WO2023016565A1 - Suspension de microsphères, formulation de microparticules et procédé de préparation de celles-ci - Google Patents

Suspension de microsphères, formulation de microparticules et procédé de préparation de celles-ci Download PDF

Info

Publication number
WO2023016565A1
WO2023016565A1 PCT/CN2022/112280 CN2022112280W WO2023016565A1 WO 2023016565 A1 WO2023016565 A1 WO 2023016565A1 CN 2022112280 W CN2022112280 W CN 2022112280W WO 2023016565 A1 WO2023016565 A1 WO 2023016565A1
Authority
WO
WIPO (PCT)
Prior art keywords
plga
microsphere suspension
active ingredient
preparation
lactide
Prior art date
Application number
PCT/CN2022/112280
Other languages
English (en)
Chinese (zh)
Inventor
陈梦伟
吕丕平
迟乐乐
王怡
苗伟
李增荣
刘月华
Original Assignee
江西济民可信集团有限公司
上海济煜医药科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 江西济民可信集团有限公司, 上海济煜医药科技有限公司 filed Critical 江西济民可信集团有限公司
Priority to CN202280053353.0A priority Critical patent/CN117858698A/zh
Publication of WO2023016565A1 publication Critical patent/WO2023016565A1/fr

Links

Images

Classifications

    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A61P23/02—Local anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the invention relates to a microsphere suspension, a microparticle preparation and a preparation method thereof, in particular to a microsphere suspension, a microsphere preparation and a preparation method thereof which can be loaded with active ingredients of small-molecule medicines.
  • Microparticle preparations also known as microparticle drug delivery systems, refer to drugs or suitable carriers (generally biodegradable materials), which are composed of particles with a certain particle size (micron or nanometer) after a certain dispersion and embedding technology.
  • Solid, liquid, semi-solid or gaseous drug preparations which can mask the bad smell and taste of drugs, solidify liquid drugs, reduce the compatibility changes of compound drugs, improve the solubility of insoluble drugs, or increase the bioavailability of drugs, or improve drug stability, or reduce adverse drug reactions, or delay drug release, improve drug targeting and other effects.
  • the dispersion system composed of dispersed phases with a diameter in the range of 10 -4 to 10 -9 m is called a particle dispersion system, in which the dispersed phase particle diameters in the range of 1 to 500 ⁇ m are collectively referred to as coarse (micron ) dispersion system, mainly including microcapsules, microspheres, etc.; the dispersed phase particle size is less than 1000nm belongs to the nano-dispersion system, mainly including liposomes, nanoemulsions, nanoparticles, polymer micelles, submicroemulsions, etc. Microcapsules, microspheres, submicroemulsions, liposomes, nanoemulsions, nanoparticles, polymer micelles, etc. can be used as drug carriers.
  • the carrier material of microsphere can be divided into natural polymer material according to its source, as: gelatin, albumin, chitin, dextran, alginate, polyhydroxyalkanoate (PHA) etc.; Semi-synthetic polymer material and Synthetic polymer materials, such as: polylactide (PLA), polyglycolide (PGA), glycolide-lactide copolymer (PLGA), polycaprolactone (PCL), polyalkylcyanoacrylate (PACA) )wait.
  • synthetic polymer materials poly(lactide glycolide) (PLGA) has the advantages of good biocompatibility and biodegradability, so it is favored by many scientific researchers and formulation researchers.
  • microsphere preparation methods mainly include: emulsification-solvent evaporation method, spray drying method, phase separation method, etc.
  • Pain is not only an unpleasant emotional experience for patients, but also an important factor affecting social productivity. According to the duration of pain, it is divided into acute pain and chronic pain. Chronic pain mainly refers to persistent pain that exists all the time or reoccurs. The degree and duration of the pain cause discomfort to the patient and affect the functional level and quality of life of the patient. Chronic pain is mainly affected by chronic degenerative diseases or caused by nerve damage, such as joint pain caused by osteoarthritis, spinal pain, postoperative chronic persistent pain, and cancer pain. Although the incidence of this type of chronic pain is lower than that of acute pain, it will affect the quality of life and physical and mental health of patients for a long time, which needs our attention.
  • Multimodal treatment strategies help to use lower doses of opioids through different mechanisms and pathways Class drugs, resulting in better pain relief, while potentially reducing adverse effects.
  • Multimodal analgesia is the combined use of analgesic drugs or analgesic methods with different mechanisms of action. Due to the different mechanisms of action, they complement each other, and the analgesic effects are additive or synergistic. Maximum effect/adverse effect ratio.
  • microspheres a new type of drug delivery system, have been developed rapidly.
  • problems with the bupivacaine microspheres involved which limits the use of bupivacaine. Due to the application of microspheres.
  • the main problems are as follows: the one is that the particle size distribution of the prepared microspheres is uneven, and the particle size is too large (generally greater than 30 ⁇ m), which is not conducive to clinical administration, and the patient's compliance is poor; the other is the drug loading of the prepared microspheres low, leading to high production costs, difficulty in drug release, and long drug release cycle, the cumulative drug release rate within seven days is only 80%, which is not conducive to acute pain management within seven days; the third is that the drug embedding rate in the preparation process is low, The embedding rate is generally not higher than 85%, which leads to higher costs in the production process and uncontrollable quality of microspheres and intermediates; fourth, the drug burst rate of the prepared microspheres is high, and a large amount of drugs adhere to the surface of the carrier or scatter Outside the sphere, the sudden release phenomenon is serious, and the drug release rate reaches 30% within half an hour, which is not conducive to druggability, and it is easy to produce toxic side effects in clinical or animal experiments, such as
  • the technical problem to be solved by the present invention is to overcome the defects of low drug loading and low embedding efficiency of microsphere preparations (such as bupivacaine microspheres) in the prior art, and provide a kind of microsphere suspension, microparticle preparation and its preparation method.
  • microsphere preparations such as bupivacaine microspheres
  • the present invention aims to provide a biodegradable long-acting sustained-release microparticle preparation and a preparation method thereof.
  • the pharmaceutical active ingredient, drug loading and drug release period can be adjusted to cover different indications and patients.
  • the microparticle preparation provided by the present invention can be used for postoperative pain management and can provide a long-acting sustained release effect, and can achieve a higher drug loading under the premise of controllable quality and safety, delay the time of local anesthesia and analgesia, and reduce opioids Drug use, and increase local drug concentration, reduce adverse reactions.
  • Postoperative pain is a complex physiological and psychological response of the human body to tissue damage and repair process. It is a prominent problem that plagues surgical patients. Postoperative pain usually lasts for several days to several weeks. According to the indication, the corresponding release period of the microparticle preparation involved in the present invention may be 2-14 days.
  • the present invention provides a microparticle formulation comprising a pharmaceutically active ingredient and PLGA; wherein:
  • the molar ratio of lactide LA and glycolide GA is (1-5.67):1, and the weight-average relative molecular weight of the PLGA is 12000-60000;
  • the content of the pharmaceutical active ingredient is 35-80%, and the percentage refers to the mass percentage in the microparticle preparation.
  • the molar ratio of lactide LA to glycolide GA is preferably 85:15 or (1-3):1, such as 75:25 or 50:50.
  • the weight average relative molecular weight of the PLGA is preferably 15000-52000, such as 15000-23000, further such as 15000 or 23000.
  • the viscosity of the PLGA (at 30° C.) may be 0.15-0.45 dL/g, such as 0.15 dL/g, 0.21 dL/g, 0.24 dL/g or 0.4 dL/g.
  • the model of the PLGA can be represented by the mol ratio of lactide and glycolide, the weight-average relative molecular mass of PLGA, such as "752515000" means that the mol ratio of lactide and glycolide is 75:25 , PLGA with a weight-average molecular mass of 15,000.
