Stabilized Glycosaminoglycan Preparations and Related Methods

Abstract

Compositions comprising a glycosaminoglycan (e.g., a hyaluronan, hyaluronic acid, hyaluronate, sodium hyaluronate, dermatan sulfate, karatan sulfate, chondroitin 6-sulfate, heparin, etc.) in combination with at least one component selected from; i) polyglycols (e.g., polyethylene glycol), ii) long chain hydroxy polyanionic polysaccharides (e.g., dextran, sodium alginate, alginic acid, propylene glycol alginate, carboxymethyl cellulose and carboxyethyl cellulose, hydroxyl ethyl starch, hydroxyl propyl methyl cellulose, hydroxy propyl ethyl cellulose, hydroxy propyl cellulose, methyl cellulose, polylysine, polyhistidine, polyhydroxy proline, poly ornithine, polyvinyl pyrolidone, polyvinyl alcohol, chitosan, etc.) and iii) long chain Nitrogen containing polymers (e.g., Polylysine, Polyvinylpyrrolidone, and polyvinyl alcohol). The invention also includes methods for using such compositions (e.g., as substance delivery materials, tissue fillers or bulking agents, as moistening or hydrating agents, etc.)

Claims

1. A composition comprising: a first component selected from the group consisting of glycosaminoglycans; and a second component selected from the group consisting of i) polyglycols, ii) long chain hydroxy polyanionic polysaccharides and iii) long chain nitrogen containing polymers and iii) long chain Nitrogen containing polymers.

2. A composition according to claim 1 wherein the second component comprises Sodium Alginate.

3. A composition according to claim 1 wherein the second component comprises Alginic Acid.

4. A composition according to claim 1 wherein the second component comprises Propylene Glycol Alginate.

5. A composition according to claim 1 wherein the second component comprises Carboxy Methyl cellulose.

6. A composition according to claim 1 wherein the second component comprises Hydroxy Propyl Methyl cellulose, Hydroxy Propyl Cellulose, and Methyl Cellulose.

7. A composition according to claim 1 wherein the second component comprises polylysine, polyhistidine, polyhydroxyl proline, poly ornithine.

8. A composition according to claim 1 wherein the second component comprises polyethylene glycol.

9. A composition according to claim 1 wherein the second component comprises polylysine.

10. A composition according to claim 1 wherein the second component comprises dextran.

11. A composition according to claim 1 wherein the second component comprises hydroxylethyl starch.

12. A composition according to claim 1 wherein the second component comprises chitosan.

13. A composition according to claim 1 wherein the second component comprises polyvinyl alcohol.

14. A composition according to claim 1 wherein the second component comprises polyvinylpyrrolidone.

15. A composition according to claim 1 wherein the second component comprises polyhydroxyprolin.

16. A composition according to claim 2 wherein the polyglycol has an average molecular weight in the range of about 200 to about 35,000.

17. A composition according to claim 2 wherein the polyglycol has an average molecular weight in the range of about 6000 to about 8000.

18. A composition according to claim 2 wherein the polyglycol comprises PEG.

19. A composition according to claim 5 wherein the PEG has an average molecular weight in the range of about 200 to about 35,000.

20. A composition according to claim 5 wherein the PEG has an average molecular weight in the range of about 6000 to about 8000.

21.-29. (canceled)

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0021] FIG. 1A is a graph of viscosity vs. shear rate for room temperature, pH 5.2 solutions of: 0.5% carboxy methyl cellulose (CMC), 0.15% hyaluronic acid having a molecular weight of 2 million Daltons (2 MDa HA) and 0.15% 2 MDa HA+0.5% CMC.

[0022] FIG. 1B is a graph of viscosity vs. shear rate for room temperature, pH 5.2 solutions of: 0.5% carboxy methyl cellulose (CMC) alone, 0.15% hyaluronic acid having a molecular weight of 1.5 million Daltons (1.5 MDa HA) alone and 0.15% 1.5 MDa HA+0.5% CMC.

[0023] FIG. 1C is a graph of viscosity vs. shear rate for room temperature, pH 5.2 solutions of: 0.5% carboxy methyl cellulose (CMC) alone, 0.15% hyaluronic acid having a molecular weight of 1 million Daltons (1 MDa HA) alone and 0.15% 1 MDa HA+0.5% CMC.

[0024] FIG. 2 is a graph of viscosity vs. shear rate for room temperature solutions of: 0.15% 2 MDa HA+0.5% CMC @ pH 7.2, 0.15% 2 MDa HA+0.5% CMC @ pH 5.2, 0.15% 2 MDa HA @ pH 7.2 and 0.15% 2 MDa HA @ pH 5.2.

