Claims:WE CLAIM:
1. A process of manufacturing an expandable biodegradable medical implant comprising:
i. preparing a medical implant from a biodegradable material, the preparing comprises:
a. preparing a template;
b. dipping the template in a dipping solution at a predefined temperature and insertion speed;
c. removing the coated template at a predefined withdrawal speed;
d. drying the coated template in the presence of an inert gas; and
e. repeating the steps b to d until a medical implant having a predefined thickness is obtained;
ii. annealing the medical implant for a specific duration;
iii. coating the annealed medical implant with one or more therapeutic drugs; and
iv. sterilizing the coated medical implant via e-beam sterilization.
2. The process as claimed in claim 1, wherein the biodegradable material includes a mixture of one or more polymers and one or more cross-linkers.
3. The process as claimed in claim 2, wherein the one or more polymers include poly L-lactide (PLLA), poly-L-lactide-co-caprolactone (PLC), poly dioxanone, poly trimethylene carbonate (PTMC), polycaprolactone (PCL), poly-dl-lactic acid (PDLLA), polyglycerol sebacate (PGS), poly (glycolic acid) (PGA), poly L-lactide co-glycolic acid (PLGA) or combinations thereof.
4. The process as claimed in claim 2, wherein the one or more cross linkers includes hexamethylene diisocyanate (HDI), butane diisocyanate (BDI), isophorone diisocyanate (IPD), lysine diisocyanate (LDI), etc.
5. The process as claimed in claim 1, wherein the insertion speed ranges from 1 mm/sec to 20 mm sec.
6. The process as claimed in claim 1, wherein the withdrawal speed ranges from 1 mm/sec to 20 mm sec.
7. The process as claimed in claim 1, wherein the predefined temperature ranges from 5°C to 25°C.
8. The process as claimed in claim 1, wherein the annealing includes heating the medical implant at a temperature ranging from 40°C to 105°C for 3 hours to 20 hours under the vacuum of 700 mmHg.
9. The process as claimed in claim 1, wherein the medical implant includes a balloon spacer.
10. The process as claimed in claim 1, wherein the one or more therapeutic agents includes a drug dosage ranging from 0.05 µg/mm2 to 3 µg/mm2.
11. The process as claimed in claim 1, wherein the therapeutic agents include antibiotics, bactericidal, antimicrobial and/or antifungal agents.
12. The process as claimed in claim 1, wherein sterilizing the medical implant includes e-beam sterilization.
, Description:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(Section 10 and Rule 13)

1. TITLE OF THE INVENTION:
MEDICAL IMPLANT AND METHOD FOR MANUFACTURING THEREOF

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

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

FIELD OF INVENTION
[001] The present invention relates to a process for manufacturing a medical implant, more specifically, the present invention relates to a process for manufacturing a balloon spacer using dip coating.
BACKGROUND
[002] Rotator cuff is a tough sheath of tendons and ligaments that supports and stabilizes a shoulder joint. The rotator cuff may be injured in people, who repeatedly perform overhead motions, for example, painters, carpenters, athletes, etc. Also, the risk of rotator cuff injuries increases with the age. The rotator cuff injuries are traumatic and when untreated, can lead to permanent loss in motion or progressive degeneration of the joint.
[003] Balloon spacers may be used for the treatment of rotator cuff injuries and/or a rotator cuff post-surgery repair support, a bone fracture, inflammation or an infection at the treatment site, etc. A balloon spacer creates a space between bone/joints or tendons/tissue at the site of the injury. The balloon spacer helps in the smooth and frictionless gliding between bones/tissues and also provides support to the bone/joints or tendons/tissue structure.
[004] Conventionally, existing balloon spacers are manufactured by dip coating process. A template is dipped in a solution of a polymer under predefined operating conditions. However, the dip coating method known in prior arts pose various challenges. One such challenge is air entrapment in the coating which leads to bubble formation within the coating. The presence of bubbles within the coating leads to a faster rate of degradation of the balloon spacer, and thereby decreasing its efficiency. Further, due to the bubbles, the strength of the conventional balloon spacers is compromised.
