Patent Application: US-201213690529-A

Abstract:
a surgical gel system for coating and adhering to a wound area to control bleeding whilst supporting wound healing comprises polyanhydroglucuronic acid or a biocompatible salt in an amount of from 1 % to 15 % by weight and pectin in an amount of in an amount of from 0 . 1 % to 9 % by weight . the gel system may be used for stopping bleeding during or after sinus surgery , for stopping bleeding in ear nose and throat procedures , for stopping bleeding in gynecological procedures , or for stopping bleeding in internal organ procedures .

Description:
although the disclosure hereof is detailed and exact to enable those skilled in the art to practice the invention , the physical embodiments herein disclosed merely exemplify the invention which may be embodied in other ways . while the preferred embodiment has been described , the details may be changed without departing from the invention . the present invention provides products and methods for controlling the bleeding from wounds such as those occurring during surgery without affecting access or visualisation of the surgical site . upon application of the gel system to the bleeding surgical site , the gel system adheres to and coats the immediate injury providing for the polysaccharide to both restrict and interact with blood flowing from injury . this interaction reduces the bleeding from the site by physical occlusion and by accelerating the hemostasis of the blood . most notably , the system of the present invention has shown beneficial qualities by successfully reducing bleeding quickly thus enabling the surgeon to continue the required procedure . further notably the system stops the bleeding in a manner that allows continuation of the surgical procedure as the system functions without occluding the view of the surgical field . in demonstration of the applicability of this system to the general surgical field , this invention disclosure has chosen as its model the difficult surgical field of endoscopic sinus surgery within the nasal passage . the present system provides advantages over other nasal hemostatic treatments not alone in its speed to controlling bleeding for the surgeon but also in the lack of pain and discomfort experienced in use by the patient associated by other methods that employ packing or stent systems . a further advantage of this system is the support of the wound healing process by the gel system that is in contrast to other nasal bleeding treatments that can have unfavourable consequences on the wound healing process . the system described herein may be applied to the injured sites in many different types of delivery device such as syringes , tubes or other such commonly used gel delivery devices . having described the invention in general terms , reference is now made to specific non - limiting examples . in this example , the raw material for preparing a calcium sodium salt of microdispersed polyanhydroglucuronic acid were cotton linters containing 99 . 1 % w / w of α - cellulose and oxidized in 60 % w / w nitric acid with an admixture of 3 . 8 % nitrous acid at a temperature of 30 ° c . max in analogy to procedure of gbp 709684 . the resulting product contained : 600 ml of water and 27 g of sodium hydroxide were transferred to a 2000 ml jacketed glass - vessel stirred by ultra - turrax stirrer t50 ( ika werke cmbh & amp ; co . kg , germany ). after dissolving of the sodium hydroxide the above defined oxidized cotton linters containing about 10 % of volatile matter were added while constantly stirring at ca 4000 rpm for at least 30 minutes . temperature was maintained on 30 ° c . max . then 80 grams of water solution of calcium chlorate hexahydrate ( 1 / 1 w / w ) and 25 g of peroxide were added and reaction mixture was stirred at 5000 rpm for next 60 minutes at temperature of 30 ° c . max . 1000 ml of 93 % ethanol were added stepwise during about 10 minutes and the resulting colloid dispersion solution was then filtered . obtained filter cake was dispersed into 55 % water - ethanol mixture and another filtration of the residue was redispersed into 500 ml isopropanol and allowed to stand for at least 5 hours . all these steps were in analogy to application wo 2007 / 026341 . isolated filter cake was again redispergated into 500 ml isopropanol and to the reaction mixture there was added 5 grams of carboxymethyl cellulose , blanose 12m31p ( aqualon hercules ; wilmington , del ., u . s . a ). mixture was allowed to stand for at least 10 hours . final prepared mixture was filtered and dried in a vacuum drier at the temperature of 70 ° c . and milled . the viscosity of the prepared gel was 617 , 000 cp at 37 degrees c . ( brookfield dv - ii + pro digital viscometer , lv - 4 spindle , 0 . 