FIELD OF THE INVENTION
The present invention relates to a covalently crosslinked alginate based wound dressing having improved structural integrity and high absorbing, holding and healing ability.
More specifically, the present invention relates to a new wound dressing material, in which alginate salts are chemically modified and both ionically and covalently crosslinked.
BACKGROUND OF THE INVENTION
The wound dressings have been used in various forms and shapes to give protection against infection, external impact, to absorb blood, promote healing and in some cases apply medication to the wound, combat odour, promote antolytic debridement etc. Generally used wound dressings are made up of cellulosic fibres in the form of woven or nonwoven gauzes. The major problem of traditional cotton dressing is the tendency to stick/adhere to the wound surface. When the dressing is removed it can cause pain and again start bleeding. This can delay the healing process, cause scaring, reopen the wound for entrance of bacteria.
Various attempts have been made to improve the wound dressings so that the ideal hydration is provided and humidity at wound and dressing interfere is mentioned. Adequate moisture in the dressing makes it removable without causing pain. It is also desired that the dressing is able to remove excess exudate.
Initially wound dressing made of cellulosic fibres such as cotton, viscose, rayon fibres were widely used in the form of woven and non woven gauzes in medical and surgical field but these dressings had the tendency to adhere to the wound
surface and microfibres of cotton tend to stick to dry scar or cells during healing process, thereby causing tremendous pain while removal from the wound and sometimes resulting in damaging the epithelial tissues. These dressings keep the wound dry and were unable to absorb large amounts of exudates. These dressings were unsuitable for extremely deep wounds.
Besides cotton dressings paraffin dressings have also been in use. These dressing have reduced sticking but can liquefy at body temperature and do not have good absorption ability. Also difficulty is faced in extracting the medication.
The use of calcium and sodium alginate materials made into wool, gauze and the like in the dressing of wounds has been well known for many years, having for example, been reported in surgery annuals as early as 1947. More recently, various alginate wound dressing products have become commercially available, mainly in the form of calcium alginate fibers.
U.K. based research in the 60's and 70's showed that alginates such as SORBON, marketed by Steriseal, produced the ideal warm moist environment for healing wounds, including long-standing infected ulcers. This was found to be due to the ability of the fiber to react with the wound exudate and form a gel which is absorbent but keeps the wound moist and which can be changed by washing the saturated dressing away with saline solution. As a result, newly formed tissue is not disturbed.
Windsor-Laboratories, yet another UK company, has introduced a woven calcium alginate dressing for over the counter pharmacy sale only. Called STOP MEMO, the sodium alginate formed with the exchange of sodium ions in the blood for the calcium ions forms a gel which acts as a dressing, while the calcium ions are said to encourage clot formation.
Other forms of alginate dressings are also known in the art, as evidenced by the patent literature. Some of the patents are illustrated below to give the fair idea of the prior art.
U.S. Patent 2,512,616 observes that alginates exist in several forms, but that fibrous forms are preferred for use in surgical dressings. Alginates woven into a gauze or in the form of loose wool similar to absorbent cotton are particularly identified as being useful.
UK Patent publication no. 1,394,742 teaches a surgical dressing material comprising a layer of knitted alginic gauze adhered to a layer of fibrous backing material, the alginic material being calcium alginate or calcium alginate in which part of the calcium content has been replaced by sodium to render the material more soluble in water (so-called "converted calcium alginate"). The preferred converted calcium alginate is said to have a calcium content of 3 to 5% by weight and a pH not less than 4.
UK Patent Application No. 8917154.0 (Publication No. 2,221,620 A) of Johnson & Johnson describes a wound dressing material comprising a fibrous substrate having a discontinuous coating of a pharmaceutical acceptable alginate deposited on a surface thereof. By applying the alginate coating directly to the surface of a fibrous substrate, it is stated that a very large surface area of alginate in relation to its weight can be achieved. Effective homeostasis can therefore be obtained with relatively small amounts of alginate.
U.S. Patent 4,421,583 describes a process for making a non woven alginate fabric by spreading a tow of calcium alginate filaments in a flow of water, overfeeding the spread filaments onto a water-pervious support so that the filaments cross over each other and drying the filaments so that the alginate filaments become bonded to each other at their paint of contact where they cross over each other in the absence of adhesive or heat.
U.S. Patent 4,562,110 describes a process for production of dried alginate fibers by forming a sheet of wet spun insoluble undried alginate fibres and conerting it to a web by pressing it through conveyor device and then dewatering the web.
