DESC:FIELD OF INVENTION
The present invention relates to a drug coated balloon catheter for treatment of any paranasal sinus cavity, additionally for the treatment of post-operative measure of Functional Endoscopic Sinus Surgery (FESS) and balloon sinuplasty. The present invention relates to a sinus DEB coated with mometasone furoate which can be used for intended localized supply of the drug at the treatment site which offers extended or prolonged anti-inflammatory effect at the treatment site.
BACKGROUND OF INVENTION
Chronic Sinusitis (CS) and Chronic Rhinosinusitis (CRS) are one of the most frequently diagnosed chronic medical conditions. Chronic Rhinosinusitis is characterized by purulent nasal discharge, usually, without fever that persists for weeks to months and symptoms of congestion often accompany the nasal discharge. Current treatment of Chronic Rhinosinusitis has focused on addressing multi-factorial etiology of Chronic Rhinosinusitis including host and environment factor as well as attenuating inflammation. Moreover, inflammation can also impede mucosal recovery, damage to optical nerve and incite polypoid disease leading to further compromising surgical results.
Currently, as a first-line intervention, initially course of conservative medical therapy is attempted to resolve the symptoms of acute sinusitis; this treatment may include antibiotics, decongestants, nasal irrigation, and steroids. In more severe cases, FESS is the most commonly used as a second-line intervention to treat medically unresponsive chronic sinusitis. FESS is an invasive and traumatic procedure with benefits like shorter surgery and healing times, less postoperative discomfort, and fewer surgical complications. However, inflammation can occur at the treatment site post FESS, resulting into various risks which may include bleeding, reaction to anesthesia, blindness, scarring, meningitis, infection, septal perforation, orbital injury, septal hematoma, airway obstruction, recurrence of sinus disease, toxic shock syndrome, decreased the sense of smell, need for further surgery, etc. Therefore, anti-inflammatory agents are given to patient for controlling edema after surgery. Additionally, FESS or nasal endoscopic surgical procedure is expensive and yet not thorough. The resulted relapse will cause the repeated treatment, which brings heavy mental and economic burdens to patients.
When FESS becomes inoperative or less acceptable, balloon ostial dilation is considered an alternative for treatment of CRS. Balloon sinuplasty or balloon ostial dilation, less invasive method has revolutionized the management of CS/CRS. Balloon sinuplasty has been extensively used for maintaining the patency of the ostium of the paranasal cavity (Frontal, Maxillary, Sphenoid, and Ethmoid sinuses). The procedure involves placing a guidewire in the sinus ostium, advancing a balloon over the guide wire, and then widening the opening by inflating the balloon. The guide wire location is confirmed with direct transillumination of the targeted sinus cavity. This technique is said to allow improved sinus drainage. However, current balloon sinuplasty is not intended to deal with inflammation occurings due to any reason after FESS or balloon ostial dilation. Moreover, it carries the risk of tissue damage, infection and inflammation, which may affect optic nerve or any other such adverse complications. So, it is desired to develop the treatment that reduces the post-operative inflammation at the treatment site for the better outcome.
Besides antibiotics, FESS surgery and balloon sinuplasty; other treatment option includes drug coated bioresorbable self-expandable implant (PropelTM) and drug encapsulated micropores device (Relieva StratusTM) to treat the sinusitis. Implant releases drug at the treatment site up to pre-decided time. PropelTM contain 370µg mometasone furoate which is control released at the treatment site after FESS up to 35-45 days. Whereas, Relieva StratusTM is contain 40mg/ml of triamcinolone acetonide. Bioresorbable stent and micropores device are implants that remain at treatment site in order to release the drug. However, implant is selected by the physician based on the severity of disease and varies from case to case. Therefore, where implant is not necessary, sinus balloon catheter with coated drug is more beneficial. The present invention deals with DEB which immediately releases anti-inflammatory agent at the desired location and provides prolonged anti-inflammatory effect at the treatment site.
Presently, sinus balloon is made up of nylon or any other material without a coating of any therapeutic agent. During balloon sinuplasty, patients are kept on medication to prevent post-operative complexity related to trauma or inflammation at the site of treatment. On the other hand, Drug Eluting Balloon (DEB) catheter will provide additional benefits of the localized release of anti-inflammatory drug for prevention of trauma, reduction in post-operative impediment, longer patency of ostium, inflammation and reduce the post-operative medication. Further, Sinus DEB aims for localized delivery of mometasone furoate thereby reducing the oral steroid dose which further reduces toxicity of drug in context to oral and systemic dose. Additionally, sinus DEB catheter also reduces the financial burden due to the reduction in oral steroids after surgery.
WO/2016/118923 discloses devices and systems for treating diseases of the nose, ear or throat with an expandable device having a drug coating and maintaining a therapeutic level of local drug delivery by the way of vapor annealing process and/or plasma treatment.
CN 105288823 discloses a drug eluting system which comprises of a balloon catheter and a drug eluting balloon such that the drug eluting balloon is provided with a wire guide cavity arranged along the axial direction and the drug coating of the balloon comprises of an inner and an outer layer. Further, EP2385848 discloses a drug eluting medical device for angioplasty catheters to prevent the restenosis of the vessel subjected to angioplasty. It discloses a catheter balloon completely or partially coated with paclitaxel in crystalline form.