  • the model of described PLGA can be 7525 15000, 5050 15000, 5050 23000 or 7525 52000, preferably 5050 15000 or 5050 23000.
  • the mass ratio of the active pharmaceutical ingredient and the PLGA is preferably (0.6-2.5):1, such as 0.61:1, 0.63:1, 0.73:1, 0.90:1, 0.92:1, 0.93:1 , 0.96:1, 1.12:1, 1.22:1, 1.23:1, 1.24:1, 1.28:1, 1.29:1, 1.31:1, 1.72:1, 1.75:1, 2.19:1, or 2.28:1.
  • the content of the pharmaceutical active ingredient may be 38.0-69.5%, such as 38.0%, 38.5%, 42.2%, 47.3%, 47.5%, 47.8%, 48.1%, 48.9%, 52.9% %, 54.9%, 55.1%, 55.4%, 56.1%, 56.3%, 56.7%, 56.8%, 63.2%, 63.6%, 68.7% or 69.5%, the percentage refers to the mass percentage in the microparticle preparation.
  • the active ingredient of the drug can be a small molecule active ingredient of a conventional drug with a relative molecular mass between 100-1500 in the art, and can be divided into amphiphilic drugs, lipophilic drugs, and water-soluble drugs according to their solubility. and hydrophobic drugs.
  • the active ingredient of the drug is a small molecule active ingredient of the drug with a relative molecular mass between 100-1500;
  • the active ingredient of the drug can be antipyretic, analgesic and anti-inflammatory drugs May include, but are not limited to: codeine, dihydrocodeine, hydromorphone, oxycodone, methadone, morphine, fentanyl, meperidine, amide local anesthetics, meloxicam, aspirin, paraacetyl One or more of aminophenols, indomethacin, naproxen, naproxen, diclofenac, ibuprofen, nimesulide, rofecoxib, celecoxib, triamcinolone acetonide, and methotrexate
  • the amide local anesthetic may be one or more of ropivacaine, bupivacaine, lidocaine and procaine, such as bupivacaine.
  • the microparticle formulation comprises active pharmaceutical ingredients and PLGA, wherein:
  • the molar ratio of lactide LA and glycolide GA is 50:50, and the weight average relative molecular weight of the PLGA is 15000-23000;
  • the content of the pharmaceutical active ingredient is 50-60%, and the percentage refers to the mass percentage in the microparticle preparation.
  • the microparticle preparation comprises bupivacaine and PLGA, wherein:
  • the molar ratio of lactide LA and glycolide GA is 50:50, and the weight average relative molecular weight of the PLGA is 15000;
  • the ratio of the bupivacaine to the PLAG is 1.24:1.
  • the microparticle preparation comprises bupivacaine and PLGA, wherein:
  • the molar ratio of lactide LA and glycolide GA is 50:50, and the weight average relative molecular weight of the PLGA is 23000;
  • the ratio of the bupivacaine to the PLAG is 1.31:1.
  • the present invention also provides a microsphere suspension A, which comprises a solvent, a pharmaceutical active ingredient and PLGA;
  • the molar ratio of lactide LA and glycolide GA is (1-5.67):1, and the weight-average relative molecular weight of the PLGA is 12000-60000;
  • the content of the active pharmaceutical ingredient is 35-80%, and the percentage refers to the sum of the "active pharmaceutical ingredient and PLGA" in the microspheres of the microsphere suspension A. % by mass.
  • the molar ratio of lactide LA to glycolide GA is preferably 85:15 or (1-3):1, such as 75:25 or 50:50.
  • the weight average relative molecular weight of the PLGA is preferably 15000-52000, such as 15000-23000, further such as 15000 or 23000.
  • the viscosity of the PLGA (at 30° C.) may be 0.15-0.45 dL/g, such as 0.15 dL/g, 0.21 dL/g, 0.24 dL/g or 0.4 dL/g.
  • the model of the PLGA can be represented by the mol ratio of lactide and glycolide, the weight-average relative molecular mass of PLGA, such as "752515000" means that the mol ratio of lactide and glycolide is 75:25 , PLGA with a weight-average molecular mass of 15,000.
  • the model of described PLGA can be 7525 15000, 5050 15000, 5050 23000 or 7525 52000, preferably 5050 15000 or 5050 23000.
  • the mass ratio of the active pharmaceutical ingredient and the PLGA can be (0.6-2.5):1, such as 0.61:1, 0.63:1, 0.73:1, 0.90:1, 0.92:1, 0.93:1 , 0.96:1, 1.12:1, 1.22:1, 1.23:1, 1.24:1, 1.28:1, 1.29:1, 1.31:1, 1.72:1, 1.75:1, 2.19:1, or 2.28:1.
  • the content of the pharmaceutical active ingredient in the microsphere suspension A, can be 38.0-69.5%, such as 38.0%, 38.5%, 42.2%, 47.3%, 47.5%, 47.8%, 48.1%, 48.9% %, 52.9%, 54.9%, 55.1%, 55.4%, 56.1%, 56.3%, 56.7%, 56.8%, 63.2%, 63.6%, 68.7% or 69.5%, the percentage refers to the The mass percentage of the sum of the mass of "pharmaceutical active ingredient and PLGA" in the microsphere.
  • the active ingredient of the drug can be a small molecule active ingredient of a conventional drug with a relative molecular mass between 100-1500 in the art, and can be divided into amphiphilic drugs, lipophilic drugs, and water-soluble drugs according to their solubility. and hydrophobic drugs.
  • the active ingredient of the drug is a small molecule active ingredient of the drug with a relative molecular mass between 100-1500;
  • the active ingredient of the drug can be antipyretic, analgesic and anti-inflammatory drugs May include, but are not limited to: codeine, dihydrocodeine, hydromorphone, oxycodone, methadone, morphine, fentanyl, meperidine, amide local anesthetics, meloxicam, aspirin, paraacetyl One or more of aminophenols, indomethacin, naproxen, naproxen, diclofenac, ibuprofen, nimesulide, rofecoxib, celecoxib, triamcinolone acetonide, and methotrexate
  • the amide local anesthetic may be one or more of ropivacaine, bupivacaine, lidocaine and procaine, such as bupivacaine.
  • the solvent may be a conventional solvent in the art that is compatible with the microspheres in the microsphere suspension A.
  • microsphere suspension A in the microsphere suspension A, one or more of an osmotic pressure regulator, a wetting agent and a suspending agent may also be included,
  • the osmotic pressure regulator may be a conventional osmotic pressure regulator in the art, such as one or more of mannitol, sucrose and sodium chloride.
  • the wetting agent may be a conventional wetting agent in the art, such as Tween 80 and/or Poloxamer 188.
  • the suspending agent can be a conventional suspending agent in the art, such as one or more of sodium carboxymethylcellulose, methylcellulose and hydroxypropylcellulose.
  • the microsphere suspension A comprises solvent, pharmaceutical active ingredient and PLGA, wherein:
  • the molar ratio of lactide LA and glycolide GA is 50:50, and the weight average relative molecular weight of the PLGA is 15000-23000;
  • the content of the pharmaceutical active ingredient is 50-60%, and the percentage refers to the "pharmaceutical active ingredient and PLGA" in the microspheres of the microsphere suspension A
  • the mass percentage of the mass sum is 50-60%, and the percentage refers to the "pharmaceutical active ingredient and PLGA" in the microspheres of the microsphere suspension A The mass percentage of the mass sum.
  • the microsphere suspension A comprises bupivacaine and PLGA, wherein:
  • the molar ratio of lactide LA and glycolide GA is 50:50, and the weight average relative molecular weight of the PLGA is 15000;
  • the ratio of the bupivacaine to the PLAG is 1.24:1.
  • the microsphere suspension A comprises bupivacaine and PLGA, wherein:
  • the molar ratio of lactide LA and glycolide GA is 50:50, and the weight average relative molecular weight of the PLGA is 23000;
  • the ratio of the bupivacaine to the PLAG is 1.31:1.
  • the present invention also provides a kind of preparation method of microsphere suspension A, it comprises the steps:
  • the oil phase and the water phase are mixed to obtain an emulsion; wherein: the oil phase comprises active pharmaceutical ingredients and PLGA; in the PLGA, the mol ratio of lactide LA and glycolide GA is (1-5.67 ): 1, the weight-average relative molecular weight of the PLGA is 12000-60000;
  • step (1) The emulsion described in step (1) is solidified to obtain the microsphere suspension A; wherein, the solidification method is rotary evaporation, volatilization under reduced pressure or blowing under positive pressure;
  • the temperature of the rotary evaporation is 10-50°C, and the rotation speed of the rotary evaporation is 50-100rpm;
  • the flow rate of the emulsion is 200-1000ml/min, and the vacuum degree of volatilization under reduced pressure is ⁇ 0Mpa and ⁇ -0.1Mpa;
  • the ratio of the pressure p (Mpa) of described positive pressure blowing and the mass sum w (g) of " described pharmaceutical active ingredient and described PLGA” is 1: (20-500).
  • the oil phase generally contains a solvent
  • the solvent can be a conventional solvent in the art that can dissolve the active pharmaceutical ingredient and the PLGA, such as dichloromethane.
