Methods And Apparatus For The In Vitro Modelling Of Drug Administration

• US 20150247864A1
• Filed: 10/03/2013
• Published: 09/03/2015
• Est. Priority Date: 10/04/2012
• Status: Active Grant

• Current Assignee: University of Bath
• Original Assignee: University of Bath
• Inventors: Mrsny, Randall Jay, Kinnunen, Hanne Maarit
• Granted Patent: US 9,733,254 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: G01N 13/00 Investigating surface or boundary effects, e.g. wetting power; Investigating diffusion effects; Analysing materials by determining surface, boundary, or diffusion effects scanning-probe techniques or apparatus G01Q
• CPC Class Codes: G01N 2013/003 Diffusion; diffusivity between liquids
• CPC Class Codes: G01N 2013/006 Dissolution of tablets or the like
• CPC Class Codes: G01N 21/64 Fluorescence; Phosphorescence
• CPC Class Codes: G01N 21/65 Raman scattering
• CPC Class Codes: G01N 2570/00 Omics, e.g. proteomics, glycomics or lipidomics; Methods of analysis focusing on the entire complement of classes of biological molecules or subsets thereof, i.e. focusing on proteomes, glycomes or lipidomes
• CPC Class Codes: G01N 33/15 Medicinal preparations ; Physical properties thereof, e.g. dissolubility drug screening with animal cells G01N33/5008
• CPC Class Codes: G01N 33/50 Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing measuring or testing processes involving enzymes or microorganisms, compositions or test papers therefor; processes for forming such compositions, condition responsive control in microbiological or enzymological processes C12Q
• CPC Class Codes: G01N 33/6842 Proteomic analysis of subsets of protein mixtures with reduced complexity, e.g. membrane proteins, phosphoproteins, organelle proteins

Abstract

Methods and apparatus for the in vitro modelling of changes that occur on administration of a drug formulation are described, in particular for studying the changes that take place on administration of protein or peptide drug formulations by subcutaneous injection.

Claims

1. An in vitro method of determining a change in a property of a drug formulation that occurs on administration, the method employing an apparatus that comprises:

a membrane cassette comprising a chamber having a membrane, the membrane having perforations through which components of the drug formulation are capable of diffusing for simulating changes that occur on administration of the drug formulation, wherein the chamber of the membrane cassette contains one or more components found in the site of administration for simulating conditions at the site;

a bath for containing the membrane cassette and a surrounding liquid medium;

a probe capable of detecting a change in a property of the drug formulation inside the membrane cassette, and optionally a change in a property of the drug formulation in the bath,

wherein the method comprises the steps of;

(a) arranging the membrane cassette in the bath;

(b) introducing the drug formulation into the chamber of the membrane cassette;

(c) optionally changing one or more components or conditions of the drug formulation or the liquid medium; and

(d) determining the change of the property of the drug formulation using the probe.

2. An apparatus for determining a change in a property of a drug formulation that occurs on subcutaneous administration, the apparatus comprising:

a membrane cassette comprising a chamber having a membrane, the membrane having perforations through which components of the drug formulation are capable of diffusing for simulating changes that occur on administration of the drug formulation, wherein the chamber of the membrane cassette contains one or more components found in the site of administration for simulating conditions at the site;

a bath for containing the membrane cassette and a surrounding liquid medium;

a probe capable of detecting a change in a property of the drug formulation inside the membrane cassette, and optionally a change in a property of the drug formulation in the bath,

wherein in use the membrane cassette is arranged in the bath and the drug formulation is introduced into the chamber of the membrane cassette thereby enabling changes in the property of the drug formulation to be determined using the probe.

3. The apparatus of claim 2, wherein the administration is by subcutaneous, intramuscular, intradermal, intrathecal or epidural routes.

4. The apparatus of claim 2, wherein the membrane cassette is adapted for modelling administration of a drug formulation to the eye, wherein the chamber of the membrane cassette contains one or more hydrogels for modelling the vitreous humour of the eye and a membrane for modelling the sclera and retina, optionally wherein the hydrogels comprise collagen and hyaluronic acid.