The existing prior art makes use of the solvent annealing step after drug coating which results in loss of nearly 10% of the drug whereas the same does not happen in the present invention.
Consequently, there existed a need in the art to provide for a way of reducing the drug loss during tracking procedure and treating inflammation of paranasal cavity by localized anti-inflammatory action at treatment site leading to quick healing.
It is the object of the present invention to provide for a way for uniform distribution of the drug by direct contact of the drug layer coated on the balloon surface at the treatment site.
It is also the object of the present invention to provide for minimal drug loss and low drug residues on balloon surface which leads to the higher tissue availability due to unique formulation of exicipients and uniform dispersion of drug as minute particle.
The present invention also fulfils the need in the art for immediate release of the drug as minutes particles with prolonged anti-inflammatory effect at the treatment site.
SUMMARY OF THE INVENTION
The present invention relates to balloon sinuplasty in which balloon surface is coated with therapeutic agent or pharmaceutically active agent or more specifically an anti-inflammatory drug. It provides for the Drug Eluting Balloon which can be used for expansion of sinus ostium as a remedy for sinusitis.
Sinusitis is a condition characterized by inflammation of the mucosal lining of the sinuses and paranasal cavity. The present invention relates to the drug eluting ballon for balloon ostial dilation of the various sinus cavities i.e. Frontal, Sphenoid, Maxillary and Ethmoid. Further, the drug formulation coated on the balloon surface comprises of an anti-inflammatory agent i.e. mometasone furoate (MF) and other excipients that allow for the immediate release of the drug from balloon surface at the treatment site.
The object of the present invention is to provide a reduction in the trauma and inflammation of the sinus cavities along with a reduction in post-operative medication for the better outcome resulting in reduction of the systemic dose, toxicity of drug and overall treatment cost. Furthermore, it also offers extended or prolonged anti-inflammatory effect at the treatment site.
According to another aspect of the invention, the sinus DEB can also be used for balloon sinuplasty and as post-operative measure of Functional Endoscopic Sinus Surgery (FESS).
According to another aspect of the invention, the sinus DEB is coated with drug formulation such that there is regulated and extended or prolonged anti-inflammatory effect at the treatment site.
According to another aspect of the invention, the drug formulation coated on the balloon comprises of an anti-inflammatory agent, solvent and/or and excipients. The solvent used in the present invention is water miscible and the excipients used are polyethylene glycol, urea and glycerol and a combination thereof.
According to another aspect of the invention, sinus DEB is useful for localized supply of mometasone furoate at the treatment site in case of re-occurrence of inflammation in post device implantation. The present invention offers localized release of mometasone furoate and therefore leads to reduction in the post-operative oral steroid dose and edema.
BRIEF DESCRIPTION OF DRAWINGS
Figure 1. is exemplary representation of various paranasal cavities
Figure 2. gives the chemical structures of various compounds listed in invention wherein 2(A) represents Mometasone Furoate, 2(B) Polyethylene Glycol 6000, 2(C) Urea and 2(D) Glycerol
Figure 3. is exemplary representation showing balloon and coating layer in the invention
Figure 4. is exemplary representation showing cross sectional view of balloon surface and coating layer
Figure 5. Illustrates the balloon surface after various process of formulation C. Appearance after (A) Pleat fold, (B) after EtO sterilization, (C) balloon surface after drug release in PBS. Images were taken at 12.5X using stereomicroscope.
Figure 6. Illustrates the balloon surface after various process of formulation D. Appearance after (A) Pleat fold, (B) after EtO sterilization, (C) balloon surface after drug release in PBS. Images were taken at 12.5X using stereomicroscope.
Figure 7. Illustrates the balloon surface after various process of formulation E. Appearance after (A) Pleat fold, (B) after EtO sterilization, (C) balloon surface after drug release in PBS. Images were taken at 12.5X using stereomicroscope.
Figure 8. is graphical representation of drug release profile of different coated balloons.

DETAILED DESCRIPTION

The following description with reference to the accompanying drawings is provided to assist in a comprehensive understanding of exemplary embodiments of the invention as defined by the claims and their equivalents. It includes various specific details to assist in understanding but these are to be regarded as merely exemplary. Accordingly, person skilled in the art will recognize that various changes and modifications of the embodiments described herein can be made without departing from the scope and spirit of the invention. In addition, descriptions of well-known functions and constructions are omitted for clarity and conciseness. The terms and words used in the following description and claims are not limited to the bibliographical meanings, but, are merely used by the inventor to enable a clear and consistent understanding of the invention. Accordingly, it should be apparent to the person skilled in the art that the following description of exemplary embodiments of the present invention are provided for illustration purpose only and not for the purpose of limiting the invention as defined by the appended claims and their equivalents.
It is to be understood that the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.
The present invention discloses a sinus DEB catheter for balloon sinuplasty in accordance with the various aspects of the present invention.
