TRIPLE ACTION CONCOCTION FOR THE COMPLETE POSTOPERATIVE MANAGEMENT AFTER PARTIAL OR TOTAL KNEE REPLACEMENT AND PROCESS FOR PREPARATION THEREOF

FIELD OF THE INVENTION

The present invention relates to a drug delivery system. More particularly, the present invention relates a biocompatible and biodegradable delivery system for the management of post-operative complications such as pain, infection, inflammation and uncontrolled bleeding, comprising a formulation of biodegradable and biocompatible polymer preferably chitosan loaded with a plurality of drug.

BACKGROUND OF THE INVENTION

Annually 200,000 knee replacements surgeries are performed in India and several million worldwide with growth rate expected of more than 600% over the next 20 years. However, many patients are not willing to do surgery, basically due to risks involved; fear of surgery, prolonged recovery period and most important complications associated with joint replacement surgery, including pain, infections and implant failure. In fact, repeat or corrective revision surgeries due to these causes are estimated to grow also by over 600%. Pain, Inflammation, and Infection (PII) plus uncontrolled bleeding are the major concerns for the surgeons and patients; due to increased hospital stay, there is increased cost of procedure; increased anxiety as well as depression, and economic hardship to patients and family.

Pain is one of the major reasons responsible for dissatisfaction and readmission of patients after surgery. According to Joint commission on accreditation of healthcare organization, Pain is the“fifth vital sign” and it is recognized that patients have a“right” to have satisfactory pain management. Poorly managed pain can lead to psychological, cardiac, respiratory, gastrointestinal problems, delayed wound healing and hyper-coagulable state.

A certain extent of inflammation is necessary for the wound healing process but after certain limits it leads to complications such as pain, swelling, cells and tissue infiltration leading to stiffness, wound drainage etc. that will delay the recovery of patient. Steroids are most commonly used for the treatment of inflammation occurring after surgery, but this is not sufficient to combat the inflammation for long term. At the same time, it results in immune- suppression thus may lead to implant rejection. Inflammation will also reduce the effectiveness of local anesthetics like bupivacaine. Thus, control of inflammatory signs after surgery is an important task to ensure complication-free recovery of patient.

Infection is the most feared complication after replacement surgery due to the biofilm formation leading to loosening of implant; revision surgery has to be done that will double the cost of treatment. The estimated cost of infected revision surgery is projected to be as high as $1.6 billion by 2020.

All of these surgical techniques require proper post-operative care for the timely and complication-free recovery of patients.

Due to above complications and challenges, the original purpose of surgery may get deviated or may not be achieved leading to increased morbidity and mortality. Considering this fact, millions of patients undergoing any major or minor surgery require optimum and proper pre- and post-operative care for both early and long-term recovery. Traditionally, peri and post operative pain is treated using patient controlled analgesia, parenteral narcotics, indwelling peripheral nerve catheters and continuous epidural injection. In peri and post-operative management large doses of antibiotics (usually administered orally or intravenously) are given as treatment. However, long-term administration of oral or intravenous antibiotics may lead to a risk of antibiotic resistance and toxicity. Further, nerve blocks and continuous epidurals are superior to patient controlled analgesia but still have some disadvantages like immobility, diminished muscle control, as well as hypotension, nerve damage, missed compartment syndromes and urinary retention.

Parenteral narcotics can be associated with significant adverse effects such as nausea, vomiting, dizziness, constipation and respiratory depression. To avoid this complication intra- articular injections have been implicated for targeted pain and inflammation control and to minimize systemic side effects. But it has drawbacks due to its short-lived action such as suboptimal control of pain and inflammation. Along with this, direct intra-articular injection of opiod and narcotics results in necrosis and tissue damage that will hinder the blood and nutrient supply causing fibrous tissue formation and complicated wound healing process. Infection is the major concern for the surgeons and researchers because it may call for revision surgery.

Antibiotic-loaded bone cement is the gold standard for drug-eluting local delivery devices. Low-dose premixed cements such as Cobalt ^™ G-HV, Palacos ^® G, DePuy 1, CMW, Cemex ^®

Genta, ersaBond AB which contain antibiotics such as penicillin, erythromycin, colistin, cephalosporines, gentamicin, polymyxin, vancomycin and tobramycin; and Simplex ^® P which contains tobramycin are not ideal as these elute antibiotics in limited quantities and for a short duration only in doses that may be insufficient to deter infection. Also, the commercially available gentamycin eluting collagen sponges such as Collatamp® and Septocoll® are widely used now a day. A major drawback of these sponges is that they are fast releasing systems and therefore not effective for long term. Despite significant advances in pre- and post-operative protocols for PII management it remains to be a major concern and area of focus for the surgeons.

