Bioadhesive chitosan gel for controlling bleeding and for promoting healing with scar reduction without obscuring or interfering with access to a surgical field

Abstract

An aqueous chitosan gel system of novel non-scarring, non-interfering, transparent, stable, solubilized chitosan that controls bleeding is described herein. The aqueous chitosan gel system can comprise water, chitosan, an acid, a plasticizer, a rheology modifying agent, an antioxidant stabilizer, an alcohol, and a multi-valent salt. Additional components of the aqueous chitosan gel system can comprise a bifunctional organic acid, a tnfunctional organic acid, a multi-functional organic acid, a phosphoric acid, a polyphosphoric acid and a salt.

Claims

1. An aqueous gel comprising: water in an amount greater than about 88% (w/w); chitosan in an amount of about 3% (w/w); an acid component including one or more of a monofunctional organic acid in an amount of about 0.5% to about 7% (w/w), a difunctional or trifunctional organic acid in an amount up to about 5% (w/w), a polyfunctional organic acid in an amount up to about 3% (w/w), or an inorganic phosphoric, triphosphoric, or polyphosphoric acid in an amount up to about 3% (w/w), and wherein lactic acid, a monofunctional organic acid, is included in an amount of about 2% (w/w); a rheology modifying agent including hydroxyl propyl methyl cellulose in an amount of about 0.5% (w/w), polyethylene oxide in an amount of about 0.2% (w/w), poloxamer in an amount of about 0.2% (w/w), and polypropylene glycol in an amount of about 0.1% (w/w); an antioxidant stabilizer in an amount of about 0.1% to about 2.5% (w/w), wherein said antioxidant stabilizer is selected from the group consisting of methylparaben, tannic acid, trolox, quercetin, catechin, glutathione, ferulic acid, carotenoid, proanthocyanidin, and ascorbic acid, and including methylparaben in an amount of about 0.2%; an alcohol in an amount of about 0.2% to about 10% (w/w), and including ethanol in an amount of about 5% (w/w); and a multi-valent salt in an amount of about 0.1% to about 0.5% (w/w), and including CaCl.sub.2 in an amount of about 0.3% (w/w).

2. The aqueous gel of claim 1, wherein the aqueous gel is at least one of clear and transparent.

3. The aqueous gel of claim 1, wherein the aqueous gel is stable for a period up to three years at about 23° C.

4. The aqueous gel of claim 1, further comprising at least one of a plasticizer in an amount up to about 5% (w/w) or an anti-microbial agent.

5. The aqueous gel of claim 1, wherein the aqueous gel is bioabsorbable and the chitosan has a percent degree of deacetylation between 20% and 40%.

6. The aqueous gel of claim 1, wherein the aqueous gel is removable and the chitosan has a percent degree of deacetylation greater than about 78%.

7. An aqueous gel comprising: water in an amount greater than about 83.5% (w/w); chitosan in an amount of about 5.7% (w/w); an acid component including one or more of a monofunctional organic acid in an amount of about 0.5% to about 7% (w/w), a difunctional or trifunctional organic acid in an amount up to about 5% (w/w), a polyfunctional organic acid in an amount up to about 3% (w/w), or an inorganic phosphoric, triphosphoric, or polyphosphoric acid in an amount up to about 3% (w/w), and wherein lactic acid, a monofunctional organic acid, is included in an amount of about 3.5% (w/w); a rheology modifying agent including hydroxyl propyl methyl cellulose in an amount of about 0.5% (w/w), polyethylene oxide in an amount of about 0.2% (w/w), poloxamer in an amount of about 0.2% (w/w), and polypropylene glycol in an amount of about 0.1% (w/w); ascorbic acid in an amount of about 1% (w/w); an alcohol in an amount of about 0.2% to about 10% (w/w), and including ethanol in an amount of about 5% (w/w); and a multi-valent salt in an amount of about 0.1% to about 0.5% (w/w), and including CaCl.sub.2 in an amount of about 0.3% (w/w).

8. The aqueous gel of claim 7, wherein the aqueous gel is at least one of clear and transparent.

9. The aqueous gel of claim 7, wherein the aqueous gel is stable for a period up to three years at about 23° C.

10. The aqueous gel of claim 7, further comprising at least one of a plasticizer in an amount up to about 5% (w/w) or an anti-microbial agent.