Sinusitis also known as the sinus infection or rhinosinusitis is an inflammation of the sinuses. Further, it is classified as acute rhinosinusitis which lasts for less than four weeks and chronic rhinosinusitis (CRS) which lasts for more than 12 weeks. Subacute rhinosinusitis is the transition between acute and chronic infection which lasts for 4 to 12 weeks. Sinusitis is predominately caused by viral and bacterial infection and also caused by infection, allergies, air pollution, or structural problems in the nose. Further, sinusitis can be classified into frontal, ethmoidal, maxillary and sphenoidal by the location as shown in Figure 1. The maxillary sinuses are the largest sinus cavity located under the eyes. The frontal sinuses are located superior to the eyes in the frontal bone. The ethmoidal sinuses, which are formed from several discrete air cells within the ethmoid bone located between the nose and the eyes. The sphenoidal sinuses are located in the sphenoid bone. There is a risk of damage to the brain and/or eyes as the frontal, maxillary, ethmoidal and sphenoidal sinuses are innervated by the trigeminal nerve.
It is estimated that sinusitis affect 35 million people alone in the USA and the similarly large population is affected in the rest of world. In general, balloon sinuplasty is performed for opening or enlargement of sinus ostium of frontal, sphenoid, maxillary and ethmoid cavities.
The present invention discloses a drug eluting balloon catheter which can be used for reduction of inflammation at the treatment site and for maintenance of ostium patency for a longer period. Further, the present invention discloses a sinus DEB catheter with anti-inflammatory agent, excipients and a solvent. The unique combination of excipients as disclosed in the present invention act as release modifier agents which regulate the release of the drug at the treatment site.
Generally, the balloons used are tubular shaped. They may be made up of materials like PET (polyethylene terephthalate), silicon, polypropylene (PP), polyethylene, nylon, polyamide polymer, latex, polyurethane or any other material commonly used for balloon catheters for medical applications. In the present invention, the sinus balloon catheter MESIRETM Balloon Catheter (FDA approved, 510(k) K172737), is used. The balloon catheter in its inflated state generates the pressure on the narrowed ostium for enlargement of sinus ostium by increasing pressure from 00 atm to 04 atm or 10 atm or 16 atm or up to indicated nominal pressure or more depending on the patient condition and surgeon intellectual but must be below the rated burst pressure (RBP). During inflation, the drug formulation coated onto the sinus DEB releases into the treatment site and gets directly absorbed by the tissue. Thus, it helps to reduce the frequency of inflammatory event at the site of surgery and hence reduce the need of medication to prevent inflammation post-treatment. Further, inflammation may re-occur due to gastro-esophageal reflux, nasal polyps, respiratory tract infections, cystic fibrosis, and other immune system-related diseases which require localized delivery of anti-inflammatory agent, even after FESS and balloon sinuplasty.
The present invention disclosed Sinus DEB which can be used to deliver more mometasone furoate to the treatment site in case of reoccurrence of inflammation and scarring post device implantation.
In the different embodiments, different therapeutic agents or anti-inflammatory agent are coated on the balloon surface. Exemplary therapeutic agents include angiotensin converting enzyme (ACE) inhibitors; antihistamines; corticosteroids (e.g., fluticasone propionate, mometasone furoate, triamcinolone, beclomethasone, flunisolide, budesonide and ciclesonide); nonsteroidal anti-inflammatory agents (e.g., aspirin, celecoxib, diclofenac, ibuprofen, and indomethacin); chymase inhibitors; cyclooxygenase2 (COX2) inhibitors; decongestants (e.g., phenylpropanolamine, synephrine, propylhexedrine, tetrahydrozoline, pseudoephedrine, xylometazoline, and tramazoline); matrix metalloproteinase (MMP) inhibitors (e.g., doxycycline, TIMP metallopeptidase inhibitor 1 and dexamethasone); mucolytics; opioids (e.g., methadone, tramadol, morphine and oxycodone); angiotensin receptor blockers (ARBS) or similar therapeutic agents and combinations thereof. If desired, other therapeutic agents for the treatment or prevention of various conditions may be employed, including analgesics, antifungal agents, anticholinergics, antiparasitic agents, biostatic compositions, antiviral agents, chemotherapeutic/antineoplastic agents, cilia enhancement agents (e.g., zinc or magnesium), cytokines, hemostatic agents (e.g., thrombin), nucleic acids, peptides, immunosuppressors, proteins, vitamins, vasoconstrictors, mixtures thereof.
In a preferred embodiment, mometasone furoate is used as an anti-inflammatory agent. Mometasone furoate, a hydrophobic drug, is a synthetic corticosteroid with anti-inflammatory activity. The drug is also available as its monohydrate having molecular formula C27H30Cl2O6 and structurally it is pregna-1,4-diene-3,20-dione,9,21-dicholoro-17-[(2-furanylcarbonyl)oxy] -11-hydroxy -16methyl -,(11ß,16a). Its structure as mometasone furoate is shown in Figure 2(A). It reduces the airway inflammation by reversing the activation of inflammatory proteins, activating the secretion of anti-inflammatory proteins, stabilizing cell membranes and decreasing the influx of inflammatory cells. Corticosteroids have been shown to have a wide range of effects on multiple cell types (e.g., mast cells, neutrophils, eosinophils, macrophages, and lymphocytes) and mediators (e.g., histamine, leukotrienes, eicosanoids, and cytokines) involved in inflammation.