[0025] FIG. 3 is a graph of viscosity vs. shear rate for 25° C., pH 7.2 solutions of: 0.15% 2 MDa HA+0.5% hydroxy propyl methyl cellulose (HPMC), 0.5% HPMC and 0.15% 2 MDa HA.

[0026] FIG. 4 is a graph of viscosity vs. shear rate for 25° C., pH 7.2 solutions of: 0.15% 2 MDa HA+0.5% sodium alginate (NaALG), 0.5% NaALG and 0.15% 2 MDa HA.

[0027] FIG. 5 is a graph of viscosity vs. shear rate for 25° C., pH 7.2 solutions of: 0.15% 2 MDa HA+0.5% propylene glycol alginate (PG-ALG), 0.5% PG-ALG and 0.15% 2 MDa HA.

[0028] FIG. 6 is a graph of viscosity vs. shear rate for 25° C., pH 7.2 solutions of: 0.15% 2 MDa HA+0.5% CMC, 0.5% CMC and 0.15% 2 MDa HA.

DETAILED DESCRIPTION

[0029] The following detailed description is intended to describe some, but not necessarily all, examples or embodiments of the invention. No effort has been made to exhaustively describe all possible examples and embodiments of the invention. Thus, the contents of this detailed description shall not limit the scope of the invention in any way.

Polyglycol Stabilized Hyaluronans

[0030] In accordance with the present invention, there are provided compositions comprising a hyaluronan combined with a polyglycol, wherein the properties of the hyaluronan (e.g., viscosity and lubricity) are maintained for a prolonged period of time. Thus, polyglycols may be added to or included in various hyaluronan preparations to prolong the shelf stability and usefulness of such preparations.

[0031] A polyglycol is defined as a polyhydric alcohol of a monomeric glycol. Polyethylene Glycols (PEGs) are a family of linear, water-soluble polyglycols. PEGs are formed by polymerization of ethylene oxide. The generalized formula for polyethylene glycol is:

H—(OCH.sub.2CH.sub.2).sub.n—OH

where “n” is the average number of repeating oxyethylene groups.

[0032] Using the methods of the present invention, hyaluronan can be complexed with a PEG to form hyaluronan preparations that remain stable at room temperature for extended periods of time (e.g., 2 years or more) without substantial chemical break down of the hyaluronan and resultant change in viscosity and lubricity.

[0033] In preparations of the present invention wherein hyaluronan is combined with a polyglycol (e.g., PEG), the polyglycol may preferably have an average molecular weight in the range of about 200 to about 35,000 and more preferably, in at least some applications, an average molecular weight in the range of about 6000 to about 8000.

[0034] Also, in preparations of the present invention wherein hyaluronan is combined with a polyglycol (e.g., PEG), the hyaluronan may preferably have an average molecular weight in the range of about 2×10.sup.3 to about 5×10.sup.6 and more preferably, in at least some applications, an average molecular weight in the range of about 2×10.sup.5-3×10.sup.6.

[0035] Also, in preparations of the present invention wherein hyaluronan is combined with a polyglycol (e.g., PEG), the weight ratio of hyaluronan to polyglycol may be in the range of from about 0.1:1 to about 10:1 and more preferably in at least some applications such weight ratio of hyaluronan to polyglycol may be in the range of from about 1:2 to about 1:10.

[0036] Also, in preparations of the present invention wherein hyaluronan is combined with a polyglycol (e.g., PEG) and any other optional components examples of which are set forth in the formulations shown in Examples 1 and 2 below, the concentration of hyaluronan in the preparation may be in the range of about 0.01% by weight to about 10% by weight.

[0037] Also, in preparations of the present invention wherein hyaluronan is combined with a polyglycol (e.g., PEG) and any other optional components examples of which are set forth in the formulations shown in Examples 1 and 2 below, the pH of the preparation may be in the range of from about 5.0 to about 9.5 or more preferably in at least some applications, from about 7.0 to about 7.4. Appropriate acidifying and/or alkaline (e.g., buffering) agents may be added in accordance with procedures well known in the art to adjust the pH of the preparation as needed or desired.

[0038] Also, in preparations of the present invention wherein hyaluronan is combined with a polyglycol (e.g., PEG) and any other optional components examples of which are set forth in the formulations shown in Examples 1 and 2 below, the tonicity of the preparation may preferably be in the range of about 200 mOsm to about 340 mOsm. Hyperosmolar and/or hypoosmolar agents (e.g., manitol, water, etc.) may be added in accordance with procedures well known in the art to adjust the tonicity of the preparation as needed or desired.

