CLIAMS:We Claim:

1. A method of packing and sterilization of drug coated scaffold without affecting the functional and structural characteristics of the scaffold which comprises:
a) keeping crimped scaffold along with the delivery system in the barrier pouch;
b) creating vacuum inside the barrier pouch for 30-40seconds;
c) purging an inert gas inside the barrier pouch for 0.1-3 seconds;
d) repeating the steps (b) and (c) at least twice followed by sealing the barrier pouch for 1-3 seconds; and
e) subjecting the packed scaffold system in the form of final sealed barrier pouch to E-beam sterilization.

2. The method of packing and sterilization of drug coated scaffold without affecting the functional and structural characteristics of the scaffold according to claim 1, wherein the method comprises:
a) keeping crimped scaffold along with the delivery system in the barrier pouch;
b) creating vacuum of 200mbar inside the barrier pouch for 30-40seconds;
c) purging an inert gas inside the barrier pouch for 1-3 seconds;
d) repeating the steps (b) and (c) at least for two times;
e) creating again reduced vacuum of 0.01mbar inside the barrier pouch for 30-40 seconds;
f) purging again inert gas inside the barrier pouch for 0.1 – 1 seconds;
g) repeating the steps (e) and (f) at least for two times;
h) sealing the barrier pouch for 1-3 seconds; and
i) subjecting the packed scaffold system in the form of final sealed barrier pouch to E-beam sterilization at a temperature between 15°C and 25°C using single exposure method or multipass method.

3. The method of packing and sterilization according to claim 2, wherein the single exposure dose of E-beam is between 15-19.5 kGy.

4. The method of packing and sterilization according to claim 2, wherein the multipass method comprises subjecting the packed scaffold system repeatedly to low dose of 3kGy to 5kGy.

5. The method of packing and sterilization according to claim 2, wherein the step of multipass method comprises;
a) keeping the packed scaffold system in a refrigerator at -30°Cto -15°C for 1hour;
b) removing the packed scaffold system from the refrigerator and exposing to low dose E-beam of 3kGy to 5kGy for 3 to 5 minutes;
c) removing the packed scaffold system from the E-beam exposure and keeping it in the refrigerator at -30°C to -15°C for 1 hour;
d) repeating steps b) to c) at least for four times;
e) removing the packed scaffold system from the refrigerator and keeping it at room temperature.

6. The method of packing and sterilization according to any one of the preceding claims, wherein the dose of E-beam ensures the acceptable bio burden of less than 3 colony forming units (CFU) and the sterility assurance level of 10-6 i.e. six log reduction of the scaffold.

7. The method of packing and sterilization according to any one of the preceding claims, wherein the change in Mn and Mw of the scaffold after E-beam sterilization is between 9%-15%.

8. The method of packing and sterilization of drug coated scaffold according to claim 1, wherein the barrier pouch is a multilayered metallized film pouch comprises of a metallized film and a polymer web.

9. The method of packing and sterilization of drug coated scaffold according to claim 8, wherein the metal used to make metallized film is preferably aluminium.

10. The method of packing and sterilization of drug coated scaffold according to claim 8, wherein the multilayered metallized film pouch comprises of three layers with varying thickness a) top layer consists of 12-15 micron thick polyester film b) middle layer consists of 15- 18 micron thick aluminium foil c) bottom layer consists of 50-60 micron thick sealant film.

11. The method of packing and sterilization of drug coated scaffold without affecting the functional and structural characteristics of the scaffold which comprises:
a) packing and sealing the scaffold system in the tyvek pouch;
b) keeping the packed scaffold system in an Ethylene Oxide (EtO) sterilization chamber at an atmospheric pressure of 1000 mbar at 40°C-50°C temperature and maintaining temperature in the same range upto step g) ;
c) creating a vacuum of 5-10 mbar in the chamber for 40-60 minutes;
d) subjecting the chamber to steam injection to achieve relative humidity of 50%-60% and holding steam exposure up to 60 minutes such that the atmospheric pressure be in the range of 300-400 mbar at the end ;
e) initiating the EtO injection in the chamber such that the atmospheric pressure of the chamber be in the range of 450-800 mbar at the end of EtO injection,
f) purging nitrogen gas for 2-5 minutes ;
g) initiating EtO injection in the chamber for 150-180 minutes such that the atmospheric pressure of the chamber be in the range of 800-1000 mbar at the end of EtO injection;
h) creating a vacuum below 1 mbar in the chamber and holding the packed scaffold at this vacuum for 60 minutes ;
i) purging nitrogen gas in the chamber at 50°C-60°C to raise the pressure of the chamber to 1000 mbar and maintaining this pressure for 120-180 minutes ;
j) creating a vacuum below 1 mbar in the chamber and holding the packed scaffold at this vacuum for 150-180 minutes ;
k) repeating the step i);
l) creating a vacuum below 1 mbar in the chamber and holding the packed scaffold at this vacuum for 180-250 minutes;
m) increasing the pressure of the chamber to 1000 mbar followed by cooling the chamber for 60-120 minutes;
n) removing the packed scaffold from the chamber after sterilization is over and keeping it in a nitrogen chamber under inert atmosphere;
o) packing the packed scaffold system in the multilayered metallized film barrier pouch wherein the multilayered metallized film pouch is prepared according to claims 8 to 10;
p) creating vacuum of 200mbar inside the barrier pouch for 30-40seconds;
q) purging inert gas inside the barrier pouch for 1-3 seconds;
r) repeating the steps (p) and (q) at least for two times;
s) creating again reduced vacuum of 0.01mbar inside the barrier pouch for 30-40 seconds;
t) purging an inert gas again inside the barrier pouch for 0.1 – 1 seconds;
u) repeating the steps (s) and (t) at least for two times;
v) finally sealing the multilayered metallized film barrier pouch for 1-3 seconds.

