Claims:WE CLAIM:
1. A therapeutic coating on a medical implant, the coating comprises:
at least one bottom layer (22) provided on a medical implant (100), the bottom layer (22) including a nano formulation having at least one polymer in a concentration of 60 weight% - 90 weight%, at least one surfactant in a concentration of 01weight% - 10weight% and at least one anti-bacterial agent in a concentration of 1 weight% - 60 weight% dissolved in at least one solvent;
at least one top layer 24 provided on the at least one bottom layer (22), the top layer (24) including a nano formulation having at least one polymer in a concentration of 60weight%-90weight%, at least one surfactant in a concentration of 01 weight% - 10 weight% and an at least one anti-inflammatory agent in a concentration of 01 weight% - 60 weight% dissolved in at least one solvent;
wherein 50% to 70% of the anti-bacterial agent is released in 45-55 days of implantation of the medical implant (100) at a treatment site from the bottom layer (22);
wherein 85%-95% of the anti-inflammatory agent is released in 1-4 days of implantation of the medical implant (100) at the treatment site from the top layer (24).
2. The therapeutic coating as claimed in claim 1 wherein the at least one polymer and the at least one surfactant of the bottom layer (22) and the top layer (24) are same.
3. The therapeutic coating as claimed in claim 1 wherein the at least one polymer and the at least one surfactant of the bottom layer (22) and the top layer (24) are different.
4. The therapeutic coating as claimed in claim 1 wherein the polymer is selected from one or more of aliphatic polyesters, poly(orthoesters), natural polymers, polyalkylcyanoacrylates, poly(ester-ether), polyanhydrides, poly(aminoacids), poly(propylene fumarate), polyphosphazenes, and poly(vinyl alcohol). Poly-L-lactide (PLLA), poly-DL-lactide-co-glycolide (PDLG), poly-D-lactide (PDLA), poly-DL-lactide (PDL), polyglycolide, poly-L-lactide-co-e-caprolactone (PLCL), and combinations thereof.
5. The therapeutic coating as claimed in claim 1 wherein the surfactant is selected from one more of poly(ethylene glycol) or their derivatives, poly(vinyl alcohol) or their derivatives, poly(vinyl pyrrolidone) or their derivatives, polyacetylene (PA), polythiophene (PT), polyparaphenylene (PPP), poloxamer, vitamin E TPGS, polyparavinylene (PPV), cellulose, starch, chitosan, dextran, glucose and combinations thereof.
6. The therapeutic coating as claimed in claim 1 wherein the anti-bacterial agent is selected from one or more of penicillins, polypeptides, polymyxins, chloramphenicols, aminoglycosides, ansamycins, cephalosporins, and combinations thereof.
7. The therapeutic coating as claimed in claim 1 wherein the anti-inflammatory agent is selected from one or more of non-steroidal anti-inflammatory drugs (NSAIDs), steroidal anti-inflammatory drugs, non-opioid analgesics, opioid analgesics, and compound analgesics.
8. The therapeutic coating as claimed in claim 1 wherein the solvent is selected from one or more of water, methanol, ethanol, Dichloromethane (DCM), ?,?'-dimethylacetamide (DMAC), ?,?'- dimethylformamide (DMF), isopropanol, dimethyl sulfoxide (DMSO), 1,3-dimethyl-2-imidazolidinone (DMEU), diethyl ether, ethyl acetate, acetone, chloroform, methyl acetate, xylene, and mixtures thereof.
9. The therapeutic coating as claimed in claim 1 wherein the bottom layer (22) and the top layer (24) have a thickness in a range of 1µm to 100µm.
10. The therapeutic coating as claimed in claim 1 wherein a base layer (20) is provided between the bottom layer (22) and the medical implant (100).
11. The therapeutic coating as claimed in claim 1 wherein the top layer (24) is coated with a protective layer (26) including a polymer dissolved in a solvent.