Example 1

A Stabilized Hyaluronan Preparation

[0039] In this example, a liquid hyaluronan preparation is prepared by combining and mixing the components of the following formulation at room temperature:

TABLE-US-00001 Hyaluronic Acid Sodium Salt 0.15% Polyethyleneglycol (PEG 0.50% 8000) Boric Acid 0.20% Sodium Chloride 0.58% Postassium Chloride 0.14% Calcium Chloride Dihydrate 0.02% Magnesium Chloride 0.011% Hexahydrate Sodium Chorite/Hydrogen 0.06% Peroxide Purified Water Q.S to 100 mL.

[0040] This results in a viscous liquid preparation that is suited for a wide variety of medical or non-medical uses, including use as a lubricant or moisturizing agent, for topical administration to the skin, mucous membranes or eyes, or as a carrier for cosmetics, pharmaceuticals or other agents.

Example 2

Stability Comparison

[0041] In this example, hyaluronan compositions were prepared under ambient, room temperature conditions according to Formulations I and II, as follows:

Formula I: Formula II:

[0042]

TABLE-US-00002 Hyaluronic Acid 0.15% Hyaluronic Acid 0.15% Sodium Salt Sodium Salt — Polyethyleneglycol 0.5% (PEG 8000) Boric Acid 0.2% Boric Acid 0.2% Sodium Chloride 0.58% Sodium Chloride 0.58% Postassium Chloride 0.14% Postassium Chloride 0.14% Calcium Chloride 0.02% Calcium Chloride 0.02% Dihydrate Dihydrate Magnesium 0.11% Magnesium 0.11% Chloride Chloride Hexahydrate Hexahydrate Sodium 0.06% Sodium 0.06% Chorite/Hydrogen Chorite/Hydrogen Peroxide Peroxide Purified Water Q.S to 100 mL. Purified Water Q.S to 100 mL.

[0043] Both Formulation I and Formulation 2 provide a lubricious liquid solution as described in Example 1 above. However, when stored at room temperature, the preparation of Formula I looses substantial viscosity and becomes substantially less lubricious within few weeks. In contrast, the preparation of Formula II remains stable and does not undergo any substantial change in viscosity or lubricity for at least two (2) years.

Long Chain Hydroxy Polyanionic Polysaccharide Stabilized Hyaluronans and Other Glycosaminoglycans

[0044] Glycosaminoglycans (Including Hyaluronic acid) are important substances in connective tissues in determining the viscoelastic properties of joints and of other structures that are subject to mechanical deformation. Hyaluronic acid is one of the major glycosaminoglycans that occur in many living substances as synovial fluid. Hyaluronic acid is a major component of the extracellular matrix and contributes to cellular migration and proliferation and neuronal morphogenesis. Hyaluronic acid also acts as a lubricant and shock absorber in joints, in the vitreous body of the eye and other parts of the body.

[0045] One drawback of administering exogenous hyaluronic acid for therapeutic or other biomedical purposes is that hyaluronic acid degrades very rapidly and consequently loses its viscosity and its lubricity. This limits the many biomedical applications of the hyaluronic acid. Some of the noteworthy therapeutic and other biomedical applications of hyaluronic acid have included its use in tissue grafting, catheter lubrication for insertion into human bodies, scope and endoscope lubrication, skin grafting, dermal wound healing, cell culture, bioengineering and cell bioengineering, eye and joint lubrication, vitreous humor replacement, artificial tears for dry eyes, contact lens storage and wear, corneal wound healing, treatment of allergic conjunctivitis, as a viscoelastic agent in cataract surgery, as an additive in cosmetics and personal care products, as a drug delivery vehicle, etc.

[0046] Applicants have discovered that hyaluronic acid can also be stabilized with Long chain hydroxy polyanionic polysaccharides (e.g., sodium alginate, alginic acid, propylene glycol alginate, carboxymethyl cellulose and carboxyethyl cellulose, etc.) in an aqueous solution of pH 5.0-9.0. It has been further discovered that the viscosity of the hyaluronic acid (HA) in aqueous solution at pH 5.0-9.0 can be increased by an order of magnitude or more with the addition of one or more long chain hydroxy polyanionic polysaccharides and such hyaluronic Acid+long chain hydroxy polyanionic polysaccharides possess a non-Newtonian fluid characteristics (shear thinning effects) (see FIG. 1, 2, 3, 4).