11. The aqueous gel of claim 7, wherein the aqueous gel is bioabsorbable and the chitosan has a percent degree of deacetylation between 20% and 40%.

12. The aqueous gel of claim 7, wherein the aqueous gel is removable and the chitosan has a percent degree of deacetylation greater than about 78%.

13. An aqueous gel comprising: water in an amount greater than about 80% (w/w); chitosan in an amount of about 2% to about 12% (w/w); an acid component including one or more of a monofunctional organic acid in an amount of about 0.5% to about 7% (w/w), a difunctional or trifunctional organic acid in an amount up to about 5% (w/w), a polyfunctional organic acid in an amount up to about 3% (w/w), or an inorganic phosphoric, triphosphoric, or polyphosphoric acid in an amount up to about 3% (w/w); a rheology modifying agent in an amount of about 0.5% to about 5% (w/w); an antioxidant stabilizer in an amount of about 0.1% to about 2.5% (w/w), wherein said antioxidant stabilizer is selected from the group consisting of methylparaben, tannic acid, trolox, quercetin, catechin, glutathione, ferulic acid, carotenoid, proanthocyanidin, and ascorbic acid; an alcohol in an amount of about 0.2% to about 10% (w/w); a multi-valent salt in an amount of about 0.1% to about 0.5% (w/w); and an anti-microbial agent, wherein the antimicrobial agent is selected from the group consisting of silver, chitosan derivatives that are polycationic between pH 6.8-7.8, chlorhexidine gluconate, iodine and polyhexamethyl biguanide.

14. The aqueous gel of claim 13, wherein the aqueous gel is at least one of clear and transparent.

15. The aqueous gel of claim 13, wherein the aqueous gel is stable for a period up to three years at about 23° C.

16. The aqueous gel of claim 13, further comprising at least one of a plasticizer in an amount up to about 5% (w/w) or an anti-microbial agent.

17. The aqueous gel of claim 13, wherein the aqueous gel is bioabsorbable and the chitosan has a percent degree of deacetylation between 20% and 40%.

18. The aqueous gel of claim 13, wherein the aqueous gel is removable and the chitosan has a percent degree of deacetylation greater than about 78%.

19. A surgical method comprising applying to an injury an aqueous gel comprising: water in an amount greater than about 88% (w/w); chitosan in an amount of about 3% (w/w); an acid component including one or more of a monofunctional organic acid in an amount of about 0.5% to about 7% (w/w), a difunctional or trifunctional organic acid in an amount up to about 5% (w/w), a polyfunctional organic acid in an amount up to about 3% (w/w), or an inorganic phosphoric, triphosphoric or polyphosphoric acid in an amount up to about 3% (w/w), and wherein lactic acid, a monofunctional organic acid, is included in an amount of about 2% (w/w); a rheology modifying agent including hydroxyl propyl methyl cellulose in an amount of about 0.5% (w/w), polyethylene oxide in an amount of about 0.2% (w/w), poloxamer in an amount of about 0.2% (w/w, and polypropylene glycol in an amount of about 0.1% (w/w); an antioxidant stabilizer in an amount of about 0.1% to about 2.5% (w/w), wherein said antioxidant stabilizer is selected from the group consisting of methylparaben, tannic acid, trolox, quercetin, catechin, glutathione, ferulic acid, carotenoid, proanthocyanidin, and ascorbic acid, and including methylparaben in an amount of about 0.2%; an alcohol in an amount of about 0.2% to about 10% (w/w), and including ethanol in an amount of about 5% (w/w); and a multi-valent salt in an amount of about 0.1% to about 0.5% (w/w), and including CaCl.sub.2 in an amount of about 0.3% (w/w), to control bleeding or facilitate hemostasis during or after one or more of sinus surgery, ear nose and throat procedures, oral and maxillofacial surgery, orthopedic surgery, urological surgery, reconstructive surgery, cosmetic surgery, vascular surgery, transplant surgery, neurological surgery, oncological resection surgery involving the biopsy and removal of tumors, gynecological surgery, and general topical bleeding.

20. The method of claim 19, wherein the chitosan interacts with components of blood in the injury to control bleeding and facilitate hemostasis.

21. The method of claim 19, further comprising allowing bioabsorption of the aqueous gel, wherein the chitosan has a percent degree of deacetylation between 20% and 40%.

