Claims:WE CLAIM
1. A method of manufacturing a stent (100) to be deployed in a biliary duct, the method comprising:
• braiding a plurality of monofilaments to form a braided structure;
• primary shape setting of the braided structure at a predefined temperature for a predefined time duration;
• back braiding of a plurality of loose ends of the monofilaments of the braided structure obtained at the first step to from a stent 100;
wherein the stent (100) is axially compressed and subjected to secondary shape setting at the predefined temperature for the predefined time period.
wherein the stent (100) includes a first segment (101) and a second segment (103).
2. The method of manufacturing the stent (100) to be deployed in the biliary duct as claimed in claim 1, wherein the first segment (101) the second segment (103) is braided at a predefined braiding angle.
3. The method of manufacturing the stent (100) to be deployed in the biliary duct as claimed in claim 1, wherein the second segment (103) is densely braided as compared to the first segment (101).
4. The method of manufacturing the stent (100) to be deployed in the biliary duct as claimed in claim 2, wherein the predefined braiding angle is in a range of 130°to 155°.
5. The method of manufacturing the stent (100) to be deployed in the biliary duct as claimed in claim 1, wherein the back braiding is performed manually.
6. The method of manufacturing the stent (100) to be deployed in the biliary duct as claimed in claim 1, wherein the predefined time period is 15 hours.
7. The method of manufacturing the stent (100) to be deployed in the biliary duct as claimed in claim 1, wherein the predefined temperature is in a range of 80°C to 100°C.
8. The method of manufacturing the stent (100) to be deployed in the biliary duct as claimed in claim 1, wherein the stent (100) includes a plurality of markers at a first end (10) and a second end (20).
9. The method of manufacturing the stent (100) to be deployed in the biliary duct as claimed in claim 1, wherein the stent (100) is made of a biodegradable polymer. , Description:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(Section 10 and Rule 13)

1. TITLE OF THE INVENTION:
BILIARY STENT AND METHOD MANUFACTURING THEREOF

2. APPLICANT:
Meril Life Sciences Pvt. Ltd., an Indian company of the address Survey No. 135/139 Bilakhia House, Muktanand Marg, Chala, Vapi- 396191, Gujarat, India

The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF INVENTION
[1] The present invention relates to a method of manufacturing stents. More specifically, it relates to a method of manufacturing biliary stents.
BACKGROUND
[2] Bile ducts are a series of thin tubes extended from the liver to the small intestine. The bile duct carries bile from the liver and gallbladder to the small intestine. Bile is a substance that helps in the digestion of fats. The bile duct stricture is a condition in which the bile duct gets smaller or narrower. The aforesaid condition of the bile duct results in reduction of passing of the bile from liver to the small intestine leading to difficulty in digestion of food. The stricture causes abnormalities in the blood and/or a rise in non-essential liver enzymes. Patients with mild biliary strictures may not show any symptoms. However, when the stricture becomes more pronounced, symptoms start to develop. The symptoms may include abdominal pain on the right side of the body, itching, yellow skin or eyes, fever, nausea, vomiting, gray-colored or pale-colored stool, etc.
[3] The bile duct stricture may be caused due to injury to the bile ducts during surgery, for example, surgery to remove gallbladder, damage, and/or scarring due to gallstone in the bile duct, cancer of the bile duct, liver or pancreas, etc.
[4] Endoscopy is a widely used approach for the treatment of biliary strictures. Endoscopic treatment is performed by implantation of a polymeric stent, followed by further sessions of stenting with multiple polymeric stents. Temporary implantation of multiple polymeric stents has been used in patients having benign biliary strictures. However, the polymeric stents are less than ideal as they are prone to occlusion due to bacterial colonization and/or build-up of biofilm on the surface. Further, polymeric stents are also known to migrate from their implanted position. Moreover, due to their relatively rigid structure, their implantation in an artery of smaller diameter and/or subsequent expansion to fit against artery’s walls is difficult to perform.
[5] Self-expandable metal stents are also utilized to treat biliary structures. However, the metal stents are known to be occluded due to tumor in-growth stent interstices. Moreover, the metal stents are permanent implants, therefore, are needed to be removed from the body by surgery, which may cause further complications to the patient. Further, because the bile duct is narrow and/or the stent is to be implanted at a slope, the stent might be at a higher risk of migration after implantation.