  • the water phase can be a conventional water phase in the art that can be used to prepare microparticle preparations, such as an aqueous solution containing polymer components.
  • the mass concentration of the polymer component may be 0.5-2.0%, such as 1.0%.
  • the polymer component may be a conventional polymer emulsifier in the art, such as polyvinyl alcohol PVA.
  • the water phase can be an aqueous solution containing PVA with a mass concentration of 0.5-2.0%.
  • the aqueous phase may not contain a pH-adjusting buffer, such as an acidic buffer or an alkaline buffer.
  • the active pharmaceutical ingredient may not undergo pretreatment to promote dissolution, such as alkaline treatment with ammonia water.
  • the active ingredient of the drug can be a small molecule active ingredient of a conventional drug with a relative molecular mass between 100-1500 in the art, and can be divided into amphiphilic drugs, lipophilic drugs, and water-soluble drugs according to their solubility. and hydrophobic drugs.
  • the active ingredient of the drug may be antipyretic, analgesic and anti-inflammatory drugs
  • the antipyretic, analgesic and anti-inflammatory drugs may include but not limited to: codeine, dihydrocodeine, hydromorphone, oxycodone Ketone, methadone, morphine, fentanyl, pethidine, amide local anesthetics, meloxicam, aspirin, acetaminophen, indomethacin, naproxen, naproxen, diclofenac, ibuprofen, One or more of nimesulide, rofecoxib, celecoxib, triamcinolone acetonide and methotrexate
  • the amide local anesthetics can be ropivacaine, bupivacaine, lidocaine One or more of caine and procaine, such as bupivacaine.
  • the molar ratio of lactide LA to glycolide GA is preferably 85:15 or (1-3):1, such as 75:25 or 50:50.
  • the weight average relative molecular weight of the PLGA is preferably 15000-52000, such as 15000-23000, further such as 15000 or 23000.
  • the viscosity of the PLGA (at 30° C.) may be 0.15-0.45 dL/g, such as 0.15 dL/g, 0.21 dL/g, 0.24 dL/g or 0.4 dL/g.
  • the model of the PLGA can be represented by the mol ratio of lactide and glycolide, the weight-average relative molecular mass of PLGA, such as "752515000" means that the mol ratio of lactide and glycolide is 75:25 , PLGA with a weight-average molecular mass of 15,000.
  • the model of described PLGA can be 7525 15000, 5050 15000, 5050 23000 or 7525 52000, preferably 5050 15000 or 5050 23000.
  • the mass ratio of the active pharmaceutical ingredient and the PLGA can be (0.67-4):1, such as 1:1, 4:1, 7:3, 1.5:1 or 2:3; it can also be (1-1.5):1.
  • the temperature may be lowered to 5-15°C or 6-10°C.
  • the cooling method can be a cold water bath or storage in a refrigerator.
  • the way of mixing the oil phase and the water phase can be injected into the online shearing machine with a peristaltic pump respectively.
  • the emulsion with the target particle size can be obtained by means of shearing, membrane passing or online shearing.
  • the shearing speed or the rotational speed of the online shearing machine may be 3000-5000 rpm, such as 3000 rpm, 4000 rpm or 5000 rpm.
  • the curing time may be a conventional time in the art, such as 0.5-6h, further such as 3-5h, further such as 3h, 4h or 5h.
  • the positive pressure blowing generally refers to the use of a gas with a certain amount of heat (a gas with a higher gas pressure than normal pressure (i.e. one atmospheric pressure)) to purge the flat emulsion, so that the solvent is quickly volatilized, thereby realizing the emulsion fast curing.
  • a gas with a certain amount of heat a gas with a higher gas pressure than normal pressure (i.e. one atmospheric pressure)
  • the curing method when the curing method is positive pressure blowing, the positive pressure blowing can be implemented by using the curing equipment shown in Figure 1 in the existing Chinese patent ZL202020705393.7 (CN 212308885 U).
  • the pressure p (Mpa) of the positive pressure blowing and the sum w (g) of the mass of "the active pharmaceutical ingredient and the PLGA" The ratio is preferably 1:(50-200), for example 1:(100-170), for example 1:100 or 1:166.7.
  • the gas pressure p of the positive pressure blowing is preferably 0.1-0.6Mpa, such as 0.1Mpa, 0.2Mpa or 0.6Mpa.
  • the emulsion when the curing method is blowing under positive pressure, the emulsion should generally be flattened into a uniform film or liquid film.
  • the gas temperature of the positive pressure blowing is preferably 10-100°C, such as 30-70°C, or 30°C, 40°C, 50°C or 70°C, also for example 60-90°C.
  • the conditions of the positive pressure blowing are preferably 0.1Mpa, 30-40°C, or 0.2Mpa, 50°C, or 0.6Mpa, 40-90°C , or 0.6Mpa, 60-90°C.
  • the positive pressure blowing gas may be compressed air.
  • the gas blown under positive pressure should generally remove water.
  • the curing when the curing method is blowing under positive pressure, the curing is generally carried out in a curing tank.
  • the temperature of the curing tank is preferably 15-25°C, such as 15°C, 20°C or 25°C.
  • the temperature difference there may be a temperature difference of 1-5° C. between the temperature inside the curing tank and the setting temperature.
  • the temperature of the rotary evaporation is preferably 20-30°C, such as 25°C.
  • the rotational speed of the rotary evaporation is preferably 50-100 rpm, such as 60 rpm.
  • the process conditions of the rotary evaporation are preferably 25° C. and 60 rpm.
  • the flow rate of the emulsion when the curing method is volatilization under reduced pressure, is preferably 400-600 ml/min, such as 500 ml/min.
  • the flow rate of the emulsion generally refers to the flow rate delivered to the thin film evaporator.
  • the vacuum degree of volatilization under reduced pressure may be -0.1 ⁇ -0.05Mpa, for example, -0.08Mpa.
  • the temperature of the emulsion when the curing method is volatilization under reduced pressure, the temperature of the emulsion may be 10-50°C, such as 20-30°C, and for example 25°C.
  • the emulsion when the curing method is volatilization under reduced pressure, the emulsion can be circulated through the membrane for 5 times after volatilization under reduced pressure.
  • the process conditions of volatilization under reduced pressure are preferably: the emulsion is transported to the thin film evaporator at a flow rate of 500ml/min, and the vacuum degree is set to be -0.08Mpa, The temperature of the emulsion was 25°C, and it was circulated through the membrane 5 times.
  • the microsphere suspension A can also be subjected to post-treatments such as centrifugation and washing according to conventional operations in the field.
  • the number of times of the centrifugal washing can be 4 times.
  • the rotational speed of the centrifugation may be 7000-9000 rpm, such as 8000 rpm.
  • the oil phase contains pharmaceutical active ingredients and PLGA; in the PLGA, the molar ratio of lactide LA and glycolide GA is 50:50, and the weight average of the PLGA is relative to The molecular weight is 15000-23000; the mass ratio of the pharmaceutical active ingredient to the PLGA is (0.67-4):1.
  • the oil phase contains pharmaceutical active ingredients and PLGA; in the PLGA, the molar ratio of lactide LA and glycolide GA is 50:50, and the weight average of the PLGA is relative to Molecular weight is 15000;
  • the mass ratio of described active ingredient of medicine and described PLGA is 3:2 (for example active ingredient of medicine 6g, PLGA 4g); Active ingredient of medicine is preferably bupivacaine.
  • the oil phase contains pharmaceutical active ingredients and PLGA; in the PLGA, the molar ratio of lactide LA and glycolide GA is 50:50, and the weight average of the PLGA is relative to Molecular weight is 23000;
  • the mass ratio of described active ingredient of medicine and described PLGA is 3:2 (for example active ingredient of medicine 6g, PLGA 4g); Active ingredient of medicine is preferably bupivacaine.
  • the microsphere suspension A may also contain one or more of an osmotic pressure regulator, a wetting agent and a suspending agent.
  • the osmotic pressure regulator may be a conventional osmotic pressure regulator in the art, such as one or more of mannitol, sucrose and sodium chloride.
  • the wetting agent may be a conventional wetting agent in the art, such as Tween 80 and/or Poloxamer 188.
  • the suspending agent can be a conventional suspending agent in the art, such as one or more of sodium carboxymethylcellulose, methylcellulose and hydroxypropylcellulose.
  • the osmotic pressure regulator, wetting agent and suspending agent is also included in the microsphere suspension A, the osmotic pressure regulator, the wetting agent and the auxiliary The suspension is dissolved in a solvent, and then mixed with the microsphere suspension A.