22. The method of claim 19, further comprising removing the aqueous gel from the injury, wherein the chitosan has a percent degree of deacetylation greater than about 78%.

23. A surgical method comprising applying to an injury an aqueous gel comprising water in an amount greater than about 83.5% (w/w); chitosan in an amount of about 5.7% (w/w); an acid component including one or more of a monofunctional organic acid in an amount of about 0.5% to about 7% (w/w), a difunctional or trifunctional organic acid in an amount up to about 5% (w/w), a polyfunctional organic acid in an amount up to about 3% (w/w), or an inorganic phosphoric, triphosphoric, or polyphosphoric acid in an amount up to about 3% (w/w), and wherein lactic acid, a monofunctional organic acid, is included in an amount of about 3.5% (w/w); a rheology modifying agent including hydroxyl propyl methyl cellulose in an amount of about 0.5% (w/w), polyethylene oxide in an amount of about 0.2% (w/w), poloxamer in an amount of about 0.2% (w/w), and polypropylene glycol in an amount of about 0.1% (w/w); ascorbic acid in an amount of about 1% (w/w); an alcohol in an amount of about 0.2% to about 10% (w/w), and including ethanol in an amount of about 5% (w/w); and a multi-valent salt in an amount of about 0.1% to about 0.5% (w/w), and including CaCl.sub.2 in an amount of about 0.3% (w/w), to control bleeding or facilitate hemostasis during or after one or more of sinus surgery, ear nose and throat procedures, oral and maxillofacial surgery, orthopedic surgery, urological surgery, reconstructive surgery, cosmetic surgery, vascular surgery, transplant surgery, neurological surgery, oncological resection surgery involving the biopsy and removal of tumors, gynecological surgery, and general topical bleeding.

24. The method of claim 23, wherein the chitosan interacts with components of blood in the injury to control bleeding and facilitate hemostasis.

25. The method of claim 23, further comprising allowing bioabsorption of the aqueous gel, wherein the chitosan has a percent degree of deacetylation between 20% and 40%.

26. The method of claim 23, further comprising removing the aqueous gel from the injury, wherein the chitosan has a percent degree of deacetylation greater than about 78%.

27. A surgical method comprising applying to an injury an aqueous gel comprising: water in an amount greater than about 80% (w/w); chitosan in an amount of about 2% to about 12% (w/w), an acid component including one or more of a monofunctional organic acid in an amount of about 0.5% to about 7% (w/w) a difunctional or trifunctional organic acid in an amount up to about 5% (w/w), a polyfunctional organic acid in an amount up to about 3% (w/w), or an inorganic phosphoric, triphosphoric, or polyphosphoric acid in an amount up to about 3% (w/w); a rheology modifying agent in an amount of about 0.5% to about 5% (w/w); an antioxidant stabilizer in an amount of about 0.1% to about 2.5% (w/w), wherein said antioxidant stabilizer is selected from the group consisting of methylparaben, tannic acid, trolox, quercetin, catechin, glutathione, ferulic acid, carotenoid, proanthocyanidin, and ascorbic acid; an alcohol in an amount of about 0.2% to about 10% (w/w); a multi-valent salt in an amount of about 0.1% to about 0.5% (w/w); and an anti-microbial agent, wherein the antimicrobial agent is selected from the group consisting of silver, chitosan derivatives that are polycationic between pH 6.8-7.8, chlorhexidine gluconate, iodine and polyhexamethyl biguanide, to control bleeding or facilitate hemostasis during or after one or more of sinus surgery, ear nose and throat procedures, oral and maxillofacial surgery, orthopedic surgery, urological surgery, reconstructive surgery, cosmetic surgery, vascular surgery, transplant surgery, neurological surgery, oncological resection surgery involving the biopsy and removal of tumors, gynecological surgery, and general topical bleeding.

28. The method of claim 27, wherein the chitosan interacts with components of blood in the injury to control bleeding and facilitate hemostasis.

29. The method of claim 27, further comprising allowing bioabsorption of the aqueous gel, wherein the chitosan has a percent degree of deacetylation between 20% and 40%.

