WO2019138416A1

WO2019138416A1 - Bilaminated stent with biodegradable mesh and a method of manufacturing thereof

Info

Publication number: WO2019138416A1
Application number: PCT/IN2018/050143
Authority: WO
Inventors: Deveshkumar Mahendralal KOTHWALA; Rajnikant Gandalal Vyas; Dr. Pramod Kumar MINOCHA
Original assignee: Meril Life Sciences Pvt Ltd
Priority date: 2018-01-12
Filing date: 2018-03-15
Publication date: 2019-07-18

Abstract

A bilaminated stent with biodegradable mesh and a method of manufacturing thereof is disclosed. The stent-mesh assembly includes a first layer of a polymer coated on the outer surface of the stent, a second layer of at least one drug coated on top of the first layer and a mesh made of a biodegradable material and provided on the outer surface of the stent. The first layer avoids peeling off or delamination of the second layer during mounting and/or knotting of the mesh over the stent.

Description

BILAMINATED STENT WITH BIODEGRADABLE MESH AND A METHOD OF MANUFACTURING

THEREOF

FIELD OF INVENTION

[001] The present disclosure relates to a drug eluting peripheral stent with a biodegradable mesh. More specifically, the present disclosure relates to a bi-laminated stent with the biodegradable mesh.

BACKGROUND

[002] Peripheral artery disease (PAD) is one of the major causes of lower extremity ischemia and limb loss. PAD is a disease in which plaque builds up in the arteries that carry blood to head, limbs and other organs. The plague may arise due to accumulation of fat, cholesterol, calcium, fibrous tissues and other substances in the blood. Over time, the plaque may harden and causes narrowing of arteries which may limit the flow of oxygen- rich blood to organs. This medical condition is known as Atherosclerosis. Similarly, carotid artery disease is a disease in which a similar waxy substance as plaque builds up inside the carotid arteries resulting in blocking of the arteries.

[003] Several treatment methods has been used to treat stenotic vessels including balloon angioplasty, atherectomy catheters, thrombectomy devices, bare metal stenting, by-pass surgeries, etc. All treatments severely injure the vessels which undergo treatment. A variety of other approaches has also been utilized to minimize the condition of Atherosclerosis which may include modifications in the stent design, use of coatings and coverings over the stent.

Conventional treatment using stents includes use of distal protection device like filters to trap the debris which may iead to complicated handling of the device and may require more time in treatment.

SUMMARY [004] The present invention discloses a stent-mesh assembly. The stent-mesh assembly includes a first layer of a polymer coated on the outer surface of the stent, a second layer of at least one drug coated on top of the first layer and a mesh made of a biodegradable material and provided on the outer surface of the stent. The first layer avoids peeling off or delamination of the second layer during mounting and/or knotting of the mesh over the stent.

BRIEF DESCRIPTION OF THE DRAWINGS

[005] The summary above, as well as the following detailed description of illustrative embodiments, is better understood when read in conjunction with the appended drawings. For the purpose of illustrating the present disclosure, exemplary constructions of the disclosure are shown in the drawings. However, the disclosure is not limited to specific methods and instrumentalities disclosed herein. Moreover, those in the art will understand that the drawings are not to scale. [006] FIG.l illustrates a mesh stent assembly in accordance with an embodiment of the present invention.

[007] FIG.2 illustrates a front view of the stent in accordance with an embodiment of the present invention.

[008] FIG.3 illustrates a front view of knotting of the mesh over the stent strut edge in accordance with an embodiment of the present invention.

[009] FIG.4 illustrates front view of the stitching pattern of the mesh in accordance with an embodiment of the present invention.

[010] FIG.5 illustrates double knotting of a monofilament over the mesh in accordance with an embodiment of the present invention. DETAILED DESCRIPTION OF THE DRAWINGS

[Oil] Prior to describing the invention in detail, definitions of certain words or phrases used throughout this patent document will be defined: the terms "include" and "comprise", as well as derivatives thereof, mean inclusion without limitation; the term "or" is inclusive, meaning and/or; the phrases "coupled with" and "associated therewith", as well as derivatives thereof, may mean to include, be included within, interconnect with, contain, be contained within, connect to or with, couple to or with, be communicable with, cooperate with, interleave, juxtapose, be proximate to, be bound to or with, have, have a property of, or the like;

Definitions of certain words and phrases are provided throughout this patent document, and those of ordinary skill in the art will understand that such definitions apply in many, if not most, instances to prior as well as future uses of such defined words and phrases.

