In vitro release testing (IVRT) apparatus for orally inhaled drug products

Abstract

An in vitro release testing (IVRT) device for an orally inhaled drug product, used in an IVRT instrument, the device comprising an air permeable filter (F) loaded with particulate material representing a certain dose of the orally inhaled drug product, the device comprising: an upper filter support element (130; 230; 330) and a lower filter support element (140; 240; 340), the loaded filter (F) being circumferentially retained between the upper support element and the lower support element, a filter cover (120; 220; 320), covering the upper surface of the loaded filter (F), and a filter cover retainer (110; 210; 310), configured to assemble and seal the IVRT device.

Description

Technical Field

[0001] The present invention relates to an in vitro release testing (IVRT) device for orally inhaled pharmaceutical products. Background Art

[0002] In vitro release testing (IVRT) has been commonly used to measure the release and diffusion of locally acting semisolid dosage forms for topical-based products. The release profile enables the determination of the in vitro release rate (IVRR), a kinetic parameter that provides critical quality attributes regarding the physical and chemical properties of the active pharmaceutical ingredient and the microstructural characteristics of the formulated product. Although IVRT has been widely recognized in the research community and shares the same basic principles as the pharmacopoeial dissolution method for orally administered dosage forms, regulatory agencies have recently begun to address the application and validation of IVRT as an alternative bioequivalence assessment tool for locally acting topical drug products. In 2016, the U.S. Food and Drug Administration (FDA) drafted guidance on the development and validation of IVRT testing methods for 5% acyclovir cream.

[0003] These IVRT key tests need to be performed in accordance with the United States Pharmacopeia (USP) general chapters. <1724> These include different models of vertical diffusion cells (VDCs), immersion cells, and flow-through cells for use with USP Apparatus 4. These systems are Figures 1 to 3 Shown in.

[0004] The most common IVRT technique is the vertical diffusion cell (VDC) system, or more commonly known as a Franz cell, such as Figure 1 As shown, it consists of two chambers (donor chamber and receptor chamber), which are separated by a film used as a physical barrier for diffusion. The ideal film needs to have minimum resistance to the mass transfer of the drug, no drug binding and minimum thickness. The VDC chamber is held together by a fixture, a screw cap or other device. For most semi-solid dosage tests, the sample of a specified amount is located on a synthetic inert film contained in the sample chamber cavity closed with a glass support plate. During the test, the receptor medium is maintained at a constant temperature and maintained under sink conditions.

[0005] The in vitro release rate can also be measured using Figure 2 The immersion cell type apparatus is shown. This system is based on the method of the USP paddle-over-disk apparatus V for testing transdermal patches, in which a Teflon cell is placed at the bottom of the dissolution vessel. The cell keeps the dosage form and receptor medium separated from the receptor medium by a synthetic membrane.

[0006] The third method is based on Figure 3USP 4 flow cell apparatus shown, where the sample is contained in a small insert cell containing a reservoir and a ring for holding the synthetic membrane. Reservoirs of different sizes are available to accommodate different volumes of semi-solid products. The cell is inserted into the USP 4 flow cell with the membrane facing downwards and the prepared cell is inserted into the heating mantle. The freed reservoir volume needs to be appropriate to achieve sink conditions and ensure precision of the analytical method.

[0007] The general principles of these techniques are very similar, requiring separation of the drug receptor and receptor compartment by an installed synthetic membrane with exposed orifices of known diffusion area for drug release. Summary of the invention

[0008] It is an object of the present invention to adapt the above system to accept a representative aerosol dose for release testing of any orally inhaled pharmaceutical product.

[0009] It is also an object of the present invention to provide an IVRT apparatus which is simple and inexpensive to manufacture and assemble and which is easy to use in a reliable manner.