SUMMARY
[005] The present invention discloses the manufacturing of an expandable biodegradable medical implant by dip coating process. The process includes preparation of the medical implant from a biodegradable material. The preparation of the medical implant includes, preparing a template, dipping the template in a dipping solution at a predefined temperature and insertion speed, and then removing the template with a coating at a predefined withdrawal speed. Further, the coating is dried in presence of an inert gas. The process is repeated until a predefined thickness is obtained. The medical implant is then annealed for a specific duration. The medical implant is coated with therapeutic drugs and subsequently sterilized via e-beam sterilization.
BRIEF DESCRIPTION OF THE DRAWINGS
[006] 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.
[007] Fig. 1 illustrates a medical implant in accordance with an embodiment of the present invention.
[008] Fig. 2 illustrates a flow chart depicting an exemplary dip coating process involved in manufacturing of the medical implant through dip coating process in accordance with an embodiment of the present invention.
[009] Fig. 3 illustrates dip coating process on a template in accordance with an embodiment of the present invention.
[0010] Fig. 4 illustrates spray coating process on a medical implant in accordance with an embodiment of the present invention.
DETAILED DESCRIPTION OF THE DRAWINGS
[0011] Prior to describing the invention in detail, definitions of certain words or phrases used throughout this patent document will be defined: the terms "include" and "comprise", as well as derivatives thereof, mean inclusion without limitation; the term "or" is inclusive, meaning and/or; the phrases "coupled with" and "associated therewith", as well as derivatives thereof, may mean to include, be included within, interconnect with, contain, be contained within, connect to or with, couple to or with, be communicable with, cooperate with, interleave, juxtapose, be proximate to, be bound to or with, have a property of, or the like; definitions of certain words and phrases are provided throughout this patent document, and those of ordinary skill in the art will understand that such definitions apply in many, if not most, instances to prior as well as future uses of such defined words and phrases.
[0012] Particular embodiments of the present disclosure are described herein below with reference to the accompanying drawings, however, it is to be understood that the disclosed embodiments are merely examples of the disclosure, which may be embodied in various forms. Well-known functions or constructions are not described in detail to avoid obscuring the present disclosure in unnecessary detail. Therefore, specific structural and functional details disclosed herein are not to be interpreted as limiting, but merely as a basis for the claims and as a representative basis for teaching one skilled in the art to variously employ the present disclosure in virtually any appropriately detailed structure.
[0013] In accordance with the present disclosure, a medical implant and method for manufacturing thereof is disclosed. In an embodiment of the present invention, the medical implant is a balloon spacer. The medical implant of the present invention is used to selectively support/separate/split two bones/ tissues (such as tendons, ligaments, etc.) at a treatment site. The medical implant helps to protect healthy bones/tissues from the effects of treatment on adjacently placed bones/tissues.
[0014] The medical implant also helps in minimizing the physiological impact of displacement of affected bone/tissue on the healthy bone/tissue.
[0015] The medical implant may include an inflated state and a deflated state. The medical implant is delivered inside the patient’s body in the deflated state through a minimally invasive technique using an introducer (or delivery sheath). In deflated state, the medical implant may be cylindrically or radially wrapped in the introducer. In an embodiment, post deployment, the medical implant is inflated at the treatment site. The medical implant may be inflated (expanded) by for example, injecting a liquid, blowing a gas, etc. via the introducer. A physiological fluid(s) may be introduced inside the medical implant for inflating it. The physiological fluid may include saline. In an embodiment, the pH of the physiological fluid is same as the pH of the treatment site.
[0016] In an embodiment, the medical implant is manufactured by a dip coating process. The dip coating is performed at a predefined temperature (sub ambient temperature) ranging from 5°C to 25°C to yield a bubble free surface of the medical implant. In an embodiment, sub ambient temperature maintained during dip coating is around 10°C to 12°C. The bubble free surface obtained by the present invention eliminates the chances of faster degradation of the medical implant and hence, the degradation rate of the medical implant is maintained till the medical implant is completely degraded and absorbed at the treatment site. Therefore, the bubble free surface imparts an increased efficiency to the medical implant.
