EP4702337A1

EP4702337A1 - A device for placing a pharmaceutical form of a drug

Info

Publication number: EP4702337A1
Application number: EP24732765.3A
Authority: EP
Inventors: Marcela Staniszewska; Grzegorz Banach; Justyna Dobosz; Krzysztof OLBINSKI; Andrii RUDENKO; Micha SMOLENSKI; Bartosz KOLODZIEJ; Jadwiga Paszkowska; Grzegorz Garbacz
Original assignee: Physiolution Polska Sp ZOO
Current assignee: Physiolution Polska Sp ZOO
Priority date: 2023-04-28
Filing date: 2024-04-24
Publication date: 2026-03-04
Also published as: PL444690A1; WO2024224321A1

Abstract

The invention provides a device (1) for placing a pharmaceutical form of a drug, comprising a body (2) in a form of a tube (3) closed at both sides by perforated closures (4). Within the body (2) an elastic sleeve (5) is provided concentrically along its entire length, and in the wall of the body a through hole is arranged for supplying a pressurized fluid to create a space between the inner wall of the body (2) and the sleeve (5) as well as tightening of the sleeve (5) symmetrically around the tested form of the drug.

Description

A device for placing a pharmaceutical form of a drug

[0001] The subject of the invention provides a device for placing a solid pharmaceutical form of a drug for performing tests on dissolution of oral drugs.

[0002] Studies on release process of solid oral forms of a drug are aimed at determining the kinetics of active substance dissolution, under conditions similar to those that are present in the digestive tract, inter alia by means of the use of fluids having properties similar to the ones of the gastro-intestinal fluids (e.g., pH, surface tension). Standard apparatuses for release of a solid pharmaceutical form of a drug are not equipped with ability to stimulate mechanical stresses acting on form of the drug within the digestive tract, and these stresses considerably influence the active substance release process. Additionally, form of the drug, in standard apparatuses, is placed directly in a vessel or a metal drug holder, so called sinker, which prevents floatation of the form of the drug. Typically, the sinker is an element to ensure fixed position of the form of the drug in the release vessel, but it does not provide any mechanical pressure simulation functionality.

[0003] Studies on the release process of solid oral forms of a drug are conventionally carried out in normalized basket apparatuses of USP1 type, blade apparatuses of USP2 type, apparatuses of USP3 type with a movable cylinder, flow-based apparatuses of USP4 type and others.

[0004] Prior art flow-based USP4 type apparatuses for release of a solid pharmaceutical form of a drug are, among others, flow chambers. Some of the flow chambers simulate conditions prevalent within the digestive tract by applying a pressure having a physiological value, which is about 500 mbar, to the oral form of the drug. Standard chambers comprise a flow vessel with defined cross-section and rigid walls.

[0005] In the prior art pharmacopeial and non-compendial methods and apparatuses are known, which enable simulation of digestive tract conditions in laboratory conditions. An example is TIM (The TNO Gastro-Intestinal Model) available from TNO Pharma, being a multi-component model of a portion of the digestive tract of a human. Another prior art known apparatus is DGM (Dynamic Gastric Model) developed by Institute of Food Research (Norwich, Great Britain) that simulates operation of a stomach for studying impact of food present in the digestive tract on decomposition and dissolution of drugs and for determining the release profile. Other known apparatuses are: Gastric Flow Simulator (for imitation of stomach peristalsis and MMC waves), IMSPA simulator (simulation of small intestine peristalsis) and Advanced Gastric Simulator.

[0006] Also known from the prior art is ESIN (Engineered Stomach and small INtestine) model, in which a sinker in a form of a basket is used and a pharmaceutical form of a drug may be placed therein. The basket is perforated to enable contact of the form of the drug with the aforementioned fluids, and additionally, the basket may be fixed on a holder in an in vitro system. However, the sinker does not allow for applying any mechanical pressure to the form of the drug.

[0007] Also known from the prior art is Stress Test apparatus in which cyclic contractions are simulated and applied to a pharmaceutical form of a drug as well as periods when the form of the drug has no contact with intestine fluid. The apparatus uses a metallic basket provided with an inflatable balloon which at specific points in time is inflated and applies pressure to the form of the drug. During the pressing, some oral forms of the drug are gradually forced through the metallic basket and the basket itself causes pointwise cutting thereof, which is an undesirable effect. Additionally, the pressure is applied asymmetrically which causes bending of the form of the drug.

