtained using a diffusion cell and a comparative example in the form of a Franz-type cell;

Figure 24 shows diclofenac epolamine permeation profiles obtained using a diffusion cell and a comparative example in the form of a Franz-type cell; and

-ΊFigure 25 shows ibuprofen permeation profiles obtained using a diffusion cell and a comparative example in the form of a Franz-type cell.

Detailed Description of Certain Embodiments

Diffusion test system

Referring to Figures 2 and 3, a diffusion test system 11 is shown. The system 11 includes a case 12 which can hold one or more base plates 13, each base plate 13 comprising a set of wells 14.

The case 12 consists of a housing 15 including a main housing 16 and a set of lids 17 (one of which is not shown). The housing 15 defines a space 18 which divided into one or more sections 19 (or “bays”) by one or more partition walls 20, each section 19 used to receive a respective base plate 13.

The case 13 contains a system 21 for controlling the temperature of the space including a fan heater 22, a controller 23, a temperature sensor 24, a user input 25 for setting the set point temperature and a display 26 for displaying the current temperature and set point temperature.

Referring also to Figure 4, the case 13 also houses one or more magnetic stirrers 27, one stirrer for bay 19, disposed under a floor 28 of the bay 19. Each magnetic stirrer 27 includes a pair of radially-orientated bar magnets 29 mounted on opposite sides of a horizontally-lying rotatable disc 30 which is arranged to rotate about a vertical central axis a. The disc 30 is driven by an electric motor (not shown).

Referring to Figure 5, a base plate 13 is shown in more detail.

The base plate 13 is generally flat and square. The base plate 13, however, need not be square or even rectangular, but can be, for example, circular. The base plate 13 is made from a suitable biocompatible polymer, such as polyether ether ketone (PEEK).

The base plate 13 includes an array 31 of blind holes 14 which form the wells. In this case, the wells 14 are cylindrical and have a width, W, of 1 cm and a depth, D, of about 0.5 cm. Other values of width, W, and/or, depth, D, can be used.

-8The wells 14 are arranged into rectangular groups 32 (in this case, each group is a twoby-three rectangular array) which are arranged in a circular array 31 (in this case at 60 degree intervals) around a central axis β. When the base plate 13 is placed in a bay 19 the axis of rotation a and the axis of the central axis β substantially coincide.

The base plate 13 may be provided with a knob 33 or other form of handle for lifting the base plate 13 in and out of the case 12. The wells 14 need not be arranged in rectangular and/or circular arrays. Moreover, there may be fewer wells or more wells, e.g. 49 well or more.

Referring to Figures 6 and 7, each well 14 can serve as the basis of a diffusion cell 34 (herein also referred to as a “TEPI cell”) which can be used to perform a diffusion test of a product 35 containing an active ingredient 36 using a receptor solution 37. The product 35 may take the form of a gel, cream or other liquid substance or a patch.

The diffusion cell 34 includes the well 14, a membrane 41, an elongate hollow plug 42 (or “insert”) which is inserted into the well 14, a magnetic agitator 43 and an optionally lid 44. In the following, only one diffusion cell 34 is described. However, each cell 34 has the same component parts and structure.

Referring also to Figures 8 and 9, the well 14 has a blind-ended bottom 51, an open top 52 and an inside wall face 53. The well 14 is circular (in plan view). However, the well 14 may can be polygonal (for example square) or be another shape. The well 14 has a diameter, W, of 1 cm and a depth, D, of 0.5 cm. However, the well 14 may be narrower or wider, and/or may be shallower or deeper.

Referring in particular to Figure 9, the bottom 51 of the well maybe stepped having a central recess 54 and an annular shoulder 55.

Referring again to Figure 6 and 7, the test product 35 is placed in the bottom 51 of the well 14. The test product 35 is covered by the membrane 41. The membrane 41 is substantially the same shape and size as the well 14. In some cases, the membrane 41 may be oversized (e.g. by up to 10 % or by 1 mm). The membrane 41 is a piece of human skin. However, artificial membranes may be used. The type of membrane 41 generally depends on the type of test being performed.

