CN113116830B - Preparation of sustained release particles - Google Patents

Preparation of sustained release particles Download PDF

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CN113116830B
CN113116830B CN201911422073.9A CN201911422073A CN113116830B CN 113116830 B CN113116830 B CN 113116830B CN 201911422073 A CN201911422073 A CN 201911422073A CN 113116830 B CN113116830 B CN 113116830B
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mixture
certain embodiments
active pharmaceutical
pharmaceutical ingredient
present disclosure
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CN113116830A (en
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刘荣
王代丰
严米娜
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Guangzhou Bositao Controlled Release Pharmaceutical Co ltd
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Guangzhou Bosia Biomedical Technology Co ltd
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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
    • 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)

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  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)

Abstract

Disclosed is a method of preparing a sustained release granule comprising: a) Mixing an active pharmaceutical ingredient (active pharmaceutical ingredient) with a biodegradable polymer, thereby obtaining a first mixture; b) Mixing the first mixture with a first solvent, thereby obtaining a second mixture, wherein the first solvent is capable of dissolving the water-ethanol mixture and of dissolving the biodegradable polymer; c) Extruding the second mixture to obtain a first extrudate; and d) dividing the first extrudate to obtain the slow release particles.

Description

Preparation of sustained release particles
FIELD
The present disclosure relates generally to the field of medicine. More specifically, the present disclosure relates to the field of slow release particles.
Background
The general procedure for preparing sustained release particles by hot melt extrusion is as follows: mixing the drug with the biodegradable polymer, adding the mixture into a hot melt extruder for high-temperature melt extrusion, and crushing and sieving the extrudate to obtain the drug-loaded slow-release particles.
SUMMARY
In one aspect, the present disclosure relates to a method of preparing a slow release granule comprising: a) Mixing an active pharmaceutical ingredient (active pharmaceutical ingredient) with a biodegradable polymer, thereby obtaining a first mixture; b) Mixing the first mixture with a first solvent, thereby obtaining a second mixture, wherein the first solvent is capable of dissolving the water-ethanol mixture and of dissolving the biodegradable polymer; c) Extruding the second mixture to obtain a first extrudate; and d) dividing the first extrudate to obtain the slow release particles.
In another aspect, the present disclosure is directed to a method of preparing a slow release particle comprising: a) Mixing an active pharmaceutical ingredient (active pharmaceutical ingredient) with a biodegradable polymer, thereby obtaining a first mixture; b) Extruding the first mixture to obtain a first extrudate; c) Dividing the first extrudate to obtain a first divided object; and d) subjecting the first partition to high temperature treatment, thereby obtaining the slow release particles.
In yet another aspect, the present disclosure is directed to a method of preparing a slow release granule comprising: a) Mixing an active pharmaceutical ingredient (active pharmaceutical ingredient) with a biodegradable polymer, thereby obtaining a first mixture; b) Mixing the first mixture with a first solvent, thereby obtaining a second mixture, wherein the first solvent is capable of dissolving the water-ethanol mixture and of dissolving the biodegradable polymer; c) Extruding the second mixture to obtain a first extrudate; d) Dividing the first extrudate to obtain a first divided object; and e) subjecting the first partition to a high temperature treatment, thereby obtaining the slow release particles.
In yet another aspect, the present disclosure relates to a sustained release particle prepared by a process comprising the steps of: a) Mixing an active pharmaceutical ingredient (active pharmaceutical ingredient) with a biodegradable polymer, thereby obtaining a first mixture; b) Mixing the first mixture with a first solvent, thereby obtaining a second mixture, wherein the first solvent is capable of dissolving the water-ethanol mixture and of dissolving the biodegradable polymer; c) Extruding the second mixture to obtain a first extrudate; and d) dividing the first extrudate to obtain the slow release particles.
