Title of Invention

"ANTIMICROBIAL GRAFTED POLYPROPYLENE SUTURE"

Abstract

The present invention relates to polypropylene monofilament grafted with 1-vinylimidazole monomer in a solvent by simultaneous radiation grafting method to obtain polypropylene- grafted vinylimidazole suture of formula (1), followed by immobilization of drug onto the suture of formula (1) to obtain antimicrobial polypropylene grafted suture. The invention also relates to the report of a new suture of formula (1) and further relates to the process of preparation of said anti microbial grafted polypropylene suture.

Full Text

Antimicrobial Grafted Polypropylene Suture Field of the invention The invention relates to antimicrobial polypropylene grafted sutures particularly relates to the report of a new suture of formula (1). The present invention also relates to polypropylene monofilament grafted with 1- vinylimidazole monomer in a solvent by radiation grafting method to obtain polypropylene grafted polyvinylimidazole suture of formula (1) followed by immbolization of drug onto the suture of formula (1) to obtain antimicrobial (polypropylene- grafted-polyvinylimidazole)-drug composite suture. The invention further relates to the process of preparation of said antimicrobial (polypropylene-grafted-poly vinylimidazole)-drug composite suture. Background and Prior art of the invention The wound care is an important aspect in today's scenario which combines the comfort with the proper healing of the wound together. In many of the countries, the infection develops in the wounds a little later when a stich is applied. The invention relates to the development of a suture that may offer advantages over the present sutures in terms of the prevention of infection during stitching period. Application of polypropylene as a suture material has long been known in the medical textile industry. Prolene sutures are available in the market, made up of polypropylene. This suture has certain advantages over other sutures that it has inert nature and least tissue reactivity. Owing to its response as a foreign material to the body tissue, as well as the bacterial contamination at the site of its application, it can evoke the tissue reaction like inflammation, redness, swelling and wound infection that may lead to even the reopening of wound. Such discrepancies are more likely when there is no proper post-operation care and where wound closures are carried out in a non-sterilized environment. In several of the countries, such as in Asian countries the post-operation care is very little and bacterial infection is very prominent. However, there is no suture commercially available that may offer antimicrobial activity. Our previous work explains the use of radiation grafting of 2-hydroxyethylmethacrylate monomer onto polypropylene filament so that the antimicrobial drug such as 8-hydroxyquinoline may be immobilized on top of it (Gupta et al. J. Macromol. Sci., 30, 303 (1993). and J. Macromol. Sci., 27, 831 (1990)). Gupta et al. Indian Patent, 190584 describes antimicrobial suture based on nylon filament developed by blending with the polyvinylpyrrolidone-iodine complex. However, the suture loses substantial strength in the fabrication process. Moreover, nylon sutures are known for having low knot security. The polypropylene suture offers better mechanical strength and knot security as compared to the nylon sutures. Zhili et al. Europ Polym J., 29, 301(1993) and 11, 1435 (1993); and Han et al J.AppI Polym Sci., 70, 1977 (1998) describes grafting of 1-vinylimidazole on polyethylene and Teflon-FEP films. The Zhili's work is to investigate the mechanism of the grafting reaction. The Han's work is to modify the polyethylene films to enhance the lamination with copper foils. Moreover the grafting was carried out by plasma exposure. The Naguib work is again to graft a mixture of two monomers and introduce dyeability in the PP. Naguib et al Polymer Testing 22, 825 (2003) describes grafting of vinylimidazole and acrylic acid monomer mixture onto polypropylene films. The process adopted utilizes monomer mixture in dioxane as the medium for grafting. The objective of this citation is to increase the dyeability of the polypropylene film which is very different from the objective of the present invention. Also, this prior art uses mixture of monomers for grafting whereas the present invention uses exclusively 1-vinylimidazole monomer in a suitable solvent medium to obtain polypropylene-grafted-polyvinylimidazole suture as a base for antimicrobial polypropylene grafted suture. The prior art describes sutures which can also form the base to prepare anti microbial sutures, but the sutures obtained will still be associated with the following limitations:- a) Poor mechanical strength and knot security of sutures. b) Immobilization restricted to limited class of drugs on sutures. In order to overcome the above limitations, Applicant has developed a polypropylene grafted suture by adopting the step of grafting of polypropylene monofilament with 1-vinylimidazole monomer to obtain polypropylene-grafted-polyvinylimidazole suture and subsequently immobilizing the antimicrobial drug onto the PP-grafted suture to provide antimicrobial PP-grafted suture, which prevents infection at the implanted site. Thus, modification of polypropylene suture through a grafting