CN115591079A - A novel microcatheter based on convection-enhanced drug delivery technology - Google Patents

Abstract

The invention belongs to the field of microcatheters, and specifically discloses a novel microcatheter based on convection-enhanced drug delivery technology. The microcatheter includes an inner tube and an outer tube, and a piston device between the inner tube and the outer tube; the opening of the inner tube protrudes a part from the opening of the outer tube to form an inner tube protrusion; the piston device includes The piston head and the elastic part connected to one side of the piston head, the piston head is nested on the inner tube, close to the outer surface of the inner tube and the inner surface of the outer tube; the piston head is elastically Under the joint action of components and external force, the microcatheter can reciprocate in the axial direction. The microcatheter of the present invention can prevent or minimize the reflux phenomenon of the drug and increase the diffusion of the drug in the tumor tissue while increasing the continuous micro positive pressure at the tip of the microcatheter to increase the flow rate of the drug and administering large doses. Distribution, increase the ratio Vd/Vi of the drug diffusion amount to the administered amount.

Description

A novel microcatheter based on convection-enhanced drug delivery technology

technical field

The invention belongs to the field of microcatheters, and specifically discloses a novel microcatheter based on convection-enhanced drug delivery technology.

Background technique

Convection-enhanced delivery (CED) technology is a targeted drug delivery technology targeting the treatment of central nervous system diseases. CED technology is used to generate continuous micro-positive pressure at the tip of the microcatheter to form a convective effect with the surrounding tissue. Broad drug distribution can be achieved in targeted regions within the brain parenchyma. Since CED technology directly targets the lesion area of the central nervous system and can bypass the blood-brain barrier, it fundamentally solves the problem of insufficient effective drug concentration in the lesion area caused by intravenous systemic administration. In recent years, CED technology has carried out large-scale basic research and clinical application in the fields of central nervous system degenerative diseases, neurotumors and epilepsy and other central nervous system diseases. At the same time, in the current large-scale clinical trials, the safety of CED technology and the possibility of clinical application have been proved.

During the application of CED technology to target drug delivery to the lesion area, the continuous micro-positive pressure generated by the tip of the microcatheter will cause the drug to diffuse along the site with a small pressure gradient, including the brain parenchyma around the tip of the microcatheter and the wall of the microcatheter space between the brain parenchyma. Since the pressure gradient in the gap between the microcatheter wall and the brain parenchyma is smaller than that of the surrounding brain parenchyma, the drug will preferentially flow to the gap between the microcatheter wall and the brain parenchyma during the administration phase of continuous slight positive pressure, thus forming Drug backflow along the outer wall of the microcatheter leads to insufficient drug diffusion in the brain parenchyma. Therefore, in order to solve this problem, researchers have done a lot of research work on the design and improvement of microcatheters in recent years, including nested microcatheters, dual microcatheters, porous microcatheters, etc., in order to further prevent or reduce The reflux of the drug increases the diffusion range of the drug in the brain parenchyma.

For the clinical application of medium and high-grade glioma, on the one hand, the pressure inside the tumor entity is often greater, so in the process of applying CED technology to the tumor entity for targeted drug delivery, in order to allow the drug to spread to the entire tumor tissue and tumor In the infiltration site, it is necessary to increase the continuous slight positive pressure generated by the tip of the microcatheter to increase the flow rate of the drug to overcome the pressure inside the tumor tissue. On the other hand, for clinical targeted drug delivery of high-grade glioma, it is often necessary to administer large doses so that the drug can fully diffuse to the entire tumor tissue and tumor infiltration sites. In view of the above two aspects, at the stage of high-flow rate and high-dose administration of various microcatheters, the phenomenon of drug backflow along the microcatheter often occurs, which reduces the diffusion and distribution of the drug in the tumor entity, and the diffusion of the drug. The ratio of dose to dose is reduced (Vd/Vi), which leads to insufficient effective drug concentration in some tumor tissues and fails to achieve the desired therapeutic effect.

