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BR-112022015142-B1 - PROCESS FOR PREPARING A BIOLOGICALLY ACTIVE COPOLYMER AND USING ACROLEIN AND POLYALKYLENE GLYCOL

BR112022015142B1BR 112022015142 B1BR112022015142 B1BR 112022015142B1BR-112022015142-B1

Abstract

PROCESS FOR PREPARING A BIOLOGICALLY ACTIVE COPOLYMER. This is a process for preparing a biologically active polymer comprising an acrolein-derived segment and a polyalkylene glycol oligomer, wherein the process comprises reacting polyalkylene glycol with acrolein in aqueous solution to form a copolymer with a molecular weight not exceeding 1000 Daltons at a temperature not exceeding 15 degrees Celsius.

Inventors

  • GRAHAM JOHN HAMILTON MELROSE
  • MICHELE KERYN DILIZIA
  • THOMAS GABRIEL WELLS JARRETT
  • Arthur Kollaras
  • JUSTIN MARK WARD

Assignees

  • Recce Pharmaceuticals Ltd

Dates

Publication Date
20260317
Application Date
20210129
Priority Date
20200131

Claims (15)

  1. 1. A process for preparing a biologically active polymer comprising an acrolein-derived segment and a polyalkylene glycol oligomer, wherein the process is characterized in that it comprises reacting polyalkylene glycol with acrolein in aqueous solution to form a copolymer of molecular weight not exceeding 1000 Daltons at a temperature of -5°C to 10°C and at an alkaline pH not exceeding 12.5, wherein the reaction of polyalkylene glycol with acrolein in aqueous solution is carried out in a reaction vessel comprising a heat exchanger to control the temperature, and wherein the solution is maintained at a temperature of -5°C to 10°C during the reaction to form the copolymer, and wherein the biologically active polymer is for use in a method of treating an individual suffering from a disease.
  2. 2. Process according to claim 1, characterized in that the aqueous solution of polyalkylene glycol and acrolein comprises water in an amount of at least 20% w/w.
  3. 3. Process according to claim 1 or 2, characterized in that the weight ratio of polyalkylene glycol:acrolein is at least 4:1.
  4. 4. Process, according to any one of claims 1 to 3, characterized in that the molecular weight of the polyalkylene glycol does not exceed 800 Daltons.
  5. 5. Process according to claim 4, characterized in that the molecular weight of the polyalkylene glycol is from 200 to 600 Daltons.
  6. 6. A process according to any one of claims 1 to 5, characterized in that acrolein is added to an aqueous solution of polyalkylene glycol.
  7. 7. Process, according to any one of claims 1 to 6, characterized in that acrolein is added to an aqueous solution of polyethylene glycol comprising at least 20% w/w water, wherein the acrolein is added in the form of an aqueous acrolein solution of concentration not exceeding 50% w/w.
  8. 8. Process according to claim 7, characterized in that acrolein is added to an aqueous solution of polyethylene glycol comprising at least 20% w/w water, wherein the acrolein is added in the form of an aqueous acrolein solution of concentration not exceeding 30% w/w.
  9. 9. A process according to any one of claims 1 to 8, characterized in that it comprises the following steps: providing a basic aqueous solution of a polyalkylene glycol; adding acrolein as an aqueous solution of a concentration not exceeding 50% w/w of the aqueous acrolein solution (generally containing a preservative); and once the acrolein monomer has been consumed, adding acid to provide a pH less than 9.
  10. 10. Process according to claim 9, characterized in that the addition of acrolein as an aqueous solution of concentration not exceeding 50% w/w of the aqueous acrolein solution is carried out slowly over a period of at least 2 minutes or at least 5 minutes.
  11. 11. Process according to claim 9 or 10, characterized in that once the acrolein monomer has been consumed, acid is added to provide a pH not exceeding 8.
  12. 12. Process, according to any one of claims 1 to 11, characterized in that the reaction of polyalkylene glycol with acrolein in aqueous solution is carried out in a stirred reaction vessel fitted with a flowing coolant jacket to control the temperature inside the reaction vessel.
  13. 13. Process according to claim 12, characterized in that the reaction conditions are regulated by computerized control of one or more reaction parameters selected from acrolein addition rate, water flow rate, water temperature inside the jacket, and speed at which the aqueous solution is stirred.
  14. 14. Use of acrolein and polyalkylene glycol characterized by being in the manufacture of a medicament and/or biologically active polymer prepared by the process defined in any one of claims 1 to 13, for the treatment of a disease selected from among bacterial infection, viral infection and cancer.
  15. 15. Use according to claim 13, characterized in that the disease is a parenteral disease.