[0010] Thus, the present invention provides an in vitro release test (IVRT) device for an orally inhalable pharmaceutical product for use in an IVRT apparatus, the device comprising an air permeable filter loaded with a particulate material representing a dose of the orally inhalable pharmaceutical product, the device comprising:

[0011] - an upper filter support element and a lower filter support element, the loaded filter being circumferentially held between the upper support element and the lower support element,

[0012] - a filter cover covering the upper surface of the loaded filter, and

[0013] - A filter cover holder provided for assembling and sealing the IVRT device.

[0014] Advantageously, the device further comprises: a retainer member accommodating the lower filter support element and cooperating with the filter cover retainer for a sealed assembly of the IVRT device.

[0015] Advantageously, a mesh is provided between the lower filter support element and the loaded filter to cover a lower surface of the loaded filter.

[0016] Advantageously, the filter cover retainer comprises feet providing a bayonet type fit on the retainer member.

[0017] Advantageously, the filter cover retainer cooperates directly with the lower filter support element for sealed assembly of the IVRT device.

[0018] Advantageously, the filter is selected from the group consisting of a woven fabric, a nonwoven fabric, a mesh and a breathable membrane.

[0019] Advantageously, the filter comprises a fabric formed from glass microfibers, a synthetic cellulose-based material, or a fabric formed from filaments of a polymeric material selected from polycarbonate, polyester, polyolefin, polyamide, polyvinyl chloride and polyetheretherketone.

[0020] Advantageously, the filter comprises a metal mesh, such as a stainless steel mesh.

[0021] Advantageously, the filter has a pore size of no greater than 5 μm, preferably no greater than 3 μm.

[0022] Advantageously, the filter has a pore size of at least 1 μm.

[0023] Advantageously, the filter has an air permeability such that the filter produces a flow rate reduction of no more than 20%, preferably no more than 15%, more preferably no more than 10% relative to the absence of the filter. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Certain embodiments of the invention will now be described with reference to the accompanying drawings, given as non-limiting examples, in which:

[0025] Figure 1 is a schematic diagram of a vertical diffusion cell system;

[0026] Figure 2 is a schematic diagram of an immersion tank type instrument;

[0027] Figure 3 is a schematic diagram of the USP 4 flow cell instrument;

[0028] Figure 4 is a cross-sectional view of a dose collection device according to an advantageous embodiment;

[0029] Figure 5 yes Figure 4 A magnified view of detail D1;

[0030] Figure 6 is a schematic exploded perspective view of an IVRT device according to a first advantageous embodiment of the present invention;

[0031] Figure 7 Shown by Figure 6 Cross section of the IVRT device;

[0032] Figure 8 shows a schematic exploded perspective view of an IVRT device according to a second advantageous embodiment of the present invention;

[0033] Fig. 9shows a schematic exploded perspective view of an IVRT device according to a third advantageous embodiment of the present invention;

[0034] Figures 10 to 18 A schematic diagram showing the steps for dose collection;

[0035] Figures 19 to 21 Shown is the Figure 6 and Figure 7 A schematic diagram of the steps of transferring a loaded filter in an IVRT apparatus is shown;

[0036] Fig. 22 and Fig.23 yes Figure 6 and Figure 7 The IVRT device is placed in Figure 2 Schematic diagram of the immersion tank apparatus shown;

[0037] Fig.24 yes Figure 8 The IVRT device is placed in Figure 1 The schematic diagram of the VDC instrument shown; and

[0038] Fig.25 yes Fig. 9 The IVRT device is placed in Figure 3 Schematic diagram of the USP 4 flow cell instrument shown. DETAILED DESCRIPTION

[0039] The present invention utilizes an instrument for collecting particles of an inhalable formulation. Document WO2017051180A1 discloses such an instrument, which is incorporated herein by reference.

[0040] The instrument of WO2017051180A1 comprises a dose collection part comprising a filter F. The filter F is arranged orthogonally with respect to the flow direction of the pneumatic flow downstream of the orifice. Advantageously, at the point of collision with the filter, the condition is a relatively uniform and low-speed pneumatic flow.

[0041] exist Figure 4 and Figure 5 An advantageous embodiment of the dose collecting part 10 is shown in FIG.

