Methods and compositions to enhance epithelial drug transport

• US 5,534,496 A
• Filed: 03/29/1994
• Issued: 07/09/1996
• Est. Priority Date: 07/07/1992
• Status: Expired due to Fees

• Current Assignee: University of Southern California
• Original Assignee: University of Southern California
• Inventors: Yen, Wan-Ching, Lee, Vincent H.
• Primary Examiner(s): Chan, Christina Y.
• Assistant Examiner(s): Lukton, David
• Application Number:
  US08/219,156
• Time in Patent Office: 833 Days
• Field of Search: 424/434, 514/17-19, 530/330, 530/331
• US Class Current: 514/5.9
• CPC Class Codes: A61K 38/1709 from mammals
• CPC Class Codes: A61K 47/183 Amino acids, e.g. glycine, EDTA or aspartame
• CPC Class Codes: A61K 47/62 the modifying agent being a protein, peptide or polyamino acid
• CPC Class Codes: C07K 5/06165 and Pro-amino acid; Derivatives thereof
• CPC Class Codes: C07K 5/0823 and Pro-amino acid; Derivatives thereof
• CPC Class Codes: C07K 5/1024 with the first amino acid being heterocyclic
• CPC Class Codes: C07K 7/06 having 5 to 11 amino acids
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
• CPC Class Codes: Y10S 977/779 Possessing nanosized particles, powders, flakes, or clusters other than simple atomic impurity doping
• CPC Class Codes: Y10S 977/906 Drug delivery
• CPC Class Codes: Y10S 977/915 Therapeutic or pharmaceutical composition
• CPC Class Codes: Y10S 977/962 for carrying or transporting

Abstract

Methods and compositions provided for enhancing the transport of drugs (including peptides, oligonucleotides, proteins and conventional drugs) across epithelial cells at mucosal sites. The methods and compositions include the use of a peptide comprising at least two amino acids, such as Pro-Leu-Gly-Pro-Arg or Pro-Leu, and a protective group such as phenylazo-benzyloxycarbonyl, N-methyl, t-butyloxycarbonyl, fluoroenylmethyloxycarbonyl or carbobenzoxy, at the N-terminus, or in a mixture of such peptides in a sufficient amount to enhance the drug transport across epithelial cells at mucosal sites. Preferably, the peptide comprises 2 to 5 amino acids; the N-terminal amino acids are preferably Pro-Leu. The peptide with the drug are introduced to the mucosal site in a physical mixture, a conjugated form or by a microcapsule, microsphere, liposome, cell, bacteria, virus or food vesicle carrier by an oral, nasal, pulmonary, buccal, rectal, transdermal, vaginal or ocular route.

Claims

1. A method for enhancing the delivery of a drug across epithelial cells at a mucosal site comprising:

(a) introducing a peptide to said mucosal site either concomitant with or prior to administration of said drug or

(b) introducing to said mucosal site a peptide which is covalently bonded to said drug;

wherein said peptide is selected from the group consisting of Pro-Leu-Gly-Pro-Arg [SEQ ID NO;

4], Pro-Leu-Gly-Pro-Lys [SEQ ID NO;

6], Pro-Leu-Gly-Pro-Glu [SEQ ID NO;

7], Pro-Leu-Gly-Pro-Asp [SEQ ID NO;

8], Pro-Leu-Gly-Pro [SEQ ID NO;

5], Pro-Leu-Gly and Pro-Leu, and having a protective group selected from the group consisting of Pz-, N-methyl, t-Boc, FMOC and CBZ at the N-terminus of said peptide to the mucosal site by an oral, nasal, pulmonary, buccal, rectal, transdermal, vaginal or ocular route in an amount sufficient to enhance the transport of said drug across epithelial cells at the mucosal site.

2. A method according to claim 1 wherein the drug and peptide are mixed prior to introducing said drug and said peptide to the mucosal site.

3. A method according to claim 1 wherein said enhanced drug delivery is achieved by administering the drug covalently attached to said peptide.

4. A method according to claim 1 wherein said drug and said peptide are introduced to the mucosal site by a microcapsule, microsphere, liposome, cell, bacteria or food vesicle carrier.

5. A method according to claim 1 wherein said drug and said peptide are introduced to the mucosal site simultaneously.

6. A method according to claim 1 wherein said peptide is first introduced to the mucosal site prior to the introduction of said drug.

7. A method according to claim 1 wherein said drug is selected from the group consisting of an insulin, a vasopressin, a leucine enkephalin, Asu-eel calcitonin, 5-fluorouracil, a salicylamide, a β

-lactone, an ampicillin, a penicillin, a cephalosporin, a β

-lactamase inhibitor, a quinolone, a tetracycline, a macrolide, a gentamicin, acyclovir, ganciclovir, a trifluoropyridine, and pentamidine.

8. A pharmaceutical composition for enhancing delivery of a drug across epithelial cells at a mucosal site comprising

a Pro-Leu-Gly-Pro-Arg [SEQ ID NO:

4] peptide with a Pz-group at the N-terminus of said peptide, said peptide further present in an amount of 0.1-10 mg;

a cyclodextrin carrier coating in which said peptide is dispersed and within which a drug selected from the group consisting of mannitol, atenolol, fluorescein, an insulin, a vasopressin, leucine enkephalin, Asu-eel calcitonin, 5-fluorouracil, a salicylamide, a β

-lactone, an ampicillin, a penicillin, a cephalosporin, a β

-lactamase inhibitor, a quinolone, a tetracycline, a macrolide, a gentamicin, acyclovir, ganciclovir, a trifluoropyridine, and pentamidine is entrapped.