MEDICAL PREPARATION WITH A CARRIER BASED ON HYALURONAN AND/OR DERIVATIVES THEREOF, METHOD OF PREPARATION AND USE THEREOF

• US 20190328891A1
• Filed: 12/19/2017
• Published: 10/31/2019
• Est. Priority Date: 12/22/2016
• Status: Abandoned Application

• Current Assignee: Contipro A.S. (Contipro Group sro)
• Original Assignee: Contipro A.S. (Contipro Group sro)
• Inventors: KAREL, Sergej, FLEGEL, Martin, SULAKOVA, Romana, FRYCAK, Roman, SOGORKOVA, Jana, BETAK, Jiri, CHMELAR, Josef, ZAPOTOCKY, Vojtech, VELEBNY, Vladimir
• Application Number:
  US16/472,635
• Publication Number:
  US 20190328891A1
• Time in Patent Office: Days
• CPC Class Codes: A61K 38/08 Peptides having 5 to 11 amino acids A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 47/61 the organic macromolecular compound being a polysaccharide or a derivative thereof
• CPC Class Codes: A61K 47/62 the modifying agent being a protein, peptide or polyamino acid
• CPC Class Codes: A61K 47/6953 the form being a fibre, a textile, a slab or a sheet
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/006 Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like

Abstract

Disclosed is a method of preparing a medical preparation with a carrier based on hyaluronan and/or its derivatives, which can be used in the field of medicine and cosmetics. The medical preparation comprises a conjugate of hyaluronic acid and/or its derivative with a medical substance, according to the general formula A-S—N, where: A is the medical substance; S is the way of linking the medical substance with the carrier; and N is the carrier based on hyaluronic acid and/or its derivatives.

Claims

1-26. -26. (canceled)

27. A method of preparing a medical preparation based on hyaluronic acid and/or palmitoyl hyaluronan or formyl hyaluronan, said method comprising binding a medical substance A comprising a terminal N-protecting group and comprising amino acids and/or peptides to a carrier N in an aprotic polar solvent, the carrier N comprising hyaluronic acid, palmitoyl hyaluronan, and/or formyl hyaluronan and having a molecular weight of from 1.5×

10⁴ to 2.5×

10⁶ g·

mol¹, and then cleaving off the terminal N-protecting group of the medical substance Abound on the carrier in a basic environment to form a conjugate;

wherein the carrier N is in solid phase during the whole preparation, is insoluble in the reaction environment, and is biodegradable; and

wherein the conjugate has the general formula X;

A-S—

N 

 

(X),

which is also represented by the formula;

28. The method according to claim 27, wherein the carrier N is in the form of an endless fibre, thread, textile, thin film, staple fibre, and/or nonwoven fabric.

29. The method according to claim 27, wherein the formation of the conjugate is performed at the temperature of from 20°

C. to 40°

C. for a time of from 2 to 48 hours.

30. The method according to claim 27, wherein the aprotic polar solvent is selected from the group consisting of N,N-dimethyl formamide, dimethyl sulphoxide, N-methyl-2-pyrrolidone, acetonitrile, dichloro methane, tetrahydrofuran, 1,4-dioxane, and combinations thereof and/or the basic environment in which the N-terminal protecting group is cleaved off is selected from the group consisting of 20% piperidine in DMF, 2% DBU in DMF, and 30% tert-butylamine in DMF.

31. The method of preparation according to claim 27, wherein binding the medical substance A to the carrier N comprises esterification;

wherein the medical substance A is an amino acid or peptide comprising the terminal N-protecting group and a carboxyl group;

wherein the medical substance A is first subjected to activation of the carboxyl group via a condensation agent in an aprotic polar solvent to form a reactive intermediate that is subsequently reacted with the carrier N in the presence of an organic base and a catalyst; and

wherein the terminal N-protecting group of the medical substance A bound on the carrier is then cleaved off in a basic environment to form the conjugate according to the general formula X, where S is —

O—

C(═

O)—

or a linear linker based on a peptide comprising hydrophobic amino acids Xaa.

32. The method according to claim 31, wherein the condensation agent comprises N,N′

-diisopropyl carbodiimide, N,N′

-dicyclohexyl carbodiimide, 1-[bis(dimethylamino) methylen]-1H-1,2,3-triazolo[4,5-b] pyridinium 3-oxide hexafluoro phosphate, 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide, propylphosphonic acid anhydride, 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl uronium hexafluoro phosphate, ethyl chloroformiate, benzotriazole-1-yl-oxy-tris(dimethylamino) phosphonium hexafluoro phosphate, O-(benzotriazole-1-yl)-N,N,N,N′

-tetramethyl uronium tetrafluoroborate, 4-triethylamino-dicyclohexyl carbodiimide p-toluen sulfonate, 4-nitrophenol, N-hydroxy succinimide, 2,4,5-trichloro phenol, 2,3,4,5,6-pentafluoro phenol, and/or 2,3,4,5,6-pentachloro phenol.