30. The method of claim 27, further comprising removing the aqueous gel from the injury, wherein the chitosan has a percent degree of deacetylation greater than about 78%.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) The invention will be more clearly understood from the following description of an embodiment thereof, given by way of example only, with reference to the accompanying drawings, in which:

(2) FIG. 1 is a graph of normalized % bleed rate (ordinate) plotted against time in minutes for control or test chitosan gel systems in a swine model of endoscopic surgical sinus bleeding. Merogel and Synaero commercial gels were used as controls in the study.

(3) FIG. 2 shows stability shelf-life at 23±2° C. trend-line for Chitosan Gel C viscosity based on zeroth order hydrolytic degradation.

DETAILED DESCRIPTION

(4) 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 that may be embodied in other ways. While the preferred embodiment has been described, the details may be changed without departing from the invention.

(5) The chitosan gel composition includes a high molecular weight (HMW) chitosan. The weight average molecular weight (Mw) of the high molecular weight chitosan determined by gel permeation chromatography (GPC) was preferably between 300 and 2000 kDa with polydispersity index (Mw/Mn) ≤3, more preferably it was between 500 kDa and 1,500 kDa with polydispersity index ≤2.5 and most preferably it was between 750 to 1,250 kDa with polydispersity index ≤2. The chitosan gel composition may also include a low molecular weight (LMW) chitosan. The low molecular weight chitosan is ≤25% w/w of the sum of the weight of the high molecular weight and the low molecular weight chitosan components. Preferably the weight average molecular weight of the low molecular weight chitosan is between 5 and 70 kDa with polydispersity index ≤3, more preferably it is between 10 and 50 kDa with polydispersity index ≤2.5, and most preferably it is between 15 and 35 kDa with polydispersity index ≤2.

(6) In the case of a fully bioabsorbable chitosan gel the percent degree of deacetylation is preferably between 20% and 40%. In the case of a dissolvable or otherwise removable chitosan gel, the percent degree of deacetylation is preferably ≥78%, more preferably ≥85% and most preferably ≥90%.

(7) The HMW chitosan was Marinard Lot 158407AR with weight average molecular weight determined as 438,500 Da with polydispersity index of 1.59 and percentage degree of deacetylation of 86.5% (as determined by Miya's FTIR method: Miya, M., Iwamoto, R., Yoshikawa, S., and Seiichi, M., I. r. spectroscopic determination of CONH content in highly deacetylated chitosan Int. J. Biol.l Macromol., 1980. 2 (5): p. 323-324). The LMW chitosan was Primex Lot 21012 gamma irradiated from Mw 400 kDa to weight average molecular weight 39,188±2862 Da with polydispersity index of 1.7 and percentage degree of deacetylation of 78% (as determined by Miya's FTIR method). Lactic acid was from JT Baker, hydroxypropyl cellulose of molecular weight 370 kDa was from Spectrum Chemicals, poloxamer 407 (Pluronic F127) of molecular weight 12.5 kDa was from Spectrum Chemicals, polyethylene oxide of molecular weight 400 kDa was from Sigma Chemicals, polypropylene glycol of molecular weight 2000 was from Fluka, calcium chloride was from JT Baker, sodium chloride was from JT Baker, methyl paraben was from Sigma Chemicals, and ethanol was from Sigma Chemicals, ascorbic acid was from Sigma.

(8) The present invention provides products and methods for controlling the bleeding from wounds such as those occurring during surgery without affecting access or visualization of the surgical site. Upon application of the chitosan gel system to the bleeding surgical site, the chitosan 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.

(9) 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.

(10) The present system provides advantages over other nasal hemostatic treatments not only 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 unfavorable consequences on the wound healing process.

(11) The present system provides the additional benefit over other systems when prepared aseptically in that it remains stable for an extended period (≥3 years) at room temperature maintaining its ability to provide visualization of the wound site after application of the gel.