U.S. Patent 5,470,576 discloses a wound of dressing comprising an absorbent led impregnated with an alginte for promoting wound heeling which upon contact with wound with exhibit haemostatic properties.
Alginate wound dressings are becoming increasingly popular in wound management, specially in treating heavily exuding wounds such as chromic leg ulcers and bed sores. On contact with the wound fluid, the calcium alginate fibres of the dressing are partially converted to water soluble-sodium alginate that swells to form a calcium-sodium alginate gel around the wound, thus it keeps the wound moist. They can be easily removed by simple rinse with warm water, so the dressing changes are pain free. These dressings have increased capacity to absorb blood compared to cotton gauzes and promote haemostasis in wounds. But the major problems associated with presently available commercial wound dressings are as follows:
(1) The dressings do not have enough structural integrity. So alginate gel
disintegrates while removing the dressing.
(2) Strength of alginate fibres is not enough, so some alginate dressings tend
to shed fibres.
(3) When alginate dressings are applied to the wound patients feel some
initial burning like sensation which is caused by local tissue dehydration
due to alginate dressing's rapid absorption tendency.
(4) Ionically crosslinked alginates (by Ca2+) loose mechanical properties over time in vitro, due to an outward flux of crosslinking Ca2+ ions into the surrounding medium.
To solve these problems present disclosure describes materials and methods which provide a covalently-crosslinked alginate wound dressing material having better properties as compared with only ionically bonded alginate dressings. U.S. Patent 5,144,016 prepared covalently crosslinked alginate gel by using epichlorohydrin U.S. Patent 5,837,747 presented crosslinked polysaccharide-based wound dressing materials. Lee et al prepared covalently crosslinked sodium alginate with methyl ester L-lysine, PEG - diamines, adipic dihydrazide which can be used as hydrogel system in various biomedical applications. But for a modern wound dressing material the properties like enhanced blood absorption, blood holding capacity, reduced bioadhesion, drug loading property etc. are required. The wound dressing should assist the dynamic healing process without causing damage to the newly formed delicate epithelium tissue, by keeping moist environment. The dressing should be easily removed and painless (reduced adhesiveness). The dressing could contain an antibacterial drug, water soluble, insoluble or protein drugs so that it becomes versatile and can be used on many types of wound. The dressing should have improved structural integrity, while maintaining its biocompatibility.
To encapsulate all the above properties a novel alginate wound dressing has been developed which has uniform gel structure and is more easily peelable without destroying blood capillaries. The wound dressing of the present invention comprises of an absorbent woven or non woven fabric made out of cotton , rayon, cotton polyester blend, cellulosic material. The present invention relates to a new wound dressing material, in which alginate salts are chemically modified and both ionically and covalently crosslinked. By controlling the reactants and the process of modification, the degree of ionic and/or covalent crosslinking can
be modified. Stable covalent bonding can be introduced by some bifunctional crosslinking agent like polyhydric alcohols, polyethylene glycols, polypropylene glycols and the like by using esterification method by using acid catalysts.
A process has been developed for crosslinking alginates, to make the gel more uniform by using non-gelling cations which will compete with Ca2* while gel formation and for making a composite with gel and nonwoven materials.
This invention relates to a alginate wound dressing having improved structural integrity, improved absorption capacity, hemostatic properties and wound healing mechanism.
The subject inventionis having an additional advantage over the conventional dressings enabling loading of water soluble, water insoluble and protein drugs.
Another possible use of the material is as an appetite inhibitor for weight reduction, based on its swelling property. By varying the crosslinked chain length the swelling property can be varied when it is introduced into stomach, after absorbing water it will swell and fill up the stomach.
Accordingly the present invention relates to a covalently crosslinked alginate based material comprising, an alginate ester obtained by esterification of wound dressing.6-6w/v % salts of alginic acid and 0.5-1.0 moles/litre non gelling salts in the presence of 0.001-0.005 gm of acid catayst at the pH value of 5.5-6.5 crosslinked with bifunctional agent in a weight ratio of 1:1-1:5 v/v by 1-5 times of crosslinking salts of the concentration range of 100mM-1M.
The invention also resides in a process for the preperation of covalently crosslinked alginate based wound dressing material comprising the following steps:
(a) preparing a solution of water soluble salts of alginic acid such as sodium,
potassium or aluminium alginates of concentration 0.6-6.0%
(b) preparing a solution of non gellic salts of chlorides of sodium, potassium
or magnisium of concentration 0.5-1.0 moles/It.