12. The therapeutic coating as claimed in claim 1 wherein the nano formulation includes a particle size of 100nm to 1500nm. , 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:
DUAL COATING ON MEDICAL IMPLANTS

2. APPLICANTS:
Meril Healthcare Pvt. Ltd, an Indian company, of the address Bilakhia House, Muktanand Marg, Chala, Vapi-Gujarat 396191, India

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

FIELD OF INVENTION
[1] The present invention relates to a coating on medical implants, more specifically relates to a therapeutic coating on the medical implants.
BACKGROUND
[2] Osteoarthritis is the most common form of arthritis which affects millions of people, over the age of 70 worldwide. It is an age-related disorder and can be identified by symptoms or clinical pathology. Though, osteoarthritis can damage any joint, the said disorder most commonly affects the joints of knee (up to 41%), hands (up to 30%), hips (up to 19%) and/or spine.
[3] In order to treat osteoarthritis, joint replacement has proved to be the most promising procedure as compared to other treatment strategies. However, joint replacement surgery may include post-surgical complications such as high risk of sepsis or infection specifically for the knee and hip surgery. Other contraindications may include critical limb ischemia, extreme pain after surgery and/or a non-functioning extensor mechanism. Moreover, such complications may severely affect the condition of a patient suffering from a life-threatening disease such as diabetes, HIV, etc.
[4] In order to mitigate such complications, re-surgery or revision surgery is required to be performed. However, re-surgery is expensive and results in worse outcomes than primary surgery.
[5] Generally, oral antibiotics and/or anti-inflammatory therapeutic drugs may be prescribed to patient for prevention of post-surgical complications such as infection and inflammation. However, in case of severe inflammation and infection, high oral dose may also be given by physicians that may lead to impairment or damage to other vital organs of body.
[6] Therefore, to overcome the aforesaid condition, it may be beneficial to apply a coating of one or more therapeutic agents on orthopedic implant which is used for replacement procedure. Further, the therapeutic coating may also be beneficial on other medical implants such as dental implants in order to ameliorate the situation of a patient. Though, such coatings have been known, however, the conventional coatings on the implant may pose several limitations such as uneven drug delivery and/or diminished drug availability.
[7] One such conventional coating as disclosed in prior art EP1812090A1 includes a formulation of one or more antibiotics to be provided on the implant. The coating formulation is applied as a single layer of coating on the implant which causes release of single drug from implant surface leading to insufficient drug availability to the patient.
[8] Therefore, there is a need for an improved coating on the orthopaedic implants which may overcome the limitations of the conventional ones.
SUMMARY
[9] The present invention discloses a therapeutic coating on a medical implant. The coating includes a bottom layer and top layer. The bottom layer and the top layer include a nano formulation having at least one polymer in a concentration of 5 weight% - 95 weight%, and at least one surfactant in a concentration of 1weight% - 10weight%. Further, the bottom layer includes at least one anti-bacterial agent in a concentration of 1 weight% - 60 weight% and the top layer at least one anti-inflammatory agent in a concentration of 01 weight% - 60 weight% dissolved in at least one solvent. The 50% to 70% of the anti-bacterial agent is released in 45-55 days of implantation from the bottom layer and the 85%-95% of the anti-inflammatory agent is released in 1-4 days of implantation at the treatment site from the top layer.
BRIEF DESCRIPTION OF DRAWINGS
[10] The summary above, as well as the following detailed description of illustrative embodiments, is better understood when read in conjunction with the appended drawings. For the purpose of illustrating the present disclosure, exemplary constructions of the disclosure are shown in the drawings. However, the disclosure is not limited to specific methods and instrumentalities disclosed herein. Moreover, those in the art will understand that the drawings are not to scale.
[11] FIG.1A represents a perspective view of a knee implant in accordance with an embodiment of the present invention.
[12] FIG.1B represents a perspective view of a hip implant in accordance with an embodiment of the present invention.
[13] FIG.2 represents a coating on the implant in accordance with an embodiment of the present invention.
[14] FIG.3 represents a flow chart depicting a process involved in coating the implant in accordance with an embodiment of the present invention.
[15] FIG.4A-4B represents a graph depicting release profile of the triclosan and indomethacin respectively in example 1 in accordance with an embodiment of the present invention.