EXAMPLE 1

Sinus Surgery Chitosan Hemostatic Gel

(12) Two chitosan gels were prepared with compositions

(13) TABLE-US-00001 Chitosan Gel A Formulation Ingredients (% (w/w)) HMW Chitosan 2.67 LMW Chitosan 0.58 Lactic Acid 2.0 Methylparaben 0.2 Hydroxy propyl cellulose 0.45 Polyethylene Oxide 0.18 Poloxamer 407 0.18 Polypropylene glycol 2000 0.1 Calcium Chloride 0.27 Ethanol 4.45 Water 89 Sodium chloride 0.0003

(14) TABLE-US-00002 Chitosan Gel B Formulation Ingredients (% (w/w)) HMW Chitosan 5.0 LMW Chitosan 0.65 Lactic Acid 3.5 Ascorbic acid 1.0 Hydroxy propyl cellulose 0.5 Polyethylene Oxide 0.2 Poloxamer 407 0.2 Polypropylene glycol 2000 0.1 Calcium Chloride 0.31 Ethanol 5.0 Water 83.54 Sodium chloride 0.0003

(15) Chitosan gel A was prepared without terminal sterilization while Chitosan gel B was terminally sterilized by gamma irradiation at 15 kGy, sufficient to produce a sterility assurance limit (SAL) of 10.sup.−6.

(16) In this example, the chemical and physical properties of a non-aseptically manufactured chitosan aqueous gel that is not terminally sterilized by gamma irradiation will be considered substantially equivalent to the chemical and physical properties of an aseptically prepared aqueous gel. This is justifiable since gamma irradiation of aqueous polymeric gels at doses typically used for gamma sterilization (11-40 kGy) causes substantial polymer chain degradation while other forms of processing do not.

(17) The viscosity of the material is suitable for dispensing through a nozzle or small orifice to the site of bleeding. The dispensing apparatus can be a syringe, a tube or any such similar device. In this example the gel was loaded into a syringe.

(18) The viscosity of chitosan Gel A was determined using a Brookfield viscometer at 25° C. as 42,253±1683 cps. The viscosity of chitosan Gel B was determined using a Brookfield viscometer at 25° C. as greater than 2,000,000 cps without sterilization and 662,500 cps after 15 kGy gamma irradiation.

(19) Epistaxis bleeding in the swine model was induced under anesthesia by bilateral mucosal stripping of the lateral nasal wall. Bleed-rates were measured by 20 second pre- and post-weighed gauze contact with freely bleeding sites. Initial bleed rates were targeted to be between 5 and 10 g/min. Actual initial bleed rates ranged between 2.0 and 20 g/min. The Normalized bleed rate is the initial rate and subsequent bleed rates at time t minutes for a given injury divided by the initial bleed rate. The gel was applied to swine nasal mucosa laceration injuries and successful hemostasis was achieved for both gamma and non-gamma irradiated chitosan gels. Application of the chitosan containing gel coated the surface of the injury, allowing interaction between the bleeding site and the chitosan. The bleeding control results are shown in FIG. 1 with controls of Merogel and HemCon polyanhydroglucuronate (Synaero™ Lot RD0610012) gels. There was 90% reduction in bleeding on average at >10 minutes, 4 minutes 5 seconds, 4 minutes 40 seconds, and 3 minutes 40 seconds for Merogel, Synaero, Chitosan Gel A and Chitosan Gel B respectively. The Synaero and Chitosan Gels were all effective in controlling bleeding with at least 90% reduction in bleeding in all three by 5 minutes. The Synaero gel was a non-transparent cream appearance that dried to an opaque film, whereas both Chitosan gels were clear liquids that dried to clear films. Chitosan Gel B had a red coloration. Both Chitosan Gels were adherent and coated vertical and inverted tissue surfaces. The animal group for Chitosan B was euthanized at the conclusion of the hemostatic testing. In the case of the Merogel, Synaero and Chitosan A, after seven days the animals were sacrificed and the injury sites evaluated for residual gel material, nasal passage patency, scarring, wound healing and inflammation. The Table I below lists the comparative results.

(20) TABLE-US-00003 TABLE I Comparative results Treatment Residual Nasal Mucosal Group Material Patency Scarring Healing Inflammation Chitosan A No Yes No Yes Yes Chitosan A No Yes No Yes No Chitosan A No Yes No Yes No Merogel No Yes No Yes Yes Merogel No Yes No Yes No Merogel No Yes No Yes No PAGA No Yes No Yes No PAGA No Yes No Yes No PAGA No Yes No Yes No

EXAMPLE 2

Stability of Chitosan Hemostatic Gel with and without Irradiation

(21) Chitosan Gel C was prepared with the following composition.