technique using a reactive and suitable monomer followed by the immobilization of drug could be one of the main routes to overcome these problems. The process that has been used for the modification of the polypropylene suture is radiation grafting and has been known since long time. The pre irradiation grafting of monomers has also been used to modify the polymers for different applications. The radiation grafting is able to introduce desirable properties in a polymer without much influencing its inherent characteristics. The modified suture of the present invention offers sites which provide binding of hydrophilic and ionic drug molecules. Once the drug loaded suture comes in contact with the tissue, the suture having hydrophilic character releases the drug onto the surrounding tissues thereby preventing bacterial invasion. The development of a antimicrobial suture is a new concept and reality. Not a single biostable suture is available in the market. The work that has been published earlier is on PP grafting of HEMA on PP filament which is capable of immobilizing only hydrophilic drugs. The nylon suture has been made by the blending process. The blending is a process where two polymers may be combined by physical interaction. In the grafting, a covalent bond exists between the two polymeric components. The nylon suture was developed by blending nylon with polyvinylpyrrolidone-iodine complex. Objects of Invention: Main object of the invention is to provide antimicrobial polypropylene grafted sutures. An object of the invention is to provide polypropylene mono filament grafted with vinylimidazole monomer. Yet another object of the invention is to provide antimicrobial grafted PP suture which releases the drug in the surrounding tissues, Still yet another object of the invention is to provide an efficient process for the preparation of polypropylene grafted polyvinylimidazole suture, Yet another object of the invention is to provide an efficient process for the immobilization of drug onto polypropylene grafted polyvinylimidazole sutures, Still another object of the invention is to provide an efficient process for obtaining antimicrobial grafted polypropylene sutures, Still yet another object of the invention is to provide PP grafted sutures possessing better mechanical strength and knot security. Yet another object of the invention is to provide polypropylene grafted polyvinylimidazole suture enabling immobilization of wider class of drugs. Summary of the invention The invention relates to antimicrobial polypropylene grafted sutures. The invention also relates to a process of the preparation of the said sutures by grafting into polypropylene filament suture 1-vinylimidazole monomer under Co60 radiation dose rate of 0.2 kGy/h and a radiation dose of 5-100 kGy by simultaneous irradiation method in presence of solvent to obtain polypropylene-grafted-polyvinylimidazole suture of formula (1), followed by immobilizing the antimicrobial drug onto the suture of formula (1) to obtain antimicrobial (polypropylene-grafted-polyvinylimidazole)- drug composite suture. Detailed description of the invention: Accordingly the present invention provides an antimicrobial polypropylene-grafted- poly vinylimidazole suture of formula (I) (Formula removed) An embodiment of the present invention provides a suture with immobilized drug to obtain (polypropylene-grafted - poly vinylimidazole) - drug composite suture Another embodiment of the present invention provides a suture immobilized with antimicrobial drug., Yet another embodiment of the present invention wherein the antimicrobial agent used is selected from a group consisting of ciprofloxacine, tetracycline hydrochloride, 8-hydroxy quinoline, benzoic acid or its pharmaceutically acceptable salts. Still another embodiment of the present invention provides an antimicrobial suture which is effective against infection caused by E.Coli, K.pneumonia and S. aureus. Still yet another embodiment of the present invention provides a suture of formula (1) having tensile strength ranging between 2.8 to 4.2 gpd. Yet another embodiment of the present invention provides a suture of formula (1) having knot strength in the range of 2.0 to 3.4gpd. Another embodiment of the present invention provides a process for the preparation of polypropylene-grafted-polyvinylimidazole-drug composite suture comprising steps of: a) preparing polypropylene monofilament suture by melt spinning of the polypropylene polymer using an extruder, b) grafting the suture of step (a) with 1-vinylimidazole monomer using Co60 radiation under radiation doses ranging between 5kGy to 100kGy in a solvent to obtain polypropylene-grafted-polyvinylimidazole suture , c) Immobilising the drug on to the polypropylene grafted suture of step(b),and d) obtaining (polypropylene-grafted- poly vinylimidazole)-drug composite suture of claim2 Still another embodiment of the present invention uses solvent for grafting selected from a group consisting of water, methanol, acetone and/or mixtures thereof. The polypropylene monofilament suture was prepared by melt spinning of the polymer using an extruder. The filament preparation was carried out in such a way that the filament matches with the commercial prolene suture in its characteristics such as diameter and strength and in addition offers antimicrobial nature. The