[012] Wherever possible, same reference numbers will be used throughout the drawings to refer to same or like parts. Moreover, references to various elements described herein are made collectively or individually when there may be more than one element of the same type. However, such references are merely exemplary in nature. It may be noted that any reference to elements in the singular may also be construed to relate to the plural and vice-versa without limiting the scope of the disclosure to the exact number or type of such elements unless set forth explicitly in the appended claims.

[013] Particular embodiments of the present disclosure are described herein below with reference to the accompanying drawings, however, it is to be understood that the disclosed embodiments are merely examples of the disclosure, which may be embodied in various forms. Well-known functions or constructions are not described in detail to avoid obscuring the present disclosure in unnecessary detail. Therefore, specific structural and functional details disclosed herein are not to be interpreted as limiting, but merely as a basis for the claims and as a representative basis for teaching one skilled in the art to variously employ the present disclosure in virtually any appropriately detailed structure. In the present description and claims, the term proximal end refers to an end of an element that is closer to a user while the distal end refers to an end of the element which is farther from the user.

[014] In accordance with the present disclosure, a self-expandable stent and a bioabsorbable mesh assembly is disclosed. The stent-mesh assembly can be used for treatment of

Atherosclerosis-related diseases without limitation, Coronary Heart Disease, Carotid Artery Disease, Peripheral Artery Disease, Chronic Kidney Disease etc. In an embodiment, the stent- mesh assembly prevents stenosis, distal embolization and facilitates revascularization of peripheral vasculature. In another embodiment, the stent-mesh assembly includes a dual coating on an upper surface of the stent and/or double knotting of the mesh over the coated stent on distal and/or proximal end of the stent. In an embodiment, the stent strut breaks down the plaque on expansion and sieves debris from entering into the stent. [015] Now referring specifically to the drawings, FIG.l illustrates a schematic view of a stent- mesh assembly 100 in accordance with an embodiment of the present invention. The stent may be a self-expanding and/or a balloon expanding stent. The stent may be made of a metallic alloy or a biodegradable material. The metallic material may have shape memory properties. The metallic material may include without limitation, L605 Cobalt-chromium alloy, 316L SS, Nickel- titanium alloy etc. The biodegradable material may include without limitation bioresorbable polymer like PLA (Poly-Lactic acid), PLGA (Poly lactide-co-glycolide) and biodegradable metal like magnesium, iron etc. In an embodiment, the stent 10 is made of nitinol having shape memory properties and strength. The mesh over the stent may be made of biodegradable material having high strength and durability.

[016] The stent-mesh assembly 100 includes a stent 10 covered with a mesh 20. In an embodiment, the mesh 20 is attached to the stent 10 by means of without limitation knotting and/or stitching. The stent-mesh assembly 100 enables treatment of highly calcified lesions artery with total protection against embolic shower and revascularization. Thus, the stent-mesh assembly 100 may facilitate carotid artery revascularization to prevent stroke in patients with carotid artery stenosis.

[017] The stent 10 of the present invention may be any continuous cylindrical structure having varied dimensions in accordance with the application. The stent 10 may be laser cut into any pattern in accordance with the application. For example, the stent may be a hybrid structure of alternate open-closed cells. In accordance with an embodiment, the open cell structure of the stent 10 is 20 and a closed cell structure is 18 present in an alternate pattern, as depicted in FIG.2. The open-closed cell structures (20, 18) may facilitate enhanced expansion of the stent 10.

[018] The stent 10 includes a proximal end 12, a distal end 14 and a plurality of strut edge 16. One or more strut edges 16 are present on each of the proximal end 12 and/or the distal end 14 of the stent 10.

[019] The stent 10 may be drug coated with an anti-proliferative agent and/or an anti-mitotic agent. The drug coating may be provided directly over the stent 10. Alternatively, the drug coating may be provided over a polymer coating of the stent 10. The drug coating may be provided in order to reduce the risk of thrombus formation and restenosis.