Contents of the invention

In order to solve the above problems, the present invention discloses a novel microcatheter based on convection-enhanced drug delivery technology. Increase the continuous micro-positive pressure at the tip of the microcatheter to increase the flow rate of drug delivery, and at the same time of large-dose drug delivery, prevent or minimize the backflow of drugs, increase the diffusion and distribution of drugs in tumor tissues, and increase the amount of drug diffusion and The ratio Vd/Vi of the drug delivery; under the switching of different drug delivery rates in the same drug delivery stage, the stability of the drug diffusion to the surrounding tissues can be kept to the greatest extent.

Technical scheme of the present invention is as follows:

A novel microcatheter based on convection-enhanced drug delivery technology, the microcatheter includes an inner tube and an outer tube, and a piston device between the inner tube and the outer tube;

The opening of the inner tube protrudes a part from the opening of the outer tube to form a protrusion of the inner tube;

The piston device includes a piston head and an elastic component connected to one side of the piston head, the piston head is nested on the inner tube, and is close to the outer surface of the inner tube and the inner surface of the outer tube;

The piston head can reciprocate in the axial direction of the microcatheter under the joint action of the elastic component and external force.

Further, in the aforementioned novel microcatheter based on convection-enhanced drug delivery technology, the head of the piston is a hollow cylinder, and the hollow part is slidably nested on the inner tube.

Further, in the aforementioned novel microcatheter based on convection-enhanced drug delivery technology, the piston head is made of PEEK material. PEEK polyether ether ketone material was chosen because of its following advantages,

1) Non-toxic: the new microcatheter will be used in the medical field, and the advantage of non-toxicity will not produce toxic effects or toxic damage to the human body;

2) Self-lubrication: The new microcatheter will use PEEK material as a piston device between the outer tube and the inner tube. PEEK material has excellent sliding properties such as low friction coefficient and wear resistance. During the conveying process, the piston can slide back and forth flexibly and smoothly. On the other hand, it can minimize the loss of materials to ensure the airtightness of the piston device and improve the accuracy of the product;

3) Superior dimensional stability: Changes in environmental conditions such as temperature and humidity have little effect on the size of PEEK materials. In fluid mechanics, the deformation of materials will have a great impact on the velocity field and pressure field of the fluid. PEEK Excellent dimensional stability will further guarantee the accuracy and precision of the product.

Further, the above-mentioned novel microcatheter based on convection-enhanced drug delivery technology, the elastic component is a precision compression spring, one end of the spring is connected to the piston head, and the other end of the spring is fixed in the microcatheter through a fixing device. The length, material, wire diameter and other parameters of the spring can be adjusted, but it is necessary to ensure that its elastic coefficient (K) is maintained in the range of 0.5-1kgf/mm to ensure that the microcatheter can function.

Further, in the aforementioned novel microcatheter based on convection-enhanced drug delivery technology, the surface of the outer tube is coated with a coating of a high-viscosity superhydrophobic material. The above-mentioned high-viscosity superhydrophobic material coating is ZnAl-LDHs film+sodium laurate surface modification coating, and its preparation method comes from the paper (Preparation Research of High-viscosity Superhydrophobic Film on Aluminum Alloy Surface Wang Xuewu CNKI: CDMD: 2.1011.262711).

The high-viscosity superhydrophobic material coating can increase the viscosity of water-soluble drugs on the coating surface. During the application of CED technology in the process of continuous micro-positive pressure administration, the drug will preferentially tend to the direction of the smaller pressure gradient When the microcatheter is placed in the brain tissue, the outer wall of the microcatheter will form a gap with the tissue, so that the pressure gradient between the outer wall of the microcatheter and the tissue is much smaller than the tip of the microcatheter for drug delivery to the tissue Therefore, the drug will preferentially flow to the gap between the outer wall of the microcatheter and the tissue, forming a state of drug reflux. Therefore, in the case of the same administration amount (Vi), the backflow of the drug will affect the diffusion amount (Vd) of the drug in the tissue. Compared with microcatheters that do not have a high-viscosity superhydrophobic material coating, the new microcatheter of the present invention will have a high-viscosity superhydrophobic material coating on the outer wall of the microcatheter, which can increase water-soluble drugs on the coating. The viscous force on the surface, thereby increasing the resistance between the outer wall of the microcatheter and the tissue, will prevent or minimize the reflux of the drug along the outer wall of the microcatheter. Further increase the amount of drug diffusion (Vd) in the tissue. Especially in the state of high-dose or high-flow drug delivery, the advantages of the novel microcatheter of the present invention will be more obvious.

