COMPOSITION CONTAINING CATIONIC HYDROXYETHYL CELLULOSE

Abstract

An aqueous solution comprising a cationic polymer dissolved in water, wherein said cationic polymer comprises a hydrophobic quaternary ammonium group covalently attached to a hydroxyethyl cellulose polymer backbone. Also, a method of delivering a drug to a mucosal surface in a living body, said method comprising applying the aqueous solution to said mucosal surface.

Claims

1. A method of delivering a physiologically active agent into a tissue and/or a bloodstream of a living body, said method comprising applying an aqueous solution to a mucosal surface and allowing the physiologically active agent to permeate through the mucosal surface, wherein the aqueous solution comprises: (a) a cationic polymer dissolved in water, wherein said cationic polymer comprises a hydrophobic quaternary ammonium group covalently attached to a hydroxyethyl cellulose polymer backbone and optionally further comprises a non-hydrophobic quaternary ammonium group covalently attached to the hydroxyethyl cellulose polymer backbone, and (b) one or more physiologically active agents, wherein, if the non-hydrophobic quaternary ammonium group is present, the molar ratio of the non-hydrophobic quaternary ammonium group to the hydrophobic quaternary ammonium group is from 0:1 to 0.1:1.

2. The method of claim 1 wherein the cationic polymer has no non-hydrophobic quaternary ammonium group covalently attached to the hydroxyethyl cellulose polymer backbone.

3. The method of claim 1 wherein said mucosal surface is in a vagina, a mouth, an eye, an ear, an esophagus, a stomach, intestines, or a nasal cavity.

4. The method of claim 1 wherein said mucosal surface is in a nasal cavity.

5. The method of claim 1 wherein the physiologically active agent is a drug.

6. The method of claim 1 wherein the amount of said cationic polymer is 0.01% to 10% by weight based on the weight of said aqueous solution.

7. The method of claim 1 wherein said cationic polymer comprises repeat units of Structure ##STR00005## wherein n is 10 or higher; wherein R.sup.a, R.sup.b, and R.sup.c is each H or [CH.sub.2CH.sub.2O].sub.xR.sup.1, and one or more of R.sup.a, R.sup.b, and R.sup.c is [CH.sub.2CH.sub.2O].sub.xR.sup.1; wherein each x is chosen from 0, 1, 2, 3, or 4, and at least one repeat unit has at least one of R.sup.a, R.sup.b, and R.sup.c in which x is 1, 2, 3, or 4; wherein each R.sup.1 in R.sup.a, R.sup.b, and R.sup.c is H or Structure III, and at least one R.sup.1 is Structure III: ##STR00006## wherein R.sup.d is a bivalent organic group, and R.sup.e is either a hydrogen atom or a hydroxyl (OH) group; wherein R.sup.2 and R.sup.3 is each an alkyl group with 3 or fewer carbon atoms; wherein R.sup.4 is an alkyl group with 10 or more carbon atoms; and wherein X is an anion of valence v.

8. The method of claim 7 wherein R.sup.d is CH.sub.2; R.sup.2 and R.sup.3 is each methyl; and R.sup.4 is an alkyl group with 12 or more carbon atoms.

9. The method of claim 7 wherein R.sup.a and R.sup.b are H, R.sup.c is [CH.sub.2CH.sub.2O].sub.xR, R.sup.1 is Structure III, and x is 1 or 2.

10. The method of claim 7 wherein X is a halide anion.

11. The method of claim 7 wherein said cationic polymer has cationic degree of substitution of 0.01 or higher.

12. The method of claim 7 wherein said cationic polymer has cationic degree of substitution of 0.02 or higher.

13. The method of claim 7 wherein said cationic polymer has cationic degree of substitution of 0.05 or higher.

14. The method of claim 1 wherein said cationic polymer has weight-average molecular weight (Mw) of 100,000 or higher.

15. The method of claim 1 wherein said cationic polymer has weight-average molecular weight (Mw) of from 100,000 to 500,000.

16. The method of claim 1 wherein the aqueous solution is a buffer solution and further comprises an inorganic salt.

17. The method of claim 16 wherein the aqueous solution is a phosphate buffered saline solution.

18. The method of claim 1 wherein the aqueous solution is a liquid aqueous solution.

19. The method of claim 18 wherein the viscosity of the liquid aqueous solution is 300 mPa.Math.s or less when measured by steady shear viscometry using cone and plate at 10 sec.sup.1 at 25 C.

20. The method of claim 18 wherein the viscosity of the liquid aqueous solution is 30 mPa.Math.s or less when measured by steady shear viscometry using cone and plate at 10 sec.sup.1 at 25 C.

Description

EXAMPLE 2

[0068] Permeation of SS using Example Polymer P7 on two different tissue samples. Permeation tests were performed as in Comparative Example 1. Results were as follows.

TABLE-US-00003 Permeation of SS Example: C2-8 C2-9 2-10 2-11 Polymer: none Chitosan P7 P7 Conc.sup.(1) 0 0.1% 0.5% 0.5% Remain.sup.(3) 102 63.5 31.9 53.6 Perm.sup.(4) 3 30.3 22.3 28.5 Peff.sup.(5) 0.35 3.5 2.6 3.3 .sup.(1)% weight of polymer on total weight of solution .sup.(3)weight % of SS remaining in donor solution based on total SS .sup.(4)weight % or SS permeated through tissue based on total SS .sup.(5)units are 10.sup.6 cm/sec

[0069] Example polymer P7 performs far better than comparative polymers Compl, Comp2, and Comp3. Also, P7 performs comparably to Chitosan.

