Claims:WE CLAIM:
1. A multi-layered coating for a prosthetic meniscus comprising:
a primary layer applied on a prosthetic meniscus and including at least one anti-bacterial agent present in a concentration of 10 wt% to 30 wt% and at least one carrier present in a concentration of 60 wt% to 90 wt% dissolved in at least one solvent; and
a secondary layer applied on the primary layer and including at least one analgesic compound present in a concentration of 10 wt% to 30 wt% and at least one carrier present in a concentration of 60 wt% to 90 wt% dissolved in at least one solvent;
wherein the primary layer and the secondary layer elute respective drug within a predefined time period;
wherein the primary layer and the secondary layer impart a composite surface roughness average on the surface of the secondary layer in a range of 4.0 µm to 12.0 µm.
2. The multi-layered coating as claimed in claim 1 wherein the antibacterial agent is selected from one of tobramycin, kanamycin, gentamicin, neomycin, streptomycin rifamycin, rifampin, cephaloridine, cephalexin, cefazolin, cephalothin, cephapirin, erythromycin, oleandomycin, spiramycin, penicillin G, penicillin V, oxacillin, methicillin, floxacillin, amoxicillin, tyrothricin, bacitracin, vancomycin, polymyxins, triclosan or combinations thereof.
3. The multi-layered coating as claimed in claim 1 wherein the carrier is selected from one of poly-L-lactide (PLLA), poly-DL-lactide-co-glycolide(PLG), poly-D-lactide(PDLA), poly-DL-lactic (PDLA), poly-L-lactide-co-e-caprolactone(PLCL), polyglycolide, poly (2-hydroxy ethyl methacrylate), poly (N-vinyl pyrrolidone), poly (methyl methacrylate), poly (vinyl alcohol), Poly (acrylic acid), polyacrylamide, poly (ethylene-co-vinyl acetate), poly (ethylene glycol), poly (methacrylic acid) or combinations thereof.
4. The multi-layered coating as claimed in claim 1 wherein the solvent is selected from one 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, or combinations thereof.
5. The multi-layered coating as claimed in claim 1 wherein the analgesic agent is selected from one of ibuprofen, paracetamol, naproxen sodium, diclofenac sodium, celecoxib, rofecoxib, etoricoxib, indomethacin, naproxen, tramadol hydrochloride, dextropropoxyphe hydrochloride, triamcinolone, hydrocortisone, mometasone, dexamethasone, betamethasone, amcinonide, desonide, capsaicin analogues, lumiracoxib, ketamine, pregabalin, duloxetine, tapentadol, co-codamol, phenacetin, caffeine, oxycodone, aspirin, leflunomide, sulfasalazine, methotrexate, hydroxychloroquine or combination thereof.
6. The multi-layered coating as claimed in claim 1 wherein the primary layer is eluted for a predefined time duration of 20 days to 90 days.
7. The multi-layered coating as claimed in claim 1 wherein the secondary layer is eluted for a predefined time duration of 2days to 14days.
8. A multi-layered coating for a prosthetic meniscus comprising:
a first layer applied on a prosthetic meniscus including at least one carrier present in concentration of 0.1 wt% to 90 wt% dissolved in at least one solvent;
a second layer applied on the first layer including at least one anti-bacterial agent present in a concentration of 10 wt% to 30 wt% and at least one carrier present in a concentration of 60 wt% to 90 wt% dissolved in at least one solvent;
a third layer applied on the second layer including at least one carrier present in concentration of 50% to 99 % dissolved in at least one solvent;
a fourth layer applied on the third layer including at least one analgesic agent present in a concentration of 10 wt% to 30 wt% and at least one carrier present in a concentration of 60 wt% to 90 wt% dissolved in at least one solvent;
a fifth layer applied on the fourth layer including at least one carrier present in concentration of 0.1 wt% to 90 wt% dissolved in at least one solvent;
wherein the second layer and the fourth layer elute respective drug within a predefined time period;
wherein the first layer, the second layer, the third layer, the fourth layer and the fifth layer impart a composite surface roughness average (Ra) on the surface of the fifth layer in a range of 3.0 µm to 22.0 µm
9. The multi-layered coating as claimed in claim 5 wherein the carrier is selected from one of poly-L-lactide (PLLA), poly-DL-lactide-co-glycolide(PLG), poly-D-lactide(PDLA), poly-DL-lactic (PDLA), poly-L-lactide-co-e-caprolactone(PLCL), polyglycolide, poly (2-hydroxy ethyl methacrylate), poly (N-vinyl pyrrolidone), poly (methyl methacrylate), poly (vinyl alcohol), Poly (acrylic acid), polyacrylamide, poly (ethylene-co-vinyl acetate), poly (ethylene glycol), poly (methacrylic acid) or combinations thereof.