-9Referring also to Figures 10 to 14, an elongate hollow plug 42 has first and second ends 61, 62 (herein referred to as “bottom and top ends” respectively) and comprises a wall 63 which runs between the ends 61, 62 which defines a cavity 64 (or “passage”) therein. The wall 63 has inner and outer surfaces 65, 66 having inner and outer diameters, di, d₂ respectively. The inner and outer diameters, di, d₂ are 0.5 and 1 cm respectively. The wall 63 has a length, L, of 1.8 mm. The inner and outer diameters, di, d₂ may be smaller or greater, and/or may the wall be shorter or longer. The plug 42 is made from a suitable biocompatible polymer, such as polyether ether ketone (PEEK).

The plug 42 is generally tubular and is generally circular in transverse cross section.

The outer surface 66 of the wall 63 has the same cross-sectional shape and size as the inner surface 53 such that it fits snuggly in the well 14.

The plug 42 has a shallow annular groove 67 which runs around the outer surface 66 of the wall 63 close to the bottom end 61. The groove 67 receives an O’-ring 68 which is used to help form a seal between the well 14 and the plug 42.

The plug 42 has an integrally-formed thin, short shelf (or “rib”) 68 which projects inwardly into the passage 64 from the wall 63 about a third of the way between the first and second ends 61, 62. The shelf 68 supporting the magnetic agitator 43 when the magnetic agitator 43 is disposed in the plug 42.

Referring in also to Figure 14, in a modified plug 42’, the first end 61 of the plug 42’ is provided with a stepped lip 69 and the groove 67 is moved away from the first end 61.

Referring again to Figures 6 and 7, the plug 42 is pressed down into the well 14 so that the bottom end 61 of the plug 42 abuts and urges against the membrane 41.

Referring also to Figures 15 to 17, a magnetic agitator 43 is positioned inside the plug

42. The agitator 43 consists of a plunger 71 (herein also referred to as an “armature”) and frame 72 for holding the agitator 43 in the plug 43 and guiding reciprocating motion of the plunger 71.

The plunger 71 comprises first and second disc-shaped magnets 73, 74 which held in a parallel, spaced-apart arrangement by a rod 75 running perpendicularly to the faces of

- 10 the magnets 73, 74. The magnets 73, 74 and rod 75 are coated with biocompatible polymer.

The frame 72 is generally disc-shaped and includes first and second concentric rings 76, 5 tj (herein referred to as “inner and outer rings” respectively) connected by radial spokes 78. The inner ring 76 defines a central aperture 79 through which the rod 75 of the plunger 71 passes and which guides the movement of the plunger 71. The first and second concentric rings 76, 77 and spokes 79 define vents 80 through which receptor solution 37 can flow.

Referring again to Figures 6 and 7, receptor solution 37 is added to the plug 42, for example, using a pipette (not shown).

Referring also to Figures 18 and 19, a cap 44 (or “lid”) maybe used to close the plug 42.

The lid 44 is generally flat having a stepped rim 81 defining a smaller first portion 82 and a larger second portion 83 (herein referred to as “lower and upper portions” respectively).

The lid 44 may be provided with one or more through holes (not shown) for allowing one or more sampling tubes to be inserted into the cavity 64 of the plug 42.

Referring to Figures 6, 7 and 20, to perform a test, one or more cells 34 is/are assembled (steps Si to S4).

The base plate 13 is placed in the case 11. Receptor solution 37 is then added, for example, using a micro-pipetting robot (not shown) (step S5). The plug 42 may take, for example, between 50 and 200 pi of receptor solution 37.

Samples of receptor solution 37 maybe taken at intervals (steps S6 & S7) and fresh receptor 37 may be added.

The diffusion test system 11 and diffusion cells 34 can provide one or more advantages over conventional Franz cell systems.