[0017] After fabrication of the medical implant, the medical implant may be subjected to annealing at predefined parameters such as temperature, time etc. The process of annealing helps to remove stickiness from the surface of medical implant, when it is cylindrically or radially wrapped in the introducer (deflated state). Also, annealing of the medical implant enables smooth transition of the medical implant from its deflated state to the inflated state. Further, annealing helps to relieve internal stress from the medical implant leading to enhanced strength and durability of the medical implant.
[0018] Further, the annealed medical implant may be coated by one or more therapeutic drug. The therapeutic drugs may reduce bioburden on the medical implant. Hence, bacterial adhesion to the medical implant is inhibited and the risk of any infection or inflammation post implantation is prevented.
[0019] Followed by therapeutic coating, the medical implant is packed and subsequently subjected to e-beam sterilization. The advantage of e-beam sterilization process is that it leaves no residual content after the sterilization process thereby decreasing the chances of toxicity.
[0020] Another advantage of e-beam sterilization process is that it takes shorter period of time to sterilize the medical implant. Moreover, e-beam sterilization can penetrate a variety of packaging materials such as foils, outer box and hence any packaging material can be used.
[0021] The e-beam sterilizing process avoids the damaging of packaging material and therefore no further packaging of the medical implant is required. Hence the medical implant is ready to be shipped without any further packaging unlike conventional processes.
[0022] Now referring specifically to diagrams, FIG. 1 illustrates the medical implant 100. The medical implant 100 is a balloon spacer, which helps to provide displacement/separation between a first tissue/bone and a second tissue/bone.
[0023] The medical implant 100 may include predefined dimensions. The predefined dimensions may be dependent upon the anatomy of the treatment site. For example, to fit a rotator cuff anatomy, the shape of the medical implant 100 may be one of a cuboid, an ellipse, a pear, a guava, etc.
[0024] Further, the diameter of the medical implant 100 in inflated state and deflated (wrapped) state may range from 6 mm to 15 mm and from 2.5 mm to 5.0 mm respectively. In an embodiment, the diameter of the medical implant 100 in inflated state is 10 mm and in deflated state is around 4.0 mm. The thickness of the medical implant 100 may range from 80µm to 400 µm. In an embodiment, the thickness of the medical implant 100 is in the range of 300 µm to 320 µm.
[0025] The medical implant 100 may be made from a biocompatible and/or biodegradable material known in the art, say, polymers. The polymers may include, without limitation, poly L-lactide (PLLA), poly-L-lactide-co-caprolactone (PLCL), poly dioxanone, poly trimethylene carbonate (PTMC), polycaprolactone (PCL), poly-dl-lactic acid (PDLLA), polyglycerol sebacate (PGS), poly glycolic acid (PGA), poly L-lactide co-glycolic acid (PLGA), poly-L-lactide-co-glycolide or combinations thereof.
[0026] The properties of polymers play a vital role in deciding the strength and degradation period of the medical implant 100. In an embodiment, the medical implant 100 maintains its shape for a time period of around 3 to 6 months and is thereafter completely degraded over a specific period of time i.e. around 12 to 24 months.
[0027] Table 1 mentions the list of polymers that may be used for manufacturing of the medical implant 100 with their respective degradation time.
Bioresorbable polymers Degradation time (months)
Poly-L-lactide acid (PLLA) 18 to 36 months
Poly-L-lactide co-caprolactone (PLCL) (70:30) 12 to 24 months
Polycaprolactone (PCL) 24 to 36 months
Poly-DL-lactide acid (PDLLA) 12 to 16 months
Poly-L-lactide co-glycolide (PLGA) (85:15) 12 to 24 months
Poly-dioxanone (PDO) 06 to 12 months
TABLE 1
[0028] In an embodiment, the medical implant 100 is made of poly-L-lactide co-caprolactone. The poly-L-lactide co-caprolactone may include 50% to 95% L-lactide and 05% to 50% of caprolactone. For example, the ratio of L-lactide: caprolactone in poly-l-lactide-co-caprolactone may be 95:05, 85:15, 70:30 or 50:50.
[0029] Alternatively, a combination of polymers PLCL (poly-l-lactide-co-caprolactone) and PCL (polycaprolactone) are used in various ratios like 50:50, 70:30, 80:20, or 90:10.