10. The multi-layered coating as claimed in claim 5 wherein the antibacterial agent is selected from one of tobramycin, kanamycin, gentamicin, neomycin, streptomycin rifamycin, rifampin, cephaloridine, cephalexin, cefazolin, cephalothin, cephapirin, erythromycin, oleandomycin, spiramycin, penicillin G, penicillin V, oxacillin, methicillin, floxacillin, amoxicillin, tyrothricin, bacitracin, vancomycin, polymyxins, triclosan or combinations thereof.
11. The multi-layered coating as claimed in claim 5 wherein the analgesic agent is selected from one of ibuprofen, paracetamol, naproxen sodium, diclofenac sodium, celecoxib, rofecoxib, etoricoxib, indomethacin, naproxen, tramadol hydrochloride, dextropropoxyphe hydrochloride, triamcinolone, hydrocortisone, mometasone, dexamethasone, betamethasone, amcinonide, desonide, capsaicin analogues, lumiracoxib, ketamine, pregabalin, duloxetine, tapentadol, co-codamol, phenacetin, caffeine, oxycodone, aspirin, leflunomide, sulfasalazine, methotrexate, hydroxychloroquine or combination thereof.
12. The multi-layered coating as claimed in claim 5 wherein the solvent is selected from 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 combinations thereof.
13. The multi-layered coating as claimed in claim 1 wherein the second layer is eluted for a predefined time duration of 20 days to 90 days.
14. The multi-layered coating as claimed in claim 1 wherein the fourth layer is eluted for a predefined time duration of 2days to 14days. , 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:
MULTI-LAYERED COATING FOR A PROSTHETIC MENISCUS

2. APPLICANTS:
Meril Healthcare 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
[1] The present invention relates to a multi-layered coating for a medical implant, more specifically, the present invention relates to the multi-layered coating for a prosthetic meniscus.
BACKGROUND
[2] A human knee includes bones (femur, tibia and fibula), ligaments, cartilage, and menisci. A meniscus is a fibro-cartilaginous structure for separating two joint cavities. More specifically the meniscus is the central band of cartilage attached to the tibia. The band goes around the knee joint in a crescent-shaped path and is located between the medial condyles of the tibia and the femur. The meniscus reduces friction between bones and facilitates smooth movement of a bone over another adjacently placed bone. Beside knee, the meniscus is found in jaws, shoulders, clavicles and wrists.
[3] In certain cases, like an extreme physical activity, gaining of excess weight or a growing age can lead to traumatic injury or deterioration of the meniscus. Once torn, the natural meniscus does not heal easily. Due to damaged meniscus, positioning, cushioning or lubrication of the joint cavity is compromised. The range of motion and flexibility of the joint can also be restricted, which may lead to development of arthritis or permanent damage of the joint.
[4] Therefore, in order to heal the damaged meniscus, a replacement of damaged meniscus with the prosthetic meniscus can be done. The prosthetic meniscus can be manufactured in various shapes that can replace the natural meniscus of any joint, including, but not limited to, the knee, hip, elbow, shoulder, jaw, fingers and even the spine.
[5] However, implantation of the conventional prosthetic meniscus leads to extreme pain to a patient. Moreover, the said implant also carries a risk of infection at a treatment site. Hence, drug eluting meniscuses were designed to reduce/eliminate pain and the chances of infection. However, such conventionally existing prosthetic meniscus may be inefficient in mitigating the pain and infection at the treatment site due to several limitations such as the drug not being released by the said meniscus, coating of drug over such drug eluting prosthetic meniscus including an inappropriate surface roughness average (Ra) etc. The inappropriate surface roughness average (Ra) may hinder in-growth of the tissues and thereby, hamper healing process of the adjoining tissues. Thus, there exists a need for an improved prosthetic meniscus, that overcomes the deficiencies of prior art.
SUMMARY
[6] A multi-layered coating for a prosthetic meniscus includes a primary layer and a secondary layer applied on a prosthetic meniscus. The primary layer includes at least one anti-bacterial agent present in a concentration of 10% w/w to 30% w/w and at least one carrier present in a concentration of 60% to 90% dissolved in at least one solvent, while a secondary layer applied on the primary layer includes at least one analgesic compound present in a concentration of 10% w/w to 30% w/w and at least one carrier present in a concentration of 60% to 90% dissolved in at least one solvent. The primary layer and the secondary layer elute respective drug within a predefined time period. The primary layer and the secondary layer impart a composite surface roughness average on the surface of the secondary layer in a range of 4.0 µm to 12.0 µm.
