Natural polymer based tissue adhesive with healing promoting properties

Abstract

A tissue adhesive with healing promotion properties formed from a mixture of natural polymers and an activating agent that enhances the adhesive properties of the natural polymer mixture is described. Use of an activating agent and a combination of the natural polymers is unique. The natural polymer tissue adhesive may be useful as a post-operative application for tonsillectomy or adenoidectomy surgery, as an internal tissue adhesive for surgery or wound repair or for application to a burn or skin donor site. For internal use, an optional treatment to improve resistance of the activated adhesive to body fluids is also described. The adhesive described not only functions as an adhesive but would also serve as a protective barrier when applied to surgery or skin sites. In addition, the natural polymers would promote healing due to the inherent properties of the polymers selected.

Claims

1. A tissue adhesive for application to a tissue site, said tissue adhesive comprising: a gel having adhesive properties comprising a mixture of natural polymers, said natural polymer mixture comprising an alginate and chitosan, wherein the ratio of alginate to chitosan is between 25:75 and 75:25, and wherein said gel comprises a first surface for application to said tissue site and a second surface opposite to said first surface; and an activating agent which enhances said adhesive properties of said gel, wherein said activating agent comprises a 4% acetic acid solution; wherein said gel is provided with a surface treatment to toughen a surface of said gel by treating said second surface of said gel with a dilute aqueous solution of a calcium salt.

2. The tissue adhesive of claim 1 wherein said alginate comprises sodium alginate.

3. The tissue adhesive of claim 2 wherein the ratio of sodium alginate to chitosan is 25:75.

4. The tissue adhesive of claim 2 wherein the ratio of sodium alginate to chitosan is 75:25.

5. The tissue adhesive of claim 1 wherein said tissue adhesive further comprises at least one from the group consisting of an analgesic, an anesthetic and a vasoconstrictive compound.

6. The tissue adhesive of claim 1 wherein said calcium salt comprises at least one from the group consisting of calcium chloride, calcium acetate and calcium carbonate.

7. The tissue adhesive of claim 1 wherein said tissue site comprises at least one from the group consisting of a surgical site created during tonsillectomy surgery, a surgical site created during adenoidal surgery, a burn site, a skin donor site, a skin graft site and a joinder site between two pieces of tissue.

Description

DETAILED DESCRIPTION

(1) A natural polymer is a polymer of plant or animal origin. An alternate term for this is a bio-polymer.

(2) Polysaccharides are polymeric carbohydrate molecules composed of long chains of monosaccharide units bound together by glycosidic linkages, which on complete hydrolysis give the constituent monosaccharides or oligosarrharides. Examples include storage polysaccharides such as starch and glycogen, and structural polysaccharides such as cellulose and chitin.

(3) A partial hydrolysis derivative of a polysaccharide is a derivative in which all or a portion of the side chain functional groups are hydrolysed but there is not complete hydrolysis of the polymeric chain to form monomers. An example is chitosan as a product of hydrolysis of the acetyl amine function of chitin.

(4) A neutralization salt of a polysaccharide is the product of the reaction between a base and the carboxylic acid function of the polysaccharide. An example is the reaction of sodium hydroxide with alginic acid to yield sodium alginate.

(5) An alginate is alginic acid or an ester of alginic acid or a salt of alginic acid.

(6) A dilute solution of an acid is an aqueous solution containing less than 20% by weight of the designated acid. Similarly, a dilute solution of a salt contains less than 20% by weight of the salt.

(7) A toughening treatment of an adhesive gel is a chemical cross-linking that allows the gel to retain firmness and/or integrity or reduce fluid absorption when exposed to bodily fluids.

(8) A workable gel is one which is easily manipulated for placement at the desired site.

(9) The device of this invention is a combination of materials which meet the criteria as outlined above. The materials suitable for this device include combinations of compounds such as chitosan or chitin powder, alginic acid or salts of this acid. Optionally, therapeutic compounds can be added to the powder (e.g. vitamins, analgesic. (such as acetaminophen or an NSAID), vasoconstrictive (such as neuropeptide Y, epinephrine) or anesthetic (examples include, but are not limited to: lidocaine, benzocaine, bupivacaine, levobupivacaine, ropivacaine, etidocaine or articaine) in any combination. Also an anti-infective (such as Primaxin or Pentamycetin) could also be incorporated into the device as a means of immediate action to prevent infection with the chitin/chitosan providing longer term infection control.

(10) The material as described could be placed inside a cavity which is then closed with the adhesive or sutures, used to create an external dressing for a surgery site by application as a gel, thin film device or dry powder, or any methods in combination.

(11) For example, as part of the tonsillectomy surgery a pouch or flap could be formed at the surgery site and a device incorporating the combined materials could be placed inside the pouch or flap before the site is closed. The device could be in the form of a gel, lozenge or similar form that is of suitable size or enclosed in an thin film, envelope or capsule formed of a material that is quickly dissolved by the body for rapid release of the active ingredients.

(12) Another option, either in combination with the implanted device described above or separately, is to apply the adhesive mixture as a dry powder externally to the surgery site after the site is closed. This would provide control of bleeding, increased rate of wound healing as well as alleviation of pain and swelling. In this case, no, additional materials for adhesion, other than the adhesion activator described, would be required due to the adhesive properties of the sodium alginate:chitosan powder. The nature of the powder applied in this manner rather than as a classic bandage would avoid creating a choking hazard as the material would be released in small, friable pieces that could be either swallowed with no harm or ejected orally. The lack of a separate adhesive compound would reduce the possibility of irritation of mucosal tissue.

