WO2018122861A1

WO2018122861A1 - Multi-stage process for manufacturing a bioabsorbable stent with enhanced shelf life

Info

Publication number: WO2018122861A1
Application number: PCT/IN2017/050155
Authority: WO
Inventors: Deveshkumar Mahendralal KOTHWALA; Rajnikant Gandalal Vyas; Pramod Kumar Minocha
Original assignee: Meril Life Sciences Pvt Ltd
Priority date: 2016-12-30
Filing date: 2017-05-02
Publication date: 2018-07-05

Abstract

The present invention discloses a multi-stage process for yielding bioabsorbable stents with enhanced shelf life. The process includes annealing a scaffold obtained from the deformed tube, coating the annealed scaffold in low humidity environment, crimping the coated scaffold, packaging the scaffold and then sterilizing the crimped scaffold. The annealing includes heating the scaffold at 100-150° C in vacuum for 10-24 hrs, and cooling the heated scaffold in the presence of an inert gas for 3-6 hrs to ambient temperature to form an annealed scaffold. The annealed scaffold has molecular weight M_wrange of 320000 g/mol to 410000, M_n between 190000-250000 g/mol and possesses narrow molecular weight distribution of poly dispersity index between 1.5 to 1.9. Each of the steps of the multi-stage process results in enhanced shelf-life of the bioabsorbable stents.

Description

MULTI-STAGE PROCESS FOR MANUFACTURING A BIOABSORBABLE STENT WITH ENHANCED SHELF LIFE

FIELD OF INVENTION

[001] The present invention is generally directed to bioabsorbable stents, more particularly, the present invention pertains to a multi-stage process for manufacturing a bioabsorbable stent with enhanced shelf life and stability.

BACKGROUND

[002] Recent developments in the treatment of heart related ailments have been directed to biocompatible endoprosthetic devices commonly acknowledged as stents. Stents (metal or bioabsorbable) are structured to treat any type of blockage present in a body lumen or to expand a narrowed lumen thereby maintaining its patency.

[003] Metal stents have long been introduced in the field of biomedical devices; however, the implantation of such devices is permanent in nature. The implant of a metal frame at any location inside the body poses threats such as increased risk for thrombosis, impaired endothelial function to name a few. Therefore, bioabsorbable (or biopolymer) stents, fabricated from polymers, are now being held as a promising alternative to the conventional stents as they do not produce any remains and are absorbed in the body within a short span of time.

[004] The only disadvantage of polymeric materials is their lower mechanical strength compared to the metals. The strength to weight ratio of polymeric materials is less than that of metals. Moreover, bioabsorbable stents are prone to degradation under long term storage, loss of stability and reduced shelf life after manufacturing process. There is a change in properties of bioabsorbable stents as storage period increases which leads to consistency associated problems thereby affecting the performance of a bioabsorbable stent.

[005] However, the aforesaid problems relating to stability, mechanical strength and shelf life can be altered via an optimized manufacturing process. SUMMARY

[006] The present invention discloses a multi-stage process for yielding bioabsorbable stents with enhanced shelf life. The process comprises deforming an extruded polymer tube in multiple stages, annealing a scaffold obtained from the deformed tube, coating the annealed scaffold in low humidity environment, crimping the coated scaffold, packaging the scaffold and then sterilizing the crimped scaffold.

[007] The annealing comprises heating the scaffold at 100-150o C in vacuum for 10-24 hrs, and cooling the heated scaffold in the presence of an inert gas for 3-6 hrs to ambient temperature to form an annealed scaffold. The annealed scaffold has molecular weight Mw range of 320000 g/mol to 410000, Mn between 190000-250000 g/mol and possesses narrow molecular weight distribution of poly dispersity index lies between 1.5 to 1.9.

[008] Each of the steps of the multi-stage process results in enhanced shelf-life of the bioabsorbable stents. BRIEF DESCRIPTION OF THE DRAWINGS

[009] 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.

[0010] FIG. 1 illustrates an overview of the entire manufacturing process for enhancing the shelf life of a bioabsorbable stent in accordance with an embodiment of the present disclosure.

[0011] FIG. 2 illustrates an exemplary of the packaging of a scaffold system in accordance with an embodiment of the present disclosure. [0012] FIG. 3 illustrates an exemplary overview of the annealing step of FIG. 1 in accordance with an embodiment of the present disclosure.

DETAILED DESCRIPTION OF DRAWINGS

[0013] 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 commu nicable 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. [0014] 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 structu ral 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 structu re.

