COMPLETESPECIFICATION(See section 10 and rule 13)
TITLESUTURABLE WOVEN IMPLANTS FROM ELECTROSPUN YARNS FOR SUSTAINED DRUG RELEASE IN BODY CAVITIESINVENTORSMENON, Deepthy, Citizen of IndiaPADMAKUMAR, Smrithi, Citizen of IndiaNAIR, Shantikumar V, Citizen of USACentre for Nanosciences and Molecular Medicine, Amrita Vishwa VidyapeethamPonekkara, Kochi –682041, Kerala, IndiaAPPLICANTSAMRITA VISHWA VIDYAPEETHAMCentre for Nanosciences and Molecular Medicine,Ponekkara, Kochi –682 041, Kerala, IndiaTHE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED
201741032588 AMRITA VISHWA VIDYAPEETHAM-2-SUTURABLE WOVEN IMPLANTS FROM ELECTROSPUN YARNS FOR SUSTAINED DRUG RELEASE IN BODY CAVITIESCROSS-REFERENCES TO RELATED APPLICATIONS[0001]This application is a complete specificationof provisional patent application no. 201741032588 entitled “WOVEN FABRIC IMPLANTS FOR INTRAPERITONEAL THERAPY”filed on September 14, 2017.FIELD OF THE INVENTION[0002]The present invention relates to drug delivery devices, method of use thereof, anda method of manufacturing thereof and in particular to suturablewoven implants for providing controlled and sustained release of a drug in body cavities. DESCRIPTION OF THE RELATED ART[0003]Polymeric biodegradable implants are desirable for various medical applications demanding localized and sustained release of any therapeutic molecule for several days to months.The use of implantable matrices helpsto achieve site-specific and targeted effects in comparison to the conventional clinical strategy of systemic intravenous therapy. Body cavities such as peritoneum, brain, bladder, eye,etc are often primary or secondary sites of several diseases or malignancies. The drug depots implanted at these targeted sites help to prevent or treat these diseases which are confined to the particular body cavity. [0004]The US patent publication US20140363484A1 is directed to the development of a fibrous flexible biodegradable drug loaded polymeric wafer system for local delivery of therapeutic agents in combination. Here, combinations of polymers have been used to deliver multiple drugs, enabling sustainedrelease over a period of one month. The US patent publication US20150037375A1is directedto 3-dimensional drug-eluting materials comprising therapeutic biodegradable polymer(s), with time-release properties
201741032588 AMRITA VISHWA VIDYAPEETHAM-3-that are described to permit the release of oneor more therapeutic agents to a subject over extended time periods.WO2016159240A1 relates to a method of producing biodegradable drug loaded fibers as non-woven structures by electrospinning and using them for local sustained drug release in the body. TheUSpatentpublication US20100303881A1provides electrospun fiber compositions comprising one or more polymers and one or more biologically active agents, whereinadjustments todensity of the electrospun fiber composition is suggested to increase or decrease the length of time that therapeutic molecules are released from the composition.All these relate to the use of non-woven, biodegradable, fibrous implants developed through electrospinning for achieving sustained releasing drug depots. [0005]The PCT application WO2008033533is related to a device having a fabric constructed from an oriented multifilament yarn loaded with a therapeutic agent. A composite drug delivery system composed of a fabric wrapped by a drug laden biodegradable matrix coating is disclosedfor facilitating drug delivery within a vascular graft. The fabric provides a mechanical reinforcement while the copolymeric matrix coating elutes the entrapped therapeutic agent/ bioactive. It is due to the co-polymer coating a predictable rate of polymer degradation and therapeutic agent release is predicted. The US patent US8974814 is directed to a layered polymeric monofilament fiber drug delivery device, where each layer of the device can contain a different polymer, drug, additive, or any combinationthereof.Anon-woven fabric comprising of thermally stable absorbable fiber population in disclosed in the US patent publication US20170167064A1, to provide a medical barrier for a range of medical applications. [0006]The main attributes of designing a drug eluting depot which can be implanted within any body cavity are the ability to control and sustain the release of the therapeutic agent for several days and the easiness to fix or implant the device to the body cavity. It is imperative to maintain adequate drug concentrations in the desirable target within cavity or site to attain and prolong the therapeutic activity. Slow and continuous release