DETAILED DESCRIPTION OF DRAWINGS
[16] 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.
[17] Particular embodiments of the present disclosure are described hereinbelow 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.
[18] The present invention relates to a therapeutic coating on medical implants. In various embodiments, the medical implant may include one of, an orthopedic implant, a dental implant, etc. The orthopedic implants further may include knee implant, hip implant, elbow implant, spine implant etc. In an embodiment, the therapeutic coating is performed on the hip and/or knee implants.
[19] The therapeutic coating may include a plurality of layers. In an embodiment, the coating includes two layers i.e. a bottom layer and a top layer. The bottom layer includes one or more of, a polymer, a surfactant and an antibacterial agent. In an embodiment, 50%-70% of the anti-bacterial agent is released in 45-55 days of treatment. Such a release profile prevents infection in early stage of treatment.
[20] The top layer includes, one or more of, a polymer, a surfactant and an anti-inflammatory/analgesic agent. In an embodiment, 85%-95% of the anti-inflammatory agent is released in 1-4 days of treatment which provides immediate relief to the patient from extreme pain and inflammation post-surgery.
[21] The dual coating as disclosed above results in better drug distribution at a treatment site leading to prevention of onset of any infection and/or chances of re-surgery for the patient.
[22] The aforesaid layers of the therapeutic coating in the present invention are prepared as nano formulations. The utilization of nano formulations in the present invention provides uniform drug distribution around a tissue at the treatment site of the implant. Further, such nano formulations also provide enhanced drug stability, better solubility, sustained release and/or improved pharmacological activity of the drug at the treatment site.
[23] Now referring specifically to drawings, FIG.1A represents a front view of the knee implant 100A. The knee implant 100A may include a femoral component 10, a spacer 12 and a tibial component 14. The knee implant 100A may be made of a metal and/or a polymeric material. The metals that may be used for fabricating the knee implant 100A may include without limitation, alumina, titanium, nickel, vanadium, other metallic alloys their combinations. The polymeric material may include without limitation, ultra-high-molecular-weight polyethylene (UHMW-PE), high density polyethylene (HDPE), polytetrafluoroethylene (PTFE), polyether ether ketone (PEEK) and polycarbonate urethanes (PCU). In an embodiment, the knee implant 100A is made of ultra-high-molecular-weight polyethylene (UHMW-PE).
[24] FIG.1B represents a front view of the hip implant 100B. The hip implant 100B may include a cup portion 11, a head 13, a neck 15, and a stem 17. The aforesaid components of the hip implant 100B are coupled to each other as depicted and further details of a hip implant 100B can be referred from the art.
[25] In accordance with the FIG.1A or FIG1B, the therapeutic coating 200 has been mentioned to be applied on the knee and/or the hip implant (100A, 100B). However, the same can be applied on any medical implant surface made of materials described in above paragraphs.
[26] In order to effectively deliver therapeutic agent(s) present in the therapeutic coating 200 of the implant at the treatment site, it is necessary that the therapeutic coating 200 is applied over a substrate ‘S’ i.e. a pre-defined surface of the implant, that has minimal friction or no friction with other parts of the implant. Hence, in case of the knee implant 100A, the therapeutic coating 200 may be applied on the spacer 12 and/or the tibial component 14. For hip implant 100B, the therapeutic coating 200 may be applied on the neck 15 (depicted in FIG.1B). The selection of such area of the knee and hip implants 100A, 100B allows larger surface area for the coating and better drug distribution at the treatment site.
[27] In an exemplary embodiment, FIG.2 represents the therapeutic coating 200 which is applied over the substrate ‘S’. The substrate ‘S’ may be any pre-defined surface of an medical implant, say, the knee implant 100A or the hip implant 100B. The substrate ‘S’ may be made of a plastic, a polymeric or a metallic material.
[28] The therapeutic coating 200 may be adhered to the substrate ‘S’ via a base layer 20. The base layer 20 acts as an adhesive layer for securing the therapeutic coating 200 to the substrate ‘S’. Further, the inclusion of the base layer ‘20’ allows extended release of the anti-bacterial agent from the bottom layer 22 thereby improves drug release kinetics of the therapeutic coating 200.
