POLYMER SOLUTION FOR VISCO-SUPPLEMENTATION

Abstract

The invention proposes a polymer solution for visco-supplementation. The polymer solution contains at least one at least partially water-soluble polysaccharide or polysaccharide derivative, one water-soluble alkali salt or alkaline earth salt of polystyrene sulfonic acid, and water, whereby the polymer solution is clear to the eye. Moreover, the invention describes a method for sterilisation of the polymer solution. This method is characterised in that a mixture of at least one at least partially water-soluble polysaccharide or polysaccharide derivative, one water-soluble alkali salt or alkaline earth salt of polystyrene sulfonic acid, and water is mixed with at least 0.5 wt. % propiolactone, and in that the polymer solution is stored at room temperature for at least 24 hours.

Claims

1. Polymer solution for visco-supplementation comprising: a) at least one at least partially water-soluble polysaccharide or polysaccharide derivative; b) at least one water-soluble alkali salt or alkaline earth salt of polystyrene sulfonic acid; and c) water.

2. Polymer solution according to claim 1, further comprising: d) 3-hydroxypropionic acid.

3. Polymer solution according to claim 1, wherein the solution is clear to the eye.

4. Polymer solution according to claim 1, wherein the mass ratio of polysaccharide or polysaccharide derivative or of a mixture of at least two polysaccharides or mixture of at least two polysaccharide derivatives or of a mixture of at least one polysaccharide and at least one polysaccharide derivative and alkali salt or alkaline earth salt of polystyrene sulfonic acid is in the range of 1 to 1 to 1 to 0.01.

5. Polymer solution according to claim 1, wherein the total polymer content of the polymer solution is 0.1 to 10 wt. %.

6. Polymer solution according to claim 1, wherein the polymer solution further comprises at least one of antiphlogistic agents, antibiotics, immunosuppressants, and cytostatic agents.

7. Polymer solution according to claim 6, wherein the polymer solution comprises at least one of dexamethasone phosphate, triamcinolone phosphate, doxycycline, chlorotetracycline, oxytetracycline, doxorubicine, ciclosporine, methotrexate, leflunomide, azathioprine, mitomycin C, tacrolimus, sirolimus, and everolimus.

8. Polymer solution according to claim 1, consisting of a) at least one at least partially water-soluble polysaccharide or at least one at least partially water-soluble polysaccharide derivative or a mixture of at least one at least partially water-soluble polysaccharide and at least one at least partially water-soluble polysaccharide derivative; b) at least one water-soluble alkali salt or alkaline earth salt of polystyrene sulfonic acid; c) water; d) optionally, 3-hydroxypropionic acid; e) optionally, at least one antiphlogistic agent; f) optionally, at least one antibiotic; g) optionally, at least one immunosuppressant; h) optionally, at least one cytostatic agent.

9. Method for producing a sterile aqueous polymer solution, comprising mixing the following ingredients: a) at least one at least partially water-soluble polysaccharide or at least one at least partially water-soluble polysaccharide derivative or a mixture of at least one at least partially water-soluble polysaccharide and at least one at least partially water-soluble polysaccharide derivative; b) one water-soluble alkali salt or alkaline earth salt of polystyrene sulfonic acid; c) water; and d) at least 0.5 wt. % β-propiolactone, to form a polymer solution; and the polymer solution thus prepared is stored for at least 24 hours at 4-40° C.

10. Method according to claim 9, wherein 0.5-2.0 wt. % β-propiolactone are added for the purpose of sterilisation.

11. Method of using a polymer solution according to claim 1 as a means for visco-supplementation.

12. Method of using a polymer solution according to claim 1 as a support for pharmaceutical agents.

Description

EXAMPLE 1

[0064] A total of 5.0 ml of the phosphate buffer at a pH of 7.4 were placed in beaded rim vials. A total of 0.25 wt. %, 0.5 wt. %, 1.0 wt. %, and 2.0 wt. % polysaccharide/polysaccharide derivative and the sodium salt of polystyrene sulfonic acid (PSS1 and PSS2) were dissolved in these buffer solutions at room temperature. The polymer solutions were inspected visually after 24 hours.

