TIGHT JUNCTION MODULATING PEPTIDES FOR ENHANCED MUCOSAL DELIVERY OF THERAPEUTIC COMPOUNDS
Compositions and methods are provided that include a biologically active agent and a permeabilizing agent effective to enhance mucosal delivery of the biologically active agent in a mammalian subject, in which the permeabilizing peptide is a tight junction modulating peptide (TJMP), a TJMP analogue, a conjugate of a TJMP, a conjugate of a TJMP analogue, or complexes thereof. The permeabilizing agent reversibly enhances mucosal epithelial paracellular transport, typically by modulating epithelial junctional structure and/or physiology at a mucosal epithelial surface in the subject.
1 . A pharmaceutical formulation comprising a biologically active agent and a mucosal delivery-enhancing effective amount of a permeabilizing peptide that reversibly enhances mucosal epithelial transport of the biologically active agent in a mammalian subject, wherein the permeabilizing peptide is a tight junction modulating peptide (TJMP), a TJMP analogue, a conjugate of a TJMP, a conjugate of a TJMP analogue, or a complex thereof.
2 . The formulation of claim 1 , wherein the TJMP is selected from the group consisting of
CNGRCGGKKKLKLLLKLL
(SEQ ID NO: 32)
LRKLRKRLLRLRKLRKRLLR-amide
(SEQ ID NO: 33)
3 . The composition of claim 2 , wherein said TJMP is conjugated to at least one water soluble chain.
4 . The formulation of claim 3 , wherein the water soluble chain is a poly(alkylene oxide) chain.
5 . The formulation of claim 4 , wherein such poly(alkylene oxide) chain is a polyethylene glycol (PEG) chain.
6 . The formulation of claim 5 , wherein the PEG has a molecular size between about 0.2 and about 200 kiloDaltons (kDa).
7 . The formulation of claim 1 , wherein the TJMP decreases electrical resistance across a mucosal tissue barrier.
8 . The formulation of claim 7 , where the decrease in electrical resistance is at least 80% of the electrical resistance prior to applying the TJMP.
9 . The formulation of claim 1 , wherein the TJMP increases permeability of the molecule across a mucosal tissue barrier.
10 . The formulation of claim 9 wherein the increase in permeability is at least two fold.
11 . The formulation of claim 9 , wherein the permeability is paracellular.
12 . The formulation of claim 9 , wherein the increased permeability results from modification of tight junctions.
13 . The formulation of claim 9 , wherein the permeability is transcellular, or a combination of trans- and paracellular.
14 . The formulation of claims 9 , wherein the mucosal tissue layer is comprised of an epithelial cell layer.
15 . The formulation of claim 14 , wherein the epithelial cell is selected from the group consisting of tracheal, bronchial, alveolar, nasal, pulmonary, gastrointestinal, epidermal or buccal.
16 . The formulation of claim 15 , wherein the epithelial cell is nasal.
17 . The formulation of claim 1 , wherein the biologically active agent is a peptide or protein.
18 . The formulation of claim 17 , wherein the peptide or protein is comprised of between 2 and 1000 amino acids.
19 . The formulation of claim 17 , wherein the peptide or protein is comprised of between 2 and 50 amino acids.
20 . The formulation of claim 17 , wherein the peptide or protein is cyclic.
21 . The formulation of claim 17 , wherein the peptide or protein forms dimers or higher-order oligomers via physical or chemical bonding.
22 . The formulation of claim 17 , wherein the peptide or protein is selected from the group comprising GLP-1, PYY 3-36 , PTH 1-34 and Exendin-4.
23 . The formulation of claim 17 , wherein the biologically active agent is a protein.
24 . The formulation of claim 23 , wherein the protein is selected from the group consisting of beta-interferon, alpha-interferon, insulin, erythropoietin, G-CSF, and GM-CSF, growth hormone, and analogues of any of these.
25 . A method of administering a molecule to an animal comprising preparing a formulation as in claim 1 and bringing such formulation in contact with a mucosal surface of such animal.
26 . The method of claim 25 , wherein such mucosal surface is intranasal.
27 . A dosage form comprising the formulation of claim 1 , wherein the dosage form is liquid.
28 . The dosage form of claim 27 , wherein the liquid is in the form of droplets.
29 . A dosage form comprising the formulation of claim 1 , wherein the dosage form is solid.
30 . The dosage form of claim 29 , wherein solid is reconstituted in liquid prior to administration.
31 . The dosage form of claim 29 , wherein the solid is administered as a powder.
32 . The dosage form of claim 29 , wherein the solid is in the form of a capsule, tablet or gel.
33 . A molecule that reversibly enhances mucosal epithelial transport of a biologically active agent in a mammalian subject, comprising a tight junction modulating peptide (TJMP) or a TJMP analogue.
34 . The molecule of claim 33 , wherein the TJMP is selected from the group consisting of
CNGRCGGKKKLKLLLKLL
(SEQ ID NO: 32)
LRKLRKRLLRLRKLRKRLLR-amide
(SEQ ID NO: 33)
35 . The molecule of claim 34 , wherein the TJMP is covalently linked to a poly(alkylene oxide) chain.
36 . The molecule of claim 35 , wherein such poly(alkylene oxide) chain is a polyethylene glycol (PEG) chain.
37 . The molecule of claim 36 , wherein the PEG has a molecular size between about 0.2 and about 200 kiloDaltons (kDa).