DE102010047317A1 - Cannula for use in implementation of photodynamic therapy of patient, for treatment of e.g. superficial skin tumor, has optical waveguide that is fixed at cannula joint through optical coupler of optical system - Google Patents

Abstract

The cannula has cannula joint, adapter (20) for syringe or infusion system, and hollow needle (21). The hollow needle is introduced into the optical waveguide (22). The optical waveguide is fixed at the cannula joint through an optical coupler (23) of optical system including light source (24) and optical adapter (25). The total cross-section of optical waveguide is smaller than inner cross-section of hollow needle.

Description

1. Field of the invention

The present invention relates to a cannula, with which a photodynamic substance can be applied and irradiated by means of light, especially for carrying out a photodynamic therapy (PDT).

2. State of the art

PDT is a treatment method in which a photodynamic substance, a so-called photosensitizer, can be applied and activated by light, thereby causing changes to cells and tissues. Primarily, the irradiation of the photosensitizer in the presence of suitable substrates leads to a photochemical reaction in which highly reactive oxygen species are formed. On the one hand, radicals or radical anions are formed, which react with molecular oxygen to form superoxide radicals (hydroxyl radicals and hydroperoxide). These radicals lead to direct and indirect cell and tissue destruction through the oxidation of various biomolecules, including phospholipids, fatty acids, collagens and cholesterols. On the other hand, highly reactive singlet oxygen ( ¹ O ₂ ) is formed, which leads to similar oxidation mechanisms, but their oxidation products trigger further reactions and lead to a stronger direct and indirect destruction. In addition to the biomolecules, the photosensitizer molecules themselves react with the reactive oxygen species with a decrease in fluorescence intensity (so-called "photobleaching") to so-called photoproducts. Thus, the formation of the reactive oxygen species is self-limiting and the therapeutic effectiveness of the photosensitizers is limited. ( TJ Dougherty et al. "Photodynamic therapy." J Natl Cancer Inst. (1998) 90: 889-905 )

The treatment of a basal cell carcinoma (basal cell carcinoma) will be described in the following, the implementation of a PDT. The basal cell carcinoma is the most common skin cancer in humans and is termed semi-malignant (semimaligne) because it infiltrates deep into the surrounding tissue but extremely rarely (in 0.03% of cases) forms metastases. Conventional therapies for the treatment of basal cell carcinoma include surgical removal, liquid nitrogen cryotherapy, or local fluorouracil chemotherapy. PDT represents a modern treatment concept in medicine. First, a precursor of the photosensitizer (eg 5-aminolevulinic acid) is applied to the patient. Within minutes, the substance is taken up, preferably by metabolically active tumor cells, and converted there into photoreactive protoporphyrin IX. Subsequently, the attending physician irradiates the tumor area for a few minutes with red light, using light-emitting diodes or diode lasers. Protoporphyrin IX is activated by the red light and forms highly reactive oxygen species that are able to destroy cells. Within the following days, the upper tissue layers of the basalioma and treated skin area will crust and peel off. The slightly deeper and irradiated cells are partially degraded by phagocytosis. After a few weeks, the wound is completely healed and new healthy skin forms on the treated area. In the days following PDT, patients should avoid direct sunlight, as the photosensitizers are only slowly eliminated from the body. Extensive basal cell carcinomas that extend deep into the tissue require multiple PDT cycles until complete tumor reduction can be achieved. ( D Fayter et al. "A systematic review of photodynamic therapy in the treatment of precancerous skin conditions, Barrett's esophagus and cancers of the biliary tract, brain, head and neck, lung, esophagus and skin" Health Technology Assessment. (2010) 14: 31-37 )