In another aspect, the present disclosure relates to slow release particles prepared by a process comprising the steps of: a) Mixing an active pharmaceutical ingredient (active pharmaceutical ingredient) with a biodegradable polymer, thereby obtaining a first mixture; b) Extruding the first mixture to obtain a first extrudate; c) Dividing the first extrudate to obtain a first divided object; and d) subjecting the first partition to high temperature treatment, thereby obtaining the slow release particles.
In yet another aspect, the present disclosure relates to a sustained release particle prepared by a process comprising the steps of: a) Mixing an active pharmaceutical ingredient (active pharmaceutical ingredient) with a biodegradable polymer, thereby obtaining a first mixture; b) Mixing the first mixture with a first solvent, thereby obtaining a second mixture, wherein the first solvent is capable of dissolving the water-ethanol mixture and of dissolving the biodegradable polymer; c) Extruding the second mixture to obtain a first extrudate; d) Dividing the first extrudate to obtain a first divided object; and e) subjecting the first partition to a high temperature treatment, thereby obtaining the slow release particles.
In yet another aspect, the present disclosure relates to a method of improving the release of an active pharmaceutical ingredient (active pharmaceutical ingredient) in an individual comprising administering to an individual in need thereof a slow release granule prepared by a process comprising the steps of: a) Mixing an active pharmaceutical ingredient (active pharmaceutical ingredient) with a biodegradable polymer, thereby obtaining a first mixture; b) Mixing the first mixture with a first solvent, thereby obtaining a second mixture, wherein the first solvent is capable of dissolving the water-ethanol mixture and of dissolving the biodegradable polymer; c) Extruding the second mixture to obtain a first extrudate; and d) dividing the first extrudate to obtain the slow release particles.
In another aspect, the present disclosure relates to a method of improving the release of an active pharmaceutical ingredient (active pharmaceutical ingredient) in a subject, comprising administering to a subject in need thereof a slow-release granule prepared by a process comprising the steps of: a) Mixing an active pharmaceutical ingredient (active pharmaceutical ingredient) with a biodegradable polymer, thereby obtaining a first mixture; b) Extruding the first mixture to obtain a first extrudate; c) Dividing the first extrudate to obtain a first divided object; and d) subjecting the first partition to high temperature treatment, thereby obtaining the slow release particles.
In yet another aspect, the present disclosure relates to a method of improving the release of an active pharmaceutical ingredient (active pharmaceutical ingredient) in an individual comprising administering to an individual in need thereof a slow release granule prepared by a process comprising the steps of: a) Mixing an active pharmaceutical ingredient (active pharmaceutical ingredient) with a biodegradable polymer, thereby obtaining a first mixture; b) Mixing the first mixture with a first solvent, thereby obtaining a second mixture, wherein the first solvent is capable of dissolving the water-ethanol mixture and of dissolving the biodegradable polymer; c) Extruding the second mixture to obtain a first extrudate; d) Dividing the first extrudate to obtain a first divided object; and e) subjecting the first partition to a high temperature treatment, thereby obtaining the slow release particles.
Brief description of the drawings
Fig. 1 shows the cumulative release profile of the drug (triamcinolone acetonide) of experiment 1 (number 1) in example 3 of the present disclosure with and without high temperature treatment of the slow release particles.
Fig. 2 shows the cumulative release profile of the high temperature treated and non-high temperature treated slow release particles of drug (huperzine a) of experiment 2 (number 2) in example 3 of the present disclosure.
Fig. 3 shows the cumulative release profile of the drug (triamcinolone acetonide) of experiment 3 (number 3) in example 3 of the present disclosure with and without high temperature treatment of the slow release particles.
Fig. 4 shows the cumulative release profile of the drug (triamcinolone acetonide) of experiment 4 (number 4) in example 3 of the present disclosure with and without high temperature treatment of the slow release particles.
Fig. 5 shows the cumulative release profile of the drug (minocycline) of experiment 5 (number 5) in example 3 of the present disclosure with and without high temperature treatment of the slow release particles.