Further, in the aforementioned novel microcatheter based on convection-enhanced drug delivery technology, the thickness of the high-viscosity superhydrophobic material coating is 0.1-10 μm.

Further, in the aforementioned novel microcatheter based on convection-enhanced drug delivery technology, the inner tube is made of fused silica, and the outer tube is made of aluminum alloy.

Further, in the aforementioned novel microcatheter based on convective enhanced drug delivery technology, the inner diameter ID of the inner tube is 0.1mm-0.2mm, and the outer diameter OD is 0.2-0.3mm;

The inner diameter ID of the piston head is 0.2-0.3mm, the outer diameter OD is 0.5-1.0mm, and the length is 1-5mm;

The inner diameter ID of the outer tube is 0.5-1.0mm, and the outer diameter is 0.5-2mm;

The length of the protrusion of the inner tube is 1-10mm;

The length of the elastic member is 20-100mm;

The distance between the piston head and the opening of the outer tube is 1-10mm in the non-use state.

Further, the application of the above-mentioned novel microcatheter in the preparation of a targeted drug delivery device in the brain parenchyma.

Compared with prior art, the present invention has following beneficial effect:

1. A novel microcatheter based on convection-enhanced drug delivery technology disclosed by the present invention, a closed pressure piston device (preferably PEEK material) is made between the inner tube and the outer tube. The gap pressure gradient between the inner tube of the microcatheter and the outer tube is smaller than the pressure gradient between the tip of the inner tube of the microcatheter and the tissue, so the drug will preferentially flow back along the inner tube.

1) Compared with the nested microcatheter, when the drug flows back to the pressure piston device, it will balance the pressure generated when the drug flows back along the inner tube, and it will also balance or reduce the sharp and rapid rise of the drug when it returns at a high flow rate The pressure can reduce the pressure difference with other gaps, thereby preventing or reducing the probability of drug backflow along the outer tube gap of the microcatheter. When the relatively balanced pressure formed by the reflux of the drug along the inner tube and the piston device is greater than the pressure between the tip of the microcatheter and the tissue, the drug will fully diffuse to the surrounding tissue under the action of the pressure field and the velocity field.

2) Compared with the nested microcatheter, the dual microcatheter will have a smaller probability of drug backflow along the outer tube space of the microcatheter, so that the drug can fully diffuse to the tissue, but the drug will occur too much along the microcatheter. If there is a gap backflow phenomenon between the inner tube and the outer tube, when the drug is administered at a high dose or a high flow rate, it will lead to a decrease in the ratio of the drug diffusion amount to the administered amount (Vd/Vi), which will further reduce the efficiency of the CED technology. Targeted drug delivery efficiency. The pressure piston device of the new microcatheter will prevent the excessive backflow of the drug along the inner tube, while ensuring the full diffusion of the drug to the surrounding tissues, increase the ratio (Vd/Vi) of the drug diffusion amount to the administration amount, and improve the targeting effect. Dosing efficiency.

2. in the preferred technical scheme, the microcatheter announced by the present invention is done a high-viscosity superhydrophobic material coating (ZnAl-LDHs film+sodium laurate surface modification; preferred thickness: 3 μ m) at the pipe wall of outer tube, The contact angle between this material and water droplets is greater than 150°, but the water droplets will firmly adhere to the hydrophobic surface, no matter how inclined the surface is, the water droplets will not roll off. Therefore, compared with the current microcatheter, the high-viscosity superhydrophobic material coating will increase the gap resistance between the outer tube wall and the tissue. When the backflow tendency occurs on the outer tube wall, it will further increase the resistance of the drug backflow, prevent the occurrence of drug backflow, increase the diffusion distribution of the drug in the brain tissue, and increase the ratio (Vd/Vi) of the drug diffusion amount to the administered amount.