3 rpm ). the gel is sterilised by gamma irradiation between 4 and 45 kgy , sufficient to produce a sterility assurance limit ( sal ) of 10 − 6 . alternatively , material may be processed aseptically from materials to produce a material with a sterility assurance limit ( sal ) of 10 − 6 . the viscosity of the sterilised gel was 311 , 000 cp at 37 degrees c . ( brookfield dvii + pro digital viscometer , lv - 4 spindle , 0 . 3 rpm ) the viscosity of the material is suitable for dispensing through a nozzle or small office to the site of bleeding . the dispensing apparatus could be a syringe , a tube or any such similar device . in this example the gel was loaded into a syringe prior to sterilsation . after opening of the syringe tip at point of use a flexible / malleable tip may be attached to the tip to facilitate insertion into a sinus cavity . the viscosity of the prepared gel was 607 , 000 cp at 37 degrees c . ( brookfield dv - ii + pro digital viscometer , lv - 4 spindle , 0 . 3 rpm ). the gel is sterilized by gamma irradiation between 4 and 45 kgy , sufficient to produce a sterility assurance limit ( sal ) of 10 − 6 . alternatively , material may be processed aseptically from materials to produce a material with a sterility assurance limit ( sal ) of 10 − 6 . the viscosity of the sterilised gel was 250 , 000 cp at 37 degrees c . ( brookfield dvii + pro digital viscometer , lv - 4 spindle , 0 . 3 rpm ) the viscosity of the material is suitable for dispensing through a nozzle or small orfice to the site of bleeding . the dispensing apparatus could be a syringe , a tube or any such similar device . in this example the gel was loaded into a syringe prior to sterilsation . after opening of the syringe tip at point of use a flexible / malleable tip may be attached to the tip to facilitate insertion into a sinus cavity . the tack of the gel was measured using en - 1719 : 1998 [ tack measurement for pressure - sensitive adhesives — determination of loop tack ] with a 1 ″× 7 ″ teflon ™ loop at 23 ± 2 ° c . and a crosshead speed of 5 mm / s . three batch lots of the gel were tested as follows as per en - 1719 : 1998 . the results of the tack test are given in fig1 with the ranges presented below . use of sterile haemostatic gel in swine nasal mucosal laceration injuries the haemostatic gel of example 1 was applied to swine nasal mucosa laceration injuries with bleeding rates between 3 to 25 ml / min and successful hemostasis was achieved . a commercially available nasal dressing and sinus stent hydrogel composed of cross - linked hyaluronic acid was used as a control gel . application of the calcium - sodium microdispersed polyanhydroglucuronic acid containing gel coated the surface of the injury , facilitates interaction between the bleeding site and the microdispersed oxidized cellulose ( fig2 ). 70 % reduction in bleeding was achieved within 1 . 5 minutes and with 90 % reduction in bleeding in as little as 3 minutes . the gel was adherent and coated vertical and inverted tissue surfaces . the control gel only achieved 70 % reduction in bleeding after approximately 6 minutes and did not achieve 90 % reduction in bleeding in the course of the study . this swine study demonstrated successfully the efficacy of the formulation to stop bleeding in a nasal injury such as that seen in sinus surgeries especially when compared to a commercially available gel for similar use . a frequent complication of functional endoscopic sinus surgery ( fess ) is the development of post - operative adhesions , which may block normal mucociliary drainage pathways of the sinuses . this blockage can cause a recurrence of sinusitis and require subsequent surgical procedures . to prevent post - operative bleeding and adhesion formation , nasal packing is often used . alternatives to nasal packing include intranasal splints and gels , though the majority of these products employ the tamponade effect to achieve haemostasis , which can contribute to abnormal nasal breathing and significant patient discomfort . an optimal haemostat for endoscopic sinus surgery would effectively control bleeding and minimise adhesion formation , scar formation and