(13) Another option is to incorporate the adhesive powder into a thin film device with a binding agent that would be dissolved by body fluids. The film could then be placed onto the surgery site (optionally after the site is wet with an activating compound) to provide a thin layer of the powder with the desired properties as described above. Optionally, once in place the thin film could be sprayed with the activating compound and/or subjected to a toughening treatment with a compound having divalent cation to increase resistance of the film to bodily fluids while maintaining adhesion.

(14) Yet another option is to incorporate the adhesive powder into a gel by mixing with an aqueous solution of the activating compound. This gel would then be placed onto the surgery site for adhesion to form a protective device. Optionally, once in place the gel could be subjected to a toughening treatment with a compound having a divalent cation to increase resistance of the gel to bodily fluids while maintaining adhesion.

(15) Alternatively, the gel as described above could be applied externally to a skin donor or graft site (for example) for protection and to promote healing. In this case, the optional toughening treatment might not be necessary.

(16) Thus it is seen that the desired properties and functions of a protective device that also promotes healing for post-surgery use may be achieved through a novel combination of compounds and thus provide a viable solution to a problem for which no practical solution has previously existed.

(17) With no additional adhesives needed and the healing properties of the combined powders, the formulations detailed here could to find uses in other applications such as burn sites and skin donor sites.

EXAMPLES

(18) In all examples the chitosan used was high molecular weight chitosan obtained from Sigma-Aldrich and the sodium alginate was obtained from willpowder.com. White vinegar was used as the acetic acid source. The vinegar and other materials were obtained locally.

(19) Shear Testing for Adhesive Strength:

(20) The shear tests (see K. Vakalopoulos, et al; Mechanical Strength and Rheological Properties of Tissue Adhesives With Regard to Colorectal Anastomosis; Annals of Surgery, Volume 261, Number 2, February 2015, pp 323-331) were performed on specimens of thin sliced () beef round bottom that were 3 centimeters by 4 centimeters in size to provide 12 square centimeters for the adhesion surface. These specimens were washed with water and blotted dry with a paper towel. Each surface was then irrigated with the activating agent solution (1 ml. per surface) and then 0.30 grams of the powder to be tested was sprinkled uniformly on each surface. The two adhesion test surfaces were again irrigated with the activating agent and the two surfaces joined. The specimen was pressed with 2 pounds of weight for 5 seconds before being placed in the shear test rig such that one surface was held stationary and the other was supporting the added weight. Weight was then added incrementally until separation of the specimen occurred. Results are shown in Table I.

(21) TABLE-US-00001 TABLE I Separation Sample ID Adhesive Used Activating Agent Weight Grams Comparative A 75:25 Sodium Normal Saline 96.6 Alginate:Chitosan Comparative B Sodium Alginate 4% Acetic Acid 163.0 Comparative C Chitosan 4% Acetic Acid 128.0 Example 1 75:25 Sodium 4% Acetic Acid 274.5 Alginate:Chitosan Example 2 50:50 Sodium 4% Acetic Acid 225.0 Alginate:Chitosan Example 3 25:75 Sodium 4% Acetic Acid 116.7 Alginate:Chitosan Example 4 75:25 Sodium 4% Lactic Acid 193.7 Alginate:Chitosan

(22) Comparative Example A versus Example 1 show that the dilute acetic acid activator provides significantly enhanced adhesion versus normal saline. Comparative Examples B and C versus Examples 1, 2 and 4 show enhanced adhesion for the mixture of the two natural polymers over the adhesion observed for the individual polymers. Example 1 demonstrates an adhesion of 22.9 grams/square centimeter.

(23) The procedure as described above was followed with the addition of 0.10 gram of a therapeutic agent to the 75:25 sodium alginate:chitosan powder. In Example 5, acetaminophen was used as the therapeutic agent and in Example 6 the therapeutic agent was naproxen. As can be seen in Table II, there was a small decrease in adhesive strength versus Example 1 with the therapeutic added but the adhesive strength was still greater than all Examples other than Example 1. Results are summarized in Table II.

(24) TABLE-US-00002 TABLE II Adhesion Separation Sample ID Therapeutic Used Decrease Weight Grams Example 5 Acetaminophen 7% 255.5 Example 6 Naproxen 12% 241.5

(25) Table II illustrates that therapeutic agents may be added to the adhesive formulation with only a small decrease in adhesive strength to maintain adhesion within a range appropriate for the applications cited.

(26) Gel Durability Testing:

(27) A gel was formed by adding first 6 ml. of the activating agent to a small ceramic cup, followed by 0.35 grams of 75:25 Sodium Alginate:Chitosan. This was thoroughly mixed to form a soft and workable gel. This was used as the Comparative Example D and to this was added 10 ml. of normal saline solution. This was then covered to prevent evaporation and allowed to sit for 48 hours. In Examples 7 and 8 the same procedure was used with the exception that the gel was treated with a 2% by weight aqueous solution of a calcium salt before being exposed to saline. Calcium chloride was used in Example 7 and calcium carbonate in Example 8. After the saline was removed the gel was weighed and subjected to a pressurized water jet to determine integrity. Water pressure at gel breakup with a normal water stream from a faucet or a waterpik type device was observed. Results are shown in Table III.

(28) TABLE-US-00003 TABLE III Calcium Salt Activating Weight Sample ID Used Agent Gain Gel Integrity Compar- None 4% Acetic 5.2 grams Soft Gel - ative D Acid No integrity Example 7 Calcium 4% Acetic 4.0 grams Firm Gel chloride Acid Breakup with water pik at 80 psig Example 8 Calcium 4% Acetic 6.0 grams Medium Firm Gel carbonate Acid Integrity lost with normal faucet stream

(29) Comparative Example D versus Examples 7 and 8 show that the resistance of the gel to body fluid is improved with the calcium treatment for retention of the integrity of the gel. Fluid absorption is decreased with the calcium chloride treatment.