[0042] Figure 4 The dose collecting device 10 from Figure 4 From top to bottom, it includes an upper adapter element 20, an upper body 30, a filter unit 40, a lower body 50 and a clamping device 60 for clamping the upper body and the lower body together.

[0043] The upper body 30 comprises a funnel 31 defining an inlet aperture 32. The funnel 31 is tapered to reduce the presence of sharp edges that may cause turbulence, and is arranged to convey the fluid flow into a clear vertical path extending downwardly from the aperture 32 towards the filter unit 40.

[0044] The filter F is supported by a filter unit 40 which will be described in more detail below.

[0045] The area of ​​the apertures 32 is similar to but slightly smaller than the exposed area of ​​the filter F where deposition occurs.

[0046] exist Figure 4 and Figure 5 In the embodiment, a suction source (not shown) is pneumatically connected to the filter F on the side remote from the orifice 32 and is used to draw air through a path including the orifice 32 and to draw the filter F in a downward direction.

[0047] A flow controller (not shown) may be associated with the suction source for maintaining proper flow conditions.

[0048] The lower body 50 accommodates the filter unit 40 on its top surface. Fig.15 As shown, the top surface includes an O-ring 70, which provides a main gas path seal of the instrument when clamped. The top surface also includes a first recess 51 to provide rotational alignment of the filter unit 40 on the lower body 50. A second recess 52 is provided to allow the filter unit 40 to be manually, semi-automatically or automatically extracted from the lower body 50 when the clamping device 60 is released.

[0049] The filter F may be any filter suitable for retaining particles up to 5 μm, for example in the range of 0.5 μm to 5 μm. For example, a filter with a pore size of up to 3 μm may be used.

[0050] Advantageously, the filter has such air permeability that the filter produces a flow rate reduction of no more than 20%, preferably no more than 15%, more preferably no more than 10% compared to the flow rate without the filter.Such a filter may, but need not, have a pore size of at least 1 μm.

[0051] For example, the filter can be selected from woven fabrics, nonwoven fabrics, nets and breathable membranes. In some embodiments, the filter includes a fabric formed by glass microfibers or by filaments of a polymeric material selected from polycarbonate, polyester, polyolefin, polyamide (e.g., nylon), acrylic resin, acrylic copolymer, polyvinyl chloride and polyetheretherketone. For example, suitable polyolefins include polyethylene, polypropylene and copolymers of ethylene and propylene with one or more other monomers. The filter can also include synthetic cellulose-based materials, for example, cellulose acetate, cellulose nitrate and mixed cellulose ester synthetic membranes.

[0052] Suitable glass microfibers include, for example, borosilicate glass, such as A / E type glass fiber filters commercially available from Pall Corporation in the United States, which have a nominal pore size of 1 μm. Examples of suitable polymer filters include acrylic propylene filters with a pore size of 3 μm or less, such as those with pore sizes of 0.2 μm, 0.45 μm, 0.8 μm, 1.2 μm, and 3 μm. Polymeric filters of polyamide or polyvinyl chloride with a nominal pore size of 3 μm or less are also widely available. This is also true for cellulose-based membranes.

[0053] In other embodiments, the filter comprises a metal mesh, for example a stainless steel mesh, which advantageously has a pore size of less than 3 μm.Other suitable materials include, for example, polymer membranes, provided they have a suitable level of gas permeability.

[0054] After using the dose collection device, the filter F containing the collected particles is subjected to IVRT and thus needs to be transferred to a corresponding IVRT instrument using an IVRT device.

[0055] Figures 6 to 9 Three embodiments of an IVRT device according to the present invention are shown.

[0056] Figure 6 and Figure 7 A first embodiment is shown, in which the IVRT device 100 is suitable for Figure 2 Immersion tank apparatus shown.

[0057] Figure 8 A second embodiment is shown, in which the IVRT device 200 is suitable for Figure 1 VDC instrument shown.