12. The method of packing and sterilization of drug coated scaffold according to any of the claim 1or claim 11, wherein the scaffold is biodegradable.

13. The method of packing and sterilization of drug coated scaffold according to any of the claim 1or claim 11, wherein the scaffold comprises of PLLA.

14. The method of packing and sterilization of drug coated scaffold according to any of the claim 1or claim 11, wherein the inert gas is argon or nitrogen.

15. The method of packing and sterilization of drug coated scaffold according to any of the claim 1or claim 11, wherein the pressure of inert gas during the packing process is kept in the range of 0.5 to 2.5 kg/cm2.

16. The method of packing and sterilization of drug coated scaffold according to any of the claim 1or claim 11, wherein oxygen level in the final sealed pouch is between 0.01% - 3 %.

17. The method of packing and sterilization of drug coated scaffold according to any of the claim 1or claim 11, wherein moisture content in the final sealed pouch is below 1100 ppm.

18. The method of packing and sterilization according to claim 11, wherein the ethylene oxide sterilization ensures the acceptable bio burden of less than 3 colony forming units (CFU) and sterility assurance level of 10-6 i.e. six log reduction of the scaffold .

19. A drug coated scaffold packed and sterilized according to the method as claimed in any of the above claims.

20. A process for preparation of biodegradable polymer stent scaffold system made of PLLA (poly-L-Lactide) with strut thickness of less than 130 micron comprising:

a) deforming the extruded PLLA tube axially at 70°C to 80°C by applying axial force till desired stretch is achieved and then radially expanding the tube at a temperature of 70°C to 80°C by pressurizing the tube with inert gas in three stages viz., 250-280 psi in stage-1, 375-410 psi in stage-2 and 500-530 psi in stage-3;

b) heating the tube after radial deformation under the same pressure conditions between 100°C and 110°C and maintained for up to 2 min and then cooled to 20°C in 20-30 sec to get finished deformed tube;

c) cutting specific pattern of scaffold structure on the deformed tube by laser machining;

d) annealing the laser cut stent at the temperature of 1000C to 1250C for a period of 3 to 16 hours before or after depositing the radio opaque markers;

e) cleaning the annealed stent with radio opaque markers using solvent to remove irregularities and to achieve smooth surface;

f) coating the cleaned stent with a formulation of antiproliferative drug and a carrier polymer PDLLA by spray coating method;

g) crimping the coated or uncoated stent on the balloon of pre-sterilized delivery catheter in clean environment at the temperature of 200C to 350C;

h) packing and sterilizing the above scaffold system along with the delivery system in a barrier pouch under inert atmosphere using inert gas by the method according to claim 1 or claim 11.

Dated this 5th day of November, 2014

Dr. P. Aruna Sree
(Regn.No.: IN/PA 998)
Agent for the Applicant
Gopakumar Nair Associates ,TagSPECI:FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)

1. TITLE OF THE INVENTION:

“A METHOD FOR PACKING AND STERILIZATION OF BIORESORBABLE SCAFFOLD SYSTEMS WITHOUT AFFECTING THE SCAFFOLD CHARACTERISTICS ”

2. APPLICANT:

(a) NAME: MERIL LIFE SCIENCES PVT. LTD.

(b) NATIONALITY: Indian Company incorporated under the
Companies Act, 1956

(c) ADDRESS: Survey no.135/139, Bilakhia House, Muktanand
Marg, Chala, Vapi- 396191, Gujarat, India.

3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be formed.

FILED OF THE INVENTION:
The present invention relates to a method for packing and sterilization of bioresorbable scaffold systems without affecting the scaffold characteristics.

BACKGROUND OF THE INVENTION:
Coronary stents are used to treat atherosclerotic stenosis or other type of blockages in body lumen like blood vessels or to expand the lumen that has narrowed due to disease. “Stenosis” is narrowing of the diameter of a bodily passage or orifice due to formation of plaque or lesion. The function of the stent is to expand the lumen diameter by pressing the plaque to the vessel wall and to maintain patency of the lumen of the blood vessel thereafter at the location of its implantation.