(22) TABLE-US-00004 Formulation Ingredients (% (w/w)) HMW Chitosan 2.65 LMW Chitosan 0.6 Lactic Acid 3.1 Methylparaben 0.2 Hydroxy propyl cellulose 0.44 Polyethylene Oxide 0.18 Poloxamer F127 0.18 Polypropylene glycol 2000 0.088 Calcium Chloride 0.27 Ethanol 4.42 Water 87.9 Sodium chloride 0.0003

(23) The Chitosan Gel C of example 2 was sealed inside 10.0 ml syringes. The syringes were either not irradiated or they were exposed to electron beam irradiation or gamma irradiation. Brookfield viscometry at 25±0.2° C. using an LV4 spindle was used to determine change in viscosity of Chitosan Gel C following gamma irradiation or electron beam irradiation at doses typically used to sterilize medical devices. The results of testing are shown in Table 2.

(24) TABLE-US-00005 TABLE 2 Treatment Gel Viscosity % Change None 42,450 ± 500  0 Gamma Irradiation 12-15 kGy  425 ± 10 −99% Electron-beam irradiation 385 ± 5 −99% 15 kGy

EXAMPLE 3

Stability of Chitosan Hemostatic Gel With and Without Irradiation for 66 Months at 23±2° C.

(25) The syringes in Example 2 were stored at 23±2° C. for 66 months with regular examination. The A bubble of air (0.33±0.03 ml) with radius less than the syringe barrel radius (6.4±0.1 mm) was included inside each syringe so that relative rate of bubble travel at 23±2° C. through the gel column of length 39.5±0.5 mm could be monitored with syringe barrel positioned vertically. This provided a simple bubble point viscometer configuration to allow monitoring change in relative solution viscosity by determination of time of controlled distance travel in a vertical syringe barrel. At storage for 66 months at 23±2° C., the bubble time for travel of the bubble to ascend through chitosan solution of density near 0.98 g/cm.sup.3 from base to top of syringe (39.5±0.5 mm) was 33.5±3.4 seconds for the non-irradiated sample and close to 2 seconds for the electron beam irradiated sample. Brookfield viscometry at 25±0.2° C. using an LV4 spindle was used to determine change in viscosity of irradiated and non-irradiated Chitosan Gel C after 66 months at 23±2° C. with results shown in Table 3.

(26) TABLE-US-00006 TABLE 3 Condition Gel Viscosity (cps) % Change Baseline no irradiation 42,450 — Baseline Electron-beam 385 — irradiation 15 kGy 66 months no irradiation 12,000 −70% 66 months Electron-beam 400  +4% irradiation 15 kGy

(27) From Table 3 and FIG. 2.

(28) Embodiments of the present invention include a clear gel system aqueous composition comprising chitosan, a monofunctional organic acid, a rheology modifying agent, an antioxidant stabilizer, an alcohol and a multivalent salt that is stable for a period up to three years at about 23° C., that can be applied directly to bleeding wounds in surgery, to displace the blood, and adhere to tissue to quickly control the bleeding without obscuring or interfering with access to the surgical site and can be removed without rebleeding. Such gel systems may include one or more of the following: chitosan present in an amount of about 2% to about 12% (w/w); a monofunctional organic acid selected from the group comprising lactic, glycolic, and carbonic acids; a monofunctional organic acid present in an amount of about 0.5% to about 7% (w/w), a bifunctional, trifunctional and polyfunctional organic acids present at up to 5.0% by weight of the gel; an inorganic phosphoric, triphosphoric and/or polyphosphoric acid present at up to 3.0% by weight of the gel; a plasticizer present at up to 5.0% by weight of the gel; a rheology modifying agent selected from a group comprising hydroxypropylcellulose, polyethylene oxide, poloxamer 407, polyethylene glycol, and polypropylene glycol 2000; a rheology modifying agent comprising about 0.5% to 5% by mass of the gel system; an antioxidant stabilizer selected from a group comprising methyl paraben, tannic acid, trolox, quercetin, catechin, glutathione, ferulic acid, carotenoid, proanthocyanidin and ascorbic acid; an antioxidant stabilizer present in an amount of about 0.1% to about 2.5% (w/w); a multivalent salt; a multivalent salt selected from the group comprising CaCl.sub.2, Ca(NO.sub.3).sub.2, Ca(SO.sub.4).sub.2, BaCl.sub.2, Ba(NO.sub.3).sub.2 and Ba(SO.sub.4).sub.2; a multivalent salt present in an amount of about 0.1% to about 0.5% (w/w); an alcohol selected from the group comprising ethanol and isopropanol; an alcohol present in an amount of about 0.2% to about 10% (w/w); a premixed gel composition for delivery from a single syringe; a gel system having a viscosity of the gel from 5,000 to 1,000,000 cP at 25° C., 50,000 to 350,000 cP at 25° C., or 75,000 to 250,000 cP at 25° C.; a gel system comprising an anti-microbial agent; an anti-microbial agent selected from the group comprising silver, chitosan derivatives that are polycationic between pH 6.8-7.8, chlorhexidine gluconate, iodine and polyhexamethyl biguanide, a gel system removable by dissolution by surgical flushing (lavage); a gel system that can remain in place for removal by dissolution, bioresorption or by bioabsorption processes without further intervention; a gel system that may be applied to complex geometries including an inverted space; and an antimicrobial gel system.