5. The apparatus of claim 2, wherein the membrane cassette is adapted for modelling administration via an intramuscular route, wherein the chamber of the membrane cassette contains one or more materials selected from actin, myosin, glycogen, myoglobin, collagen, troponin and/or tropomysin and a membrane having permeability properties that simulate muscle.

6. The apparatus of claim 2, wherein the membrane cassette is adapted for modelling administration via a subcutaneous injection route, wherein the chamber of the membrane cassette contains hyaluronic acid and collagen.

7. The apparatus of claim 2, wherein the membrane cassette is adapted for modelling administration via an intradermal injection route, wherein the chamber of the membrane cassette contains collagen and dermatan sulphate.

8. The apparatus of claim 2, wherein the membrane cassette is adapted for modelling administration via a intrathecal route, wherein the chamber of the membrane cassette contains simulated cerebrospinal fluid as a buffer solution.

9. The apparatus of claim 2, wherein the membrane cassette is adapted for modelling administration via a epidural route, wherein the chamber of the membrane cassette contains one or more of collagen and hyaluronic acid for modelling filling the epidural space.

10. The apparatus of claim 2, wherein the method comprises optionally modifying one or more components or conditions present in the chamber of the membrane cassette.

11. The apparatus of claim 2, wherein the introduction of the drug formulation is by injection.

13. The apparatus of claim 2, wherein the drug formulation is a polypeptide, peptide or antibody formulation.

14. The apparatus of claim 2, wherein the chamber of the membrane cassette contains components found in the extracellular matrix for simulating conditions at an injection site.

15. The apparatus of claim 14, wherein the extracellular matrix component comprises a hyaluronic acid or a salt thereof, a collagen, a fibronectin, a laminin, dermatan sulphate and/or one or more cell lines.

16. The apparatus of claim 2, wherein the chamber of the membrane cassette has a volume between 0.5 ml and 10 ml.

17. The apparatus of claim 2, wherein the membrane is transparent.

18. The apparatus of claim 2, wherein the membrane is an unmodified microfiltration membrane or dialysis membrane.

19. The apparatus of claim 2, wherein the membrane is formed from regenerated cellulose, cellulose acetate or ester or mixture of thereof, polycarbonate, polyester, polyestersulfone, nylon, polyvinyldinefluoride (PVDF), polyvinylchloride (PVC) or polytetrafluoroethylene (PTFE).

20. The apparatus of claim 2, wherein the perforations in the membrane are obtainable by treatment with a microneedle roller or a laser.

21. The apparatus of claim 20, wherein the microneedle roller is a Dermaroller.

22. The apparatus of claim 2, wherein the perforations are between about 0.1 and about 200 microns in size.

23. The apparatus of claim 2, wherein the perforations are between about 1 micron and 10 mm apart.

24. The apparatus of claim 2, wherein the apparatus comprises a heat control and measurement system.

25. The apparatus of claim 2, wherein the bath has a stirrer.

26. The apparatus of claim 2, wherein the apparatus comprises a temperature measurement system and control for maintain temperature control and maintaining convective flow to simulate a subcutaneous injection site.

27. The apparatus of claim 2, wherein the cassette has an injection port for introducing samples of drug formulation or probes into the chamber of the cassette.

28. The apparatus of claim 2, wherein the surrounding liquid medium is a buffer solution.

29. The apparatus of claim 2, wherein the apparatus comprises means for adjusting the height or volume of the liquid medium above the membrane cassette for changing the hydrostatic pressure in the chamber.

30. The apparatus of claim 2, wherein the apparatus comprises a plurality of probes.

31. The apparatus of claim 30, wherein the probes comprise a Raman probe and/or fluorescence spectroscopy probe for monitoring the conformational changes the protein undergoes after the injection and for monitoring the protein and excipient concentrations, a temperature probe, a pressure transducer, a pH probe, a probe for measuring optical density for determining precipitation of components of the formulation, such as a spectrophotometer.

12. (canceled)

32-34. -34. (canceled)