radiation grafting into polypropylene suture was carried out with a 1-vinylimidazole monomer using a Co60 radiation under radiation at a dose rate of 0.2 kGy/h using simultaneous irradiation method. Polypropylene suture and the vinyl imidazole monomer is irradiated under nitrogen atmosphere with gamma radiation for sufficient time to achieve sufficient graft levels. The grafting was investigated under different monomer concentrations in a suitable solvent medium as diluent. Other diluents such as methanol and the acetone were also investigated. The variation in the nature of additives was also investigated. The grafting up to 38% is achieved under adopted grafting procedures. The various properties of the monomer were evaluated such as crystalline nature, tensile strength and knot security and surface morphology etc. (Figure removed) The following examples further illustrate the embodiments within the scope of the present invention. The examples are given solely for the purposes of illustrations and not to be construed as limitations of the present invention as many variations are possible without departing from its scope. Examples: Example 1 - General Procedure a) Preparation of Polypropylene monofilament suture: The polypropylene monofilament suture is prepared by melt spinning of the polymer using an extruder. (b) Grafting method: The polypropylene monofilament is grafted with 1-vinylimidazole monomer by simultaneous radiation grafting method. The polypropylene filament is placed in a reaction tube and the vinylimidazole monomer in a solvent is added to this tube. The tube is subsequently placed in the Gamma chamber The reaction is carried out for specific period and the filament is taken out. The grafted suture was cleaned by soxhlet extraction in the water for 6 h so that the homopolymer is separated out. The grafted PP suture is then dried in oven at 60°c under vacuum and the degree of grafting is measured by percentage increase in the weight of the starting PP suture. A classical example of how the grafting is influenced by reaction conditions is shown below. Following figure shows the effect of monomer concentration of the degree of grafting where a maximum is obtained at 30% vinyl imidazole. However, an innmase in the temperature may used to enhance the graft levels. (Figure removed) (c) Drug immobilization: The grafted PP sutures of(b)are immersed in a 20 % aqueous solution of tetracycline hydrochloride for 24 h. The samples are taken out, washed thoroughly with distilled water and dried under vacuum at 40°C for 2 h. The percent add on of the drug is calculated by the following expression. (Figure removed) where, Wd is the weight of the drug immobilized sample and W, is the weight of the sample before immobilization. (d) Antimicrobial Activity (in vitro): Nutient Agar plates is prepared by dissolving 31 gms of readymade Muller Hinton agar (Hi Media Laboratories, Mumabai) in 1 litre water and the pH is adjusted to 7.3±0.2. The contents are sterlised by autoclaving at 15 lbs pressure (121C) for 30 minutes. The media when still hot, is poured in sterile petriplates (approximately 20 ml), and were allowed to coll so that the agar solidified. The composition of nutrient agar medium is beef extract 3 gm/litre, peptone 5 gm/litre, NaCI 8gm/ litre and agar 15gm/ litre. The antimicrobial properties of the drug loaded sutures are assesed against E. coli, K. pneumonia and S. aureus. Nutrient agar plates were prepard and a lawn of bacteria were laid over the plate using a sterile cotton swab. A weighed amount of drug immobilized suture is placed on the plate using sterile forcep. An unmodified suture is palced in each plate as control. The plates are incubated at 37°C for 24 h and the clear zone around the sample was measured the next day as a measure of antimicrobial activity of the drug loaded suture. (e) Animal Studies(in vivo): The resistance of modified sutures to infection against S. aureus is studied in vivo on albino rats. Sutures are stiched on approximately 2.5 cm area parallel and equidistant from vertebral column after shaving and sterlizing it with 70 % ethyl alcohol. The designated number of bacteria is injected into the tissue around the middle of each suture. The number of bacteria at the implantation site varied in the range of 104-105. The sutures are analyzed for infection growth on 1st and 3rd post operative day of suturing. Some of the drugs that may be used for the immobilization are as follows. Ciprofloxacin, 8-hydroxyquinoline, Tetracycline, Benzoic acid or its pharmaceutically acceptable salts. Example 2 PP filament and the monomer 1-vinylimidazole are exposed to 29 KGy radiation from a Co-60 source. The vinyl imidazole grafting on PP filament is carried out at 5-60% monomer concentration in water at 60°C for a period of 6h. The graft yield is 2-26%. Example 3 PP filament and the monomer 1-vinylimidazole are exposed to 5-100KGy radiation from a Co-60 source. The vinylimidazole grafting on PP filament is carried out at 5-60% monomer concentration in water at 60°C for a period of 6h. The graft yield is 2-34%. Example 4 PP filament and the monomer 1-vinylimidazole are exposed to 29KGy radiation from a Co-60 source. The vinyl imidazole grafting on PP filament is carried out at 60% monomer concentration in water at 80°C for a period of 6h. The graft yield is 