Description of drawings

Fig. 1 is the schematic diagram of longitudinal section of nested microcatheter in the prior art;

Fig. 2 is the schematic diagram of the longitudinal section structure of the dual-type micro-catheter in the prior art;

Fig. 3 is a schematic diagram of the longitudinal section structure of a novel microcatheter based on convection-enhanced drug delivery technology disclosed by the present invention;

4 is a schematic cross-sectional view of a novel microcatheter based on convection-enhanced drug delivery technology disclosed by the present invention;

Fig. 5 is a comparison diagram of a dual-type microcatheter (left) and a novel microcatheter of the present invention (right).

detailed description

The following clearly and completely describes the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only some of the embodiments of the present invention, but not all of them. Based on the embodiments of the present invention, all other embodiments obtained by persons of ordinary skill in the art without making creative efforts belong to the protection scope of the present invention.

The reagents, materials or instruments used in the examples of the present invention are not indicated by the manufacturer, but are all commercially available conventional reagent products.

Example 1

As shown in Figure 1, it is the longitudinal section schematic diagram of the nested microcatheter in the prior art, and the gap between its inner tube and the outer tube is sealed from the 3mm place of the tip of the outer tube with an adhesive, and when a large dose or a high flow rate state is given When taking medicine, it is easy for the drug to flow back along the space of the outer tube of the microcatheter, and the drug cannot be accumulated in the target brain parenchyma, which will lead to a decrease in the ratio of the drug diffusion amount to the administered amount (Vd/Vi), which will further reduce Targeted drug delivery efficiency of CED technology.

As shown in Figure 2, it is a schematic diagram of the longitudinal section of the dual-type microcatheter in the prior art, although compared with the nested microcatheter, the probability of drug backflow along the outer tube gap of the microcatheter is smaller, so that the drug can fully flow into the microcatheter. The target brain parenchyma tissue is diffused, but the drug will have too much backflow along the gap between the inner tube and the outer tube of the microcatheter, so when the drug is administered at a high dose or at a high flow rate, the increase in the back flow will also cause the drug to The ratio of diffusion volume to dose volume is reduced (Vd/Vi), which further reduces the targeted delivery efficiency of CED technology.

The schematic diagram of the longitudinal section structure of the new microcatheter of the present invention is shown in Figure 3, and the schematic diagram of the cross-sectional structure is shown in Figure 4; a novel microcatheter based on convection-enhanced drug delivery technology, the microcatheter includes an inner tube and an outer tube , and a piston device located between the inner tube and the outer tube;

The opening of the inner tube protrudes a part from the opening of the outer tube to form a protrusion of the inner tube;

The piston device includes a piston head and an elastic component connected to one side of the piston head, the piston head is nested on the inner tube, and is close to the outer surface of the inner tube and the inner surface of the outer tube;

The piston head can reciprocate in the axial direction of the microcatheter under the joint action of the elastic component and external force.

The piston head is a hollow cylinder, and the hollow part is slidably nested on the inner tube;

The piston head is made of PEEK material;

The elastic component is a precision compression spring, one end of the spring is connected to the head of the piston, and the other end of the spring is fixed in the microcatheter by a fixing device;

Spring parameter setting:

Spring length: 50mm

Spring material: stainless steel, modulus of rigidity = 7000kg/mm ²

Spring wire diameter (d): 0.15mm

Spring outer diameter (D): 0.4mm

Number of effective spring coils (N): 56 coils

Coefficient of elasticity (K): 0.5kgf/mm

The surface of the outer tube is coated with a high-viscosity super-hydrophobic material coating, which is ZnAl-LDHs film + sodium laurate surface modification coating, and the thickness of the high-viscosity super-hydrophobic material coating is 3 μm;

The production of the spring and the piston head is entrusted to the manufacturer to produce and provide;

The inner tube is made of fused silica, and the outer tube is made of aluminum alloy;

The inner diameter ID of the inner tube is 0.15mm, and the outer diameter OD is 0.23mm;

The inner diameter ID of the piston head is 0.23mm, the outer diameter OD is 0.60mm, and the length is 2mm;

The inner diameter ID of the outer tube is 0.60mm, and the outer diameter is 1.00mm;

The length of the protrusion of the inner tube is 3mm;

The length of the spring is 50mm;

In the non-use state, the distance between the piston head and the opening of the outer tube is 3 mm.

