WO2013038120A2

WO2013038120A2 - Device for storing and dispensing liquid

Info

Publication number: WO2013038120A2
Application number: PCT/FR2012/052080
Authority: WO
Inventors: Thierry Rimlinger; Pascal Dugand
Original assignee: Rexam Healthcare La Verpilliere; Stephan, Nolwenn
Priority date: 2011-09-16
Filing date: 2012-09-17
Publication date: 2013-03-21
Also published as: WO2013038120A3

Abstract

The present invention relates to a device for storing and dispensing pharmaceutical liquid, such as ophthalmic liquid. More particularly, the ophthalmic liquid comprises, as active principle, at least one prostaglandin, at least one analogue of a prostaglandin or at least one protein, especially for the treatment of glaucoma. The device according to the invention comprises, on at least one part of an inner surface of the device, a coating that reduces the sorption of liquid on the coated surface, this coating being hydrophilic.

Description

Device for storing and dispensing liquid

The present invention relates to a device for storing and dispensing pharmaceutical liquid such as ophthalmic liquid. More particularly, the ophthalmic liquid comprises, as active principle, at least one prostaglandin or a prostaglandin analogue, especially for the treatment of glaucoma.

Prostaglandins or prostaglandin analogues are well known active ingredients, generally administered to humans or animals topically in the form of eye drops for the treatment of glaucoma. These active ingredients can also be used in combination with a second anti-glaucoma agent such as, for example, a beta-blocker, a carbonic anhydrase inhibitor or an alpha-adrenergic agonist.

The majority of prostaglandins or prostaglandin analogues are not soluble in water, their dissolution in the preparation of eye drops presents some difficulties. Indeed, it is necessary to go through a preliminary step of solubilization of the active ingredient to obtain an aqueous solution ready to be distributed.

Moreover, in order to guarantee the sterility of the solution after the opening of the device, an anti-microbial preservative was often added. However, these preservatives, which could contribute to the solubilization of the active ingredient and its stabilization within the solution, are now deprecated because they can be toxic and pose problems of tolerance, especially in the context of a treatment of long-term such as the treatment of glaucoma. The solubilization of the active ingredient and its stability in the device is therefore likely to be affected.

Finally, the solution comprising the active ingredient must also be stable over time. Indeed, the liquid can be stored for up to thirty-six months in the device before its first opening, then about 1 month after its first opening, for example for administration at the rate of one drop in each eye per day. However, there is, over time, a reduction in the concentration of active ingredient in the drops delivered. This reduction in concentration may be due to absorption phenomena of the active ingredient in the parts of the device in contact with the solution and / or adsorption phenomena on these same parts. It may also be due to the absorption or adsorption of any other species present in the solution which could, by modifying the equilibrium of the solution, promote the adsorption or absorption of the active ingredient by parts of the solution. device in contact with the solution. These phenomena are particularly critical at low concentrations because they do not ensure the delivery of the required amount of the active ingredient over time. Indeed, if the active ingredient reacts, reversibly or not, with one of the component materials of the device when in contact, its concentration in the solution decreases and may become too low to have an optimal therapeutic effect. However, for example, prostaglandins or prostaglandin analogues are generally introduced into the solution at low concentrations, such as a concentration of less than 1% by weight, or even less than 0.01% by weight.

One solution to this problem is to modify the formulation of the solution in order to make the solution stable and inert with respect to the material of the storage and dispensing device, even at low concentrations. However, it is common for a device for dispensing product with or without a preservative, for example, to comprise different polymer materials for the reservoir and for the various constituents of the dispensing nozzle, such as a valve support, a dispensing valve, air take-up member, filter element, filter element support, etc.

It is therefore difficult to adapt the formulation of the solution to all the polymeric materials of the device in contact with the solution.

Similar problems of protein sorption also arise when using proteins as an active ingredient in low concentrations for other therapeutic uses or not.

In the invention, the term "protein" covers the following proteins or polypeptides: protein hormones, growth factors, cytokines, especially interleukins and interferons, chemokines, proteins of blood plasma, in particular albumin in the form of proteins. its different forms, coagulation factors or thrombosis, immunoglobulins, vaccine antigens from bacteria or viruses or parasites, extracellular matrix proteins, including collagen, elastin or others. The previous list is not limiting in nature, and one skilled in the field of the invention is capable of determining the proteins of interest.

The object of the invention is to propose a device for storing and dispensing pharmaceutical liquids that makes it possible to guarantee the active ingredient content of the solution for a given time interval, without having to adapt the composition of the solution to the various materials of the device. .

