WO2018131010A2

WO2018131010A2 - Dynamic chamber for in vitro permeability assays

Info

Publication number: WO2018131010A2
Application number: PCT/IB2018/052688
Authority: WO
Inventors: Antonio ARIAS; Audino MONTENEGRO; Sebastian VELARDE; Christian GÓMEZ
Original assignee: Absorption Systems
Current assignee: Absorption Systems
Priority date: 2018-04-13
Filing date: 2018-04-18
Publication date: 2018-07-19
Anticipated expiration: 2020-10-13
Also published as: WO2018131010A3

Abstract

The invention refers to a permeability dynamic chamber with a cylindrical shape having a rounded bend at its bottom together with a filter coupled by means of magnet fixing and protrusions at the sides thereof. Furthermore, the invention also refers to a gastrointestinal simulating device for in vitro permeability assays comprising a dynamic chamber being coupled thereto, in a set of four, to the cover of a standard dissolution vessel.

Description

Dynamic chamber for in vitro permeability assays

OBJECT OF THE INVENTION The present invention may be included in the technical field of health science, in particular in models for studying dissolution and absorption models occurring simultaneously in the stomach and intestine, such as in vitro permeability assays, in such a way that these are reproduced with higher accuracy.

BACKGROUND OF THE INVENTION

For most clinical indications, oral administration of medicaments is the most convenient and the one with best patient compliance. The medicaments administered orally in the solid form thereof (e.g., tablets and capsules) are disintegrated and dissolved in the stomach and are absorbed in the intestine.

Due to solubility and permeability of the active principles and the product dissolution, being key determinants for intestinal absorption, it is necessary to depend on in vitro tools for suitably obtaining these parameters, since these are extremely difficult to obtain in vivo. There are in vitro techniques for performing these measures; however the assays are performed independently to one another, so the data being obtained can rarely be extrapolated to clinical results.

Thus, there is a great need to develop systems that allow establishing a connection between the medicament properties and intestinal absorption of the active principles in vivo. The in vitro systems being commonly used for determining permeability require the compound to be applied as a solution or a suspension. Therefore, considering the previous documents it is necessary to find alternatives directed to quick, efficient and non-harmful for third parties assessment of drugs permeability in the organic system of an individual. DESCRIPTION OF THE INVENTION

The device of the invention allows concomitant assessment of (a) the dissolution characteristics of intact (without being milled or processed) tablets or capsules and in the actual clinical size thereof, and of (b) permeability of the active principles through a cell membrane.

As well as the application thereof for solid dosage forms in their original size, the device of the invention will simulate the gastrointestinal condition by using the expected dose/gastric volume ratio after swallowing the tablet or capsule with a glass of water, and after incorporation of the relevant physiological components (bile acid, taurocholic acid, in the mucosal chamber, and plasmatic protein, albumin, in the serum chamber).

The distinctive physiological significance of the device of the invention will lead to a higher and better in vivo performance of medicaments based on the in vitro dissolution and permeability assays results. Furthermore, it will cause a great positive impact on development and optimization of medicament formulations since the most novel molecules are Class 2 compounds (low solubility and high permeability), a type of compound which in general requires substantial efforts in their formulation, even when this does not guarantee success thereof. It will likewise allow assessment of the food effect on absorption of orally administered medicaments of Class 2.

Therefore, the device of the invention will have the following functions: (i) providing for understanding of the relationship between the medicament dissolution (tablet or capsule) and permeability of the active principle; (ii) reducing the number of assays performed in animals, such as dogs, for routine assessment of formulations, for which, furthermore, there are no possible alternatives; (iii) optimizing in vitro formulations for increasing the success probability in the bioequivalence studies; and (iv) assessing the food effect of food on absorption of the orally administered medicaments of Class 2, among others, given that the prior studies have found that the mostly used animal model, the dog, is not capable of suitable prognosis of the effect of food in humans.

Thus, a first aspect of the invention refers to a dynamic chamber for in vitro permeability assays characterized by having a cylindrical shape and comprising:

- a magnetized cover at the upper part thereof;

- a rounded bend at the bottom for facilitating stirring without affecting the experiment, and comprising at the end thereof, magnetized material used for fixing a filter without the risk of damaging it upon exerting inadequate pressure thereon, wherein the filter may be made of polycarbonate, a fabric or any other biomaterial, such that the biological permeability process can be produced, and

- a set of protrusions arranged at the side walls thereof, the purpose of which is to mitigate possible turbulence in the liquid in the dissolution vessel when the liquid is stirred by a stirring blade.

Furthermore, at the top there can be ducts for automatic liquid sampling and adding, the latter being proportional to that taken in said sampling. This liquid sampling and adding can be made by a conventional device designed for that purpose.

Fixing the filter by means of magnets is a safer mechanism, thus preventing thread-like fixing mechanisms from damaging said filters or the biomaterials.