[6] The use of biodegradable stents has been used to address the aforesaid problems of stenting in the bile duct. However, conventional bioresorbable stents are prone to the risk of migration due to weak radial forces. Moreover, bioresorbable stents have shown insufficient strength and/or low recovery, leading to elastic recoil of the stent. Further, the bioresorbable stent may not be well adapted to the biliary lumen, thus leading to complications such as inflammation and/or restenosis.
[7] Therefore, there exists a need for an improved stent system that can overcome the limitations of the existing ones.
SUMMARY
[8] The present invention relates to a method of manufacturing a stent to be deployed in a biliary duct is disclosed. The method includes braiding a plurality of monofilaments to form a braided structure, primary shape setting of the braided structure at a predefined temperature for a predefined time duration and back braiding of a plurality of loose ends of the monofilaments of the braided structure obtained at the first step to from a stent. The stent is axially compressed and subjected to secondary shape setting at the predefined temperature for the predefined time period. The stent includes a first segment and a second segment.
[9] The foregoing features and other features as well as the advantages of the invention will become more apparent from the following detailed description, which proceeds with reference to the accompanying figures.
BRIEF DESCRIPTION OF DRAWINGS
[10] 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.
[11] Fig.1 depicts an expanded view of a stent 100 in accordance with an embodiment of the present invention.
[12] Fig.2 depicts a flow chart of a process involved in manufacturing of the stent 100 in accordance with an embodiment of the present invention.
DETAILED DESCRIPTION OF ACCOMPANYING DRAWINGS
[13] 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 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.
[14] Reference throughout this specification to “one embodiment,” “an embodiment,” or similar language means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, appearances of the phrases “in one embodiment,” “in an embodiment,” and similar language throughout this specification may, but do not necessarily, all refer to the same embodiment, but mean “one or more but not all embodiments” unless expressly specified otherwise. The terms “including,” “comprising,” “having,” and variations thereof mean “including but not limited to” unless expressly specified otherwise. An enumerated listing of items does not imply that any or all of the items are mutually exclusive and/or mutually inclusive, unless expressly specified otherwise. The terms “a,” “an,” and “the” also refer to “one or more” unless expressly specified otherwise.
[15] Although the operations of exemplary embodiments of the disclosed method may be described in a particular, sequential order for convenient presentation, it should be understood that the disclosed embodiments can encompass an order of operations other than the particular, sequential order disclosed. For example, operations described sequentially may in some cases be rearranged or performed concurrently. Further, descriptions and disclosures provided in association with one particular embodiment are not limited to that embodiment, and may be applied to any embodiment disclosed herein. Moreover, for the sake of simplicity, the attached figures may not show the various ways in which the disclosed system, method, and apparatus can be used in combination with other systems, methods, and apparatuses.
[16] Furthermore, the described features, advantages, and characteristics of the embodiments may be combined in any suitable manner. One skilled in the relevant art will recognize that the embodiments may be practiced without one or more of the specific features or advantages of a particular embodiment. In other instances, additional features and advantages may be recognized in certain embodiments that may not be present in all embodiments. These features and advantages of the embodiments will become more fully apparent from the following description and appended claims, or may be learned by the practice of embodiments as set forth hereinafter. It should be noted that the term bio-resorbable, biodegradable or bio-absorbable are having same meaning and used either one in this submission.
[17] In accordance with the present disclosure, a stent and a method of manufacturing the stent are disclosed. The stent is a self-expanding stent. The stent is made of a biodegradable material. The stent can be implanted in narrow arteries of the digestive tract, respiratory tract, etc. In an embodiment, the stent is implanted in a biliary duct of the digestive tract of a patient. The stent can be absorbed in the body within a time period of six to eight months, thus avoiding elastic recoil of the stent and preventing various long-term complications such as inflammation and/or blockage, etc.