Mometasone furoate is glucocorticoids which has potent anti-inflammatory activity regardless of inflammations cause. The primary action of mometasone furoate is through suppression of phospholipase A2 through the production of lipocortin-1 (annexin-1), thereby blocking eicosanoid production, and inhibits leukocyte-mediated inflammatory events such as epithelial adhesion, emigration, chemotaxis, phagocytosis, respiratory burst, etc. Apart from suppressing an immune response, it inhibits prostaglandins and leukotrienes, two main products of inflammation. The molecular mechanism of corticosteroids may regulate the gene expression in several ways to control inflammation. This may be through trans-activation, cis-repression and trans-repression. In case of trans-activation, once corticosteroids have bound to glucocorticoid receptors (GR), changes in the receptor structure result in dissociation of molecular chaperone proteins, thereby exposing nuclear localization signals on GR and results in rapid transport of the activated GR-corticosteroid complex into the nucleus, where it binds to DNA at specific sequences in the promoter region of corticosteroid-responsive genes known as glucocorticoid response elements (GRE). Two GR molecules bind together as a homodimer and bind to GRE, leading to changes in gene transcription. Interaction of GR with GRE classically leads to an increase in gene transcription (trans-activation). These activate genes that have anti-inflammatory effects, including annexin-1 (lipocortin-1), SLPI, interleukin-10 (IL-10) and the inhibitor of NF-kB (IkB-a). Also switch on the synthesis of proteins that affect inflammatory signal transduction pathways, glucocorticoid-induced leucine zipper protein (GILZ). In case of cis-repression, binding of GR to negative GRE sites leads to gene suppression. There are few well-documented examples of negative GREs, but some are relevant to corticosteroid side effects, including genes that regulate the hypothalamic-pituitary axis (pro-opiomelanocortin and corticotrophin-releasing factor), bone metabolism (osteocalcin) and skin structure (keratins). In case of predominant trans-repression, corticosteroids switch off multiple inflammatory genes (encoding cytokines, adhesion molecules, chemokines, receptors, inflammatory enzymes, and proteins) that have been activated during the chronic inflammatory process.
Currently, 100 µg to 400 µg of mometasone furoate per day is recommended by a physician in case of CS, CRS, post FESS and balloon sinuplasty as metered nasal spray and through other routes. Further, the dose of the mometasone furoate varies from patient to patient depending on the severity of the disease.
In the present invention, sinus DEB offers localized drug delivery thereby reducing systemic dose and toxic drug effect to various organs in context to oral or other conventional routes of administration. The amount of mometasone furoate in formulation may be 10 % to 90%, preferably 30% to 80%, and most preferably 40-70%. The coating of drug on balloon surface may vary from 0.01µg/mm2 to 3.0µg/mm2, preferably 0.2µg/mm2 to 2.0µg/mm2 and more preferably 0.4µg/mm2 to 1.5µg/mm2. The drug formulation coated exhibits immediate release of mometasone furoate from sinus balloon surface at treatment site with prolonged anti-inflammatory effect.
The coating composition comprises of drug and excipient and a solvent. The example of solvent can include, but not limited to, water, dimethyl sulfoxide (DMSO), ?,?'- dimethylformamide (DMF), ?,?'-dimethylacetamide (DMAC), N-methyl-2-pyrrolidone (NMPO), 1,3-dimethyl-2-imidazolidinone (DMEU), 1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidinone (DMPU), methanol, ethanol, 1-propanol, isopropanol, methyl acetate, ethyl acetate, acetone, diethyl ether, xylene, and mixtures of thereof, preferably the solvent is acetone or water or mixture thereof.
In one embodiment, the drug release is controlled by addition of one or more excipients or plasticizers. In some variations, the plasticizers include but are not limited to, low molecular weight polymers, amides, oligomers, polyethers, phospholipids, polyols, glycols, glycol esters, ethers and polyethers and combination thereof. In the preferred embodiment, polyethylene glycol (PEG) acts as the main drug carrier. Polyethylene glycols (PEG) are polymers of ethylene oxide, with a molecular weight (Mw) usually falling in the range 200-30000 which is widely used in pharmaceutical formulations. For the manufacture of solid dispersions and solutions, PEGs with molecular weights of 1500-20000 are usually employed. A particular advantage of PEGs for the formulation of solid dispersions is that they also have good solubility in many organic solvents. The melting points (m.p.) of the PEGs is around 65°C in every case (e.g., the m.p. of PEG 1000 is 30-40°C, the m.p. of PEG 4000 is 50-58°C and the m.p. of PEG 20000 is 60-63°C). PEGs of Mw 4000-6000 are the most frequently used in pharmaceutical industries for the manufacture of solid dispersions, because in this Mw range, water solubility is very high, but hygroscopy is not a problem and the melting point is over 50°C temperature. If a PEG with too low Mw is used, it can lead to a product with a sticky consistency. Thus, in current embodiment PEG-6000 is preferred.
