PROVISION OF BACTERIOPHAGES IN VARIOUS DOSAGE FORMS AND BACTERIOPHAGE APPLICATION DEVICE

Abstract

The invention relates to bacteriophage means, namely intracorporal bacteriophage means, nasopharyngeal and pulmonary bacteriophage means, cutaneous bacteriophage means, and bacteriophage suture means, and in addition a two-syringe bacteriophage means, a nasopharyngeal and pulmonary bacteriophage means device, and a bacteriophage sensitive testing application.

Claims

1-8. (canceled)

9. An intracorporal bacteriophage material or composition, comprising: a) a sterile bacteriophage gel, wherein said gel is release-modulatable; or b) sterile bacteriophage soft capsules comprising a gel; or c) sterile soft capsule chain comprising a bacteriophage soft capsules having a gel on a monofilamentous hydrolytically degradable filament or on a non-degradable material; or d) a sterile bacteriophage sponge, wherein the sponge is sprayed with a bacteriophage solution or a bacteriophage gel, or a bacteriophage gel is freeze-dried.

10. A naso-pharyngeal and pulmonary bacteriophage material or composition, comprising: a bacteriophage solution or as a bacteriophage powder, wherein the bacteriophage material or composition is nebulizable using at least one of the following: nebulization via respirator using a phage nebulization device; nebulization via pressurized gas metered dose aerosols; nebulization via jet nebulizer; nebulization via membrane nebulizer; nebulization via powder inhaler.

11. A cutaneous bacteriophage material or composition, comprising a) a sterile bacteriophage powder; or b) a sterile bacteriophage sponge including a bacteriophage gel or a bacteriophage powder as wound dressing.

12. A bacteriophage suture material or composition, comprising: characterized in that a) a monofilament surture material is circularly sprayed with a bacteriophage solution or with a bacteriophage gel or b) a polyfilament suture material is wetted with a bacteriophage solution or with a bacteriophage gel, wherein the solution or gel is provided on the suture material and/or in the contact zones.

13. A two-syringe bacteriophage material or compoisition, comprising: a first syringe is prepared with a bacteriophage solution and a second syringe is prepared with a gel, the two syringes being connectable to each other, wherein mixing of the gel with the bacteriophage solution is possible and this mixture is then present in a syringe ready for application.

14. The two-syringe bacteriophage means according to claim 13, whereindifferent gels and/or different bacteriophage solutions can be kept in stock for different combination among each other and accordingly mixed with each other to form a dedicated bacteriophage solution gel.

15. A naso-pharyngeal and pulmonary bacteriophage material or composition, comprising: a) a bacteriophage solution or a bacteriophage powder is nebulizable using at least one of the following devices, and the bacteriophage nebulization device is formed as: a ventilator including a nebulization device or a pressurized gas-dosing aerosol chamber; a pressurized gas metered dose aerosol applicator a container inhalation arrangement including a nebulization chamber and a jet nebulizer or a membrane nebulizer; an inhalation device including a pressurized gas metered-dose inhaler; a powder inhaler.

16. A bacteriophage sensitive testing application comprising bacteriophages, a bacterial nutrient solution, and a dye are arranged in a container, wherein the dye can interact with bacterial cell walls.

Description

[0080] Example embodiments of the invention will be described in detail while making reference to the accompanying drawings in the description of figures, and additional embodiments will be shown below which are not shown in the figures. These embodiments are to explain the invention and are not intended to be limiting.

[0081] In the figures:

[0082] FIG. 1 is a schematic representation of an embodiment of a first bacteriophage application device;

[0083] FIG. 2 is a schematic representation of an embodiment of a second pulmonary bacteriophage application device;

[0084] FIG. 3 shows a hard capsule appropriately filled with bacteriophage and carrier material and designed for suitably operating devices;

[0085] FIG. 4 is another application variant, wherein an intracorporal bacteriophage application is shown herein; FIG. 5 shows another application, wherein a sterile bacteriophage soft capsule application is represented;

[0086] FIG. 6 shows a bacteriophage soft capsule chain application;

[0087] FIG. 7 shows a bacteriophage sponge-gel application variant;

[0088] FIG. 8 is a schematic representation of an embodiment of a bacteriophage sensitive testing application shown in the initial state; and

[0089] FIG. 9 is a schematic representation of an example embodiment of the bacteriophage sensitive testing application of FIG. 9 in the testing phase.

[0090] FIG. 1 is a schematic representation of an example embodiment of a first application, wherein a pulmonary bacteriophage application to be used for the lungs and respiratory tract is shown, wherein a bacteriophage solution for nebulization is provided through pulmonary bacteriophage application devices.