Another aspect of the present invention refers to a simulating gastrointestinal device for in vitro permeability assays characterized in that it comprises: - a U-shaped dissolution vessel;

- a dissolution vessel cover divided into two parts attached to each other by means of a magnetized material and having suitable orifices for vertically accommodating and fitting at least two dynamic chambers, described in the present invention, thus being arranged inside the dissolution vessel, and

- a stirring blade located inside the dissolution vessel.

In a preferred embodiment of the device of the invention, the dissolution vessel cover accommodates four dynamic chambers and comprises, at the inner part thereof, anchoring orifices for the magnetized material of the chamber cover and two openings on the surface thereof.

DESCRIPTION OF THE DRAWINGS

FIG.1 It shows a front and side view of a dynamic chamber of the invention.

FIG.2 It shows a side and upper view of the configuration of the cover for accommodating four dynamic chambers.

FIG.3 it shows a cross-sectional view of the device of the invention.

PREFERRED EMBODIMENT OF THE INVENTION The following is a description of a preferred embodiment based on the attached figures.

FIG.1 This first image represents a general view of the dynamic chamber, in the most basic form thereof, and shows its main characteristics. It shows the chamber (1 ), the cover (2) with the magnetized material that will subsequently fix it to said cover (2) and that will also allow direct sampling (6a) with pipettes or any other device, the cover/washer (3) fixing the filters (3a) to the chamber with a magnetized material and the protrusions (4) intended for mitigating the possible turbulences in the liquid in the dissolution vessel once it starts being stirred. Furthermore, it shows the ducts (5) which will be in charge of adding sampled liquid and the ducts (6) in charge of removing said liquid so as to analyse it as a sample.

FIG.2 shows the cover configuration for accommodating four dynamic permeability chambers (7). This cover comprises two parts (9, 10), which are attached to each other by a magnetized material (1 1 ). The figure also shows the openings (8) the cover is provided with so as to perform a manual sampling.

FIG.3 This image shows the position of the cover (13) and the permeability dynamic chambers (1 ) in a dissolution vessel (14) in a cross-sectional view, as well as the stirring blade (15), typical of any standard dissolution apparatus, and the fixing points by means of a magnetized material of the chambers (12). Said figure also shows the expected level (16) of the liquid or fluid using the dissolution vessel. The following is a description of an example of a typical assay to be realized by the device of the invention:

Firstly, a significant amount of liquid is introduced at a pH being similar to that of the stomach (distilled water, in case of not using a biorelevant means, or any other biorelevant fluid with the suitable pH) in the dissolution vessel (14) until the level (16) indicated by the laboratory operator. In said liquid, the tablet or tablets of medicaments to be analysed and stirring is started by the standard stirring blade (15). When the operator, or the assay protocol, finds it adequate (based on time and stirring variables), the pH of the liquid is modified so as to adapt it to the conditions expected in the intestine. When the desired pH is stable, the permeability dynamic chambers (1 ) are introduced, having previously fitted therein filters or any other bio-material containing cells or tissues being the expected for the permeability process to be produced from the chamber outer side (17) or donor, to the inner side (17) or receptor. Meanwhile, stirring continues with the standard stirring blade (15). According to what is established by the assay protocol, sampling is performed at known intervals, using the inner ducts of the chamber (6) (for an automatic sampling process) or the upper opening of said chamber (6a) (for manual sampling). The operator shall also be able of taking samples from the donor side at previously established intervals thanks to the openings (8) that the dissolution vessel has. Once taken the sample from the receptor side, the same volume of liquid being removed is replaced through the inner ducts (5) which have been installed for that purpose in the chamber (in case of automatic addition of liquid), or using the opening at the top thereof (6a). This automatic sampling and adding process may be performed constantly, that is, simulating the bloodstream speed in the intestine. By performing the experiment in such a dynamic way, the results will be significantly more relevant, since these will be much more similar to the in vivo model.

Claims

C L A I M S

1. - Dynamic chamber for permeability assays in vitro characterized by having a cylindrical shape and comprising:

- a cover of magnetized material inside thereof;

- a rounded bend at the bottom, comprising at the end thereof a magnetized material used for fixing a filter without the risk of damaging it upon exerting inadequate pressure thereon, and

- a set of protrusions arranged at the side walls thereof.

2. - A gastrointestinal simulating device for in vitro permeability assays characterized by comprising:

- a U-shaped dissolution vessel;

- a dissolution vessel cover divided into two parts attached to each other by means of a magnetized material and having suitable orifices for accommodating and fitting between two and four chambers two chambers, as described in claim 1 , being arranged inside the dissolution vessel, and

- a stirring blade located inside the dissolution vessel.

3.- Device according to claim 2, where the dissolution vessel cover accommodates four dynamic chambers and comprises at the inner part thereof anchoring orifices for the magnetized material of the chambers and two openings at its surface.