[0030] Additionally, a cross-linker may be added for preparing the medical implant 100. The addition of the cross-linker improves the performance of the medical implant 100 by enhancing the mechanical strength and elasticity (i.e. it is expandable in nature) of the polymer to be employed for preparation of the medical implant 100.
[0031] The cross-linkers may include one or more of, hexamethylene diisocyanate (HDI), butane diisocyanate (BDI), isophorone diisocyanate (IPD), lysine diisocyanate (LDI), etc. In an embodiment, the cross-linker used in the present invention is hexamethylene diisocyanate (HDI). The concentration of HDI may range from 0.01% to 0.1% v/v.
[0032] In an embodiment, the medical implant 100 is manufactured by a dip coating process (as elaborated in figure 2) which imparts high tensile strength and flexibility to the medical implant 100. The tensile strength of the medical implant 100 ranges between 80 N/mm2 and 130 N/mm2. In an embodiment, the tensile strength of the medical implant 100 is 109 N/mm2. The said tensile strength imparts high resistance to the medical implant 100 against breakage under tension as exerted by adjoining bones and/or tissues.
[0033] Alternatively, the techniques used for manufacturing of the medical implant 100 may include but not limited to, spray coating, dip coating, spin coating, plasma coating, etc.
[0034] As represented in FIG. 1, the medical implant 100 includes an inner surface 101, an outer surface 103, a distal end 105 and a proximal end 107.
[0035] The inner surface 101 of the medical implant 100 may be a uniform/non-uniform surface. In the inflated state, the inner surface 101 lies in direct contact with the physiological fluid(s). In deflated state, the inner surface 101 is devoid of any foreign material like physiological fluid(s), etc.
[0036] The outer surface 103 of the medical implant 100 may be a uniform/non-uniform surface. In an embodiment, the outer surface 103 may include various three-dimensional surface structures such as pimples, grooves, bumps, ridges or any combination thereof. Such three-dimensional surface structures help to provide enhanced friction between the medical implant 100 and the first and second tissues/bones without affecting the functionality of the medical implant 100.
[0037] The outer surface 103 may also include a coating of therapeutic drug(s). The therapeutic drugs may reduce bioburden of the medical implant 100. Hence, bacterial adhesion to the medical implant 100 is inhibited and the risk of any infection or inflammation post implantation is prevented.
[0038] The proximal end 107 of the medical implant 100 includes an opening 109.The opening 109 is used as a cavity for securing a valve (not shown). The dimensions of the opening 109 correspond to the dimensions of the valve. The valve may be integral to the medical implant 100. Alternately, the valve is attached at a distal end of the introducer and is secured to the opening 109 at the time of its delivery by the introducer. The valve helps to secure the physiological fluid inside the medical implant 100 thereby preventing its back flow when the medical implant 100 is in inflated state.
[0039] The valve may be fabricated from a biodegradable material such as without limitation poly L-lactide co-caprolactone (PLC), polycaprolactone, gelatin, polydioxanone (PDO), poly-L-lactide co-glycolide (PLGA) and poly-L-lactide (PLA) or their combination. The different types of valve can be used, for example a duckbill valve, a slit valve, a flapper valve, an umbrella valve, etc.
[0040] The medical implant 100 as disclosed in paragraphs above may be delivered or deployed at the treatment site using the introducer. The medical implant 100 is first mounted inside the introducer in its deflated state. The introducer having the medical implant 100 is then introduced inside a patient’s body through a minimal invasive technique. Once the medical implant 100 positioned at the treatment site, the physiological fluid is introduced inside the medical implant 100 to expand and/or inflate it. As soon as a desired amount of physiological fluid is filled and the medical implant 100 attains the predefined diameter, the introducer is retrieved back. In an embodiment, the medical implant 100 is sealed with the valve on complete retrieval of the introducer.
[0041] Fig. 2 illustrates a flow chart which represents an exemplary process of the manufacturing of the medical implant 100 via dip coating. Before the manufacturing of the medical implant 100 is initiated, a template (not shown) is prepared to create a base for dip coating process. The template may be made of, without limitation, polysaccharides like agarose (ultra pure low melting point), agar, gelatin, chitosan, dextran and other synthetic polymers or their blends.