Thus, there is a need for a drug delivery system for treatment and/or prevention of pain, infection and inflammation. The present invention provides novel, long acting, safe, and cost effective therapies that will greatly reduce postoperative pain, inflammation and infection all together locally as well as by acting centrally, and improves patient satisfaction and minimizes risks of revision due to these causes.

SUMMARY OF THE INVENTION

In an aspect, the present invention provides a drug delivery system comprising a formulation of layered chitosan loaded with a plurality of drugs for pre and/or post-operative treatment.

In another aspect, the present invention provides a process for the preparation of the aforementioned drug delivery system.

OBJECTS OF THE INVENTION

An object of the present invention is to provide a drug delivery system comprising a formulation of layered chitosan loaded with a plurality of drugs for pre and/or post-operative treatment.

Another object of the present invention is to provide a biocompatible and biodegradable drug delivery system.

Yet another object of the present invention is to prevent the burst release of the drug from the chitosan matrix.

Yet another object of the present invention is to provide a process for the preparation of the aforementioned drug delivery system.

Yet another object of the present invention is to provide a layered formulation based drug delivery system for the prevention and treatment post-surgical site infections or wounds. Yet another object of the present invention is to provide complete management of postoperative complications using concoction layered formulation, which will prevent and treat pain, infection, inflammation and uncontrolled bleeding, for early recovery of patients after any surgical procedure.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing summary, as well as the following detailed description of the invention will be better understood when read in conjunction with the appended drawings. For the purpose of assisting in the explanation of the invention, there are shown in the drawings embodiments, which are presently preferred and considered illustrative. It should be understood, however, that the invention is not limited to the precise arrangements and instrumentalities shown therein. In the drawings:

Figure 1: Schematic representation of concoction for postoperative management

Figure 2: A] Stack of chitosan sponges and films containing single drug and compressed version of thin implant having concoction of drugs B] individual drugs loaded compressed sponges.

Figure 3: FTIR spectra of individual drugs and mixture after 1 week and 14 days

Figure 4: XRD spectra of chitosan sponge and drug loaded chitosan sponge

Figure 5: Morphology of individual drug loaded sponge and compressed sponges using SEM

Figure 6: A) Compressive stress required for compression of individual drug loaded chitosan sponges; B) Compressive modulus

Figure 7: Cumulative drug release study of individual drug from combined compressed sponge

Figure 8: Anti-inflammatory activity of the Diclofenac drug and Diclofenac release from the sponge

Figure 9: zone of inhibition obtained from cefuroxime release samples using Staphylococcus aureus

DESCRIPTION OF THE INVENTION

In describing the invention, the following terminology will be used in accordance with the definitions set forth below. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described herein. As used herein, each of the following terms has the meaning associated with it in this section. Specific and preferred values listed below for individual process parameters, substituents, and ranges are for illustration only; they do not exclude other defined values or other values falling within the preferred defined ranges.

As used herein, the singular forms "a," "an," and "the" include plural reference unless the context clearly dictates otherwise.

The terms“preferred” and“preferably” refer to embodiments of the invention that may afford certain benefits, under certain circumstances. However, other embodiments may also be preferred, under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, and is not intended to exclude other embodiments from the scope of the invention.

When the term“about” is used in describing a value or an endpoint of a range, the disclosure should be understood to include both the specific value or the end-point referred to.

As used herein, the terms“comprises”,“comprising”“including,”“havi ng,”“containing,” “involving,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to.

Thus, before describing the present invention in detail, it is to be understood that this invention is not limited to particularly exemplified systems or process parameters that may of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments of the invention only, and is not intended to limit the scope of the invention in any manner.

The use of examples anywhere in this specification including examples of any terms discussed herein is illustrative only, and in no way limits the scope and meaning of the invention or of any exemplified term. Likewise, the invention is not limited to various embodiments given in this specification.

As used herein, the terms“loaded”,“loading”,“embedded” or“incorporated” may be used interchangeably and refers to uniform or non-uniform incorporation of the drug loaded polymeric microparticles or the drug inside or throughout or through the surface of the chitosan matrix.

As used herein, the term“drug loaded”,“drug loading”,“entrapped”,“encapsulating” or “encapsulated” may be used interchangeably and refers to the incorporation or absorption or adsorption of a drug or a therapeutic agent by any means, in the interior or membrane of the microparticles or the chitosan matrix.

As used herein, the term“biocompatible” refers to any substance, composition, formulation or material which when introduced into a host or a subject, does not provoke an adverse immune response or is toxic to the host or the subject.

As used herein, the term“biodegradable” refers to the ability of a substance, composition, formulation or material to break down into harmless substances by the action of living organisms.

As used herein, the term "subject" refers to any mammal, in particular a human, at any stage of life.