For this purpose, the subject of the invention is a device for the storage and dispensing of pharmaceutical liquid comprising, on at least part of a surface internal device, a coating reducing the sorption of at least one of the species present in the liquid on the coated surface characterized in that the coating is hydrophilic.

By "at least one of the species present in the liquid" is meant an active principle or any other species present in the solution which could, by modifying the equilibrium of the solution, promote the sorption of the active ingredient on the coated surface. Advantageously, the species are chosen from a protein, a prostaglandin or a prostaglandin derivative.

By "sorption" is meant the phenomena, combined or not, of absorption and adsorption of a molecule in or on a surface.

The term "storage and distribution device", a device comprising a storage tank of the liquid to be dispensed and a product dispensing tip. These devices may also for example be intended for dispensing drops and comprise a liquid distribution valve and / or an air permeable member. These devices may also be intended for the injection of liquid, for example in the form of a syringe provided with an injection needle.

The elements of the device are generally made of thermoplastic polymer materials such as polyethylene (PE), polypropylene (PP), polyethylene terephthalate (PET), polybutylene terephthalate (PBT), polyoxymethylene (POM), polyarylate (PAr), polyetherketone (PEK) fluorinated polymers (for example: polyvinylidene fluoride (PVDF), cycloolefinic polymers (COC) (for example the polymers sold under the trademark "TOPAS"), cycloolefinic copolymers (COP) (for example the copolymers sold under the trademark " Zeonex "), polytetrafluoroethylene (PTFE), polychlorotrifluoroethylene (PCTFE), polysulfone (PSU), ethylene-propylene-diene monomer (EPDM, or thermosetting type such as synthetic rubbers (for example: halobutyl rubber, nitrile rubber, polyisoprenes, and polychloroprene) or else of the thermoplastic elastomer type (for example: copolymer EPDM-PP commercia under the trademark "Santoprene", styrene-ethylene-butylene-styrene block copolymer (SEBS), etc.), alone or in mixtures. These devices may also comprise polysiloxane, such as, for example, polydimethylsiloxane (PDMS) and polydimethylvinylsiloxane.

Preferably, the materials of the device are chosen from PE, PP, PET, PBT, COP and PDMS, alone or in mixtures. The different elements of the device may be of different types of materials. Thus, the reservoir may be PE, the PDMS air permeable member and the chlorobutyl rubber valve. It will be understood that these elements of the device may comprise one or more of the materials listed above, taken alone or in a mixture. "Mixed" also refers to the copolymers of these materials.

The term "internal surface" of the device each surface that can be in contact with the liquid to be dispensed before the latter is expelled out of the device through the liquid dispensing orifice carried by the dispensing nozzle.

The term "coating reducing the sorption of the liquid on the coated surface", a coating which significantly reduces the sorption of the active ingredient on the surface of the device carrying the coating that is to say a coating that reduces the sorption of minus 10% relative to an untreated surface, preferably at least 20%, more preferably at least 30%, more preferably at least 50%.

Thus, thanks to the invention, a device is obtained which makes it possible to guarantee the stability of the solution, in particular of an ophthalmic solution comprising prostaglandins, prostaglandin analogs or proteins, in that the active ingredient remains in solution. solution within a defined concentration range and for a given time interval. Thus, with each delivery of a drop of product, the quantity of active ingredient delivered is indeed that required.

In addition, since the sorption is very limited, or even zero, it is no longer necessary to store the device in a refrigerator before or during use.

According to a first embodiment, the coating is chosen from the group consisting of organosilicone molecules. Preferably, the coating is chosen from the groups consisting of organosilicon molecules of silane and silazane type. More preferably, the coating is chosen from 2- (methoxy (polyethyleneoxy) propyl) trimethoxysilane.

(trimethoxysilylpropyl) ethylenediamine, 7-octenyltrimethoxysilane and alkylsilazanes, for example N-octyldimethyl (dimethylamino) silane.

According to a second embodiment, the coating may be chosen from derivatives of polysaccharides, in particular cellulose. More particularly, the coating is chosen from hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), methylcellulose (MC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), ethylhydroxyethylcellulose (EHEC), nitrocellulose, hydroxyethyl methylcellulose (HEMC), carboxymethylcellulose (CMC) and alginates.

According to a third embodiment, the coating may be chosen from the group consisting of polyvinyl and polyethylene polymers and their derivatives. Preferably, the coating is chosen from polyvinylsulphonic acid and its derivatives, polyvinylphosphoric acid, polyvinylpyrrolidone (PVP), polyvinylalcohol (PVA), poly (ethylene glycol) (PEG), polyoxyethylene (POE) and polyethyleneimine (PEI).

