WO2018012829A1 - Procédé de fabrication en continu de microsphères polymères, et appareil associé - Google Patents

Procédé de fabrication en continu de microsphères polymères, et appareil associé Download PDF

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Publication number
WO2018012829A1
WO2018012829A1 PCT/KR2017/007359 KR2017007359W WO2018012829A1 WO 2018012829 A1 WO2018012829 A1 WO 2018012829A1 KR 2017007359 W KR2017007359 W KR 2017007359W WO 2018012829 A1 WO2018012829 A1 WO 2018012829A1
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Prior art keywords
polymer
emulsifier
organic solvent
aqueous solution
polymer microsphere
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Ceased
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English (en)
Korean (ko)
Inventor
김봉오
장혜진
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Samyang Biopharmaceuticals Corp
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Samyang Biopharmaceuticals Corp
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Publication of WO2018012829A1 publication Critical patent/WO2018012829A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes

Definitions

  • the present invention relates to a continuous method for producing a polymer microsphere, and to a continuous device for producing a polymer microsphere for performing the method.
  • Drug delivery techniques using polymers can generally be classified into four techniques: long-term sustained-release formulations of drugs, sustained-release formulations of drugs, promotion of absorption of poorly soluble drugs, and targeted drug delivery.
  • polymeric microsphere (PMS) technology is applied to the technique of sustained-release formulation of the drug.
  • Sustained-release formulations of drugs are injected into the body of drug depots such as nano / micro particles or hydrogels in vivo, and the drug is continuously released into the body through diffusion due to the difference in concentration and release of the drug due to degradation of the biodegradable polymer.
  • Drug delivery system to be released PLGA (poly (lactide-co-glycolide)) copolymers have been used to make bioabsorbable sutures, but research has also been conducted to utilize them as drug carriers for biopharmaceuticals.
  • PLGA is not only able to control the decomposition rate by changing the molecular weight and the composition of the copolymer, but also has been widely used in sustained release drug delivery because of its excellent biocompatibility, and several products have been commercialized.
  • An object of the present invention is to provide a manufacturing process and an apparatus therefor capable of continuously producing a polymer microsphere as a poorly water-soluble drug sustained release formulation.
  • the first aspect of the present invention is to prepare a polymer microsphere by 1) injecting a polymer drug solution in which a poorly water-soluble drug and a biocompatible biodegradable polymer is dissolved in an organic solvent, into a reactor for preparing a polymer microsphere having an aqueous solution containing an emulsifier. and; 2) transferring the resultant of step 1) to a polymeric microsphere reservoir; 3) recycling the emulsifier-containing aqueous solution from the result of step 2) to the polymer microsphere preparation reactor of step 1), repeating steps 1) and 2); 4) It can provide a continuous method for producing a polymer microsphere, comprising the step of obtaining a polymer microsphere from the product of step 3).
  • the second aspect of the present invention is 1) a polymer microsphere production reactor for preparing a polymer microsphere by injecting a polymer drug solution in which a poorly water-soluble drug and a biocompatible biodegradable polymer is dissolved in an organic solvent in an aqueous solution containing an emulsifier; 2) a polymer microsphere storage tank in which the resultant product of step 1) is transferred and stored; And 3) a device for recycling the emulsifier-containing aqueous solution from the result of step 2) to the polymer microsphere production reactor, wherein the polymer microsphere continuous production apparatus for use in the method according to the second aspect of the present invention is provided. can do.
  • FIG. 1 is a schematic diagram of a device used in the polymer microsphere continuous manufacturing method of the present invention.
  • FIG. 2 is a flow chart of a polymer microsphere continuous manufacturing method of the present invention.
  • Figure 4 is a graph showing the results of animal pharmacokinetic experiments of the polymer microspheres prepared according to an embodiment of the present invention.
  • 5 is a graph showing the results of the in vitro release experiment of the polymer microsphere prepared according to an embodiment of the present invention.
  • FIG. 6 is a graph showing the results of animal pharmacokinetic experiments of the polymer microspheres prepared according to an embodiment of the present invention.
  • FIG. 7 is a scanning electron microscope image of a polymer microsphere prepared according to an embodiment of the present invention.