The spring end is fixed at the end of the microcatheter, which is also made of PEEK material.

FIG. 5 is a comparison diagram of the dual-type microcatheter (left) and the novel microcatheter described in this embodiment (right).

The novel microcatheter of the convection-enhanced drug administration technology prepared in this embodiment has a closed pressure piston device (PEEK material) between the inner tube and the outer tube. The gap pressure gradient between the tubes is smaller than the pressure gradient between the tip of the inner tube of the microcatheter and the tissue, so the drug will preferentially flow back along the inner tube. Further, the wall of the outer tube is made of a high-viscosity superhydrophobic material coating (ZnAl-LDHs film+sodium laurate surface modification; preferred thickness: 3 μm), the contact angle of this material and water droplets is greater than 150 °, but Water droplets will firmly adhere to the hydrophobic surface, no matter how inclined the surface is, the water droplets will not roll off. Therefore, compared with the current microcatheter, the high-viscosity superhydrophobic material coating will increase the gap resistance between the outer tube wall and the tissue. When the backflow tendency occurs on the outer tube wall, it will further increase the resistance of the drug backflow, prevent the occurrence of drug backflow, increase the diffusion distribution of the drug in the brain tissue, and increase the ratio (Vd/Vi) of the drug diffusion amount to the administered amount.

The descriptions of the limited preferred embodiments of the invention are relatively specific and detailed, but should not be construed as limiting the patent scope of the invention. It should be noted that those skilled in the art can make several modifications and improvements without departing from the concept of the present invention, and these all belong to the protection scope of the present invention.

Claims (10)

1. A novel microcatheter based on convection-enhanced drug delivery technology, characterized in that, said microcatheter comprises an inner tube and an outer tube, and a piston device positioned between the inner tube and the outer tube; The opening of the inner tube protrudes a part from the opening of the outer tube to form a protrusion of the inner tube; The piston device includes a piston head and an elastic component connected to one side of the piston head, the piston head is nested on the inner tube, and is close to the outer surface of the inner tube and the inner surface of the outer tube; The piston head can reciprocate in the axial direction of the microcatheter under the joint action of the elastic component and external force. 2. A novel microcatheter based on convection-enhanced drug delivery technology according to claim 1, wherein the head of the piston is a hollow cylinder, and the hollow part is slidably nested in the inner tube superior. 3. A novel microcatheter based on convection-enhanced drug delivery technology according to claim 1, wherein the piston head is made of PEEK material. 4. A novel microcatheter based on convection-enhanced drug delivery technology according to claim 1, wherein the elastic member is a precision compression spring, one end of the spring is connected to the piston head, and the other end of the spring is Fixed in the microcatheter by the fixation device. 5 . A novel microcatheter based on convection-enhanced drug delivery technology according to claim 1 , wherein the spring coefficient K of the spring is in the range of 0.5-1kgf/mm. 6. A novel microcatheter based on convection-enhanced drug delivery technology according to claim 1, wherein the surface of the outer tube is coated with a high-viscosity superhydrophobic material coating. 7. A novel microcatheter based on convection-enhanced drug delivery technology according to claim 6, wherein the thickness of the high-viscosity superhydrophobic material coating is 0.1-10 μm. 8. A novel microcatheter based on convection-enhanced drug delivery technology according to claim 1, wherein the inner tube is made of fused silica, and the outer tube is made of aluminum alloy. 9. a kind of novel microcatheter based on convection-enhanced drug delivery technology according to claim 1, is characterized in that, The inner diameter ID of the inner tube is 0.1mm-0.2mm, and the outer diameter OD is 0.2-0.3mm; The inner diameter ID of the piston head is 0.2-0.3mm, the outer diameter OD is 0.5-1.0mm, and the length is 1-5mm; The inner diameter ID of the outer tube is 0.5-1.0mm, and the outer diameter is 0.5-2mm; The length of the protrusion of the inner tube is 1-10mm; The length of the elastic member is 20-100mm; The distance between the piston head and the opening of the outer tube is 1-10mm in the non-use state. 10. The application of the novel microcatheter according to any one of claims 1-9 in the preparation of intraparenchymal targeted drug delivery device.

Images