Polymer composition for controlled release of active ingredients in response to pH, and a process of preparing the same

• US 5,851,546 A
• Filed: 03/14/1996
• Issued: 12/22/1998
• Est. Priority Date: 06/14/1995
• Status: Expired due to Term

• Current Assignee: Council of Scientific & Industrial Research
• Original Assignee: Council of Scientific & Industrial Research
• Inventors: Kulkarni, Mohan Gopalkrishna, Mashelkar, Raghunath Anant, Karmalkar, Rohini Nitin
• Primary Examiner(s): Nutter, Nathan M.
• Application Number:
  US08/615,431
• Time in Patent Office: 1,013 Days
• Field of Search: 424/484, 424/426, 424/428, 424/433, 424/457, 424/468, 424/475, 424/486
• US Class Current: 424/426
• CPC Class Codes: A01N 25/10 Macromolecular compounds
• CPC Class Codes: A61K 47/58 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin

Abstract

The present invention provides a polymer for the controlled release of a pendent chain linked active ingredient, and a process for the preparation of such a polymer for the controlled release of an active ingredient in response to pH. The process involves selecting a vinyl monomer to which the active ingredient molecule is covalently linked through a pendent group, and selecting monomers bearing catalytic groups. The active ingredient-bearing monomer and the catalytic group-containing monomer are brought in juxtaposition either by complexation or molecular imprinting, and then polymerized with a hydrophilic monomer and crosslinker under an inert atmosphere with a suitable polymerization initiator.

Claims

1. A polymer for the controlled release of an active ingredient, the polymer having the general formula A_x B_y C_z S_q wherein A is an imidazole group-bearing vinyl monomer, B is a hydroxyl group-bearing vinyl monomer, C is a carboxyl group-bearing vinyl monomer, and S is a vinyl monomer covalently bonded to an active ingredient through an amide or an ester;

and

x+y+z+q=1; and

x, y, z, q can vary such that 0<

x<

1, and 0<

q<

1, and y and z can vary between 0 to 1.

2. The polymer according to claim 1, wherein the active ingredient is selected from the group consisting of a drug, insecticide, fungicide, herbicide, pesticide, and weedicide.

3. The polymer according to claim 1, wherein the active ingredient is linked to the S vinyl monomer through an --OH, --COOH or --NH₂ group.

4. The polymer according to claim 1, wherein the (s) vinyl monomer is selected from the group consisting of 1-vinyl imidazole, 4-vinyl pyridine, N-methacryloyl L-histidine, and N-acryloyl L-histidine.

5. The polymer according to claim 1, wherein the hydroxyl group-bearing vinyl monomer (B) is selected from the group consisting of 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, p-styrene phenol, N-methacryloyl serine, 2-hydroxyethyl methacrylamide, N-methacryloyl serine, methacryloyl 6-aminocaproyl serine, and p-vinyl benzoyl 6-aminocaproyl serine.

6. The polymer according to claim 1, wherein the imidazole group-bearing vinyl monomer (A) is selected from the group consisting of N-methacryloyl L-histidine, N-acryloyl L-histidine, 4(5)-vinyl imidazole, N-methacryloyl histamine, methacryloyl 6-aminocaproyl histidine, and p-vinyl benzoyl 6-aminocaproyl histidine.

7. The polymer according to claim 1, wherein the carboxyl group-bearing vinyl monomer (C) is selected from the group consisting of acrylic acid, methacrylic acid, N-methacryloyl L-glutamic acid, N-methacryloyl aspartic acid, methacryloyl 6-aminoaproyl aspartic acid, and p-vinyl benzoyl 6-aminocaproyl aspartic acid.

8. The polymer according to claim 1, wherein the active ingredient is releasable from the polymer at about pH 5-10.

9. A process of preparing a polymer as recited in claim 1, comprising:

(a) bringing into juxtaposition, said vinyl monomers releasably linked through a pendent group to an active ingredient with (i) a second vinyl monomer bearing a catalytic group, or (ii) a preorganized assembly of vinyl monomers bearing catalytic groups to form a mixture;

(b) in the presence of a polymerization initiator at a temperature of about 55°

-75°

C. under an inert atmosphere, or (ii) by Γ

irradiation at a temperature of about 4°

-40°

C.; and

(c) combining the polymerized mixture with an aqueous medium, at a temperature of about 25°

-80°

C.