As used herein, the terms "delivery" and "delivering" refers to conveyance of a therapeutic agent or a drug to a subject using the methods of the invention. Delivery may be localized to a particular location in a subject, such as a tissue, an organ, or cells of a particular type.

As used herein,“treatment” refers to the prevention of a disease or condition, the reduction or elimination of symptoms associated with a disease or condition, or the substantial or complete elimination of a disease or condition. Preferred subjects are vertebrate subjects, more preferably mammalian subjects and more preferably human subjects.

As noted above, “therapeutic agents,” “drugs,” “pharmaceutically active agents,” “pharmaceutically active materials,” and other related terms may be used interchangeably herein. These terms include genetic therapeutic agents, non-genetic therapeutic agents and cells.

As used herein, the terms "sponge" refers to a three dimensional porous matrix. In accordance with the present invention, there is provided a biocompatible and biodegradable drug delivery system comprising a formulation of layered chitosan loaded with a plurality of drugs for management of pre and/or post-operative treatment.

The drug delivery system of the present invention comprises a formulation of layered chitosan loaded with a plurality of drugs for delivering the drug at controlled or sustained release rate.

In an embodiment the formulation of layered chitosan loaded with at least one drug is applied locally at target site before closing surgical area to take care of post-surgical pain, inflammation and infection together. The system will work as triple action therapy of pain management, mitigation of inflammation as well as prevention of infection, which is of prime importance for the fastest recovery of a patient.

In an embodiment the formulation of the present invention is provided as a drug delivery system containing concoction of medication used for the post-operative management, which is minimally invasive and provides sustained release of drugs to avoid frequent painful injections.

In an aspect if the present invention, there is provided a drug delivery system comprising a stack of five layered polymer films;

a drug loaded into each of said layered polymer films.

Each of the polymer film has a size in the range of 2 mm to 5 mm.

The drug loaded on chitosan films can be hydrophobic or hydrophilic in nature.

In accordance with the embodiments of the present invention, the polymer is selected from chitosan, Alginate, gellan gum, collagen, xanthan gum, HPMC, poly anhydrides, PLA, polycarbonates, poly ortho esters, dextran, hyaluronic acid, PHBV, gelatin, polyamides, and polycaprolactone.

In an embodiment of the present invention, the polymer is chitosan.

In an embodiment, the drug delivery system of the present invention comprises

a stack of five layered polymer films;

anesthetics;

opioid analgesic; corticosteroids;

NS AID’s; and

an antibiotic agent.

In still another embodiment of the present invention, the drug is selected from the group consisting of Aztreonam; Chlorhexidine Gluconate; Nibroxane; Pirazmonam Sodium; Propionic Acid; Pyrithione Sodium; Sanguinarium Chloride; Tigemonam Dicholine; Acedapsone; Acetosulfone Sodium; Alamecin; Alexidine; Amdinocillin; Amdinocillin Pivoxil; Amicycline; Amifloxacin; Amifloxacin Mesylate; Amikacin; Amikacin Sulfate; Aminosalicylic acid; Aminosalicylate sodium; Amoxicillin; Amphomycin; Ampicillin; Ampicillin Sodium; Apalcillin Sodium; Apramycin; Aspartocin; Astromicin Sulfate; Avilamycin; Avoparcin; Azithromycin; Azlocillin; Azlocillin Sodium; Bacampicillin Hydrochloride; Bacitracin; Bacitracin Methylene Disalicylate; Bacitracin Zinc; Bambermycins; Benzoylpas Calcium; B erythromycin; Betamicin Sulfate; Biapenem; Biniramycin; Biphenamine Hydrochloride; Bispyrithione Magsulfex; Butikacin; Butirosin Sulfate; Capreomycin Sulfate; Carbadox; Carbenicillin Disodium; Carbenicillin Indanyl Sodium; Carbenicillin Phenyl Sodium; Carbenicillin Potassium; Carumonam Sodium; Cefaclor; Cefadroxil; Cefamandole; Cefamandole Nafate; Cefamandole Sodium; Cefaparole; Cefatrizine; Cefazaflur Sodium; Cefazolin; Cefazolin Sodium; Cefbuperazone; Cefdinir; Cefepime; Cefepime Hydrochloride; Cefetecol; Cefixime; Cefinenoxime Hydrochloride; Cefmetazole; Cefmetazole Sodium; Cefonicid Monosodium; Cefonicid Sodium; Cefoperazone Sodium; Ceforanide; Cefotaxime Sodium; Cefotetan; Cefotetan Disodium; Cefotiam Hydrochloride; Cefoxitin; Cefoxitin Sodium; Cefpimizole; Cefpimizole Sodium; Cefpiramide; Cefpiramide Sodium; Cefpirome Sulfate; Cefpodoxime Proxetil; Cefprozil; Cefroxadine; Cefsulodin Sodium; Ceftazidime; Ceftibuten; Ceftizoxime Sodium; Ceftriaxone Sodium; Cefuroxime; Cefuroxime Axetil; Cefuroxime Pivoxetil; Cefuroxime Sodium; Cephacetrile Sodium; Cephalexin; Cephalexin Hydrochloride, Cephaloglycin; Cephaloridine; Cephalothin Sodium; Cephapirin Sodium; Cephradine; Cetocycline Hydrochloride; Cetophenicol; Chloramphenicol; Chloramphenicol Palmitate; Chloramphenicol Pantothenate Complex; Chloramphenicol Sodium Succinate; Chlorhexidine Phosphanilate; Chloroxylenol; Chlortetracycline Bisulfate; Chlortetracycline Hydrochloride; Cinoxacin; Ciprofloxacin; Ciprofloxacin Hydrochloride; Cirolemycin; Clarithromycin; Clinafloxacin Hydrochloride; Clindamycin; Clindamycin Hydrochloride; Clindamycin Palmitate Hydrochloride; Clindamycin Phosphate; Clofazimine; Cloxacillin Benzathine; Cloxacillin Sodium; Cloxyquin; Colistimethate Sodium; Colistin Sulfate; Coumermycin; Coumermycin Sodium; Cyclacillin; Cycloserine; Dalfopristin; Dapsone; Daptomycin; Demeclocycline;