[29] The base layer 20 may be formulated in a defined proportion. The formulation of the base layer 20 may include one or more bioabsorbable polymers and one or more solvents. The bioabsorbable polymers may include without limitation, aliphatic polyesters, poly(orthoesters), natural polymers, polyalkylcyanoacrylates, poly(ester-ether), polyanhydrides, poly(aminoacids), poly(propylene fumarate), polyphosphazenes, and poly(vinyl alcohol). Poly-L-lactide (PLLA), poly-DL-lactide-co-glycolide (PDLG), poly-D-lactide(PDLA), poly-DL-lactide (PDL), polyglycolide, poly-L-lactide-co-e-caprolactone (PLCL), Poly (2-hydroxy ethyl methacrylate), poly (ethylene-co-vinyl acetate), poly (methyl methacrylate), poly (N-vinyl pyrrolidone), poly (vinyl alcohol), poly (acrylic acid), poly (methacrylic acid), polyacrylamide, poly (ethylene glycol) or their derivatives.
[30] The solvents may be selected from one or more of water, methanol, ethanol, dichloromethane (DCM), ?,?'- dimethylformamide (DMF), 1,3-dimethyl-2-imidazolidinone(DMEU), isopropanol, ?,?'-dimethylacetamide (DMAC), diethyl ether, chloroform, methyl acetate, ethyl acetate, dimethyl sulfoxide (DMSO), acetone, xylene, and mixtures thereof. In an embodiment, the solvent is used is dichloromethane.
[31] In an embodiment, the polymer used in the base layer 20 is polyethylene glycol (PEG) dissolved in dichloromethane (DCM). The concentration of the PEG may be in the range of 2 weight% to 20 weight%. In an embodiment, the concentration of the PEG used in the base layer 20 is 5 weight%.
[32] The therapeutic coating 200 as depicted in FIG. 2 includes two layers. The layers of the therapeutic coating 200 include a bottom layer 22 and a top layer 24. The bottom layer 22 may be coated on the base layer 20 and the top layer 24 may be coated on the bottom layer 22.
[33] The bottom layer 22 and the top layer 24 may be formulated in a pre-defined proportion. In an embodiment, the bottom layer 22 and the top layer 24 is prepared as a nano particle formulation.
[34] The size of nano particles in the bottom later 22 and the top layer 24 may be same or different. The particle size may range from 100nm to 1500nm. In an embodiment, the particle size is in a range of 300nm to 1000nm. The nano particle formulation of the bottom layer 22 and the top layer 24 may be prepared using a conventional technique(s), say, high-speed homogenization (HSH) and/or high-pressure homogenization (HPH) as known in the art. In an embodiment, the nano particle formulation is prepared by high-speed homogenization. The high-speed homogenization (HSH) may be performed at a speed of 5000 to 20000 rpm for 10 minutes to 50 minutes, more preferably at 11000 to 14000 rpm for 25 minutes to 45 minutes.
[35] The nano particle formulation of the bottom layer 22 and the top layer 24 may provide uniform drug distribution throughout tissue area and/or quick delivery of drug at the treatment site. Moreover, the nano particle formulation may also provide enhanced drug stability, better solubility, sustained release of the drug from the bottom layer 22 and the top layer 24 and/or improved pharmacological activity at the treatment site.
[36] The nano particle formulation of the bottom layer 22 and the top layer 24 may include one or more polymers, one or more surfactants, one or more solvents and one or more therapeutic agent(s). In an embodiment, the therapeutic agent of the bottom layer 22 includes one or more anti-bacterial agent(s). In another embodiment, the therapeutic agent of the top layer 24 includes one or more anti-inflammatory agent/analgesic agents. The anti-bacterial agent(s) in the bottom layer 22 may prevent onset of infection and the anti-inflammatory agent(s) in the top layer 24 may prevent inflation post-surgery.
