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EP-4734906-A1 - METHOD FOR SUCCESSIVE, PRESSURE-DRIVEN DISPENSATION OF SINGLE DOSES OF A MULTIPHASIC MIXTURE WITH CONTROLLED CONCENTRATION AND DOSE FROM A LARGER RESERVOIR TO SMALLER RECIPIENTS AND APPARATUS FOR PERFORMING THE METHOD

EP4734906A1EP 4734906 A1EP4734906 A1EP 4734906A1EP-4734906-A1

Abstract

The method serves for successive, pressure-driven dispensation of single doses of a multiphasic mixture comprising a fluid phase and a solid phase from a reservoir into single recipients, maintaining the composition of the mixture in the dispensed doses within pre-determined ranges. The method comprises the following steps: a) a pre-set range of the ratio between the fluid phase and solid phase of the multiphasic mixture is defined; b) a pre-set threshold value for the pressure Ptarget used to dispense the multiphasic mixture is defined; c) a pre-set target for the weight and/or volume dispensed is defined; d) weight and/or volume of the dispensed doses is measured after each dispense and is compared to the target weight and/or volume; e) deviation from target volume and/or target weight are compensated for by adjusting the pressure; f) the change of the pressure necessary to deliver the target volume or target weight is detected; g) an amount of fluid phase is added to the mixture remaining in the reservoir to restore the composition of the multiphasic mixture within the pre-determined range of ratio between the fluid phase and solid phase of the multiphasic mixture when the pressure exceeds the pre-set target value P target .

Inventors

  • BÉDUER, Amélie
  • BRASCHLER, THOMAS
  • BERNHARD, Armand
  • RIVIER, Laurence

Assignees

  • Volumina Medical SA

Dates

Publication Date
20260506
Application Date
20230628

Claims (20)