Demeclocycline Hydrochloride; Demecycline; Denofungin; Diaveridine; Dicloxacillin; Dicloxacillin Sodium; Dihydrostreptomycin Sulfate; Dipyrithione; Dirithromycin;

Doxycycline; Doxycycline Calcium; Doxycycline Fosfatex; Doxycycline Hyclate; Droxacin Sodium; Enoxacin; Epicillin; Epitetracycline 12 Hydrochloride; Erythromycin; Erythromycin Acistrate; Erythromycin Estolate; Erythromycin Ethylsuccinate; Erythromycin Gluceptate; Erythromycin Lactobionate; Erythromycin Propionate; Erythromycin Stearate; Ethambutol Hydrochloride; Ethionamide; Fleroxacin; Floxacillin; Fludalanine; Flumequine; Fosfomycin; Fosfomycin Tromethamine; Fumoxicillin; Furazolium Chloride; Furazolium Tartrate;

Fusidate Sodium; Fusidic Acid; Gentamicin Sulfate; Gloximonam; Gramicidin; Haloprogin; Hetacillin; Hetacillin Potassium; Hexedine; Ibafloxacin; Imipenem; Isoconazole; Isepamicin; Isoniazid; Josamycin; Kanamycin Sulfate; Kitasamycin; Levofuraltadone; Levopropylcillin Potassium; Lexithromycin; Lincomycin; Lincomycin Hydrochloride; Lomefloxacin;