Coronary stents are generally made from biocompatible materials such as metals which are bio -stable. Metallic stents have been used effectively for quite a long time and their safety and efficacy are well established. Metal has high mechanical strength that provide adequate radial and fatigue strength to the stent that prevent early and later recoil. However, the metallic stent remains at the implant site indefinitely. Leaving the stent at the implanted site permanently causes compliance difference in the stented segment and the healthy vessel segment. The main issues of a metallic stent are restenosis and in-stent thrombosis. One of the important causes of these adverse effects is injury of the artery caused by implantation of the stent. The injury leads to restenosis and delayed endothelialisation. In addition, there is possibility of permanent interaction between the metallic stent and the surrounding tissue resulting in a risk of endothelial dysfunction causing delayed healing and late thrombosis.

Drug-eluting stents (DES) were developed to mitigate the above mentioned disadvantages of metallic stents. DES are a breakthrough in the development of stents with their ability to significantly reduce restenosis rates and the need for repeat revascularization. However, they are still associated with sub-acute and late thrombosis that necessitates prolonged antiplatelet therapy for at least 12 months. Also as DES were developed on metallic stent platform the disadvantages of metallic stents persists with DES also.

Drug eluting bioresorbable stents are being developed which unlike the metallic stent do not remain at the implant site indefinitely. Bioresorbable stent (scaffold) will provide the support to the lumen for specific time period and will disappear after it is no longer needed.

These bioresorbable scaffolds are generally made up of biocompatible and bioabsorbable polymers which are very sensitive to moisture, oxygen, pressure, temperature and radiation. Also the bioresorbable scaffolds are coated with drugs which too are sensitive to moisture, oxygen, temperature, light and radiation. Hence an effective packing and sterilization methods are needed which should not affect the functional and structural characteristics of drug eluting bioresorbable scaffold.

US8471229 and US8461561 describe method of sterilizing a stent system which is enclosed in a package by exposing the stent system to radiation from a radiation source, wherein the package comprises one or more modifier sections, the modifier sections selectively modify the radiation from the radiation source that is delivered to the selected section/s of the assembly. The source of radiation is E-beam. This method does not teach any specific dose of E-beam and its impact on functional and structural characteristics of the stent. The method also does not teach how to control moisture and oxygen levels in the packaging system which may impact the structural and functional integrity of the scaffold as well as on the drug coated on stent.

US8613880 describes a method for conditioning a polymeric stent after sterilization, such that the properties of the polymeric stent fall within a narrower range of values. The stent is exposed to a controlled temperature at or above ambient for a specific period of time after radiation sterilization. As a result, the polymeric stent properties, particularly radial strength and number-average molecular weight of the polymer of the polymeric stent fall within a narrower range. This method does not teach an effective method of controlling the polymeric stent properties prior to or during sterilization. Also, this method does not teach how to control moisture and oxygen levels in the packaging system which may impact the structural and functional integrity of the stent scaffold and the drug coated on the polymeric stent.
US8715569 describes a method for chemically stabilizing a polymer stent after sterilization. The stent is exposed to a temperature above ambient for a specific period of time after radiation sterilization. The exposure reduces the concentration of free radicals generated by the E-beam radiation dose which is in the range of 20 to 31 kGy. This method does not teach an effective method of controlling the polymeric stent properties prior to sterilization. Also this method does not teach how to control moisture and oxygen levels in the packaging system which may impact the structural and functional integrity of the stent scaffold and the drug coated on the polymeric stent.

US7794776 describes a method of modifying stent properties like molecular weight by exposing the stent to desired dose of radiation. Radiation dose can be selected to get desired drug release rate and/or degradation rate for a polymer. This method does not define the dose of the radiation sterilization which may impact the polymeric stent properties. This method does not teach how to control moisture and oxygen levels in the packaging system which may impact the structural and functional integrity of the drug coated on the polymeric stent and the polymeric stent itself.

US2013032967 describes the ethylene oxide sterilization method of a biodegradable stent wherein the temperature is maintained especially below 400C during exposure. This method does not teach how to control moisture and oxygen levels in the packaging system after ethylene oxide sterilization which may impact the structural and functional integrity of the drug coated on the polymeric stent and the polymeric stent itself.

Hence, there is a need for an effective method of packing and sterilizing the drug coated bioresorbable scaffold (referred as “scaffold” hereafter) which does not affect the functional and structural characteristics of the scaffold and thereby maintaining the stability of the scaffold.

OBJECT OF THE INVENTION:
In the light of the above, it is an object of the present invention to provide an effective method of packing and sterilizing the drug coated scaffold which does not affect the functional and structural characteristics of the scaffold.
Another object of the invention is to provide a method of packing such that, it does not affect the scaffold and the drug coated on it.