inflammation of the mucosal tissue . the purpose of this study was to evaluate the post - operative performance of the haemostatic gel . singer et al [ 20 ] describes a porcine model to mimic functional and morphological changes in mucosa following fess . mucosal stripping of the lateral nasal wall induced bleed rates characteristic of fess in 10 yorkshire pigs and the haemostatic gel of example 2 was applied to control bleeding . defect sites ( n = 10 ) were treated and allowed to heal for 2 weeks . at euthanasia , each site was qualitatively assessed for scarring , clot formation , nasal cavity patency and residual hemostatic material . histological sections were taken from each defect site , stained with hematoxylin and eosin ( h & amp ; e ) and blindly evaluated by an independent pathologist to assess cell morphology , mucosal re - epithelialization and granulation tissue . all animals tolerated the surgeries well and returned to normal activity immediately . intra - operative assessment showed that bleeding was effectively controlled at all defect sites in an average of 3 . 1 minutes following application of the haemostatic gel of example 2 . endoscopic evaluation at necropsy indicated no evidence of adhesions , scarring or residual hemostatic material . no clots or signs of recent bleeding were observed and no gross inflammation or erythema was noted in any defect . histological evaluation showed excellent re - epithelization of all defect sites with no cellular abnormalities ( fig3 ). no foreign material or granuloma formation was identified in any specimen . quality of the underlying tissue was shown to be in a “ healing ” phase suggestive of a response to the mucosal stripping injury . a small amount of epithelial scarring was present in the normal range for this stage of healing , but no hypertrophic scarring was observed . the investigation demonstrates that the haemostatic gel of the invention can effectively control bleeding associated with fess . furthermore , the gel enables re - epithelialisation of the mucosa and subsequent natural wound healing without adhesion or granuloma formation . the purpose of the post - market clinical evaluation was to summarise the clinical use to - date of the haemostatic gel . specifically , the objectives of the clinical evaluation were to evaluate the gel &# 39 ; s intra - operative haemostatic efficacy , its ability to coat the mucosal surface , delivery device ergonomics and various elements of the gel &# 39 ; s application technique . the haemostatic gel of example 2 was utilised by five surgeons in nine separate cases . the nine cases can be broken down as follows : five functional endoscopic sinus surgeries ( fess ), two fess procedures combined with septoplasty and two fess procedures combined with sub - mucosal resection ( smr ) of the inferior turbinate . surgeon reaction to the haemostatic gel was uniformly positive and the summarised responses to the individual questions are tabulated in the table below . surgeons appreciated the flexible applicator tip supplied with the gel that allowed surface application of the gel throughout the sinus cavities . moreover , all surgeons indicated that application of the product controlled observed bleeding to their satisfaction . traditional products used to impart haemostasis depend upon a tamponade effect , whereby the pressure applied by volume - filling gel helps to control bleeding ; however , the haemostatic gel was able to control bleeding at the mucosal surface while keeping the nasal passages open . in summary , the device of the invention successfully controlled minimal - moderate bleeding typically associated with ent surgical procedures . data has also been collected from patient follow - up visits to evaluate tissue healing characteristics , incidence of post - operative bleeding and nasal patency . these results serve as confirmatory data of the product &# 39 ; s ability to minimise oedema and prevent adhesions post - operatively . the follow - up data indicates that the gel cleared from the patient following surgery with no adverse tissue reactions the haemostatic gel of the invention effectively coats the mucosal tissue while simultaneously controlling bleeding typically associated with ent surgical procedures . the prepared gel had a viscosity of cp at 37 degrees c . ( brookfield dv - ii + pro digital viscometer , lv - 4 spindle , 0 . 