Other excipients such as urea, cellulose, glycerol, chitosan and others were also reported to have a positive effect on dispersion of the drug in pharmaceutical formulations. Urea and glycerin/ glycerol is widely used as a smoothening agent, humectants, lubrication agent, tonicity agent, plasticizer, sweetening agent, sustained-release ingredient and coating agent. Further, urea, being hydrotropic compound, has been extensively used in pharmaceutical preparation for increasing the aqueous solubility and dissolution of various drugs. For instance, addition of urea in solid formulation of aceclofenac, theophylline, diclofenac sodium lead to 1.7 fold improvement in-vitro dissolution, about 150 times improvement in aqueous solubility, and 250 times improvement in aqueous solubility, respectively (Dhapte Vividha, and Piyush Mehta. St. Petersburg Polytechnical University Journal: Physics and Mathematics 1.4 (2015): 424-435).
In preferred embodiment, urea, polyethylene glycol, glycerol and their combination are used as excipients. The weight ratio of urea, polyethylene glycol and glycerol ranges from 3:4:3 to 2:6:2, preferably from 2.5:5:2.5 to 1.5:7:1.5 and more preferably from 2:6:2 to 1:7:1. Further, the weight ratio of mometasone furoate to excipient varies from 8:2 to 5:5, preferably 7:3 to 4:6 or more preferably 6:4. The structures of various compounds of the invention are illustrated in figure 2.
In one embodiment, the drug may be coated on the balloon in different layers. It may have single coating layer, two different coating layers, or three different layers. In case of two or more layers, the layers are referred to as the base, intermediate and top layer. The base layer may act as release regulator or layers which support coating of drug containing layer. In case of three layers, third layer may be porous that reduces the loss of drug during tracking procedure and act as a protective layer. Further first, second or third layer may have nano formulated coating which further enhances the tissue absorption of drug due to the nano-characteristics of drug.
Additionally, drug may be encapsulated in nano-carrier and after that drug will be released from carrier as nano-sized particles at the treatment site. In various embodiments, liposomes, micelles, polymer microspheres, polyethylene glycol (PEG) and many other are reported as nano carrier for drug delivery. Further, the formulation may be made up of Phosphatidylcholine, Glyceryl monostearate, Glyceryl behenate, Precirol ATO5, Compritol 888ATO, Dynasan 114, Captex 355, Pluronic F68, Poloxamer188, Tween-80, Tween-20 or their mixture. Further, drug nanoparticles may be made by one of the several techniques. The technique includes but not limited to hot homogenization, cold homogenization, high shear homogenization, solvent diffusion, micro-emulsion, pyrolysis, ion implantation, chemical precipitation, sol-gel method and ultrasonication or combination of them.
In some embodiments, Solid Lipid Nanoparticles (SLN) is more preferred for controlled drug release in a various pharmaceutical application. The particles size may range from 1 to 900 nm, preferably 50 to 700 nm, and more preferably 100-500 nm. Apart from particle size, the thickness of the coating layer is crucial for the modifying drug release characteristics. The thickness of coating layer may vary from 05 to 60µm and more preferably 10 to 30µm as shown in Figure 3 and 4.
In the current embodiment, the formulation, containing a drug, excipient and solvent, are subjected to ultra-sonication for a period of 10 minutes to 30 minutes before spray coating. The sinus balloon catheter size used for coating may have different diameter. The diameter of balloon may be 5.0 mm to 7.0 mm and length is 15.0 mm to 17.0 mm.
In the different embodiment, the drug coating on the balloon can be accomplished by any coating methods available like spray coating, rolling, sputtering, spin coating, electro-spin coating, vapor deposition and the like. The coating parameters include amount of coating solution, distance between spray gun and balloon, rotation, nitrogen gas pressure and solution flow rate. The amount of coating solution may vary from 0.1ml to 5ml, preferably from 0.3 ml to 2.5 ml, more preferably from 0.5 ml to 1.5ml. The distance between the spray gun and balloon may vary from 2 cm to 8 cm, more preferably 4 cm to 6 cm to achieve smooth and uniform for coating surface. The rotation of balloon may be between 10 to 50 rotations per minute and more preferably 25 to 45 rotations per minute. The pressure of inert nitrogen gas may range from 3psi to 12psi, preferably from 5psi to 10psi, more preferably from 6psi to 8psi. The flow rate of the coating solution ranges from about 0.02ml per minute to 3ml per minute, preferably from 0.05ml to 2ml per minute, more preferably from 0.08ml or 1.2ml per minute. The parameters are set to form a thin, uniform and smooth coating over the balloon surface.
