Prostate biopsy needle

Present invention solved the problem of complications occurred during transrectal prostate biopsy, mostly infectious and bleeding complications. Thus, the prostate biopsy needle according to the invention comprising a cannula (1), a pointed stylet (2), which is mounted slidably in the cannula (1), handles (3a, 3 b) for the biopsy gun, which are located on the back side of the needle. An inner surface (4) of the cannula (1) and/or an outer surface (5) of the cannula (1) and/or a surface of the stylet (2) is coated with at least one active layer (6) comprising a biologically active agent, wherein the active layer (6) preferably forms a biodegradable structure enabling controlled release of the biologically active agent.

RELATED APPLICATIONS

This application is the U.S. National Phase of and claims priority to International Patent Application No. PCT/PL2016/000006, International Filing Date Jan. 21, 2016, entitled Prostate Biopsy Needle; which claims benefit of Polish Application No. PL P.411023 filed Jan. 22, 2015; both of which are incorporated herein by reference in their entireties.

The present invention relates to the prostate biopsy needle for performing transrectal prostate biopsy.

Prostate cancer is the most common malignancy diagnosed in men in Europe, Australia and North America. The average chance to develop this cancer during lifetime is approximately 15% and its incidence rate is estimated to be about 150 per 100 000 male. It is associated with high costs of diagnosis and treatment, which are estimated at 8.43 billion € per year in Europe.

Transrectal ultrasound-guided prostate biopsy is the standard method for pathological diagnosis of prostate cancer and is one of the most common urological procedures performed around the world. Only in the United States of America, there are approximately 800 000 prostate biopsies performed annually.

Patent application U.S. Pat. No. 5,014,717 discloses a punch-biopsy apparatus for prostate biopsy comprising a cannula, a stylet that is mounted slidably in the cannula, handles for a biopsy gun which are located on the back side of the needle. Known prostate biopsy needle is inserted into the prostate under transrectal ultrasound guidance. Triggering the spring mechanism results in a rapid sliding of the stylet, and then pulling the cutting cannula on the stylet. This enables to collect the tissue sample from the desired area of a prostate. During the biopsy at least eight cores should be taken from different parts of the prostate. This multiplies the risk of complications mentioned below.

The most common complications following transrectal prostate biopsy performed by known prostate biopsy needles are hematuria and hematospermia. However, the most serious clinical problems are infectious complications occur after the prostate biopsy. During the procedure, after introduction of the needle through the rectum, the intestinal bacteria are transferred into the blood and the prostate. Patients undergoing prostate biopsy are exposed to urinary tract infections, prostatitis, and even severe septic complications. Therefore, it is recommended that periprocedural oral antibacterial prophylaxis should be administrated. The most commonly used antibiotics in antibacterial prophylaxis prior transrectal prostate biopsy are oral fluoroquinolones. In recent years, numerous scientific publications have reported the rapid spread of intestinal bacterial strains resistant to this group of antibiotics. This phenomenon is responsible for an increase in the percentage of severe infectious complications occurring after the prostate biopsy performed by the known biopsy prostate needle.

Hitherto, an effective and fully accepted strategy to reduce the infections caused by transrectal prostate biopsy still has not been defined. Attempts to use oral or intravenous antibiotics from other groups appear to be insufficiently effective. While, simultaneous use of multiple antibiotics in prophylaxis can result in significant side effects.

The known prostate biopsy needle does not allow to overcome the problem of hematuria, hematospermia and infectious complications which occur as a result of transrectal invasive procedures of prostate biopsy.

A known solution of this problem is a transperineal prostate biopsy. However this method has some significant disadvantages including the need for epidural or general analgesia, which is an additional burden for the patient and special equipment requirements, which increases the costs of diagnosis.

There are known multiple methods to modify the surface of medical devices for insertion into human organs and body cavities for long-term period. Examples of such medical devices include: stents, vascular grafts, catheters, urological, orthopedic implants and contact lenses. Their surface is usually coated with a bioactive layer. The presence of a bioactive layer enables to release biologically active substances from the surface of such devices. Biologically active agents are usually used to reduce the risk of vessels occlusion (stents and vascular grafts) or prevent infection (orthopedic implants or dental catheters, urology, contact lenses, vascular prostheses) that can develop due to long exposure to medical device implanted into the body.