According to a fourth embodiment, the coating may be chosen from the group consisting of acrylate derivatives. More preferably, the coating is chosen from polyhydroxyethylmethacrylate (pHEMA), ethylmethacrylate (EMA), aminoethylmethacrylate (AEMA), polymethacrylate and polyacrylate.

According to a fifth embodiment, the coating is chosen from the group consisting of proteins such as albumin.

According to a sixth embodiment, the coating may be chosen from the group consisting of the group consisting of the hydrophilic charged polymers. Preferably, the coating is selected from the groups consisting of acrylamides, polysaccharides and polypeptides. More preferably, the coating is selected from polyacrylamide, poly (acrylamide co acrylic acid), hyaluronate, alginate, polylysine and chitosan.

Finally, according to a seventh embodiment, the coating is chosen from the group consisting of amphiphilic polymers based on poly (ethylene glycol), preferably the triblock copolymer (poly (ethylene glycol) -block-poly (propylene glycol) -block- ( poly (ethylene glycol) (PEG-PPG-PEG), the diblock polyvinylalcohol-poly (ethylene glycol) copolymer (PVA-PEG).

It will be understood that the coating may comprise or consist of one or more of all of these above-listed molecules for coating, taken singly or in admixture. By "in a mixture", the copolymers of these molecules are also targeted. It should also be noted that the molecules listed above for the coating may be in admixture with polysorbates (for example: polyoxyethylene (20) sorbitan monolaurate (Tween 20), polyoxyethylene (20) sorbitan monopalmitate (Tween 40), polyoxyethylene (20) ) sorbitan monostearate (Tween 60), polyoxyethylene (20) sorbitan monooleate (Tween 80)).

The device may include the coating over the entire inner surface or a portion of the inner surface. The coated portion of the inner surface depends on the nature of the material composing the various elements and / or the punctual or permanent nature of the contacting of said element with the liquid or the solution. Advantageously, the portion of the inner surface coated by the coating is a member permeable to air, a reservoir and / or any surface intended to be in prolonged contact with the solution. By "prolonged contact" is meant contact greater than 6 months. The invention also relates to a method of manufacturing a device according to the invention, wherein the coating is applied to at least a portion of the inner surface of the device.

Advantageously, before depositing the coating, the inner surface or the inner surface portion is pre-treated by plasma treatment, by corona treatment, by a flame (treatment consisting in exposing the surface of a polymer material to an oxidizing flame) or again by a treatment by the method known as "Pyrosil".

The invention finally relates to the use of a coating chosen from the group of organosilicon molecules, cellulose derivatives, polyvinyl and polyethylene polymers and their derivatives, acrylate derivatives, proteins, hydrophilic polymers. and charged amphiphilic polymers based on poly (ethylene glycol), for reducing the sorption of at least one prostaglandin, at least one prostaglandin analogue or at least one protein on an internal surface of a device.

Advantageously, the invention relates to the use of a coating chosen from organosilicon molecules, polysaccharide derivatives, in particular cellulose and alginates, polymers of polyvinyl and polyethylene types and their derivatives, acrylate derivatives, proteins, hydrophilic charged polymers and amphiphilic polymers based on poly (ethylene glycol), for reducing the sorption of at least one protein or at least one prostaglandin or at least one prostaglandin analogue on a surface internal of a device.

It is understood that this use for reducing the sorption of prostaglandin, prostaglandin analogue or protein may be contemplated with a coating comprising or consisting of any of the molecules listed above for coating, taken alone. or mixed with each other.

In one embodiment, the coating is used to reduce the sorption of at least one prostaglandin or at least one prostaglandin analogue.

In another embodiment, the coating is used to reduce the sorption of at least one protein.

Example 1 Device With 900,000 PEG Coating

The inner surface of the air permeable member is activated by plasma treatment with a power of 200 W with a flow rate of dinitrogen (N ₂ ) of 10 sccm ("standard cubic centimeters per minute") for about 5 minutes .

A 10% solution of polyethylene glycol solution of molecular weight 900,000 g is produced. mol ^"1 in water. This solution is applied on the activated inner surface of the member to form a continuous film. The organ and the liquid film are then dried in an oven at 50 ° C for 24 hours to obtain an air permeable member whose surface comprises a PEG coating.