Lomefloxacin Hydrochloride; Lomefloxacin Mesylate; Loracarbef; Mafenide; Meclocycline; Meclocycline Subsalicylate; Megalomicin Potassium Phosphate; Meropenem; Methacycline; Methacycline Hydrochloride; Methenamine; Methenamine Hippurate; Methenamine Mandelate; Methicillin Sodium; Metioprim; Metronidazole Hydrochloride; Metronidazole Phosphate; Mezlocillin; Mezlocillin Sodium; Minocycline; Minocycline Hydrochloride; Mirincamycin lydrochloride; Monensin; Monensin Sodium; Nafcillin Sodium; Nalidixate Sodium; Nalidixic Acid; Natamycin; Nebramycin; Neomycin Palmitate; Neomycin Sulfate; Neomycin Undecylenate; Netilmicin Sulfate; Neutramycin; Nifuradene; Nifuraldezone; Nifuratel; Nifuratrone; Nifurdazil; Nifurimide; Nifurpirinol; Nifurquinazol; Nifurthiazole; Nitrocycline; Nitrofurantoin; Nitromide; Norfloxacin; Novobiocin Sodium; Ofloxacin; Ormetoprim; Oxacillin Sodium; Oximonam; Oximonam Sodium; Oxolinic Acid; Oxy tetracycline; Oxytetracycline Calcium; Oxytetracycline Hydrochloride; Paldimycin; Parachlorophenol; Paulomycin; Pefloxacin; Pefloxacin Mesylate; Penamecillin; Penicillin G Benzathine; Penicillin G Potassium; Penicillin G Procaine; Penicillin G Sodium; Penicillin V; Penicillin V Benzathine; Penicillin V Hydrabamine; Penicillin V Potassium; Pentizidone Sodium; Phenyl Aminosalicylate; Piperacillin Sodium; Pirbenicillin Sodium; Piridicillin Sodium; Pirlimycin Hydrochloride; Pivampicillin Hydrochloride; Pivampicillin Pamoate; Pivampicillin Probenate; Polymyxin B Sulfate; Porfiromycin; Propikacin; Pyrazinamide; Pyrithione Zinc; Quindecamine Acetate; Quinupristin; Racephenicol; Ramoplanin; Ranimycin; Relomycin; Repromicin; Rifabutin; Rifametane; Rifamexil; Rifamide; Rifampin; Rifapentine; Rifaximin; Rolitetracycline; Rolitetracycline Nitrate; Rosaramicin; Rosaramicin Butyrate; Rosaramicin Propionate; Rosaramicin Sodium Phosphate; Rosaramicin Stearate; Rosoxacil; Roxarsone; Roxithromycin; Sancycline; Sanfetrinem Sodium; Sarmoxicillin; Sarpicillin; Scopafungin; Sisomicin; Sisomicin Sulfate; Sparfloxacin; Spectinomycin Hydrochloride; Spiramycin; Stallimycin Hydrochloride; Steffimycin; Streptomycin Sulfate; Streptonicozid; Sulfabenz; Sulfabenzamide; Sulfacetamide; Sulfacetamide Sodium; Sulfacytine; Sulfadiazine; Sulfadiazine Sodium; Sulfadoxine; Sulfalene; Sulfamerazine; Sulfameter; Sulfamethazine; Sulfamethizole; Sulfamethoxazole; Sulfamonomethoxine; Sulfamoxole; Sulfanilate Zinc; Sulfanitran; Sulfasalazine; Sulfasomizole; Sulfathiazole; Sulfazamet; Sulfisoxazole; Sulfisoxazole Acetyl; Sulfisoxazole Diolamine; Sulfomyxin; Sulopenem; Sultamicillin; Suncillin Sodium; Talampicillin Hydrochloride; Teicoplanin; Temafloxacin Hydrochloride; Temocillin; Tetracycline; Tetracycline Hydrochloride; Tetracycline Phosphate Complex; Tetroxoprim; Thiamphenicol; Thiphencillin Potassium; Ticarcillin Cresyl Sodium: Ticarcillin Disodium; Ticarcillin Monosodium; Ticlatone; Tiodonium Chloride; Tobramycin; Tobramycin Sulfate; Tosufloxacin; Trimethoprim; Trimethoprim Sulfate; Trisulfapyrimidines; Troleandomycin; Trospectomycin Sulfate; Tyrothricin; Vancomycin; Vancomycin Hydrochloride; Virginiamycin; Zorbamycin; Difloxacin Hydrochloride; Lauryl Isoquinolinium Bromide; Moxalactam Disodium; Omidazole; Pentisomicin; Sarafloxacin Hydrochloride; Benzalkonium Chloride; Cetylpyridinium Chloride; Chlorhexidine Digluconate; Polyhexamethylene Biguanide; Octenidine Dihydrochloride; Mild Silver Protein; Povidone Iodine; Silver Nitrate; Silver Sulfadiazine; Triclosan; Cetalkonium Chloride; Myristalkonium Chloride; Tigecyclin; Lactoferrin; Quinupristin/dalfopristin; Linezolid; Dalbavancin; Doripenem; Imipenem; Meropenem; Iclaprim; l,-D-ribofuranosyl- 1,2,4- triazole- 3 carboxamide; 9-2-hydroxy- ethoxy methylguanine; adamantanamine; benzoic acid; undecylenic alkanolamide; imidazoles; allylamine; thicarbamates; amphotericin