There are also known urological catheters, contact lenses, vascular, orthopedic or dental implants, which surface is coated with a bioactive layer releasing antimicrobial agents. Furthermore, there are known medical devices such as catheters, urological and vascular stents, which surface is coated with an additional protective layer that enables stable release of active agents and/or with additional binder layer which strengthens the connection of bioactive layer with the surface of the medical device.

The application of beta-cyclodextrin complex with vancomycin on the surface of the vascular prosthesis made of poly(ethylene terephthalate) is known from the publication [Blanchemain N et al. European Journal of Vascular and Endovascular Surgery 2005, 29, 628-632]. Cyclodextrins are cyclic oligosaccharides with a toroid-shaped molecular structure, characterized by a hydrophilic outer surface and a lipophilic central cavity which enable them to form inclusion compounds with antibiotics.

The formation of the antimicrobial bioactive layer on the surface of titanium medical implant using poly(vinyl alcohol), chitosan and silver ions is known from the publication [Mishra S K et al. Mechanically stable antimicrobial chitosan-PVA-silver nanocomposite coatings Deposited on Titanium Implants, Carbohydrate Polymers, 2015, 121, 37-48]. The contact lenses with a bioactive layer formed of poly(L-glutamic acid) containing ciprofloxacin are known from literature [Ciolino J B et al., Drug-Eluting A Contact Lens. Investigative Ophthalmology and Visual Science, 2009, 50 (7), 3346-3352].

Patent No PL214742 discloses a method for preparing an antibacterial layer on the surface of the catheters by immobilization of antimicrobial substances due to fixed connection through the use of the polysaccharide.

There are known silicone catheters with antibacterial properties, where the bioactive layer is formed by immersing the catheter in a solution composed of polymers: poly(ethylene-co-vinyl acetate), poly(ethyleneoxide) and poly(dimethylsiloxane) containing antibiotics [Park J H et al., Journal of Biomaterials Science, Polymer Edition, 2003, 14 (9), 951-962].

All of the known medical devices coated with bioactive layer are designed for implantation into the human body permanently or for a long period of time. The biopsy prostate needle is not such a device since it is introduced into the body for relatively short time only during duration of procedure.

The object of the invention is to provide the prostate biopsy needle, which reduces the periprocedural complications. The invention therefore relates to prostate biopsy needle, which provide protection against potential infection and perioperative bleeding complications. In particular the biopsy needle with specific construction that allow the administration of biologically active agents during the prostate biopsy.

Unexpectedly, we found that adequate and very distinctive coating of biopsy needle with bioactive layer or relevant mechanical construction of a biopsy needle enables release or direct application of the biological active compounds to a prostate gland.

Thus according to the invention the prostate biopsy needle comprising a cannula, a pointed stylet mounted slidably in the cannula, handles for a biopsy gun located on the back side of the needle, characterized in that an outer surface of the cannula and/or a surface of the stylet is coated with at least one active layer comprising a an antibacterial substance. The active layer preferably forms a biodegradable structure enabling controlled release of the biologically active agent.

In a preferred embodiment, the outer surface of the cannula and/or the surface of the stylet form an extended surface in a form of a grooved and/or rough and/or porous surface.

In a preferred embodiment, the extended surface forms pits with depth ranged from 0.001 mm to 0.1 mm, preferably from 0.01 mm to 0.06 mm.

In a further embodiment, the part of outer surface of the cannula is coated with the active layer, wherein the coated part is an area ranged from 0.1 cm to 10 cm in length, preferably from 4 cm to 8 cm, and/or the part of the surface of the stylet is coated with the active layer, wherein the coated part is the area ranged from 0.1 cm to 10 cm in length, preferably from 4 cm to 8 cm. In an embodiment, the coated part of the outer surface of the cannula extends from a tip of the cannula and/or the coated part of the surface of the stylet extends from the tip of the stylet.

In a further embodiment, the active layer is applied on a binder layer wherein the outer surface of the cannula and/or the surface of stylet is coated with the binder layer.

In a further embodiment, the active layer contains a binder agent.

In a further embodiment, the surface of active layer is coated with a protective layer enabling stable release of the biologically active agent, preferably in the form of polymer layer.

In an embodiment, the protective layer has a form of a fine mesh with the cells size from 1 μm to 500 μm, preferably 10 μm to 100 μm.

In an embodiment, the antibacterial substance is an antibiotic and/or the chemotherapeutic agent and/or zinc ions and/or silver ions.