Example 2 Device with PEI Coating

A 2% solution of polyethyleneimine solution (for example sold under the trademark Lupasol) is made in water. This solution is applied to the activated inner surface of the organ to form a continuous film.

The member and the liquid film are then allowed to dry in an oven at 50 ° C for 24 hours to obtain an air permeable member whose surface comprises a PEI coating.

Example 3: Device having a PEG-silane coating: 2- (methoxy (polvethyleneoxy) propyl) trimethoxysilane

The surface of the air permeable member is activated by a cold plasma treatment. The cold plasma surface treatment is carried out in MVD type deposition equipment: the plasma is generated using an HF generator (200 Watt, 450 sccm) in a chamber whose diameter is compatible with plates Silicon diameter 200mm. Under these conditions, the heating induced by the surface reactions remaining very low, the physical properties of the material are retained. The plasma, generated from 0 ₂ gaseous breaks the chemical bonds of the PDMS and form the hydroxyl groups that make the surface hydrophilic. This treatment, easy to implement and to introduce into a production line, induces not only a surface modification as such, but also intervenes as surface pre-modification before the covalent grafting of molecules chosen a priori to avoid the non-specific adsorption phenomenon.

Subsequently, a SiO ₂ silicon oxide deposit is deposited (under SiCl 4 atmosphere) to create a hook layer in order to improve the subsequent silane grafting.

Finally, covalent grafting in the liquid phase of 2- (methoxy (polyethyleneoxy) propyl) trimethoxysilane is carried out. The solvents used during these silanization reactions, and washes are as follows:

- anhydrous ethanol

- ultra pure water.

After drying, an air permeable member is obtained, the surface of which comprises a PEG-silane coating.

Claims

1. Device for the storage and dispensing of pharmaceutical liquid comprising, on at least a part of an internal surface of the device, a coating reducing the sorption of at least one protein or a prostaglandin or a prostaglandin derivative present in the liquid on the coated surface characterized in that the coating is hydrophilic.

2. Device according to the preceding claim, wherein the coating is selected from the group consisting of organosilicon molecules.

3. Device according to the preceding claim, wherein the coating is selected from 2- (methoxy (polyethyleneoxy) propyl) trimethoxysilane), the N-

(trimethoxysilylpropyl) ethylenediamine, 7-octenyltrimethoxysilane and N-octyldimethyl (dimethylamino) silane.

4. Device according to claim 1, wherein the coating is selected from polysaccharide derivatives, especially cellulose.

5. Device according to the preceding claim, wherein the coating is chosen from hydroxypropylmethylcellulose, ethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, ethylhydroxyethylcellulose, nitrocellulose, hydroxyethylmethylcellulose, carboxymethylcellulose, and alginates.

6. Device according to claim 1, wherein the coating is selected from the group consisting of polyvinyl and polyethylene polymers and their derivatives.

7. Device according to the preceding claim, wherein the coating is selected from polyvinylpyrrolidone, polyvinylalcohol, polyethylene glycol, polyoxyethylene and polyethyleneimine.

8. Device according to claim 1, wherein the coating is selected from the group consisting of acrylate derivatives.

9. Device according to the preceding claim, wherein the coating is selected from polyhydroxyethyl methacrylate, ethyl methacrylate, aminoethyl methacrylate polymethacrylate and polyacrylate.

The device of claim 1, wherein the coating is selected from the group consisting of proteins such as albumin.

1 1. The device of claim 1 wherein the coating is selected from the group consisting of hydrophilic charged polymers.

12. Device according to the preceding claim, wherein the coating is selected from acrylamides, polysaccharides, polyvinylisulfonic acid and its derivatives, polyvinylphosphoric acid and polypeptides.

13. Device according to claim 1, wherein the coating is selected from the group consisting of amphiphilic polymers based on polyethylene glycol.

14. Device according to any one of the preceding claims, wherein the portion of the inner surface coated by the coating is an air permeable member or a reservoir.

15. A method of manufacturing a device according to any one of claims 1 to 14, wherein the coating is applied on at least a portion of the inner surface of the device.

16. Method according to the preceding claim, wherein, before depositing the coating, the portion of the inner surface is pre-treated by plasma treatment or by corona treatment.

17. Use of a coating chosen from organosilicon molecules, polysaccharide derivatives, in particular cellulose and alginates, polyvinyl and polyethylene type polymers and their derivatives, acrylate derivatives, proteins, hydrophilic polymers and charged amphiphilic polymers based on poly (ethylene glycol), for reducing the sorption of at least one protein or at least one prostaglandin or at least one prostaglandin analogue to an internal surface of a device.