Fig. 6 shows the cumulative release profile of the drug (naltrexone) of experiment 6 (number 6) in example 3 of the present disclosure with and without high temperature treatment of the slow release particles.
Fig. 7 shows the cumulative release profile of the drug (risperidone) of experiment 1 (No. 1) in example 4 of the present disclosure with and without high temperature treatment of the slow release particles.
Fig. 8 shows the cumulative release profile of the drug (risperidone) of experiment 2 (number 2) in example 4 of the present disclosure with and without high temperature treatment of the slow release particles.
Fig. 9 shows the cumulative release profile of the drug (risperidone) of experiment 3 (number 3) in example 4 of the present disclosure with and without high temperature treatment of the slow release particles.
Fig. 10 shows the cumulative release profile of the drug (risperidone) of experiment 4 (No. 4) in example 4 of the present disclosure with and without high temperature treatment of the slow release particles.
Fig. 11 shows the cumulative release profile of the drug (risperidone) of experiment 5 (No. 5) in example 4 of the present disclosure with and without high temperature treatment of the slow release particles.
Fig. 12 shows the cumulative release profile of the drug (risperidone) of experiment 6 (No. 6) in example 4 of the present disclosure with and without high temperature treatment of the slow release particles.
Fig. 13 shows the cumulative release profile of the drug (risperidone) of experiment 7 (No. 7) in example 4 of the present disclosure with and without high temperature treatment of the slow release particles.
Detailed description of the preferred embodiments
In the following description, certain specific details are included to provide a thorough understanding of various disclosed embodiments. One skilled in the relevant art will recognize, however, that the embodiments may be practiced without one or more of the specific details, or with other methods, components, materials, etc.
Throughout the specification and the claims which follow, unless the context requires otherwise, the words "comprise", "comprising", "include" and "have" are to be construed in an open-ended, inclusive sense, i.e. "including but not limited to.
Reference throughout this specification to "one embodiment," "an embodiment," "in another embodiment," or "in some embodiments" means that a particular reference element, structure, or feature described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrase "in one embodiment" or "in an embodiment" or "in another embodiment" or "in certain embodiments" appearing in various places throughout the specification are not necessarily all referring to the same embodiment. Furthermore, the particular elements, structures, or features may be combined in any suitable manner in one or more embodiments.
Definition of the definition
In the present disclosure, the term "sustained release particles" is a microparticle dispersion system in which an active pharmaceutical ingredient is dispersed or adsorbed in a polymeric, polymeric matrix.
In the present disclosure, the term "active pharmaceutical ingredient (active pharmaceutical ingredient)" refers to a chemical entity that is effective in treating a target disorder, disease, or condition.
In the present disclosure, the term "biodegradable polymer" refers to a type of polymer material that can be degraded or enzymatically decomposed in an organism, and whose generated small molecular substances can be absorbed by the organism and discharged outside the body.
In the present disclosure, the term "polylactic-co-glycolic acid (PLGA)" refers to a copolymer formed by randomly polymerizing lactic acid and glycolic acid.
In the present disclosure, the term "polylactic-co-glycolic acid (PLGA)" refers to a copolymer formed by randomly polymerizing lactic acid and glycolic acid.
In the present disclosure, the term "polylactic acid" refers to a polymer polymerized from lactic acid as a main raw material.
In the present disclosure, the term "polycaprolactone" refers to polyepsilon caprolactone, which is a polymeric organic polymer formed by ring-opening polymerization of epsilon caprolactone monomers under the catalysis of a metal anion complex catalyst.
In the present disclosure, the term "heat-sensitive drug" refers to a pharmaceutically active ingredient having a decrease in the amount of the pharmaceutically active ingredient of more than 3% within 3 days when stored in a solid or solution state under a sealed condition at 60 ℃ in the absence of light.