[0008] An exemplary patent application disclosing a holder for a form of a drug, having a form of a basket is the application US2010037713A1. The basket is made of materials which are able to withstand long-term exposure to acidic and basic pH with and/or without surfactants commonly used in pharmaceutical substance dissolution analysis. In this specification, sinkers are also disclosed, in a form of perforated tubes the function of which is weighting down a floating form of the drug (e.g., a capsule), with minimum possible obstruction of the release process. Such sinkers do not allow for a possibility to generate or transfer uniform mechanic pressure to be applied to the form of the drug. [0009] From the patent application US2010221838A1 a sinker (adapter) for in vitro release testing of dispersed pharmaceutical forms is known. The disclosed adapter is a container in a form of a cylinder with a lid and a base connected by posts, and a dialysis membrane is placed around the cylinder. The dialysis membrane is secured to the upper and lower portions of the cylinder and is tightly connected to the cylinder by means of rings having a circular crosssection. The dialysis membrane is made from a special material configured to enable flow of a dissolving agent and dissolved pharmaceutical form, and at the same time to prevent trespassing of the solid dispersed pharmaceutical form through the membrane.

[0010] The above presented sinkers and apparatuses as well as models enable dissolving a form of a drug, but they do not allow for simultaneous pressure application to the form of the drug, much less applying uniform pressure to the form of the drug. The subject invention enables uniform pressure effect on the form of the drug, which resolves the problem of nontransference of the pressure to the tested form of the drug and the problem of floating of the form of the drug and its unique positioning within the apparatus for release of a solid pharmaceutical form of the drug.

SUBJECT-MATTER OF THE INVENTION

[0011] A device for placing a pharmaceutical form of a drug, comprising a body in a form of a tube, closed at both sides, characterized in that at least one closure is releasably secured to the body and at least one closure is perforated, wherein within the body, concentrically along its entire length, an elastic sleeve is arranged within which the form of the drug is placed, wherein a through hole is provided in a wall of the body, for supplying a pressurized fluid between the inner wall of the body and the sleeve to create a space between the inner wall of the body and the sleeve, and tightening of the sleeve symmetrically around the tested form of the drug.

[0012] Preferably, the body, on its external wall, comprises an outwardly oriented tongue, perpendicularly to the central axis of the body and comprising a through channel which is coaxial with and connected to the through hole in the body.

[0013] Preferably, the tongue comprises a port for a fastening element. [0014] Preferably, the through channel is configured to receive a fastening element.

[0015] Preferably, the pressurized fluid is supplied via the through channel.

[0016] Preferably, at least one end of the elastic sleeve is turned outside onto the outer wall of the body of the device at the end of the body and is secured by means of at least one ring, wherein the ring is immobilized by the closure and the outer wall of the body.

[0017] Preferably, at least one closure is in a form of a cylinder closed at one side with a lid, and the cylinder has its internal diameter larger than the external diameter of the body.

[0018] Preferably, perforation of the closure has a form of at least one opening arranged in the lid.

[0019] Preferably, the device comprises two identical closures.

[0020] Preferably, at least one closure is mounted on the outer wall of the body by press-fit.

[0021] Preferably, at least one closure is mounted on the outer wall of the body by the means of a threaded connection.

[0022] Preferably, in the inner wall of the body, a cavity is provided on the entire perimeter thereof.

[0023] Preferably, the cavity is positioned symmetrically at the centre of the body.

[0024] Preferably, the length of the body is comprised between 15 mm and 100 mm, and preferably is 30 mm.

[0025] Preferably, the external diameter of the body is comprised between 10 mm and 50 mm, and preferably is 20 mm.

[0026] Preferably, the body is made of one of Teflon, PMMA, metal or glass.

[0027] Preferably, the elastic sleeve is made of latex.

[0028] Preferably, the pressurized fluid for the device is supplied by means of at last one of a valve, a pump, a compressor or a pressurized fluid cylinder.

[0029] Preferably, the pressure of the pressurized fluid is controlled by means of a regulator. [0030] Preferably, the device is configured so that it may be positioned in an apparatus for testing solubility of a pharmaceutical form of a drug.