[37] The concentration of the polymer and surfactant in both the layers (22, 24) may be same or different. The polymer and surfactant may be present in a range of 60-90 weight% and 1 to 10 weight% respectively. The therapeutic agent(s) in the bottom layer 22 and the top layer 24 may be present in a range of 1 weight% to 60 weight%, preferably in a range of 05 weight% to 40 weight%.
[38] The surfactant may help to regulate particle size, adsorption, desorption and/or prevent agglomeration of the nano particles of both coating layers (22, 24). The surfactant may be selected from but not limited to poly(ethylene glycol) or their derivatives, poly(vinyl alcohol) or their derivatives, poly(vinyl pyrrolidone) or their derivatives, polyacetylene (PA), polythiophene (PT), polyparaphenylene (PPP), poloxamer, vitamin E TPGS, polyparavinylene (PPV), cellulose, starch, chitosan, dextran, glucose or their combination. In an embodiment, the surfactant is a mixture of vitamin E TPGS and poloxamer. The concentration of the surfactant may be in a range of 0.01 to 40 weight%. In an embodiment, the concentration of the surfactant is 1 to 10 weight%.
[39] The polymer(s) acts as an excipient and regulates the release profile of the therapeutic agent(s) from the bottom layer 22 and the top layer 24. The release profile of the therapeutic agent(s) from the bottom layer 22 and the top layer 24 may be tuned by the polymer(s) as each polymer has different resorption rates inside human body. The polymer(s) may be a bioresorbable polymer. The bioresorbable polymer may be selected from one or more of without limitation, aliphatic polyesters, poly(orthoesters), natural polymers, polyalkylcyanoacrylates, poly(ester-ether), polyanhydrides, poly(aminoacids), poly(propylene fumarate), polyphosphazenes, and poly(vinyl alcohol). Poly-L-lactide (PLLA), poly-DL-lactide-co-glycolide (PDLG), poly-D-lactide (PDLA), poly-DL-lactide (PDL), polyglycolide, poly-L-lactide-co-e-caprolactone (PLCL), and their combination. In different embodiments, various other polymers can be used which include without limitation poly (2-hydroxy ethyl methacrylate), poly (ethylene-co-vinyl acetate), poly (methyl methacrylate), poly (n-vinyl pyrrolidone), poly (vinyl alcohol), poly (acrylic acid), poly (methacrylic acid), polyacrylamide, poly (ethylene glycol) or their derivatives.
[40] In an embodiment, the bottom layer 22 includes poly-DL-lactide (PDL). The concentration of the poly-DL-lactide (PDL) may be in a range of 60 to 90 weight%. In an embodiment, the concentration of the poly-DL-lactide (PDL) in the bottom layer 22 is around 74 weight%. The molecular weight of PDL ranges from 10,000 g/mol to 1,50,000 g/mol, preferably ranges from 25,000 g/mol to 1,20,000 g/mol and more preferably ranges from 45,000 g/mol to 80,000 g/mol.
[41] In an embodiment, the top layer 24 includes poly-DL-lactide-co-glycolide (PDLG). The concentration of the poly-DL-lactide-co-glycolide (PDLG) may be in a range of 60 to 90 weight%. In an embodiment, the concentration of the poly-DL-lactide-co-glycolide (PDLG) in the top layer 24 is 75 weight%. The molecular weight of PDLG ranges from 15,000 g/mol to 1,70,000 g/mol, preferably ranges from 30,000 g/mol to 1,45,000 g/mol and more preferably ranges from 55,000 g/mol to 1,10,000 g/mol. The ratio of L-lactide to glycolide in the PDLG ranges from 40:60 to 60:40.
[42] The poly-DL-lactide (PDL) and poly-DL-lactide-co-glycolide (PDLG) are selected as they are suitable for controlled release of therapeutic agent(s) from the bottom layer 22 and the top layer 24 respectively. The poly-DL-lactide (PDL) and the poly-DL-lactide-co-glycolide (PDLG) are not prone to early degradation and both possess different resorption rate inside body. Therefore, the aforesaid polymers may provide required release profile of the therapeutic agent(s) from the bottom layer 22 and the top layer 24 respectively.