(c) Mixing solution (a) with solution (b) and adding .001-.005 gm. Of acid
catalyst to catalyse esterification reaction maintaining the pH between the range
of 5.5-6.5.
(d) adding bifunctional crosslinking agents of 1:1-1:5 ratio to the said
solution.
(e) mixing the said solution thoroughly by magnetic stirrers to obtain a
homogenate.
(f) keeping the said homogenate overnight and adding to it crosslinking salt
of concentration range of 100mM-1M to obtain the alginate wound dressing
material.
The invention also resides in the composite alginate wound dressing including covalently crosslinked alginate based wound dressing material having a nonwoven cellulose based backing sheet preferably made of a blend of cellulosic and man made fibres having been soaked in cross linking salts impregnated with said covalently crosslinked alginate based wound dressing material on one of its sides and dipped in the solution of crosslinking salt.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a novel alginate-based wound dressing material having improved structural integrity, blood absorbing and holding capacity and wound healing ability.
Alginate wound dressing are becoming increasingly popular in wound management day-by-day. But the poor structural integrity poor strength of alginate fibre, uncontrolled high absorbing property of alginate dressings are acting as bottle neck in Alginate wound dressing to become the most predominant type of wound dressing material. It is the main object of the present invention to prepare a stable, more stronger covalently bonded alginate by using bifunctional crosslinkers using esterification reaction.
Water soluble salts of alginic acid such assodium, potassium, ammonium alginate etc. are used at the concentration of 0.6 - 6% w/v range and to this solution a solution of 0.5-1.0 mole/It of non-gelling salts such as sodium chloride, Potassium chloride, Magnisium chloride etc. are added to make the more uniform gel solution. 0.001-0.005 gm of acid catalysts such as para-toluene sulphonic acid can be added to catalyse the esterification reaction, maintaining pH range 5.5-6.5. This is followed by the addition of bifunctional crosslinking agents like polyglycols e.g. polyhydric alcohols, polyethylene glycols, polypropylene glycols and the like having molecular weight of 200, 400, 800, 6000 delton or a combination thereof in the 1:1 - 1:5 v/v ratio and mixing thoroughly by magnetic stirrers to prepare uniform gel solution. This solution is kept overnight and 1-5 times of crosslinking salt such as Calcium chloride , Calcium carbonate, Calcium sulphate etc. of the concentration range 100mM - 1 M is added. The temperature for the crosslinking esterification reaction is as not critical as the concentration range, and thus it is preferred to conduct the reaction at room temperature with or without using vacuum.
The present invention also relates to the method of preparing the composite with the gel described above with nonwoven backing sheet. The nonwoven backing sheet preferably be cellulose-based to have better absorption capacity, air permeability. But blended nonwovens prepared by mixing man made fibres with cellulosic materials also can be used. The nonwoven materials also can be
used. The nonwoven material is soaked with crosslinking salt such as Calcium chloride , Calcium carbonate, Calcium sulphate etc. in the concentration range 100 mM - 1 M and covalently crosslinked alginate gels are coated/impregnated above the nonwoven sheet in one side and then again dipped in the solution of crosslinking salt.
In order to make the present invention more clear and readily understood reference is made to the following examples which are intended to be illustrative only and not intended to be limited in scope.
The covalently crosslinked alginate gel can be made as described in the following examples.
Example 1
Water soluble alginate salt 2.5% (w/w) - 20 ml
p-toluene sulfonic acid 0.002 gm
Nacl 0.05mol/lt-10ml
polyethylene glycol (mol. wt 600) 1 gm
The molecular weight of crosslinker can be varied, as for example in the Example - 1 one canuse polyglycols of molecular weight range 200 - 6000. Depending upon the molecular weight, chain length the strength of the alginate gel, structural integrity of the gel, swelling property, blood holding and absorbing property will be varied. So the following recipe will also result to improved structurally integrated alginate gel.
Example - 2
Water soluble alginate salt (Na-Algimate) 2% (w/w_ - 25 ml

p-toluene sulphonic acid 0.003 gm
Nacl 0.05mol/lt, 10ml
Polypropylene glycol (mol. wt 6000) 0.5 gm
Instead of using soluble alginate salts one can use slightly esterified alginates (as for example propylene glycol alginate esters, 10 - 25% degree of esterification) as starting material, with or without using sodium alginate.