[0015] The present invention discloses a process for manufacturing a bioabsorbable stent with enhanced shelf life and additionally improved strength than conventional bioresorbable stents. The manufacturing process in accordance with the present invention involves a series of steps, one or more of which enhance the shelf life of the stent and must be performed under controlled condition(s). The series of steps in an exemplary embodiment includes deforming a tube, annealing the scaffold, coating the stent, crimping the scaffold and/or sterilizing the stent. In an embodiment, each of the aforesaid step results in enhanced shelf-life as described below. [0016] FIG. 1 depicts an overview of the process for manufacturing a bioabsorbable stent with enhanced shelf life. I n an embodiment of the present invention, the bioabsorbable stent is balloon expandable. I n an embodiment of the present invention, a biodegradable stent made of PLLA (poly-L-Lactide) with strut thickness of less than 130μιη is manufactured by the said process. The terms "bioabsorbable", "bioresorbable" and "biodegradable" are used interchangeably throughout the specification and the same may be appreciated as such by the person skilled in the art. The terms "stent" and "scaffold" are used interchangeably throughout the specification and the same may be appreciated as such by the person skilled in the art. [0017] At step 102, a biopolymer tube formed by extrusion process is provided. A bioabsorbable stent can be formed from a tu be or a sheet rolled into a tube. A sheet or tu be, for example, may by formed by various methods known in the art such as extrusion or injection blow molding. The process conditions such as temperature and magnitude of stress applied during extrusion process influence the mechanical properties of the extruded tube. In an embodiment, the extrusion of the tube is performed at a predefined temperature, for example, approximately at a melting point of the polymer. Alternately, extrusion may be performed at 170°C-230°C temperature.

[0018] Certain properties of the polymer are considered. For example, the initial molecular weight (M_w) of poly-l-lactide resin raw material ranges from 500000-600000 g/mol, M_n of resin ranges from 300000 g/mol to 400000 g/mol and PDI to resin is in the range of 1.4-2.0. Here, M_w represents average molecular mass of various molecular chains of a polymer which includes even those having same types of individual macro molecules of different chain lengths. M _n represents the average of different sizes of various polymer chains and it is arithmetic mean or average of the molecular masses of the individual macromolecules. Poly dispersity index (PDI) is the ratio of M_w to M_n (M_w/M_n). This parameter provides an indication of how narrow the molecular distribution is. [0019] At the end of 102, an extruded tube with desired internal diameter d , and external diameter d₀ is obtained. In an embodiment of the present invention, M_w of the extruded tube ranges from 320000 g/mol to 410000 g/mol and M _n ranges from 190000-250000 g/mol. Moreover, PDI of the extruded tube is in the range of 1.55-1.9 and crystallinity ranges from 6% to 12%. The low crystallinity of the extruded tube reduces brittleness and increases ductility which results in easy deformation of the extruded tube with increased mechanical strength of the extruded tube.

[0020] At step 104, the extruded tube of step 102 undergoes first stage of shelf life enhancement. The first stage includes deformation of the extruded tube. In an embodiment of the present invention, radial deformation is performed by centrally placing the extruded tube inside a tubular mold which leads to uniform radial expansion of the extruded tube. The mold may be constructed of a material having high thermal conductivity known in the art. In an embodiment, the tubular tube is made of beryllium copper.

[0021] In an exemplary embodiment of the present invention, the extruded tube undergoes three- stage biaxial deformation in an inert atmosphere. I n an embodiment, the inert gas pressure applied to the tube in stage 1 is 480-530 psi followed by 560-610 psi in stage 2 and finally 630-680 psi in stage 3. The primary temperature is maintained near the glass transition temperature of the polymer i.e., between 65°C to 80°C. The pressure and temperature conditions are maintai ned for a short period of time, for example, 15-20 seconds, to set the tube under each of these conditions. While maintaining the pressure of stage 3, the tube is heated to a temperature 90°C-130°C, prefera bly 100°C-120°C and maintained at the said temperature for 30 sec to 2 minutes. The tube is then immediately cooled to 20-25°C in 20-30 sec. The pressure is then released and deformed tube is removed from the mold .

[0022] The stage wise application of such relatively higher pressures and maintenance of near gla ss transition temperature during step 104 ensures tight tolerance and results in a fairly transparent finished tube. In an embodiment of the present invention, the deformed tube obtained at the end of stage 3 has a lower PDI with a narrow molecular weight distribution as compared to single stage deformation. The narrow distribution of molecular weight results in more stable properties (for example, consistent deformed tube properties) of the bioabsorbable stent. The consistency and stability attained by the said step minimizes deterioration during storage without compromising the performance of bioabsorbable stent, thereby su pport in enhancement of its shelf life.

[0023] Smooth tu be surface with uniform thickness and consistent properties throughout the tu be length ensures optimum laser cutting parameters which reduce heat affected zones and deterioration of polymer property from the edges of a cut stent. This improves stability of the stent and enhances shelf-life period without deviation in stent performance and repeatability. [0024] Moreover, heating the deformed tube obtained at stage 3 provides adequate fatigue strength. Fu rther, immediate cooling controls the crystallinity of polymer in a narrow range indicating consistency in polymer structure. Therefore, the uniformly deformed tu bes with minimum tube thickness variation and consistent polymer structure provide adequate mechanical properties. In an embodiment, tensile strength and crystallinity of the deformed tu be obtained is 85-105 N/mm² and 45% respectively.

Example-1

[0025] Following Table 1 shows the effect of parameters maintained during deformation process on the extruded tube. Sample Primary Hold Pressure Tube M_w M„ PDI Tensile %

Temperat Time applied Appearance (g/mol) (g/mol) Strength strain ure (°C) (sec)

N/mm2 @ break

Extrude 67 75 3 stages Transparent 335722 214024 1.5 99.4 177.7 d Tube- & glassy 7

1 tube surface

Extrude 68 75 3 stages Transparent 381710 207208 1.8 103.0 184.5 d Tube- & glassy 0

2 tube surface

Extrude 76 25 1 stage Little Hazy 366195 163008 2.2 71.6 93.07 d Tube- tube 4

3

Table 1

[0026] As seen in Table 1, there is a significant effect of primary temperature, pressure applied and hold time on the molecular distribution of deformed tube. After the deformation process, tube-1 and tube-2 possess narrow molecular distribution of polydispersity index and more tensile strength as compared to tube-3. Also, tube-3 obtained has hazy appearance compared to tube-1 and tube- 2. The haziness of tube-3 indicates more brittleness compared to glassy finished tube-1 and tube-2.