[0042] In an embodiment, agar is dissolved in purified water to form an agar solution. The agar may have a concentration ranging from 02 % to 20 % in purified water. Further, the agar solution may be heated above its melting point to result in complete dissolution of agar in purified water. Subsequently, the agar solution may be introduced into a precursor mold of a desired shape (based on anatomy of treatment site). In an embodiment, a mandrel (not shown) is inserted immediately after the agar solution is introduced into the precursor mold to create an opening that helps the mandrel to firmly hold the medical implant 100. The mandrel acts as a support during dip coating process (as shown in Fig. 3).
[0043] The solution within the precursor mold is allowed to solidify resulting in formation of the template. Finally, the template is removed from the mold.
[0044] The precursor mold may be made up of any non-reactive material, for example, stainless steel of 316 LVM grade, silicon, Teflon, etc. In an embodiment, the precursor mold used to form the template is stainless steel material which has a smooth mirror polished surface from inside, to achieve smooth surface of the template.
[0045] The process of manufacturing the medical implant 100 commences at step 201 via dip coating process. In an embodiment, the dip coating process is performed in an apparatus 300 as shown in Fig. 3. The template 303 is mounted on a mandrel 301. Further, the mandrel 301 is attached to a collate rotator 311 which helps in changing the side of the template 303 during the dip coating process.
[0046] The template 303 is dipped in a dipping solution 307. The dipping solution is used to generate a coating film on the template 303 to form the medical implant 100. The dipping solution is made up of a bioresorbable polymer solution.
[0047] An ice bath 305 may be placed beneath the apparatus 300 to regulate the temperature of the dipping solution 307. The temperature may be monitored at regular intervals with the help of a thermometer 309.
[0048] The process parameters of dip coating such as insertion speed, withdrawal speed, and temperature and coating thickness play a vital role in formation of the medical implant 100. The aforesaid parameters help to achieve a thin, uniform, durable and transparent coating surface. The parameters for the dip coating may be altered based upon the desired dimensions of the medical implant 100.
[0049] The insertion speed refers to the speed at which the template 303 is inserted in the dipping solution 307 while the withdrawal speed refers to the speed at which the template 303 is withdrawn from the dipping solution 307. The parameters for the dip coating may be altered based upon the desired dimension of the medical implant 100.
[0050] The insertion speed and the withdrawal speed helps to achieve uniform, smooth and transparent coating layer on the template 303. The insertion speed and the withdrawal speed may be same or different. In an embodiment, the insertion speed and the withdrawal speed during the dip coating process are same and range between 1 mm/sec to 20 mm sec. In an embodiment, the insertion speed and the withdrawal speed is around 3.5 mm/sec to 4.0 mm/sec.
[0051] In an embodiment, sub ambient temperature is maintained during the dip coating over the template 303 to achieve a bubble free surface of the medical implant 100. The bubble free surface obtained by the present invention eliminates the chances of faster degradation of the medical implant 100 and hence, the degradation rate of the medical implant 100 is maintained till the medical implant 100 is completely degraded and absorbed at the treatment site. Therefore, the bubble free surface imparts an increased efficiency to the medical implant 100. The temperature maintained during the dip coating process ranges between 5°C and 25°C. In an embodiment, the temperature maintained during the dip coating process is around 10° to 12°.The medical implant 100 obtained by the dip coating process at sub ambient temperature imparts high tensile strength and flexibility to the medical implant 100. The tensile strength of the medical implant 100 formed is obtained between 80 N/mm2 to 130 N/mm2. The improved strength helps the medical implant 100 to withstand the pressure during implantation of the medical implant 100 at the treatment site for a required period of time.
[0052] The desired thickness of the medical implant 100 is achieved by increasing the number of dipping cycles and concentration of the dipping solution 307 (bioresorbable polymer solution). The concentration of dipping cycle ranges from 5% to 20%, and the dipping cycles may range from 2 to 20. In an embodiment, the medical implant 100 with thickness around 300 µm is obtained by performing dip coating for 4 dipping cycles and concentration of the dipping solution 307 to be 16 %.
[0053] Optionally, the rotation of the template 303 may be done between each dipping cycle to attain a uniform coating thickness throughout the template 303. An inert gas such as nitrogen can be applied post each dipping cycle to make the surface dry and facilitate better adherence of the next layer of coating. Introduction of the inert gas may also avoid bubble formation on the coating layer.