[0058] Fig. 9 A third embodiment is shown, in which an IVRT device 300 is suitable for Figure 3 USP 4 flow cell apparatus shown.

[0059] The IVRT device 100 according to the first embodiment includes a filter cover holder 110 , a filter cover 120 , an upper filter support element 130 , a filter F, a lower filter support element 140 , a net 145 interposed between the filter F and the lower filter support element 140 , and a holder member 150 .

[0060] The IVRT device 200 according to the second embodiment includes a filter cover holder 210 , a filter cover 220 , an upper filter support member 230 , a filter F, a lower filter support member 240 , a holder member 250 , and an O-ring 260 .

[0061] The IVRT device 300 according to the third embodiment includes a filter cover holder 310 , a filter cover 320 , an upper filter support member 330 , a filter F, and a lower filter support member 340 .

[0062] Figures 10 to 18 The basic steps involved in dose collection for all three IVRT devices using the above described dose collection device 10 are shown. At dose collection, there are different options for sealing membranes depending on the IVRT device to be used, which will be described in detail later.

[0063] like Figures 10 to 18 The steps for processing the filter F are shown in relation to the lower body 50 and are shown from above the lower body. The steps are the same for all three IVRT devices.

[0064] Fig.10 The lower body 50 is shown viewed from above and has a first recess 51 and a second recess 52 .

[0065] Fig.11 A lower body 50 is shown provided with a filter base which is either permanently bonded to the lower body 50 or which can be assembled to or removed from the lower body.

[0066] Fig.12 A lower filter support element 140 is shown added to the filter base.

[0067] Fig.13 A filter F is shown added to the lower filter support element.

[0068] Fig.14 An upper filter support element 130 added to the filter F is shown.

[0069] Fig.15 The assembly and clamping of the upper body 30 on the lower body 50 is shown, compressing the O-ring 70 and retaining the filter F in its dose collecting position. In this position, the dose collecting device 10 can be used to collect doses on the filter F as described above.

[0070] Fig.16 The device is shown after the upper body 30 has been removed, thus Fig.14 Similar to , but filter F is loaded with particles.

[0071] Fig.17 A filter cap 120 is shown fitted onto the drug coated filter F to enclose and protect the collected dose.

[0072] Fig.18The lower body 50 is shown removed with the filter base if not incorporated into the lower body. Fig.18 As shown, this step is accomplished by turning the lower body upside down.

[0073] At this stage, there remains a unit formed by the lower filter support element 140, the loaded filter F, the upper filter support element 130 and the filter cover 120. This unit is then placed in an IVRT device for use in a corresponding IVRT instrument.

[0074] Figures 19 to 21 Shows how to target Figure 2 Immersion cell apparatus assembly shown. Fig.19 is seen from below, and Fig. 20 and Fig.21 is seen from above. The unit formed by the lower filter support element 140, the loaded filter F, the upper filter support element 130 and the filter cover 120 is positioned in the holder member 150 by adding a suitable mesh 145. The filter cover holder 110 includes three legs and has a spring 111 to control the compressive load between the holder member 150, the lower filter support element 140, the filter F, the upper filter support element 130 and the filter cover 120. The filter cover holder 110 clamps the assembly together and ensures that the drug coated filter F is enclosed by the receptor medium in the dissolution vessel and can therefore be fully immersed. Fig.21 As shown, the filter cover retainer 110 is assembled onto the retainer member 150 and rotated to seal the assembly via a well-known bayonet fitting.

[0075] like Fig. 22 and Fig.23 As shown, the assembled cell can then be inserted into the dissolution vessel. The outer dimensions and pitch of the retainer member 150 are designed to be located in a horizontal position within the glass container relative to the curvature of the container. This enables control of the correct height of the cell within the container and ensures alignment of the cell surface relative to the stirring paddle of the immersion cell instrument.