The process is performed in a clean room environment (class 10000) to avoid the interference of temperature and moisture during the spray coating. The temperature and humidity of clean room is maintained at 22±3°C and 45%, respectively. For smooth coating operation, tapered ends of the balloon are covered with thin protective covering to form the drug coated layer at the specified area of a balloon. The thin protective covering may be made of, without limitation, parafilm, nescofilm, molded polypropylene or teflon caps etc. The thin protective covering may be in the form of molds with shapes corresponding to the distal; and proximal ends. The thin protective covering may be easily detached from the balloon post coating. The coating procedure may continue for 10 minutes to 40 minutes and more preferably from 20 minutes to 30 minutes. On the other hand, the coating may be performed in discontinued manner with coating (on) and resting (off) cycle. The coating cycle may range from 10 seconds to 250 seconds, more preferably from 50 to 100 seconds. Whereas, resting cycle may range from 10 seconds to 150 seconds, more preferably from 20 seconds to 40 seconds. The coated balloon may then be kept for another 10 - 12 hours under vacuum desiccator to remove the residual solvents.
The coated balloon is further processed for pleat folding. In general, three or more pleats are preferred depending on the size of the balloon and the desired tracking profile. For instance, balloon profile of about 1.9 mm to 2.3 mm may have a better tracking profile with four to six or more pleats.
In the preferred embodiment, the number of the pleats of the drug coated balloon is 06. The temperature of wrapping or pleat folding process is a critical parameter as it affects the characteristics of coating layer such as appearance, drug release profile and release of particle size. The temperature of wrapping process may range from 20°C to 70°C, preferably from 30°C to 50°C, more preferably from 35°C to 45°C. The process time may range from 01 minutes to 10 minutes, preferably from 02 minutes to 06 minutes, and more preferably 03 minutes to 05 minutes. The dwell time may range from 50 to 120 seconds, preferably from 60 to 100 seconds more preferably from 80 to 90 seconds. The balloon pressure during pleating process may between 5psi and 40psi, more preferably between 15psi and 30psi. Further crossing profile of the pleat-folded balloon may vary from 1.6mm to 2.4mm, preferably from 1.7mm to 2.3mm, more preferably from 1.8mm to 2.2mm. The pleat folded balloon may have the protective sheath or peel off tube as the protective barrier to prevent the damage to coating surface during handling and storage. Pleat folded sinus DEB catheter is then transferred to primary packaging before sterilization and final packaging.
The sinus DCB catheter packed in the tray may be made up of High Impact Polystyrene (HIPS), Polyethylene Terephthalate Glycol (PETG), Polyvinyl Chloride (PVC), and Acrylonitrile, High density polyethylene (HDPE) or any other. The sinus DEB catheter is packed in other protective packaging such as Paper, PET, Aluminum foil, Tyvek® to perform sterilization and for maintaining the sterility. In the preferred embodiment, HDPE and Tyvek® are used as packaging material. The primary packed sinus DEB catheter may be sterilized by ethylene oxide (EtO), radiation sterilization like gamma or E-beam to obtain the SAL level of 10-6.
In the current embodiment, ethylene oxide sterilization is preferred for sterilization of sinus DEB catheter. This process includes conditioning, sterilization and aeration. The first sterilization cycle may have aeration time range from 02 hours to 05 hours, more preferably from 03 hours to 04 hours with ethylene oxide (EtO) gas exposure time around 45minutes. After completion of the first cycle, if sterility does not comply, then additional cycles of EtO exposure around 90 minutes may be performed with an aeration time of 03 hours to 05 hours.
Estimation of Mometasone furoate
The drug release profile of various formulations are represented in Figure 8. The drug release of various formulations varies from 30% to 90%. Quantification of mometasone furoate drug on balloon surface following sterilization can be determined using high performance liquid chromatography (HPLC). HPLC analysis is carried out using Agilent instrument. The identification of mometasone furoate is determined by the retention time of mometasone furoate. The concentration of mometasone furoate is determined from peak area in sample and standard. Balloon coated samples containing mometasone furoate is submerged in an extraction solvent and sonicated for 10 minutes. Samples are further diluted to concentrations within the calibration range if needed. All samples and standards are protected from light during preparation. HPLC chromatography parameters are mentioned in table 1.
Table 1: HPLC parameters
Column Inertsil C8 column
Size 250 x 4.6mm
Particle size 5.0µm
Mobile phase methanol:water (65:35)
Flow rate 1.7ml/min
Run time 30min
Injection volume 20µl
Purge solvent Acetonitrile
Wash solvent Methanol
Column temperature 25°C
UV detector wavelength 254nm

The present invention will be further understood by reference to the following non-limiting examples as listed below in Table 2.
Table 2: Coating Formulations for Sinus Drug Eluting Balloon (Sinus DEB)
Formulation Mometasone furoate (wt.%) Polyethylene glycol – 6000 (wt.%) Urea
(wt.%) Glycerol (wt.%) Acetone
(ml) Water
(ml)
A 40.00 60.00 - - 10 -
B 63.00 37.00 - - 10 -
C 60.00 28.00 8.00 4.00 09 01
D 61.85 29.89 - 8.24 10 -
E 59.41 27.72 4.95 7.92 09 01

The various process parameters crucial to deduce the present invention are entailed below in Table 3 and Table 4.