There is now a wide range of photosensitizers that can generally be classified as porphyrins, chlorins and dyes and used in a wide variety of applications. Photosensitizers usually show a high absorption in the long wavelength range. Light in the wavelength range of 700-850 nm can better penetrate tissue and thus reach areas in deeper layers of the body. Ideally, the photosensitizer should have a high singlet oxygen yield while having low photobleaching. For optical dose control, the substance should have natural fluorescence so that the concentration in vivo can be determined by fluorescence spectroscopic measurements. As medicines, photosensitizers should have low dark toxicity and high chemical stability. Preferably, the photosensitizers should selectively accumulate in the tissue to be treated. Modern photosensitizers (see Table 1) differ mainly in the application areas, in that they preferentially accumulate in certain cells and tissues. ( RR Allison et al. "Photosensitizers in clinical PDT" Photodiagnosis Photodyn Ther. (2004) 1: 27-42 ) Tab. 1 Typical photosensitizers photosensitizer Excitation wavelength [nm] * scope of application porphyrins 5-ALA-induced porphyrins 380-670 Photofrin ^® 650 Lung carcinoma, esophageal carcinoma Levulan ^® 595 Actinic keratosis Metvix ^® 630 Basal Cell Carcinoma Verteporfin (Visudyne ^® ) 693 macular degeneration Chlorine 640-700 Photo chlorine ^® 665 Lung carcinoma, esophageal carcinoma Temoporfin (Foscan ^®) 652 Head and neck carcinoma Talaporfin 664 lung cancer dyes Phthalocyanines (Photosens ^®) 600-800 macular degeneration riboflavin 365 keratoconus Cationic dyes 660 Wavelengths used in the PDT of corresponding photosensitizers

Depending on the location of the treatment, the application of the photosensitizers according to the current state of the art can take place in different ways. In easily accessible areas of the body, for example, for the treatment of a superficial skin tumor (eg Basaliom), the photosensitizer can be applied directly to the tumor area. On areas of the body that are difficult to access, such as. B. for the treatment of non-small cell lung carcinoma, photosensitizers can be administered by inhalation as aerosols. Internal organs, for example, the vascular side of the retina in the eye, can be achieved today via an intravenous administration of the photosensitizer. One possibility in this case is the application of a precursor substance (for example 5-aminolevulinic acid), which is converted in the cells into a photoreactive substance (eg protoporphyrin IX). The application of the photosensitizers represents, according to the currently used methods, a compromise between accessibility of the target area and the total body burden by the substance (inter alia, by the dark toxicity).

Irradiation of the photosensitizers takes place, depending on the field of application and the photosensitizer used, via a lamp, light-emitting diode, laser diode, a laser or a comparable light source. Depending on the treatment area, it can be irradiated directly (eg for superficial skin tumors) or indirectly via an optical waveguide (eg in gastrointestinal tumors). With a longer irradiation duration, the optical waveguide is temporarily implanted in the treatment area. Typically, in clinical PDT porfimer sodium (Photofrin ^®) with a light energy of 50-500 J / cm ² is irradiated at 650 nm. Newer photosensitizers have a higher photoreactive efficiency and therefore require lower light energies. Temoporfin (Foscan ^® ) for the treatment of cervical carcinoma requires light energy of only 10 J / cm ² at 652 nm wavelength with comparable efficacy. The absorption spectrum and the optimal activation wavelength depend essentially on the molecular configuration of the photosensitizer. For this reason, sophisticated PDT light sources cover a wavelength range of 220-2200 nm. ( TJ Dougherty et al. "Photodynamic therapy." J Natl Cancer Inst. (1998) 90: 889-905 )

Contrary to most alternative treatment methods, PDT has the advantage that the site of action can be selectively limited by the irradiation. The resulting highly reactive oxygen species have a very short half-life and range. If no radiation is applied, the photosensitizers are inactive and are eliminated biologically from the organism over time. Furthermore, the mobility of the photosensitizers can be limited by the nature of the application. In addition, precursors of photosensitizers can be used, which are specifically activated in metabolically active cells. As a result, the PDT is gentler for the patient and the duration of treatment is shorter comparable procedures. Patients often require weeks to recover from surgery, with PDT usually taking only a few hours. However, the supposed advantages also represent potential disadvantages of the method. Thus, the tissue range of the PDT according to the current state of the art is limited to about 1 cm. This is a critical limitation in the treatment of large tumors and metastases. Another disadvantage of the systemic administration of precursors of photosensitizers are undesirable drug effects (ADRs, including anaphylactic shock), which may be due in particular to metabolism and daylight absorption via the skin.