[0091] In this regard, the pulmonary bacteriophage application is performed using several types of pulmonary bacteriophage application devices that are directly held against a user’s airway or are connectable to an existing respiratory supply device.

[0092] A first pulmonary bacteriophage application device comprises a pressurized gas metering aerosol chamber through which bacteriophage solution(s) are coupleable to the respiratory device. The bacteriophage solution is held in a container compatible with a pressurized gas aerosol.

[0093] FIG. 2 shows a second pulmonary bacteriophage application device comprising a nebulization chamber through which bacteriophage solution(s) can be coupled to the respiratory device, the nebulization chamber having j et nebulizers and/or membrane nebulizers.

[0094] Bacteriophage nebulization via the respirator is performed using a phage nebulization device, which is to be fitted as an intermediate member in the respiratory tube and is to be connected downstream of the respiratory filter. The bacteriophages are entrained by a flutter valve during ventilation of the patient. Due to the set ventilation pressure, the same amount of BPH solution is constantly applied per ventilation. The flutter valve closes by reversing the pressure during exhalation, so that no bacteriophage solution is delivered during exhalation. Between the BPH solution and the flutter valve is a mesh that sets the nebulization droplet size. Different meshes can be provided for different therapeutic targets and bacteriophage target regions, and thus different droplet sizes can be generated. Since the phage nebulization device does not interfere with the airflow, CO.sub.2 measurements and nebulization of other therapeutic agents remain unrestricted. The bacteriophage solution will preferably be packaged as a stable solution in single doses and will be added to the appropriate device before inhalation.

[0095] Another pulmonary bacteriophage application device (not shown in the figures) has a powder inhaler. The bacteriophages are applied to a carrier material and maintained in bulk or as a single dose (capsule, blister, or the like) for appropriate inhalation. The inhalative powder inhaler uses spray drying, thereby dissolving a suitable carrier material, for example lactose, in the bacteriophage solution. The solution is reconverted into the solid aggregate state by spray drying resulting in a solid, amorphous carrier material state. This state causes immediate dissolving of the material by extracellular fluid and accompanying release of the bacteriophages.

[0096] Another way of applying the appropriate bacteriophage solution to the respective carrier material is by the spray-on method, wherein the carrier material is brought under nozzles through which the bacteriophage solution is sprayed. It is particularly advantageous for the carrier material to flow to cause allover wetting.

[0097] All of the pulmonary bacteriophage applications mentioned above may be used to inhale the therapeutic dose of bacteriophage - sealed from the environment. The solution is especially nebulized in droplet sizes smaller than 5 micrometers, reaching the bronchial trees up to the alveoli by appropriately inhaling.

[0098] FIG. 3 shows a hard capsule appropriately filled with bacteriophages and carrier material and designed for suitably operating devices.

[0099] FIG. 4 shows another application variant, wherein an intracorporal bacteriophage application is shown producing a sterile bacteriophage gel from a bacteriophage solution which can be applied intracorporally at all places using bacteriophage application devices.

[0100] During manufacture, a gel is prepared using a gel builder, for example HPMC or the like, without any water portion of the subsequent bacteriophage solution, and will be sterilized. Adhesive substances can be added for improving adhesion to different materials (PTFE, ceramic, Dacron, titanium, zinc oxide...).

[0101] The bacteriophage solution is sterile-filtered under sterile conditions and maintained in a sterile state, e.g. in a syringe. The sterilized gel is maintained under sterile conditions e.g. in a syringe. For better storage, the two components will be mixed in time using a two-syringe technique not earlier than immediately before an application.

[0102] The properties of the resulting gel as well as the bacteriophage release rate therefrom are set by the amount of gel builder used. For this reason, different gel bases are kept in stock, e.g. in syringes. All bacteriophage solutions, which differ in their bacteriophage composition, can be combined with all gel bases using the two-syringe technique.

[0103] Other ways of gel providing are e.g. a stepwise procedure wherein, using automated production, e.g. bacteriophage solutions are mixed with a first portion of the gel and will be sterile-filtered, and modulation of this basic gel by appropriate admixing of gel builder under sterile conditions in a downstream production step will subsequently be performed.

[0104] Furthermore, it is possible to perform automated sterile filling of BPH solution and the base gel, and subsequently sterilizing the base gel in the final container. Contacting the BPH and the base gel may then be performed as required.

[0105] Moreover, it is also possible to sterile-fill the BPH solution and base gel by machine and then sterilize the base gel in the final container. Contacting the BPH and the base gel may then be performed as required.