[020] In an embodiment of the present invention, the stent 10 is coated with a first layer of polymer followed by a second layer of drug. The first layer avoids peel off or delamination of the second layer during mounting and/or knotting of a mesh 20 over the stent 10. The first layer may include polymers such as PDLA (poly-D-lactide), PDLLA (poly-DL-lactide), PLCL Poly(lactide- co-caprolactone), PLA (Polylactic Acid), PGA poly(glycolic acid), and PCL (Polycaprolactone), Poly-DL-lactide co-glycolide and/or combination thereof. The second layer may include a therapeutic drug in combination with a polymer. The therapeutic drug may include without limitation, Sirolimus, Paclitaxel etc. The coating may be performed with the help of without limitation, spray coating technique. The therapeutic drug may be blended with a carrier and is dissolved in a solvent in order to facilitate uniform coating of the stent 10. The carrier may include without limitation, the polymers used in first layer, PDLLA co-polymer or mixture of Poly L-lactide and 50:50 Poly DL-lactide co-glycolide, etc. The solvent may include without limitation, acetone, dichloromethane, etc.

[021] In an exemplary embodiment, the first layer coated on the stent 10 is of PDLLA (Poly DL- lactic acid) with IV ranging from 0.50 to 0.60 dl/g. The PDLLA polymer may be dissolved in an organic solvent and is spray coated on the stent 10. The second layer may consist of the polymer and the drug in an approximate range of 60 to 65% and 35 to 40% respectively. In an embodiment, the second layer consists of a mixture of Poly L-lactide, 50:50 Poly DL-lactide co- glycolide (IV range 0.90-1. lOdL/g and 0.55-0.75dL/g respectively) and a drug in an approximate ratio of 36.4:63.6 and a drug for example, Sirolimus. The second layer may release therapeutic drug in the body lumen in a controlled manner and reduce risks of thrombus formation and restenosis. In an embodiment, the drug dose is 1.25pg/mm². In an embodiment, the thickness of the first layer is around 3 to 5 micron and second layer is around 5 microns.

[022] The coating may be performed with the help of without limitation, a spray gun. The spray coating may include accurate holding of scaffold through collets, distance between the spray gun and the stent, inert gas pressure and solution flow rate. The parameters while performing coating may be controlled in order to obtain a uniform coating over the stent 10. In an embodiment, the distance between the stent 10 and the spray gun tip may be maintained at a distance of approximately 03 cm to 06 cm, the collate rotation of the spray gun may be maintained around 05 rpm to 20 rpm. The inert gas pressure is maintained around 1.5 to 2.5 kg/cm². In an embodiment, the residual solvent may be removed from the stent 10 by means of evaporation under vacuum condition at a room temperature of 12-48 hours.

[023] The mesh 20 may be made of monofilaments of biodegradable polymer. The

biodegradable polymer may include without limitation, PLGA, PLLA, PGLA etc. In an

embodiment, the mesh 20 is made of PLGA monofilaments having a diameter of around 25 to 50 micron, preferably 25 to 30 microns. The PLGA monofilaments may be extracted from PLGA granules by an extrusion process known in the art. The PLGA granules may consist of L-lactide and Glycolide in a range of without limitation, such as 85:15, 75:25 and 50:50. Degradation time of PLGA granules may vary in a range of 5-6 months, 4-5 months and 1-2 months respectively for aforesaid concentration of the L-lactide and Glycolide in PLGA. The melting point of the PLGA granules may range between 126.7 - 144.8 °C temperature. The PLGA monofilaments exhibits high strength and modulus and are able to degrade completely in body within a time span of 05-06 months.

[024] The mesh 20 may be manufactured by weft knitting and/or warp knitting technique. The knitting technique may be performed by any circular knitting machine with the number of needles ranging from 48 to 120. The needle used for knitting may be a thin needle which may create tiny porous structure of the mesh 20 in order to restrict plague from dislodging, entrap the plague over the mesh 20 and/or may prevent thrombosis. The size of the mesh 20 resulting by utilizing .016" - .018" needle density may depend upon type of artery to be treated such as without limitation, coronary, peripheral, intracranial, carotid, etc.

[025] The weft knitted structure of the mesh 20 may include a plurality of consecutive interlocking loops 22. In an embodiment, the loop 22 may be around 300 microns in length and 80-140 microns in width. The aperture size of the of the loop 22 may be controlled by monofilament tension and stitch value of around 0 to 40, preferably 30 to 35. The weft machine may run at around 40 to 55mm/min. The weft knitted structure of the mesh 20 may provide seamless expansion of the mesh 20 along with the stent 10. [026] In an embodiment, the mesh 20 is processed by heat treatment under controlled environmental condition to stabilize the knitted structure and to relieve internal stress which helps in seamless expansion upon deployment.

