Controlled release mucoadhesive systems
Formulations for chemoprevention of oral cancer and precancerous lesions, and for methods for preparing the formulations are described.
1. A formulation, comprising:
from about 5 wt % to about 95 wt %, based on the total weight of the formulation, mucoadhesive material, wherein the mucoadhesive material comprises a methacrylate copolymer;
from about 0.1 wt % to about 5 wt %, based on the total weight of the formulation, fenretinide or a pharmaceutically acceptable salt thereof;
a transmucosal permeation enhancer agent comprising a mixture of:
from about 1 wt % to about 2.5 wt %, based on the total weight of the formulation, propylene glycol (PG), and
from 1 wt % to about 5 wt %, based on the total weight of the formulation, menthol; and,
at least one solubilizer agent selected from the group consisting of a nonionic surfactant, a bile salt, a phospholipid, a polymeric solubilizer, and combinations thereof.
2. The formulation of claim 1 , wherein the at least one solubilizer agent is selected from the group consisting of sodium deoxycholate, a polyoxy-ethylene-sorbitan higher fatty acid ester, a polyoxyethylene (20) oleyl ether, and combinations thereof.
3. The formulation of claim 2 , wherein the polyoxy-ethylene-sorbitan higher fatty acid ester is selected from polysorbate 20, polysorbate 80, and mixtures thereof.
4. The formulation of claim 1 , wherein the fenretinide and the permeation enhancer agent are adapted to be in contact with the same mucosal membrane.
5. The formulation of claim 4 , wherein the mucosal membrane is the buccal mucosa.
6. The formulation of claim 1 , wherein the formulation contains a predetermined amount of fenretinide in an amount selected from the group consisting of 10 μg, 15 μg, 25 μg, 50 μg, 100 μg, 500 μg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, and 10 mg and an adhesive material, the adhesive material providing for adherence to the oral mucosal membrane of a subject.
7. The formulation of claim 1 , wherein the amount of the fenretinide absorbed via the oral mucosa is at least 35% of the drug in the formulation.
8. The formulation of claim 1 , wherein the methacrylate copolymer comprises ethyl acrylate, methyl methacrylate, and methacrylic acid ester.
9. The formulation of claim 1 , wherein the solubilizer agent comprises a bile salt selected from the group consisting of sodium glycocholate, sodium deoxycholate, sodium cholate, sodium taurocholate, and combinations thereof.
10. A mouth product comprising the formulation of claim 1 , wherein the mouth product is selected from the group consisting of a toothpaste, a mouthwash or mouth rinse, a gel or paste, a spray, a chewing gum, and a lozenge.
11. A mucoadhesive patch comprising the formulation of claim 1 .
12. A transmucosal drug delivery system comprising at least one drug-release layer comprised of the formulation of claim 1 , at least one adhesive layer, and at least one backing layer.
13. A drug dosage form for oral transmucosal administration, comprising:
the formulation of claim 1 ; and an adhesive material, the adhesive material providing for adherence of the drug dosage form to the oral mucosa membrane.
14. A method of treating a disease or disorder, comprising: administering the formulation of claim 1 to a subject in need thereof.
15. The method of claim 14 , wherein the disease or disorder is a cancerous or precancerous condition.
16. The method of claim 14 , wherein the disease or disorder comprises one or more of: oral squamous cell carcinoma, intraoral dysplastic lesions, head and neck squamous carcinoma.
17. A method of treating a tumor comprising head and neck squamous carcinoma cells, comprising administering an effective amount of the formulation of claim 1 to a subject in need thereof.
18. A method of treating actinically induced precancerous lesions, comprising administering an effective amount of the formulation of claim 1 to a subject in need thereof.
19. A method for chemoprevention of a precancerous condition, comprising topically administering to a subject in need of such chemoprevention the formulation of claim 1 .
20. The method of claim 19 , wherein the formulation is administered to an interior of an oral cavity of the subject.
21. The method of claim 20 , wherein a single or repeated oral transmucosal administration to a subject results in a bioavailability of greater than 70%.
22. The method of claim 20 , wherein the oral transmucosal administration to a subject is repeated and results in a bioavailability with a coefficient of variation of less than 40%.
23. The method of claim 20 , wherein a single oral transmucosal administration of the formulation to a subject results in a Tmax of from about 6 hours to about 12 hours.
24. A method of using the formulation of claim 1 , comprising:
i) providing a transmucosal system comprised of the formulation of claim 1 ;
ii) applying the transmucosal system to a mucosal membrane of a subject; and,
iii) keeping the transmucosal system in contact with the mucosal membrane for a therapeutically effective period of time; and,
iv) optionally removing the transmucosal system when a desired therapeutic effect has been achieved.
25. The method of claim 24 , wherein the transmucosal system includes an adhesive material.
26. The method of claim 25 , wherein the formulation and the adhesive material are present in separate compartments.
27. A method for making a buccal drug delivery system, comprising:
i) preparing a drug-release layer comprised of the formulation of claim 1 ;
ii) preparing an adhesive layer; and,
iii) assembling the drug layer and the adhesive layers onto a backing layer.
28. A method for increasing permeation of a fenretinide formulation from a drug-releasing layer into a mucosa of a subject in need thereof, comprising:
i) admixing from about 5 wt % to about 95 wt %, based on the total weight of the formulation, mucoadhesive material, wherein the mucoadhesive material comprises a methacrylate copolymer;
from about 0.1 wt % to about 5 wt %, based on the total weight of the formulation, fenretinide or a pharmaceutically acceptable salt thereof;
a transmucosal permeation enhancer agent comprising a mixture of: from about 1 wt % to about 2.5 wt %, based on the total weight of the formulation, propylene glycol, and from 1 wt % to about 5 wt %, based on the total weight of the formulation, menthol;
and at least one solubilizer agent selected from the group consisting of a nonionic surfactant, a bile salt, a phospholipid, a polymeric solubilizer, and combinations thereof, and
ii) forming the admixture into a drug-release layer.
29. A method for making the formulation of claim 1 , comprising:
i) mixing a quantity of the at least one solubilizer agent, the mucoadhesive material, and the transmucosal permeation enhancer agent in a solvent to form a solvent mixture;
ii) adding the fenretinide or pharmaceutically acceptable salt thereof to the solvent mixture of step i); and, optionally adjusting a volume thereof to 10 mL with the solvent mixture of step i);
iii) forming a layer of the fenretinide mixture of step ii); and,
iv) drying the layer of step iii).
30. The method of claim 29 , wherein the at least one solubilizer agent is selected from the group consisting of sodium deoxycholate, a polyoxyl-ethylene-sorbitan higher fatty acid ester, a polyoxyethylene(20) oleyl ether, and combinations thereof.