To solve the problem, the present invention also provide prostate biopsy needle comprising a cannula and pointed stylet mounted slidably in the cannula which is characterized by longitudinal pass-through-hole channel formed in the wall of the cannula. The channel has closed profile in cross-section view, and the channel extends through the entire length of the wall of cannula or the part the length thereof. In preferred embodiment of this invention, the channel is circular-shaped in cross-section with the diameter of 0.1 mm to 2.0 mm, preferably from 0.5 mm to 0.7 mm.

In further embodiment, the channel protrudes over the outer surface of the cannula, preferably protrudes over the area of 130 mm to 155 mm from the cannula.

According to the invention, biopsy needle enables for direct delivery surface elution of different antibiotics, and/or anti-inflammatory drugs and/or other substances with a biological activity into the prostate. This does not require additional punctures of the prostate since biologically active agents are released simultaneously during prostate biopsy. The positive effect of this invention is that biologically active agents are introduced through the needle precisely to the starting point of potential infection. This allows for reduction or complete elimination of oral or intravenous antimicrobial prophylaxis prior transrectal prostate biopsy. Furthermore, the effective dose of drugs administered directly into the prostate may be significantly lower than in intravenous or oral form. The invention enables simultaneous topical application of a set of antibiotics, which can broaden the spectrum of antimicrobial protection, with a lower risk of side effects. The invention set a completely new approach of periprocedural antimicrobial prophylaxis for prostate biopsy. The invention also enables the simultaneous administration of several active agents like anesthetics and/or anti-inflammatory and/or antibacterial and/or antihemmorrhagic substances.

A steel biopsy needle with 200 mm length, comprises a pointed cannula1, pointed stylet2mounted slidably in the cannula1and in the back the polypropylene holders for the biopsy gun—a cannula holder3aand stylet holder3b. The outer diameter of the cannula1is 1.93 mm, the inner diameter of the cannula1is 1.70 mm, and the stylet2diameter is 1.65 mm.

The inner surface4of the cannula1and the outer surface5of the cannula1and the surface of the stylet2, over the entire length of the steel needles are coated with the active layer6containing the biologically active agents, as shown inFIGS. 1-5. Active layer6has a biodegradable form allows for the controlled release of the biologically active agent by dissolving in water contained in the blood and biopted tissue. The active layer contains two antibiotics—ciprofloxacin and amikacin which form inclusion complex with β-cyclodextrin. An active layer6was obtained by mixing in a centrifuge (5 min, 30 rpm), ciprofloxacin, amikacin and β-cyclodextrin in a molal ratio 1:1:2. The mixture of compounds was dissolved in 0.14% aqueous solution of a nitrogen hydride (III). The obtained solution was filtered. After immersion of the steel cannula1and stylet2in solution, the freeze-drying process was carried out to perform the active layer6fixation. As shown inFIG. 39by using the biopsy gun and a biopsy needle under transrectal ultrasound, prostate cores s were collected in a standard way. During the procedure, ciprofloxacin and amikacin were directly release from the biodegradable active layer6into the prostate tissue by disintegration of inclusion complex of β-cyclodextrin with antibiotics. In vitro and in vivo studies confirmed the release of drugs from the active layer6applied to the steel surface of the biopsy needle and the antibacterial effect in the action area o of bioactive agents.

The needle is made as described in Example 1, except that the inner surface4of the cannula1and part of the outer surface5of the cannula1, 5 cm long from the tip of it, is coated with an active layer6as shown inFIG. 6andFIG. 7. The active layer6contains two antibiotics: ciprofloxacin and amikacin, as described in Example 1.

The needle is made as described in Example 1, except that the part of stylet2surface, 7 cm long from the tip of it, is coated with an active layer6, as shown inFIG. 8andFIG. 9. The active layer6contains two antibiotics: ciprofloxacin and amikacin, as described in Example 1.

The needle is made as described in Example 1, except that the active layer6is applied on the binder layer7, which is placed on the outer surface5of the cannula1and the inner surface4of the cannula1and the surface of the stylet2, as shown inFIG. 10andFIG. 11. The binder layer7is made of poly(vinyl alcohol). The binder layer7was obtained by dipping the cannula1in a solution of acetone and drying, and then dipping in an aqueous solution of 0.5 mM/L, of poly(vinyl alcohol) (molecular weight of 49,000 g mol-1). On such binder layer7the active layer6, obtained as described in Example 1, was applied.