[0076] Fig.24 Involving Figure 8 The VDC instrument of the IVRT device. Fig.24 This enables the enclosed cell to be inserted directly into contact with the receptor medium in a jacketed vertical diffusion cell as shown. Diffusion communication occurs between the enclosed aerosol dose and the reservoir through the contact of the receptor medium with the filter. It should be noted that the diameters of the exposed filter, donor chamber, and receptor chamber, which define the dose delivery surface area for testing, need to be similar and within ±5% of the specified diameter.

[0077] Fig.25 Involving Fig. 9The USP 4 flow cell apparatus of the IVRT device of FIG. The holder assembly of the USP 4 flow cell is completely different from the other two assemblies described above. It has a different lower filter support element 340 (which has three parts for clamping) in the lower air chamber, capable of clamping and enclosing an aerosol dose without a holder member. Fig.25 The assembled and sealed insert cell in a USP 4 flow cell is shown in FIG. When the assembly is sealed and closed, the area for initial alignment of the three-legged clamp allows sufficient clearance for the flow of the receptor medium (in either an open or closed system) to contact the diffusion area of ​​the exposed filter and discharge the continuous flow through the top of the USP 4 cell.

[0078] In the foregoing description, reference is made to wholes or elements that have known, obvious or foreseeable equivalents, and these equivalents are incorporated herein as if set forth separately. Reference should be made to the claims for determining the true scope of the invention, which should be interpreted as including any such equivalents. The reader will also understand that wholes or features of the invention described as preferred, advantageous, convenient, etc. are optional and do not limit the scope of the independent claims. In addition, it should be understood that such optional wholes or features, although they may have benefits in some embodiments of the invention, may not be ideal in other embodiments and therefore may not exist.

Claims

1. An IVRT device for in vitro release testing of an orally inhaled pharmaceutical product, for use in an IVRT apparatus, the device comprising an air permeable filter (F) loaded with a particulate material representing a dose of an orally inhaled pharmaceutical product, the device comprising: - an upper filter support element (130; 230; 330) and a lower filter support element, between which the loaded filter (F) is circumferentially held, - a filter cover (120; 220; 320) covering the upper surface of the loaded filter (F), and - A filter cover retainer, arranged for assembling and sealing the IVRT device, the filter cover retainer having a spring to control the compressive load between the lower filter support element, the filter (F), the upper filter support element (130; 230; 330) and the filter cover (120; 220; 320).

2. The apparatus according to claim 1, further comprising: A retainer member (150; 250) receives the lower filter support element and cooperates with the filter cover retainer for a sealed assembly of the IVRT device.

3. The device according to claim 2, wherein: A net (145) is disposed between the lower filter support element and the loaded filter (F) to cover a lower surface of the loaded filter.

4. The device according to claim 2 or claim 3, wherein: The filter cover retainer includes feet that provide a bayonet-type fit on the retainer member (150; 250).

5. The device according to claim 1, wherein: The filter cover retainer mates directly with the lower filter support element for sealed assembly of the IVRT device.

6. The device according to claim 1 or 2, wherein: The filter (F) is selected from the group consisting of woven fabrics, nonwoven fabrics, nets and breathable films.

7. The device according to claim 6, wherein: The filter (F) comprises a fabric formed of glass microfibers, a synthetic cellulose-based material, or a fabric formed of filaments of a polymeric material selected from the group consisting of polycarbonate, polyester, polyolefin, polyamide, polyvinyl chloride and polyetheretherketone.

8. The device according to claim 6, wherein: The filter (F) comprises a metal mesh.

9. The device according to claim 1 or 2, wherein: The filter (F) has a pore size of not more than 5 μm.

10. The device according to claim 9, wherein: The filter (F) has a pore size of not more than 3 μm.

11. The device according to claim 1 or 2, wherein: The filter (F) has a pore size of at least 1 μm.

12. The device according to claim 1 or 2, wherein: The filter (F) has an air permeability such that the filter produces a flow rate reduction of no more than 20% relative to the absence of the filter.

13. The device according to claim 12, wherein: The flow rate is reduced by no more than 15%.

14. The device according to claim 13, wherein: The flow rate is reduced by no more than 10%.

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