[0031] The subject-matter is shown in the drawings in which: fig. 1 shows a device for placing a solid pharmaceutical form of a drug, in an isometric view; fig. 2 A shows a device for placing a solid pharmaceutical form of a drug, in a side view, with section planes A and B indicated therein; fig. 2B shows a cross-section of the device along the plane A of fig. 2A; fig. 3 shows a device in an embodiment with a fluid inlet and a fastening element mounted in the device, in an isometric view; fig. 4 shows the device of fig. 4 in an exploded view; fig. 5A shows a cross-section of the device along the plane B of fig. 2A, with an elastic sleeve without the pressurized fluid supplied; fig. 5B shows a cross-section of the device along the plane B of fig. 2A, with the elastic sleeve with the pressurized fluid partially supplied; fig. 5C shows a cross-section of the device along the plane B of fig. 2A, with the elastic sleeve, wherein the space between the elastic sleeve and the body is completely filled with the pressurized fluid; figs. 6A, 6B, and 6C show cross-sections of the device, corresponding to the ones of figs. 5A, 5B, and 5C of the device in the embodiment with a cavity arranged in the central portion of the tube on the inner wall of the body.

[0032] In an embodiment, as shown in fig. 1, a device 1 for placing a pharmaceutical form of a drug, which may be used in apparatuses for testing solubility of the pharmaceutical form of the drug, comprises a body 2 in a form of a tube closed at both sides with closures 3 which are releasably connected to the body 2 and thus it is possible to introduce tested pharmaceutical form of the drug into the body 2. In another embodiment, only one closure 3 is releasably connected to the body 2 while the other closure 3 is fixedly connected to the body 2. The closures 3 are perforated, and more specifically, they have a form or cylinders with an internal diameter larger than the external diameter of the body 2. Each cylinder is closed at one side with a lid in which there are four openings to enable flow of a fluid in which the tested pharmaceutical form of a drug is released, which is a fluid that simulates the fluid present in the target environment for the drug form release. In other embodiments, the number of openings may be different and may be 3, for example. In further embodiments, the closures 3 have a different form than a cylinder with a lid. The closures 3 do not have to be identical. [0033] Within the body 2, concentrically along its entire length, an elastic sleeve 4 is arranged within which the form of the drug is to be placed.

[0034] In a wall of the body 2 a through hole 5.1 is provided for supplying a pressurized fluid, between the inner wall of the body 2 and the sleeve 4, for example a pressurized gas, preferably such as air. Supplying of the fluid causes that a space 6 is created between the inner wall of the body 2 and the sleeve 4 as well as tightening of the sleeve 4 symmetrically around the tested form of the drug .

[0035] In the embodiment shown in fig. 1, device 1 comprises, on the outer wall of the body 2, a tongue 7 comprising a through channel 5.2 that is connected to the through hole 5.1 in the body 2 and a port 8 for a fastening element, for securing the device 1 in the apparatuses for testing solubility of drugs, such as in flow chambers, for example, and there are numerous ways for securing the device 1 in the apparatuses for testing solubility.

[0036] Fig. 2A shows that the tongue 7 is oriented outwardly from the tube-shaped body 2, perpendicularly to the central axis of the body 2, wherein the central axis of the body 2 is concurrent with the cross-section plane B indicated in fig. 2A. In fig. 2B it is shown that the tongue 7 comprises a through channel 5.2 connected to the through hole 5.1 in the body and a port 8 for a fastening element.

[0037] In an alternative embodiment shown in figs. 3 and 4 the tongue 7 may comprise a through channel 5.2 mounted concentrically with the through opening 5.1, without a separate port 8 for fastening element. Then, the through channel 5.2 is configured to receive the fastening element. Preferably, in this variant, the through channel 5.2 may be positioned in the central part of the tongue 7. This example is applicable to apparatuses in which it is possible to connect the device 1 to a source of pressurized fluid, for example air.

[0038] Pressurized fluid may be supplied via the through channel 5.2 and the through opening 5.1 to create a sealed space 6 between the inner wall of the body 2 and the elastic sleeve 4 and tightening of the sleeve 4 symmetrically around tested form of the drug, as shown in figs. 5 A, 5B, 5C, 6A, 6B, and 6C.