[18] The stent of the present invention includes a first segment and a second segment. The first segment is manufactured by a process of braiding a plurality of monofilaments at a first predefined braiding angle to form a braided structure. The predefined angle may be in a range of 120° to 160°. In an embodiment, the predefined angle is 145°. The second segment is manufactured by a process of back braiding of the loose ends of the plurality of monofilaments at a second predefined braiding angle. The back braiding process helps to maintain the shape and/or radial strength of the stent. In addition to the above, the back braiding forms closed ends of the stent. The closed ends of the stent are smooth therefore, avoiding injury to the vessel during deployment.
[19] Following the back braiding process, the stent is axially compressed at both ends. The process of axial compression improves shape memory and/or radial strength of the stent leading to enhanced shape recovery of the stent.
[20] The shape recovery of the stent may be in the range of 50% to 100%. In an embodiment, the shape recovery of the stent is 95%. The change in length and diameter of the stent after expansion may range from 1% to 20%. In an embodiment, the change in length and diameter of the stent is 5%. The enhanced shape recovery is an indicator of the improved radial strength of the stent. The radial strength of the stent may range from 9N to 12N.
[21] Now moving specifically to drawings, Fig.1 represents an expanded view of a stent 100. The stent 100 may include a first end 10, a second end 20, and a length ‘L’ extending between the first end 10 and the second end 20. The length ‘L’ of the stent 100 may play a crucial role in determining the performance of the stent 100 in the native organ, for example, the biliary duct. The greater length of the stent 100 enables a greater area of the biliary duct to be lesion-free and/or provide a more uniform passage in the biliary duct after degradation of the stent 100. The length ‘L’ may be in the range of 40mm to 100mm. In an embodiment, the length ‘L’ is 50mm.
[22] The stent 100 may have a predefined diameter ‘D’. The diameter ‘D’ of the stent 100 plays a crucial in mitigating the risk of stent 100 migration while eliminating blockage and/or helps to impart required strength to the stent 100 after implantation at the treatment site. The diameter ‘D’ of the stent 100 may depend upon the location of the implantation. The diameter ‘D’ may be in the range of 8mm to 10mm. In an embodiment, the diameter ‘D’ is 8mm.
[23] The stent 100 may be a braided structure. The stent 100 may include a plurality of monofilaments braided together to form the braided structure. The number of a plurality of monofilaments may be in a range of 8 to 16. In an embodiment, the number of monofilaments is 12. The monofilaments may have a predefined diameter ranging from 0.300mm to 0.500mm. In an embodiment, the monofilaments have a diameter 0.400mm. The lower diameter of the monofilaments results in a lower crimped profile of the stent 100 while maintaining desired strength of the stent 100 required for biliary stenting. The crimped profile of the stent 100 may be in a range of 70mm to 170mm. In an embodiment, the crimped profile of the stent 100 is 80mm. The stent 100 may be deployed through a delivery sheath of diameter ranging from 11F to 14F. In an embodiment, the diameter of the delivery sheath is 12F.
[24] The stent 100 may include at least two segments, for example, a first segment 101 towards the first end 10 and a second segment 103 towards the second end 20. The two segments may have different braiding densities to impart the required strength, stiffness, and flexibility to the stent 100.
[25] In an embodiment, the second segment 103 may be densely braided as compared to the first segment 101. The second segment 103 may help in providing enhanced radial strength and/or stiffness to the stent 100. In addition, the second segment 103 help in better shape recovery of the stent 100.
[26] The first segment 101 may include a length ‘L1’ in a range of 50% to 70% of the length L of the stent 100. In an embodiment, the length of the first segment 101 is 60% of the length ‘L’. The second segment 103 may include a length ‘L2’ in a range of 30% to 50% of the length L of the stent 100. In an embodiment, the length of the second segment 103 is 30% of the length ‘L’.
[27] The first segment 101 and the second segment 103 may have same and/or different braiding angles. In an embodiment, the first segment 101 and the second segment 103 have same braiding angle. The first segment 101 and the second segment 103 may be braided at a predefined braiding angle ranging from 130° to 155°. In an embodiment, the predefined angle is 155°. The aforesaid braiding angle imparts enhanced radial strength to the stent 100.
[28] In an embodiment, the first end 10 and the second end 20 of the stent 100 are closed ends. The closed ends are smooth and/or avoid injury to the vessel during deployment. Moreover, the closed ends at the first end 10 and the second end 20 help in maintaining stress distribution on the stent 100 resulting in uniform expansion of the stent 100 post deployment without affecting the strength of the stent 100.