[027] In an embodiment, the balloon expandable mesh-stent assembly 100 is used to treat renal arteries in which the mesh 20 with an aperture of around 200 microns is incorporated to trap debris. In other exemplary embodiment of the invention, a balloon expandable drug eluting stents 10 with the mesh 20 is used for the treatment of coronary and peripheral arteries.

[028] In an embodiment, the mesh- stent assembly 100 is obtained by mounting the stent 10 on a knotting mandrel (not shown) followed by covering an upper surface of the stent 10 with the mesh 20. The mesh 20 may be mounted over the stent 10 by means of without limitation tweezers. Following mounting of the mesh 20 over the stent 10, the mesh 20 may be knotted at a proximal end 12 and distal end 14 of the stent 10 by a plurality of surgeon's knot. The mesh 20 may be secured over the stent 10 in a manner that provides strong hold of the stent 10 and/or seamless and uniform expansion of the mesh 20 along with the stent 10 during loading and deployment procedure by distributing equal stress along the knitted mesh geometry.

[029] In an embodiment, the mesh 20 having thickness of approximately 28micron and is mounted over the stent 10 by using without limitation, micro forceps. The use of micro forceps may facilitate easy handling of the mesh 20. The knotting of the mesh 20 over the stent 10 may include any top strut edge of the stent 10, nearby loop 22 of the mesh 20 and a single monofilament 30. In an embodiment, the process is initiated by fastening the monofilament 30 on the top strut edge 16 of the stent 10. In an embodiment, the fastening is achieved by double knotting of the monofilament over the strut edge 16 of the stent 10 (as shown in FIG.3).

[030] FIG.4 illustrates the knotting of the monofilament 30 over the stent 10. In an

embodiment, the monofilament 30 is first double knotted on the strut 16, at a first position A1 with wale of the mesh 20 by keeping an end 32 of the monofilament 30 free. The first knot is followed by a second knot at the strut 16, at a second position A2. In an embodiment, the monofilament 30 is passed through each wale of the mesh 20 and the same knotting pattern is repeated at each of the strut of the stent 10 by keeping the other end 34 of the monofilament 30 free. Lastly, following double knotting at each of the strut 16 of the stent 10, the two ends (32, 34) are double knotted at an end of the stent 10 as depicted in FIG. 5.

[031] In an embodiment, followed by knotting of the mesh 20 over the stent 10, the stent- mesh assembly 100 is positioned between a plurality of radiopaque markers and crimped to lower diameter for ease of visibility and accurate positioning inside the lumen. Following marker attachment, the stent- mesh assembly 100 may be loaded into the delivery system in order to allow ease of operation in body lumen and/or at specific sites. In an embod iment, stent-mesh assembly 100 is advanced axially into the sheath by stent pusher. During deployment, the sheath may be withdrawn to release the stent-mesh assembly 100 at the treatment site.

[032] The stent-mesh assembly 100 of the present invention possesses high radial strength between 20N to 30N. The stent-mesh assembly 100 is checked for performance by subjecting the device to various in-vitro biomechanical forces in order to test the bending deformation at the treatment site. It is observed that no fracture on the stent 10 and on the mesh 20 is seen after 518610 cycles which is equivalent to 06 months under accelerated simulated in-vitro conditions

[033] The invention is now explained with the help of following examples.

EXAMPLE 1

[034] The extruded bioabsorbable monofilament is annealed at approximately 125°C for 60 minutes under vacuum condition and stored at ambient temperature in vacuum condition for half an hour. The annealed bioabsorbable monofilament is then utilized for knitting of a mesh. The mesh is knitted by means of circular weft knitting machine. The mesh 20 is knitted with a stitch length of around 300 microns, stitch width around 120 microns and diameter of 4.5 - 5.0 mm by a 48-needle circular knitting head. The mesh is them heat treated at a temperatu re of around 115 °C for 60 minutes. The heat treatment helps to stabilize the knit structure and relieve internal stress in monofilament of the mesh.

[035] The stent is coated with a therapeutic agent by spray coating process. The therapeutic agent with a carrier is dissolved in a suitable solvent to facilitate spray coating process. In order to perform coating over the stent, distance between stent and a spray gun is kept at 3cm, collate rotation is maintained around 10 rpm and inert gas pressure is around 1.5 kg/cm².