[0039] In fig. 5A device 1 is shown upon introduction of pharmaceutical form of a drug, but before supplying pressurized fluid, and thus the elastic sleeve 4 is in its non-stretched state and remains at rest, and then it may be in contact with the inner wall of the body 2, and the pharmaceutical form of the drug is surrounded by free space.

[0040] In fig. 5B device 1 is shown during introduction of pressurized fluid between the inner wall of the body 2 and the elastic sleeve 4 to create space 6 between the inner wall of the body 2 and the sleeve 4 and stretching and symmetrical tightening of the sleeve 4 around the tested from of the drug . With the space 6 between the inner wall of the body 2 and the sleeve 4 enlarging, the free space around the pharmaceutical form of the drug decreases, and as a result the sleeve 4 begins to uniformly apply pressure to the form of the drug.

[0041] In fig. 5C a device 1 is shown with a maximum possible stretching of the elastic sleeve 4, the sleeve 4 being in direct contact with the tested form of the drug.

[0042] In the cross-section in fig. 5A-C pharmaceutical form of the drug positioned within the body 2 can be seen. The elastic sleeve 4 is arranged within the body 2, concentrically along its entire length. Each of the ends of the elastic sleeve 4 is turned outwards onto the outer wall of the body 2 of the device 1 at the end of the body 2 and secured by means of a ring 9. Rings 9 are fixed by closures 3 and the outer wall of the body 2, so that the closures 3 of the device 1 are superimposed on the rings 9, which closures 3 additionally hold the sleeve 4 in place.

[0043] In one embodiment, each of the ends of the elastic sleeve 4 is secured by means of two rings 9.

[0044] In one embodiment, closures 3 are releasably superimposed on the body 2, the sleeve 4 and the rings 9 by press-fit.

[0045] Alternatively, closures 3 may comprise threads at their inner side, on the sides of their cylindrical parts. In such a case, on the outer side of the body 2, on its both ends, threads are provided suitable for connection with the threads of the closures 3. Then the sleeve 4 on the portions that are turned outwards has a form suitable to be fitted into the threads, between the body 2 and the closures 3, and in a possible embodiment, on the elastic sleeve 4 on the sleeve portions that are turned outwards onto the body 2, grooves are arranged which are configures to receive the rings 9.

[0046] With the threaded side wall of the body 2, the device 1 may be connected to means for providing medium (fluid) for the release of the drug, such as a pump, which allows for creation of a flow chamber for testing the release of the active pharmaceutical form of the drug. This means that then the device 1 does not constitute a complementary element for the USP 2 type apparatus but - in combination with means to provide a uniform temperature of the medium (preferably, a water bath), with means to supply medium at a predefined flow rate (preferably, a pump) and to discharge the medium from the device 1 - may define an autonomous apparatus for testing oral drug forms. In this embodiment, the device 1 does not have to contain port 8 for the fastening element.

[0047] In figs. 6A-C, a device 1 is shown in another embodiment, wherein in the inner wall of the body 2 , a cavity 10 is provided on the entire perimeter thereof, preferably positioned symmetrically at the centre of the body 2. Due to the cavity 10, if a negative pressure is generated within the space between the inner wall of the body 2 and the elastic sleeve 4, for example by means of a vacuum pump or a Bernoulli reducing tube, the elastic sleeve 4 will stick to the inner wall of the body 2 and the form of the drug will place itself inside the created space and thus the exact place of the form of the drug will coincide the cavity. Figs. 6A-C show a device 1 in situations analogous to the ones described above for figs. 5A-C.

[0048] The size of the device 1 is such that it enables free introduction thereinto of any solid standard pharmaceutical form of a drug to be orally administered, intended for dissolution.

[0049] In embodiments, the length of the body 2 is comprised between 15 mm and 100 mm, and preferably is 30 mm.

[0050] In further embodiments, the external diameter of the body 2 is comprised between 10 mm and 50 mm, and preferably is 20 mm. [0051] The body 2 of the device 1, in embodiments, is made of Teflon or PMMA or a metal or glass.

[0052] The elastic sleeve 4 in an embodiment is made of latex.

