WO2015074641A1 - Method for storing and reconstituting a dried active substance and syringe therefor - Google Patents

Abstract

The invention relates to the storing of active substances in a dried form and also the reconstituting of the active substances in a manner that is easy and reliable in the application concerned. The active substance, which was originally in solution and has been dried, is deposited in a pore storage means (12) that can be flowed through by fluid. The fluid is located in a carpule (5), the septum (16) of which can be pierced by a cannula (10). The carpule is emptied in a single operation by actuating a syringe plunger through the pore storage means. For this purpose, an inner cannula sleeve (9) is immovably arranged between the pore storage means and the carpule and the inner cannula thereof protrudes with its sharp needle end in the direction of the septum of the carpule and at the rear opens out in a throughflow opening that can be dimensioned independently of the diameter of the inner cannula.

Description

Process for storing and reconstituting a dried

Drug and syringe to description

The invention relates to the storage of active ingredients present in dried form as well as the simple and safe reconstitution of the active ingredients in the application. The stable and safe storage of drugs, insbesonde ^¬ re of drugs based on proteins, is a basic ^¬ major problem the pharmaceutical formulation. In solution, these substances are often unstable and lose their effect after a short time. Since the storage in the dried state promises a considerably higher stability, such substances are lyophilised ^¬ Siert and usually stored in this form in ampoules or glass vials. Your Rekonst itut ion by adding a complementary and ^¬ means of then requires considerable manual effort. In general, a complete release of the active ingredient is to be sicherge ^¬ by repeated shaking or swirling the bottle. Subsequently, the dissolved product is drawn up in a syringe and can then be applied (eg Bio ^¬ test - haemoctin). It should always check whether ei ^¬ ne full Rekonst itut is ion occurs before the active ingredient can be administered. The complete reconstitution is often not always perfectly recognizable and subjective due to the formation of foam during dissolution. In addition, the active substance can be damaged by excessive foaming when Recon ^¬ stituieren and the process takes time, so that the pharmaceutical substance or the active substance to be negatively affected ^¬ additionally. Since the process also has the potential for user error, storage and application systems has been trying to develop that this complex pre ^¬ simplify transition and integrate multiple steps. Thus, DE 101 40 704 A1 describes the mixing of a heavy soluble pharmaceutical substance in a double chamber carpule with bypass. Here, the mixing and full ^¬ permanent reconstitution of the dried substance by more ^¬ times the movement of a piston rod and the flow through is achieved with a solvent through a bypass. The after ^¬ part lies here in the susceptibility to failure by the user, who must pay close attention to the number of piston movement depending on the drug and the formation of foam. The subject of US 2012/0197210 Al is an arrangement in which a metering device by means of a so-called needle hub, a cannula exhibiting two, external housing ^¬ part can be placed, in which a first drug was deposited in a porous carrier. Distal protrudes from the ex- remote housing part from a first cannula, which is punctured when pressurized, the septum of a liquid second drug-containing carpule. Proximal goes over the external housing part in an injection cannula. The arrangement of a second drug to vermischen- the first drug in a to be connected to external Ge ^¬ casing part makes this solution structurally very complicated. The Lö ^¬ solution only affects the mixing and applying very clotting drug ^¬ gen volumes in subcutaneous injection. To provide greater volumes of the active ingredient would nülenhohlraum Ka or the volume of the porous support are formed entspre ^¬ accordingly larger. This ei ^¬ ner application would exit a correspondingly large amount of air through the injection needle at the beginning. In subcutaneous injections but only very small volumes of air are not critical. For a domestic travenöse administration of such a substance provided active ^¬ this solution is pop u la ^¬ lig unsuitable for the above mentioned reasons.

An expression of the air made before the application, until the air-free escape of the active substance lost thereby, is not an age ^¬ native especially for very valuable drugs.