[7] A multi-layered coating for a prosthetic meniscus includes a first layer, a second layer, a third layer, a fourth layer and a fifth layer. The first layer applied on a prosthetic meniscus includes at least one carrier present in concentration of 0.1 w/w to 90w/w dissolved in at least one solvent. The second layer applied on the first layer includes at least one anti-bacterial agent present in a concentration of 10% w/w to 30% w/w and at least one carrier present in a concentration of 60% to 90% dissolved in at least one solvent. The third layer applied on the second layer including at least one carrier present in concentration of 50% to 99 % dissolved in at least one solvent. The fourth layer applied on the third layer including at least one analgesic agent present in a concentration of 10% w/w to 30% w/w and at least one carrier present in a concentration of 60% to 90% dissolved in at least one solvent. The fifth layer applied on the fourth layer including at least one carrier present in concentration of 0.1 w/w to 90w/w dissolved in at least one solvent. The second layer and the fourth layer are the drug eluting layer, which elute respective drug within a predefined time period. The first layer, the second layer, the third layer, the fourth layer and the fifth layer impart a composite surface roughness average (Ra) on the surface of the fifth layer in a range of 3.0 µm to 22.0 µm
BRIEF DESCRIPTION OF THE DRAWINGS
[8] 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.
[9] Figure. 1. Illustrates a prosthetic meniscus from different views, in accordance with an embodiment of the present invention.
[10] Figure. 1a shows a schematic representation of a two layers coated prosthetic meniscus in accordance with an embodiment of the present invention.
[11] Figure. 1b shows a schematic representation of a five layer coated prosthetic meniscus in accordance with an embodiment of the present invention.
[12] Figure. 2. Illustrates a schematic representation of spray coating of the multi-layered coating over the prosthetic meniscus in accordance with an embodiment of the present invention.
DETAILED DESCRIPTION OF THE DRAWINGS
[13] Prior to describing the invention in detail, definitions of certain words or phrases used throughout this patent document will be defined: the terms "include" and "comprise", as well as derivatives thereof, mean inclusion without limitation; the term "or" is inclusive, meaning and/or; the phrases "coupled with" and "associated therewith", as well as derivatives thereof, may mean to include, be included within, interconnect with, contain, be contained within, connect to or with, couple to or with, be communicable with, cooperate with, interleave, juxtapose, be proximate to, be bound to or with, have a property of, or the like; Definitions of certain words and phrases are provided throughout this patent document, and those of ordinary skill in the art will understand that such definitions apply in many, if not most, instances to prior as well as future uses of such defined words and phrases.
[14] 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.
[15] In accordance with the present disclosure, a multi-layered coating is disclosed. The multi-layered coating may be provided over a medical implant. With reference to the present invention, the medical implant is a prosthetic meniscus.
[16] The prosthetic meniscus may be used to replace a damaged natural meniscus for a patient suffering from meniscus tear. The prosthetic meniscus may lead to restoration of normal function of knee joint. In an embodiment, the multi-layered coating reduces the chances of infection and/or pain due to implantation at the treatment site. In another embodiment, the multi-layered coating provides a textured surface which may allow the in-growth of nearby tissue and may improve the healing process of knee joint.
[17] The multi-layered coating may include at least two layers. In an embodiment, the multi-layered coating includes two layers i.e. a primary layer and a secondary layer. The primary layer is in direct contact with the prosthetic meniscus while the secondary layer is placed over the primary layer. The composition of the primary layer includes at least one antibacterial agent for example, triclosan, and at least one primary carrier, for example, poly-DL-lactide (PDL). The composition of the secondary layer includes at least one analgesic agent, for example, indomethacin and at least one secondary carrier, for example, poly-DL-lactide-co-glycolide (PDLG).
[18] In an alternative embodiment, the multi-layered coating includes five layers i.e. a first layer, a second layer, a third layer, a fourth layer and a fifth layer. The first layer is in direct contact with the prosthetic meniscus, while the other layers are consecutively placed over the first layer. The first layer includes at least one “first carrier”. In an embodiment, the first carrier is polyethylene glycol or its derivatives, polyvinyl alcohol, polyvinylpyrrolidone, carboxymethyl cellulose or its derivatives and their combination. The second layer includes at least one anti-bacterial agent and a “second carrier”. In an embodiment, the anti-bacterial agent is triclosan, while the second carrier is poly-DL-lactide (PDL). The third layer includes at least one “third carrier”. In an embodiment, the third carrier may include polycaprolactone (PCL), poly-DL-lactide-co-glycolide (PDLG), poly-L-lactide (PLA) or combinations thereof. The fourth layer includes at least one analgesic agent and a “fourth carrier”. In an embodiment, the analgesic agent is indomethacin, while the fourth carrier is poly-DL-lactide-co-glycolide (PDLG). The fifth layer includes at least one “fifth carrier”. In an embodiment, the fifth carrier may include polyvinylpyrrolidone (PVP), polyethylene glycol (PEG) or combinations thereof. The fifth layer, being the outermost layer, protects the multi-layered coating from damage during handling and storage of the prosthetic meniscus. Presence of adhesive (first layer) and/or protective layer (fifth layer) in the five-layer coating may prevent peeling of drug/layer during long term storage or transportation.