3 rpm ). the gel of example 5 was filled into 15 ml tube dispensers and was not sterilized . the gel was applied to a bleeding grazed hand wound by application from the tube . gentle spreading of the gel over the bleeding wound stopped the bleeding from the wound in 2 minutes . the gel prepared in example 5 was tested for its ability to support wound healing . a rat excisional model ( biopharm , study code : 179 / 2006 efficiency of the test items on dermal wound healing in rats ) was used to examine the potential wound healing effects of the haemostatic gel . the rats underwent experimental wounding on dorsal region of the animal . experimental wounds were made under general ketamine and xylazine anaesthesia ( ketamine 100 mg / kg + xylazine 10 mg / kg of body weight ). the anaesthetic agents were administered intraperitoneally into abdominal region . an appropriate sized shaved area was created on the rats back region and 3 wounds ( 1 cm diameter ) were made with a steel punch appliance on this area . all animal work was performed under local guidelines and regulations and to glp standard . the gel of example 5 ( or a non treatment control ) was topically administered twice a day on the wounds with sufficient gel applied to cover the exposed wound . the wound area reduction , closure and healing ( incidence of wound secretion , haemorrhagic crust and scar formations ) were monitored daily . at the end of healing process all rats were sacrificed by co2 inhalation and dermal samples were taken for histological examination . the wound area was measured for each wound daily and the results for the untreated control and the gel can be seen in fig4 . the results found showed significantly improved dermal healing from day 5 through day 8 . subsequently by the end of the study the control group had also shown reduction in wound area . it can be concluded from these results that the gel did have a stimulatory effect on wound healing process and was certainly quicker to achieve wound closure of the experimental injuries . the gel prepared in example 5 was tested for its ability to be antimicrobial . the antimicrobial efficacy of the gel was tested against a number of strains of micro - organisms consisting of bacteria , fungi and yeast . in summary , strains of micro - organisms were inoculated into tested preparations with storage of the inoculated preparations at the prescribed temperature , and sampling at determined time intervals and testing for viable counts of colony forming units ( cfu ) by us pharmacopeia method 28 . the decrease in cfus was measured and the results re presented in the table below . it could be seen that the gel formulation was antimicrobial as it did reduce the numbers of microorganisms tested . the prepared mixture can be used successfully as a haemostatic agent for a surgical gel intended to reduce bleeding . modifications and additions can be made to the embodiments of the invention described herein without departing from the scope of the invention . for example , while the embodiments described herein refer to particular features , the invention includes embodiments having different combinations of features . the invention also includes embodiments that do not include all of the specific features described . the invention is not limited to the embodiments hereinbefore described which may be varied in detail . 1 . valentine , r ., p . j . wormald , and r . sindwani , advances in absorbable biomaterials and nasal packing . otolaryngol clin north am , 2009 . 42 ( 5 ): p . 813 - 28 , ix . 2 . virgin , f . w ., b . s . bleier , and b . a . woodworth , evolving materials and techniques for endoscopic sinus surgery . otolaryngol clin north am , 2010 . 43 ( 3 ): p . 653 - 72 , xi . 3 . bugten , v ., et al ., effects of nonabsorbable packing in middle meatus after sinus surgery . laryngoscope , 2006 . 116 ( 1 ): p . 83 - 8 . 4 . chandra , r . k . and r . c . kern , advantages and disadvantages of topical packing in endoscopic sinus surgery . curr opin otolaryngol head neck surg , 2004 . 12 ( 1 ): p . 21 - 6 . 5 . huggins , s ., control of hemorrhage in otorhinolaryngologic surgery with oxidized regenerated cellulose . eye ear nose throat mon , 1969 . 48 ( 7 ): p . 420 - 3 . 6 . shaw , c . l ., et al ., effect of packing on nasal mucosa of sheep . j laryngol otol , 2000 . 114 ( 7 ): p . 506 - 9 . 7 . von schoenberg , m ., p . robinson , and r . ryan , nasal packing after routine nasal surgery — is it justified ? 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