B; clindamycin; econaxole; fluconazole; flucytosine; griseofulvin; nystatin; ketoconazole; voriconazole; morphine; hydromorphone; oxymorphone; levorphanol; levallorphan; methadone; meperidine; fentanyl; codeine; dihydrocodeine; oxycodone; hydrocodone; propoxyphene; nalmefene; nalorphine; naloxone; naltrexone; buprenorphine; butorphanol; nalbuphine; pentazocine; aspirin; diclofenac; diflusinal; etodolac; fenbufen; fenoprofen; flufenisal; flurbiprofen; ibuprofen; indomethacin; ketoprofen; ketorolac; meclofenamic acid; mefenamic acid; nabumetone; acetamidophen, naproxen; oxaprozin; phenylbutazone; piroxicam; sulindac; tolmetin; zomepirac or a pharmaceutically acceptable salt thereof; aprobarbital; butabarbital; butabital; mephobarbital; metharbital; methohexital; pentobarbital; phenobartital; secobarbital; talbutal; theamylal; thiopental or a pharmaceutically acceptable salt thereof; celecoxib; rofecoxib; valdecoxib; cumidin; heparin; calcium salts; Alclofenac; Alclometasone Dipropionate; Algestone Acetonide; Alpha Amylase; Amcinafal; Amcinafide; Amfenac Sodium; Amiprilose Hydrochloride; Anirolac; Anitrazafen; Apazone; Balsalazide Disodium; Bendazac; Benoxaprofen; Benzydamine Hydrochloride; Bromelains; Broperamole; Budesonide; Carprofen; Cicloprofen; Cintazone; Cliprofen; Clobetasol Propionate; Clobetasone Butyrate; Clopirac; Cloticasone Propionate; Cormethasone Acetate; Cortodoxone; Deflazacort; Desonide; Desoximetasone; Dexamethasone Dipropionate; Diclofenac Potassium; Diclofenac Sodium; Diflorasone Diacetate; Diflumidone Sodium; Difhmisal; Difluprednate; Diftalone; Dimethyl Sulfoxide; Drocinonide; Endrysone; Enolicam Sodium; Epirizole; Etodolac; Etofenamate; Felbinac; Fenamole; Fenbufen; Fenclofenac; Fenclorac; Fendosal; Fenpipalone; Fentiazac; Flazalone; Fluazacort; Flufenamic Acid; Flumizole; Flunisolide Acetate; Flunixin; Flunixin Meglumine; Fluocortin Butyl; Fluorometholone Acetate; Fluquazone; Flurbiprofen; Fluretofen; Fluticasone Propionate; Furaprofen; Furobufen; Halcinonide; Halobetasol acetamidophen, Propionate; Halopredone Acetate; Ibufenac; Ibuprofen; Ibuprofen Aluminum; Ibuprofen Piconol; Ilonidap; Indomethacin; Indomethacin Sodium; Indoprofen; Indoxole; Intrazole; Isoflupredone Acetate; Isoxepac; Isoxicam; Ketoprofen; Fofemizole Hydrochloride; Fornoxicam; Foteprednol Etabonate; Meclofenamate Sodium; Meclofenamic Acid; Meclorisone Dibutyrate; Mefenamic Acid; Mesalamine; Meseclazone; Methylprednisolone Suleptanate; Morniflumate; Nabumetone; Naproxen; Naproxen Sodium; Naproxol; Nimazone; Olsalazine Sodium; Orpanoxin; Oxaprozin; Oxyphenbutazone; Paranyline Hydrochloride; Phenbutazone Sodium Glycerate; Pirfenidone; Piroxicam; Piroxicam Cinnamate; Piroxicam Olamine; Pirprofen; Prednazate; Prifelone; Prodolic Acid; Proquazone; Rimexolone; Salcolex; Salnacedin; Salsalate; Sanguinarium Chloride; Seclazone; Sermetacin; Sudoxicam; Sulindac; Suprofen; Talmetacin; Talniflumate; Talosalate; Tebufelone; Tenidap; Tenidap Sodium; Tenoxicam; Tesicam; Tesimide; Tetrydamine; Tiopinac; Tixocortol Pivalate; Tolmetin; Tolmetin Sodium; Triclonide; Triflumidate; Zidometacin; Zomepirac Sodium, amylocaine, ambucaine, articaine, benzocaine, benzonatate, butacaine, bupivacaine, butanilicaine, cinchocaine, cocaine, cyclomethycaine, dibucaine, diperodone, dimethacaine, eucaine, etidocaine, hexylcaine, fomocaine, fotocaine, hydroxyprocaine, isubucaine, levobupivacaine, lidocaine, xylocaine, lignocaine, mepivacaine, meprylcaine, metabutoxycaine, nitracaine, orthocaine, oxetacaine, oxybuprocaine, paraethoxycaine, phenacaine, piperocaine, piridocaine, pramocaine, prilocaine, primacaine, procaine, procainamide, proparacaine, propoxycaine, pyrrocaine, quinisocaine, ropivacaine, trimecaine, tetracaine, tolycaine, tropacoccaine or derivatives thereof or analogues thereof.