Example 3

Comparison of Viscosity Enhancement and Shear Thinning Effects

[0047] In this example, the viscosities of various test samples were measured at shear rates ranging from 1-200 1/sec. The compositions of the test samples were as follows:

TABLE-US-00003 Sample Sample Composition Sample A 0.15 g of 1 MDa Sodium (1 MDa HA Alone/pH 5.2.) Hyaluronate in 100 mL of the borate buffer solution @ pH 5.2 Sample B 0.15 g of 1.5 MDa Sodium (1.5 MDa HA Alone/pH 5.2) Hyaluronate in 100 mL of the borate buffer solution @ pH 5.2 Sample C 0.15 g of 2 MDa Sodium (2 MDa HA Alone/pH 5.2) Hyaluronate in 100 mL of the borate buffer solution @ pH 5.2 Sample D 0.15 g of 2 MDa Sodium (2 MDa HA Alone/pH 7.2) Hyaluronate in 100 mL of the borate buffer solution @ pH 7.2 Sample E 0.5 g of CMC in 100 mL of the (CMC Alone/pH 5.2) borate buffer solution @ pH 5.2 Sample F 0.5 g of CMC in 100 mL of the (CMC Alone/pH 7.2) borate buffer solution @ pH 7.2 Sample G 0.15 g of 1 MDa Sodium (1 MDa HA + CMC/pH 5.2) Hyaluronate + 0.5 g of CMC in 100 mL of the borate buffer solution 0.15 g of 2 MDa Sodium Hyaluronate in 100 mL of the borate buffer solution @ pH 5.2 Sample H 0.15 g of 15M Sodium Hyaluronate + (1.5 MDa HA + CMC/pH 5.2) 0.5 g of CMC in 100 mL of the borate buffer solution 0.15 g of 2 MDa Sodium Hyaluronate in 100 mL of the borate buffer solution @ pH 5.2 Sample I 0.15 g of 2 MDa Sodium (2 MDa HA + CMC/pH 5.2) Hyaluronate + 0.5 g of CMC in 100 mL of the borate buffer solution @ pH 5.2 Sample J 0.15 g of 2 MDa Sodium (2 MDa HA + CMC/pH 7.2) Hyaluronate + 0.5 g of CMC in 100 mL of the borate buffer solution @ pH 7.2 Sample K 0.5 g HPMC in 100 mL of the borate (HPMC Alone/pH 7.2) buffer solution @ pH 7.2 Sample L 0.15 g of 2 MDa Sodium (2 MDa HA + HPMC/pH 7.2) Hyaluronate + 0.5 g of HPMC in 100 mL of the borate buffer solution @ pH 7.2 Sample M 0.5 g NaALG in 100 mL of the (NaALG Alone/pH 7.2) borate buffer solution @ pH 7.2 Sample N 0.15 g of 2 MDa Sodium (2 MDa HA + NaALG/pH 7.2) Hyaluronate + 0.5 g of HPMC in 100 mL of the borate buffer solution @ pH 7.2 Sample O 0.15 g of 2 MDa Sodium (2 MDa HA + Pluronic F127/pH Hyaluronate + 0.5 g of Pluronic 5.2) F127 in 100 mL of the borate buffer solution @ pH 5.2 Sample P 0.15 g of 2 MDa Sodium (2 MDa HA + PEG/pH 5.2) Hyaluronate + 0.5 g of Pluronic F127 in 100 mL of the borate buffer solution @ pH 5.2

[0048] Each sample was prepared in a borate buffer solution. The formulation of this borate buffer solution was as follows:

TABLE-US-00004 Component Amount Boric Acid 0.20 g Sodium Chloride 0.58 g Potassium Chloride 0.14 g Calcium Chloride Dihydrate 0.02 g Magnesium Chloride 0.011 g  Hexahydrate Purified Water Q.S. to 100 mL

[0049] To prepare the buffer, 1 g of boric acid, 2.9 g of Sodium chloride, 0.7 g of potassium chloride, 0.1 g of calcium chloride dihydrate and 0.055 g magnesium chloride hexahydrate were dissolved in distilled water. The solution was diluted to 500 mL. The pH of this buffer solution was adjusted to either 5.2 or 7.2 at room temperature, as indicated.

[0050] To insure samples were thoroughly dissolved and well mixed, stock solutions of the polymers in borate buffer were prepared when possible. For hyaluronic acids, 2% stock solutions were used. All stock solutions were vortex mixed and then placed on a shaker until clear and homogeneous.

[0051] Hyaluronic acid samples (0.15% HA) were prepared by diluting approximately 0.75 g of the HA stock solution to 10 g using the borate buffer. Again, samples were vortex mixed and placed in a shaker until the solutions were clear and homogeneous.

