Process for producing polymeric microspheres

{
  "publication_number": "US10471013B2",
  "country": "US",
  "kind": "B2",
  "title": "Process for producing polymeric microspheres",
  "abstract": "The present disclosure disclosed a microsphere-producing process involving three integrated unit operations, 1) microspheres formation; 2) microsphere quality control; 3) post formation microsphere treatment. The first unit operation, i.e. unit operation 1) is integrated with four essential functions: forcing the particle forming materials to pass through a porous membrane to form embryonic micropsheres; enforcing the embryonic microspheres to detach the porous membrane; solidifying the embryonic microspheres; collecting and outputting the solidified microspheres. The quality control unit operation consists discrimination and ejection of oversized microspheres. The post treatment unit operation is integrated with two essential functions, smoothing the microsphere surfaces and reducing organic solvents trapped inside of microsphere matrix.",
  "claims": [
    "1. A method to prepare polymeric microspheres of designed sizes and 90%+ encapsulation efficiency, comprising a) Pressing a solution of microsphere-forming materials to pass through a membrane possessing designed pore size into a receiving medium that is immiscible with the solution but dissolves the solvent of microsphere-forming materials in some extent; b) Applying a shear stress or a vibration to detach the embryonic microspheres formed by passing through the porous membrane in step a) from the membrane surface; c) Making the embryonic microspheres detached in step b) to move along a path filled with receiving medium parallelly without breaking by stirring and fusing by collision during sedimentation or flowing for extracting the solvent of the microsphere-forming materials into the receiving phase; d) Collecting the microspheres hardened by solvent extraction in step c).",
    "2. The method of claim 1, wherein the porous membrane possesses defined pore size and is cylindrical, round, or planer in shape.",
    "3. The method of claim 1, wherein the shear stress is generated by flowing or stirring the receiving medium which the porous membrane is placed in.",
    "4. The method of claim 3, wherein the shear stress is generated by a nozzle which generates a straight flow through cylindrical porous membrane or a rounded flow around the porous membrane.",
    "5. The method of claim 1, wherein the vibration is generated by shaking or beating the porous membrane or its holder outside or inside.",
    "6. The method of claim 5, of which the frequency of generated vibration is adjusted between 100/min to 600/min.",
    "7. The method of claim 6, of which the frequency of generated vibration is adjusted between 200/min to 400/min.",
    "8. The method of claim 1, wherein the path of microsphere receiving medium is water-based, immiscible with the microsphere-forming solution, and able to extract the solvent of the microsphere-forming materials.",
    "9. The method of claim 1, wherein the solution of the microsphere-forming materials is a polymer solution immiscible with water.",
    "10. The method of claim 1, wherein the hardened microspheres are collected at the end of the path of microsphere-receiving medium.",
    "11. The method of claim 1, wherein the path of microsphere-receiving medium is set as vertical, horizontal or in between.",
    "12. The method of claim 1, wherein polymer solution is loaded with a bioactive agent.",
    "13. The method of claim 12, wherein the bioactive agent is in particulate form suspending in the polymer solution by stirring or shaking.",
    "14. The method of claim 1, wherein the collected hardened microspheres are transferred to a container for post microsphere-formation treatment and rinsing.",
    "15. The method of claim 14, wherein a quality control unit is mounted within the path for transferring the microspheres to discriminate and eject oversized microspheres.",
    "16. The method of claim 15, wherein the quality control unit consists a screen mesh to block the oversized microspheres and a three-way valve to eject the blocked microspheres out of the production line.",
    "17. The method of claim 14, wherein post treatment comprises annealing the hardened microspheres for surface smoothing or for reducing solvent residues.",
    "18. The method of 14, wherein the post-treatment container is equipped with floating socket to drain the liquids for post treatment or for rinsing from the top so as not to interrupt the sedimentation of the microspheres during the treatment.",
    "19. The method of claim 1, wherein the bottom of the microsphere collector may shape as round, cylindrical, cone-shaped or in between of them.",
    "20. The method of claim 1, wherein solvent to dissolve microsphere-forming polymers is methylene dichloride and the receiving phase is aqueous solution of polyvinyl alcohol and NaCl.",
    "21. The method of claim 1, wherein a final formulation container is included to receive the post-treated microspheres, and to blend additives in."
  ],
  "description_excerpt": "This disclosure demonstrates a novel process (method) to prepare polymeric microspheres of designed uniform sizes, improved encapsulation efficiency for soluble ingredients, and reduced number of unit operations. These microspheres may be used to encapsulate bioactive agents (including therapeutic agents) with high loading efficiency and/or preserved native conformation for controlled or sustained release delivery to human and other animals.\n\nPolymeric microspheres are successfully used for controlled- or sustained-release delivery of some active agents comprising therapeutics such as chemical drugs or therapeutic peptides. This type of dosage forms has also been used in the attempts to achieve controlled- or sustained-release delivery of proteins. The ability of polymeric microspheres to control or retard release rate of the active or therapeutic ingredients loaded wherein offers a great compliance improvement to patients who have to receive frequent injections of medicine for prolonged period or even life time. With controlled- or sustained-release functions, the in vivo concentration of the medicines (drugs or vaccines) may well be maintained within the therapeutic window (a situation of which in vivo level of a drug/medicine is above the minimum effective concentration but below the minimum toxic concentration). The frequency of the hateful injections may therefore be greatly reduced.\n\nAccompany with the benefits above are some drawbacks. A major challenge for preparing protein-loaded microsphere dosage forms is their sterilization process.",
  "cpc": [
    "A61K 9/1694",
    "A61K 38/1816",
    "A61K 38/26",
    "A61K 9/0019",
    "A61K 9/1647"
  ],
  "ipc": [
    "A61K 38/18",
    "A61K 38/26",
    "A61K 9/16",
    "A61K 9/00"
  ],
  "assignees": [
    "Blodvery Pharmatech Ltd"
  ],
  "inventors": [
    "Tuo Jin"
  ],
  "filing_date": "2016-01-21",
  "publication_date": "2019-11-12",
  "grant_date": "2019-11-12",
  "priority_date": "2015-02-20",
  "application_number": "US-201615567840-A",
  "family_id": "56691984",
  "cited_by_count": 1,
  "citations": [
    "EP0481892B1",
    "CN1487258A",
    "US20080217222A1",
    "WO2009053885A2",
    "US20130137782A1",
    "WO2014139168A1"
  ]
}