  • the solvent can be a conventional solvent in the art that is compatible with the microspheres in the microsphere suspension A.
  • the preparation method of described microsphere suspension A is simple and is beneficial to suitability for industrialized production, and it can comprise but not limited to following experimental steps:
  • oil-water phase preparation fully dissolve or disperse the active pharmaceutical ingredients and PLGA in an organic solvent to form a uniform oil phase.
  • the PLGA used includes but is not limited to the mixed use of one or more types of PLGA; the water phase is composed of mass volume Concentration is the formation of polymer solution of 0.5-2%, and described polymer can be selected from emulsifiers such as PVA; Wherein:
  • the oil phase contains pharmaceutical active ingredients and PLGA; in the PLGA, the molar ratio of lactide LA and glycolide GA is (1-5.67):1, and the weight average relative molecular weight of the PLGA is 12000-60000 ;
  • oil-water phase emulsification the oil phase and water phase prepared in S1 are sheared or passed through the membrane or online shearing to obtain the emulsion with the target particle size;
  • emulsion curing the emulsion prepared in S2 is rapidly solidified to obtain a suspension of particles; wherein, the rapid solidification method is selected from rotary evaporation, decompression volatilization or positive pressure blowing; wherein:
  • the temperature of the rotary evaporation is 10-50°C, and the rotation speed of the rotary evaporation is 50-100rpm;
  • the flow rate of the emulsion is 200-1000ml/min, and the vacuum degree of volatilization under reduced pressure is ⁇ 0Mpa and ⁇ -0.1Mpa;
  • the ratio of the pressure p (Mpa) of described positive pressure blowing and the mass sum w (g) of " described pharmaceutical active ingredient and described PLGA” is 1: (20-500);
  • the rapid solidification in S3 refers to that compared with low temperature stirring and natural volatilization of solvents, it means that the emulsion forms a mixture of solid particles within 30min-6h under artificially provided conditions that are conducive to solvent volatilization. Suspension.
  • Conditions favorable to solvent volatilization may include: providing higher heat, lowering the boiling point of the solvent, increasing the solubility of the solvent in the external water phase, accelerating gas-liquid substance exchange, and the like.
  • positive pressure air blowing is used for rapid curing, and sterile gas with a certain amount of heat is used to purge the flat emulsion, so that the solvent is quickly volatilized, thereby realizing rapid curing of the emulsion.
  • the present invention also provides a kind of preparation method of microsphere suspension A, it comprises the steps:
  • the oil phase and the water phase are mixed to obtain an emulsion; wherein: the oil phase comprises active pharmaceutical ingredients and PLGA; in the PLGA, the mol ratio of lactide LA and glycolide GA is (1-5.67 ): 1, the weight-average relative molecular weight of the PLGA is 12000-60000;
  • step (1) The emulsion described in the step (1) is solidified to obtain the microsphere suspension A; wherein, the solidification method is blowing under positive pressure;
  • the flow velocity of the emulsion is set to make the emulsion of 1/2 to 1/20 of the emulsion volume flow through the tray to solidify in 1min, and the air flow velocity is 10-100 times of the emulsion flow velocity.
  • the solvent of the oil phase can be as mentioned above.
  • composition of the water phase can be as described above.
  • the molar ratio of lactide LA and glycolide GA can be as mentioned above.
  • the weight-average relative molecular weight, viscosity, and model of the PLGA can be as described above.
  • the type of the pharmaceutical active ingredient can be as mentioned above.
  • the mass ratio of the active pharmaceutical ingredient and the PLGA can be as mentioned above.
  • the present invention also provides a microsphere suspension A, which is prepared by the above method.
  • the present invention also provides a microparticle preparation, which is prepared by the following method, that is, the aforementioned microsphere suspension A is dried.
  • the drug loading range of the microparticle preparation may be 40-80%, such as 40%, 50%, 60%, 70% or 80%.
  • the calculation method of the drug loading is the total weight of active pharmaceutical ingredients/weight of microparticle preparation*100%.
  • the content of the pharmaceutical active ingredient can be 38.0-69.5%, such as 38.0%, 38.5%, 42.2%, 47.3%, 47.5%, 47.8%, 48.1%, 52.9%, 54.9%, 55.1%, 55.4%, 56.1%, 56.3%, 56.7%, 56.8%, 63.2%, 63.6%, 68.7% or 69.5%, the percentage refers to the mass percentage in the microparticle preparation.
  • the microparticle preparation may also contain a lyoprotectant.
  • the freeze-drying protectant can protect the ingredients of the drug efficacy during the freeze-drying process and the storage stage after freeze-drying, and can also be used as a carrier to form a hard uniform skeleton to improve the appearance of the freeze-dried preparation in a glass bottle.
  • Dry protectants include sugars, albumin, polyethylene glycol, etc., and the sugars can be mannitol.
  • the mass ratio of the lyoprotectant to the microparticle preparation may be 0-20%, such as 1.25%.
  • the microparticle preparation also includes a lyoprotectant
  • the microsphere suspension A and the lyoprotectant are mixed and then dried.
  • the drying method may be spray drying, vacuum evaporation, rotary evaporation or freeze drying.
  • freeze-drying is carried out by means of freeze-drying.
  • sieving and filling can also be carried out after the drying.
  • the dried particle powder is sieved, mixed evenly to obtain a fine and uniform particle powder, and filled according to the filling capacity to obtain a sample of the particle preparation.
  • the actual drug loading of a single drug active ingredient can be as high as 69.5%.
  • the present invention also provides a microsphere suspension B, which is prepared by the following method, that is, dissolving the microparticle preparation in a solvent.
  • the solvent may be a special solvent compatible with microspheres conventional in the art, and the microparticle preparation may be used after uniformly dispersing the microspheres with this solvent before use.
  • the type of PLGA in the microparticle formulation will significantly affect the embedding rate and dissolution rate of the pharmaceutical active ingredient of the microparticle formulation.
  • Example 1 shows that the embedding ability of PLGA with different molar ratio monomers is different.
  • the embedding ability of 5050 PLGA is stronger than that of 7525; The larger the molecular weight of PLGA, the slower the dissolution rate and the longer the drug release period.
  • the microparticle preparations prepared with different drug loadings in the microparticle preparations have different shapes, the larger the drug loading, the rougher the surface of the microparticles; the drug dissolution rate and drug release period of the microparticles with different drug loadings are different, As shown in Example 4: the higher the proportion of drugs in the preparation of microspheres, the higher the actual drug loading of the prepared microspheres, the faster the in vitro dissolution, the higher the drug burst release rate in the early stage, and the shorter the drug release period. short.
  • the drug release behavior and cycle of microparticle preparations with different particle sizes are different, as shown in Example 5: the higher the shear rate when preparing microspheres, the smaller the particle size of the microspheres produced, and the burst release The rate is improved to a certain extent, the in vitro dissolution is also faster, and the release cycle is shorter. It is easy to understand that the smaller the particle size, it will greatly reduce the difficulty of drug administration during injection by doctors and nurses and improve the medication compliance of patients.
  • the emulsion is solidified, and the organic solvent volatilizes, leading to the precipitation of the active pharmaceutical ingredient.
  • the precipitation forms of active pharmaceutical ingredients are different.
  • the solidification process is accompanied by the recrystallization process of the drug molecules.
  • vacuum degree atmospheric pressure-absolute pressure
  • the reagents and raw materials used in the present invention are all commercially available.
  • microsphere suspension and microparticle preparations in the present invention have high drug loading and high embedding efficiency.
  • the theoretical drug loading is 60%
  • the actual drug loading can be as high as 56.8%