[19] The antimicrobial agent such as triclosan may fight against bacterial infections. Triclosan possesses antibacterial and antifungal property.
[20] Indomethacin may be used to achieve analgesia and/or relief from pain. Indomethacin treats pain, fever stiffness, swelling and inflammation at the treatment site after knee implant surgery.
[21] The above components of the multi-layered coating present in the predefined concentration as disclosed in following description, may affect the surface roughness average (Ra) of the prosthetic meniscus. In the present invention, the multi-layered coating over the prosthetic meniscus 100 imparts a surface roughness average (Ra) average in a range of 4µm to 12µm. The textured surface may allow tissue in-growth, thereby improving the healing process at the treatment site.
[22] The prosthetic meniscus along with the aforesaid multi-layered coating of the present invention is used to artificially support/separate/stabilize/cushion the joint cavity of the knee by controlled drug delivery at the treatment site with reduced or negligible chances of infection and pain.
[23] Now referring specifically to the figures, Figure.1 depicts a prosthetic meniscus 100. The present invention is related to the prosthetic meniscus 100.
[24] The prosthetic meniscus 100 coated with a therapeutic drug may be used to replace a damaged natural meniscus. In an embodiment, the prosthetic meniscus 100 goes around the knee joint in a crescent-shaped configuration. The prosthetic meniscus 100 may be designed to mimic the function of the natural meniscus and/or function as a shock absorber by adequate load distribution within the knee joint.
[25] In an exemplary embodiment of the present invention, the prosthetic meniscus 100 as shown in figure 1, has an upper surface 10, a lower surface 14 and a circumferential edge 12 (area indicated with vertical lines on the circumferential edges is coated as shown in Figure.1). The prosthetic meniscus 100 may be implanted in a knee, to replace naturally occurring meniscus between the joint cavities of the knee. The prosthetic meniscus 100 may be made of biocompatible, deformable, flexible and resilient material for bearing compressive loads.
[26] In an embodiment, the prosthetic meniscus 100 is made of a resilient plastic material UHMW-PE (Ultra High Molecular Weight Poly Ethylene). UHMW-PE has a characteristic of high-density polyethylene (HDPE) with an ability of resistance against concentrated acids and alkalis, as well as numerous organic solvents. It is highly resistant to corrosive chemicals and has an extremely low moisture absorption trait. Also, UHMW-PE possesses a very low coefficient of friction and is highly resistant to abrasion. The UHMW-PE is a subset of the polyethylene thermoplastic but with better abrasion resistance. UHMW-PE is an outstanding bearing material with exceptional sliding properties and remains tough even at low temperatures.
[27] The prosthetic meniscus 100 has a multi-layered coating 200 (as shown in figure. 1a and 1b) on the circumferential edges 12 of the prosthetic meniscus 100. The coating on the circumferential edges 12 may enhance efficiency of the prosthetic meniscus 100. Alternately, it is possible to provide coating on all the surfaces of the prosthetic meniscus 100. However, because the prosthetic meniscus 100 is sandwiched between tibia and femur, the overall coating on the surface of the prosthetic meniscus 100 may be damaged due to the friction during the movement within the knee joint. Therefore, the multi-layered coating 200 should be avoided on upper surface 10 and lower surfaces 14 of the prosthetic meniscus 100.
[28] Figure 1a of the present invention discloses the multi-layered coating 200. In an embodiment, the multi-layered coating 200 includes at least two layers. As shown in figure 1a, there are two layers i.e. a primary layer 201 and a secondary layer 203. The primary layer 201 may be in a direct contact with the circumferential edge 12 of the prosthetic meniscus 100 and the secondary layer 203 may be placed over the primary layer 201.
[29] The therapeutic drugs may include but not limited to anti-inflammatory agent, anti-bacterial agent, analgesic agent, antihistamines, steroidal or non-steroidal anti-inflammatory agents, matrix metalloproteinase (MMP) inhibitors, mucolytics, opioids, anti-proliferative agent, anticholinergics, antifungal agents, antiparasitic agents, antiviral agents, biostatic compositions, vasoconstrictors, and combinations thereof. In the present invention, the anti-bacterial agent and/or the analgesic agents are used as therapeutic drugs.