Detailed Description
In one aspect, the present disclosure relates to a method of preparing a slow release granule comprising:
a) Mixing an active pharmaceutical ingredient (active pharmaceutical ingredient) with a biodegradable polymer, thereby obtaining a first mixture;
b) Mixing the first mixture with a first solvent, thereby obtaining a second mixture, wherein the first solvent is capable of dissolving the water-ethanol mixture and of dissolving the biodegradable polymer;
c) Extruding the second mixture to obtain a first extrudate; and
D) The first extrusion is divided, thereby obtaining the slow release particles.
In certain embodiments, the active pharmaceutical ingredient and the biodegradable polymer are separately milled and then mixed to provide a first mixture.
In certain embodiments, the active pharmaceutical ingredient is mixed with the biodegradable polymer and then ground to provide a first mixture.
In certain embodiments, the mass ratio of active pharmaceutical ingredient to biodegradable polymer is about 1:99 to about 10:90.
In certain embodiments, the mass ratio of active pharmaceutical ingredient to biodegradable polymer is about 5:95 to about 10:90.
In some embodiments of the present invention, in some embodiments, illustrative examples of pharmaceutically active ingredients that can be used in the methods of preparing the sustained release particles of the present disclosure include, but are not limited to, yu Teli Paraguesin, somatotropin, leuprorelin, goserelin, triptorelin, octreotide, lanreotide, pasireotide, cetirizine, ganirelix, oxytocin, vasopressin, corticotropin, epidermal growth factor, prolactin, luteinizing hormone, gonadotropin-releasing hormone, luteinizing hormone gonadotropin-releasing hormone agonist, gonadotropin-releasing hormone antagonist, auxin, ghrelin, insulin, erythropoietin, somatostatin, glucagon, interleukin, interferon-alpha, interferon-beta, interferon-gamma, gastrin, tetrapeptide gastrin, pentagastrin, urostatin, glucagon, calcitonin, enkephalin, endorphin, angiotensin, glucagon, peptide-binding agent, and peptide-binding agent thyrotropin releasing hormone, tumor necrosis factor, parathyroid hormone, nerve growth factor, granulocyte colony stimulating factor, granulocyte macrophage colony stimulating factor, heparinase, vascular endothelial growth factor, bone morphogenic protein, glucagon-like peptide, exenatide, liraglutide, cable Ma Lutai, dolraglutide, ghrelin, renin, bradykinin, bacitracin, polymyxin, gracilin, cyclosporin, follicle stimulating hormone, thymine, thymosin, serum thymus factor, motilin, neurotensin, urokinase, angiotensin II, melanogenesis hormone, thyroid hormone releasing hormone, parathyroid hormone, thyroid stimulating hormone, human chorionic gonadotropin, gastric inhibitory peptide, vasoactive intestinal peptide, hypothalamic release factor prolactin, bupivacaine, buprenorphine, paclitaxel, huperzine A, steroidal anti-inflammatory drugs, minocycline, doxycycline, meloxicam, carmustine, granisetron, naltrexone, risperidone and paliperidone.
In certain embodiments, illustrative examples of steroid anti-inflammatory drugs that can be used in the present disclosure include, but are not limited to, dexamethasone, triamcinolone acetonide, cortisone, fluocinolone acetonide, hydrocortisone, methylprednisone, prednisolone, prednisone, levonorgestrel, and triamcinolone.
In certain embodiments, illustrative examples of pharmaceutically active ingredients that can be used in the methods of preparing the sustained release particles of the present disclosure include, but are not limited to, heat sensitive drugs.