The influence of light on superficial tumors was first extensively studied by Niels Finsen. Finsen was able to show that skin manifestations of tuberculosis (lupus vulgaris) can be treated by sunlight. For his discovery in 1903 he received the Nobel Prize for Medicine. Later, Friedrich Meyer-Betz introduced the use of porphyrins as part of a radiation therapy on humans. It was not until 1970 that Thomas Dougherty introduced PDT into the clinical routine as a treatment concept. Since then, PDT has been considered for the treatment of a variety of diseases. First and foremost, PDT is now used in oncology. Currently, PDT is used to treat skin cancer and precancerous tumors, Barrett's esophagus, esophageal carcinoma, lung cancer, biliary tract carcinoma, brain tumors, urinary bladder tumors, breast cancer and head and neck cancer. The oncological treatment spectrum is constantly being expanded, among other things, the use for the treatment of gynecological and gastrointestinal tumors is being investigated. Furthermore, the PDT for the treatment of degenerative diseases such. As the age-related macular degeneration (AMD) used. ( RR Allison et al. "Oncologic photodynamic therapy photosensitizers: a clinical review." Photodiagnosis Photodyn Ther. (2010) 7: 61-75 ) Recent developments in PDT not only exploit the effects on degenerate and mutant cells, but aim to alter tissue properties. For example, in the treatment of keratoconus, a continuous thinning of the cornea, UVA irradiation of riboflavin is used to crosslink collagen and thus to ensure mechanical stabilization. ( G Wollensak et al. Collagen fiber in the rabbit cornea old collagen crosslinking by riboflavin / UVA. "Cornea. (2004) 23: 503-507 )

Future developments in PDT are primarily aimed at improving the properties of photosensitizers. Antibody photosensitizer conjugates, which bind specifically to antigens and can act locally, are under discussion. Also, conjugates with magnetic or thermosensitive nanoparticles are investigated, which can be controlled by their physical properties. With regard to irradiation, a metronomic therapy (low-dose long-term irradiation) with a low photosensitizer concentration is discussed. For future irradiation therapies organic light-emitting diodes, soluble, time-controlled as well as activatable light sources are described. ( RR Allison et al. "Future PDT." Photodiagnosis Photodyn Ther. (2009) 6: 231-234 ; RR Allison et al. "Future of oncologic photodynamic therapy." Future Oncol. (2010) 6: 929-940 )

Numerous technical solutions already exist to enable adequate illumination by means of glass fibers and optical waveguides. In contrast, the proportion of described technical solutions that simultaneously allow for application of liquids, low. KP Luloh describes in the U.S. Patent No. 5,425,730 a specially designed for the operation on the vitreous system through which instruments and infusions in the vitreous space can be introduced and thereby a continuous illumination of the surgical area can be ensured by glass fibers. The patent, however, makes no reference to the benefits of a PDT. SJ Rychnovsky et al. describe in their patent application no. WO 2004/012805 a catheter system for PDT in hollow organs. This catheter includes four lumens, one for the guidewire, one for the fiber optic cable, one for infusion, and one for dilating the balloon at the distal end of the catheter. In this case, the guide wire is the controlled advancement of the catheter and the infusion lumen rinsing the hollow organ, z. B. bleeding. Essentially, only lighting of the hollow organ through the optical fiber cable should be achieved by the described technical solution. By doing U.S. Patent No. 4,998,930 SL Lundahl describes a catheter for carrying out a PDT, which has an inflatable balloon at its distal end, in the center of which there is the mouth of a fiber optic cable, and which can thus provide a radial illumination of the hollow organ. MV Oritz describes in his U.S. Patent No. 6,096,030 a catheter for PDT in a blood vessel. To stow the blood in a vessel also this catheter has at the distal end of an inflatable balloon, in the center of which is an optical waveguide for the irradiation. MB van der Mark et al. describe in their patent application no. WO 2009/050667 the use of a cannula for tissue function, in which an optical waveguide can be introduced. The purpose of their invention is to determine the dignity of a pathological tissue. For this purpose, a contrast agent or a fluorescent dye is applied through the cannula and measured spectroscopically via the glass fiber. M Martinez describes in the U.S. Patent No. 4,222,375 a lighting system in which a fiber optic cable into a cannula is introduced and via a second instrument with an optical adapter, the light is coupled into the optical waveguide. In the description of the invention, however, Martinez makes no reference to the benefit of a PDT.

