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. An aqueous solution comprising (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 (b) one or more physiologically active agents

2. The aqueous solution 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.

3. The aqueous solution of claim 1, wherein said cationic polymer has repeat units of structure II ##STR00005## wherein n is 10 or higher; R.sup.a, R.sup.b, and R.sup.c is each H or [CH.sub.2CH.sub.2O].sub.xR.sup.1, wherein each x is chosen from 0, 1, 2, 3, or 4; wherein R.sup.1 is H or 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 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 one or more of R.sup.a, R.sup.b, and R.sup.c has the structure [CH.sub.2CH.sub.2O].sub.xR.sup.1; wherein R.sup.2 and R.sup.3 is each an alkyl group with 3 or few 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.

4. The aqueous solution of claim 3, wherein R.sup.d is CH.sub.2; R.sup.e is OH; R.sup.2 and R.sup.3 is each methyl; and R.sup.4 is an alkyl group with 12 or more carbon atoms.

5. A method of delivering a drug to a mucosal surface in a living body, said method comprising applying the aqueous solution of claim 1 to said mucosal surface, wherein said aqueous solution of claim 1 comprises said drug.

6. The method of claim 5 wherein said mucosal surface is in a vagina, a mouth, an eye, an ear, an esophagus, a stomach, intestines, or a nasal cavity.

7. The method of claim 5 wherein said mucosal surface is in a nasal cavity.

Description

COMPARATIVE EXAMPLE 1: PERMEATION OF SUMATRIPTAN SUCCINATE (SS) IN PBS BUFFER with Various Comparative Cationic Polymers in the Solution

[0065] Results were as follows:

TABLE-US-00002 Permeation of SS Example: C1-1 C1-2 C1-3 C1-4 C1-5 C1-6 C1-7 Poly- none Comp1 Comp1 Comp2 Comp3 Comp3 Chi- mer: tosan Conc.sup.(1) 0 0.5% 0.1% 0.1% 0.5% 0.1% 0.1% N.sup.(2) 2 3 2 3 2 2 2 Re- 62.1 51.5 55.7 65.8 52.5 64.2 38.9 main.sup.(3) Perm.sup.(4) 2.0 2.2 1.8 2.3 1.4 1.8 37.6 Peff.sup.(5) 0.23 0.25 0.21 0.27 0.16 0.21 4.4 .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 (for example, Peff of C1-1 was 0.23 ? 10.sup.?6 cm/sec)

[0066] All of the synthetic polymers tested (Comparative Examples C1 through C6) showed far worse performance than Chitosan (Comparative Example C7).

EXAMPLE 2: PERMEATION OF SS USING EXAMPLE POLYMER P7 ON TWO DIFFERENT TISSUE SAMPLES

[0067] 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

[0068] Example polymer P7 performs far better than comparative polymers Comp1, Comp2, and Comp3. Also, P7 performs comparably to Chitosan.

EXAMPLE 3: TEER TESTING

[0069] 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

[0070] 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

[0071] 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

[0072] 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

[0073] 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

[0074] 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

[0075] 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 Poly- P7-2 P7-2 P7-1 P7-1 P7-1 P7-1 P7-2 P7-2 P7-1 mer: Tis- S1 S2 S1 S2 S1 S2 S1 S2 sue.sup.(7) 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 Re- 31.9 53.6 60.0 88.7 15.5 16.7 15.5 11.9 44.2 main.sup.(3) 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: PERMEATION TESTING OF VARIOUS EXAMPLE POLYMERS

[0076] 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 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 (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

[0077] All of the example polymers P1 through P8 show significant improvement to permeability over the control sample that has no polymer.