[30] The primary layer 201 may include at least one antibacterial agent and at least one primary carrier. In an embodiment, the ratio of the anti-bacterial agent(s) and primary carrier(s) used ranges between 50:50 to 20:80.
[31] The anti-bacterial agent used herein may include, but is not limited to aminoglycosides, such as tobramycin, kanamycin, gentamicin, neomycin, streptomycin; ansamycins, such as rifamycin, or rifampin; cephalosporins, such as cephaloridine, cephalexin, cefazolin, cephalothin, cephapirin; chloramphenicols; such as erythromycin, oleandomycin, or spiramycin; penicillins, such as penicillin G and V, oxacillin, methicillin, floxacillin, amoxicillin; polypeptides, such as tyrothricin, bacitracin, vancomycin, polymyxins, triclosan and likewise.
[32] The concentration of the anti-bacterial agent may be in a range of 10 wt% to 30 wt%. The drug dosage of the anti-bacterial agent may be in a range of 1.0µg/mm2 to 2.0µg/mm2.
[33] In an embodiment, the anti-bacterial agent is triclosan. The concentration of triclosan used herein may range from 10 wt% to 30 wt%. In an embodiment, the concentration of triclosan ranges from 17 wt% to 23 wt%. The dosage of triclosan in the present invention may range from 0.1µg/mm2 to 3µg/mm2. In an embodiment, the dosage of triclosan ranges from 1.0µg/mm2 to 2.0µg/mm2.
[34] The primary carrier used for controlled drug delivery may be chemically inert, free of leachable impurities and/or possess high solubility in solvent. The above set of features may allow easy, smooth and/or transparent coating on the surface of prosthetic meniscus 100. The concentration of the primary carrier in the primary layer 201 may range between 50 wt% to 99 wt%.
[35] The primary carrier(s) may include but not limited to, aliphatic polyesters, natural carriers for example poly(orthoesters), polyanhydrides, poly(aminoacids), polyphosphazenes, polyalkylcyanoacrylates, poly(ester-ether), poly(propylene fumarate) and poly(vinyl alcohol). poly-L-lactide (PLLA), poly-DL-lactide-co-glycolide(PLG), poly-D-lactide(PDLA), poly-DL-lactic (PDLA), poly-L-lactide-co-e-caprolactone(PLCL), polyglycolide, poly (2-hydroxy ethyl methacrylate), poly (N-vinyl pyrrolidone), poly (methyl methacrylate), poly (vinyl alcohol), Poly (acrylic acid), polyacrylamide, poly (ethylene-co-vinyl acetate), poly (ethylene glycol), poly (methacrylic acid) or their combinations.
[36] In an embodiment, the primary carrier is poly-DL-lactide (PDL). The concentration of the PDL may range from 60% to 90%. In an embodiment, the concentration of PDL is 80%. The inherent viscosity of PDL ranges from 0.1 dL/g to 1.0 dL/g
[37] In an alternate embodiment, a combination of PDL and PDLG is used as the primary carrier. In an embodiment, the ratio of poly-DL-lactide PDL to PDLG ranges from 80:20 to 20:80.
[38] The primary carrier in the primary layer 201 may regulate the release of the anti-bacterial agent(s) at the treatment site over a specified period of time. In an embodiment, the anti-bacterial agent is released for predefined time duration of 20 days to 90 days.
[39] The primary layer 201 may impart textured surface to the prosthetic meniscus 100. The textured surface of the prosthetic meniscus 100 may enhance tissue in growth leading to rapid healing of a knee joint. The textured surface may be estimated by surface roughness average (Ra). The surface roughness average (Ra) average of the prosthetic meniscus 100 after coating the primary layer 201 is in a range of 0.1 µm to 10.0 µm. In an embodiment, surface roughness average (Ra) average after coating the primary layer is in a range of 0.5 µm to 3.0 µm.
[40] The secondary layer 203 may include an analgesic agent and at least one secondary carrier. In an embodiment, the ratio of the analgesic agent(s) and secondary carrier(s) ranges between 30:70 to 20:80.