In an embodiment of the present invention, the anesthetic is Triamcinolone.

In an embodiment of the present invention, the opioid analgesic is tramadol.

In an embodiment of the present invention, the corticosteroid is Bupivacaine.

In an embodiment of the present invention, the NS AID is diclofenac.

In an embodiment of the present invention, the antibiotic agent is cefuroxime.

The amount of drug present in the drug delivery system of the present invention is in the range of 1% w/w to 15% w/w of the delivery system.

In another aspect of the present invention, there is provided a process for preparing a drug delivery system, said process comprising the following steps:

a. dissolving a polymer in an acidic solution to obtain a polymer solution;

b. preparing a saline solution comprising a drug;

c. adding said polymer solution to said saline solution to obtain a first mixture;

d. stirring said first mixture for a time period in the range of 5 hours to 10 hours to obtain a homogeneous mixture;

e. sequentially moulding, freezing and lyophilizing said first mixture to obtain a drug loaded chitosan sponge;

f. neutralizing said drug loaded chitosan sponge using 1M NaOH solution to obtain neutral chitosan sponge;

g. drying said neutral chitosan sponge to obtain dried sponge;

h. repeating steps (a-g) five times to obtain five different drug loaded sponges dried sponges;

i. stacking and compressing said five sponge to obtain said drug delivery system, wherein all five sponges consist of drug different from each other.

In an embodiment of the present invention, the acidic solution is 0.5 % to 1% v/v of acetic acid in water In an embodiment of the present invention, the chitosan solution consists of 3%w/v chitosan.

In an embodiment the formulation of the present invention comprises local anesthetics, opioid analgesic, NSAID’s, corticosteroids, and antibiotic agent.

In an embodiment the formulation of the present invention comprises

The drugs are composed in biodegradable, bio adhesive, biocompatible, antibacterial and hemostatic polymer such as chitosan. The polymer selected for making the formulation of present invention has added advantage of having the antibacterial and hemostatic properties.

In an embodiment of the present invention, the chitosan is loaded with a drug which may be either hydrophobic or hydrophilic in nature.

In an embodiment of the present invention, the process for preparing layered formulation comprises preparing chitosan solution by dissolving in sodium acetate buffer solution and adding drug to the chitosan solution; the mixture is stirred continuously to obtain drug-loaded solution. This viscous solution is added into mold and kept for freezing overnight and lyophilized to get drug loaded chitosan sponge. Similarly four sponges of other drugs preferably, Cefuroxime, diclofenac, tramadol, Bupivacaine, and Triamcinolone is prepared and all five chitosan drug loaded sponges are stacked and compressed into a thin, which could be easily placed at the surgical site for the post-operative management of pain, inflammation and infection all together. The drug delivery system of the present invention is analyzed by various studies such as scanning electron microscopy, FTIR, In vitro drug release study, encapsulation efficiency, antibacterial study, cell biocompatibility, cell attachment and morphology study.

In another aspect, the drug delivery system of the present invention is used for the prevention and treatment of target site.

The present invention will now be more particularly described with reference to the following examples. It is to be understood that these are intended to illustrate the invention and in no manner to limit its scope.

EXAMPLES

Example 1:

Materials

Medium molecular weight (MMW) chitosan (degree of de- acetylation 75-85%) purchased from Sigma, Aldrich, and USA. Sodium acetate purchased from Sd-fine chemicals. All drugs were obtained as gift samples from Breach Candy hospital, Mumbai. Water from Milli-Q system was used in all experiments.

Preparation of concoction in the form of a film

Cefuroxime (750mg) was added in saline solution under magnetic stirring. 3%w/v chitosan was added to the drug loaded saline solution followed by 0.5 %v/v acetic acid. The mixture was stirred till homogeneous mixture was formed. This viscous solution was then added into mold and kept for freezing overnight and lyophilized to get each drug loaded chitosan sponge. Similarly chitosan sponge of diclofenac (30mg), Tramadol (200pg), Bupivacaine (2.5 mg/kg), and Triamcinolone (40mg), were prepared. Each chitosan drug loaded sponge was stacked one above the other and compressed into a thin film of about 5mm, which could be easily placed at the surgical site for the post-operative management of pain, inflammation and infection all together.

Example 2:

Characterization and analysis of sponge:

Morphology of individual drug loaded sponge:

Figure 9 represents the disc shaped chitosan sponges loaded with individual drug to be incorporated into the layered concoction system. SEM micrographs of individual drug loaded sponge:

SEM micrographs showed difference in morphology of each drug loaded chitosan sponges. Figure 10 showed differences in morphology of the sponge before and after compression. Bupivacaine and tramadol loaded sponges showed highly compact structure even before compression indicating the scope for sustained release. Diclofenac sponge established highly porous structure before compression. There are no significant changes in the morphology of triamcinolone loaded chitosan sponges.

XRD spectroscopy analysis:

XRD data revealed the crystalline and amorphous properties of the drugs and drug loaded chitosan composition compared to the blank chitosan and chitosan powder. As shown in figure 11 there was very less change in nature of chitosan composition after the drug loading. Diclofenac and triamcinolone seems to exhibit semi-crystalline nature, while others resembling the chitosan sponge properties

FTIR spectroscopy analysis:

Interaction study was done by FTIR spectroscopy. The formulations were subjected to the FTIR characterization using Spectrum 1 IR spectrometer (Perkin Elmer, USA) in the range of 400-4000 cm ¹ . The spectrum was collected under a dry nitrogen atmosphere with 20 scans. FTIR analysis was done for understanding the interaction between components of the sponge. Individual drugs and mixture incubated for 7 days and 14 days was analyzed. This study showed that there is no interaction between the individual drug components in mixture even after 14 days.