  1. 1. Method for successive, pressure-driven dispensation of single doses of a multiphasic mixture (7) comprising a fluid phase and a solid phase from a reservoir (6) into single recipients (4), maintaining the composition of the multiphasic mixture (7) in the dispensed doses within predetermined ranges, characterized in that a) a pre-set range of the ratio between the fluid phase and solid phase of the multiphasic mixture (7) is defined; b) a pre-set threshold value for the pressure Pt arg et used to dispense the multiphasic mixture (7) is defined; c) a pre-set target for the weight and/or volume dispensed is defined; d) weight and/or volume of the dispensed doses is measured after each dispense and is compared to the target weight and/or volume; e) deviation from target volume and/or target weight are compensated for by adjusting the pressure; f) the change of the pressure necessary to deliver the target volume or target weight is detected; g) an amount of fluid phase is added to the multiphasic mixture (7) remaining in the reservoir (6) to restore the composition of the multiphasic mixture (7) within the pre-determined range of ratio between the fluid phase and solid phase of the multiphasic mixture (7) when the pressure exceeds the pre-set target value Ptarget.
  2. 2. Method according to claim 1 , characterized in that prior to the start of the first dispense, a calibration of the relationship between the ratio between the fluid phase and solid phase of the multiphasic mixture and the pressure is performed to define the target pressure Ptarget.
  3. 3. Method according to claim 1 or 2, characterized by the following steps A) defining a target value for the Pressure (Ptarget) to be used for the dispensing and defining a target value for the weight or volume to be dispensed; B) filling a reservoir with a multiphasic mixture; C) dispensing a dose of the mixture into a recipient using a first pressure Pi; D) measuring the weight or the volume of the dispensed dose; E) comparing the weight or volume measured in step D with the pre-determined target value for the weight or volume as defined in step A; F) adjusting the first pressure Pi by a calculated amount AP to a different pressure P2 = Pi + AP; G) repeating steps C-E using the adapted pressure P2 for the filling of further recipients with doses of the mixture; H) optionally adopting one or more further pressure modifications according to step F; I) adding or subtracting a calculated amount of fluid phase, possibly zero, to the mixture for compensating the loss or the excess of fluid phase in the mixture, whereby the amount of fluid is calculated using the actual and target pressures .
  4. 4. Method according to one of the claims 1 to 3, characterized in that fluid is only added when the pressure is above a threshold pressure Pmax, distinct from and above the target pressure Ptarget-
  5. 5. Method according to one of the claims 1 to 4, characterized in that fluid is withdrawn from the multiphasic mixture when the pressure is below the target pressure Ptarget.
  6. 6. Method according to one of the claims 1 to 5, characterized in that fluid addition and/or fluid withdrawal are only operated if the weight or volume of the dispensed dose is within the range of the target pressure Ptarget-
  7. 7. Method according to one of the claims 1 to 6, characterized in that the fluid phase comprises one of the following substances: aqueous solutions, physiological saline (0.9% NaCI), buffers, pharmacologically acceptable solutions, hyaluronic acid, glycosaminoglycans, alginate, agarose, methylcellulose, carboxymethylcellulose, chitosan, anaesthetic solutions and solutions containing lidocaine.
  8. 8. Method according to one of the claims 1 to 6, characterized in that the fluid phase comprises one of the following substances: water, isotonic solutions, isotonic buffers, hydrogels, solutions containing polysaccharides, deacetylated hyaluronic acid, hyaluronic acid modified with alkyne derivatives such as cyclooctynes, azide modified hyaluronic acid, thiolated hyaluronic acid, hyaluronic acid derivatives, hyaluronan oligosaccharides, heparosan and derivatives, polyfructose polyvinylalcohol, polyacrylates, nucleic acids, DNA, RNA, synthetic polymers, viruses, transfection agents, contrast agents, albumin, cell culture medium, xylocaine, bupivacaine, tetracaine, mepivacaine, rhopivacaine, mepivacaine and/or other anaesthetics of the -caine family; solutions containing antibiotics, penicillin, cephalosporine, tetracycline, amoxicylline, clavulanate, cephalexin, ciprophloxazine, metronidazole, azithromycine; organic solvents, in particular ethanol, isopropylalcohol, dimethylsulfoxide; oils, triglycerides, lipid emulsions, fatty acids, oleic acid, linoleic acid, palmitic acid, or mixtures of all the aforementioned substances.
  9. 9. Method according to one of the claims 1 to 6, characterized in that the solid phase comprises one of the following substances: porous scaffolds, porous scaffold particles, crosslinked polysaccharides, in particular porous crosslinked polysaccharides, crosslinked hyaluronic acid, crosslinked glycosaminoglycans, alginate crosslinked ionically, agarose, crosslinked carboxymethylcellulose, chitosan, decellularized tissue, decellularized adipose tissue.
  10. 10. Method according to one of the claims 1 to 6, characterized in that the solid phase comprises one of the following substances: foams, foam particles, hydrogels, hyaluronic acid crosslinked with butanedioldiglycid ether, hyaluronic acid modified with alkynes and azide moieties and crosslinked by the reaction of these groups, crosslinked deacetylated hyaluronic acid, hyaluronic acid crosslinked with disulfide bridges, divinylsulfone, crosslinked hyaluronic acid derivatives, crosslinked hyaluronan oligosaccharides, crosslinked heparosan and derivatives, alginate crosslinked with Ca 2+ ions, Fe 2+ or Fe 3+ ions, Ba 2+ ions, covalently crosslinked alginate, crosslinked polyfructose, (porous) crosslinked peptides, (porous )crosslinked proteins, decellularized plant material, decellularized human adipose tissue, porous silk particles, extracellular matrix, collagen, laminin, polyurethane foams and foam fragments, polyolefin foams and fragments. Polysaccharides, extracellular matrix, proteins, peptide precipitated in organic solvents, optionally crosslinked. Reconstituted cellulose as fibers, foam, foam fragments. Fibers, electrospun fibers: PLGA, PLA, polycaprolactones, polyurethane, polysaccharides, proteins. Extruded fibers such as regenerated cellulose, polysaccharides, proteins, peptides extruded into non-solvent, optionally crosslinked, or mixtures thereof, capsules, beads, DNA, RNA calcium hydroxyapatite, ice crystals, ceramics, frozen substances, solidified fats, oils, microparticles, silicone oil droplets, solid silicone particles, crosslinked cells, crosslinked tissue, living cells, organoids, vesicles, liposomes, capsules, capsules containing cells, lipid-loaded beads, PNIPAAM, thermosensitive materials, ice, insoluble or partially soluble salts.
  11. 11. Method according to one of the claims 1 to 10, characterized in that the proportion of the weight or volume of the solid phase in relation to total heterogeneous product in the reservoir is between 0.05% and 95%, preferably between 0.1% and 50%, more preferably between 0.2% and 30%, most preferentially between 1% and 20%.
  12. 12. Method according to one of the claims 1 to 11 , characterized in that the multiphasic mixture is composed of several liquid phases and/or of several solid phases.
  13. 13. Method according to one of the claims 1 to 12, characterized in that the multiphasic mixture is a viscoelastic material with an elastic modulus G’ between 1 Pa and 1 Mpa, preferably between 10Pa and 100kPa and most preferably between 100Pa and 1OkPa and/or a loss modulus G” between 0.01 Pa and 100kPa, preferably between 0.1 Pa and 10kPa, and more preferably between 1 Pa and 1kPa.
  14. 14. Method according to one of the claims 1 to 13, characterized in that the multiphasic mixture is biocompatible.
  15. 15. Method according to one of the claims 1 to 14, characterized in that the viscosity of the multiphasic mixture is adjusted to render it injectable.
  16. 16. Method according to one of the claims 1 to 15, characterized in that the multiphasic mixture has a yield stress between from 0.1 Pa to 100kPa, preferably between 1 Pa to 10kPa, most preferably between 5Pa to 5kPa.
  17. 17. Method according to one of the claims 1 to 16, characterized in that the fluid phase has a viscosity between 0.0005 Pa s to 10 Pa-s, preferably 0.0006 Pa-s to 0.1 Pa-s
  18. 18. Method according to one of the claims 1 to 17, characterized in that the fluid phase is a physiological saline solution or a solution of polysaccharides.
  19. 19. Method according to one of the claims 1 to 18, characterized in that the fluid phase comprises a contrast agent.
  20. 20. Method according to one of the claims 1 to 19 characterized in that the solid phase has a yield strain between 0.1 Pa to 100kPa, preferably between 1 Pa to 10kPa and more preferably between 5Pa to 5kPa.