10. The process of claim 9, wherein the active ingredient is selected from the group consisting of a drug, insecticide, fungicide, herbicide, pesticide, and weedicide.

11. The process of claim 9, wherein the active ingredient is linked to the S vinyl monomer through an --OH, --COOH or --NH₂ group via an amide or ester bond.

12. The process of claim 9, wherein the first vinyl monomer is selected from the group consisting of p-nitrophenyl p-vinyl benzoate, 2,4 dinitrophenyl p-vinyl benzoate, 2-methylacryloyl ethyl p-nitro benzoate, 2-methacryloyl ethyl p-amino benzoate, N-methacryloyl 6-amino caproyl p-nitrophenol, and N-methacryloyl B-alanine p-nitroanilide.

13. The process of claim 9, wherein the catalytic group-bearing vinyl monomer in step (a) is selected from the group consisting of N-vinyl imidazole, 4(5) vinyl imidazole, N-methacryloyl histidine, N-acryloyl histidine, N-vinyl pyridine, 2-vinyl pyridine, methacryloyl aspartic acid, methacrylic acid, acrylic acid, acryloyl aspartic acid, N-methyl hydroxamic acid, 1-vinyl imidazole, 4-vinyl pyridine, N-methacryloyl L-histidine, and N-acryloyl L-histidine.

14. The process of claim 9, wherein the hydrophilic monomer of step (b) is selected from the group consisting 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, acrylamide, methacrylamide, N-isopropyl acrylamide, isopropyl acrylamide, methacrylic acid, and acrylic acid.

15. The process of claim 9, wherein step (a) is effected by donor-acceptor complex formation by electrostatic interaction, hydrophobic interaction, metal coordination, or a combination thereof.

16. The process of claim 9, wherein polymerizing step (b) is carried out in the presence of a metal ion selected from the group consisting of Co⁺⁺, Ni⁺⁺, Cu⁺⁺, Zn⁺⁺, Mg⁺⁺, Mn⁺⁺, and Fe⁺⁺⁺.

17. The process of claim 9, wherein polymerizing step (b) is carried out by thermal polymerization at a temperature of about 50°

-90°

C., or by irradiation at about 4°

-40°

C.

18. The process of claim 9, wherein polymerizing step (b) is initiated thermally or by irradiation in the absence of a chemical initiator.

19. The process of claim 9, wherein polymerization step (b) is effected for about 6-24 hours.

20. The process of claim 9, wherein polymerizing step (b) employs a free radical initiator selected from the group consisting of azobisisobutyronitrile and t-butyl hydroperoxide.

21. The process of claim 9, wherein the inert atmosphere is maintained by an inert gas selected from the group consisting of nitrogen, argon, helium, neon, and carbon dioxide.

22. The process of claim 9, further comprising removing unreacted monomers by combining the mixture with a solvent selected from the group consisting of methanol, acetone, ethanol, propanol, butanol, dichloromethane, ethyl acetate, methyl acetate, carbon tetrachloride, methyl ethyl ketone, and methyl isobutyl ketone.

23. The process of claim 9, wherein the active ingredient is a drug selected from the group consisting of p-nitrophenol p-nitroaniline, p-nitro benzoic acid, p-amino benzoic acid, paracetamol, chloroamphenicol, ibuprofen, salicylic acid, p-methoxy phenol, metronidazole, daunomycin, pholcodine, theophylline, 5-fluorouracil, naproxen, ketoprogen, salicylic acid, sulfanilamide, 8-hydroxy quinoline, naphthyl acetic acid, niclosamide, metribuzin, nicotinic acid, 2,4-dichloro phenoxy acetic acid, and 2,4,5-trichloro phenoxy propionic acid.