  • a polymer microsphere is prepared by injecting a polymer drug solution in which a poorly water-soluble drug and a biocompatible biodegradable polymer are dissolved in an organic solvent, into a reactor for preparing a polymer microsphere having an aqueous solution containing an emulsifier.
  • a polymer drug solution in which a poorly water-soluble drug and a biocompatible biodegradable polymer are dissolved in an organic solvent
  • To manufacture 2) transferring the resultant of step 1) to a polymeric microsphere reservoir; 3) recycling the emulsifier-containing aqueous solution from the result of step 2) to the polymer microsphere preparation reactor of step 1), repeating steps 1) and 2);
  • It can provide a continuous method for producing a polymer microsphere, comprising the step of obtaining a polymer microsphere from the product of step 3).
  • the poorly water-soluble drug may be selected from drugs having a solubility in water (25) of 10 mg / mL or less, for example, an antipsychotic agent, an antineoplastic agent, an antifungal agent. ), Immunosuppressants, analgesics, anti-inflammatory agents, antiviral agents, anxiolytic sedatives, contrasting agents, corticosteroids, diagnostic drugs diagnostic agents, diagnostic imaging agents, diuretics, prostaglandins, radiopharmaceuticals, sex hormones including steroids and combinations thereof However, this may not be limited.
  • the recirculation may be performed by an external or internal pump, but may not be limited thereto.
  • the result of step 3) may include the polymer microspheres that are recycled only in the aqueous solution containing the emulsifier and remain in the polymer microsphere reservoir.
  • the emulsifier-containing aqueous solution can be recycled without separate filtration.
  • the organic solvent may be a mixture of a water immiscible organic solvent and a water miscible organic solvent, but may not be limited thereto.
  • the volume ratio of the water miscible organic solvent to the water immiscible organic solvent may be 0 to 50% by volume, but may not be limited thereto.
  • the water immiscible organic solvent may be a halogenated aliphatic hydrocarbon solvent, and the water miscible organic solvent may be a ketone, nitrile, acetate or alcohol solvent, but may not be limited thereto.
  • the halogenated aliphatic hydrocarbon solvent may be selected from methylene chloride and dichloromethane (DCM), but may not be limited thereto.
  • the ketone may be acetone or methyl ethyl ketone
  • the nitrile is acetonitrile
  • the acetate is methyl acetate or ethyl acetate
  • the alcohol may include methanol, ethanol, propanol or butanol, but is not limited thereto. Can be.
  • the polymer drug solution in step 1) may be injected into the polymer microsphere production reactor at a rate of about 0.1 to about 10 ml / min, but may not be limited thereto.
  • the polymer drug solution may be injected into a polymer microsphere production reactor through a solvent filter.
  • the emulsifier-containing aqueous solution may be recycled at a rate of 20 to 100 ml / min, but may not be limited thereto.
  • the aqueous solution containing the emulsifier may be recycled through a tube line installed in the upper layer than the product of step 2).
  • the organic solvent in step 3), may be removed, and heating, nitrogen bubbling, or a combination thereof may be used.
  • nitrogen bubbling it is preferable to blow nitrogen into the upper layer than the result of step 2).
  • the emulsifier-containing aqueous solution may have a controlled pH, but may not be limited thereto.
  • the emulsifier-containing aqueous solution may be about 6 to 10, about 7 to 10, about 8 to 10, about 9 to 10, about 6 to 7, about 6 to 8, about 6 to 9, about 7 to 10, or It may have a pH of about 8 to 10, but may not be limited thereto.
  • the pH control of the emulsifier-containing aqueous solution may further affect the encapsulation efficiency of the drug.
  • sodium carbonate, sodium bicarbonate or citric acid may be added to the aqueous solution containing emulsifier to adjust the pH, but may not be limited thereto.
  • the material used for adjusting the pH of a solution If it is, it can be selected and used by those skilled in the art without limitation.
  • the emulsifier may include polyvinyl alcohol, poloxamer, polysorbate, or a mixture thereof, but may not be limited thereto.
  • the biocompatible biodegradable polymer may include a copolymer made of polylactide, polyglycolide, polycaprolactone, polypyrrolidone, or a combination thereof, but may not be limited thereto. have.
  • the weight average molecular weight of the polymer used to prepare the microspheres may range from about 10,000 to 200,000, and a polymer having an appropriate molecular weight may be selected in consideration of the type of drug and the sustained release period.
  • the second aspect of the present invention 1) a polymer microsphere production reactor for preparing a polymer microspheres by injecting a polymer drug solution in which a poorly water-soluble drug and a biocompatible biodegradable polymer dissolved in an organic solvent in an aqueous solution containing an emulsifier; 2) a polymer microsphere storage tank in which the resultant product of step 1) is transferred and stored; And 3) a device for recycling the emulsifier-containing aqueous solution from the result of step 2) to the polymer microsphere production reactor, wherein the polymer microsphere continuous production apparatus for use in the method according to the first aspect of the present invention is provided. can do.
