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BR-112020001262-B1 - PROCESS FOR PREPARING A DRUG DELIVERY COMPOSITION

BR112020001262B1BR 112020001262 B1BR112020001262 B1BR 112020001262B1BR-112020001262-B1

Abstract

The present invention relates to a process for preparing a drug delivery composition comprising the steps of a) preparing a master batch comprising a drug and a first polymer by (i) extruding the first polymer, wherein said first polymer has a melting temperature below 140 °C; and (ii) introducing the drug during the extrusion of the first polymer, with a drug content between 0.1% and 90%, based on the total weight of the master batch; and b) introducing the master batch into a polymer-based die during the production of the drug delivery composition, wherein step a) is carried out at a temperature at which the first polymer is in a partially or fully molten state, and step b) is carried out at a temperature at which both the first polymer and at least one polymer of the polymer-based die are in a partially or fully molten state.

Inventors

  • Philippe Pouletty
  • FRÉDÉRIQUE GUILLAMOT

Assignees

  • PK Med SAS

Dates

Publication Date
20260317
Application Date
20180725
Priority Date
20170725

Claims (20)

  1. 1. Process for preparing a drug delivery composition comprising at least one drug characterized by comprising the steps of (a) preparing a master batch comprising a drug and a first polymer by (i) heating the first polymer, wherein said first polymer has a melting temperature below 140 °C; and (ii) introducing the drug during the heating of the first polymer, with a drug content between 0.1% and 90%, based on the total weight of the master batch; (b) introducing the main batch into a polymer-based die during the production of the drug delivery composition, wherein step (a) is carried out at a temperature at which the first polymer is in a partially or fully molten state, preferably below 140 °C, preferably by extrusion, and step (b) is carried out at a temperature at which both the first polymer and the polymer of the polymer-based die are in a partially or fully molten state, and wherein the drug has a molecular mass above 10 kDa, preferably above 14 kDa, more preferably above 15 kDa.
  2. 2. Process according to claim 1, characterized in that the drug is devoid of any polymer degradation activity.
  3. 3. A process, according to any of the preceding claims, characterized in that the drug is selected from proteins, particularly enzymes, antibodies, and hormones.
  4. 4. A process, according to any of the preceding claims, characterized in that the drug represents between 0.1% and 80%, based on the total weight of the main batch, preferably between 0.1% and 70%, more preferably between 0.1% and 60%.
  5. 5. Process, according to any of the preceding claims, characterized in that the main batch comprises, based on the total weight of the main batch, 50% +/- 10% by weight of a first polymer and 50% +/- 10% by weight of drug.
  6. 6. A process, according to any of the preceding claims, characterized in that the drug represents between 0.01 and 49% by weight of the drug delivery composition, based on the total weight of the drug delivery composition.
  7. 7. A process, according to any of the preceding claims, characterized in that the first polymer is a polyester and/or polyether, preferably a polyester, preferably selected from polycaprolactone (PCL), polybutylene succinate adipate (PBSA), polybutylene adipate terephthalate (PBAT), polyhydroxyalkanoate (PHA), polylactic acid (PLA), polyglycolic acid (PGA) or copolymers.
  8. 8. Process, according to any of the preceding claims, characterized in that step b) is carried out at a temperature T between 50 °C and 200 °C.
  9. 9. Process, according to any of the preceding claims, characterized in that step b) is carried out by extrusion, internal mixing, co-kneading, compound-forming extrusion, extrusion blow molding, fused film extrusion, calendering, thermoforming, injection molding, compression molding, extrusion swelling, spin molding, lamination, coating, layering, expansion, pultrusion, compression-granulation and 3D printing.
  10. 10. Process, according to any one of claims 1 to 9, characterized in that the main batch is introduced into the polymer-based matrix at a temperature T between the glass transition temperature (Tg) and the melting temperature of at least one polymer in the polymer-based matrix.
  11. 11. A process according to any one of claims 1 to 9, characterized in that the main batch is introduced into the polymer-based matrix at a temperature T that is above the glass transition temperature (Tg) of at least one polymer in the polymer-based matrix, preferably at or above the melting temperature of said polymer.
  12. 12. A process, according to any of the preceding claims, characterized in that the polymer-based matrix comprises a polyester, preferably selected from PLA, PCL, polybutylene adipate terephthalate (PBAT), polyhydroxyalkanoate (PHA), polyglycolic acid (PGA), polybutylene succinate (PBS), poly(ethylene adipate) (PEA), and copolymers or blends thereof.
  13. 13. A process, according to any of the preceding claims, characterized in that the polymer-based matrix contains PLA, preferably PLLA and/or PDLA, preferably as the only polymer.
  14. 14. Process, according to any of the preceding claims, characterized in that the polymer-based matrix contains PLGA copolymer, preferably as the only polymer.
  15. 15. Process, according to any of the preceding claims, characterized in that the main batch comprises PCL and the polymer-based matrix comprises at least one polymer selected from PLA, PLGA and PGA.
  16. 16. Process, according to any of the preceding claims, characterized in that the main batch comprises PLGA and the polymer-based matrix comprises at least one polymer selected from PLA, PLGA and PGA.
  17. 17. A process, according to any of the preceding claims, characterized in that the drug delivery composition additionally contains a polymer-degrading enzyme suitable for degrading at least one polymer from the polymer-based matrix, preferably selected from proteases, esterases, cutinases, or lipases.
  18. 18. Process according to claim 17, characterized in that the polymer degradation enzyme is introduced into the main batch during step a) and/or in that the polymer degradation enzyme is introduced into the polymer-based matrix during step b), simultaneously or sequentially with the main batch.
  19. 19. A process, according to any of the preceding claims, characterized in that the drug delivery composition is a pharmaceutical composition, preferably selected from tablets, gels, coatings, particles, and microspheres.
  20. 20. A process according to any one of claims 1 to 18, characterized in that the drug delivery composition is shaped to form a drug delivery device, preferably a medical device, more preferably selected from an implant, film, stent, leaflet, valve, roll, frame, dressing, rod, adhesive, fibers, suture fibers, thread, bone plate or implant, bone cement and prostheses.