Yet another object of the invention is to provide a method of E-beam sterilization of scaffold with an optimum E-beam dose which has minimal impact on the molecular weight of the bioabsorbable polymer of scaffold.

One more object of the present invention is to provide a method of Ethylene Oxide (EtO) sterilization of scaffold which does not affect the functional and structural characteristics of the scaffold.

SUMMARY OF THE INVENTION:
In accordance to the above objects, the present invention provides an effective method of packing and sterilizing the drug coated scaffold which does not affect the functional and structural characteristics of the scaffold.

The present invention also provides a method of packing such that it does not affect the scaffold and the drug coated on scaffold, by maintaining an optimum level of oxygen between 0.01% - 3% and moisture level below 1100 ppm in the packaging system.

The present invention also provides a method of E-beam sterilization of scaffold with a E-beam dose less than 20kGy, which has minimal impact on the molecular weight of the bioabsorbable polymer of scaffold. E-beam sterilization can be done by single exposure method and multipass method. Multipass method includes exposing the final packed scaffold system at least four times to the single E-beam source emitting low dose of 3kGy to 5kGy.

The present invention also provides a method of packing and sterilizing by Ethylene Oxide (EtO) sterilization of drug coated scaffold which does not affect the functional and structural characteristics of the scaffold. This method brings oxygen level between 0.01% - 3% and moisture level below 1100 ppm in the packed scaffold system.

DETAILED DESCRIPTION OF THE INVENTION:
The terms “bioabsorbable” and “biodegradable” are used interchangeably throughout the specification.

The terms “scaffold” and “stent” are used interchangeably throughout the specification.

The drug and the polymeric scaffold are very sensitive to oxygen and moisture and therefore, an effective packing system and process are required for packing the scaffold and delivery system which can keep the oxygen and moisture level as low as possible in the package. Accordingly, the present invention provide an effective methods of packing and sterilization of the drug coated scaffold which does not affect the functional and structural characteristics of the scaffold and thereby increasing the stability of the scaffold which comprises:
a) keeping crimped scaffold along with the delivery system in the barrier pouch;
b) creating vacuum inside the barrier pouch for 30-40seconds;
c) purging an inert gas inside the barrier pouch for 0.1-3 seconds;
d) repeating the steps (b) and (c) at least twice followed by sealing the barrier pouch for 1-3 seconds and
e) subjecting the packed scaffold system in the form of final sealed barrier pouch to E-beam sterilization at a temperature between 15°C and 25°C.
The scaffold of the present invention has thin struts (strut thickness 130 µ or less, preferably 100-110 µ) with adequate fatigue and radial strength as well as low recoil, made from tube of biocompatible and bioabsorbable polymer. The various embodiments of the present invention describe the polymer properties and manufacturing steps of the scaffold. The present invention can be applied to balloon expandable stents, stent grafts or stents for other vascular applications having polymer scaffold.

The mechanical properties of a polymer depend largely on characteristics like average molecular weight and molecular weight distribution. The polymer has different size and types of monomer chains. Molecular weight of a polymer can be described by weight average molecular weight Mw and number average molecular weight Mn. Mw represents average molecular mass of various molecular chains of the polymer which includes even those having same types of individual macro molecules of different chain lengths. Mn 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. The Mw and Mn can be determined by gel permeable chromatography (GPC). Another important parameter for a polymer is the poly dispersity index (PDI) which is the ratio of Mw to Mn (Mw/Mn). This parameter gives an indication of how narrow the molecular distribution is. A parameter closely related to Mw and Mn is the intrinsic viscosity which can be measured using instrument like Brookfield viscometer model LVDV E230.

In addition, glass transition temperature Tg, and melting temperature Tm are important thermal properties. Processing of a polymer at elevated temperatures results in the change in morphology of a polymer and influences its crystallinity Xc. Xc defines the degree of crystallinity of a polymer in percentile value. A totally amorphous polymer has Xc value of 0% and a fully crystalline polymer has Xc value of 100%. Polymers with higher microcrystalline regions (higher Xc) are generally tougher and more impact-resistant than polymers with lower microcrystalline regions (lower Xc).

Apart from the above properties, polymers formed from an optically active monomer have a specific rotation which is also an important characteristic. Polymers obtained from optically active monomers are semi crystalline while optically inactive monomers give amorphous polymers. Crystalline polymer has higher mechanical and thermomechanical properties as described above.

All these characteristics influence the mechanical properties of the polymer used for the process of making the scaffold.

The scaffold of the embodiments of the present invention can be made from a single or combination of biodegradable polymers including, but not limited to, poly(L lactide) (PLLA), polymandelide (PM), poly(DL-lactide) (PDLLA), polyglycolide (PGA), and poly (L-lactide-co-glycolide), polycaprolactone (PCL), poly(trimethylene carbonate) (PTMC), polydioxanone (PDO), poly(4-hydroxy butyrate) (PF1B), poly ethylene glycol (PEG), and poly(butylene succinate) (PBS) or any combination thereof.
This invention applies to bioabsorbable polymers in general. However, PLLA is used as an example to demonstrate this invention. The difference in mechanical properties are related to the stereoregularity of the PLLA chains which are characterized by presence of only S(-) chiral centers. For example, the propensity for the lactide monomer to undergo racemization to form meso-lactide can impact optical purity and thus material properties of the polymer at higher temperatures.