A further problem of the solution according to US 2012/0197210 A1 is that in each case a concentration gradient occurs during the reconstitution of the drug during the passage of a carrier containing the drug. This means that in the liquid which leaves the jektionsvorrichtung ^¬ In the beginning of the application, the dissolved drug concentration much higher than is present at the end of the application. For certain subcutaneous Injekti ^¬ tions such a concentration gradient is largely harmless again because the deposited under the skin drug is slowly absorbed and thereby homogenized by diffusion. In particular, since certain highly active drugs can contribute to high local concentrations lead to undesirable side effects, intravenous administration such be ^¬ riding asked drugs with this solution is again not possible.

The occurrence of a concentration gradient and out of the clearly ^¬ particularly re ^¬ Levant when necessary removing air unavoidable loss of valuable active ingredient, since it is the liquid tends austre- the beginning of the reconstitution has the highest concentration of active ingredient on ^¬.

The totality of the handling of the device can not gen satisfactory way ^¬ clearly a defined reconstitution. Thus, in particular with a manual pressure load ^¬ supply of Karpulenstopfens for the purpose of emptying the carpule contained the liquid drug component not ge ^¬ ensures that even with a defined amount of FLÜS ^¬ sigen drug component, a solid drug is dissolved completeness dig out of the respective support material. So will if too fast a flow through the carrier may not reconstitute the entire active ingredient.

The object of the invention is to specify a method and a device in the form of a syringe, with which an active substance initially present in solution can be dried and stored over a longer period of time and the process of reconstitution of the active substance and further use for the user is thus simplified, that the known from the prior art problems do not occur and user errors are largely avoided.

Including intravenous administration of rekonstituier ^¬ th drugs should be possible to easily and relatively quickly after reconstitution. The drug reconstituted with the device of the present invention must be provided with simple and aseptically safe means for intravenous administration. For this purpose, the apparatus is intended in particular to the syringe output the essential features of a conventional syringe having such case ^¬ play a luer-lock connector or a conventional Ka nülenanschluss. The realization of different flow rates must be possible with the simplest possible structural means.

This object is achieved by a method according to claim 1 and a syringe according to claim 2. Advantageous For ^¬ designs of the invention are specified in the dependent claims.

The advantages of the invention are, in particular, that by transferring the reconstituted active substance into a syringe, when applying no Konzentrationsgradi- ent is more effective. In the inner cannula sleeve formed independently of the diameter of the inner cannula through-flow opening can be dimensioned matched in its diameter to the particular drug and the particular mode of application, whereby the maximum flow rate can be on the respective application is ^¬ represents. This has the effect that only a defined amount of the solvent can flow through the pore storage even when an excessive pressure force is applied to the syringe die. Manufacturing technology, it is particularly advantageous ^¬ way to make the inner cannula sleeve in one piece as a separate component, so that different flow rates can be realized in a structurally simple, without the eigentli ^¬ chen syringe body or on the porous reservoir structural Verände- must be made requirements. The formation of an independent of the diameter of the inner cannula flow opening allows only the required flow rate limitation. A flow rate limitation over the diameter of the in ^¬ nenkanüle would be very expensive to produce or with certain materials not feasible.

The proposed inventions syringe can fully charged, are already connected to a syringe and packaged aseptically provided so that a fast and handling errors free use is guaranteed ^¬ guaranteed. This is particularly important when, for example, in emergency medicine generic drugs must be administered without delay and under extreme conditions.

According to the invention, the dissolved active substance is introduced into a 3-dimensional porous support (in the following pore storage) with pores of ^5-100 .mu.m, preferably 50 .mu.m, with a porosity of ^20-70 %, preferably 40%, and dried there , preferably lyophilized. The pore Memory may consist of organic polymers (polyethylene, polyethersulfone, polymethyl methacrylate, ethylene vinyl acetate, cellulose acetate), glass or inorganic ceramics and in its basic structure based on fibers, particles or sponges. The inner surface can be zusätz ^¬ Lich provided with a passivation layer.

Particularly advantageous for a pore storage gesinter ^¬ tes particulate ultra high molecular weight polyethylene (UHMW-PE) having an average particle diameter of 200 pm and a pore content of 34%. If this carrier is provided with a pas ^¬ sivierungsschicht of polyvinyl alcohol (PVA), lyophilized, protein-based drugs can almost completely reconstitute.