[0027] Tubes with higher tensile strength, % strain @ break and narrow molecular distribution of deformed tube increase the fracture toughness and stabilize polymer properties which support enhancement in shelf life by preventing brittleness upon long term storage. Scaffold fabricated from tube-1 and tube-2 when stored for 3 months at ambient temperature, performed significantly better and upon expansion at 37°C, strut remained free of cracks due to balanced distribution of crystalline and amorphous region throughout deformed tube length. However, scaffold fabricated from tube-3 resulted in cracks and notches, when expanded after 3 months storage period at ambient temperature. [0028] In an embodiment, the radial deformation is preceded or followed by axial deformation of the polymer tube.

[0029] At the end of step 104, M_w of the deformed tube ranges from 320000 g/mol to 400000 g/mol and M_n ranges from 200000-250000 g/mol. Moreover, PDI of the deformed tube is in the range of 1.5-1.9, the deformed tube is laser cut in a predefined structure to form a scaffold at step 106. I n an embodiment, laser cutting of the deformed tube is performed using femto seconds equipment and laser beam of 1250 to 1750 nm wavelength to cut polymer scaffold structu re on the deformed tube. The laser cutting process at step 106 creates a scaffold structure which may consist of struts which are structural elements formed on the tube. The overall configuration of the stent affects the radial strength, flexibility and fatigue resistance of the stent. The dimensions of each cell and their spacing are adjusted to prevent protrusion of the plaque or any part of the body lumen where the stent is implanted. At the same time, these dimensions are adjusted to achieve trouble free crimping of the stent over the ba lloon of the catheter without compromising the flexibility of the stent.

[0030] In an exemplary embodiment of the present invention, the scaffold structure consists of multiple rows of sinusoidal wave type cylindrical elements with regular or irregular shapes with plurality of peaks and valleys across its axial length . The cells are formed by connecting upper and lower rows of cylindrical elements with straight or curved links ("cross linking elements" or "cross linking struts"). These cross lin king elements connect upper and lower rows of cylindrical elements anywhere along the length of the sides of the elements. These interconnections form cylindrical scaffold structure. Closed cells at the end of a scaffold at both sides control stent expansion which improves performance stability (prevent damage) /provides radial strength.

[0031] The shape of the rows and the way the rows are interconnected can be altered to get desired mechanical strength and other essential properties of the stent like flexibility (pushability and trackability), lumen to stent surface area ratio, desired side branch access, desired crimping profile etc.

[0032] In an embodiment of the present invention, one or more holes or depots are cut in the cross linking elements located on proxi mal and distal ends of the scaffold structure where radio opaque markers are fixed. I n an embodiment of the present invention, platinum markers are fixed on the scaffold for radio-opacity. The number of markers in each scaffold can range from six to fourteen markers. In an embodiment, twelve platinum markers are fixed on the scaffold, three pairs at each end of the scaffold equi-spaced circumferentially at 120° to each other. This en hances the visibility of a scaffold patency under fluoroscopy.

[0033] The surface of the laser cut scaffold may be cleaned for example using iso propyl alcohol (IPA) to remove su rface defects.

[0034] The laser cut scaffold is then employed for second stage of shelf life enhancement at step 108. The laser cut scaffold is annealed for enhancing the shelf life at step 108. I n an exemplary embodiment of the present invention, the laser cut scaffold is mounted and fixed on a mandrel. The shape and diameter of the mandrel may vary based upon the shape and diameter of the stent required to be furnished. The mand rel may be of any material for example, Teflon. The mounted scaffold is fixed on the hank by using a Teflon fixer. The hank is then loaded onto a shaft placed inside an annealing chamber. The annealing process takes place inside an annealing chamber and the different parameters such, drum speed, temperature, pressure, etc. are fixed. In an embodiment, the rotation (Drum) speed is maintained at 2 rpm and rotation (Drum) time is 30 mins.

[0035] The annealing chamber may be constructed of any material which is able to withstand high temperatures required to be maintained inside the chamber for heating the scaffold. The annealing chamber is heated under controlled conditions for a specified duration of time in order to anneal the scaffold. For example, the annealing chamber is heated at 100-150° C under vacuum conditions for a period of 10-24 hrs below the melting point of the polymer thereby resulting in changes in physical properties and its crystalline structure. The vacuum pressure inside the annealing chamber can be maintained around 100 kPa or 1 bar.

[0036] The said step of annealing helps to remove residual monomers present in the scaffold. The removal of residual monomer prevents the bioabsorbable stent from degradation du ring long term storage and provides consistent polymer morphology.