TABLE-US-00001 Polymer solution Composition of the polymer solution Appearance 1 0.25 wt. % NaHya 0.25 wt. % PSS1 clear to the eye 2 0.25 wt. % CMC 0.25 wt. % PSS1 clear to the eye 3 0.25 wt. % MC 0.25 wt. % PSS1 clear to the eye 4 0.25 wt. % HEC 0.25 wt. % PSS1 clear to the eye 5 0.25 wt. % NaHya 0.25 wt. % PSS2 clear to the eye 6 0.25 wt. % CMC 0.25 wt. % PSS2 clear to the eye 7 0.25 wt. % MC 0.25 wt. % PSS2 clear to the eye 8 0.25 wt. % HEC 0.25 wt. % PSS2 clear to the eye 9 0.5 wt. % NaHya 0.5 wt. % PSS1 clear to the eye 10 0.5 wt. % CMC 0.5 wt. % PSS1 clear to the eye 11 0.5 wt. % MC 0.5 wt. % PSS1 clear to the eye 12 0.5 wt. % HEC 0.5 wt. % PSS1 clear to the eye 13 0.5 wt. % NaHya 0.5 wt. % PSS2 clear to the eye 14 0.5 wt. % CMC 0.5 wt. % PSS2 clear to the eye 15 0.5 wt. % MC 0.5 wt. % PSS2 clear to the eye 16 0.5 wt. % HEC 0.5 wt. % PSS2 clear to the eye 17 1.0 wt. % NaHya 1.0 wt. % PSS1 clear to the eye 18 1.0 wt. % CMC 1.0 wt. % PSS1 clear to the eye 19 1.0 wt. % MC 1.0 wt. % PSS1 clear to the eye 20 1.0 wt. % HEC 1.0 wt. % PSS1 clear to the eye 21 1.0 wt. % NaHya 1.0 wt. % PSS2 clear to the eye 22 1.0 wt. % CMC 1.0 wt. % PSS2 clear to the eye 23 1.0 wt. % MC 1.0 wt. % PSS2 clear to the eye 24 1.0 wt. % HEC 1.0 wt. % PSS2 clear to the eye

EXAMPLE 2

[0065] Polymer solutions were prepared analogous to example 1, but also contained, in addition, the antibiotic doxycycline. Doxycycline-hyalate (doxycycline hydrochloride-hemiethanolate-hemihydrate) was used for this purpose. The polymer solutions were checked visually after 24 hours of storage at room temperature.

TABLE-US-00002 Polymer solution Composition of the polymer solution Appearance 25 0.5 wt. % 0.5 wt. % 0.01 wt. % clear to the NaHya PSS1 Doxycycline- eye hyalate 26 0.5 wt. % 0.5 wt. % 0.01 wt. % clear to the CMC PSS1 Doxycycline- eye hyalate 27 0.5 wt. % 0.5 wt. % 0.01 wt. % clear to the MC PSS1 Doxycycline- eye hyalate 28 0.5 wt. % 0.5 wt. % 0.01 wt. % clear to the HEC PSS1 Doxycycline- eye hyalate

EXAMPLE 3

[0066] Polymer solutions were prepared analogous to example 1, but also contained, in addition, the antibiotic gentamicin sulfate. Gentamicin sulfate (with an activity coefficient of 580) was used for this purpose. The polymer solutions were checked visually after 24 hours of storage at room temperature.

TABLE-US-00003 Polymer solution Composition of the polymer solution Appearance 25 0.5 wt. % 0.5 wt. % 0.01 wt. % clear to the NaHya PSS1 gentamicin eye sulfate- 26 0.5 wt. % 0.5 wt. % 0.01 wt. % clear to the CMC PSS1 gentamicin eye sulfate- 27 0.5 wt. % 0.5 wt. % 0.01 wt. % clear to the MC PSS1 gentamicin eye sulfate- 28 0.5 wt. % 0.5 wt. % 0.01 wt. % clear to the HEC PSS1 gentamicin eye sulfate-

EXAMPLE 4

[0067] Polymer solutions were prepared analogous to example 1, but also contained, in addition, the antiphlogistic agent dexamethasone phosphate. The sodium salt of dexamethasone phosphate (NaDexP) was used for this purpose. The polymer solutions were checked visually after 24 hours of storage at room temperature.