Description

Method for successive, pressure-driven dispensation of single doses of a multiphasic mixture with controlled concentration and dose from a larger reservoir to smaller recipients and apparatus for performing the method. BACKGROUND OF THE INVENTION 1. Field of the Invention The invention relates to a method according to the preamble of claim 1 and a device for performing the method according to the preamble of claim 27. The invention relates in particular to methods for filling containers with liquids, suspensions or flowables, and more particularly for filling syringes or vials with heterogeneous mixtures while maintaining composition and dispensed dose within desired bounds. 2. Description of the Related Art Different filling machines are available for filling a variety of products into a variety of containers. Syringe filling machines typically fill a liquid, or viscoelastic liquid into empty syringes. The main parameter to control is the amount filled, but other parameters such as the flawless filling with the avoidance of bubbles are also important. Filling machines of various designs are well adapted to the filling of homogeneous, liquid, viscous or viscoelastic products, as well as powders. However, they show shortcomings when filling heterogenous products, particularly products that can separate into a liquid and solid part. The aim of this invention is to describe technical solutions to the problem of phase separation during filling. A variety of physical principles can be used to drive the substance to be filled from a reservoir to the target recipient. Piston-based volumetric pumps are a wide-spread technology. For instance, US5961303A describes servo-control of a volume displacement pump where predetermined cavities in rotating pistons accept and transmit flowable material in predetermined amounts. Such volumetric pumps typically have precise control over the pumped amount by design, the dispensed volume is indeed given by the geometrical features of the piston, and little backflow can occur due to precise mechanical design. However, with heterogeneous mixtures, there is no guarantee that the volume dosed by the pump has the same composition as the mixture in the reservoir. Indeed, while the overall volume is very precisely controlled, the composition is not and one component may be pumped preferentially. The pump also does not provide information about the composition being dispensed. Peristaltic pumps are also used for volumetric dispensing. In this case, the physical properties of the flowable to be dispensed are more important than with volumetric displacement pumps, and calibration can be used to relate the movement of the pumping head to the volume being dispensed, as described in US4715786A. US6453927 further described the use of an additional flow line with lower flow rates to better control flow in precision peristaltic pump. Similarly, to volumetric pumps, there is no guarantee as to maintenance of composition upon dispensing of heterogeneous mixtures. Auger screws are deeply grooved screws advancing material in the grooves when rotating. Augers are used for dosing, typically, albeit not exclusively, for powders. US4696329A describes retrocontrol on the rotation rate of the Auger as a function of the dispensed weight, as assessed by weighing a number of dispensed units and taking the average of the weights. With Auger screw dispensers, there is no guarantee as to maintenance of composition upon dispensing of heterogeneous mixtures. Pressure or gravity driven flow along with flow control valves is another frequently used scheme. EP1847459A1 describes a multiport machine for filling bottles with liquids. The machine uses a plurality of electric valves to stop filling bottles placed under the valves, whenever a predetermined weight is reached in the bottle under the valve. The weights are measured with load cells, one per bottle. US9493254 describes topping, where additional pharmaceutical substance is added if the weighing after filling finds that not enough substance was dispense. A critical element in the filling process is to control the driving force for advancing the fluid being filled as a function of the filling level. This is described in terms of turns of an Auger screw as a function of the achieved dispensed weight in US4696329A, in US2645447 in terms variation of the volume of volumetric filling chamber as a function of momentaneous density of powders, and in US4715786A regarding calibration of the rotation rate of a peristaltic pump head in order to dispense the desired amount of liquid. US3662517A uses photo-sensitive elements to interrupt filling when the desired level is reached. In pressure-driven filling, the control over the volume can be achieved by controlling the opening time, for example by closing the filling valve when a given target weight is reached (US3422916, EP1847459A1), or alternatively by using back-pressure from a sensing tube (US5161586, US3783913, US483