[0037] The vacuum conditions prevailing inside the annealing chamber can be broken by pu rging an inert gas at a pressure of approximately 25-30 psi for a period of 25 to 30 seconds inside the chamber. The inert gas may be nitrogen or argon gas. The inert gas purging inside the an nealing chamber aids in the establishment of an atmosphere for subsequent cooling process. The employment of an inert atmosphere (argon, helium, nitrogen, etc.) for the subsequent cooling step prevents oxidation in the polymer utilized in the scaffold. Further, employment of an inert atmosphere cools the chamber without moisturization of scaffold. The annealing chamber is cooled to about 30-50°C at a constant rate in a period of 3-6 hours to avoid sudden cooling shock to produce an annealed scaffold . In an embodiment of the present invention, the crystallinity of the annealed scaffold is 45-55%.

[0038] The greater crystallinity obtained from slow cooling in the inert atmosphere thereby confers mechanical strength to the scaffold as the degree of freedom for the molecular chains to move is cu rtailed. M_w of the annealed scaffold ranges from 310000 g/mol to 390000 g/mol to and M_n ranges from 190000 g/mol to 250000 g/mol. Moreover, PDI of the annealed scaffold is in the ra nge of 1.5-1.9.

[0039] It is known that the crown region of the scaffold is more susceptible to stress during long term storage. The slow cooling of heated scaffold to ambient temperature rel ieves internal/residual stress and results in a narrow range of crystallinity thereby producing uniform polymer structure distribution with transparent surface. Due to the said annealing process, optimal performance of the scaffold is maintained and this supports in the enhancing shelf life of the scaffold.

Example-2

[0040] Condition 1: I n this condition, annealing was done in a controlled manner. The scaffold was mounted on a suitable Teflon mandrel and fixed on the hank with the help of Teflon fixer. It was placed in the annealing chamber at a drum speed of 2 rpm. Drum rotation time was maintained at 30 minutes. The annealing chamber was heated to 140 °C in about 4 hou rs under vacuum of 96 Kpa and maintained for about 21 hours. The annealing chamber was then cooled gradually in about 5 hours to get 35°C and then vacuum was released by slowly purging argon gas of pressure 25 psi in 20 seconds.

[0041] Condition 2: I n this condition, the scaffold was kept for annealing in a similar annealing chamber as described in above case, having identical mandrel, drum speed and rotation time as condition 1. The annealing chamber was heated to 140°C in one hour at atmospheric pressu re of air and maintained for 21 hours. Finally, it was cooled to 35°C in about 40 minutes by opening the annealing chamber and the scaffold was taken out.

[0042] Table 2 shows comparative results obtained in the above two conditions:

Table 2

[0043] At step 110, the third stage of shelf life enhancement takes place. The bioabsorbable stent obtained after annealing is coated with an antiproliferative drug (or bioactive agent), for example, Sirolimus in a predefined dosage and proportion. The coating of antiproliferative drug on the scaffold surface can be performed by any method known in the art. In an embodiment of the present invention, a formulation of solution containing sirolimus and PDLLA is coated on the scaffold by spray coating in 50:50 proportion w/w and Sirolimus dose of 1.25 μg per mm2 area of the scaffold surface. The said solution may be formed by dissolving the antiproliferative drug and polymer in a solvent. The solvent is selected without limitation, from methylene chloride, chloroform, acetone, methanol and mixtures thereof.

[0044] In an embodiment, the said coating is performed by pouring coating solution in spray gun. The distance between spray gun tip and stent is maintained adequately to achieve uniform and smooth coating surface. Scaffold rotation speed and spray gun oscillation play vital role in achieving uniform coating thickness. The pressurizer nitrogen gas and solution flow rate support in good adhesion and quick drying of coating solution on scaffold surface.

[0045] The said coating is performed in a low humidity environment such as controlled humidity of RH 18-20% which enhances adhesion of drug/polymer coating and provides smooth transparent coating layer on scaffold surface. Coating under low humidity conditions also prevents formation of any peel or crack on the coating surface. Thus, maintaining coating integrity at prolonged storage du ration enhances the shelf life of the bioabsorbable stent.

Example-3

[0046] The scaffolds were coated in three different hu midity conditions under standard spray coating parameters namely RH 20 %, 38 % and high humidity at RH 58 % respectively. After coating process, all scaffolds were crimped and stored for 3 months period at ambient condition.

[0047] The scaffolds coated in high humidity condition of RH 58% were observed to show delamination, peeling and cracking of coating surface after 03 months period. Damage on coating surface may lead to reduced stent protection and finally affect stent performance in long term storage.

[0048] The intermediate humidity conditions (RH 38%) resulted in less deterioration in coating surface compared to RH 58% and showed minor cracking and peeling of coating surface at stress region after 03 months storage duration.

[0049] However, the scaffolds coated in RH 20% were observed to show no peeling or cracking of the coating surface after 03 months as well as after six months storage period at ambient temperature.

[0050] The coated scaffold may then be kept under vacuum to remove the residual solvent.

[0051] At step 112, the coated scaffold obtained from step 110 is employed for fourth stage of shelf life enhancement. The fourth stage of shelf life en hancement involves crimping of a coated or a non-coated scaffold and may be directly performed post step 108 or after step 110.

[0052] Crimping parameters include diameter of stent after crimping, pressure of crimping, dwell time and temperature etc. These parameters maintained at the crimping process may alter the properties of polymer and hence the properties of bioabsorbable stent. The scaffold length and balloon size affect the crimping operation. I ncreasing the balloon profile results in a greater probability of crimped scaffold to reduce chances of slippage as dislodgement force becomes higher. The scaffold when crimped on a balloon catheter with higher profile decreases the change in scaffold diameter du ring crimping resulting in uniformly crimped scaffold and even expansion with no notches and cracks.