33. The method according to claim 31, wherein the organic base is selected from the group consisting of triethylamine, pyridine, morpholine, N-methyl morpholine, N,N′

-diisopropyl ethylamine, imidazole, and/or the catalyst is selected from the group consisting of ethyl(hydroxyimino) cyanoacetate, hydroxybenzo triazole, 1-hydroxy-7-azabenzotriazole, or N,N-dimethylamino pyridine.

34. The method according to claim 31, wherein the conjugate is further repeatedly reacted with the reactive intermediate which can be the same or different from the reactive intermediate of the previous step.

35. The method according to claim 31, wherein the condensation agent is N,N′

-diisopropyl carbodiimide, the aprotic polar solvent is N,N-dimethyl formamide, the catalyst is a combination of ethyl (hydroxyimino) cyanoacetate and N,N-dimethylamino pyridine, and the basic environment is 20% piperidine in N,N-dimethyl formamide.

36. The method according to claim 27, wherein the amount of the medical substance A corresponds to 1 to 5 equivalents, with respect to a dimer of hyaluronic acid or a derivative thereof.

37. The method according to claim 31, wherein the amount of the condensation agent corresponds to 0.1 to 5 equivalents, with respect to a dimer of hyaluronic acid or a derivative thereof, and/or the amount of the organic base corresponds up to 10 equivalents, with respect to a dimer of hyaluronic acid or a derivative thereof, and/or the amount of the catalyst corresponds 0.1 to 5 equivalents, with respect to a dimer of hyaluronic acid or a derivative thereof.

38. The method according to claim 31, wherein 3 equivalents of ethyl(hydroxyimino) cyanoacetate as the catalyst and 0.3 equivalents of N,N-dimethylamino pyridine as the organic base are used, each with respect to a dimer of hyaluronic acid or a derivative thereof.

39. The method according to claim 31, wherein the amount of the medical substance A corresponds to 3 equivalents, the amount of the condensation agent corresponds to 3 equivalents, and the amount of the catalyst corresponds to 3 equivalents, each with respect to a dimer hyaluronic acid or a derivative thereof.

40. The method according to claim 31, wherein the amount of the medical substance A corresponds to 1 equivalent, the amount of the condensation agent corresponds to 1 equivalent, and the amount of the catalyst corresponds to 1 equivalent, with respect to a dimer of hyaluronic acid or a derivative thereof.

41. The method of preparation according to claim 27, wherein binding the medical substance A to the carrier N comprises reductive amination in the presence of a polar aprotic solvent and a reduction agent;

and wherein the terminal N-protecting group of the medical substance A bound on the carrier is then cleaved off in a basic environment to form the conjugate according to the general formula X, where S is —

NH—

, or a linear linker based on a peptide comprising hydrophobic amino acids Xaa.

42. The method according to claim 31, wherein the conjugate is further repeatedly reacted with the medical substance A that can be the same or different from the medical substance A of the previous step.

43. The method of preparation according to claim 31, wherein the polar aprotic solvent is DMF, the reduction agent is picBH₃, and the basic environment is 20% solution of piperidine in DMF.

44. The method according to claim 27, wherein the medical substance A is bound to the carrier via a linear linker having the general formula Xaa-Ahx-Ahx-Xaa.

45. A medical preparation with a carrier based on hyaluronic acid and/or palmitoyl hyaluronan or formyl hyaluronan, the medical preparation comprising a conjugate according to the general formula:

A-S—

N 

 

(X),

which is also represented by the formula;

46. The medical preparation according to claim 45 for use in medical applications as a dosage form of an active peptide or amino acid, wherein the medical preparation is formulated for administration dermally, sublingually, buccallly, or locally into an open wound.

47. The medical preparation according to claim 45, wherein the medical preparation is formulated for dermal application and comprises the peptide Dalargin as the medical substance A.

48. The medical preparation according to the claim 45, wherein the medical preparation is formulated for oral or sublingual application and comprises, as the medical substance A, a peptide selected from the group consisting of Desmopressin, Lysipressin, and Glypressin.

49. The medical preparation according to claim 45, wherein the medical preparation is formulated for buccal application and comprises, as the medical substance, a peptide selected from the group consisting of antivirotics and adjuvants, releasing factor for luteinizing and follicle-stimulating hormones, and combinations thereof.

50. The medical preparation according to claim 45, wherein the medical preparation is formulated for direct application into an open wound and comprises, as the medical substance, a peptide selected from the group consisting of Glypressin, Dalargin, and AdDP.