The diffusion cells 34 can be cheaper and/or easier to manufacture since the component parts, such as the base plate 13 and plugs 43, can be formed by a moulding

- 11 process or by other high-volume, low-cost plastics manufacturing method. The use of an automated manufacturing and milling process can help to ensure each sample cell is of uniform shape and size.

The system 11 is suited to being a multiplexing system which is cheaper and more compact than a conventional multi-station Franz cell system. Moreover, an even greater density and number of cells 34 can be provided which can increase the number of tests which can be performed and/or shorten the time taken to conduct a given number of tests.

The cells 34 are generally smaller and so smaller quantities of product 35 and membrane 41 can be used.

The receptor solution 37 lies on top of the membrane 41 which helps not only to avoid bubbles at the interface with membrane 4, but also to provide hydrostatic pressure to urge the membrane against the product 35.

A greater proportion of receptor solution 37 can be sampled. Unlike a conventional Franz cell which no more than 20 to 30 % of the solution can be taken (due to the position of the sampling port), more than 30 %, even 100% of the receptor solution 37 can be taken. This can lead to greater accuracy since it can minimise and even avoid accumulation of residual active ingredient.

The system 11 can be used in a wide range of applications, e.g. blood serum analysis.

Experimental results

Diffusion cells 34 were compared with conventional Franz cells 1 (Figure 1) employing commercially-available medicinal products and Strat-M (RTM) membranes (available from Merck Millipore). Such an approach allowed for a direct comparison of both types of cell. Details of tested transdermal patches are given in Table 1 below.

- 12 Table ι

No	Product	Active pharmaceutical ingredient	Dose, mg cm ²
1	Salonpas (RTM)	Methyl salicylate	1-5
2	Niquitin (RTM)	Nicotine	5-1
3	Lidoderm (RTM)	Lidocaine	5-0
4	Flector (RTM)	Diclofenac epolamine	i-3
5	Ibupas (RTM)	Ibuprofen	1.0

Experimental conditions were kept the same for both systems to avoid any deviations 5 and are set out below:

Membrane type: Strat-M (RTM) transdermal diffusion testing membrane Acceptor medium: mixture of pH 7.4 PBS/Transcutol (90/10 vol.)

Temperature: 32 ± 1 °C (by keeping acceptor medium at 36 °C)

Samples taken at: 1, 2, 4 and 6 hours Sample volume: 200 pL

Franz-cell orifice: -1.15 cm²TEPI-cell orifice: 0.5 cm²Analysis: validated HPLC method

Sample patches were cut to size, applied to the membrane and equilibrated for 15 minutes prior to experiment start.

Figures 21 to 25 show the permeation profiles obtained for Salonpas (RTM), Niquitin (RTM), Lidoderm (RTM), Flector (RTM) and Ibupas (RTM) respectively when measured using Franz cells 1 (Figure 1) and TEPI cells, i.e. the diffusion cells 34 (Figure 6).

The experiments show that, despite having a different configuration and smaller dimensions, the TEPI cell provides similar profiles to those of a conventional Franz cell.

-13Modifications

It will be appreciated that various modifications may be made to the embodiments hereinbefore described. Such modifications may involve equivalent and other features which are already known in the design, manufacture and use of diffusion test systems and component parts thereof and which may be used instead of or in addition to features already described herein. Features of one embodiment maybe replaced or supplemented by features of another embodiment.

The plug, stirrer and/or the base plate may be formed from or have a coating formed 10 from, for example, glass, stainless steel, titanium, fluoropolymers (such as polytetrafluoroethylene), polyethers (such as polyether ether ketone) or other materials that are suitable for medical applications which are chemically inert and mechanically robust and which are able to be machined using automated lathes and milling equipment.

Plugs, stirrers and/or one or more base plates may be provided as a kit of parts. In some cases, the stirrers need not be provided as part of the kit.

Other forms of agitator maybe used. In some cases, an agitator need not be used.