[0052] Viscosity measurements were performed on an AR 1000 rheometer (T A Instruments) using a cone and plate geometry. The cone was 6 cm in diameter with an angle of 1 degree and a truncation gap of 29 mm. The range of torques applied was adjusted to cover shear rates ranging (at minimum) from 25 sec.sup.−1 to 160 sec.sup.−1. Shear rates were first increased and then during the experiment. A new sample was loaded for each experiment.

[0053] FIG. 1A is a graph showing viscosity vs. shear rate for samples C, E and I. As shown, at pH 5.2, the viscosity of Sample I (2 MDa HA+CMC) was synergistically increased over the viscosity of Samples C (2 MDa HA alone) and E (CMC alone).

[0054] FIG. 1B is a graph showing viscosity vs. shear rate for samples B, E and H. As shown, at pH 5.2, the viscosity of Sample H (1.5 MDa HA+CMC) was synergistically increased over the viscosity of Samples B (1.5 MDa HA alone) and E (CMC alone).

[0055] FIG. 1C is a graph showing viscosity vs. shear rate for samples A, E and G. As shown, at pH 5.2, the viscosity of Sample G (1 MDa HA+CMC) was synergistically increased over the viscosity of Samples A (1 MDa HA alone) and E (CMC alone).

[0056] Also, when FIGS. 1A-1C are viewed in comparison, it is apparent that the viscosity enhancing effect of CMC was most pronounced in the sample containing 2 MDa HA (Sample K) and least pronounced in the sample containing 1 MDa HA (Sample G). Thus, the viscosity enhancing effect of CMC is greater with higher molecular weight HA.

[0057] FIG. 2 is a graph showing viscosity vs. shear rate for samples C, D, I and J. The viscosities of samples D (2 MDa HA alone at neutral pH 7.2) and J (2 MDa HA+CMC at neutral pH 7.2) were greater than the viscosities of samples C (2 MDa HA alone at alkaline pH 5.2) and I (2 MDa HA+CMC at alkaline pH 5.2). Thus, the viscosity of HA, whether alone or in combination with CMC, increases as pH changes from alkaline (5.2) to neutral (7.2).

[0058] FIG. 3 is a graph showing viscosity vs. shear rate for samples D, K and L. These data indicate that, at pH 7.4, the viscosity of Sample L (2 MDa HA+HPMC) was synergistically increased over the viscosities of Samples D (2 MDa HA alone) and K (HPMC alone). Thus, the addition of 0.5% HPMC caused a supraadditive (e.g., synergistic) increase in viscosity of the HA.

[0059] FIG. 4 is a graph showing viscosity vs. shear rate for samples D, M and N. These data indicate that, at pH 7.4, the viscosity of Sample N (2 MDa HA+NaALG) was synergistically increased over the viscosities of Samples D (2 MDa HA alone) and M (Na-ALG alone). Thus, the addition of 0.5% Na-ALG caused a supraadditive (e.g., synergistic) increase in viscosity of the HA.

[0060] FIG. 5 is a graph showing viscosity vs. shear rate for samples D, N and O. These data indicate that, at pH 7.4, the viscosity of Sample O (2 MDa HA+PG-ALG) was synergistically increased over the viscosities of Samples D (2 MDa HA alone) and N (PG-ALG alone). Thus, the addition of 0.5% PG-ALG caused a supraadditive (e.g., synergistic) increase in viscosity of the HA.

[0061] FIG. 6 is a graph showing viscosity vs. shear rate for samples D, F and J. These data indicate that, at pH 7.4, the viscosity of Sample J (2 MDa HA+CMC) was synergistically increased over the viscosities of Samples D (2 MDa HA alone) and F (CMC alone). Thus, the addition of 0.5% CMC caused a supraadditive (e.g., synergistic) increase in viscosity of the HA.

[0062] In the following table, the shear thinning grade ratio (STG ratio) was calculated as the ratio of the viscosity at 160 sec.sup.−1 to the viscosity at 40 sec.sup.−1 at 30° C., pH 5.2. The following table

TABLE-US-00005 Sample STG Ratio Sample C 1.42 (2 MDa HA Alone/pH 5.2) Sample I 1.50 (2 MDa HA + CMC/pH 5.2) Sample P 1.53 (2 MDa HA + PEG/pH 5.2) Sample O 1.45 (2 MDa HA + Pluronic F127/pH 5.2)

[0063] Pluronic F-127 is a registered trademark of BASF Corporation, Florham Park, N.J. It is a difunctional block copolymer surfactant terminating in primary hydroxyl groups also known as Poloxamer 407.