  • FIG. 1 A schematic diagram of a polymer microsphere continuous manufacturing apparatus according to the present invention is shown in FIG. 1.
  • a polymer drug solution 100 is injected into a polymer microsphere manufacturing reactor 200 containing an aqueous solution containing an emulsifier, and a polymer microsphere is prepared therein.
  • the prepared polymer microspheres are transferred to and stored in the polymer microsphere storage tank 400 together with the emulsifier-containing aqueous solution, and the emulsifier-containing aqueous solution is recycled to the polymer microsphere production reactor 200 by the peristaltic pump 300.
  • the polymer microspheres are continuously produced and stored in the polymer microsphere reservoir 400, from which the polymer microspheres can be separated and obtained.
  • FIG. 1 shows a schematic of a polymeric microsphere (PMS) continuous manufacturing apparatus and process.
  • PMS polymeric microsphere
  • the PMS produced in the reactor 200 flows along the tube line and is collected in a reservoir, and particles prepared by installing a tube on the upper layer of the solution so that only an aqueous solution of polyvinyl alcohol (PVA) used as an emulsifier can be circulated again.
  • PVA polyvinyl alcohol
  • PVA aqueous solution was circulated using the peristaltic pump 300, the circulation rate was maintained at a rate of 50 ml / min.
  • the polymer and the drug was dissolved in the organic solvent (100), using a syringe pump was introduced into the PMS manufacturing reactor 200 while changing at a rate of 25 ⁇ 100 ml / hour.
  • the organic solvent in which the polymer is dissolved is usually injected into the reactor through a needle, but in this embodiment, a solvent filter used for HPLC was used. By using a solvent filter, the organic solvent injection rate can be increased, which is advantageous in mass synthesis, and also has a smaller particle size and a uniform advantage than using a needle at the same injection rate.
  • the particle size was set to 25-150 ⁇ m and separated using a sieve. The separated particles were washed and dried in vacuo to give the final PMS.
  • risperidone-PMS For the preparation of risperidone-PMS, the pH of the PVA aqueous solution was adjusted to increase the encapsulation efficiency, and the prepared PMS particles were washed to remove risperidone from the surface to reduce initial over-emissions generated during the release experiment. PMS particle manufacturing process flow diagram is shown in FIG. 2.
  • MC methylene chloride
  • microspheres filled with risperidone were prepared using two polymers (DLG 7525 7E and DLG 6535 5E) having different composition ratios and molecular weights. Preparation conditions and results are shown in Table 2.
  • the sustained release effect was observed by performing a release experiment of risperidone-PMS prepared according to the process flow diagram shown in FIG. 2.
  • the solvent used in the release experiment was an aqueous solution of Tween 80 and sodium azide, respectively.
  • Preparation conditions and analysis results of risperidone-PMS used in the release experiment are shown in Table 2 above.
  • Tamsulosin-HCl has a salt structure and is a water-soluble drug.
  • HCl was removed to prepare poorly soluble tamsulosin that is insoluble in water.
  • Step 4) was repeated three more times.
  • MgSO 4 Magnetic Sulfate, anhydride
  • the drug obtained here was dissolved in an organic solvent to prepare PMS particles by an experimental method similar to the risperidone-PMS preparation process.
  • the difference from the risperidone-PMS preparation process of FIG. 2 is that NaHCO 3 and Na 2 CO 3 were not added when the PVA aqueous solution was prepared, and citric acid was not added when the ethanol aqueous solution was prepared. This is because the solubility of tamsulosin is not affected by pH, so it is not necessary to adjust the pH of the solution used.
  • PMS particles were prepared by setting the target content of the drug to ⁇ 20%. The results of the prepared PMS particles are shown in Table 3.
  • tamsulosin is a drug with low solubility in water, high encapsulation efficiency was obtained.
  • the sustained release effect was observed by conducting a release experiment of tamsulosin-PMS according to Table 3.
  • the solvent used in the release test was an aqueous solution of 0.02% of Tween 80 and sodium azide.
  • Three release test samples were prepared for reproducibility confirmation (FIG. 5).
  • the release pattern was an S-shaped curve, showing that the initial release was suppressed by the polymer, and that the drug release proceeded rapidly after about 20 days. Since the drug content was prepared at -20% and the polymer content was relatively high, it was thought that the drug was distributed in the core of PMS particles. It was confirmed that all the encapsulated drugs were released in about 35 days or more. In anticipation of animal PK from these release results, blood levels could be expected to increase after about two weeks.
  • Aqueous circulation peristaltic pump (5 mL ⁇ 10 L / hr) + silicone tube