Although claims have been formulated in this application to particular combinations of features, it should be understood that the scope of the disclosure of the present invention also includes any novel features or any novel combination of features disclosed herein either explicitly or implicitly or any generalization thereof, whether or not it relates to the same invention as presently claimed in any claim and whether or not it mitigates any or all of the same technical problems as does the present invention. The applicants hereby give notice that new claims may be formulated to such features and/or combinations of such features during the prosecution of the present application or of any further application derived therefrom.

Claims

Claims

1. A diffusion test system comprising:

a plurality of wells, each well having an open end and a blind end and having a 5 depth between the ends;

at least one elongate hollow plug, each plug comprising a wall running between first and second open ends and defining a cavity therein, each plug configured to be removably securely-insertable into a respective well, each plug having a length between the ends greater than the depth of the well; and io at least one magnetic agitator, each magnetic agitator configured to be receivable in a respective cavity.
2. A system according to claim l, wherein the plug includes a shelf inwardlyprojecting from the wall into the cavity for supporting the magnetic agitator.
3. A system according to claim l or 2, further comprising at least one cap, each cap configured to close the open end of a respective well.
4. A system according to any preceding claim, comprising a base plate, wherein the 20 bae plate comprises the plurality of wells.
5. A system according to any preceding claim, wherein each magnetic agitator includes a magnet which is arranged to be able to reciprocate axially in the plug.

25
6. A system according to any preceding claim, wherein each magnetic agitator comprises:

a plunger comprising the magnet disposed at an end of a rod; and a frame configured to span the cavity and which is positionable between the first and second ends of the plug, the frame including an axially-aligned guide for the rod.
7. A system according to claim 6, wherein the end of the rod is a first end and the magnet is a first magnet, wherein the rod includes a second end and wherein the plunger includes a second magnet disposed at the second end of the rod.

35 8. A system according to any preceding claim, wherein each magnetic agitator comprises a disc-shaped magnet.

-159- A system according to any preceding claim, wherein each plug has a length between the ends of the plug which is greater than the depth of the well

5 to. A system according to any preceding claim, wherein well and plug are cylindrical.

it. A system according to any preceding claim, wherein each cavity has a transverse area equal to or greater than o.i cm² and equal to or less than io cm².

io 12. A system according to any preceding claim, wherein each cavity has length equal to or greater than l cm and equal to or less than io cm.

13. A system according to any preceding claim, further comprising:

at least one membrane, each membrane having an area at least each to a 15 transverse area of the cavity and which is interposable between the blind end of a well and the first end of a plug.

14. A system according to claim 13, further comprising:

a portion of test product, each portion interposable between the blind end of the 20 well and the membrane.

15. A system according to claim 14 comprising, in one or more wells, test product disposed at the blind end of a respective well, a membrane in contact with and overlying the test product and a plug, the first end of the plug abutting the membrane.

16. A system according to claim 15, further comprising a respective agitator disposed in the cavity in the one or more wells.

17. A system according to claim 15 or 16, further comprising receptor solution 30 disposed in the cavity.

18. A system according to any preceding claim, wherein there are at least three wells, at least nine wells, at least 25 wells, at least 36 wells or at least 49 wells.

35 19. A system according to any preceding claim, further comprising:

a case for holding one or more sets of wells, the case comprising:

-ι6a housing defining a space;

a system for controlling the temperature of the space; one or more magnetic stirrers.

5 20. A system according to claim 19, wherein the temperature controlling system comprises a fan heater.

21. A method of performing a diffusion test using a system according to any preceding claim, the method comprising constructing an assembly:
10 providing a respective portion of test product in one or more wells;

providing a respective membrane over each test product portion in the one or more wells;

inserting a respective plug into in the one or more wells such that the first end of the plug abuts the membrane;
15 providing a respective magnetic agitator in the one or more wells; and providing receptor solution in the one or more wells.

22. A method according to claim 21, further comprising: placing the assembly in a temperature controlled housing.

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Application No: Claims searched:

GB1702956.2

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