[0054] Once the desired thickness is achieved, the medical implant 100 is allowed to dry using vacuum desiccators for minimum of 12 to 24 hours to remove excess solvents from the medical implant 100.
[0055] Further, the template 303 is gently removed through the opening 109 .The agar can either be removed manually i.e. by gently pressing the medical implant 100 or by dipping the medical implant 100 in heated purified water, which leads to melting of agar. Once the agar is removed, the medical implant 100 is washed in purified water and the process is repeated until the template 303 is removed completely.
[0056] At step 203, following fabrication of the medical implant 100 at the previous step, the medical implant 100 is subjected to a process of annealing in vacuum at a predefined annealing temperature. The annealing temperature may be selected based on glass transition temperature (Tg) and melting temperature (Tm) of polymers used in the fabrication of the medical implant 100. For Instance, the glass transition temperature of poly-L-lactide co-caprolactone is around 20°C to 25°C and melting point ranges from 107°C to 112°C temperature, so the annealing temperature of the poly-L-lactide co-caprolactone is 90°C
[0057] The process of annealing is performed by mounting the medical implant 100 on a mandrel (not shown), at a temperature of 40°C to 105°C under vacuum of 700 mmHg. In an embodiment, process of annealing is performed at the temperature of 90°C.
[0058] In another embodiment, the medical implant 100 is subjected to one or more cycles of annealing.
[0059] The process of annealing at step 203 helps to enhance the strength and flexibility of the medical implant 100. Annealing also relieves internal stress and strain developed during the dip coating at the previous step or at the time of loading the medical implant 100 into the delivery sheath. Further, the process of annealing enhances the smoothness and transparency of the medical implant 100. Annealing also imparts shape memory and stability to the medical implant 100 to withstand the pressure between joints for example shoulder’s bone. Increased durability results in reducing injury to sponge like tissue and helps in improvement of rotator cuff injuries. Annealing may also help in avoiding bonding or sticking of the medical implant 100 in deflated state and promotes the smooth transition of the medical implant 100 to easily regain its original shape when inflated during treatment at the treatment site. Annealing also helps to maintain structural integrity during degradation of the medical implant 100 as compared to non-annealed medical implant 100 by providing consistent polymer morphology.
[0060] In the next step 205, therapeutic drug(s) may be coated over an outer surface 103 of the medical implant 100. The coating may be performed by means of without limitation spray coating, dip coating and/or crush coating. In an embodiment, the spray coating is performed using a spray gun 403 as shown in FIG. 4. The medical implant 100 is attached to a mandrel 405 and positioned in front of the spray gun 403. Spray coating may result in a smooth, uniform and/or seamless/ crack free coating on the medical implant 100.
[0061] Various therapeutic drugs may be used for coating the outer surface 103 of the medical implant 100. The therapeutic drugs may include but not limited to antibiotics, bactericidal/antimicrobial and antifungals agents. In an embodiment, an antibacterial agent is used for coating the medical implant 100. The antibacterial agent may be selected from but not limited to gentamicin, vancomycin, tobramycin, ciprofloxacin, rifamycins or their combination. Antifungals may be selected from but not limited to amphotericin, ketoconazole, fluconazolecan. Antibiotics may be selected from but not limited to cefazolin, and linezolid.
[0062] In an embodiment, a therapeutic drug formulation may be prepared by dissolving the therapeutic drug and a biodegradable polymer(s) in a suitable solvent to facilitate spray coating process. The biodegradable polymer may act as a carrier and facilitate controlled release of drug from the medical implant 100. In an embodiment, the medical implant 100 may initially burst release the therapeutic drug followed by moderate release and finally sustained slow drug release for longer period of time.
[0063] The biodegradable polymers may include without limitation poly DL-lactide co glycolide (PDLG), poly-L-lactide (PLA), poly L-lactide co-glycolide (PLGA), poly DL-lactide (PDL), poly-L-lactide co-caprolactone (PLC), polycaprolactone (PCL) or combination thereof. The therapeutic agent and the biodegradable polymer may be dissolved in a ratio of 20:80, 30:70, 40:60, or 50:50.