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne un procédé de fabrication en continu de microsphères polymères, ainsi qu'un appareil permettant la fabrication en continu de microsphères polymères pour la mise en œuvre du procédé de fabrication.
PCT/KR2017/007359 2016-07-11 2017-07-10 Procédé de fabrication en continu de microsphères polymères, et appareil associé Ceased WO2018012829A1 (fr)

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KR10-2016-0087319 2016-07-11

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2816188C1 (ru) * 2023-07-12 2024-03-26 Ильян Чанхович Кан Способ получения инъекционного имплантата для подкожного или внутрикожного введения без остаточного растворителя на поверхности полимера

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KR102051044B1 (ko) * 2019-05-27 2019-12-02 주식회사 울트라브이 생분해성 고분자 필러의 제조 방법, 및 이를 포함하는 주사제의 제조 방법
KR20240071913A (ko) 2022-11-16 2024-05-23 (주)디에스다산 생분해성 고분자 미세구체 제조 방법 및 이에 의해 제조된 생분해성 고분자 미세구체를 포함하는 필러

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KR20010002589A (ko) * 1999-06-16 2001-01-15 김윤 생리활성물질 함유 생분해성 고분자 마이크로스피어의 제조방법
KR20050001896A (ko) * 2003-06-26 2005-01-07 주식회사 펩트론 서방성 미립구의 혼합 제형을 연속한 단일 공정으로제조하는 방법
KR20110022096A (ko) * 2005-12-20 2011-03-04 주식회사 삼양사 고분자 마이크로스피어의 제조 방법 및 제조 장치
JP5457680B2 (ja) * 2006-01-24 2014-04-02 アンサン バイオファーマ，インコーポレイテッド 高分子マイクロスフェアの調製技術
KR101543507B1 (ko) * 2013-05-15 2015-08-11 씨제이헬스케어 주식회사 연속 공정의 미립구의 제조 방법 및 이로부터 제조된 미립구

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2816188C1 (ru) * 2023-07-12 2024-03-26 Ильян Чанхович Кан Способ получения инъекционного имплантата для подкожного или внутрикожного введения без остаточного растворителя на поверхности полимера

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