Brief description of the illustrations

For a better understanding, as well as a clear view of the cannula and its use according to the present invention, several illustrations are attached with reference to the description.

1 Figure 12 shows the schematic cross section of an eye into which the cannula described in this invention is inserted and is intended to be used to perform local photodynamic therapy (PDT) on the inner retinal layers. 2 shows possible designs of the cannula described in this invention.

LIST OF REFERENCE NUMBERS

10

vitreous

11

lens

12

anterior chamber

13

cornea

14

Macula of the retina

15

optic nerve

16

Ora serrata

17

Cannula hollow needle

18

cannula shoulder

19

optical coupler

20

infusion adapter

21

cannula

22

optical fiber

23

optical coupler

24

led

25

optical adapter

26

Round hollow needle end with lateral perforation

27

ground hollow needle point

28

straight end of hollow needle

Detailed Description of the Preferred Embodiments

Preferred embodiments

The present invention relates to a novel cannula for performing photodynamic therapy to improve handling and control during the application and irradiation of photosensitizers.

A feature of this cannula is that the photosensitizers can be applied directly to the site of action. Under vision or with the help of imaging techniques (including ultrasound and X-rays), the cannula can be pushed towards the target area and placed at the site of treatment depot of photosensitizers. In order to adequately fulfill this characteristic, it may be important that the fluid must be forced through a long, thin cannula with positive pressure. As a first feature, the described cannula must be correspondingly secure against overpressure on a commercially available syringe. This can be achieved, inter alia, by a screw, turn, snap or click connection. The cannula sleeve is to be produced from a mechanically stable material, which at the same time allows the representation by means of a conventional imaging. For this purpose, it must be a sound or radiopaque material. After setting a photosensitizer depot at the treatment site, it should be possible to irradiate the tissue without changing the instrument or moving the cannula. Retraction of the cannula could result in reflux of the applied photosensitizers or translocation of mutant cells via the puncture channel. For this purpose, at least one optical waveguide is located in the cannula. The optical fiber should be chosen so that it transmits the light at the excitation wavelength of the photosensitizer used. The distal end of the optical waveguide is to be processed, for example by fracture techniques, in such a way that it enables homogeneous irradiation. The proximal end of the optical waveguide is fixed to the cannula shoulder. At the cannula shoulder is via an optical adapter or a light source coupled to the transmitted light in the optical waveguide. The transition between optical waveguide and the coupling unit must be sufficiently adapted to the pressure conditions in the cannula. The optical waveguide should preferably be coated so that a biological compatibility is given and unwanted effects (including allergic reactions, thrombosis) do not occur. Of particular importance is that the optical adapter or the light source is fixed directly on the cannula shoulder. In addition to improved handleability, this configuration provides the ability to leave the cannula in the patient's body for extended periods of time in a metronomic therapy to ensure long-term exposure of the tissue without risking kinking or breaking of the fibers. After applying the photosensitizers by means of a syringe via the cannula, the syringe can be detached from the cannula and the cannula can be closed. This offers the advantage that only the cannula adapter is located on the body surface and the patient can move without restriction. If a continuous application of photosensitizers is desired or required, an infusion machine can be connected via the cannula adapter. Depending on the anatomical requirements, the distal end of the cannula can be straight, pointed or round. It can, for. B. on mechanically sensitive structures, such as the retina or the spinal cord, be advantageous to use a smooth or round cannula tip to protect the tissue. Likewise, the distal end of the optical waveguide may be processed such that light radiates diffused radially to inner tissue structures, eg. As metastases, to irradiate evenly. Depending on the anatomical conditions, it may be advantageous to make the cannula straight, curved or angled. As a further feature, it would be desirable for the optical adapter at the cannula shoulder not only to couple light into the optical waveguide, but also to transmit reflected light and thus allow spectroscopic detection of fluorescence radiation. The dynamics of the fluorescence radiation can be used to determine the dose of the active photosensitizers.