(29) Embodiments of the present invention include an aqueous gel system comprising chitosan, a monofunctional organic acid, a rheology modifying agent, an antioxidant stabilizer, an alcohol and a multivalent salt. Such gel systems may include one or more of the following: chitosan present in an amount of about 2% to about 12% (w/w); a monofunctional organic acid selected from the group comprising lactic, glycolic and carbonic acids; a monofunctional organic acid present in an amount of about 0.5% to about 7% (w/w); a bifunctional, trifunctional and polyfunctional organic acids present at up to 5.0% by weight of the gel; an inorganic phosphoric, triphosphoric, and polyphosphoric acids present at up to 3.0% by weight of the gel; a plasticizer present at up to 5.0% by weight of the gel; a rheology modifying agent selected from a group comprising hydroxypropylcellulose, polyethylene oxide, poloxamer 407, polyethylene glyclol, and polypropylene glycol 2000; a rheology modifying agent comprising about 0.5% to 5% by mass of the gel system; an antioxidant stabilizer selected from a group comprising methyl paraben, tannic acid, trolox, quercetin, catechin, glutathione, ferulic acid, carotenoid, proanthocyanidin, and ascorbic acid; an antioxidant stabilizer present in an amount of about 0.1% to about 2.5% (w/w); a multivalent salt; a multivalent salt selected from a group comprising CaCl.sub.2, Ca(NO.sub.3).sub.2, Ca(SO.sub.4).sub.2, BaCl.sub.2, Ba(NO.sub.3).sub.2 and Ba(SO.sub.4).sub.2; a multivalent salt present in an amount of about 0.1% to about 0.5% (w/w); an alcohol selected from the group comprising ethanol and isopropanol; an alcohol present in an amount of about 0.2% to about 10% (w/w); a premixed gel composition for delivery from a single syringe; a gel system having a viscosity of the gel from 5,000 to 1,000,000 cP at 25° C., 50,000 to 350,000 cP at 25° C., or 75,000 to 250,000 cP at 25° C.; an anti-microbial agent; an anti-microbial agent selected from the group comprising silver, chitosan derivatives that are polycationic between pH 6.8-7.8, chlorhexidine gluconate, iodine and polyhexamethyl biguanide; a gel system removable by dissolution by surgical flushing (lavage); a gel system that can remain in place for removal by dissolution, bioresorption or by bioabsorption processes without further intervention; a gel system that may be applied to complex geometries including an inverted space; an antimicrobial gel system; a tack greater than 65 mN, greater than 80 mN, or greater than 95 mN.

(30) Further embodiments of the present invention include use of any gel system described herein to control bleeding or facilitate hemostasis during or after sinus surgery, in ear nose and throat procedures, in oral and maxillofacial surgery, in orthopedic surgery, in urological surgery, in reconstructive surgery, in cosmetic surgery, in vascular surgery, in transplant surgery, in neurological surgery, in oncological resection surgery involving the biopsy and removal of tumors, and in gynecological surgery, and for general topical bleeding.

CONCLUSIONS

(31) The herein described, easily administered, stable, clear chitosan gel system is readily administered to bleeding surgical fields to displace blood and to adhere to tissue to effectively control bleeding, to promote wound healing with reduced scarring, to allow visualization and access to the same surgical fields and can be removed subsequently without rebleeding by saline lavage.

(32) The invention is not limited to the embodiments herein before described which may be varied in detail.

REFERENCES

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