Example 3
Sodium alginate 2%, 1 gm
Propylene glycol alginate 3%, 1 gm
Nacl 1%
p-toluene sulphonic acid 0.003 gm
Propylene glycol (mole wt. 800) 5 gm
The covalently crosslinked alginate gel network structure and uniform gel structure helped to obtain much stable gel as compared with only ionically crosslinked alginate, by measuring the gel strength by compression measurement. The shear strength can be varied by varying the composition, mol. wt, chain length of the crosslinker. As the length of the crosslinking chain increases, the rigidity of the gel network reduces and the gel can withstand more force, it becomes more flexible. The networking helps in holding the absorbed blood or physiological fluids coming from the exuding wound. The water soluble, insoluble and protein drugs can be loaded into the network structure to have controlled release wound dressing material. Due to the presence of covalently
bonded crosslinkers (as for example polyethylene glycol) the dressing will be easily peeled off from wound surface without applying much force.
While particular embodiments of the present invention have been illustrated and described, it would be obvious to those skilled in art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.

WE CLAIM
1 A covalently crosslinked alginate based wound dressing material comprising, an alginate ester obtained by esterification of 0.6-6w/v % salts of alginic acid and 0.5-1.0 moles/litre non gelling salts in the presence of 0.001-0.005 gm of acid catayst at the pH value of 5.5-6.5 crosslinked with bifunctional agent in a ratio of 1:1-1:5 v/v by 1-5 times of crosslinking salts of the concentration range of 100mM-1M.
2. A covalently crosslinked alginate based wound dressing material as
claimed in claim 1 wherein the said salts of alginic acid are selected from
alginates of sodium, potassium or aluminium.
3. A covalently crosslinked alginate based wound dressing material as
claimed in claim 1 wherein the said non gellic salts are selected from chlorides of
sodium, potassium or magnisium.
4. A covalently crosslinked alginate based wound dressing material as
claimed in claim 1 wherein the said acid catalyst is para toluene sulphonic acid.
5. A covalently crosslinked alginate based wound dressing material as
claimed in claim 1 wherein the said bifuctional agents are polyglycols such as
polyhydric alcohols, poly ethylene glycol, polypropylene glycol and the like.
6. A covalently crosslinked alginate based wound dressing material as
claimed in claim 5 wherein the said polglycol has the molecular weight of 6000
delton.
7. A covalently crosslinked alginate based wound dressing material as
claimed in claim 5 wherein the said polglycol has the molecular weight of 400
delton.
8. A covalently crosslinked alginate based wound dressing material as
claimed in claim 5 wherein the said polglycol has the molecular weight of 200
delton.
9. A covalently crosslinked alginate based wound dressing material as
claimed in claim 1 wherein the said crosslinked salts are selected from Calcium
chloride , Calcium carbonate or Calcium sulphate.
10. A process for the preperation of covalently crosslinked alginate based
wound dressing material comprising the following steps:

(a) preparing a solution of water soluble salts of alginic acid such as sodium,
potassium or aluminium alginates of concentration 0.6-6.0%
(b) preparing a solution of non gellic salts of chlorides of sodium, potassium
or magnisium of concentration 0.5-1.0 moles/It.
(c) mixing solution (a) with solution (b) and adding .001-.005 gm. Of acid
catalyst to catalyse esterification reaction maintaining the pH between the range
of 5.5-6.5.
(d) adding bifunctional crosslinking agents of 1:1-1:5 ratio to the said
solution.
(e) mixing the said solution thoroughly by magnetic stirrers to obtain a
homogenate.
(f) keeping the said homogenate overnight and adding to it crosslinking salt
of concentration range of 100mM-1M to obtain the alginate wound dressing
material.
12. An alginate wound dressing composite including covalently crosslinked
alginate based wound dressing material as claimed in claim 1 comprising:
a nonwoven cellulose based backing sheet preferably made of a blend of cellulosic and man made fibres having been soaked in cross linking salts impregnated with said covalently crosslinked alginate based wound dressing material on one of its sides and dipped in the solution of crosslinking salt.
13. An alginate wound dressing as claimed in claim 10 wherein the
concentration range of said solution of crosslinking salt is 100mM-1M.
14 A covalently crosslinked alginate based wound dressing material
substantially as hereinbefore described with reference to the accompanying
examples.
15 A process for preparing a covalently crosslinked alginate based wound
dressing material substantially as hereinbefore described with reference to the
accompanying examples.
16. A covalently crosslinked alginate based wound dressing substantially as hereinbefore described with reference to the accompanying examples.