[0053] No change in M_w, M_n and PDI is observed after this stage. Instead, change in diameter du ring crimping process is reduced due to increase in balloon diameter. This enhances its overall uniformity which further supports its shelf life. The expansion of crimped stent is also found more uniform thereby reducing the chances of notches and cracks during expansion.

[0054] In an embodiment, the coated scaffold is crimped on balloon of a sterilized catheter in a clean environment in one or multiple stages. I n an embodiment, crimping is performed on a high balloon profile ranging from 1.3-1.5 mm in 6 to 8 stages with dwell time between 200 to 310 seconds and crimping temperature of 25°C-60°C, more preferably 45°C-55°C (near glass transition temperature).

[0055] Crimping performed by the said process (crimping temperature kept near glass transition and by taking higher balloon profile) reduces chances of slippage of scaffold during implant as dislodgement forces are higher. This also minimizes bioabsorbable stent recoil during storage of bioabsorbable stent at ambient temperature. The crimped scaffold obtained by the said crimping process at the end of step 112, stabilizes the polymer properties and results in uniform expansion of bioabsorbable stent by minimizing stress and strain at crown region during longer storage du ration thereby enhancing its stability and shelf life at ambient temperature.

Example-4

[0056] The scaffold was crimped on a low profile 1.2 mm balloon catheter and stored for 3 - 6 months at ambient temperature. The same stent when expanded at 37°C temperature resulted in notches and cracks near the crown regions at 3 months storage period.

[0057] On the other hand, another scaffold was crimped on a balloon catheter having balloon profile as high as 1.4 mm and stored at 3, 6 months' time at ambient temperature. The higher profile stent when expanded after 3 and 6 months showed even and uniform expansion of stent resulting in crack/notches free surface at crown regions.

[0058] The crimped scaffold is employed for fifth stage of shelf life enhancement at step 114. The fifth stage of shelf life enhancement involves the addition of at least one oxygen absorber (or scavenger). [0059] In an embodiment of the present invention, the oxygen absorber is composed of activated iron powder, carbon and other electrolytes. I n an embodiment, the oxygen absorber used in this process are comprise of I ron (Fe), Calcined diatomaceous earth (Si0₂), Calcium Chloride (CaCI₂) filled in PET packaging material (40 x 20 mm). I n an embodiment, oxygen absorbers are placed in an aluminium pouch containing scaffold to eliminate oxygen and prevent it from deterioration due to present of oxygen.

[0060] I n the preferred embodiment, a fully impermeable aluminum pouch consists of a top part wherein the oxygen absorbers are adhered using surgical adhesive and the remaining part of aluminum pouch consists of the bioabsorbable scaffold system. The aluminum pouch may be sealed with an inert gas purge (argon, nitrogen), and kept at ambient temperature for a predefined time such as 05-35 hours. Within this specific duration of storage, the concentration of residual oxygen may reduce to 0.05% or less. The oxygen absorbers may be evicted, cut-off from the pouch by performing additional sealing. The aluminum pouch containing only scaffold system may be then subjected to e-beam sterilization.

[0061] In an exemplary embodiment, as depicted in FIG. 2, four oxygen absorbers (205a, 205b, 205c and 205 d) are placed in an aluminium pouch 201 and fixed with surgical adhesive tapes 203. The pouch may be a gas impermeable package made up of any material known in the art such as aluminum or plasma coated multi-layered structu re. The scaffold 209 system and the four oxygen absorbers (205a, 205b, 205c and 205d) are placed in two different chambers of the alu minum pouch separated by a seal 207. [0062] The packaging of the scaffold system and oxygen absorbers may be performed in a controlled environment in order to control the concentration of oxygen. I n an embodiment, the packaging is performed in an inert gas. The controlled environment may be achieved by vacuum evacuation of the packaging followed by a backfill of the packaging with an inert gas such as argon. The successive rounds of evacuation and backfill may ensure complete elimination of oxygen. The final oxygen content after packaging in the said environment may be approximately 0.002% or less, 0.002% to 0.01%, 0.01% to 0.015%, 0.015% to 0.02%, or 0.02% to 0.04%. In an embodiment, the packaging is designed to prevent exposu re of the scaffold system to any bio-burden such as bacteria as well as non-inert gases such as oxygen as well as moisture. I n an embodiment, the average bio-burden of the scaffold system ranged from 3 to 8 CFU. [0063] Sterilizing the scaffold fabricated from semicrystalline PLLA by irradiation may induce chemical and physical alteration within the polymeric material in the presence of atmospheric oxygen. Moreover, moisture can also cause degradation of the scaffold. The said step of addition of oxygen absorber helps to stabilize the properties of bioabsorbable stent and thus improves its stability during prolonged storage at ambient temperature. Example-5

[0064] The example shows a comparative of three cases provided with different oxygen content inside the sealed aluminum pouch having identical scaffold systems. The oxygen content without oxygen absorber in crimped scaffold system was found in range of 1.45 %.

