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1. (WO2019067596) DELIVERY PHARMACEUTICAL COMPOSITIONS INCLUDING PERMEATION ENHANCERS
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CLAIMS:

What is claimed is:

1 . A pharmaceutical composition, comprising:

a polymeric matrix;

a pharmaceutically active component including octreotide in the polymeric matrix; and a permeation enhancer including a surfactant.

2. The pharmaceutical composition according to claim i , wherein the surfactant is a cationic surfactant.

3. The pharmaceutical composition according to claim 1 , wherein the surfactant includes a dodecyltrimethylammonium bromide.

4. The pharmaceutical composition according to claim 1 , wherein the surfactant includes a glycine betaine ester.

5. The pharmaceutical composition according to claim 1 , wherein the surfactant includes CTAB.

6. The pharmaceutical composition according to claim 1 , wherein the surfactant includes BAC.

7. The pharmaceutical composition according to claim 1 , wherein the surfactant includes CPC.

8. The pharmaceutical composition according to claim 1 , wherein the surfactant is combined with a non-ionic or anionic surfactant.

9. The pharmaceutical composition according to claim 1 , wherein the surfactant is combined with a chelator.

i 0, The pharmaceutical composition according to claim 1 , wherein the surfactant is combined with a cyciodextrin.

1 1 . The pharmaceutical composition according to claim i , wherein the surfactant is combined with a fatty acid.

12. The pharmaceutical composition according to claim I , wherein the permeation enhancer is biodegradable.

13. The pharmaceutical composition according to claim 1 having a suitable nontoxic, nonionic alkyl glycoside having a hydrophobic alky 1 group joined by a linkage to a hydrophilie saccharide in combination with a mucosal delivery-enhancing agent selected from; (a) an aggregation inhibitory agent; (b) a charge-modifying agent; (c) a pH control agent; (d) a degradative enzyme inhibitory agent; (e) a mucolytic or mucus clearing agent; (f) a ciliosiatie agent; (g) a membrane penetration-enhancing agent selected from; (i) a surfactant; (ii) a bile salt; (ii) a phospholipid additive, mixed micelle, liposome, or carrier; (iii) an alcohol; (iv) an enamine; (v) an NO donor compound; (vi) a long chain amphipathic molecule; (vis) a small hydrophobic penetration enhancer; (vii i) sodium or a salicylic acid derivative; (ix) a glycerol ester of acetoacetic acid; (x) a cyciodextrin or beia-cyclodextrin derivative; (xi) a medium-chain fatty acid; (xii) a chelating agent; (xiis) an amino acid or salt thereof; (xiv) an N-acety!ammo acid or salt thereof; (xv) an enzyme degradative to a selected membrane component; (ix) an inhibitor of fatty acid synthesis; (x) an inhibitor of cholesterol synthesis; and (xi) any combination of the membrane penetration enhancing agents recited in (i)-(x); 0Ό a modulatory agent of epithelial junction physiology; (i) a vasodilator agent; (j) a selective transport-enhancing agent; and (k) a stabilizing delivery vehicle, carrier, mucoadhesive, support or complex-forming species with which the compound is effectively combined, associated, contained, encapsulated or bound resulting in stabil ization of the compound for enhanced mucosal delivery, wherein the formulation of the compound with the transmucosal delivery-enhancing agents provides for increased bioavailability of the compound in a blood plasma of a subject.

14. The pharmaceutical composition according ΐο claim 1 , wherein the octreotide is delivered from a pharmaceutical film having an occlusive layer and an active layer.

15. The pharmaceuiical composition according to claim S , wherein the octreotide and permeation enhancer are embedded in an active layer of a pharmaceuiical composition film.

16. The pharmaceutical composition according to claim ! wherein the permeation activity of DDTMAB is concentration dependent.

17. The pharmaceutical composition according to claim 1 , wherein the permeation enhancer is 5% wt DDTMAB.

1 8. The pharmaceutical composition according to claim i , wherein the permeation enhancer is 1 % wt DDTMAB.

1 . The pharmaceutical composition according to claim ί , wherein the permeation enhancer is 0.5% wt DDTMAB.

20. The pharmaceutical composition according to claim i , wherein the permeation enhancer is 0. 1 % wt DDTMAB.

2 1 . The pharmaceutical composition according to claim 1 , with a critical micel le

concentration of 0.3%.

22. The pharmaceutical composition according to claim 1 , wherein the permeation enhancer is 10% wt glycine beiaine ester.

23. The pharmaceutical composition according to claim I , wherein the permeation enhancer is 5% wt glycine betaine ester.

24. The pharmaceutical composition according to claim 1 , wherein the permeation enhancer is 0.5% wt glycine betaine ester,

25. The pharmaceutical composition according to claim i , wherein the permeation enhancer is 0. 1 % wt glycine betaine ester.