  • the embedding efficiency can reach 94.6%.
  • the microparticle preparation in the present invention has the characteristics of low burst release rate, stable drug release in the body, no stagnation period in the drug release cycle, good sustained release performance, and can realize 89-98% release in 7 days; Increase the frequency of medication, prolong the duration of drug effects, and improve patient compliance.
  • Fig. 1 is a schematic diagram of the preparation process of particles involved in the present invention
  • Fig. 2 is a schematic diagram of the particle solidification equipment involved in the present invention (the reference numerals are the same as Fig. 1 in Chinese patent ZL202020705393.7);
  • Fig. 3 is the microscope result of embodiment 1, shows the drug embedding situation of the prepared microsphere of different PLGA models
  • Fig. 4 is the drug release result of embodiment 1, shows the in vitro drug dissolution behavior of microspheres prepared by different PLGA models
  • Fig. 5 is the schematic diagram of the guinea pig efficacy test model of embodiment 1;
  • Fig. 6 is the drug effect test result of each prescription in the guinea pig in embodiment 1 in 24h;
  • Fig. 7 is the drug effect test result in 96h of each prescription in embodiment 1 on guinea pig;
  • Figure 8 is the in vitro dissolution results of microparticle preparations prepared by different curing methods in Example 2;
  • Figure 9 is a scanning electron micrograph of each prescription microparticle preparation in Example 4, showing the morphology of microparticle preparations prepared by different theoretical drug loadings;
  • Figure 10 is the in vitro dissolution results of microparticle preparations with different shear speeds in Example 5, showing the drug dissolution of microparticle preparations with different particle sizes;
  • Fig. 11 is the photo of the sample after lyophilization without adding a lyoprotectant in Example 6;
  • Fig. 12 is the sample photo after adding lyoprotectant freeze-drying in embodiment 6;
  • Figure 13 is the in vitro dissolution results of microparticle preparations with and without lyoprotectant added in Example 6;
  • Fig. 14 is the XRD collection of patterns of bupivacaine base used in embodiment 7;
  • Fig. 15 is the XRD pattern of the microparticle preparation prepared in embodiment 7;
  • Fig. 16 is the XRD pattern of the microparticle preparation prepared in embodiment 8.
  • Figure 17 is the in vitro dissolution results of the microparticle preparations prepared in Examples 7 and 8;
  • Fig. 18 is the polarizing microscope result of two kinds of curing modes curing 1h in embodiment 9;
  • Fig. 19 is the results of polarized light microscopy of the two curing methods in Example 9 for 4 hours.
  • the microparticle preparation provided by the present invention includes but is not limited to pain management, and is mainly used for the prevention and improvement of acute pain and chronic pain.
  • the microparticle preparations involved in the present invention are all long-acting sustained-release microparticle preparations, and the cycle for pain management is 2-7 days. Different microparticle preparations are given according to the patient's indications and individual conditions.
  • the above microparticle preparation is mainly suitable for local infiltration and peripheral nerve block, so as to improve and prevent pain of patients.
  • the main method of use is to subcutaneously, intradermally or intramuscularly inject the suspension of the above-mentioned microparticle preparation at the wound or pain site.
  • PLGA short for lactide-lactide copolymer, also known as lactide-glycolide copolymer, polylactic acid-glycolic acid copolymer.
  • PLGA viscosity Indicates the intrinsic viscosity of PLGA when the temperature is 30°C.
  • PVA short for polyvinyl alcohol.
  • Oil phase Indicates that the active ingredients of the drug and the glycolide-lactide copolymer are dissolved in an organic reagent to form a uniform organic solution.
  • Aqueous phase means an aqueous solution of polyvinyl alcohol.
  • Drug loading means that the mass of the active pharmaceutical ingredient contained in the prepared microparticle preparation accounts for the total weight of the entire microsphere sample, and the calculation formula is (mass of the active pharmaceutical ingredient/mass of the microparticle preparation)*100%. In the calculation method of the above-mentioned drug loading, the mass of PVA in the microparticle preparation can be ignored, and after washing the ball, the content of PVA in the microsphere powder is extremely low, which is undetected.
  • Embedding rate Indicates that the mass of the active pharmaceutical ingredient contained in the prepared microparticle preparation accounts for the mass of the active pharmaceutical ingredient in the amount of the prescription, and the calculation formula is (mass of the active pharmaceutical ingredient in the microparticle preparation/mass of the active pharmaceutical ingredient in the prescription)* 100%.
  • D 50 Indicates the particle size of microspheres in which the cumulative distribution of particles is 50% in the particle size distribution of the entire sample, that is, the volume content of particles smaller than this particle size accounts for 50% of all particles. D 50 is also often used to represent the average particle size of particles.
  • the preparation methods of the microparticle preparations in the following examples all adopt the emulsification-solvent evaporation method.
  • Other terms, methods, equipment, devices, etc. that are not explicitly stated in the present invention can be understood and obtained according to the conventional knowledge in the industry, or obtained according to the product instructions.
  • the active pharmaceutical ingredients selected in the following examples are selected from codeine, dihydrocodeine, hydromorphone, oxycodone, methadone, morphine, fentanyl, pethidine, ropivaca bupivacaine, lidocaine, procaine, meloxicam, aspirin, acetaminophen, indomethacin, naproxen, naproxen, diclofenac, ibuprofen, nimesul One or more of rofecoxib, celecoxib, triamcinolone acetonide and methotrexate.
  • the high-performance liquid chromatography (HPLC) method for determining the drug loading of microparticle preparations refers to the 2020 edition Pharmacopoeia Part II related substance detection method and general rule 0512 of bupivacaine hydrochloride.
  • the oil phase and the water phase were respectively injected into an online shearing machine (4000 rpm) with a peristaltic pump to obtain a uniform emulsion.
  • the emulsion was rapidly cured (the curing temperature was 20° C., the temperature of the jacket of the curing tank was set at 20° C., and the curing time was 3 hours) to obtain a suspension of PLGA microspheres.
  • the emulsion curing adopts the method of positive pressure blowing for rapid curing.
  • the pressure provided is 0.1Mpa is preheated to 30°C and the positive pressure gas that removes water purges the top of the liquid film to perform rapid exchange of matter and energy between the gas and the liquid.
  • the gas is compressed air.
  • microsphere suspension was centrifuged and washed 4 times (the centrifugal speed was 8000 rpm), a clean and concentrated microsphere suspension was obtained.
  • the microsphere suspension is freeze-dried to obtain a microsphere powder, and the powder is sieved and filled to obtain a sample of the microparticle preparation.
  • prescription PLGA model PLGA viscosity Theoretical drug loading (%) 01 7525 15000 0.15dL/g 60.0 02 5050 15000 0.21dL/g 60.0 03 5050 23000 0.24dL/g 60.0 04 7525 52000 0.40dL/g 60.0
  • the model of PLGA is represented by the molar ratio of lactide and glycolide and the weight-average relative molecular mass, such as "7525 15000" means that the molar ratio of lactide and glycolide is 75:25, and the weight-average relative molecular mass PLGA of 15000.
  • the D50 measured by Malvern particle size analyzer and high performance liquid chromatography (HPLC) (HPLC method refers to the bupivacaine hydrochloride related substance detection method and general rule 0512 in the second part of the Pharmacopoeia of the 2020 edition) measured the drug loading capacity of the microparticle preparation, respectively.
  • HPLC method refers to the bupivacaine hydrochloride related substance detection method and general rule 0512 in the second part of the Pharmacopoeia of the 2020 edition
  • Table 2-1 under the same preparation conditions, the greater the molecular weight of different types of PLGA, the greater the median particle size D50 of the prepared microparticle preparations, and the higher the drug loading and embedding efficiency.