[43] The anti-bacterial agents used in the bottom layer 22 may be selected from one more of penicillin, such as penicillin G and V, methicillin, oxacillin, amoxicillin, floxacillin; polypeptides, such as tyrothricin, vancomycin, bacitracin, polymyxins; chloramphenicols; such as erythromycin, oleandomycin, or spiramycin; aminoglycosides, such as kanamycin, tobramycin, neomycin, gentamicin, streptomycin; ansamycins, such as rifamycin, or rifampin; cephalosporins, such as cephaloridine, cephalexin, cefazolin, cephalothin, cephapirin, triclosan and likewise.
[44] In an embodiment, triclosan is used as the anti-bacterial agent in the bottom layer 22. The concentration of triclosan in the bottom layer 22 may be in a range of 0.5gm to 8gm. In an embodiment, the concentration of triclosan is around 2.5gm. The anti-bacterial agent is released over a period of 2 to 90 days. In an embodiment, 50%-70% of the anti-bacterial agent is released in the first 45-55 days of treatment which leads to elimination of probable infection at the treatment site. The remaining anti-bacterial agent is gradually released from the surface of the implant within 35-45 days. The dose of triclosan may range from 0.1µg/mm2 to 10µg/mm2, preferably range from 0.5µg/mm2 to 5µg/mm2, more preferably range from 1.0µg/mm2 to 2.0µg/mm2.
[45] The anti-inflammatory agent used in the top layer 24 may be selected from but not limited to non-steroidal anti-inflammatory drugs (NSAIDs), non-opioid analgesics, opioid analgesics, and compound analgesics. Non-opioid analgesics may include without limitation, capsaicin analogues, COX-2 inhibitors, duloxetine, lumiracoxib, pregabalin, ketamine, tapentadol. The compound analgesics may include without limitation, oxycodone, co-codamol, caffeine, phenacetin, aspirin. The steroidal anti-inflammatory drug may include without limitation, hydrocortisone, triamcinolone, dexamethasone, mometasone, betamethasone, amcinonide, desonide or their combination. The opioids may include without limitation, codeine phosphate, dextropropoxyphe hydrochloride, tramadol hydrochloride, and their derivatives. The non-steroidal anti-inflammatory drug (NSAIDs) may include without limitation, ibuprofen, diclofenac, paracetamol, etoricoxib, naproxen, rofecoxib, celecoxib and indomethacin or their combination. Other drug may include without limitation, hydroxychloroquine, sulfasalazine, methotrexate, leflunomide. Clinical studies suggest that non-aspirin NSAIDs exhibit superior properties in joint swelling, reducing pain and duration of morning stiffness, improving strength and mobility.
[46] In an embodiment, the anti-inflammatory agent is indomethacin. The concentration of the indomethacin in the top layer 24 may be in a range of 0.5gm to 10gm. In an embodiment, the concentration of the indomethacin is around 4.5gm. The anti-inflammatory agent is released over a period of 2 to 14 days. In an embodiment, 85%-95% of the anti-inflammatory agent is released in the first 1-4 days of treatment which leads to immediate relief from extreme pain to the patient post-surgery. The remaining anti-inflammatory agent is gradually released from the surface of the implant within 5- 10 days. The dose of the indomethacin ranges from 0.1µg/mm2 to 50µg/mm2, preferably from 5µg/mm2 to 25µg/mm2, more preferably from 10µg/mm2 to 20µg/mm2.
[47] The solvent(s) provides a base for mixing the polymer, the surfactant and the therapeutic agent(s). The solvent(s) may be selected from one of water, methanol, ethanol, Dichloromethane (DCM), ?,?'-dimethylacetamide (DMAC), ?,?'- dimethylformamide (DMF), isopropanol, dimethyl sulfoxide (DMSO), 1,3-dimethyl-2-imidazolidinone (DMEU), diethyl ether, ethyl acetate, acetone, chloroform, methyl acetate, xylene, and mixtures thereof. The solvent must be volatile, less toxic, inert as well as insoluble to the material of the implant where coating is being applied. In an embodiment, the solvent is dichloromethane.