The needle is made as described in Example 1, except that the active layer6is applied on the binder layer7, which covers the outer surface5of the cannula1, as shown inFIG. 12andFIG. 13. The binder layer7is made of polyethylene (vinyl alcohol). Binder layer7was obtained as described in Example 4 except that in the solution was immersed temporarily sealed cannula1. Then, the outer surface5of the cannula1was coated by spraying with antihemorrhagic substance—potassium aluminum sulfate dodecahydrate, thus leading to formation of an active layer6. In vitro and in vivo studies have confirmed the role of this biopsy needle to accelerate the coagulation process.

The needle is made as described in Example 1, except that the outer surface5of the cannula1is coated with the active layer6, as shown inFIG. 14andFIG. 15. The active layer6contains a biologically active agent—fibrinogen, a protein which is involved in the coagulation process. Temporarily sealed cannula1was dipped ten times in an aqueous solution of fibrinogen (10 mg/ml), and dried temporarily. In vitro and in vivo studies have confirmed the role of this biopsy needle to accelerate the coagulation process and thus minimize the risk of bleeding.

The needle is made as described in Example 1, except that the active layer6is applied to the binder layer7, which is applied on the outer surface5of the cannula1and the surface of the stylet2, as shown inFIG. 16andFIG. 17. The active layer6contains a biologically active antiseptic agent—zeolite, comprising of 2.5% silver ions and 14% zinc ions. The binder layer7is made of poly(vinyl alcohol). The binder layer7was obtained by biopsy needle immersion in acetone solution and drying. Then temporarily sealed cannula1was immersed in an aqueous solution of 0.5 mM/L of poly(vinyl alcohol) (molecular weight about 49 000 g·mol-1). Then, the binder layer7was coated by spraying with zeolit. The needle was dried in 50° C. for 1 hour to obtain the active layer6fixation.

The needle is made as described in Example 1, except that the outer surface5of the cannula1is coated with active layer6as shown inFIGS. 18-20. The surface of the active layer6is covered with a protective layer8to achieve stable release of the biologically active agent during whole prostate biopsy procedure. The protective layer8is made of poly(glycolic acid). The surface of the active layer6was coated by spraying with poly(glycolic acid) which forms a net-like protective layer8. This layer delays the release of the biologically active agent from the active layer6. The active layer6was obtained by mixing in a centrifuge (5 min, 30 rpm) antibiotic—levofloxacin with β-cyclodextrin in molal ratio 1:1. Further procedure was as described in Example 1, except that in the solution was immersed the temporarily sealed cannula.

The needle is made as described in Example 1, except that the outer surface5of the cannula1and stylet2surface have an extended form with porous pits, as shown inFIGS. 21-23. Pores9awere obtained by micro laser engraving with a diameter of 0.1 mm and a depth of 0.05 mm. The active layer6is applied on an extended porous form9aof the outer surface5of the cannula1and on an extended porous surface9aof the stylet2. The outer surface5of the cannula1and stylet surface2were coated with a mixture of β-cyclodextrin with ciprofloxacin in the molal ratio 1:1. Further procedure was as described in Example 1, except that in the solution was immersed the temporarily sealed cannula.

The needle is made as described in Example 1, except that the outer surface5of the cannula1and surface of stylet2have an extended form with grooved pits. The active layer6containing a complex of β-cyclodextrin with an antibiotic—ciprofloxacin was formed on extended grooved form9bof the outer surface5of the cannula1and on the extended grooved form9bof stylet2, as shown inFIG. 24-26. Grooves9bwere formed parallel to the axis of the cannula1and stylet2to accumulate the antibiotic complex what allow an increase dose of active compound of the layer. The dimensions of the grooves9bwere 0.05 mm×0.05 mm×100 mm. Grooves9bwere obtained by micro laser engraving from the tip of the cannula1and stylet2. The active layer6is applied on an extended grooved form9bof the outer surface5of the cannula1and on an extended grooved surface9bof stylet2. The outer surface5of the cannula1and stylet surface2were coated with a mixture of β-cyclodextrin with ciprofloxacin in the molal ratio 1:1. Further procedure was as described in Example 1, except that in the solution was immersed the temporarily sealed cannula.