26. The pharmaceutical composition according to claim I , having a therapeutic window 300 minutes or less.

27. The pharmaceutical composition according to claim 1 , having a therapeutic window of 200 minutes or less.

28. The pharmaceutical composition according to claim i , having a therapeutic window of 150 minutes or less.

29. The pharmaceutical composition according to claim ί , having a therapeutic window of 100 minutes or less.

30. The pharmaceutical composition according to claim i , having a therapeutic window of 50 minutes or less.

3 1 . The pharmaceutical composition according to claim 1 , having a therapeutic window of 50-400 minutes.

32. The pharmaceutical composition according to claim 1 , having 50-600 ug of octreotide permeation in a therapeutic window.

33. The phamiaceutical composition according to claim I , wherein the polymeric matrix comprises at least one polymer selected from the group of: pullulan, polyvinyl pyrrolidone, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tragancanth gum, guar gum, acacia gum, arabic gum, po!yacrylic acid, raethylrnethacryiate copolymer, carboxyvinyl copolymers, starch, gelatin, ethylene oxide-propylene oxide co-polymers, collagen, albumin, poly-amino acids, polyphosphazenes, polysaccharides, chitin, chitosan, and derivatives thereof.

34. The pharmaceutical composition according to claim 1 , further comprising a stabilizer.

35. The pharmaceutical composition according to claim I , wherein the polymeric matrix comprises a dendritic polymer.

36. The pharmaceutical composition according to claim 1 , wherein the polymeric matrix comprises a hyperbranched polymer.

37. A method of making a pharmaceutical composition of claim 1 , comprising:

mixing a permeation enhancer including a surfactant with a pharmaceutically active component including octreotide and

embedding the pharmaceutically active component including octreotide in a pharmaceutical film.

38. A device comprising

a housing that holds an amount of a pharmaceutical composition, comprising:

a polymeric matrix;

a pharmaceutical ly active component including octreotide in the polymeric matrix; and a permeation enhancer including a surfactant; and

an opening that dispenses a predetermined amount of the pharmaceutical composition.

39. The pharmaceutical composition of claim 1 , wherein the surfactant has the following structure:

Rl


R2

wherein:

A is either nitrogen or phosphorus;

C is a cleavable linkage;

B is a group connecting A with C and is an a!ky!ene. alkenylene, cycioalkylene or aralkylene group or a derivatives thereof optionally containing one or more hetero atoms;

each of R!, R2 and " , independently, is selected from the group consisting of hydrogen, alkyl, alkeny!, alkynyi, cycloaikyi and araikyl group optionally having one or more heteroatoms;

R4 is selected from the group consisting of alkyl, alkenyl, alkynyi, cycioalkyl and araikyi group optionally having one or more heteroatoms;

D- is an anionic counter ion to A

40. The pharmaceutical composition of claim 39, wherein each of R¾, R2 and R3 jindependently, is a Ci-so alkyl, C2-so alkenyl, C2-io alkynyi, Ο¾_ιο cycioalkyl, C -10 araikyl or derivative thereof optionally having one or more heteroatoms.

4 1 . The pharmaceutical composition of claim 39 wherein B is a G-20 aikyiene, C2-20

aikenyiene, C2-20 alkynyiene, C3.20 eycioaikyiene, C4- 20 aralkylene group or derivative thereof optionally having one or more heteroatoms.

42. The pharmaceutical composition of claim 39 wherein R4 is a d.30 alkyl, C2-30 alkenyl, C2-30 alkynyl, C3-30 cycloaikyi, C4-30 aralkyl group or derivative thereof optionally having one or more heteroatoms.

43. The pharmaceutical composition of claim 39 wherein C is a degradable group through acid/base hydrolysis, enzymatic reaction or radical cleavage.

44. The pharmaceuti cal composition of claim 39 wherein C is selected from the group consisting of a carbonate linkage, an amide linkage, an ester linkage, acetal linkage, hemiacetal linkage, orthoester linkage, carbamide, sulphonate, phosphonate, thioester, urea, isocyanate linkages, hydrozone, disulfide linkages or any combination thereof.

45. The pharmaceutical composition of claim 39 wherein D is chloride, bromide, iodide, sulfate, sulfonate, carbonate, or hydroxide ion.

46. A method of treating a medical condition comprising:

administering a pharmaceutical composition including;

a polymeric matrix;

an effective amount of a pharmaceutically active component including octreotide in the polymeric matrix; and

a permeation enhancer including a surfactant

47. The method of claim 46, wherein treating a medical condition includes inhibiting the release of growth hormone.

48. The method of claim 46, wherein the medical condition includes growth hormone producing tumors and pituitary tumors, diarrhea and flushing episodes associated with carcinoid syndrome, diarrhea associated with vasoactive intestinal peptide-secreting rumors, or acute hemorrhage from esophageal varices in liver cirrhosis.