[036] Paclitaxel is the active ingredient used for coating of the stent. The drug dose is

1.25pg/mm² with a coating thickness of less than 03 pm. The mesh 20 is mounted on self- expandable stent by slow-expansion to ensure proper mounting of knitted mesh. The proximal and distal end of the mesh 20 is secured with the help of double knotting of a monofilament on the stent. A PLGA monofilament of diameter around 28pm is used for knotting process. The stent-mesh assembly 100 is crimped in a crimped head. Following crimping, the stent-mesh assembly is loaded into a sheath for delivery. [037] After mesh-stent assembly 100 is loaded into the sheath, peeling and cracking of drug coated layer is observed and also during expansion/deployment of stent-mesh assembly 100, delamination of the coating is observed.

EXAMPLE 2

[038] The knitting process of the mesh 20 in the present example is same as the previous example. The stent 10 is spray coated with two layers. The first layer is coated on the outer surface the stent and a second layer is coated on the first layer. The first layer prevents delamination of the second layer and facilitates controlled release of the drug. The first layer includes PDLLA polymer with a thickness around 05pm. The PDLLA polymer is dissolved in a suitable solvent to facilitate spray coating process. The second layer includes a polymer with a drug. The second layer is well adhered to the stent outer surface due to presence of first polymer layer. The thickness of the second layer is less than 03 pm and the drug dose is 1.25pg/mm². The coating parameters and loading mechanism is same as mentioned in previous example. During mesh-stent assembly 100 loading into the sheath and deployment from the catheter, no peeling or cracking of drug coated layer is observed. [039] The scope of the invention is only limited by the appended patent claims. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and/or configurations will depend upon the specific application or applications for which the teachings of the present invention is/are used.

Claims

WE CLAIM:

1. A stent-mesh assembly comprising: i. a stent including an outer surface, the outer surface comprising:

• a first layer of a polymer coated on the outer surface; and · a second layer of at least one drug coated on top of the first layer; ii. a mesh made of a biodegradable material and provided on the outer surface of the stent, wherein the first layer avoids peeling off or delamination of the second layer during mounting and/or knotting of the mesh over the stent.

2. The stent-mesh assembly as claimed in claim 1 wherein the first layer includes one or more of PDLA (poly-D-lactide), PDLLA (poly-DL-lactide), PLCL Poly(lactide-co-caprolactone), PLA Poly(lactic Acid), PGA Poly(glycolic acid), PCL (Polycaprolactone), Poly-DL-lactide co- glycolide or combination thereof.

3. The stent-mesh assembly as claimed in claim 1 wherein the second layer includes a therapeutic drug in combination with a polymer.

4. The stent-mesh assembly as claimed in claim 3 wherein the therapeutic drug includes one or more of Sirolimus, and Paclitaxel.

5. The stent-mesh assembly as claimed in claim 1 wherein the stent comprises a metallic stent or a biodegradable stent.

6. The stent-mesh assembly as claimed in claim 1 wherein the mesh is double-knotted with the help of a monofilament over the stent.

7. A method of manufacturing a stent-mesh assembly, the method comprising: i. providing a stent; ii. providing a first layer of a polymer on an outer surface of a stent; providing a second layer of at least one drug on top of the first layer; and iii. mounting a mesh made of a biodegradable material on top of the second layer, wherein the first layer avoids peeling off or delamination of the second layer during mounting and/or knotting of the mesh over the stent.

8. The method as claimed in claim 7 wherein the first layer includes one or more of PDLA (poly-D-lactide), PDLLA (poly-DL-lactide), PLCL Poly(lactide-co-caprolactone), PLA Polylactic Acid, PGA poly(glycolic acid), PCL (Polycaprolactone), Poly-DL-lactide co-glycolide or combination thereof.

9. The method as claimed in claim 7 wherein the second layer includes a therapeutic drug in combination with a polymer.

10. The method as claimed in claim 7 wherein the therapeutic drug includes one or more of Sirolimus, and Paclitaxel.

11. A method of manufacturing mesh, the method comprising:

I. providing a biodegradable monofilament; and

II. knitting the biodegradable monofilament to form interlocking loops using one or more 0.016" to 0.018" thin needles.

12. The method as claimed in claim 11 wherein the biodegradable monofilament includes one or more of PLGA (poly(lactic-co-glycolic acid)), PLLA (Poly(L-lactic acid)), PGLA

(poly(lactic-co-glycolic acid))etc.

13. The method as claimed in claim 11 wherein the knitting comprises weft knitting technique.

14. The method as claimed in claim 11 wherein the loop comprises length of 300 microns and width between 80-140 microns.