[41] The analgesic agents may include but not limited to non-steroidal anti-inflammatory drugs (NSAIDs), opioid analgesics, non-opioid analgesics and compound analgesics. The non-steroidal anti-inflammatory drug (NSAIDs) such as ibuprofen, paracetamol, naproxen sodium, diclofenac sodium, celecoxib, rofecoxib, etoricoxib, indomethacin and naproxen or their combination; opioids drugs containing codeine phosphate, tramadol hydrochloride, dextropropoxyphe hydrochloride and their derivatives; steroidal anti-inflammatory drug such as triamcinolone, hydrocortisone, mometasone, dexamethasone, betamethasone, amcinonide, desonide or their combination; non-opiod analgesics such as COX-2 inhibitors, capsaicin analogues, lumiracoxib, ketamine, pregabalin, duloxetine, tapentadol; compound analgesics such as co-codamol, phenacetin, caffeine, oxycodone, aspirin. Other therapeutic drug includes but not limited to leflunomide, sulfasalazine, methotrexate, or hydroxychloroquine.
[42] The concentration of the analgesic agent(s) may range between 10 wt% to 30 wt%. The drug dosage of the analgesic agent(s) may range between 3µg/mm2 to 5µg/mm2.
[43] In an embodiment, the analgesic agent is indomethacin. The concentration of indomethacin ranges between 15 wt% to 25 wt%. In an embodiment, the concentration of indomethacin ranges from 17 wt% to 23 wt%. The dosage of indomethacin ranges from 0.1µg/mm2 to 10µg/mm2. In an embodiment of the multi-layered coating 200, the dosage of indomethacin ranges from 3µg/mm2 to 5µg/mm2.
[44] The analgesic agent in the present invention may reduce pain, joint swelling, and duration of morning stiffness at the treatment site after knee implant surgery; and also improves strength and mobility of the knee joint. The analgesic agent for example, indomethacin may be used as it is a non-steroidal anti-inflammatory drug (NSAID).
[45] The analgesic agent (s) in the secondary layer 203 may be required to be released immediately after the prosthetic meniscus 100 is implanted at the treatment site as after a knee implant surgery, a patient might experience severe pain for 12 hours to 3 days. The secondary carrier may facilitate release of the analgesic agent. In an embodiment, the analgesic agent is released for a predefined time duration of 2 days to 14 days. In an embodiment, the prosthetic meniscus 100 is capable of providing sustained release of analgesic agent post knee implantation surgery into the synovial fluid at the treatment site.
[46] The secondary carrier may be same as the primary carrier. The secondary carriers may be selected as provided in the description above. It may be noted that features of the secondary carrier like examples of secondary carriers, ratio of the secondary carrier(s) to analgesic agent(s) (the ratio will be same as ratio of primary carrier and antibacterial agent), etc., may be referred from the description of primary carrier(s) and has not been repeated for brevity.
[47] In an embodiment, the secondary carrier is poly-DL-lactide-co-glycolide PDLG. The concentration of the PDLG may range from 60% to 90%. In an embodiment, concentration of PDLG is around 80%. The inherent viscosity of PDLG ranges from 0.1 dL/g to 1.2 dL/g.
[48] The surface roughness average (Ra) of the prosthetic meniscus 100 after coating the secondary layer 203 may be in a range of 1.0 µm to 8.0 µm. In an embodiment, the surface roughness average (Ra) may vary in a range of 2.0 µm to 6.0 µm.
[49] In another embodiment, the composite surface roughness average (Ra) due to coating of primary layer 201 and the secondary layer 203 on the surface of secondary layer 203 may be in a range of 0.1 µm to 15.0 µm. In an embodiment, the composite surface roughness average (Ra) on the surface of secondary layer 203 is in a range of 4.0 µm to 12.0 µm.
[50] In an alternative embodiment as shown in figure.1b, the multi-layered coating 200 includes five layers i.e. a first layer 205, a second layer 207, a third layer 209, a fourth layer 211 and a fifth layer 213, consecutively placed with respect to each other. In an embodiment, the multi-layered coating 200 as represented in Figure. 1b includes a single drug (antibacterial agent and analgesic agent), a carrier in each layer or combination thereof.
[51] It may be noted that specific features like examples of therapeutic drug and carrier, inherent viscosity of carrier, amount of therapeutic drug and carrier and the ratio of combination of the carriers may be referred from the embodiment mentioned above and has not been repeated for brevity.
[52] The first layer 205 may be in a direct contact with the prosthetic meniscus 100, while the other layers may be consecutively placed over the first layer 205. The first layer 205 may include at least one first carrier. In an embodiment, the first carrier includes at least one of polyethylene glycol or its derivatives, polyvinyl alcohol, polyvinylpyrrolidone, carboxymethyl cellulose or its derivatives and their combination. The second layer 207 may include at least one anti-bacterial agent and a second carrier. In an embodiment, the anti-bacterial agent is triclosan, while the second carrier is poly-DL-lactide (PDL). The third layer 209 may include at least one third carrier. In an embodiment, the third carrier includes polycaprolactone (PCL), poly-DL-lactide-co-glycolide (PDLG), poly-L-lactide (PLA) or combinations thereof. The fourth layer 211 may include at least one analgesic agent and a fourth carrier. In an embodiment, the analgesic agent is indomethacin, while the fourth carrier is poly-DL-lactide-co-glycolide (PDLG). The fifth layer 213 may include at least one fifth carrier. In an embodiment, the fifth carrier is at least one of polyvinylpyrrolidone (PVP), polyethylene glycol (PEG) or combinations thereof. The fifth layer 213, being the outermost layer may protect the multi-layered coating 200 from damage during handling and/or storage of the prosthetic meniscus having the multi-layered coating 200.