[29] The stent 100 may be provided with a plurality of markers (not shown) for enabling radiopacity of the stent 100. The markers may be attached on the first end 10 and the second end 20 of the stent 100. The markers may have a predefined shape but not limited to sleeve, circular etc. In an embodiment, the markers are in the shape of a sleeve.
[30] The stent 100 may be made of biodegradable polymer. The biodegradable polymer may be selected from a group consisting of poly-L-lactide-co-caprolactone (PLC), poly dioxanone, poly ethylene glycol (PEG), polycaprolactone (PCL), poly-DL-lactic acid (PDLLA), poly L-lactide (PLLA), poly (glycolic acid) (PGA), poly L-lactide-co-glycolic acid (PLGA), and/or a combination thereof. In an embodiment, the stent 100 is made of polydioxanone. The polydioxanone has good shape retention and a rapid degradation rate of around six to eight months.
[31] In accordance with an embodiment of the present invention, Fig.2 depicts a process involved in the manufacturing of the stent 100. The process of manufacturing commences by braiding a plurality of monofilaments to form a braided structure at step 201. The plurality of monofilaments may be in a range of four to eight. In an embodiment, the plurality of monofilaments is six.
[32] The monofilaments may be attached to a mandrel (not shown), including a plurality of hooks. The plurality of monofilaments may be grooved on the plurality of hooks. The mandrel may have a predefined diameter ranging from 6mm to 12mm. In an embodiment, the diameter of the mandrel is 8mm. The braiding of the plurality of monofilaments may be performed using an automatic braiding machine to form a braided structure. The braiding machine may include a plurality of carriers. In an embodiment, the braiding machine includes 24 carriers. The carriers may be present in 12 sets of two carriers. The process of braiding may be performed by wrapping each portion of the six monofilaments in spools of one set of the carriers in an alternate manner.
[33] Post braiding at step 201, the braided structure is subjected to a process of primary shape setting at step 203. The primary shape setting may be performed to obtain the desired shape. The process of primary shape setting may be performed by heating the braided structure in an oven at a predefined temperature for a predefined time duration. The predefined temperature and time duration may be in a range of 80°C to 100°C and 14hours to 16 hours, respectively. In an embodiment, the process of primary shape setting is performed at a temperature of 90°C for 15 hours.
[34] After the process of primary shape setting, a plurality of loose ends of the braided structure is subjected to a process of back braiding to form the stent 100 at step 205. The process of back braiding may be performed by loading the first segment 101 on the mandrel in a reverse direction. All the loose ends of the first segment 101 may be cut to a predefined length ranging from 40mm to 100mm. In an embodiment, the predefined length is 55mm. The process of back braiding may be performed manually.
[35] Post back braiding, at step 207, the stent 100 is axially compressed to from the compressed stent. The process of axial compression may be performed at both the ends of the stent 100. The stent 100 may be axially compressed to a predefined length L3. The length ‘L3’ may be in a range of 25% to 15% of the length ‘L’ of the stent 100. In an embodiment, the length ‘L3’ is reduced to 20% from the length L. The process of axial compression may be performed by means of compression using a mandrel with a fixture. The fixture of the mandrel may be pressed manually, leading to the desired compression of the stent 100.
[36] The process of axial compression of the stent 100 increases the braiding angle and decreases the length of the stent 100. The braiding angle and length after the compression may range from 150° to 170° and 30mm to 90mm respectively. In an embodiment, the braiding angle is 155°and the length is 40mm. The increased braiding angle enhances the radial strength of the stent 100. The process of axial compression enhances the strength and/or recoil capacity of the stent 100. Moreover, axial compression renders the stent 100 with better shape memory and/or retention capacity. Therefore, the stent 100 has minimal changes in the length and diameter after it is expanded from the compressed state at the implantation site.
[37] Following axial compression, the compressed stent is subjected to a process of secondary shape setting at step 209. The process of secondary shape setting may be performed in a vacuum heating oven at the predefine temperature ranging from 80°C to 100°C for the predefined time duration of 14 hours to 16 hours. In an embodiment, the process of secondary shape setting is performed at a temperature of 90°C for 15 hours. The vacuum may be applied between 600 to 700 mmHg pressure to remove internal stress from monofilaments.