[0064] As seen in the table above, at pH 5.2, the STG ratio is greater when 2 MDa HA is combined CMC or PEG than for 2 MDa HA alone or in combination with a stabilizing amount of Pluronic F127. For example, an aqueous gel containing 30% CMC (a stabilizer) contained in a syringe fitted with a 29 gauge needle cannot be injected through the 29 gauge needle at room temperature (or may be forced through that needle only with great difficulty). However, the addition of 0.15 g HA (0.15%) into the CMC gel makes the gel become much thinner when a mechanical force is applied on it due to the shear thinning effects. Accordingly, the HA+CMC gel may be injected through the 29 gauge needle easily using a standard syringe and standard injection technique. This shear thinning property of the gel is of great value in preparations that are intended to be injected through needles or otherwise passed through small diameter lumens, passageways or openings. Examples of specific applications where these shear thinning effects will be of value will be in glycosaminoglycan gels (e.g., HA gels) and other preparations intended for use as substance delivery depots/carriers or dermal/tissue fillers.

[0065] Accordingly, the hyaluronic acid/long chain hydroxy polyanionic polysaccharides system becomes thinner as a mechanical force is applied on it. Thus, it can be ideally used as an injectable formulation alone (e.g., as a viscoelastic agent or tissue filler/bulking agent) or may be combined with diagnostic or therapeutic agents (e.g., as a drug deliver carrier/depot) such that the diagnostic or therapeutic agents are then released kinetically.

[0066] Glycosaminoglycans, like hyaluronic acid, are made up of disaccharide repeating units containing a derivative of an amino sugar, either glucosamine or galactosamine in which one of the sugars has a negatively charged carboxylate or sulfate. Thus, glycosaminoglycans can be stabilized by the long chain hydroxyl polyanionic polysaccharides. Some major glycosaminoglycans are Dermatan Sulfate, Karatan Sulfate, Chondroitin 6-Sulfate and Heparin.

[0067] Glucosaminoglycans, like hyaluronic acid, are made up of disaccharide repeating units containing a derivative of an amino sugar, either glucosamine or galactosamine in which one of the sugars has a negatively charged carboxylate or sulfate group. Thus, Aginic acid, Polyethylene glycol alginate, CMC, etc. can also stabilize the glycosaminoglycans.

[0068] The term glycosaminoglycan as used ehrein includes but is not limited to hyaluronans, dermatan sulfate, keratan sulfate, chondroitin 6-sulphate and heparin.

[0069] In addition the stabilization of the above mentioned glycosaminoglycans can be performed using Carboxyethyl Cellulose as well as many other Carboxymethyl and Carboxyethyl cellulose compounds.

[0070] In summary, the combination of hyaluronic acid with a long chain hydroxyl polyanionic polysaccharides (e.g., Alginic acid, sodium alginate, Propylene glycol alginate, dextran, CMC, etc.) results in a composition having unique properties, including but not limited to: [0071] 1. Addition of the Long Chain Hydroxy Polyanionic Polysaccharides stabilizes the unstable Hyaluronic acid (Glycosaminoglycans) [0072] 2. Addition of the Long Chain Hydroxy Polyanionic Polysaccharides increases the viscosity of Hyaluronic Acid synergically in aqueous solution at pH 5.0-9.0 by an order of magnitude-, or more. [0073] 3. Addition of the Long Chain Hydroxy Polyanionic Polysaccharides enhances the shear thinning effects where the enhancement is pronouncedly higher with a higher molar mass of Hyaluronic Acid. [0074] 4. Addition of the hydroxy polysaccharides as well as nitrogen containing hydroxyl polysaccharides and long chain nitrogen containing polymers. [0075] 5. Polyhydroxy linear polymers.

[0076] The following are non-limiting examples of formulations of the present invention.

Formulation Examples

Formulation 1

[0077]

TABLE-US-00006 Sodium Hyaluronate 0.001%-50.0% Sodium Alginate 0.001%-50.0% Boric Acid 0.01%-1.0% Sodium Chloride  0.1%-10.0% Potassium Chloride  0.01%-10.0% Calcium Chloride dehydrate 0.001%-10.0% Magnesium Chloride hexahydrate 0.001%-1.0%  HCl or NaOH Adjust pH to 7.2 Purified water, USP Q.S. to 100 mL

Formulation 2

[0078]

TABLE-US-00007 Sodium Hyaluronate 0.001%-50.0% Alginic Acid 0.001%-50.0% Boric Acid 0.01%-1.0% Sodium Chloride  0.1%-10.0% Potassium Chloride  0.01%-10.0% Calcium Chloride dehydrate 0.001%-10.0% Magnesium Chloride hexahydrate 0.001%-1.0%  HCl or NaOH Adjust pH to 7.2 Purified water, USP Q.S. to 100 mL

Formulation 3

[0079]