Accordingly, in a preferred embodiment, the invention provides a detailed method for manufacturing a polymer (PLLA) stent as described below:

A process for preparation of biodegradable polymer stent scaffold system made of PLLA (poly-L-Lactide) with strut thickness of less than 130 micron comprising:

a) The polymer tube is made by extrusion or injection molding. The process conditions and equipment should produce the tube with desired internal diameter di and external diameter do. In the instant invention, the polymer tube was made by extrusion process and Mw of the polymer tube ranged from 590000 to 620000, Mn ranged from 350000 to 370000, and crystallinity ranged from 7% to 12%.

b) Deforming the extruded PLLA tube axially at 70°C to 80°C by applying axial force till desired stretch is achieved and then radially expanding the tube at a temperature of 70°C to 80°C by pressurizing the tube with inert gas in three stages viz., 250-280 psi in stage-1, 375-410 psi in stage-2 and 500-530 psi in stage-3;

c) Heating the tube after radial deformation under the same pressure conditions between 100°C and 110°C and maintained for up to 2 min and then cooled to 20°C in 20-30 sec to get finished deformed tube;

d) Cutting specific pattern of scaffold structure on the deformed tube by laser machining;

e) Annealing the laser cut scaffold at the temperature of 1000C to 1250Cfor a period of 3 to 16 hours before or after depositing the radio opaque markers;

f) Cleaning the annealed scaffold with radio opaque markers using solvent to remove irregularities and to achieve smooth surface;

g) Coating the cleaned scaffold with a formulation of antiproliferative drug and a carrier polymer PDLLA by spray coating method;

h) Crimping the coated or uncoated scaffold on the balloon of pre-sterilized delivery catheter in clean environment at the temperature of 200C to 350C;

i) Packing the above scaffold system along with the delivery system in a barrier pouch under inert atmosphere using inert gas.

j) Sterilizing the packed scaffold and catheter system by E-beam via single exposure method of or by multipass method. The single exposure method can be done by exposing the scaffold system at E-beam dose of 15kGy-19.5 kGy. Multipass method refers to exposing the final packed scaffold system at least four times under the single E-beam source emitting low E-beam dose of 3kGy- 5kGy. Alternatively the packed scaffold system can be sterilized by ethylene oxide sterilization method.

Each manufacturing step described above affects polymer properties like molecular weight, crystallinity, molecular orientation etc. This in turn changes the mechanical properties of the polymer. The mechanical properties of the finished stent should be adequate to demonstrate sufficient radial and fatigue strengths as well as low recoil.

The antiproliferative drug coated on the scaffold according to above method can be selected from sirolimus, paclitaxel, docetaxel, estradiol, 17-beta-estradiol, nitric oxide donors, super oxide dismutases, super oxide dismutase mimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4 amino-TEMPO), biolimus, tacrolimus, dexamethasone, dexamethasone derivatives, glucocorticoids, rapamycin, rapamycin derivatives, 40-O-(2-hydroxy)ethyl-rapamycin, 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin, 40-epi-(N1tetrazolyl)-rapamycin, temsirolimus, deforolimus, ?-hiridun, clobetasol, pimecrolimus, imatinib mesylate, midostaurin, fenofibrate, prodrugs thereof, co-drugs thereof, and combinations thereof. In a preferred embodiment of the invention the antiproliferative drug is sirolimus.
As the drug and the polymeric scaffold are very sensitive to oxygen and moisture, an effective packing system and process are required for packing the scaffold and delivery system which can keep the oxygen and moisture level as low as possible in the package.
After crimping the scaffold on the balloon of delivery catheter, the system is packed in a pouch.

Accordingly, in a preferred embodiment of the invention the method of packing is described as below:
a) First the crimped scaffold along with the delivery system is kept in the barrier pouch
b) Vacuum of 200mbar is created inside the barrier pouch for 30-40seconds.
c) An inert gas is purged inside the barrier pouch for 1-3 seconds.
d) Again vacuum of 200mbar is created inside the barrier pouch for 30-40 seconds.
e) Again an inert gas is purged inside the barrier pouch for 0.1 – 1 second.
f) Vacuum of 0.01mbar is created inside the barrier pouch for 30-40 seconds.
g) Again an inert gas is purged inside the barrier pouch for 0.1 – 1 second.
h) Again vacuum of 0.01mbar is created inside the barrier pouch for 30-40 seconds.
i) Again an inert gas is purged inside the barrier pouch for 0.1 – 1 second.
j) The barrier pouch is then sealed for 1-3 seconds.