example 1

According to the German patent application DE 10 2009 056 597 a PDT can be used to treat pathological processes on the inner border membrane of the retina ( 1 ). Due to the blood-retinal barrier, systemic administration of photosensitizers to perform PDT on the inner border membrane is not possible. Instead, it is necessary to use the photosensitizer, e.g. B. riboflavin, from the inside of the eye over the vitreous cavity ( 10 ) on the retina ( 14 ) to apply. The irradiation of the site to be treated on the retina is possible via the optical beam path (roughly dashed lines) of the eye. However, the dosage of the light and the control of the exposure of many individual factors (eg, scattered radiation or absorption of short wavelength light by the lens ( 11 )). Controlled and safe irradiation provides one of the cannulas provided in this invention. The described cannula allows the surgeon to apply the highly viscous riboflavin to the retina and then perform a local irradiation with UVA light (dense dashed lines). UVA light could be transmitted through the natural ray path of the eye due to the absorption of the lens ( 11 ), Anterior chamber ( 12 ) and the cornea ( 13 ) are not transmitted. At the same time, the cannula saves the operator from having to change the instruments.

Example 2

The use of PDT to treat tumors and metastases in solid organs such as the liver and kidney has been very limited. The main cause is again and again the low tissue penetration depth of the light. With the aid of a cannula described in this invention it will be possible to photosensitize z. B. targeted to apply under ultrasound guidance and irradiate the pathological focus from the inside. For a radial illumination of the focus, it is preferable to use an optical waveguide with a diffuse surface at the distal end. In a continuous, metronomic radiation therapy over several hours, the cannula can be separated from the syringe and closed without affecting the internal irradiation of the focus itself.

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• US 5425730 [0010]
• WO 2004/012805 [0010]
• US 4998930 [0010]
• US 6096030 [0010]
• WO 2009/050667 [0010]
• US 4222375 [0010]
• DE 102009056597 [0015]

Cited non-patent literature

• TJ Dougherty et al. "Photodynamic therapy." J Natl Cancer Inst. (1998) 90: 889-905 [0002]
• D Fayter et al. "A systematic review of photodynamic therapy in the treatment of precancerous skin conditions, Barrett's esophagus and cancers of the biliary tract, brain, head and neck, lung, esophagus and skin" Health Technology Assessment. (2010) 14: 31-37 [0003]
• RR Allison et al. "Photosensitizers in clinical PDT" Photodiagnosis Photodyn Ther. (2004) 1: 27-42 [0004]
• TJ Dougherty et al. "Photodynamic therapy." J Natl Cancer Inst. (1998) 90: 889-905 [0006]
• RR Allison et al. "Oncologic photodynamic therapy photosensitizers: a clinical review." Photodiagnosis Photodyn Ther. (2010) 7: 61-75 [0008]
• G Wollensak et al. Collagen fiber in the rabbit cornea old collagen crosslinking by riboflavin / UVA. "Cornea. (2004) 23: 503-507 [0008]
• RR Allison et al. "Future PDT." Photodiagnosis Photodyn Ther. (2009) 6: 231-234 [0009]
• RR Allison et al. "Future of oncologic photodynamic therapy." Future Oncol. (2010) 6: 929-940 [0009]

Claims (5)

Cannula for carrying out a photodynamic therapy consisting of a cannula shoulder ( 18 ) with an adapter ( 20 ) for a syringe or a comparable infusion system and a hollow needle ( 21 ) into which at least one optical waveguide ( 22 ), characterized in that the optical waveguide at the cannula shoulder in an optical Einkoppler ( 23 ), consisting of an optical system with light source ( 24 ) or an optical adapter ( 25 ), is fixed. Cannula according to claim 1, characterized in that the total cross section of the optical waveguide is smaller than the inner cross section of the hollow needle. Cannula according to claim 1 and 2, characterized in that the cannula can be connected by the adapter overpressure resistant with a screw, turn, snap or click closure. Cannula according to claim 1, characterized in that the optical adapter can couple light via a lens and filter system in the optical waveguide and can transmit back-beaming light for detection. Cannula according to claim 1, characterized in that the hollow needle consists wholly or partly of a material which can be represented by means of ultrasound or X-rays in the human body.

Images