TABLE-US-00008 Sodium Hyaluronate 0.001%-50.0% Carboxymethylcellulose 0.005%-40.0% Boric Acid 0.01%-1.0% Sodium Chloride  0.1%-10.0% Potassium Chloride  0.01%-10.0% Calcium Chloride dehydrate 0.001%-10.0% Magnesium Chloride hexahydrate 0.001%-1.0%  HCl or NaOH Adjust pH to 7.2 Purified water, USP Q.S. to 100 mL

Formulation 4

[0080]

TABLE-US-00009 Sodium Hyaluronate 0.001%-50.0% Propylene Glycol Alginate 0.001%-50.0% Boric Acid 0.01%-1.0% Sodium Chloride  0.1%-10.0% Potassium Chloride  0.01%-10.0% Calcium Chloride dehydrate 0.001%-10.0% Magnesium Chloride hexahydrate 0.001%-1.0%  HCl or NaOH Adjust pH to 7.2 Purified water, USP Q.S. to 100 mL

Formulation 5

[0081]

TABLE-US-00010 Sodium Hyaluronate 0.001%-50.0% Hydroxy propyl methyl cellulose 0.001%-50.0% Boric Acid 0.01%-1.0% Sodium Chloride  0.1%-10.0% Potassium Chloride  0.01%-10.0% Calcium Chloride dehydrate 0.001%-10.0% Magnesium Chloride hexahydrate 0.001%-1.0%  HCl or NaOH Adjust pH to 7.2 Purified water, USP Q.S. to 100 mL

Formulation 6

[0082]

TABLE-US-00011 Sodium Hyaluronate 0.001%-50.0% Sodium Alginate 0.005%-40.0% Sodium Phosphate Monobasic, monohydrate 0.01%-0.1% Sodium Phosphate Dibasic, anhydrous .sup. 0.02-1.0% Sodium Chloride 0.01%-1.0% HCl or NaOH Adjust pH to 7.2 Purified water, USP Q.S. to 100 mL

Formulation 7

[0083]

TABLE-US-00012 Sodium Hyaluronate 0.001%-50.0% Alginic Acid 0.005%-40.0% Sodium Phosphate Monobasic, monohydrate 0.01%-0.1% Sodium Phosphate Dibasic, anhydrous    0.02-1.0% Sodium Chloride 0.01%-1.0% HCl or NaOH Adjust pH to 7.2 Purified water, USP Q.S. to 100 mL

Formulation 8

[0084]

TABLE-US-00013 Sodium Hyaluronate 0.001%-50.0% Propylene Glycol alginate 0.005%-40.0% Sodium Phosphate Monobasic, monohydrate 0.01%-0.1% Sodium Phosphate Dibasic, anhydrous    0.02-1.0% Sodium Chloride 0.01%-1.0% HCl or NaOH Adjust pH to 7.2 Purified water, USP Q.S. to 100 mL

Formulation 9

[0085]

TABLE-US-00014 Sodium Hyaluronate 0.001%-50.0% Carboxymethylcellulose 0.005%-40.0% Sodium Phosphate Monobasic, monohydrate 0.01%-0.1% Sodium Phosphate Dibasic, anhydrous    0.02-1.0% Sodium Chloride 0.01%-1.0% HCl or NaOH Adjust pH to 7.2 Purified water, USP Q.S. to 100 mL

Formulation 10

[0086]

TABLE-US-00015 Sodium Hyaluronate 0.001%-50.0% Hydroxy propyl methyl cellulose 0.005%-40.0% Sodium Phosphate Monobasic, monohydrate 0.01%-0.1% Sodium Phosphate Dibasic, anhydrous    0.02-1.0% Sodium Chloride 0.01%-1.0% HCl or NaOH Adjust pH to 7.2 Purified water, USP Q.S. to 100 mL

Formulation 11

[0087]

TABLE-US-00016 Sodium Hyaluronate 0.15%-3.0% Sodium Alginate  0.50%-15.0% Sodium Phosphate Monobasic, monohydrate 0.01%-0.1% Sodium Phosphate Dibasic, anhydrous    0.02-1.0% Sodium Chloride 0.01%-1.0% HCl or NaOH Adjust pH to 7.2 Purified water, USP Q.S. to 100 mL

Formulation 12

[0088]

TABLE-US-00017 Sodium Hyaluronate 0.15%-3.0% Alginic Acid  0.50%-15.0% Sodium Phosphate Monobasic, monohydrate 0.01%-0.1% Sodium Phosphate Dibasic, anhydrous    0.02-1.0% Sodium Chloride 0.01%-1.0% HCl or NaOH Adjust pH to 7.2 Purified water, USP Q.S. to 100 mL