[0065] First Condition : The crimped scaffold system was packed in aluminum pouch containing two oxygen absorbers. The two oxygen absorbers were adhered with surgical adhesive tapes and then sealed with argon gas purge. This pouch was stored at the am bient temperature 22 ± 3°C for 5 hours before e-beam sterilization. The concentration of residual oxygen content was measured with oxygen analyzer (Make: Quantek I nstruments, Model 905) was found to be 0.4 %.

[0066] Second Condition : The crimped scaffold system was packed in aluminum pouch containing four numbers of oxygen absorbers. The four oxygen absorbers were adhered with surgical adhesive tapes and then sealed with argon gas purge. This pouch was stored at the ambient temperature 22 ± 3°C for period of 24 hours before e-beam sterilization. The concentration of residual oxygen content was measured with oxygen analyzer (Make: Quantek Instruments, Model 905) and was found to be 0.12 %. [0067] Third Condition : The crimped scaffold system was packed in aluminum pouch containing four numbers of oxygen absorbers. The four oxygen absorbers were adhered with surgical adhesive tapes and then sealed with argon gas purge. The pouch was stored at the ambient temperature 22 ± 3°C for period of 35 hours before e-beam sterilization. The concentration of residual oxygen content measured with oxygen analyzer (Make: Quantek Instru ments, Model 905) and was found to be 0.011 %.

[0068] All the above three devices were then subjected to e-beam sterilization process. The sterilized stents were stored for 6 months. These stents were expanded under identical conditions. [0069] The stent kept in first and second conditions resulted in strut cracks and notches at various crown regions. However, the stent kept in the third conditions was found to be free of cracks and notches. This indicates delay of aging process in finished polymer stent in absence of residual oxygen. Thus, oxygen absorbers have significant effect in the enhancing the storage life of biodegradable stent. [0070] At the end of step 114, the scaffold is employed for sixth stage of shelf life enhancement at step 116 which involves sterilization. The sterilization of the scaffold and the rest of the assembly including catheter, etc. may be performed together or separately. In an embodiment, the sterilization process of the scaffold is performed by e-beam sterilization and the rest of the components are sterilized by UV sterilization. [0071] The scaffold is exposed to e-beam radiation at a predetermined dosage and a predetermined temperature. The parameters maintained such as dosage of e-beam at the time of e-beam sterilization affect the exposure of the polymer stent to e-beam and hence, affect its degradation. Prolonged exposure of the scaffold to e-beam result in increased degradation of the scaffold. In an embodiment, the instant invention reduces the degradation of the scaffold by reducing the dose of e-beam to less than 22 kGy without compromising effective sterilization and without use of a stabilizer. In an embodiment, the e-beam dosage is between 18 and 24 kGy and the temperatu re between 2°C and 8°C. The low temperatures prevent molecular weight degradation and conserve properties of scaffold during prolonged storage.

[0072] I n an embodiment of the present invention, the M_w of scaffold after e-beam sterilization ranges from 150000 g/mol to 210000 g/mol and M_n ranges from 80000 to 140000 g/mol. Moreover, PDI of the scaffold after e-beam is in the range of 1.6-1.9.

[0073] The e-beam dose affects the scaffold but not the other components of the scaffold system such as catheter, etc. All the other components of the scaffold system may be sterilized using Ethylene Oxide (ETO), UV or e-beam. In an embodiment, a compact UV cabinet is employed to sterilize the components of the scaffold system excluding the scaffold. The said components are exposed to a predetermined wavelength for a predetermined time such as 253.7 nm for 3 hou rs. I n an embodiment, the UV cabinet has dimensions 49 x 27 x 20 (L x D x H) and is manufactured by Frago Impex Sdn Bhd, Kuala Lu mpur, Malaysia. The UV cabinet is designed in way to maximize the effect of the radiation.

[0074] The UV cabinet may also be provided with at least one strip which changes its color when exposed to UV radiation. The said strip may be employed to determine the dose of UV radiation by comparing the change in color of the strip to comparative dose chart. Each tested strip can be correlated to the milli-joule range of UV energy that each color pattern of the chart represents. For example, exposure for maximum of 2 hou rs resulted in decoloration of the strip, which on correlating to the comparative dose chart, i ndicated 200 mJ/cm2.

[0075] At step 118, a balloon expandable bioabsorbable stent is produced with enhanced shelf life. Example-6 [0076] The starting material for making the stent was PLLA tube with M_w of 386259 g/mol, M_n of 224930 g/mol, PDI 1.72, glass transition temperature 59-62°C, crystallinity 11.29%. The tube was deformed at 67°C by applying axial force till desired stretch was achieved to get axial expansion ratio of 1.4. The conditions were maintained for 10-20 sec and then the axial force was removed. The radial expansion was then carried out by pressurizing the tube with nitrogen in 3 stages at 67°C.

Stage-1: 510 psi. Stage-2: 580 psi. Stage-3: 650 psi.

At each stage, the conditions were maintained for 05-20 sec. [0077] While maintaining the pressure, the tube was heated to 110°C and this temperature was maintained for 30 to 60 seconds. The tube was cooled to 20°C over 30 sec and pressure was released. The deformed tu be obtained had tight tolerance and glassy finished tube.

