Terpolymers and their use in pharmaceutical dosage forms

Patent metadata

Field	Value
Publication number	US-12016926-B2
Application number	US-201816772273-A
Country	US
Kind code	B2
Filing date	Dec 7, 2018
Priority date	Dec 20, 2017
Publication date	Jun 25, 2024
Grant date	Jun 25, 2024

Abstract

Terpolymer, wherein 20 to 35% by weight of the structural units are derived from acrylic acid, 45 to 60% by weight of the structural units from a hydrophobic methacrylate selected from a group consisting of isopropyl methacrylate, tert-butyl methacrylate and cyclohexyl methacrylate and 15 to 40% by weight of the structural units from a third olefinic monomer selected from the group consisting of N-vinyl lactam, hydroxy ethyl methacrylate and phenoxyethyl acrylate with the proviso that the total amount of structural units derived from the three monomer groups adds up to 100% by weight, and the use of the terpolymers as crystallization inhibitors in pharmaceutical dosage forms for inhibiting the recrystallization in an aqueous environment of a human or animal body of an active ingredient.

First claim

The invention claimed is:

1. A pharmaceutical dosage form, comprising (a) a terpolymer, wherein 20 to 35% by weight of the structural units are derived from acrylic acid, 45 to 60% by weight of the structural units from a hydrophobic methacrylate selected from a group consisting of isopropyl methacrylate, tert-butyl methacrylate and cyclohexyl methacrylate and 15 to 40% by weight of the structural units from a third olefinic monomer selected from the group consisting of N-vinyl lactam, hydroxy ethyl methacrylate and phenoxyethyl acrylate with the proviso that a total amount of structural units derived from the three monomer groups adds up to 100% by weight and (b) an active pharmaceutical ingredient with a solubility in water at standard conditions of less than 0.1% by weight, wherein the active ingredient is present in an amorphous form, and
wherein the pharmaceutical dosage form is an oral pharmaceutical dosage form.

2. The pharmaceutical dosage form according to claim 1 , wherein a solubility for the terpolymer in phosphate buffer of a pH of 6.8 under standard conditions is such that a content of insoluble substances remaining on a membrane filter having an average pore size of 8 μm when a 0.3% by weight aqueous preparation of the terpolymer is filtered with the filter, is not higher than 25% by weight of the amount of terpolymer in the aqueous preparation.

3. The pharmaceutical dosage form according to claim 1 , wherein the hydrophobic methacrylate is tert-butyl methacrylate.

4. The pharmaceutical dosage form according to claim 1 , wherein the N-vinyl lactam is N-vinyl pyrrolidone.

5. The pharmaceutical dosage form according to claim 1 , wherein the N-vinyl lactam is N-vinyl caprolactam.

6. The pharmaceutical dosage form according to claim 1 , wherein the terpolymer has a calculated glass transition temperature in a range of 80 to 150° C.

7. The pharmaceutical dosage form according to claim 1 , wherein the terpolymer has a calculated glass transition temperature in the range of 100 to 150° C.

8. The pharmaceutical dosage form according to claim 1 , wherein an amount of tert-butyl methacrylate derived structural units lies in a range of 45 to 55% by weight.

9. The pharmaceutical dosage form according to claim 1 , wherein the amount of acrylic acid derived structural units lies in the range of 20 to 30% by weight.

10. The pharmaceutical dosage form according to claim 1 , wherein the amount of structural units derived from the third olefinic monomer lies in the range of 20 to 35% by weight.

11. The pharmaceutical dosage form according to claim 1 , wherein the terpolymer has a weight average molecular weight in the range of 7,000 to 100,000 g/mol.

12. The pharmaceutical dosage form according to claim 1 , wherein the terpolymer is partly neutralized to provide a pH in the range of 5 to 9 upon dissolution in water.

13. The pharmaceutical dosage form of claim 1 in a form of a solid dispersion.

14. The pharmaceutical dosage of claim 13 wherein the active pharmaceutical ingredient is present in the solid dispersion at a loading of 9.4% to 27.5%, by weight, based on the weight of terpolymer (a) and active pharmaceutical ingredient (b).

15. A method of inhibiting recrystallization of an active ingredient in an aqueous environment of a human or animal comprising administering an oral dosage form comprising the active ingredient and a terpolymer of claim 1 , wherein the active ingredient has a solubility in water at standard conditions of less than 0.1% by weight and is present in the pharmaceutical dosage form in an amorphous form.

Assignees

• Basf Se

Inventors

• Brandl Ferdinand Paul
• Smit Theo
• Guth Felicitas
• Kolter Karl
• Angel Maximilian
• Schmidt Frank

Classifications

• C08F226/10

  N-Vinyl-pyrrolidone · CPC title

• C08F220/1806

  C6-(meth)acrylate, e.g. (cyclo)hexyl (meth)acrylate or phenyl (meth)acrylate · CPC title

• C08F220/1803

  C3-(meth)acrylate, e.g. (iso)propyl (meth)acrylate · CPC title

• C08F220/06

  Acrylic acid; Methacrylic acid; Metal salts or ammonium salts thereof · CPC title

• A61K31/635

  having a heterocyclic ring, e.g. sulfadiazine · CPC title