[0064] The solvents may include without limitation acetone, methylene chloride, chloroform, ethanol, methanol, water or their mixture.
[0065] The parameters require for spray coating play a vital role in achieving thin uniform coating on the medical implant 100. The parameters may include collate rotation (with the help of collate rotator 401, as shown in Fig. 4), distance between medical implant 100 and spray gun tip, solution flow rate and inert gas pressure used for spraying. In the process of spray coating, the solution flow rate ranges between 0.10 and 0.40 ml/min. In an embodiment, the solution flow rate is 0.2 ml/min, to achieve the desired coating thickness. The drug dose maintained ranges between 0.05 µg/mm2 to 3.0µg/mm2. In an embodiment, the drug dose is 1.25 µg/mm2. The drug-polymer coating thickness over the medical implant 100 ranges from 1 µm to 30 µm. In an embodiment, the thickness of the drug-polymer coating is around 5 µm to 15 µm.
[0066] After the coating process, the medical implant 100 may be kept under vacuum for solvent evaporation to remove residual solvent. The vacuum may be provided ranges from 650 to 700mmHg. The time duration to be maintained ranges about 12 hours to 24 hours.
[0067] At step 207, after coating, the medical implant 100 is packed with a delivery system kit in an aluminum pouch and is subjected to sterilization i.e. e-beam sterilization. The advantage of e-beam sterilization process is that it leaves no residual content after sterilization process and thereby decreasing the chances of toxicity.
[0068] Another advantage of e-beam sterilization process is that it takes shorter period of time to sterilize the medical implant. Moreover, e-beam sterilization can penetrate a variety of packaging materials such as foils, outer box and hence any packaging material can be used.
[0069] The e-beam sterilizing process avoids the damaging of packaging material and therefore no further packaging of the medical implant 100 is required. Hence the medical implant is ready to be shipped without any further packaging unlike conventional processes.
[0070] The present invention may be sterilized using various sterilization methods includes but not limited to radiation sterilization, gas sterilization or liquid chemical sterilization. Radiation sterilization is not limited to gamma or electron beam sterilization and gas sterilization. Sterilization includes but not limited to ethylene oxide, formaldehyde, hydrogen per oxide (H2O2) or propylene oxide sterilization. For e-beam sterilization 15 kGy to 25 kGy is used. In an embodiment, the average dose of e-beam sterilization is around 20 to 21 kGy is used. In an embodiment, the medical implant 100 with the delivery system kit is packed in a pouch and subjected to the sterilization process to achieve a sterility assurance level of 10-6.
[0071] In an alternate embodiment depicting the manufacturing of the medical implant 100 using stretch blow molding process. In this process, a biodegradable tube is structured to form a medical implant 100. The stretch blow molding process enhances strength of the formed medical implant 100 having balanced flexibility. The medical implant 100 obtained by said process can easily withstand pressure during implantation of the medical implant 100 at the treatment site for a time period of around 3 to 6 months and is thereafter completely degraded over a specific period of time i.e. around 12 to 24 months.
[0072] The process of manufacturing the medical implant 100 via stretch blow molding commences with stretching and/or blowing the tube, wherein a biodegradable tube is placed inside a mold. The mold for stretch blow molding process may be made of a metallic material having a thermal conductivity. The metallic material may include without limitation beryllium copper.
[0073] The stretching and/or blowing the tube include heat treatment, followed by pressure application on the tube.
[0074] In the next step, the biodegradable tube inside the mold is heated to a temperature between a glass transition temperature and a melting point of polymer. For example, the glass transition temperature of poly-L-lactide co-caprolactone is around 20°C to 25°C and melting point ranges from 107°C to 112°C, so the process of heat treatment is performed at the temperature 60°C. The application of heat treatment stabilizes the biodegradable tube.
[0075] Further, the heated biodegradable tube is subjected to a pressure in a range of 15 bars to 45 bars by means of an inert gas. In an embodiment the pressure applied on heated biodegradable tube is around 20 bars to 25 bars. The inert gas may include without limitation nitrogen, argon etc. The pressurization of the biodegradable tube leads to expansion of the biodegradable tube against the inner walls of the mold.