The above process brings oxygen level between 0.01% - 3% and moisture level below 1100 ppm in the sealed pouch. The above packing process is especially designed for E-beam sterilization. This process can be used after ethylene oxide sterilization.

The barrier pouch used in packing the scaffold system should act as barrier for exposure to light, air, and moisture. This kind of barrier pouch involves the use of material either a single film or a laminated structure of polymer films, foils, paper, coatings or metallized film pouch.

In a preferred embodiment of the invention the barrier pouch used is a multilayered metallized film pouch. Metallization improves the moisture and gas-barrier properties of the film and prevents light from reaching the scaffold. The multilayered metallized film pouch comprises of metallized film and a polymer web. Metallized film is developed by vaporizing molten metal, depositing it onto a polymer web, and then applying it to the film. The preferable metal used in making the metallized film pouch is aluminium. The polymers used in making the polymer web can be selected from the group consisting of polyethylene terephthalate (PET), low density polyethylene (LDPE), high density polyethylene (HDPE), polyester or combinations thereof. The multilayer metallized film pouch comprises of preferably three layers viz. a) top layer consists of 12-15 micron thick polyester film b) middle layer consists of 15- 18 micron thick aluminium foil c) bottom layer consists of 50-60 micron thick sealant film. The inert gases used in the packing process can be selected from the group of nitrogen, argon or helium. Argon is preferred over nitrogen and helium due to its higher density. This property of argon allows it to stay for longer time during the packing process in the pouch as it will settle down due to its dense nature. The pressure of argon is preferably kept 0.5 to 2.5 kg/cm2.

After the scaffold system is packed in the barrier pouch, it is sterilized via single exposure of E-beam radiation. This method is commonly used for the sterilization of medical devices because E-beam radiation can provide much higher dosing rate compared to gamma rays or X-rays which reduces the exposure time which in turn reduces potential degradation of the polymer. Another advantage is that the sterilization process leaves no residue. The sterilization is conducted at ambient or lower than ambient temperature to avoid temperature related degradation of polymer.

It is known that E-beam radiation causes degradation of polymer and thus has a significant effect on the number average molecular weight Mn and average molecular mass Mw of the bioabsorbable polymers and hence its mechanical properties.
We have studied the effect of single exposure E-beam radiation over a wide range of doses varying from as low as 8 kGy to as high as 150 kGy as described in Table 1. The objective was to study the effect of E-beam dose on Mw and Mn. The reduction in Mw varied from as low as 7.9% for E-beam dose of 8 kGy to as high as 79.9% for dose of 150 kGy. Reduction in Mn varied from as low as 6.3% for E-beam dose of 8 kGy to 73% for dose of 150 kGy.

It is hence very essential to reduce the E-beam dose to minimize the polymer degradation. The effect of E-beam dose on the degradation of polymer can be reduced to some extent by adding a stabilizer in the polymer matrix. This stabilizer should be biocompatible and should not create any adverse clinical effect.

Conventional dose of E-beam for effective sterilization is more than 20 kGy. The instant invention however, reduces the degradation by reducing the dose of E-beam considerably without compromising effective sterilization and without use of a stabilizer. The sterilization process of instant invention is done in two parts as described hereafter.

The scaffold system consists of components like scaffold, and delivery catheter. The E-beam dose affects the polymer scaffold and not the other components. All components of the stent system other than the stent are sterilized separately using either Ethylene Oxide (EtO) or E-beam. The assembly along with the crimped and packed scaffold system is then subjected to E-beam sterilization at a temperature between 15°C and 25°C.

Using this process, the effective sterilization was achieved with single exposure E-beam dose lower than 19.5 kGy; preferably between 8 kGy and 19.5 kGy, which is lower than the conventional effective dose of more than 20 kGy. The change in average molecular weight Mw and Mn of the polymer after sterilization was less than 15%, more preferably in the range of 6.3% to 15%. This method resulted in acceptable bio burden of less than 3 colony forming units (CFU) and Sterility Assurance Level (SAL) of “six log reduction” (10-6). The sterilization did not have any significant effect on the optical rotation or crystallinity.
In another preferred embodiment of the invention, the method of sterilization for scaffold system can be done by E-beam in a multipass method. Multipass method as mentioned herein above refers to exposing the final packed scaffold system in the multilayered metallized film pouch at least four times under the single E-beam source emitting low dose of 3kGy to 5kGy. The scaffold system is allowed to cool before each exposure. The multipass method can be described as below:
a) The packed scaffold system is kept in a refrigerator at -30°C to -15°C for 1hour.
b) The packed scaffold system is removed from the refrigerator and is kept on the conveyor belt of E-beam system.
c) The packed scaffold system is then conveyed to the E-beam source where it is exposed to low dose of 3kGy to 5kGy for 3 to 5 minutes.
d) The packed scaffold system is removed from the conveyor and kept in the refrigerator at -30°C to -15°C for 1 hour.
e) Steps b) to d) are repeated at least for four times.
f) Finally the packed scaffold system is removed from the refrigerator and is kept at room temperature.
The E-beam source has beam current and beam voltage of 13 to 15 mA and 3.0 to 5.0 MEV respectively. The line speed of conveyor belt of the E-beam system is kept at 6.5 m/min. Cooling the packed scaffold system at -30°C to -15°C before each exposure ensures that the rise in temperature during sterilization don’t go beyond the Tg of the scaffold and remains in between 10°C and 25°C.