[0078] The M_w, M_n and PDI of the deformed tube at the end were 383330 g/mol, 226030 g/mol and 1.69 respectively. It is evident that the molecular weight distribution was narrower after tube deformation process resu lting in stable properties and minimized deterioration during prolong storage duration. The crystallinity obtained at this step 51 %. [0079] The deformed tube was cleaned with iso propyl alcohol and then cut on laser machine using laser beam of 1500 nm wavelength to form the scaffold.

[0080] The laser cut scaffold was fixed with twelve platinum markers equi-spaced circumferentially at 120° to each other at both ends of stent for better fluoroscopy.

[0081] Marker deposited stent was annealed at temperature of 110°C for 16 hours under vacuum. The annealing chamber was allowed to cool at a constant cooling rate of about 30°C temperature to produce an annealed scaffold for a period of 3 to 4 hours with better polymer structure distribution by relieving internal stress and strain and removal of residual monomer. Thus, deterioration of stent during prolonged storage period was prevented. After prolonged storage, the scaffold was found without any notches at crown region when expanded at 37°C temperature. The M_w of annealed scaffold was found to be 382585 g/mol, M_n was 222945 and PDI was 1.71 respectively.

[0082] The annealed scaffold was further coated under low humidity environment (RH 19%) for better drug/polymer adhesion on stent surface, which support to maintain coating integrity and prevent coating damage from any peel or crack even after prolong stent storage period. [0083] The coated scaffold was then crimped on pre-sterilized PTCA catheter at 50°C in 8 stages and total dwell time of 240-260 sec. The crimping was done on higher balloon profile of 1.4 mm which increases dislodgement force of scaffold. The temperature near glass transition during crimping process supports to stabilize polymer properties at ambient temperature and result in uniform expansion of stent by minimizing stress/strain at crown region and thereby enhancing shelf life of device at ambient storage condition.

[0084] The crimped scaffold system was then placed in an aluminum pouch. Four oxygen absorbers were adhered using surgical adhesive tape in top part of aluminium pouch and sealed with argon gas purge. The pouch was stored at ambient temperature for period minimum 35 hours to get residual oxygen concentration 0.011%. The additional sealing was done after removing the oxygen absorbers and device was almost without any residual oxygen concentration.

[0085] The oxygen free aluminum pouch containing scaffold system was subjected to e-beam sterilization process at 22 kGy dose. The final M_w obtained was 187997 g/mol, M_n was 95199 g/mol and PDI was 1.98 respectively. The oxygen free environment in final pouch containing device supports in enhancement of shelf life at ambient temperature by preventing deterioration of polymer properties. The performance of scaffold remain intact even after prolong storage period.

[0086] The overall manufacturing process when performed under controlled conditions as mentioned above supported in enhancement of shelf life at ambient temperature for minimum up to 18 months or more. The performance characteristics of stent remained intact and within acceptable range immediate after manufacturing process and after 18 months.

[0087] FIG. 3 depicts an exemplary overview of the entire process for annealing of a scaffold. The process is initiated at step 302 where a scaffold is mounted and fixed on a mandrel. In an embodiment, an extruded polymer tube is mounted on the mandrel. The scaffold to be employed on the mandrel may be of, without limitation, any polymeric material. In an embodiment of the present invention, the scaffold is constructed of poly (L-lactide) (PLLA). The shape and diameter of the mandrel may vary based upon the shape and diameter of the scaffold required to be furnished. The mandrel may be of any material for example, Teflon.

[0088] In an embodiment, the scaffold to be mounted on the mandrel is a radially deformed scaffold. In another embodiment, the scaffold to be mounted on the mandrel is an axially deformed scaffold. In yet another embodiment of the present invention, the scaffold is axially as well as radially deformed scaffold. The scaffold may be machine braided or a laser cut stent with or without radio opaque markers. In an embodiment of the present invention, the mounted stent is fixed on the hank by using a Teflon fixer.

[0089] The hank is then loaded onto a shaft placed inside an annealing chamber at step 304. The annealing process takes place inside the annealing chamber and the different parameters such, drum speed, temperature, pressure, etc. are fixed. In an embodiment of the present invention, the rotation (Drum) speed is maintained at 2 rpm and rotation (Drum) time is 30 mins. The annealing chamber may be constructed of any material which is able to withstand the high temperatures required to be maintained inside the chamber for heating the scaffold. [0090] At step 306, the annealing chamber is heated under controlled conditions for a predetermined time in order to anneal the scaffold. In an embodiment of the present invention, the annealing chamber is heated at 110° C under vacuum conditions for a period of 15-17hrs. In another embodiment, the scaffold is heated under vacuum conditions below the melting point of the polymer employed thereby resulting in changes in physical properties and its crystalline structure. In an embodiment, the vacuum pressure inside the annealing chamber can be maintained around 100 kPa or 1 bar.

[0091] At step 308, vacuum conditions inside the annealing chamber are disrupted. I n an embodiment, the vacuum conditions prevailing inside the annealing chamber can be broken by pu rging any inert gas inside the chamber at a particular pressure and for a predefined time. I n a preferred embodiment of the present invention, nitrogen gas is purged inside the an nealing chamber at a pressure of approximately 27 psi for a period of 25 to 30 seconds. The inert gas pu rging inside the annealing chamber aids in the establishment of an atmosphere for subsequent cooling process. The employment of an inert atmosphere (vacuum, helium, nitrogen, etc.) for the subsequent cooling step prevents oxidation in the polymer utilized in the stent. Further, employment of an inert atmosphere cools the chamber without moisturization of polymeric stent.