EXAMPLE 3

TEER Testing

[0070] TEER tests were performed on the sample reported in Example 2 above. Resistance drops from the initial value prior to permeation testing to the final value at the end of the permeation test; a larger drop indicates greater permeability. Results were as follows:

TABLE-US-00004 TEER tests Example: C3-8 C3-9 3-10 3-11 Polymer: none Chitosan P7 P7 Conc.sup.(1) 0 0.1% 0.5% 0.5% Resistance (ohms) initial 425 450 510 430 final 305 60 80 70 .sup.(1)% weight of polymer on total weight of solution

[0071] P7 and Chitosan show far greater drop in resistance (and therefore a greater tendency to assist permeation) than does the buffer solution alone.

EXAMPLE 4

Tissue Viability Testing

[0072] After performing a permeation test as described above, tissues were given the viability test as described above. The samples contained SS. One sample had Triton X-100 surfactant at a level of 0.2% by weight. Results were as follows:

TABLE-US-00005 Viability Test Example: C4-8 4-10 4-12 Excipient: PBS P7 Surfactant Conc.sup.(1) 0 0.5% 0.2% Viability (%) 100 110 1 .sup.(1)% weight of polymer on total weight of solution

[0073] The sample with surfactant had low viability. It is considered that the surfactant is likely to enhance permeation but cause a degradation of cell viability. The sample with P7 showed good permeability (as demonstrated above in a previous example) and good viability.

EXAMPLE 5

Membrane Recovery by the TEER Method

[0074] Samples were also tested for recovery in the TEER method. Samples had 2 mg/L SS. Results were as follows:

TABLE-US-00006 TEER Recovery test Example: C5-12 C5-13 5-14 Excipient: surfactant.sup.(6) none P7 Conc.sup.(1) 0.2% 0 0.2% Resistance (ohms) initial 800 710 510 at 4 hours permeation 1 580 80 24 hours after permeation 2 530 610 .sup.(1)% weight of polymer on total weight of solution .sup.(6)Triton X-100 surfactant described above

[0075] In Example 5, only example 5-14 with polymer P7 shows both (1) a drop in TEER at 4 hours permeation (which demonstrates good permeability) and good recovery of TEER 24 hours later (which demonstrates that the membranes recover from the treatment without permanent damage).

EXAMPLE 6

Permeation Testing of Formulations Using Example Polymer P7

[0076] Permeation tests were performed as in Comparative Example 1. Two different batches of example polymer P7 were used, labeled P7-1 and P7-2. Results were as follows.

TABLE-US-00007 Permeation of SS Example: 6-15 6-16 6-17 6-18 6-19 6-20 6-21 6-22 6-23 Polymer: P7-2 P7-2 P7-1 P7-1 P7-1 P7-1 P7-2 P7-2 P7-1 Tissue.sup.(7) S1 S2 S1 S2 S1 S2 S1 S2 Conc.sup.(1) 0.5 0.5 0.2 0.2 0.2 0.2 0.2 0.2 0.02 day 1 1 2 2 3 3 3 3 3 Remain.sup.(3) 31.9 53.6 60.0 88.7 15.5 16.7 15.5 11.9 44.2 Perm.sup.(4) 22.3 28.5 37.5 14.1 73.6 55.6 72.5 72.5 44.2 Peff.sup.(5) 2.6 3.3 4.3 1.6 8.5 6.4 8.4 8.4 5.1 .sup.(1)% weight of polymer on total weight of solution .sup.(3)weight % of SS remaining in donor solution based on total SS .sup.(4)weight % or SS permeated through tissue based on total SS .sup.(5)units are 10.sup.6 cm/sec .sup.(7)Pairs of examples (such as 6-15 and 6-16) that are identical except for tissue are replicate examples performed on two tissue samples that were different from each other. Each example was performed on a separate individual tissue sample; therefore, for example, the tissue S1 of 6-15 is not the same tissue sample as S1 of 6-17.

EXAMPLE 7

[0077] Permeation testing of various example polymers. Further permeation testing was conducted as in Comparative Example 1. Two batches of P7 were used: P7-1 and P7-2. Results were as follows:

TABLE-US-00008 Permeation of SS Example: 7-24 7-25 7-26 7-27 7-28 7-29 Polymer: P1 P2 P3 P4 P5 P6 Conc.sup.(1) 0.2 0.2 0.2 0.2 0.2 0.2 Remain.sup.(3) 20.2 36.5 16.5 38.3 22.5 33.8 Perm.sup.(4) 56.6 44.2 39.5 40.4 34.9 23.1 Peff.sup.(5) 6.6 5.1 4.6 4.7 4.0 2.7 Permeation of SS Example: 7-30 7-31 7-32 C7-33 C7-34 Polymer: P7-1 P8 P7-2 Chitosan none Conc.sup.(1) 0.2 0.02 0.2 0.2 0 Remain.sup.(3) 16.7 42.5 11.9 51.6 86.4 Perm.sup.(4) 55.6 37.9 72.5 32.4 1.7 Peff.sup.(5) 6.4 4.4 8.4 3.8 0.19 .sup.(1)% weight of polymer on total weight of solution .sup.(2)number of replicate samples tested. Results shown are averages over the replicates .sup.(3)weight % of SS remaining in donor solution based on total SS .sup.(4)weight % or SS permeated through tissue based on total SS .sup.(5)units are 10.sup.6 cm/sec

[0078] All of the example polymers P1 through P8 show significant improvement to permeability over the control sample that has no polymer.