TABLE-US-00004 Polymer solution Composition of the polymer solution Appearance 25 0.5 wt. % 0.5 wt. % 0.01 wt. % clear to the NaHya PSS1 NaDexP eye 26 0.5 wt. % 0.5 wt. % 0.01 wt. % clear to the CMC PSS1 NaDexP eye 27 0.5 wt. % 0.5 wt. % 0.01 wt. % clear to the MC PSS1 NaDexP eye 28 0.5 wt. % 0.5 wt. % 0.01 wt. % clear to the HEC PSS1 NaDexP eye

EXAMPLE 5

[0068] A 0.25 wt. % solution of NaHya was prepared using phosphate buffer pH 7.4. Then 10 mg, 1.0 mg, 0.1 mg, and 0.01 mg PSS1 were added to 40.0 g of the solution each. For the addition of 0.1 mg and 0.01 mg PSS1, a solution of 10 mg PSS1 in phosphate buffer was prepared and corresponding aliquots of this solution were added to the NaHya solution. A solution containing 26.7 IU/pl of a bovine hyaluronidase (Kraeber, 329 IU/mg) in phosphate buffer pH 7.4 was prepared. Then, 150 pl aliquots of this hyaluronidase solution were added to 40 g of the NaHya-PSS1 solutions. The solutions were then maintained at 37° C. for 15 minutes in an Ubbelohde viscometer (capillary I). Then the passage time of the polymer solution was determined. The polymer solutions were then kept at 37° C. in the Ubbelohde viscometer. The passage time of the polymer solution was measured again in successive one-hour intervals. In addition, the passage time of a 0.25 wt. % NaHya solution with added hyaluronidase was measured as a reference.

TABLE-US-00005 Composition of the 0.25 wt. % NaHY polymer solutions NaHya 0.25 0.25 0.25 0.25 0.25 0.25 wt. % wt. % wt. % wt. % wt. % wt. % Hyalur- − + + + + + onidase PSS1 — — 0.025 0.0025 0.00025 0.000025 wt. % wt. % wt. % wt. % Time [h] Passage time [min] 0.25 19 min 12 min 22 min 22 min 20 s 18 min 56 s 9 min 14 s 12 s 28 s 5 s 1.0 19 min 7 min 22 min 22 min 5 s  19 min 1 s  6 min 15 s 26 s 16 s 0 s 2.0 19 min 5 min 21 min 21 min 58 s 19 min 12 s 4 min 52 s 17 s 26 s 50 s 3.0 19 min 4 min 21 min 22 min 3 s  19 min 13 s 3 min 56 s 19 s 31 s 42 s 4.0 19 min 3 min 21 min 22 min 6 s  19 min 13 s 3 min 31 s 11 s 55 s 40 s 5.0 19 min 3 min 21 min 22 min 11 s 19 min 22 s 3 min 10 s 10 s 31 s 44 s

[0069] The passage times of the polymer solutions are proportional to the molar mass of the dissolved polymers. A reduction of the passage time is related to a decrease of the molar masses. The results show that polymer solutions containing hyaluronic acid and polystyrene sulfonic acid basically show no reduction of the passage times in the Ubbelohde viscometer within the test period of 5 hours. The hyaluronic acid contained in the polymer solution is obviously not being degraded by the hyaluronidase.

[0070] For a control, the influence of the hyaluronidase on the polystyrene sulfonic acid was investigated in another experiment. The experimental set-up was the same as in the preceding experiment.

TABLE-US-00006 Composition of the polymer solutions PSS1 0.25 wt. % — PSS2 — 0.25 wt. % Time [h] Passage time [min] 0.25 1 min 36 s 4 min 28 s 1 1 min 37 s 4 min 27 s 2 1 min 37 s 4 min 29 s 3 1 min 36 s 4 min 26 s 4 1 min 37 s 4 min 28 s 5 1 min 37 s 4 min 26 s

[0071] The results showed that aqueous polystyrene sulfonic acid solution cannot be degraded by hyaluronidase at 37° C.