The needle is made as described in Example 1, except that the active layer6is applied on the outer surface5of the cannula1, as shown inFIG. 27andFIG. 28. The active layer6contains a biologically active antimicrobial agent—levofloxacin. The active layer6was obtained by mixing in a centrifuge (5 min, 30 rpm) antibiotic—levofloxacin with β-cyclodextrin in molal ratio 1:1. Further procedure was as described in Example 1, except that in the solution was immersed the temporarily sealed cannula. The surface of the active layer6is coated by spraying with the aqueous solution of 0.5 mM/L of poly(vinyl alcohol) (molecular weight about 49 000 g·mol-1) to form a protective layer8which was made to achieve stable release of the biologically active agent. The protective layer8had a thickness of 0.02 mm.

The biopsy needle is made as described in Example 1, except that the outer surface5of the cannula1is coated with two active layers6, as shown inFIGS. 29-31. The first active layer6is applied to the binder layer7which is located on the outer surface5of the cannula1. Binder layer7was obtained by dipping the cannula1in a solution of acetone and drying, and then dipping in an aqueous solution of 0.5 mM/L of poly(vinyl alcohol) (molecular weight of 49,000 g·mol-1). On such binder layer7the first active layer6, obtained as described in Example 1, was applied, except that the cannula1was temporarily sealed. Then, the first active layer6was coated by spraying with poly(glycolic acid) which forms a net-like protective layer8. This layer delays the release of the biologically active agent from the first active layer6. The second active layer6, was applied on the protective layer8. The second active layer was obtained as in Example 1, except that the cannula1was temporarily sealed.

A steel biopsy needle with 200 mm length, comprises a pointed cannula1, pointed stylet2slidably located in the cannula1and in the back the polypropylene holders for the biopsy gun—a cannula holder3aand stylet holder3b. The outer width of the cannula1is 1.52 mm, its height is 2.22 mm, and the stylet2diameter is 1.27 mm as shown inFIGS. 32-36. The cannula1has a circular cross-section and one axis of symmetry. The cannula1contains main channel with diameters of 1.32 mm (for the stylet) and a longitudinal pass-through-hole channel10of cannula1. The additional channel10of circular shaped in cross section with the diameter of 0.5 mm, passes through 150 mm of cannula1, beginning at its pointed end, protrudes over the outer surface5of the cannula1and then transfer into the steel connector11. The connector11has a tube form, a length of 25 mm, an inner diameter of 0.5 mm and an external diameter 0.65 mm. The connector11of the channel10is connected to a flexible tube12, made of poly(vinyl chloride), with an internal diameter of 0.5 mm and a length of 200 mm. The flexible tube12is connected with a 5 ml syringe13. As shown inFIG. 39by using the biopsy gun and a biopsy needle under transrectal ultrasound, prostate cores s were collected in a standard way. During the procedure, at each sequence of collecting biopsy samples 0.1 ml of an aqueous solution of levofloxacin (5 mg/ml) and 0.1 ml of lidocaine hydrochloride (20 mg/ml) were administered through the additional channel10. In vitro and in vivo studies confirmed the antibacterial effect in the action area o of bioactive agents. The analgesic effect was confirmed in vivo.

A steel biopsy needle with 200 mm length, comprises a pointed cannula1, pointed stylet2slidably located in the cannula1and in the back the polypropylene holders for the biopsy gun—a cannula holder3aand stylet holder3b. The outer width of the cannula1is 1.52 mm, its height is 2.22 mm, and the stylet2diameter is 1.27 mm as shown inFIGS. 34-38. Cannula1has a circular cross-section and one axis of symmetry. The cannula1contains main channel with diameters of 1.32 mm (for the stylet) and a longitudinal pass-through-hole channel10of cannula1. The additional channel10of circular shaped in cross section with the diameter of 0.5 mm, passes through the entire length of the cannula1, from its pointed end to the holder3a. As shown inFIG. 39by using the biopsy gun and a biopsy needle under transrectal ultrasound, prostate cores s were collected in a standard way. During the procedure, at each sequence of collecting biopsy samples 0.1 ml of an aqueous solution of levofloxacin (5 mg/ml) and 0.1 ml of lidocaine hydrochloride (20 mg/ml) were administered through the additional channel10. In vitro and in vivo studies confirmed the antibacterial effect in the action area o of bioactive agents. The analgesic effect was confirmed in vivo.