Method of converting a drug to an orally available form by covalently bonding a lipid to the drug

• US 5,411,947 A
• Filed: 12/16/1992
• Issued: 05/02/1995
• Est. Priority Date: 06/28/1989
• Status: Expired due to Term

• Current Assignee: Chimerix Incorporated
• Original Assignee: Vestar, Inc. (Advanced Micro Devices, Inc.)
• Inventors: Hostetler, Karl Y., Kumar, Raj
• Primary Examiner(s): Naff, David M.
• Assistant Examiner(s): MELLER, MICHAEL V
• Application Number:
  US07/991,166
• Time in Patent Office: 867 Days
• Field of Search: 536/26.5, 514/43, 514/885, 514/12, 514/2, 514/18, 514/192, 514/199, 514/200, 514/50
• US Class Current: 514/43
• CPC Class Codes: A61K 47/54 the modifying agent being an organic compound
• CPC Class Codes: A61K 47/542 Carboxylic acids, e.g. a fatty acid or an amino acid
• CPC Class Codes: A61K 47/544 Phospholipids
• CPC Class Codes: A61K 47/548 Phosphates or phosphonates, e.g. bone-seeking phospholipids A61K47/544
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C07F 9/3891 Acids containing the structure -C(=X)-P(=X)(XH)2, (X = O, S, Se)
• CPC Class Codes: C07F 9/4006 Esters of acyclic acids which can have further substituents on alkyl
• CPC Class Codes: C07F 9/4065 Esters of acids containing the structure -C(=X)-P(=X)(XR)2, (X = O, S, Se)
• CPC Class Codes: C07F 9/65512 condensed with carbocyclic rings or carbocyclic ring systems
• CPC Class Codes: C07H 15/04 attached to an oxygen atom of the saccharide radical
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/16 Purine radicals

Abstract

The oral delivery of many classes of drugs is facilitated by converting drugs having suitable functional groups to 1-O-alkyl-, 1-O-acyl-, 1-S-acyl, and 1-S-alkyl-sn-glycero-3-phosphate derivatives. The method confers the ability to be absorbed through the digestive tract to drugs that are not orally bioavailable in the non-derivatized state, and enhances the effectiveness of drugs that are poorly absorbed or rapidly eliminated. The method provides orally bioavailable lipid prodrugs of pharmaceutical compounds having diverse physiological activities, including anticancer and antiviral agents, anti-inflammatory agents, antihypertensives and antibiotics. Potency of the lipid prodrugs is comparable to that of the corresponding non-derivatized drugs.

Claims

1. A method of converting a drug that is unavailable or poorly available in a mammal through the oral route of administration to an orally available form, comprising:

(a) covalently linking a lipid species selected from the group consisting of 1-O-alkyl-sn-glycerol-3-phosphates, and 1-O-acyl-sn-glycerol-3-phosphates to a functional group of said drug either directly through the phosphate group of the lipid species or through a multifunctional linker molecule to form a lipid derivative of the drug;

(b) recovering the lipid derivative of the drug from the linking reaction mixture of step (a); and

(c) incorporating the lipid derivative of the drug into a therapeutic formulation suitable for oral administration.

2. The method of claim 1 wherein said lipid derivative is a 1-O-alkyl-sn-glycerol-3-phosphate derivative of a drug, of the formula ##STR4## wherein R is a substituted or unsubstituted, saturated or unsaturated, straight or branched chain, or cyclic C_1-24 alkyl group, covalently linked to the glycerol moiety in an ether linkage;

n=0 to 2;

L is a linking molecule, of the formula X--(CH₂)_n --Y

wherein X and Y are functional groups independently selected from hydroxyl, sulfhydryl, carboxyl and amine groups, and n=1 to 24;

or

L is absent; and

D is a drug having a functional group selected from the group consisting of hydroxyl, sulfhydryl, carboxyl, or amino groups.

3. The method of claim 2, wherein the drup is an anticancer nucleoside having a carboxyl, hydroxyl, or amino group available for covalent binding.

4. The method of claim 3, wherein the drug is 9-β

-D-arabinofuranosylcytosine (ara-C), 5-fluorouridine, 6-mercaptopurine riboside, 9-β

-D-arabinofuranosyladenine (ara-A), or 2'"'"'-arafluoro-2-chloro-deoxyadenosine.

5. The method of claim 2, wherein the drug is 5-amino-4-imidazole carboxamide ribonucleoside (AICA-riboside).

6. The method of claim 2, wherein D is a therapeutic peptide, or a peptidomimetic of from 3 to 35 amino acid residues or analogues thereof.

7. The method of claim 6, wherein the drug is n-muramyl tripeptide.

8. The method of claim 6, wherein the drug is enalkiren.

9. The method of claim 2, wherein the drug is selected from the group consisting of antibiotics of the penicillin and cephalosporin class.

10. The method of claim 9, wherein the drug is selected from the group consisting of penicillin G, cefazolin, ceftazidime, ceftriaxone, piperacillin.

11. The method of claim 1, wherein said drug is 3'"'"'-azido-3'"'"'-deoxythymidine (AZT).

12. The method of claim 1, wherein said drug is 3'"'"'-azido-3'"'"'-acycloguanosine (ACG).