EXAMPLE 6

[0072] A 0.25 wt. % solution of NaHya was prepared using phosphate buffer pH 7.4. Then 10 mg, 1.0 mg, 0.1 mg, and 0.01 mg PSS2 were added to 40.0 g of the solution each. For the addition of 0.1 mg and 0.01 mg PSS2, a solution of 10 mg PSS2 in phosphate buffer was prepared and corresponding aliquots of this solution were added to the NaHya solution. A solution containing 26.7 IU/μl of a bovine hyaluronidase (Kraeber, 329 IU/mg) in phosphate buffer pH 7.4 was prepared. Then, 150 μl aliquots of this hyaluronidase solution were added to 40 g of the NaHya-PSS2 solutions. The solutions were then maintained at 37° C. for 15 minutes in an Ubbelohde viscometer (capillary I). Then the passage time of the polymer solution was determined. The polymer solutions were kept at 37° C. in the Ubbelohde viscometer for this purpose. The passage time of the polymer solution was measured again in successive one-hour intervals. In addition, the passage time of a 0.25 wt. % NaHya solution with added hyaluronidase was measured as a reference.

TABLE-US-00007 Composition of the 0.25 wt. % NaHY polymer solutions NaHya 0.25 0.25 0.25 0.25 0.25 0.25 wt. % wt. % wt. % wt. % wt. % wt. % Hyalur- − + + + + + onidase PSS2 — — 0.025 0.0025 0.00025 0.000025 wt. % wt. % wt. % wt. % Time [h] Passage time [min] 0.25 19 min 12 min 19 min 22 min 26 s 22 min 12 s 18 min 17 s 12 s 28 s 52 s 1.0 19 min 7 min 20 min 22 min 16 s 22 min 5 s  18 min 05 s 26 s 16 s 2 s 2.0 19 min 5 min 19 min 22 min 24 s 22 min 3 s  18 min 10 s 17 s 26 s 50 s 3.0 19 min 4 min 19 min 22 min 24 s 22 min 5 s  17 min 58 s 19 s 31 s 57 s 4.0 19 min 3 min 19 min 22 min 22 s 22 min 3 s  18 min 5 s  11 s 55 s 53 s 5.0 19 min 3 min 20 min 22 min 23 s 22 min 4 s  18 min 7 s  10 s 31 s 1 s

[0073] The passage times of the polymer solutions are proportional to the molar mass of the dissolved polymers. A reduction of the passage time is related to a decrease of the molar masses. The results show that polymer solutions containing hyaluronic acid and polystyrene sulfonic acid basically show no reduction of the passage times in the Ubbelohde viscometer within the test period of 5 hours. Obviously, the hyaluronic acid in the hyaluronic acid/polystyrene sulfonic acid solutions is not being degraded by the hyaluronidase.

EXAMPLE 7

[0074] Firstly, solutions of the polysaccharides containing polystyrene sulfonic acid were prepared using 30.0 mL phosphate buffer (pH value 7.4) each. A total of 10.sup.6 cfu of a spore suspension of Bacillus atropheus were added to 5.0 mL each of the polysaccharide solutions in a sterile 25 mL plastic tube. Then the spores were suspended homogeneously using a vortex mixer. Subsequently, 0.5 wt. %, 1.0 wt. %, and 2.0 wt. % β-propiolactone were added to 5.0 mL each of the polysaccharide solution previously mixed with the spores. The sample was then homogenised again in a vortex mixer. Polysaccharide solutions not treated with β-propiolactone were used as positive control. After 48 hours of storage at room temperature, the polysaccharide solutions were tested for sterility in accordance with DIN EN ISO 11737, part 2. The assays were done in duplicate.

TABLE-US-00008 Result of the test of sterility Concentration of β-propiolactone [wt. %] 0.0 Composition of the (positive polymer solution control) 0.5 1.0 2.0 0.5 wt. % 0.5 wt. % +/+ −/− −/− −/− NaHya PSS1 0.5 wt. % 0.5 wt. % +/+ −/− −/− −/− CMC PSS1 0.5 wt. % 0.5 wt. % +/+ −/− −/− −/− MC PSS1 0.5 wt. % 0.5 wt. % +/+ −/− −/− −/− HEC PSS1 0.5 wt. % 0.5 wt. % +/+ −/− −/− −/− NaHya PSS2 0.5 wt. % 0.5 wt. % +/+ −/− −/− −/− CMC PSS2 0.5 wt. % 0.5 wt. % +/+ −/− −/− −/− MC PSS2 0.5 wt. % 0.5 wt. % +/+ −/− −/− −/− HEC PSS2 (+) growth (−) no growth

[0075] The polysaccharide solutions sterilised with β-propiolactone showed no discolouration whatsoever as compared to the untreated polysaccharide solutions used as positive control.