The inventors of the instant invention studied the effect of multipass method (as described above) on Mw and Mn by exposing the final packed scaffold system two, three, four and five times under the single E-beam source emitting low dose of 3kGy to 12kGy as per Table 2. The percentage change in Mw and Mn after exposing scaffold two times at the dose of 12 kGy was highest i.e. 24.38% and 23.73% respectively. The percentage change in Mw and Mn after exposing packed scaffold system five times at the dose of 3 kGy was 10.13% and 11.30% respectively. The percentage change in Mw and Mn after exposing packed scaffold system four times at the dose of 4 kGy was 8.90% and 10.10% respectively. The percentage change in Mw and Mn after exposing packed scaffold system three times at the dose of 5 kGy was 18.40% and 19.70% respectively. This method resulted in acceptable bio burden of less than 3 colony forming units (CFU) and Sterility Assurance Level (SAL) of “six log reduction” (10-6). The sterilization did not have any significant effect on the optical rotation or crystallinity.

Hence it can be concluded that exposing the final packed scaffold system at least four times under the single E-beam source emitting low dose of 3kGy to 5kGy will be an appropriate method of sterilization as it leads to low molecular weight change and thus have minimal effect on the mechanical properties of scaffold.

In an alternative embodiment, the scaffold system is packed in a tyvek pouch instead of the multilayered metallized pouch and this packed scaffold system can also be sterilized by Ethylene Oxide (EtO) sterilization. In this method ethylene oxide gas is used to sterilize the packed scaffold system. As this method also requires steam, vacuum and higher temperature for an efficient sterilization, the process parameters are needed to be controlled effectively as it may affect the scaffold and drug coated on it adversely. One such preferred method is given below for sterilization of packed scaffold system without affecting the scaffold functional and structural characteristics comprises of :
a) The scaffold system is packed and sealed in the tyvek pouch.
b) The packed scaffold system is kept in an EtO sterilization chamber at atmospheric pressure of 1000 mbar at 40°C-50°C temperature. This temperature range is maintained in the process up to step g).
c) Then the vacuum of 5-10 mbar is created in the chamber. This process will take 40-60 minutes. An initial vacuum is drawn to remove air and prevent an unsafe mixture when EtO is injected.
d) Then steam is injected in the chamber. Steam injection will take 5-8 minutes. This will increase the relative humidity (RH) of the chamber. When RH of the chamber reaches 50%-60%, then steam exposure is hold for 60 minutes. The atmospheric pressure of the chamber at the end of 60 minutes would be 300-400 mbar. Steam is added to the chamber to replace that moisture which is lost during the initial vacuum phase.
e) At the end of steam exposure, EtO injection is initiated inside the chamber. The injection time is 10-12 minutes. The atmospheric pressure of the chamber at the end of EtO injection would be 450-800 mbar.
f) At the end of EtO injection, nitrogen purging is done for 2-5 minutes.
g) At the end of nitrogen purging, again EtO is injected in the chamber for 150-180 minutes. The atmospheric pressure of the chamber at the end of this injection would be 800-1000 mbar. The temperature of the chamber for all the above steps is kept 40°C-50°C, which is lower than the glass transition temperature (Tg) of PLLA.
h) Again a vacuum below 1 mbar is created in the chamber. The packed scaffold will be held at this vacuum for 60 minutes.
i) At the end of the step h) nitrogen gas is purged in the chamber and the pressure of the chamber is raised to 1000 mbar. The temperature at this step is kept 50°C-60°C. This pressure is maintained for 120-180 minutes. This is a drying step which will remove the moisture and reduce the EtO residuals.
j) Again a vacuum below 1 mbar is created in the chamber. The packed scaffold will be held at this vacuum for 150-180 minutes.
k) At the end of the step j) nitrogen gas is purged in the chamber and the pressure of the chamber is raised to 1000 mbar. The temperature at this step is kept 50°C-60°C. This pressure is maintained for 120-180 minutes.
l) Again a vacuum of below 1 mbar is created in the chamber. The packed scaffold will be held at this vacuum for 180-250 minutes.
m) The pressure of the chamber is then increased to 1000 mbar and the chamber is allowed to cool for 60-120 minutes.
n) After sterilization is over, the packed scaffold is removed from the chamber and kept in a nitrogen chamber under inert atmosphere.
o) The packed scaffold is then packed in the multilayered metallized film barrier pouch.
p) Vacuum of 200mbar is created inside the barrier pouch for 30-40seconds;
q) An inert gas is purged inside the barrier pouch for 1-3 seconds;
r) Repeating the steps (p) and (q) at least for two times;
s) Again reduced vacuum of 0.01mbar is created inside the barrier pouch for 30-40 seconds;
t) An inert gas is purged again inside the barrier pouch for 0.1 – 1 second;
u) Repeating the steps (s) and (t) at least for two times;
v) Finally the barrier pouch is sealed for 1-3 seconds.