[0053] Pressurized fluid is supplied to the device 1 by means of any machine capable to supply pressurized fluid, from which fluid is supplied via standard connections such as pipes or hoses, to the through channel 5.2 of the device 1. Preferably, in the embodiments, the fluid is supplied by means of a valve or a pump or a compressor or a pressurized fluid cylinder.

[0054] In the embodiments, the pressure of the pressurized fluid is controlled by means of a regulator.

[0055] Embodiments herein are provided solely as non-limiting indications relating to the invention and they cannot limit in any way the scope of protection which is defined by the patent claims. It should be understood that each of the technical solutions used in the device according to the invention may be embodied by means of equivalent technologies without going beyond the scope of protection. All terms used in the specification are purely explanatory, to enable understanding of the spatial arrangements in the invention and by no means can limit the scope of protection provided in the patent claims.

Claims

1. A device (1), for placing a pharmaceutical form of a drug, comprising a body (2) in a form of a tube, closed at both sides, characterized in that at least one closure (3) is releasably secured to the body (2) and at least one closure (3) is perforated, wherein within the body (2), concentrically along its entire length, an elastic sleeve (4) is arranged within which the form of the drug is placed, wherein a through hole (5.1) is provided in a wall of the body (2), for supplying a pressurized fluid between the inner wall of the body (2) and the sleeve creating a space (6) between the inner wall of the body (2) and the sleeve (4) and tightening the sleeve (4) symmetrically around the tested form of the drug .

2. The device ( 1 ) according to claim 1 , characterized in that the body (2), on its outer wall, comprises a tongue (7) oriented outwardly, perpendicularly to the central axis of the body (2) and comprising a through channel (5.2) which is coaxial with and connects to the through hole (5.1) in the body.

3. The device (1) according to claim 2, characterized in that the tongue (7) comprises a port (8) for a fastening element.

4. The device (1) according to claim 2, characterized in that the through channel (5.2) is configured to receive the fastening element.

5. The device (1) according to claim 2, characterized in that the pressurized fluid is supplied via the through channel (5.2).

6. The device (1) according to any one of claims 1-5, characterized in that at least one end of the elastic sleeve (4) is turned outwards onto the outer wall of the body (2) of the device (1) at the end of the body (2) and is secured by means of at least one ring (9), wherein the ring (9) is immobilized by the closure (3) and the outer wall of the body (2).

7. The device (1) according to any one of claims 1-6, characterized in that at least one closure (3) is in a form of a cylinder closed at one side with a lid, and the cylinder has an internal diameter larger than the external diameter of the body (2).

8. The device (1) according to any one of claims 1-7, characterized in that perforation of the closure (3) is in a form of at least one opening arranged in the lid.

9. The device (1) according to any one of claims 1-8, characterized in that it comprises two identical closures (3).

10. The device (1) according to any one of claims 1-9, characterized in that at least one closure (3) is mounted on the outer wall of the body (2) by press-fit.

11. The device (1) according to any one of claims 1-9, characterized in that at least one closure (3) is mounted on the outer wall of the body (2) by the means of a threaded connection.

12. The device (1) according to any one of claims 1-11, characterized in that in the inner wall of the body (2), a cavity (10) is provided on the entire perimeter thereof.

13. The device (1) according to claim 12, characterized in that the cavity (10) is positioned symmetrically at the centre of the body (2).

14. The device (1) according to any one of claims 1-13, characterized in that the length of the body (2) is comprised between 15 mm and 100 mm, and preferably is 30 mm.

15. The device (1) according to any one of claims 1-14, characterized in that the external diameter of the body (2) is comprised between 10 mm and 50 mm, and preferably is 20 mm.

16. The device (1) according to any one of claims 1-15, characterized in that the body (2) is made of one of Teflon, PMMA, metal or glass.

17. The device (1) according to any one of claims 1-16, characterized in that the elastic sleeve (4) is made of latex.

18. The device (1) according to any one of claims 1-17, characterized in that the pressurized fluid for the device (1) is supplied by means of at least one of a valve, a pump, a compressor or a pressurized fluid cylinder.

19. The device (1) according to any one of claims 1-18, characterized in that the pressure of the pressurized fluid is controlled by means of a regulator.

20. The device (1) according to any one of claims 1-19, characterized in that it is configured to be positioned within an apparatus for testing solubility of a pharmaceutical form of a drug.