[0092] At step 310, the annealing chamber is cooled to ambient temperature under the inert atmosphere established in the step 308. In an embodiment of the present invention, the annealing chamber is cooled at a constant cooling rate of about 50°C for a period of 4 to 5 hrs. In another embodiment, slow recrystallization derived from a lower cooling rate yields a more crystalline scaffold while rapid cooling with a faster cooling rate or inadequate heating at the step 106 resu lts in a lower degree of recrystallization . The greater crystallinity obta ined from slow cooling in the inert atmosphere thereby confers mechanical strength to the scaffold as the degree of freedom for the molecular chains to move is curtailed. [0093] At step 312, after successful annealing, the scaffold is withdrawn from the annealing chamber. I n an embodiment of the present invention, the annealed scaffold is subjected to quality inspection for surface defects like scratches, strut damage, foreign particles, brownish coloration, etc.

[0094] The aforesaid invention provides the process of annealing the scaffold which is conducted in two different environments. The scaffold is heated u nder vacuum conditions while cooling takes place in nitrogen atmosphere by pu rging nitrogen at a predefined pressure in order to break the vacuu m.

Claims

We claim:

1. A process for yielding bioabsorbable stents with enhanced shelf life, the process comprising: a. annealing a scaffold obtained from a deformed tube, the annealing comprising heating the scaffold at 100-150° C in vacuum for 10-24 hrs, and cooling the heated scaffold in the presence of an inert gas for 3-6 hrs to ambient temperature resulting in an annealed scaffold, the annealed scaffold having molecular weight M_w range of 320000 g/mol to 410000, M_n between 190000-250000 g/mol and possesses narrow molecular weight distribution of poly dispersity index between 1.5 to 1.9.

2. The process of claim 1 further comprising deforming an extruded polymer tube in multiple stages with relatively higher pressures at near glass transition temperature.

3. The process of claim 1 further comprising one or more of: a. coating the annealed scaffold in low humidity environment, b. crimping the coated scaffold at a predefined temperature using a high balloon profile; c. packaging the stent in aluminium pouch containing oxygen absorber; and d. sterilizing the crimped scaffold at a low temperature in significantly reduced residual oxygen environment, the sterilized scaffold obtained with molecular weight Mw ranging from

150000 g/mol to 210000 g/mol and Mn ranges from 80000 g/mol to 140000 g/mol with narrow polydispersity index between 1.6 to 1.9 wherein, each of the steps a-d result in enhanced shelf-life of the bioabsorbable stents.

4. A multi-stage process for yielding bioabsorbable stents with enhanced shelf life, the process comprising: a. deforming an extruded polymer tube in multiple stages with relatively higher pressures at near glass transition temperature; b. annealing a scaffold obtained from the deformed tube, the annealing comprising heating the scaffold at 100-150° C in vacuum for 10-24 hrs, and cooling the heated scaffold in the presence of an inert gas for 3-6 hrs to ambient temperature resulting in an annealed scaffold, the annealed scaffold having molecular weight M_w range of 320000 g/mol to 410000, M_n between 190000-250000 g/mol and possesses narrow molecu lar weight distribution of poly dispersity index between 1.5 to 1.9; c. coating the annealed scaffold in low humidity environment; d . crimping the coated scaffold at a predefined temperature using a high balloon profile; e. packaging the scaffold in aluminium pouch containing oxygen absorber; and f. sterilizing the crimped scaffold at a low temperature in significantly reduced residual oxygen environment, the sterilized scaffold obtained with molecu lar weight M_w ranging from 150000 g/mol to 210000 g/mol and M_n ranges from 80000 g/mol to 140000 g/mol with narrow polydispersity index between 1.6 to 1.9 wherein, each of the steps a-f result in enhanced shelf-life of the bioabsorbable stents.

5. The process of claim 4 further comprising providing an extruded PLLA tu be.

6. The process of claim 4 wherein deforming an extruded polymer tube includes biaxial deforming an extruded polymer tube.

7. The process of claim 4 wherein deforming the tube includes pressu rizing the tube in three stages with a first stage having a pressure of approximately 480-530 psi, a second stage having a pressure of approximately 560-610 psi and a third stage having a pressure of approximately 630- 680 psi.

8. The process of claim 4 wherein the near glass transition temperatu re is 65°C to 80°C.

9. The process of claim 4 wherein the inert gas is nitrogen gas.

10. The process of claim 4 wherein subjecting the annealed scaffold to removal of residual monomer.

11. The process of claim 4 wherein the low humidity environment is 20-40% RH.

12. The process of claim 4 wherein the high balloon profile is 1.3-1.5 mm.

13. The process of claim 4 wherein the crimped stent is added to an aluminum pouch containing at least one iron based oxygen absorber.

14. The process of claim 4 wherein the oxygen absorbers are kept in a pouch and stored at an ambient temperature for 5 to 35 hours.

15. The process of claim 4 wherein the residual oxygen concentration is between 0.05% to 0.00 % prior to the sterilization step.

16. The process of claim 4 wherein other components of the scaffold system other than scaffold may be sterilized using Ethylene Oxide (ETO), UV or e-beam radiation .

17. The process of claim 4 wherein the crimped scaffold is sterilized by e-beam sterilization without containing oxygen absorber.