[53] In an exemplary embodiment, the first layer 205 includes the first carrier. The first layer 205 may include at least one of polyethylene glycol or its derivatives, polyvinyl alcohol, polyvinylpyrrolidone, carboxymethyl cellulose or its derivatives and their combination. The concentration of “first carrier” used herein may range from 0.1 wt% to 90 wt%. In an embodiment, “first carrier” includes polyethylene glycol or polyvinylpyrrolidone.
[54] In an exemplary embodiment, the second layer 207 includes the anti-bacterial agent and the second carrier. In an embodiment, the anti-bacterial agent is triclosan and the second carrier is poly-DL-lactide (PDL). The concentration of triclosan may range from 10 wt% to 30 wt% and the concentration of poly-DL-lactide may ranges from 60 wt% to 90 wt%. In an embodiment, the concentration of triclosan ranges from 17 wt% to 23 wt% and the concentration of poly-DL-lactide ranges from 70 wt% to 90 wt%.
[55] The dosage of triclosan used herein may range from 0.5µg/mm2 to 2.5µg/mm2. In an embodiment the dosage of triclosan is in a range of 1.0µg/mm2 to 2.0µg/mm2.
[56] In an exemplary embodiment, the third layer 209 includes at least one “third carrier”. The “third carrier” may include polycaprolactone (PCL), poly-DL-lactide-co-glycolide (PDLG), poly-L-lactide (PLA) or combinations thereof. In an embodiment, the third carrier used herein is polycaprolactone (PCL), poly-DL-lactide-co-glycolide (PDLG), poly-L-lactide (PLA) or combinations thereof. The concentration of “third carrier” used herein may range from 50% to 99%. In an embodiment, the concentration of “third carrier” used is in a range of 60 wt% to 90 wt%.
[57] In an exemplary embodiment, the fourth layer 211 includes the analgesic agent and the fourth carrier. In an embodiment, the analgesic agent is indomethacin and the fourth carrier is poly-DL-lactide-co-glycolide (PDLG). The concentration of indomethacin used herein may range from 10 wt% to 30 wt%, while the concentration of PDLG may range from 60 wt% to 90 wt%. In an embodiment, the concentration of indomethacin is in a range of 17 wt% to 23 wt% and the concentration of the PDLG is in a range of 70 wt% to 90wt%.
[58] Further, the dosage of indomethacin ranges from 1µg/mm2 to 5µg/mm2. In an embodiment, the dosage of indomethacin ranges from 3µg/mm2 to 5µg/mm2.
[59] In an exemplary embodiment, the fifth layer 213 includes at least one “fifth carrier”. The “fifth carrier” may include polyvinylpyrrolidone (PVP), polyethylene glycol (PEG) or combinations thereof. In an embodiment “fifth carrier” includes polyvinylpyrrolidone (PVP) or polyethylene glycol (PEG). The concentration of “fifth carrier” used herein ranges from 0.1% w/w to 90 % w/w.
[60] The composite surface roughness average (Ra) due to multi-layered coating 200 (five-layer coating) on the surface of the fifth layer 211 may be in a range of 0.5 µm to 30.0 µm. In an embodiment, The composite surface roughness average (Ra) due to multi-layered coating 200 (five-layer coating) on the surface of the fifth layer 211 may be in a range of 3.0 µm to 22.0 µm
[61] The fifth layer 213, being the outermost layer, protects the multi-layered coating 200 from damage during handling and storage of the prosthetic meniscus.
[62] In an embodiment, the anti-bacterial agent from the second layer 207 is released for predefined time duration of 20 days to 90 days. In another embodiment, the analgesic agent from the fourth layer 211 is released for predefined time duration of 2 days to 14 days.
[63] The aforesaid coating formulation of the multi-layered coating 200 may include at least one therapeutic drug and/or at least one carrier dissolved in a solvent. In various embodiments, different solvents are used for different coating formulations. The solvent may include, but not limited to, 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 combinations thereof. Highly volatile and less toxic solvent is advantageous as it get evaporates easily and minimum amount of residual solvent remains after coating and post processing. In the present embodiment, dichloromethane is used as a solvent.