201741032588 AMRITA VISHWA VIDYAPEETHAM-23-paclitaxel in PDS yarns.Quantitatively, PTXentrapmentefficiency in PDSyarns was estimated by HPLC to be 86±10%.[0092]Example 9 :Thermal analysis of degraded yarns [0093]FIG. 12shows the DSC spectra of Paclitaxel (PTX)-PDSyarns at 0, 30, 90 and 120 days indicating the shift in melting endotherms of degraded PTX-PDSyarns from 105.03°C to lower temperatures (102.37, 98.19, 93.32°C) over 30, 90 and 120 days in the course of degradation.It is known that, during hydrolytic degradation, water entry into the amorphous regions of PDSwould be faster than its crystalline regions. This would lead to chain scission of hydrolytically unstable ester bonds found in amorphous parts of PDSwhich ultimately reduces the molecular weight of polymer, which is reflected in the shift in melting endotherms of degraded yarns.[0094]Example 10: In vivoimplantation of woven fabric in mice [0095]FIG. 13A-Cshows the in vivoimplantation of woven fabric in mice. FIG. 13A shows a photograph of flexible lace of loosely packed woven fabricafter plain weaving process. FIG. 13Bshows surgical implantation of fabric into healthy BALB/c mouse (inset: 1x1cm2 1/1 LPfabricimplant weighing 20mg) by suturing to mouse peritoneal cavity walland subsequent closure of the peritoneal wall and skin. FIG. 13C shows post mortem view of the mouse peritoneum upon euthanasia at 1 weekshowing the intact implant fixed at its sutured site. [0096]The implants remained intact at sutured site at all euthanasia time points (1, 3, 7, 14,28, 42, 56 days). Post-mortem examination of peritoneum revealed no signs of infection,inflammation or fibrous encapsulation of implant. In contrast to woven nanotextile, non-woven electrospun PTX-PDS mats could not be suturedalong the peritoneal wall owing to their inferior mechanical integrity. When placed withoutsuturing in peritoneal cavity, mats migrated to distant locations and hence were fixed toperitoneal wall bya surgical suture-knot. However, these animals could not survive for morethan 4 weeks, with considerably reduced food intake and fecal excretion. Post-mortemexamination of morbid animals revealed the migration and attachment of
201741032588 AMRITA VISHWA VIDYAPEETHAM-24-implant to peritonealorgans, mainly the intestine, with high fibrous encapsulation of implant, bowel obstruction,swollen-abdomen with blood-filled cavity and feces accumulation. Similarly, the exemplified implant may be implanted in any body cavity. [0097]Example 11: In vivodrug release of woven fabric in mice [0098]FIG. 13D shows the in vivo Paclitaxel release profile until 8 weeks (n=5/ time point)analyzedby HPLCshowing the sustained drug release profile from woven fabric in mice peritoneal cavity for 2 months with 83.4±6.47% of total drug released in about 2 months and thereby indicating the possibility to elute further.[0099]Although release rates were somewhat higher than for thein vitro case, sustained release over a sixty day period could still be obtained which has not beenpossible with conventional polymers before. 11.67±3.77% of encapsulated-PTX was released on day 1 and 51.67±3.44% on day 3. This initial burst, which could becompared to PTX loading dose administered in current IP therapy is a benefit, owing tothe PK advantages of PTX, giving enhanced therapeutic efficacy. The initial burst wasfollowedby a steady increase in drug concentration with nearly 83.4±6.47 % of total PTXcontentreleased within 8 weeks, implying its potential to elute drug further. [00100]Example 12: In vivolong term stability of woven fabric in mice [00101]FIG. 13Eshows the photographs of mice implanted with woven fabric implant (indicated by arrow marks) euthanized at different time points until 8 weeks. The fabric remains intact at the sutured location throughout the treatment periodwithout intense fibrous tissue formation around the implant.