[48] Optionally, a protective layer 26 may be applied as an outermost layer on the top layer 24. The protective layer 26 may prevent damage during transportation and handling. The protective layer 26 may include polymer dissolved in a solvent. The polymer may be selected from without limitation, poly vinylpyrrolidone or its derivatives. In an embodiment, the polymer used in the protective layer 26 is poly vinylpyrrolidone. The concentration of the polymer used may be in a range of 0.1 weight% to 10 weight%. In an embodiment, the concentration of the polymer is 1 weight% to 5 weight%. The solvent may be selected from without limitation, water, methanol, ethanol, dichloromethane (DCM), ?,?'-dimethylacetamide (DMAC), ?,?'- dimethylformamide (DMF), isopropanol, dimethyl sulfoxide (DMSO), 1,3-dimethyl-2-imidazolidinone (DMEU), diethyl ether, ethyl acetate, acetone, chloroform, methyl acetate, xylene, and mixtures thereof. In an embodiment, the solvent used in the protective layer 26 is dichloromethane (DCM).
[49] FIG.3 represents a flow chart depicting a process for providing the therapeutic coating 200 over the substrate ‘S’ of the implant 100. As a prerequisite, the substrate ‘S’ may be cleaned using nitrogen air and/or isopropyl alcohol to provide a clean surface for the coating procedure. However, it should be noted that cleaning of the substrate ‘S’ using any other conventionally used agent(s) is also within the scope of the present invention.
[50] The process of coating the substrate ‘S’ of the implant 100 commences at step 301. At this step, the base layer 20 is provided on the substrate ‘S’. The formulation of the base layer 20 may be coated over the substrate ‘S’ by means of any conventionally known technique such as, without limitation, spray coating, dip coating, vapour deposition, spin coating, etc. In an embodiment, the coating in the present invention is performed using spray coating. The coating may be performed in one or more cycles such that a uniform base layer 20 of a pre-defined thickness is obtained. In an embodiment, the thickness of the base layer 20 of the present invention lies between 05µm to 40µm.
[51] At step 303, the bottom layer 22 of the therapeutic coating 200 is provided over the base layer 20. The nano formulation of the bottom layer 22 is coated over the substrate ‘S’ by means of spray coating on the implant 100. However, other conventionally known processes may also be used for coating the nano-formulation of the bottom layer 22.
[52] After coating, the implant 100 coated with bottom layer 22 is dried for a time duration say, for 12 to 16 hours prior to coating the top layer 24. The coating may be dried in, for example, a vacuum desiccator.
[53] At step 305, the top layer 24 is provided over the bottom layer 22. Like, the base layer 20 and the bottom layer 22, the coating of the nano-formulation of the top layer 24 may be performed by means of spray coating.
[54] The parameters maintained at the time of spray coating for all the layers (20, 22, 24) may include, without limitation, distance between a spray gun and the implant, amount of coating solution, nitrogen gas pressure, rotational speed of the implant and/or solution flow rate. The coating parameters for providing the bottom layer 22 and the top layer 24 may be same or different. In an embodiment, the coating parameters are same. The distance between the spray gun and the substrate ‘S’ may range between 0.5cm and 8cm, preferably 2cm and 5cm such that smooth and uniform layers are achieved. The amount of nano-formulation required for coating may range from 1ml to 30ml, preferably 5ml to 25ml.
[55] During the spray coating process, the implant 100 may be rotated at a pre-defined rate continuously or periodically. In an embodiment, the implant 100 is rotated continuously at a speed ranging between 10 and 60 rotations per minute, preferably from 25 to 40 rotations per minute. The flow rate of the nano-formulations maintained during spray coating may range between 0.05ml per minute and 2ml per minute, preferably 0.08ml and 1ml per minute.
[56] A pressure may be applied via inert nitrogen gas. The pressure may range between 0.1kg/cm2 and 2.0 kg/cm2, preferably between 0.6 kg/cm2 and 1.4 kg/cm2. The above parameters are maintained resulting in formation of a uniform, thin, crack free and/or smooth bottom layer 22 and top layer 24 on the implant 100.