[0076] Following pressurization, the mold is again annealed at a temperature of 60°C to 130°C. In an embodiment the heat set temperature is 90°C.
[0077] Further the immediate cooling of expanded tube is done within the mold. The advantage of immediate cooling helps to solidify the expanded tube. Also, immediate cooling helps to control degree of crystallization of the material used for medical implant 100, which affect the strength and flexibility of the medical implant 100.
[0078] At next step the medical implant 100 is thus obtained and is removed from the mold.
[0079] It may be noted that other specific process parameter required for manufacturing of medical implant 100, like annealing 203, Spray coating with therapeutic agents 205 and e-beam sterilization 207 of medical implant 100 may be referred from description of FIG. 2 and has not been repeated for brevity.
[0080] The process of manufacturing the medical implant 100 by the dip coating process is illustrated with the help of below examples, corresponding to the number of dipping cycles and its resultant average thickness.
[0081] Example 1:
The dipping solution 307 was prepared using poly-l-lactide caprolactone having a concentration of 10% w/v. The template 303 was dipped in dipping solution 307 to achieve desired coating thickness. The insertion speed and the withdrawal speed during dipping coating was around 4 mm/sec. The process was repeated with 12 dipping cycles. The average coating thickness obtained was 280 µm. During the dip coating process, the sub-ambient temperature was maintained around 10°C to 12°C to achieve bubble free coating surface. Further the medical implant 100 was subjected to annealing process for duration of 16 hours at 90°C. The structural integrity of medical implant 100 was around 10 days to 14 days during accelerated In-vitro degradation at 70°C temperature. The therapeutic drug was spray coated on the medical implant 100 to minimize the infection post implantation at treatment site. The solution flow rate was kept around 0.2ml/min to achieve smooth and uniform coating. Finally, the medical implant is sterilized by e-beam sterilization process at around 20kGy to 25kGy.
Example 2
The dipping solution 307 was prepared using poly-lactide caprolactone polymer having 12% w/v concentration. The template 303 was dipped inside dipping solution 307 to achieve desired coating thickness. The insertion speed and withdrawal speed was kept around 8 mm/sec and process was repeated with 06 to 08 dipping cycles. The dip coating process was performed at ambient temperature and between each cycle, medical implant was allow to air dry for 5 minutes for next coating cycle. The average coating thickness obtained was 290 µm. By following the above process, the medical implant was observed with tiny bubbles throughout the surface and was less smooth compare with other examples. The medical implant formed was further spray coated with therapeutic drug as discuss in above example and was sterilized using e-beam sterilization process. The medical implant maintains its structural integrity for around 07 days to 09 days during accelerated In-vitro degradation at 70°C temperature.
[0082] Example 3:
The dipping solution 307 was prepared using poly-l-lactide caprolactone polymer having the concentration of 16% w/v. The template 303 was dipped in dipping solution 307 to achieve desired and uniform coating thickness. The insertion speed and withdrawal speed during dipping was kept around 5 mm/sec and process was repeated with 04 to 06 dipping cycles and nitrogen was applied between each dipping cycle for around 5 minutes. The application of nitrogen after each dipping cycle helps to adhere second layer of coating and avoids the formation of uneven surface of the medical implant 100. The average coating thickness obtained was 320 µm. The dip coating process was performed at sub-ambient temperature was maintained between 10°C to 12°C to achieve bubble free coating surface. It was observed that higher concentration leads to less number of dipping cycles to achieve desired coating film. The prepared medical implant 100 was further subjected to annealing process for duration of 16 hours at 90°C temperature. It helps to imparts shape memory and stability to implant which helps to maintain structural integrity of medical implant 100 around 11 days to 14 days during accelerated In-vitro degradation at 70°C temperature. The therapeutic drug was spray coated on the medical implant 100 to minimize infection post implantation at treatment site. The solution flow rate was kept around 0.15ml/min to achieve smooth and uniform coating. Coating integrity is also maintained during loading of implant by radially folding into delivery sheath. Finally, the medical implant 100 was sterilized by e-beam sterilization process at around 20kGy to 25kGy
[0083] The scope of the invention is only limited by the appended patent claims. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and/or configurations will depend upon the specific application or applications for which the teachings of the present invention is/are used.