[00102]Example 12: In vivobiodistribution of Paclitaxel woven fabric in mice in comparison to IP Taxol injected mice. [00103]FIG. 14 shows the drug levels in mice implanted with Paclitaxel–PDSwoven fabric implant at various time pointsanalyzedby HPLC(A)peritoneal lavage and plasma samples (B) various tissues (inset table: average weight of organs after dissection)(n=5). (C) Drug biodistribution in mice injected with IP Taxol as control group (20mg/kg) at
201741032588 AMRITA VISHWA VIDYAPEETHAM-25-day 1 (n=5). (D) Drug excretion profile of mice with woven fabric and IP Taxol (inset table: average feces weight at various time points). Data shown as mean±SD, *p<0.05.[00104]Peritoneal lavage collected post-implantation on days 1,3 and 7 yielded PTX concentrations of 4.31±1.9, 1.54±1.5 and 0.6±0.21μg/ml respectively, indicating high PTX retention in peritoneumrelative to plasma, and therefore the PK advantage of IP therapy.PTX distribution to various vital organs was analyzed post implantation of woven nanotextileup to8 weeksshows PTX peaks in all peritoneal organs (intestine, spleen, stomach,liver, and kidney) till day 56, with no traces of PTX in heart and lungs. Thus, the extended drugrelease from woven nanotextile was also evident from PTX biodistribution profile. [00105]Mice injected with IP taxol did not show Paclitaxel in plasma or peritoneal lavage at 24hours and thereafter,indicating the rapid clearance of the drug. The sustained drug levels in plasma and peritoneal lavage were noted for mice bearing woven fabric. Peritoneal organs showed drug peaks only for day 1 for mice injected with IP Taxol whereas all peritoneal organs retained drug peaks throughout the treatment period (8 weeks) for mice implanted with woven fabric implants. This result was also observed for drug peaks in feces, confirming the sustained drug release from woven fabric when implanted in vivo.
201741032588 AMRITA VISHWA VIDYAPEETHAM-26-WE CLAIM:1.A device, comprising: a flexiblewovenfabric (100) having a variable packing density, dimension and weight, the fabric comprising electrospuncontinuousfibrous yarn with individual micro-or nano-fibers (105), the fiber comprising a single polymer matrix (107) loadedwith at least one therapeutic agent(109), wherein the at least one therapeutic agent is loadedin the single polymer matrixat a predeterminedconcentration,andwherein the device is configured to be sutured tothe wall of a body cavity of a subject to provide controlled and sustained release of the therapeutic agent. 2. The device of claim 1, wherein diameter of the electrospun fibrousyarn is in the range of 1 μm to 500μmand individual fiber diameter of the electrospun fibrous yarnis in the range of 200nm to 2000 nm.3. The device of claim 1, wherein weave pattern of the first wovenfabric is selected from the group of plain weave, twill weave, satin weave, dobby weave, basket weave, jacquard weave, rib weave, leno weave, oxford weave, or a combination thereof.4.The device of claim1, wherein the device provides controlled and sustained release of the therapeutic agent for at least 1month. 5.The device of claim 1, wherein the single polymer is selected from the group of polyesters, polyethers, polyanhydrides, polycarbonates, polyphosphazenes, poly(amino acids), polypeptides, glycosaminoglycans, polysaccharides, polydioxanone (PDS), poly(lactide-coglycolide) (PLGA), polyglycolic acid (PGA), polylactic acid (PLA), or polycaprolactone (PCL)or the non-biodegradable polymers such as poly(ether urethanes), polystyrene, polyethylene,polyacetylene, poly(propylene), poly(tetrafluroethylene), poly(methymethacrylate), poly(ethylene-co-vinylacetate), poly(dimethylsiloxane), poly(ethylene terphthalate) and poly(sulphone).