Description

FIELD OF TECHNIQUE [0001] The invention relates to a process for preparing a biologically active copolymer comprising a segment derived from acrolein monomer and a polyalkylene glycol segment. The invention further relates to the use of the biologically active agent in the treatment of diseases, particularly in the treatment of bacterial infection, viral infection or cancer. BACKGROUND OF THE INVENTION [0002] There is a growing need for effective antimicrobial, antiviral, and anticancer agents. The evolution of antimicrobial resistance in pathogens has given rise to serious health risks due to the inability to control infection with many conventional antimicrobials. The emergence of new viral strains leads to a demand for broad-spectrum treatments, especially for severe viral infections. The emergence of the global pandemic in 2020 caused by SARS-CoV-2 led to millions of infections worldwide, a high number of fatalities, mainly among the elderly and people with comorbidities. This led to an urgent need for effective treatments for SARS-CoV-2 infection. [0003] There is also an urgent need for effective treatments for bacterial infections, particularly severe and potentially fatal bacterial infections such as sepsis. The global incidence and mortality of sepsis in 2017 is estimated at 48.9 million, with 11 million sepsis-related deaths (The Lancet Vol 395, Issue 10219 pages 200-211 (January 18, 2020)). Interventions targeting antimicrobial resistance are imperative to improve sepsis outcomes. [0004] Copending patent applications WO2016/077879 and WO2017/139849 disclose an antimicrobial copolymer comprising an acrolein monomer-derived segment and a polyalkylene glycol segment. The copolymers are formed by reacting polyacrolein with polyalkylene glycol at a temperature of 25 °C to 35 °C to provide an antimicrobial with good activity against a wide range of bacteria and viruses. Polymeric antibiotics represent a significant advance in the treatment of infections such as sepsis due to their activity and the reduced propensity of bacterial and viral strains to develop resistance due to the mode of action of the copolymers. [0005] There is a continuing need to provide biologically active compounds with enhanced activity, particularly antimicrobial activity. SUMMARY OF THE INVENTION [0006] It has now been found that the biological activity of the polymer comprising an acrolein-derived segment and a polyalkylene glycol oligomer is significantly increased if the copolymer is formed at a low temperature. Consequently, a process is provided for the preparation of a biologically active polymer comprising an acrolein-derived segment and a polyalkylene glycol oligomer segment, the process comprising reacting polyalkylene glycol with acrolein in aqueous solution to form a copolymer of molecular weight not exceeding 1000 Daltons at a temperature not exceeding 15 °C, preferably not exceeding 12 °C, such as not exceeding 10 °C or not exceeding 8 °C. [0007] In a further embodiment, a method is provided for treating an individual suffering from a disease selected from microbial infection, viral infection and cancer which comprises administering to the individual an effective amount of the biologically active agent prepared in accordance with the process. [0008] Also provided is a use of acrolein and polyalkylene glycol in the manufacture of a medicament for the treatment of a selected disease from among bacterial infection, viral infection and cancer wherein the use comprises the process. [0009] The process is particularly suitable for the treatment of cancer, bacterial infection or viral infection. [0010] It has been found that the activity of the copolymer formed at low temperature increases very significantly. In fact, the minimum inhibitory concentration (MIC), the lowest concentration that prevents the visible growth of a bacterium or bacteria, is significantly lower at lower temperatures. For example, the MIC is generally at least three times higher at 40 °C than at 10 °C. In fact, for many bacteria, the MIC is four times higher and even at least six times higher at 40 °C than at 10 °C. BRIEF DESCRIPTION OF THE DRAWINGS [0011] Examples of the invention are described with reference to the accompanying drawings. In the drawings: [0012] Figure 1 is a graph with four arguments referenced in Example 2 comparing the colony forming unit count (Log10CFU/swab) of a burn wound infection model treated with (i) a process copolymer composition of the invention (E1), (ii) a comparative process copolymer composition not of the invention (CE3), (iii) a positive control using a known antimicrobial (Safromycin), and (iv) an untreated control. [0013] Figure 2 is a graph with four arguments referenced in Example 2 comparing wound contraction four days after infection following treatment with the compositions referenced in Figure 1. [0014] Figure 3 is a graph with five arguments referenced in Example 3 comparing the colony-forming unit count (