[64] The multi-layered coating 200 may be accomplished by various available coating methods. For example sputtering, spray coating, plasma coating, dip coating, vapor deposition, spin coating, electro-spin coating. In preferred embodiment, the spray coating is used for multi-layered coating 200 on the surface of prosthetic meniscus 100 as shown in Figure. 3.
[65] The spray coating parameters include the amount of coating formulation, a distance between spray gun 302 and the prosthetic meniscus 100, a collate 310, a nitrogen gas pressure 304 and solution flow rate. The above parameters for the spray coating play a vital role in achieving a uniform coating of desired thickness on the prosthetic meniscus 100. The prosthetic meniscus 100 is fitted on the fixture 306 (supported by a stand 308) which only exposes a particular surface area on which the therapeutic drug coating is desired. For achieving the uniform coating on specific area of the prosthetic meniscus 100, fixture or mold is made using teflon, stainless steel, polyethylene and others materials by injection molding or 3D printing technology.
[66] The parameters are set to form a thin, uniform and/or smooth coating over the prosthetic meniscus 100 surfaces. Subsequently, the multi-layered coating 200 over the prosthetic meniscus 100 is kept under vacuum for 10-12 hours to evaporate the residual solvent. The process is performed in a clean room environment (class 10000) to avoid the interference of the temperature and moisture during the spray coating. The temperature and humidity of clean room is maintained at 22±3°C temperature and 45%, respectively.
[67] The components of the multi-layered coating 200 are present in the predefined concentration as disclosed above, which may affect the surface roughness average (Ra) of the prosthetic meniscus 100. The surface roughness average is measured by forward and backward movement of a stylet over a particular length of the prosthetic meniscus 100 at a definite pressure.
[68] The surface roughness average (Ra) of an uncoated prosthetic meniscus 100 may be in a range of 0.1µm to 1.0µm. In an embodiment, the composite surface roughness average (Ra) of the multi-layered coating 200 (two-layer coating) is 4.0 µm to 12.0 µm and the composite surface roughness average (Ra) of the multi-layered coating 200 (five-layer coating) ranges from 3.0µm to 22.0 µm.
[69] The surface roughness average (Ra) mentioned in the above range provides a textured surface to the multi-layered coating 200. The textured surface allows the tissue in-growth, thereby improving the healing process at the treatment site. The surface texture of the multi-layered coating 200, affect’s the integration of bone by osseointegration process.
[70] The present invention will be further understood by reference to the following non-limiting examples.
[71] Example 1:- A known coating formulation (prior art) was made by dissolving 58.53wt% PDL and 41.47wt% triclosan in dichloromethane for coating a layer over the prosthetic meniscus and to observe the obtained surface roughness average (Ra). The aforesaid coating formulation was coated on the prosthetic meniscus by spray coating. The resultant coating layer on the surface of the prosthetic meniscus was non-uniform and had minor flakes. The non- uniform coating leads to uneven distribution of therapeutic agent at the site of treatment. The minor flakes reduce drug availability at the treatment site, due to the removal of the coating during implantation of the prosthetic meniscus therefore results in less efficient treatment. The surface roughness average (Ra) of the prosthetic meniscus ranges from 18 µm to 25 µm, and hence there was a need for further reduction of the surface roughness average (Ra).
[72] Example 2:- The spray coating is applied in two layers, i.e., the primary layer and the secondary layer. The coating formulation of the primary layer included 50 wt% of PDL and 50 wt% of triclosan in dichloromethane. The coating formulation of the secondary layer included 50 wt% of PDLG and 50 wt% of indomethacin in dichloromethane. The resultant coating layer on the surface of the prosthetic meniscus is powdery and sticky. Due to the powdery coating, the therapeutic agent may tend to release from the coating surface during storage, transportation and handling. Therefore, the prior release of the therapeutic agent reduces the efficiency of rapid healing at the treatment site. The prosthetic meniscus with sticky coating results in formation of lumps and/or reduces therapeutic agent uptake at the treatment site. The surface roughness average (Ra) of the prosthetic meniscus after coating the primary layer and the secondary layer ranges from 18 µm to 25 µm and hence there was a need for further reduction of the surface roughness average (Ra).
[73] Example 3:- The coating formulation of example 2 is further used with certain modification. The ratio of the carrier and therapeutic drug in both the coating formulations was revised to 80:20. After coating, the surface of the prosthetic meniscus was found to be transparent, non-sticky and smooth. The surface roughness average (Ra) of coated surface ranged from 4µm to 12µm. With the said coating formulation, better coating integrity, non-stickiness and uniform coating was observed.
[74] 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.