[0106] Other ways to provide sterile bacteriophage gels include embedding the phages homogeneously distributed in a hydrogel matrix. Release from the hydrogel is ruled by the proportion of hydrogel builder in relation to the proportion of water. The product does not interact with skin or mucosal cells, will be incorporated into the human organism and may be used intra- and extra-corporally, or the phages can be embedded into a lipophilic gel matrix. Release from the hydrogel will be determined by the proportion of lipophilic gel builder in relation to the proportion of water. In addition to the antibacterial mechanism, the product is highly moisturizing, supporting the intrinsic wound healing process in addition to antibacterial therapy/prevention. It may be applied extra-corporally, especially cutaneously, or the phages may be embedded in an amphiphilic gel matrix. In this case, release from the hydrogel will be determined by the proportion of amphiphilic gel builder in relation to the proportion of water. The product may also be used extra-corporally.

[0107] All gels may also be introduced in a minimal-invasive manner via a syringe. Percutaneous application, e.g. into an abscess, now has become possible for the first time.

[0108] The viscosity, release rate and BPH composition can immediately be adjusted prior to application. Release in lower viscosity gels is fast and in high viscosity BPH gels release is over a longer period of time.

[0109] FIG. 5 shows another application, wherein a sterile bacteriophage soft capsule application is shown, wherein initially a gel is produced, which, contrary to the previously described gel, already provides the final product as a gel, i.e. no further production steps are required. This gel, which may be varied in viscosity, bacteriophage content and composition, as required, is sterile-filled into soft capsules using the rotary die process, the dripping process or other technical processes suitable for generating soft capsules. For example, gelatin is used as the capsule material. The capsule material is selected according to requirements. Applicable requirements may be the release rate and the scope of the therapy. What is meant herein is that low viscosity forms liquefy more quickly and more strongly due to body fluid and body temperature, for example, thus effluent of these forms from the site of application is stronger and is across a larger area. If the BPH formulation is more likely to be retained at the site of application, a higher viscosity form should be used, which is less rapidly liquefied by body temperature and body fluid and remains at the site of application for a longer period of time.

[0110] Moreover, different thicknesses of the capsule shell and different sizes of the capsule itself can be used in in the process.

[0111] The bacteriophage soft capsule application thus provides a bacteriophage depot or phage depot as a unit in which at least one bacteriophage or phage is provided as a phage application that retains stability after introduction into a body in a manner definable in time.

[0112] In addition to the previous embodiments, FIG. 6 shows another application, wherein a sterile bacteriophage soft capsule chain application is provided. As in the bacteriophage soft capsule application, soft capsules are prepared according to appropriate requirements. Following appropriate manufacture, the capsules are mounted in a fixed distance from each other, especially on a monofilamentous hydrolytically degradable thread. This allows application during surgery, even in body cavities.

[0113] FIG. 7 shows a variant bacteriophage sponge-gel application. Another application shows a sterile bacteriophage sponge-gel application based on the gels already presented. They are freeze-dried / lyophilized under precise adjustment and control of the influencing parameters, as well as under sterile conditions. Furthermore, all drying options for the production of a solid bacteriophage application from the appropriate gels are allowed.

[0114] The phages can be provided after freeze-drying in a form embedded in a solid matrix, embedded in a now solid lipophilic gel matrix or embedded in a now solid lipophilic gel matrix as a bacteriophage sponge-gel application. In each case, release will be radial - from the outside to the inside. This corresponds to a sustained release mechanism. Release will be determined by the proportion of gel builder in relation to the proportion of water.

[0115] This galenic form leads to sustained release of the antibiotic agent. The release rate will be determined by the surface area to volume ratio. Furthermore, collagen fibers may be added to the starting gel to support the corresponding gel matrix as a stabilizer.

[0116] FIG. 8 and FIG. 9 show a bacteriophage sensitive testing application, wherein a container holds appropriate bacteriophages, a bacterial nutrient solution (liquid), and a dye that interacts with bacterial cell walls. When interacting, the dye is visible A. / the dye is colorless B. A sample, e.g. a swab (sampler included in the set) is placed directly into the container as a test sample. The dye interacts with the bacteria and is A. visible / B. not visible. The testing is incubated for 12 h to 24 h at 36° C. After this time, the sensitivity of the bacteria to the BPH present is indicated in that the solution is less intensely stained A. / is stained B.

Other Applications

[0117] This list of bacteriophage applications is not exhaustive. Combinations of the bacteriophage applications can also be provided and materials can be coated with the bacteriophage applications prior to use, thus generating further applications.

[0118] A particularly noteworthy example application for a specific phage application is prosthetics.

[0119] Even today, prosthesis infections represent one of the most serious complications of reconstructive surgery. Prosthesis infections, especially with the aorta being affected, often have a lethal course; this technical field in particular is not only highly complicated, but also particularly prone to complications due to the large number of plastics prostheses used.