  • guinea pigs are timid and easily startled, and are very sensitive to chemical or mechanical stimuli
  • guinea pigs were selected as pharmacodynamic experimental animals to study the effects of bupivacaine hydrochloride injection and the prepared microparticle preparations on guinea pigs. Implications for the study of local analgesia in the skin.
  • the animal model is shown in Figure 5, and the method flow is as follows:
  • Guinea pigs were divided into groups, 3 in each group;
  • FIG. 5 is a schematic diagram of the experimental design.
  • the gray area is the position of the bulge after sample injection, with a diameter of about 2 cm and a width of the outer ring of about 1 cm. Indicates the acupuncture position, the selected position is randomly distributed.
  • the evaluation index of this animal experiment comes from the avoidance and screaming responses of the guinea pigs in the pen after being prodded by acupuncture recorded in the experiment. According to the degree of pain response of avoidance and screaming, pain index of 10% for avoidance and 90% for screaming were given respectively.
  • the formula for calculating pain index is:
  • Pain index screaming times/effective acupuncture times*90%+dodging times/effective acupuncture times*10%.
  • Negative response (negative response) 100%-pain index, to represent the effectiveness of the sample.
  • the analgesic effect of each prescription within 24h and 72h is shown in Figure 6 and Figure 7, respectively.
  • the results show that the PLGA model of 5050 23000 has better analgesic effect than the other three prescriptions, and the duration of drug effect is as long as 72h .
  • the prescription is 7525 52000, the drug is released slowly, the analgesic effect on guinea pigs is poor, and the drug release cycle is longer.
  • the oil phase and the water phase were respectively injected into an online shearing machine (4000 rpm) with a peristaltic pump to obtain a uniform emulsion.
  • the emulsion was rapidly cured by rotary evaporation, vacuum evaporation and positive pressure blowing to obtain the suspension of PLGA microspheres. in:
  • the temperature of the rotary evaporation is set at 25°C. After the emulsion is diluted, take 500ml and put it into a flask for rotary evaporation. The rotation speed is 60rpm, and the curing time is 3h;
  • the emulsion is flattened into a uniform film/liquid film, and provided
  • the pressure is 0.1Mpa, preheated to 30°C and the positive pressure gas that removes water purges the top of the liquid film to perform rapid exchange of matter and energy between the gas and the liquid.
  • the gas is compressed air, the curing temperature is 20°C, and the jacket of the curing tank is set. The temperature is 20°C, and the curing time is 3 hours.
  • microsphere suspension was centrifuged and washed 4 times (centrifugal speed: 8000 rpm), a clean and concentrated microsphere suspension was obtained.
  • microsphere suspension is freeze-dried to obtain a microsphere powder, and the powder is sieved and filled to obtain a sample of the microparticle preparation.
  • the percentages of bupivacaine base actually loaded in the microparticle preparations measured by high performance liquid chromatography (HPLC) are shown in Table 3-1 and Table 3-2 respectively.
  • the drug loading and embedding rate of the microparticle preparation obtained by this method are higher; the drug dissolution results (as shown in Figure 8) also show that the burst release rate of the microparticle preparation obtained by positive pressure blowing is lower, and the drug release within 96h is more stable.
  • the oil phase and the water phase were respectively injected into an online shearing machine (4000 rpm) with a peristaltic pump to obtain a uniform emulsion.
  • the emulsion was rapidly cured (the curing temperature was 20° C., the jacket temperature of the curing tank was set at 20° C., and the curing time was 3 h) to obtain a suspension of PLGA microspheres.
  • the emulsion curing adopts the method of positive pressure blowing for rapid curing.
  • the pressure provided is 0.1Mpa is preheated to 30°C and the positive pressure gas that removes water purges the top of the liquid film to perform rapid exchange of matter and energy between the gas and the liquid.
  • the gas is compressed air.
  • microsphere suspension was centrifuged and washed 4 times (centrifugal speed: 8000 rpm), a clean and concentrated microsphere suspension was obtained.
  • microsphere suspension is freeze-dried to obtain a microsphere powder, and the powder is sieved and filled to obtain a sample of the microparticle preparation.
  • the oil phase and the water phase were respectively injected into an online shearing machine (5000 rpm) with a peristaltic pump to obtain a uniform emulsion.
  • the emulsion curing adopts the method of positive pressure blowing for rapid curing.
  • the pressure provided is 0.1Mpa is preheated to 30°C and the positive pressure gas that removes water purges the top of the liquid film to perform rapid exchange of matter and energy between the gas and the liquid.
  • the gas is compressed air.
  • the curing temperature is 20°C
  • the jacket temperature of the curing tank is set at 20°C
  • the curing time is 3 hours.
  • microsphere suspension was centrifuged and washed 4 times (the centrifugal speed was 8000 rpm), a clean and concentrated microsphere suspension was obtained.
  • microsphere suspension is freeze-dried to obtain a microsphere powder, and the powder is sieved and filled to obtain a sample of the microparticle preparation.
  • the drug loading of microparticle preparations measured by high performance liquid chromatography is shown in Table 5 below.
  • Table 5 The higher the theoretical drug loading under the same oil phase concentration, the higher the content of bupivacaine base in the prepared microparticle preparations. also gradually increased, but the embedding rate gradually decreased.
  • the morphologies of the three groups of samples observed under a scanning electron microscope are shown in Figure 9. As the drug loading increases, the surface of the particles becomes rougher. The in vitro dissolution results showed that the higher the drug loading and the rougher the surface, the higher the burst release rate of the microparticle preparation at 0.5 h, the higher the cumulative release within 7 days, and the shorter the release cycle.
  • the oil phase and the water phase are respectively injected into the online shearing machine with a peristaltic pump, and the shearing speed is set according to the following table 6-1 to obtain emulsions with uniform particle sizes.
  • the emulsion curing adopts the same positive pressure blowing method for rapid curing.
  • the emulsion is flattened into a uniform film/liquid film, and the pressure is provided.
  • the positive pressure gas preheated to 0.1Mpa to 40°C and removes water is used to purge the top of the liquid film to perform rapid exchange of matter and energy between the gas and liquid, and the gas is compressed air.
  • the curing temperature is 20°C
  • the jacket temperature of the curing tank is set at 20°C
  • the curing time is 4 hours.
  • microsphere suspension was centrifuged and washed 4 times (the centrifugal speed was 8000 rpm), a clean and concentrated microsphere suspension was obtained.
  • microsphere suspension is freeze-dried to obtain a microsphere powder, and the powder is sieved and filled to obtain a sample of the microparticle preparation.
  • the particle size distribution data measured by the Malvern particle size analyzer and the drug loading capacity of the microparticle preparations measured by high performance liquid chromatography (HPLC) are shown in Table 6-1 and Table 6-2 respectively: Under the same preparation conditions, the shear The higher the rotation speed, the smaller the particle size of the prepared microparticle preparation, and the drug loading and embedding rate will be reduced to a certain extent.
  • the results of the drug release curve are shown in Figure 10. Faster rotational speed during shearing will lead to more microspheres with small particle size, increased burst release rate at 0.5 h, and shortened drug release period.
  • the particle size distribution span is a parameter of the particle size distribution and a measure of the width of the particle size distribution of the sample. It is defined as follows:
  • D 10 The particle size corresponding to when the cumulative particle size distribution number of a sample reaches 10%. Its physical meaning is that particles with a particle size smaller than it account for 10%. D 10 is often used to indicate the particle size index of the fine end of the particle.