38%. Example 5 PP filament and the monomer 1-vinylimidazole are exposed to 29KGy radiation from a Co-60 source. The vinyl imidazole grafting on PP filament is carried out at 60% monomer concentration in water/methanol mixture (80:20) at 60°C for a period of 6h. The graft yield is 6%. Example 6 PP filaments with a graft level of 2-38% are evaluated for the tensile strength and knot strength. The PP grafted sutures has a tensile strength in the range of 2.8 to 4.2gpd and a knot strength in the range of 2.0-3.4gpd. Example 7 PP filaments are used for immobilizing the antimicrobial drug and the drug could not be immobilized. Example-8 PP filaments with a graft level of 2-38% are immobilized with fluoroquinolone class of drug (ciproflaxin). The PP grafted sutures has the drug loading upto 0.4-7.4%. Example 9 PP filaments with a graft level of 12% and the Ciprofloxacin loading of 3 mg/g is studied for drug release. The observations showed that the E. coli infection originated in unmodified sutures but the modified sutures did not show any infection. ExamplelO PP filament grafted with 1-vinylimidazole suture without immobilization of drug is tested and found ineffective against E.coli infection. Example11 PP filaments with a graft level of 12% and the Ciproflaxacin loading of 3 mg was subcutaneousiy implanted in mouse. The bacterial growth at the implanted site was found to be negligible suggesting that the suture offers protection against infection. The release behavior of the drug is shown in the following figure, where bacterial growth is prohibited in specific area. (Figure removed) Main advantages 1) The invention provides an antimicrobial polypropylene grafted suture for preventing bacterial and fungicidal invasion; 2) The invention provides a sutures with better mechanical and knot security; 3) The invention provides radiation grafting as a unique process for suture development as it introduces the desired properties in the suture without much affecting the inherent properties. 4) The vinylimidazole grafted polypropylene suture provides excellent site for drug immobilization.The nitrogen lone pair provides electron density for the interaction with the drugs. 5) The immobilized suture shows drug release for 4 days and offers the antimicrobial activity 6) The invention provides simple process for the preparation of suture without any side reaction during fabrication steps. 7) The invention provides a suture with anti microbial property having enhanced drug mobilization capacity. We claim 1. A polypropylene-grafted-ploy vinylimidazole suture of formula (I) (Formula Removed) 2. A suture of claim 1 further comprising an immobilized drug to obtain polypropylene-grafted-poly vinylimidazole-drug composite suture. 3. A suture of claim 2, wherein the drug is antimicrobial agent, 4. A suture of claim 3, wherein the antimicrobial agent is selected from the group consisting of ciproflozxacine, tetracycline hydrochloride, 8-hydroxy quinoline, benzoic acid or its pharmaceutically acceptable salts. 5. A suture of claim 2 is effective against infection caused by E. Coli, K. pneumonia and S. aureus. 6. A suture of claim 1 having tensile strength in the page of 2.8 to 4.2 gpd. 7. A suture of claim 1 having knot strength in the range of 2.0 to 3.4 gpd. 8. A process for the preparation of suture of claim 2, the said process comprising steps of: a) preparing polypropylene monofilament suture by melt spinning of the polypropylene polymer using an extruder, b) grafting the suture of step (a) with 1-vinylimidazole monomer using Co60 radiation under radiation doses ranging between 5kGy to 100kGy in a solvent to obtain polypropylene-grafted-polyvinylimidazole suture, c) immobilising the drug on to the polypropylene grafted suture of step (b), and d) obtaining (polypropylene-grafted-poly vinylimidazole) - drug composite suture of claim 2 9. A process of claim 8 wherein step (b) solvent is selected from a group consisting of water, methanol, acetone and / or mixtures thereof 10. A process of claim 8, wherein in step (c) the drug is an antimicrobial agent. 11. A process of claim 8 wherein, the antimicrobial agent is selected from a group consisting of Ciprofloxin, Tetracycline, 8-hydroxyquininoline, benzoic acid or its pharmaceutically acceptable salts. 12. A process of claim 8, wherein in step (d) the suture obtained, is effective against infection caused by E. Coli, K. pneumonia and S. aureus. 13. An antimicrobial polypropylene grafted poly vinylimidiazole-drug composite suture substantially as herein described in the specification and with illustrative examples. 14. A process for the preparation of an antimicrobial polypropylene grafted poly vinylimidiazole-drug composite suture as herein described in the specification and with lustrative examples.

Documents:

1049-DEL-2004-Abstract-(05-03-2012).pdf

1049-del-2004-abstract.pdf

1049-DEL-2004-Claims-(05-03-2012).pdf

1049-del-2004-claims.pdf

1049-DEL-2004-Correspondence Others-(05-03-2012).pdf

1049-DEL-2004-Correspondence Others-(15-02-2012).pdf

1049-del-2004-correspondence-others.pdf

1049-del-2004-description (complete).pdf

1049-del-2004-form-1.pdf

1049-del-2004-Form-13 (05-03-2012).pdf

1049-del-2004-form-18.pdf

1049-del-2004-form-2.pdf

1049-del-2004-form-26.pdf

1049-del-2004-form-3.pdf

1049-del-2004-form-5.pdf

1049-DEL-2004-GPA-(15-02-2012).pdf