Table 3: Drug Coating parameters
Distance between balloon and spray Gun tip 5.0cm ± 0.2cm
Angle of spray To be adjusted as per balloon Length
Spray gun Oscillation 50 ± 5rpm
Collate rotation 18 ± 2rpm
Machine run time 50 ± 5sec
Machine hold time 20 ± 5sec
Nitrogen pressure 7.0 ± 0.5psi

Table 4: Pleat-fold parameter of drug coated balloon
Pleating process parameter
Temperature 40 ± 5°C
Dwell time 90 ± 9seconds
Balloon pressure 30 ± 5psi
Vacuum delay 20 ± 5seconds
Folding process parameter
Temperature 40 ± 5°C
Dwell time 90 ± 9seconds
Pressure 90 ± 10psi
Different formulations containing mometasone furoate, and the combination of excipients namely urea, glycerol and polyethylene glycol in acetone or water mixture were prepared as shown in table 2. The coating was applied on balloon surface as discussed earlier. The release of the drug observed in Phosphate Buffer Saline (PBS), pH 6.3, after pleat fold and EtO sterilization. Different body sites have different pH value due to the role of organ or site, structural changes and functional attributes. The pH of nasal cavity varies in the different region of the nasal cavity. The average pH of an anterior nose is 6.40 and of a posterior nasal cavity is 6.27. The overall range in pH was 5.17 - 8.13 for the anterior cavity and 5.20 - 8.00 for the posterior cavity. Therefore the average baseline human nasal cavity pH is 6.3 (Washington N, Steeler, Jackson. Journal of Pharmaceutical 198 (2000): 139146). For the estimation of Mometasone Furoate released, drug coated balloon is gently put into the PBS buffer (pH 6.3) and balloon is inflated-deflated for 4 to 5 times at nominal pressure (7 ATM). The dilution buffer containing Mometasone Furoate was subjected to HPLC analysis.
Formulation A: Coating of invention containing Mometasone furoate (40 wt.%) and Polyethylene glycol – 6000 (60 wt.%)
The mixture of mometasone furoate and Polyethylene glycol 6000 dissolved in 10ml acetone and homogenize by ultrasonication bath. The 0.6ml of mixture was applied on balloon (6.0 x17.0 mm) by spray coating methods. Coated balloon were kept under vacuum for overnight to dry at room temperature to evaporate the residual solvent and for drying of coating and then processed for pleat fold followed by EtO sterilization. Surface of balloon was uniform after pleat fold and minor deterioration of surface of coating observed after EtO treatment. However, very low, only 30%, drug release was observed in PBS (pH 6.3).
Formulation B: Coating of invention containing Mometasone furoate (63 wt %) and Polyethylene glycol – 6000 (37 wt %)
The mixture of mometasone furoate and Polyethylene glycol 6000 dissolved in 10ml acetone and homogenize by ultrasonication bath. The 0.6ml of mixture was applied on balloon (6.0 x17.0 mm) by spray coating methods. Coated balloon were kept under vacuum for overnight to dry at room temperature and then processed for pleat fold followed by EtO sterilization. Surface of balloon was found to be slightly damaged after pleat fold. Marginal decrease in the drug release (25 %) observed. Drug particles during inflation of balloon were seen to release as micro flakes in PBS (pH 6.3).
Formulation C: Coating of invention containing Mometasone furoate (63 wt%), Polyethylene glycol – 6000 (28 wt%), Urea (8 wt%), and Glycerol ( 4 wt%)
The mixture of mometasone furoate, Polyethylene glycol 6000, urea, and glycerol was dissolved in mixture of acetone and water. Thereafter mixture was homogenized by ultrasonication bath. The 0.6ml of mixture was applied on balloon (6.0 x17.0 mm) by spray coating methods. Coated balloon were kept under vacuum for overnight to dry at room temperature and then processed for pleat fold followed by EtO sterilization. The deterioration of the balloon surface after pleat fold was observed along with elevated surface destruction as micro-cracks. However, drug release observed twice than previous formulation in PBS (pH 6.3) but still dispersion was in form of micro-flakes and high amount of drug remains on balloon surface (Fig 5).
Formulation D: Coating of invention containing Mometasone furoate (61.85 wt %), Polyethylene glycol – 6000 (29.89 wt %), and Glycerol (8.24 wt %)
The mixture of mometasone furoate, polyethylene glycol 6000, and glycerol was dissolved in mixture of acetone. Thereafter mixture homogenized by ultrasonication bath. The 0.6ml of mixture was applied on balloon (6.0 x17 mm) by spray coating methods. Coated balloon were kept under vacuum for overnight to dry at room temperature and then processed for pleat fold followed by EtO sterilization. The addition of glycerol at mentioned ratio leads to improvement in the balloon surface after pleat fold. However micro fracture on balloon surface was observed after ETO sterilization. Although, it was far better than observed balloon coated with formulation C. Further improvement in drug (60%) release is observed in PBS (pH 6.3) as minute particles instead of flakes (Fig 6).