  • D 50 Indicates the particle size of microspheres in which the cumulative distribution of particles is 50% in the particle size distribution of the entire sample, that is, the volume content of particles smaller than this particle size accounts for 50% of all particles. D 50 is also often used to represent the average particle size of a sample. D 50 is often used to represent the average particle size of particles.
  • D 90 The particle size corresponding to when the cumulative particle size distribution number of a sample reaches 90%. Its physical meaning is that particles with a particle size smaller than it account for 90%. D 90 is often used to indicate the particle size index of the butt end of particles.
  • the oil phase and the water phase were respectively injected into an online shearing machine (4000 rpm) with a peristaltic pump to obtain a uniform emulsion.
  • the emulsion curing adopts the method of positive pressure blowing for rapid curing.
  • the emulsion is flattened into a uniform film/liquid film, and the pressure is 0.2 Mpa is preheated to 50°C and the positive pressure gas that removes water purges the top of the liquid film to perform rapid exchange of matter and energy between the gas and the liquid.
  • the gas is compressed air.
  • the curing temperature is 20°C
  • the jacket temperature of the curing tank is set at 20°C
  • the curing time is 4 hours.
  • microsphere suspension was centrifuged and washed 4 times (the centrifugal speed was 8000 rpm), a clean and concentrated microsphere suspension was obtained.
  • the microsphere suspension was divided into two parts on average, one part was added with 5ml of purified water, and the other part was added with 5ml of mannitol aqueous solution containing 250mg of mannitol.
  • the microsphere powder was obtained by freeze-drying.
  • the samples after freeze-drying were shown in Fig. As shown in 12, after freeze-drying without adding mannitol, the upper layer of the sample is relatively loose and a small amount of sample floats out, while the lower layer of the sample is denser; after adding mannitol, the samples are evenly distributed in the plate, and the sample is as a whole lumpy, with a smooth surface and no Sample overflow.
  • the oil phase and the water phase were respectively injected into an online shearing machine (4000 rpm) with a peristaltic pump to obtain a uniform emulsion, and the emulsion was added to the remaining water phase for dilution.
  • the diluted emulsion is quickly solidified by blowing air under positive pressure, using the curing equipment in the authorized ZL202020705393.7 patent (as shown in Figure 2), and after the emulsion is spread into a uniform film/liquid film, provide
  • the pressure is 0.6Mpa, preheated to 70°C and the positive pressure gas that removes water is used to purge the top of the liquid film to perform rapid exchange of matter and energy between the gas and liquid.
  • the gas is filtered compressed air.
  • the curing temperature is 15°C
  • the jacket temperature of the curing tank is set at 15°C
  • the curing time is 4 hours.
  • microsphere suspension is centrifuged and filtered to obtain a clean and concentrated microsphere suspension.
  • microsphere suspension is freeze-dried to obtain a microsphere powder, and the powder is sieved and filled to obtain a sample of the microparticle preparation.
  • the crystal form results of bupivacaine base and microparticle preparation samples detected by X-ray diffractometer are shown in Figure 14 and Figure 15 respectively.
  • the range of its melting point is 84-102°C;
  • the crystalline form of bupivacaine base is type I, which is a thermodynamically stable crystalline powder, and its melting point range is 105-110°C.
  • the oil phase and the water phase were respectively injected into an online shearing machine (4000 rpm) with a peristaltic pump to obtain a uniform emulsion, and the emulsion was added to the remaining water phase for dilution.
  • the diluted emulsion is quickly solidified by blowing air under positive pressure, using the curing equipment in the authorized ZL202020705393.7 patent (as shown in Figure 2), and after the emulsion is spread into a uniform film/liquid film, provide
  • the pressure is 0.6Mpa, preheated to 40°C and the positive pressure gas that removes water is used to purge the top of the liquid film to perform rapid exchange of matter and energy between the gas and liquid.
  • the gas is filtered compressed air.
  • the curing temperature is 15°C
  • the jacket temperature of the curing tank is set at 15°C
  • the curing time is 5 hours.
  • microsphere suspension is centrifuged and filtered to obtain a clean and concentrated microsphere suspension.
  • microsphere suspension is freeze-dried to obtain a microsphere powder, and the powder is sieved and filled to obtain a sample of the microparticle preparation.
  • the crystal form results of bupivacaine base and microparticle preparation samples detected by X-ray diffractometer are shown in Figure 14 and Figure 16 respectively.
  • Its melting point range is wide, being 84-99 ° C, 100-110 ° C, and it is a mixture of metastable state and type I crystal form; the crystal form of bupivacaine base is type I, which is a thermodynamically stable crystalline powder.
  • the melting point range is 105-110°C.
  • Example 7 The dissolution curves of Examples 7 and 8 are shown in Figure 17: the burst release rate of Example 7 is low, only 6.7%, and the subsequent drug release is stable and can maintain the effective in vitro drug concentration for up to 96h; while the burst release rate of Example 8 High, being 32.6%, the post-dissolution rate is slow, and the overall drug release is gentle.
  • the oil phase and the water phase were respectively injected into an online shearing machine (4000 rpm) with a peristaltic pump to obtain a uniform emulsion, and the emulsion was added to the remaining water phase for dilution.
  • Divide the diluted emulsion into two parts (each 5L emulsion): one part is stirred and solidified at normal temperature and pressure, and a 20L transfer tank is selected, the curing temperature is set at 15°C, the stirring speed is 100rpm, and the curing time is 4h;
  • One part is quickly cured by means of positive pressure blowing, and the curing equipment in the authorized ZL202020705393.7 patent (as shown in Figure 2) is used to spread the emulsion into a uniform film/liquid film and provide a pressure of 0.1Mpa
  • the positive pressure gas preheated to 30°C and dehydrated sweeps the top of the liquid film to perform rapid exchange of matter and energy between the gas and the liquid.
  • the gas is filtered compressed air.
  • the curing temperature is 15°C
  • the jacket temperature of the curing tank is set at 15°C
  • the curing time is 4 hours. Samples were taken during the curing process to confirm whether the bupivacaine base was embedded in the microspheres.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Anesthesiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pain & Pain Management (AREA)
  • Inorganic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Dispersion Chemistry (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une suspension de microsphères, une formulation de microparticules et un procédé de préparation de celles-ci. La formulation de microparticules comprend un ingrédient pharmaceutique actif et un PLGA. Le rapport molaire du lactide LA au glycolide GA dans le PLGA est de (1-5,67) : 1, et la masse moléculaire relative moyenne en poids du PLGA est de 2 000 - 60 000. Dans la formulation de microparticules, la teneur en principe pharmaceutique actif est de 35 - 80 %, et le pourcentage se réfère au pourcentage en masse dans la formulation de microparticules. La formulation de microparticules a des effets de libération lente et de libération contrôlée, peut être utilisée pour l'administration et la libération lente de médicaments à petites molécules, présente les caractéristiques d'une capacité élevée de charge médicamenteuse, de taux d'incorporation élevé, de faible taux de libération en rafales, de stabilité de libération de médicament in vivo et ne présente pas de phase de latence dans une période de libération du médicament, et peut réduire la fréquence d'administration du médicament à un patient, prolonger le temps d'action du médicament et améliorer l'observance du patient. De plus, le procédé de préparation de microparticules est simple et facile à produire.
PCT/CN2022/112280 2021-08-13 2022-08-12 Suspension de microsphères, formulation de microparticules et procédé de préparation de celles-ci WO2023016565A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202280053353.0A CN117858698A (zh) 2021-08-13 2022-08-12 一种微球悬液、微粒制剂及其制备方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202110932149 2021-08-13
CN202110932149.3 2021-08-13