[57] The thickness of the bottom layer 22 and the top layer 24 may be same or different. In an embodiment, the thickness of the bottom layer 22 and top layer 24 ranges from 1µm to 100µm, preferably from 05µm to 40µm.
[58] Post following the aforesaid steps, the implant 100 is dried at step 307. The process of drying may be performed to evaporate residual solvent present on the implant. The process of drying may be performed in a vacuum desiccator for overnight.
[59] At step 309, the dried implant 100 is packaged into a tyvek pouch and/or aluminum pouch. The packaged implant 100 is then subjected to a process of sterilization. Sterilization may be performed by radiation or gas sterilization. Post sterilization, the implant 100 may be tested for drug release pattern in an In-vitro test. The in-vitro test may be performed by immersing the implant in phosphate buffer saline (PBS, pH 7.4) at a temperature of 37°C and storing in incubator for specific period of time. The release profile of the agent(s) from the bottom layer 22 and the top layer 24 may be checked by sampling at predefined time intervals. In an embodiment, the release profile is calculated by performing high performance liquid chromatography (HPLC) of 2ml of phosphate buffer. Release profile of anti-bacterial drug from bottom layer 22 and anti-inflammatory drug 24 from the top layer 24 ranges from 2days to 90days and 2days to 14days respectively.
[60] The present invention will be further understood by reference to the following non-limiting examples.
[61] Example 1: The implant was coated with a base layer 20, a bottom layer 22 and a top layer 24. The base layer included 5% of polyethylene glycol in dichloromethane for better adherence of drug coating layers on the implant surface. The bottom layer 22 included 74% PDL, 7% surfactant and 19% triclosan in 100ml dichloromethane-water emulsion. The top layer 24 included 75% PDLG, 6% surfactant and 19 % indomethacin in 100ml of dichloromethane- water emulsion. The total concentration of drug was around 20%, total concentration of surfactant was around 7% and total concentration of polymer was around 75% in both layers (22, 24). In the bottom layer 22 and the top layer 24, the surfactant was dissolved in water and homogenized at 13000rpm for 20minutes. Thereafter, coating solution containing therapeutic agent(s) and polymer(s) in solvent was added into surfactant solution and homogenized at 13000rpm for further 20minutes. Then, resultant suspension was homogenized at 20000psi in HPH. The average particle size in both suspensions was found to be around 500nm. The coating was performed by the spray coating method at a rotational speed of 25 to 40 rpm, flow rate of 0.1ml to 0.5ml and at a pressure of inert nitrogen ranging from 0.8kg/cm2 to 1.2kg/cm2. Post coating, the implant was subjected to packaging and sterilization. Further, during in-vitro study, it was found that, around 60% of triclosan was released in first 50 days and around 90% indomethacin was released in initial 48 hours. The aforesaid release profile of the therapeutic agents from the implant leads to adequate bioavailability of the drug, thereby eliminating onset of any early infection and pain to the patient post-surgery. FIG.4A and FIG.4B represents a graph depicting release profile of the triclosan and indomethacin inside body. Moreover, the coating was observed to be uniform without any flaking.
[62] Example 2 (Prior art): The implant was coated with the bottom layer and the top layer. Bottom layer included 55 weight% of PDL and 45 weight% an anti-bacterial agent in 100ml of dichloromethane. The top layer included 55 weight% of PDLG and 45 weight % of anti-inflammatory agent in 100ml of dichloromethane. The total concentration of drug was 45 weight %and total concentration of polymer was 55 weight % in both the layers. The average particle size of the therapeutic agent(s) in both layers (22, 24) is more than 1500nm. The coating was performed by the method of spray coating. Post coating, the implant was subjected to packaging and sterilization. Further, during in-vitro study, it was found that more than 60% of anti-bacterial agent is released in just 10-15 days causing very fast uptake of the anti-bacterial agent from the implant leading to minimum bioavailability of the anti-bacterial agent to the patient.
[63] 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.