For reconstitution, the loaded pore store is perfused with solvent at a linear velocity in the range from 0.3 cm / s to 0.7 cm / s from one direction. In ^¬ be voted applications, for example in an intravenous administration of the drug, it is necessary to collect the rekonstituier ^¬ th active ingredient prior to further treatment or administration in a further reservoir. For this purpose it is particularly advantageous if this further reservoir is formed for example as a conventional hypodermic syringe which is connectable via a screw or plug-in connection to the outlet of the syringe Invention ^¬ proper. In this context, it is advantageous if the syringe designed according to the invention corresponds in terms of its outer structure to the connection conditions of conventional hypodermic syringes. This requirement is inter alia the constructive feature, according to which the pore storage is arranged at the syringe outlet, but still in the actual syringe barrel.

The application of a suitable passivation layer to the surfaces of the pore storage device reliably prevents that damage to the drug occurs as a result of reaction with the material of the pore reservoir, for example by absorption. It is thus ensured that the active ingredient is dissolved without residue from the storage material.

According to the invention, the cylindrically shaped pore reservoir with the dried active substance is inserted into the correspondingly ausgebil ^¬ finished front end of the syringe barrel. The pore ^¬ memory must have a firm and on the circumference accurately fitting seat in the syringe barrel. Characterized in that the liquid solvent is completely ge through the pores memory ^¬ suppressed in operating the printer ^¬ generating means and does not flow on its outer surface passing is ensured. For the complete passage of the pore storage spacers are formed on the front side of the Spritzenzhülse, which prevent the pore storage rests with its front end face at the bottom of the syringe barrel. This ensures that the solvent can not only flow out of the pore storage in the area of the diameter of the syringe outlet.

The solvent is Karpu ^¬ le filled in a reservoir in the form of a sterile, which is inserted into the device. Between the pore reservoir and the reservoir, an inner cannula sleeve is arranged. This is with its front end face, in which a flow opening is formed, beab ^¬ standet from the rear end surface of the porous storage, whereby the solvent can penetrate over the entire cross sectional area of the pores ^¬ memory therein. Pore storage and inner cannula sleeve are fixed in position to each other. The amount of pre-preserved solution ^¬ means is matched to the respective capacity of the Porenspei ^¬ Chers and the active substance to be dissolved. Behind the reservoir, a reducing sleeve is used, ^whose wall thickness corresponds to that of the reservoir. Thus ge ^¬ ensures that a diameter corresponding dimensio ^¬ ned pressure generating element, which is guided in the Reduzierhül ^¬ se, strikes the plunger stopper of the reservoir, whereby the latter can be pushed down.

The piercing of the reservoir septum is carried out by linear movement of the pressure-generating element, which by the pressure on the reservoir, this shifts towards Innenkanülenhülse, which leads at high enough force to pierce the septum. Then, by further linear movement of the pressure-generating element of the piston stopper in the Reser ^¬ voir be moved forward and the solvent is pressed through the flow opening in the end face of Innenkanülenhül ^¬ se on the pore storage.

As it flows through the pore reservoir, the dried active substance is dissolved out of the pore reservoir. The dissolved active substance can be collected in a commercially available syringe, preferably a Luer-Lock syringe, which is screwed onto the female Luer-Lock connection of the device.

The flow rate of the solvent through the Po ^¬ renspeicher is crucial for the uniform and full ^¬ constant reconstitution of the dried substance. This will Invention ^¬ according realized in that the diameter of the flow opening in the inner cannula sleeve relative to the, is In ^¬ reduced nendurchmesser of the inner cannula so that the solvent does not exceed regardless of the pressure applied to the pressure generating element pressure, a maximum flow rate. Characterized the maximum solvent flow is limited by the pore memory, and set to a fully ^¬ permanent reconstitution of the dried active ingredient is guaranteed ^¬ guaranteed. An embodiment of a syringe designed according to the invention will be described in more detail below.