Publications (1)

Publication Number Publication Date
WO2023016565A1 true WO2023016565A1 (fr) 2023-02-16

Family

ID=85199868

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/112280 WO2023016565A1 (fr) 2021-08-13 2022-08-12 Suspension de microsphères, formulation de microparticules et procédé de préparation de celles-ci

Country Status (3)

Country Link
CN (1) CN117858698A (fr)
TW (1) TW202308595A (fr)
WO (1) WO2023016565A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6217911B1 (en) * 1995-05-22 2001-04-17 The United States Of America As Represented By The Secretary Of The Army sustained release non-steroidal, anti-inflammatory and lidocaine PLGA microspheres
CN101296685A (zh) * 2005-08-31 2008-10-29 阿斯利康(瑞典)有限公司 制剂
CN101346130A (zh) * 2005-12-22 2009-01-14 诺瓦提斯公司 包含奥曲肽和两种或更多种聚丙交酯-共-乙交酯聚合物的缓释制剂
CN104127367A (zh) * 2008-01-30 2014-11-05 诺华股份有限公司 包含奥曲肽和三种线形聚丙交酯-共-乙交酯聚合物的缓释制剂
CN106344521A (zh) * 2016-09-30 2017-01-25 沈阳药科大学 一种高载药量可生物降解布比卡因微球的制备及其应用
US20190209538A1 (en) * 2016-05-05 2019-07-11 Liquidia Technologies, Inc. Precision Controlled Load and Release Particles for Post-Operative Pain

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6217911B1 (en) * 1995-05-22 2001-04-17 The United States Of America As Represented By The Secretary Of The Army sustained release non-steroidal, anti-inflammatory and lidocaine PLGA microspheres
CN101296685A (zh) * 2005-08-31 2008-10-29 阿斯利康(瑞典)有限公司 制剂
CN101346130A (zh) * 2005-12-22 2009-01-14 诺瓦提斯公司 包含奥曲肽和两种或更多种聚丙交酯-共-乙交酯聚合物的缓释制剂
CN104127367A (zh) * 2008-01-30 2014-11-05 诺华股份有限公司 包含奥曲肽和三种线形聚丙交酯-共-乙交酯聚合物的缓释制剂
US20190209538A1 (en) * 2016-05-05 2019-07-11 Liquidia Technologies, Inc. Precision Controlled Load and Release Particles for Post-Operative Pain
CN106344521A (zh) * 2016-09-30 2017-01-25 沈阳药科大学 一种高载药量可生物降解布比卡因微球的制备及其应用

Also Published As

Publication number Publication date
TW202308595A (zh) 2023-03-01
CN117858698A (zh) 2024-04-09

Similar Documents

Publication Publication Date Title
JP6318271B2 (ja) 初期過多放出が減少された高分子微小粒子の製造方法及びその方法により製造された高分子微小粒子
Giri et al. Prospects of pharmaceuticals and biopharmaceuticals loaded microparticles prepared by double emulsion technique for controlled delivery
KR102507678B1 (ko) 아리피프라졸 서방형 미소구체 및 이의 제조 방법
US10624854B2 (en) Method for preparing degradable drug-loaded microsphere for embolization, and product obtained therefrom
WO2017133419A1 (fr) Microsphère chargée en médicament, et procédé de préparation et utilisation de cette dernière
Liu et al. A high bioavailability and sustained-release nano-delivery system for nintedanib based on electrospray technology
CN107049985B (zh) 一种抗帕金森病药物的长效缓释制剂及其制备方法
CN111329845A (zh) 一种提高纳曲酮微球包封率的制备工艺
CN108295045B (zh) 一种液晶凝胶微囊及其制备方法
CN106474070B (zh) 一种克服停滞期、恒速释放疏水性药物的微球及制备方法
CN102100663B (zh) 一种pH敏感型原位凝胶纳米缓释眼药水的制备方法
Martinez-Sancho et al. Poly (D, L-lactide-co-glycolide) microspheres for long-term intravitreal delivery of aciclovir: influence of fatty and non-fatty additives
CN114748428B (zh) 一种高载药量的盐酸卡利拉嗪长效缓释微球及其制备方法
WO2023016565A1 (fr) Suspension de microsphères, formulation de microparticules et procédé de préparation de celles-ci
Tian et al. Tamibarotene-loaded PLGA microspheres for intratumoral injection administration: preparation and evaluation
CN103893129A (zh) 帕潘立酮缓释微球及其注射剂和该缓释微球的制备方法
EP2421517A2 (fr) Dispositif d'administration à libération contrôlée
CN112121028B (zh) 一种辛伐他汀固体纳米粒制剂及其制备方法
CN113546060A (zh) 一种纳曲酮微球
RU2800062C2 (ru) Микросфера с пролонгированным высвобождением арипипразола и способ ее получения
CN1969825A (zh) 一种氟尿嘧啶及其增效剂的缓释剂
Shete Microspheres as a Unique Drug Carrier for Controlled Drug Delivery: A Review
US11834428B2 (en) Dihydromyricetin nanocrystals and preparation method and application thereof
CN1204922C (zh) 新的眼科用组合物
CN105616359A (zh) 一种多嵌段聚合物纳米纤维载药微球及其制备方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22855545

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 202280053353.0

Country of ref document: CN

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22855545

Country of ref document: EP

Kind code of ref document: A1