Formulation E: Coating of invention containing Mometasone furoate (59.41 wt %), Polyethylene glycol – 6000 (27.72 wt%), Urea (4.95 wt.%) and Glycerol (7.92 wt%)
The mixture of mometasone furoate, polyethylene glycol 6000, urea, and glycerol was dissolved in mixture of acetone and water. Coating solution was homogenized by ultrasonication bath. The 0.6ml of mixture was applied on balloon (6.0 x17.0 mm) by spray coating methods. Coated balloon were kept under vacuum for overnight to dry at room temperature and then processed for pleat fold and EtO sterilization. Formulation E leads to improvement in the smooth coating on balloon surface. Further balloon was subjected to pleat fold and EtO sterilization and it was observed no peel or crack on balloon surface. Around 90% of drug is finely dispersed in PBS (pH 6.3) solution. Also, it is seen that most of drug is released from the balloon leaving the balloon surface almost clear (Figure 7). The addition of urea and Polyethylene glycol – 6000 at specified concentration lead to the equilibrium between precipitation and solubilization of drug which promotes the rapid release of drug from balloon surface in form of small particles. Further, addition of glycerol acts as a humectant and smoothening agent and avoids peeling and cracking of the layer during pleat fold process.
While the present disclosure has been particularly shown and described with respect to various embodiments thereof, it will be understood by those skilled in the art that the foregoing and other changes in forms and details may be made without departing from the spirit and scope of the present disclosure. It is therefore intended that the present disclosure not be limited to the exact forms and details described and illustrated, but fall within the scope of the appended claims.
Although the invention herein is described with various specific embodiments, it will be obvious for a person skilled in the art to practice the embodiments herein with modifications. However, all such modifications are deemed to be within the scope of the invention. It is also to be understood that the description is intended to cover all of the generic and specific features of the embodiments described herein and all the statements of the scope of the embodiments which as a matter of language might be said to fall there between.

,CLAIMS:

We Claim:

1. A drug eluting balloon for localized delivery of drug to any paranasal cavity, wherein the balloon is coated with a single layer of drug formulation comprising mometasone furoate and/or its derivatives, water miscible solvent and/or water and excipients, wherein the drug to excipient ratio is in the range of 20:80 to 60:40 by weight.
2. The drug eluting balloon as claimed in claim 1, wherein the amount of mometasone furoate on balloon surface is in the range of 0.4 µg/mm2 to 1.5µg/mm2.
3. The drug eluting balloon as claimed in claim 1, wherein the excipients used are urea, polyethylene glycol, glycerol and the mixture thereof, in the ratio of 2:6:2 to 1:7:1.
4. The drug eluting balloon as claimed in claim 1, wherein the amount of urea and glycerol in the range of 2 to 10 wt%.
5. The drug eluting balloon as claimed in claim 1, wherein the drug coated balloon has six folds wrapped.
6. The drug eluting balloon as claimed in claim 1, wherein the cross profile of the drug coated balloon after wrapping/pleat folding ranges from 1.8mm to 2.2mm.
7. A method of preparation of drug eluting balloon for localized delivery of drug to any paranasal cavity, comprising:
coating of the balloon surface with single layer of drug formulation,
wrapping/pleat folding of the drug coated balloon at temperature range of 20°C to 60°C,
sterilization of the pleat folded balloon.
8. The method as claimed in claim 7, wherein drug formulation is applied on the inflated unfolded balloon.
9. The method as claimed in claim 7, wherein drug formulation is applied as a single layer on the inflated balloon through coating methods like spray coating, spin coating, electro-spin coating, rolling, sputtering, and more preferably spray coating technique.
10. The method as claimed in claim 7, wherein drug formulation comprises of an anti-inflammatory drug, a solvent and/or water, and excipients.
11. The method as claimed in claim 10, wherein an anti-inflammatory drug can be selected from glucocorticoid class, triamcinolone, cortisone, beclomethasone, mometasone furoate, methylprednisolone and other non-steroidal drugs, anti-inflammatory agents or their combination.
12. The method as claimed in claim 10, wherein the anti-inflammatory agent or therapeutic agent is mometasone furoate or its derivatives, the solvent is acetone, water or the mixture thereof and the excipients used are urea, polyethylene glycol, glycerol and the mixture thereof, in the ratio of 2:6:2 to 1:7:1.
13. The method as claimed in claim 12, wherein the polyethylene glycol used is polyethylene glycol 6000 acts as sustain release agent and plasticizer and its concentration is in the range of 10 to 30 wt%.
14. The method as claimed in claim 12, wherein urea and glycerol are used as dispersant and smoothening agent and the amount of urea and glycerol is in the range of 2 to 10 wt%.
15. The method as claimed in claim 7, wherein pleat folding or wrapping temperature is in the range of 20°C to 60°C, more preferably 35°C to 45°C, the dwell time for the process is between 80 and 90 seconds and pressure applied is in the range of 15psi to 30psi.
16. The method as claimed in claim 7, wherein the pleat folded balloon is sterilized using Ethylene Oxide processing with an aeration time of 2 hours to 5 hours.

Dated this 29th day of March, 2018