Show it:

Fig. 1 is a syringe in longitudinal section

Fig. 2, the inner cannula sleeve as a detail

 in longitudinal section

The syringe 1 according to FIG. 1 has the Luer lock connection 15 at the front end, on the end wall of the syringe sleeve 4. Behind its end wall a Spei ^¬ cherraum for the cylindrical pore storage 12 is formed in the syringe barrel 4. By the spacer ribs 14 of the pore storage 12 is spaced from the end wall of the syringe barrel 4, whereby the fluid chamber 13 is formed.

Behind the pore storage 12, the inner cannula sleeve 9 is inserted adjacent to a projection in the syringe barrel 4. This results between the rear end face of the pore ^¬ memory 12 and the end wall of the inner cannula sleeve 9, the fluid space 11. From the inside of the end wall of Innenkanü ^¬ lenhülse 9, the inner cannula 10 protrudes to the rear. From the inner cannula sleeve 9 spaced carpule 5 is fixed in position, but slidably disposed by applying force. In this fixed position the septum cap is still spaced from the in ^¬ nenkanüle 10. 6 At the open end of the syringe barrel 4, the reduction sleeve 3 is inserted. The length of the reducing sleeve 3 is dimensioned such that its circumferential rear flange 17 abuts against the flange 18 of the syringe sleeve 4 when the septum cap 6 has reached the predetermined distance from the inner ^cannula 10. The wall of the Reduzierhülse 3 and the diameter of the guided in her syringe plunger 2 is dimensioned so that the syringe plunger 2 when pressurized in the carpule. 5 dive in and hit the carpule plug 7. Infol ^¬ ge of hydraulic power transmission, the carpule is 5 since pushed in so far towards inner cannula sleeve 9 ^¬ until the inner cannula 10 pierces the septum into the septum cap 6 and the solvent 8 via the inner cannula 10 and the flow opening can flow sixteenth In this case, the fluid space 11 is completely filled with the solvent 8, so that it can flow over the entire rear end face of the pore storage 12 in this. When flowing through the pores of the memory 12, the dried substance is reconstituted with the solvent occurs and 8 on the front face of the Po ^¬ renspeichers 12 from. Here, the fluid chamber 13 is filled, be ^¬ flows before liquefied drug over the luer lock connector 15 and connected by a syringe is collected.

The flow opening 16 in the inner cannula sleeve 4 is so reduced compared to the inner diameter of the cannula 10 that the solvent 8 can reach a maximum linear velocity of 0.7 cm / s. The maximum solvent flow is thus adjusted so that a complete reconstitution of the dried active ingredient is ensured.

Two exemplary examples of the passivation of pore storage are listed for loss-free edition of Fak ^¬ tor VIII protein.

PVA passivation via esterification with maleic anhydride: Porous reservoirs made of polyethylene (Porex Technologies GmbH) with an average particle diameter of about 200 μm and a pore content of about 34% are used to passivate the surface for a low adsorption of the active ingredient with polyvinyl alcohol (PVA). coated. For this purpose, 10 pores storage (diameter 10 mm, height 15 mm) in the beaker are stirred twice with about 100 ml of acetic anhydride (for synthesis, VWR) for 5 min each. In dry reflux, 80 ml of heated acetic anhydride to 80 ° C, 4 g of maleic ^¬ anhydride (for synthesis, Merck) dissolved in it and added the washed Po ^¬ reservoirs. When reaching 100 ° C., 0.22 g of benzoic peroxide (97% with 25% water, Alpha Aesar) are added and the mixture is stirred at 100 ° C. for 6 hours. Subsequently, the ten pore stores are washed four times in about 100 ml acetone (VWR) with stirring and then stirred for about 12 h in about 200 ml of acetone. The pore stores are abundant with deion. Washed three times for about 5 min under vacuum and then for 2 h in 0.1 M HCl (VWR) just under ^¬ if stirred under vacuum. Thereafter, the pore stores are stirred in 300 ml of PBS pH 7.4 buffer under vacuum for 10 min and, in parallel thereto, 0.5 g of PVA (Sigma-Aldrich, MW: 9,000-10,000 g / mol) are dissolved in 100 ml of PBS pH 7.4. The pore stores are added to the PBS-PVA solution and ^{stirred for} 1 h under vacuum. Subsequently, 0.25 g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (98%, Alpha Aesar) (dissolved in 50 ml PBS pH 7.4) are added to the PVA-PBS solution and the pore storage and submerged for 3 h Vacuum stirred. Thereafter, the pore reservoirs are in abundant deion. H ₂ O several times over several hours under vacuum. The drying is carried out under vacuum by lyophilization or with dry air in a fluidized bed dryer. PVA passivation via saponification of polyvinyl acetate:

PVA (stabilized, for synthesis, Merck) by plasma polymerization of vinyl acetate and subsequent saponification with NaOH alka ^¬ Lischer (VWR) are brought up to the pore memory. By 10 pore memory (Porex Techno ^¬ gies GmbH) (diameter 10 mm, height 15 mm) activated for 20 minutes at 0.5 mbar and about 5 sccm O ₂ with Low pressure oxygen-plasma. The pore stores are then exposed to pulsed vinyl acetate plasma for 60 minutes (0.5 mbar, approx. 0.3 sccm volume flow of gas). By again 10 minutes Sauer ^¬ substance and pulsed 60-minute vinyl acetate plasma treatment on the PE surface polyvinyl acetate (PVAc) is abgeschie- the. By stirring the pore stores at 50 ° C. in 1% NaOH (in water or ethanol) for 60 minutes, polyvinyl acetate is saponified to give polyvinyl alcohol. Thereafter, the pore reservoirs are in abundant deion. H ₂ O several times over several hours under vacuum. The drying takes place under vacuum by lyophilization or with dry air in a fluidized bed dryer.

LIST OF REFERENCE NUMBERS

1 fuel ze

 2 fuel piston

3 reducing sleeve

 4 syringe barrel

 5 carpule

 6 septum cap

 7 carpule plugs

8 solvents

 9 inner cannula sleeve

10 inner cannula

 11 fluid space

 12 pore storage

 13 fluid space

 14 spacer ribs

 15 Luer lock connector

16 flow opening

17 flange

 18 flange

Claims

claims 1. A method for storing and reconstituting a ^{Wirkstof ¬} fes, wherein the present in solution drug dried can be stored for a long time, wherein the process of reconstitution of deposited in a pore ^¬ memory active ingredient in a syringe by means of a solvent provided in a reservoir , characterized in that the storage and reconstitution of the active ingredient in a first syringe he follows ^¬ , of which the again brought into solution Wirk ^¬ substance is transferred into a connected to the output of the first syringe injection syringe, with which then the Ap ^¬ plication he follows. 2. syringe for storing and reconstituting an active substance, which is initially present in solution and stored abge dried in a flow-through by a fluid pore storage ^¬ , wherein the fluid is in a carpule, the septum is durchstechbar by a cannula and the carpule can be emptied through the pore storage by actuating a syringe plunger, characterized in that between the pore storage (12) and the carpule (5) an inner cannula sleeve (9) is arranged non-displaceable, the inner cannula (10) with its sharp needle end in Direction of the septum of the carpule (5) protrudes and back in a flow opening (16) Mün ^¬ det. 3. Syringe according to claim 2, characterized in that the pore store (12) is arranged in front of the syringe outlet, but still within the syringe barrel (4). 4. syringe according to claim 2 or 3, marked thereby, that the diameter of the flow opening (16) GE ^¬ compared to the inner diameter of the inner cannula (10) is redu ^¬ ed. 5. Syringe according to one of the claims 2 to 4, characterized in that the diameter of the flow ^{opening ¬} opening (16) is 0.1 mm to 0.3 mm. 6. Syringe according to one of the claims 2 to 5, characterized in that the inner surfaces of the pore ^¬ memory (12) have a passivation layer.