Description

FIELD OF THE INVENTION [0001] The present invention relates to a process for preparing a drug delivery composition comprising at least one drug included, and preferably integrated, in a polymer-based matrix. More particularly, the present invention relates to the use of a master batch containing a high amount of drug to prepare a drug delivery composition comprising a control amount of drug. The present invention also relates to a drug delivery device, preferably a medical device made with, or formed from, said drug delivery composition. BACKGROUND OF THE INVENTION [0002] Drug delivery devices are well known in the medical field. Among these, drug delivery devices have been developed to allow the release of a drug in vivo at a more or less controlled rate. Most often, the drug is associated with a polymer, used as a vehicle for the drug. For example, there are delivery devices composed of biodegradable polymers, in which the drug is coated on the outer surface of the polymeric structure. Alternatively, some delivery devices consist of a polymeric structure in which a drug is incorporated using a solvent. The use of a solvent is limited to incorporating a soluble drug into a solvent with the capacity to solubilize the polymer. For example, drugs that are only water-soluble cannot be incorporated into non-water-soluble polymers, such as those used for applications where specific mechanical properties are required, such as for suturing, tissue modification, structuring, etc. The amount of drug incorporated is also limited by the solubility threshold. Furthermore, only a small number of solvents are usable in the medical field. Additionally, the production process using solvents is of low and critical quality. In fact, such a production process includes solvent drying steps and cleaning of the composition to ensure the total absence of any solvent trace in the final device. Production is also generally carried out in batches, each requiring stringent quality control. Some other drug delivery devices consist of a polymeric structure comprising pores filled with a permeable liquid for drug passage. However, the use of a porous polymer does not result in a homogeneous distribution or uniformity of drug content within the polymeric structure. The use of solid drugs is excluded with these devices, which additionally require a liquid medium or carrier for drug diffusion. [0003] It is also known as dispersing a drug in a polymeric structure by means of hot melt extrusion. Hot melt extrusion allows the preparation of a wide variety of dosage forms and formulations, such as granules, pellets, tablets, ophthalmic inserts, implants, stents, or transdermal systems. This shows several advantages compared to solvent-based production processes, including continuous process and the absence of solvent use that would be removed with the use of expensive and time-consuming steps. However, hot melt extrusion involves heat treatment that can impact the drug's activity. And, the temperature at which a drug is at least partially inactivated can vary depending on the nature of the drug and/or the extrusion conditions. Additionally, to date, only small drugs can be dispersed by hot-melt extrusion, such as oligopeptides (e.g., goserelin acetate 1269 g/mol, melanotan 1024 g/mol). In fact, thermal processes are not suitable for heat-sensitive drugs, such as proteins (Maniruzzaman et al., 2012 “A review of hot-melt extrusion: process technology to pharmaceutical products”; Stankovic et al., 2014 “Innovative platform technologies for stabilization and controlled release of proteins from polymer depots”). Furthermore, precise drug dosage can be difficult to achieve by hot-melt extrusion when a small amount of drug needs to be introduced. [0004] Consequently, there is a need for a process to prepare a drug delivery composition that results in both controlled drug dosage and homogeneous drug distribution throughout the entire polymeric structure, without impairing the drug activity in the composition and applicable to all drugs regardless of their solubilities, sizes and thermosensitivities. CAPTION FOR THE FIGURES [0005] Figure 1: Degradation of PLGA and release of naltrexone from a drug delivery composition produced by the process of the invention comprising PLGA and 5% or 10% naltrexone. [0006] Figure 2: Degradation of PLGA and release of lysozyme activity from a drug delivery composition produced by the process of the invention comprising PLGA and 10% lysozyme. SUMMARY OF THE INVENTION [0007] The present invention now proposes a process for preparing a drug delivery composition comprising a drug homogeneously integrated into a polymer-based matrix. The process of the invention further allows for the preservation of drug activity in the polymer-based matrix of the drug delivery composition. More particularly, the inventors have shown that high quantities of drugs (i.e., quantities greater than the final dose required in the drug delivery co