The above process brings oxygen level between 0.01% - 3% and moisture level below 1100 ppm in the sealed pouch. This method also resulted in acceptable bio burden of less than 3 colony forming units CFU and Sterility Assurance Level (SAL) of “six log reduction” (10-6). The sterilization did not have any significant effect on the optical rotation or crystallinity.

Table 1
Sr. no. E-beam dose (kGy) Mw
(Daltons) % change in Mw Mn
(Daltons) % change in Mn Sterility assurance level of 10-6
1 Without E-beam exposure 350281 - 168381 - Fail
2 8 322609 7.90% 157773 6.30% Pass
3 15 315953 9.80% 151206 10.20% Pass
4 19.5 298790 14.70% 145818 13.40% Pass
5 25 265163 24.30% 128643 23.60% Pass
6 50 172338 50.80% 79981 52.50% Pass
7 100 98429 71.90% 51525 69.40% Pass
8 150 70406 79.90% 43947 73.90% Pass

Table 2
Sr. no. E-beam dose (kGy) No of exposure Mw
(Daltons) % change in Mw Mn
(Daltons) % change in Mn Sterility assurance level of 10-6
1 Without E-beam exposure 350281 - 168381 - Fail
2 12 2 264882 24.38% 128424 23.73% Pass
3 5 3 314798 10.13% 149354 11.30% Pass
4 4 4 319106 8.90% 151375 10.10% Pass
5 3 5 285829 18.40% 135210 19.70% Pass

The following examples are given as illustration to describe the packing and sterilization methods as mentioned above. It should be noted that the present disclosure is not limited to the specific details embodied in the examples.

Example 1
Method of packing and sterilization
First the crimped stent scaffold made of PLLA along with the delivery system was kept in the barrier pouch. A Vacuum of 200mbar was created inside the barrier pouch for 30-40seconds followed by an inert gas was purged inside the barrier pouch for 1-3 seconds. The creation of vacuum followed by purging with inert gas was done at least for two times. Further, a reduced vacuum of 0.01mbar was created inside the barrier pouch for 30-40 seconds followed by an inert gas was purged inside the barrier pouch for 0.1 – 1 second. This step also repeated twice so as to reduce oxygen and moisture content to acceptable levels prior to sealing the barrier pouch for 1 to 3 seconds.

The above process brings oxygen level between 0.01% - 3% and moisture level below 1100 ppm in the sealed pouch.

The packed scaffold system thus obtained is subjected to E-beam sterilization at a temperature between 15°C and 25°C with an E-beam dose lower than 20 kGy, preferably an E-beam dose of between 15-19.5 kGy. This E-beam exposed packed scaffold system resulted in acceptable bio burden of less than 3 colony forming units (CFU) and Sterility Assurance Level (SAL) of “six log reduction” (10-6).

Example 2
Method of packing and sterilization by multipass method
First the crimped stent scaffold made of PLLA along with the delivery system was kept in the barrier pouch. A Vacuum of 200mbar was created inside the barrier pouch for 30-40seconds followed by an inert gas was purged inside the barrier pouch for 1-3 seconds. The creation of vacuum followed by purging with inert gas was done at least for two times. Further, a reduced vacuum of 0.01mbar was created inside the barrier pouch for 30-40 seconds followed by an inert gas was purged inside the barrier pouch for 0.1 – 1 second. This step also repeated twice so as to reduce oxygen and moisture content to acceptable levels prior to sealing the barrier pouch for 1 to 3 seconds.

The above process brings oxygen level between 0.01% - 3% and moisture level below 1100 ppm in the sealed pouch.

The packed scaffold system thus obtained is kept in a refrigerator at -30°Cto -15°C for 1hour. The system is removed from the refrigerator and is kept on the conveyor belt of E-beam system. The system is then conveyed to the E-beam source where it is exposed to low dose of 3kGy to 5kGy for 3 to 5 minutes. The system is removed from the conveyor and kept in the refrigerator at -30°Cto -15°C for 1 hour. These above steps are repeated at least four times. Finally the packed scaffold system is removed from the refrigerator and is kept at room temperature. This E-beam exposed packed scaffold system resulted in acceptable bio burden of less than 3 colony forming units (CFU) and Sterility Assurance Level (SAL) of “six log reduction” (10-6).