Compression study:

Chitosan sponge was prepared by lyophilization in a 24-well tissue culture plates to prepare columned sponge (l3mm diameter, 6mm height). The stress-strains curves of sponges were determined using a Universal testing machine (UK) at a loading of 2 mm/min at a constant displacement rate. Compressive modulus of sponges was calculated 10. The compressive properties of blank and drug loaded chitosan sponges were studied at room temperature. Figure 12A represents the compressive stress and compressive modulus of the prepared sponges. Bupivacaine showed the highest stress values and triamcinolone lesser values. Diclofenac showed highest compressive modulus compared to all other drug loaded sponges. Drug polymer interactions might have contributed to the increase mechanical properties of the sponges.

Stability study

Mixture of all drugs in saline solution was kept undisturbed for 14 days to check the stability concoction. Results showed that even after 14 days of storage the concoction remains stable. There were no signs of precipitation or color change.

Example 3

In vitro drug release study

All experiments were performed in PBS (pH 7.4) at 37 °C to mimic the in-vivo conditions. Individual drug loaded and composite combined compressed sponge. Sponge was suspended in PBS solution (30 ml) in a glass vial and kept in well-stirred water bath at 100 rpm. Sample (1 ml) was collected at regular intervals up to 21 days. Sink condition was maintained by replacing the aliquot of release medium with fresh PBS solution each time. The absorbance of released medium was measured using UV-Vis spectrophotometer at 27lnm, 27lnm, 280nm, 243nm, and 276nm for tramadol, bupivacaine, cefuroxime, triamcinolone, and diclofenac respectively.

Compressed film formulation showed sustained release of diclofenac drug, which showed sustained release for longer periods. In vitro drug release profile of drugs provides clear indication for the complete post-operative management.

All drugs have maintained their activity even after incorporation into the film. The sample was then studied for anti-inflammatory and antibacterial activity of diclofenac and cefuroxime respectively.

Example 4

Biological study

Anti-inflammatory activity was analyzed by inhibition of albumin denaturation method 11. Briefly, 200 pl of albumin (egg-white) was added in the PBS (pH 7.4). Then 2 ml Diclofenac released from the formulation was added to the above mixture. Concentration of Diclofenac was adjusted to 50, 100, 200, 400, 600, 800, 1000 pg/ml. The reaction mixture was incubated for at 37±2°C in incubator for 20 min and then heated at 70°C for 5 min. After cooling, absorbance was measured at 660 nm. For comparison, varying concentrations of standard Diclofenac i.e. 100, 200, 400, 600, 800, 1000 pg/ml was added to albumin for denaturation and absorbance was measured. The percentage inhibition of protein denaturation was calculated by using the following formula,

Where, Ab _c is an absorbance of control and Ab _t is an absorbance of test sample.

Diclofenac from the elution samples showed comparatively similar % inhibition profile as shown by pure Diclofenac drug. Results indicate the efficacy of Diclofenac loaded into chitosan composition is active even after released from the formulation.

Example 5

Antibacterial activity

Antimicrobial efficacy of cefuroxime loaded chitosan sponge was studies using Kirby-Bauer method as reported in N. Pharm. Res. 2012, 29 (11), 3110-3121. Efficacy was tested against Staphylococcus aureus cultured in nutrient agar plates. Bacterial inoculum was spread homogeneously onto the surface of agar plates followed by antibiotic loaded sample disc mounted at center of agar plate. Incubate the plates for 12-16 hours. Then, zone of inhibition was measured. Cefuroxime showed increasing zone of inhibition with time corresponding to the release profile. Results showed the effectiveness of cefuroxime after incorporation into the sponge matrix.

Example 6

Cell biocompatibility assay

Cell biocompatibility was assessed by MTT assay using L929 fibroblast cell lines procured from NCCs Pune. Cells were grown in DMEM medium supplemented with fetal bovine serum (FBS) and 1% antibiotic. Cells were seeded in 96 well tissue culture plate and incubated for 24 hours followed by addition of extract collected at particular time from the compressed sponges. After 24 hours cell culture MTT solution was added into each well and incubated for 4 hours. After DMSO was added to dissolve formazan crystals followed by absorbance measurement at 560nm to measure the % cell viability.

Results showed more than 80% cell viability for compressed sponge extracts indicating good compatibility of the cells with sponge and its release rate.