[38] The process of secondary shape setting enhances the longitudinal and radial strength of the stent 100 and/or prevents changes in the braiding angle of the monofilaments after expansion. The strength of the stent 100 may be in a range of 9N to 12N. In an embodiment, the strength of the stent 100 is 11N. Post-secondary shape setting, the braided structure is allowed to cool gradually till it attains 25°C to 30°C temperature over a period of duration. Additionally, post-secondary shape setting, a plurality of loose ends of the plurality of monofilaments are manually cut and attached to adjacent monofilaments. The loose ends of the plurality of monofilaments are attached together by means of welding, adhesives, etc. In an embodiment, the plurality of monofilaments is attached by means of adhesives.
[39] Post cutting, radiopaque markers are attached at both ends of the stent 100 at step 211. The markers may be attached by means of without limitation, crimping, bonding, welding, adhesive, etc. In an embodiment, the markers are attached by means of crimping.
[40] The stent 100 is subjected to a process of packaging at step 213. The process of packaging may be performed by placing the stent 100 in an aluminum pouch. After placement, the pouch is vacuum-sealed and packed inside a box at room temperature.
[41] Post packaging, the stent 100 is subjected to a process of sterilization 215. The sterilization may be performed using a radiation sterilization process, such as without limitation e-beam radiation sterilization or gamma sterilization. In an embodiment, the coated implant is sterilized using gamma radiation sterilization. The sterilization is done at a dose of gamma radiation in a range of 20 kGy to 30 kGy, more preferably 23 kGy to 27 kGy.
[42] The invention will now be described with the help of the following examples.
[43] Example 1 (Present Invention): Commercially available polydioxanone (PDO) monofilaments having diameter of 350 micron was used to make the braided tubular structure. The six monofilaments were loaded into 24 carrier automatic braiding machine. There were a total 12 sets of the carrier with each set containing two carriers. The mandrel had six hook pins at one end. The six monofilaments were grooved in the hook pins. Following, the monofilaments were braided automatically to form a braided tubular structure of length 50mm at a braiding angle of 145°. Post braiding, the braided structure was subjected to a process of primary shape setting. The process of primary shape setting was performed at a temperature of 90°C for 15 hours. Further, the braided structure was back braided. After back braiding, the stent 100 was axially compressed to a length of 40mm. The compressed stent was subjected to a process of secondary shape setting.
[44] The stent 100 was then loaded in a delivery sheath in a crimped state and subjected to expansion at the implantation site. It was found that the length of the stent 100 after expansion was increased to 44mm which is less than 10% increase in original length. The braiding angle was also increased to 155°. Therefore, it was observed that the stent 100 recovered 90% of its shape which is an indicator of enhanced radial strength. The radial strength of the stent 100 was measured and found to be 11 N. Therefore, the stent 100 was able to restore the patency of the biliary duct.
[45] Example 2 (Prior art): The commercially available polydioxanone (PDO) monofilaments having diameter of 350 micron was used to make the braided tubular structure. The six monofilaments were loaded on to 24 carrier automatic braiding machine. There was total 12 sets of the carrier with each set containing two carriers. The mandrel had six hook pins at one end. The six monofilaments were grooved in the hook pins. Following, the monofilaments were braided automatically to make a braided structure of length 50mm at a braiding angle of 145°. Post braiding, the braided structure was subjected to a process of primary shape setting. The process of primary shape setting was performed at a temperature of 90°C for 15 hours. Further, the braided tubular structure was back braided and again shape set at the temperature of the 90°C for 15 hours. After that stent was loaded in a delivery sheath in crimped state and was subjected to expansion at the implantation site.
[46] After expansion, it was observed that the stent did not recover its shape. The length and diameter of the stent were measured using vernier caliper. The length of the stent was found to increase to 63mm and the diameter was decreased to 6.3mm. The change in length and diameter of the stent was more than 20% its original length and diameter. Further, the braiding angle of the stent was reduced to 135°. The stent was tested for measuring the radial strength which was found to 8N which is less than the required range. The stent was not able to restore the patency of the biliary duct.
[47] 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.