Formulation 13

[0089]

TABLE-US-00018 Sodium Hyaluronate 0.15%-3.0% Propylene Glycol Alginate  0.50%-15.0% Sodium Phosphate Monobasic, monohydrate 0.01%-0.1% Sodium Phosphate Dibasic, anhydrous    0.02-1.0% Sodium Chloride 0.01%-1.0% HCl or NaOH Adjust pH to 7.2 Purified water, USP Q.S. to 100 mL

Formulation 14

[0090]

TABLE-US-00019 Sodium Hyaluronate 0.15%-3.0% Carboxymethylcellulose  0.50%-15.0% Sodium Phosphate Monobasic, monohydrate 0.01%-0.1% Sodium Phosphate Dibasic, anhydrous    0.02-1.0% Sodium Chloride 0.01%-1.0% HCl or NaOH Adjust pH to 7.2 Purified water, USP Q.S. to 100 mL

Formulation 15

[0091]

TABLE-US-00020 Sodium Hyaluronate 0.15%-3.0% Hydroxy propyl methyl cellulose  0.50%-15.0% Sodium Phosphate Monobasic, monohydrate 0.01%-0.1% Sodium Phosphate Dibasic, anhydrous    0.02-1.0% Sodium Chloride 0.01%-1.0% HCl or NaOH Adjust pH to 7.2 Purified water, USP Q.S. to 100 mL

Formulation 16

[0092]

TABLE-US-00021 Sodium Chondroitin Sulfate 0.001%-50.0% Alginic Acid 0.001%-40.0% Sodium Phosphate Monobasic, monohydrate 0.01%-0.1% Sodium Phosphate Dibasic, anhydrous    0.02-1.0% Sodium Chloride 0.01%-1.0% HCl or NaOH Adjust pH to 7.2 Purified water, USP Q.S. to 100 mL

Formulation 17

[0093]

TABLE-US-00022 Sodium Chondroitin Sulfate 0.001%-50.0% Sodium alginate 0.001%-40.0% Sodium Phosphate Monobasic, monohydrate 0.01%-0.1% Sodium Phosphate Dibasic, anhydrous    0.02-1.0% Sodium Chloride 0.01%-1.0% HCl or NaOH Adjust pH to 7.2 Purified water, USP Q.S. to 100 mL

Formulation 18

[0094]

TABLE-US-00023 Sodium Chondroitin Sulfate 0.001%-50.0% Propylene Glycol alginate 0.001%-40.0% Sodium Phosphate Monobasic, monohydrate 0.01%-0.1% Sodium Phosphate Dibasic, anhydrous    0.02-1.0% Sodium Chloride 0.01%-1.0% HCl or NaOH Adjust pH to 7.2 Purified water, USP Q.S. to 100 mL

Formulation 19

[0095]

TABLE-US-00024 Sodium Chondroitin Sulfate 0.001%-50.0% Hydroxy propyl methyl cellulose 0.001%-40.0% Sodium Phosphate Monobasic, monohydrate 0.01%-0.1% Sodium Phosphate Dibasic, anhydrous    0.02-1.0% Sodium Chloride 0.01%-1.0% HCl or NaOH Adjust pH to 7.2 Purified water, USP Q.S. to 100 mL

Formulation 20

[0096]

TABLE-US-00025 Sodium Hyaluronate 0.001%-50.0% Dextran 0.005%-40.0% Sodium Phosphate Monobasic, monohydrate 0.01%-0.1% Sodium Phosphate Dibasic, anhydrous    0.02-1.0% Sodium Chloride 0.01%-1.0% HCl or NaOH Adjust pH to 7.2 Purified water, USP Q.S. to 100 mL

Formulation 21

[0097]

TABLE-US-00026 Sodium Hyaluronate 0.001%-50.0% Dextran 0.005%-50.0% Boric Acid 0.01%-1.0% Sodium Chloride  0.1%-10.0% Potassium Chloride  0.01%-10.0% Calcium Chloride dehydrate 0.001%-10.0% Magnesium Chloride hexahydrate 0.001%-1.0%  HCl or NaOH Adjust pH to 7.2 Purified water, USP Q.S. to 100 mL

[0098] The invention has been described hereabove with reference to certain examples or embodiments of the invention but that various additions, deletions, alterations and modifications may be made to those examples and embodiments without departing from the intended spirit and scope of the invention. For example, any element or attribute of one embodiment or example may be incorporated into or used with another embodiment or example, unless to do so would render the embodiment or example unsuitable for its intended use. All reasonable additions, deletions, modifications and alterations are to be considered equivalents of the described examples and embodiments and are to be included within the scope of the following claims.