In some embodiments of the present invention, in some embodiments, illustrative examples of heat-sensitive drugs that can be used in the methods of preparing the sustained-release particles of the present disclosure include, but are not limited to, yu Teli Paraguesin, somatotropin, leuprorelin, goserelin, triptorelin, octreotide, lanreotide, pasireotide, cilexetil, ganirelix, oxytocin, vasopressin, corticotropin, epidermal growth factor, prolactin, luteinizing hormone, gonadotropin-releasing hormone, luteinizing hormone gonadotropin-releasing hormone agonist, gonadotropin-releasing hormone antagonist, auxin, ghrelin, insulin, erythropoietin, somatostatin, glucagon, interleukin, interferon-alpha, interferon-beta, interferon-gamma, gastrin, tetrapeptide gastrin, pentagastrin, urostatin, glucagon, calcitonin, enkephalin, endorphin, angiotensin, glucagon, peptide-binding agent, and peptide-binding agent thyrotropin releasing hormone, tumor necrosis factor, parathyroid hormone, nerve growth factor, granulocyte colony stimulating factor, granulocyte macrophage colony stimulating factor, heparinase, vascular endothelial growth factor, bone morphogenic protein, glucagon-like peptide, exenatide, liraglutide, cable Ma Lutai, dolraglutide, ghrelin, renin, bradykinin, bacitracin, polymyxin, gracilin, cyclosporin, follicle stimulating hormone, thymine, thymosin, serum thymus factor, motilin, neurotensin, urokinase, angiotensin II, melanogenesis hormone, thyroid hormone releasing hormone, parathyroid hormone, thyroid stimulating hormone, human chorionic gonadotropin, gastric inhibitory peptide, vasoactive intestinal peptide and hypothalamic release factor prolactin.
In certain embodiments, illustrative examples of biodegradable polymers that can be used in the methods of making the sustained release particles of the present disclosure include, but are not limited to, polyglycolic acid, polylactic-co-glycolic acid (PLGA), polycaprolactone, polyorthocarbonate, polyacetal, poly (lactic-caprolactone), polyorthoester, poly (glycolic acid caprolactone), polyanhydrides, and hyaluronic acid.
In certain embodiments, the second mixture is obtained after spraying the first solvent onto the first mixture.
In certain embodiments, the first solvent is added dropwise to the first mixture to provide a second mixture.
In certain embodiments, the second mixture is obtained after the first solvent is added to the first mixture in other mixing manners.
In certain embodiments, after the first solvent is added to the first mixture, it may be formed into a uniform mixed system in a suitable manner, thereby obtaining a second mixture.
In certain embodiments, the second mixture is fed into an extrusion device and extruded to obtain a first extrudate.
In certain embodiments, illustrative examples of extrusion devices that can be used in the present disclosure include, but are not limited to, screw extrusion devices.
In certain embodiments, the first mixture is added to an extrusion device prior to the addition of the first solvent, and the first mixture is mixed with the first solvent to provide a second mixture, and the second mixture is extruded to provide a first extrudate.
In certain embodiments, the methods of the present disclosure further comprise immersing the first extrudate in a water-ethanol mixture.
In certain embodiments, the methods of the present disclosure further comprise immersing the first extrudate in a low temperature water-ethanol mixture.
In certain embodiments, the methods of the present disclosure further comprise immersing the first extrudate in a water-ethanol mixture having a temperature of about-100 to 0 ℃.
In certain embodiments, the methods of the present disclosure further comprise immersing the first extrudate in a water-ethanol mixture having a temperature of about-30 to-10 ℃.
In certain embodiments, the concentration of ethanol in the water-ethanol mixture is about 5 to 99% based on the mass of the water-ethanol mixture.
In certain embodiments, the concentration of ethanol in the water-ethanol mixture is about 25 to 60% based on the mass of the water-ethanol mixture.
In certain embodiments, the concentration of the first solvent is about 1 to 50% by mass based on the mass of the first mixture.
In certain embodiments, the concentration of the first solvent is about 1 to 20% by mass based on the mass of the first mixture.
In certain embodiments, the concentration of the first solvent is about 8 to 12% by mass based on the mass of the first mixture.
In certain embodiments, the extrusion is performed at an extrusion temperature of about-10 to 60 ℃.
In certain embodiments, the extrusion is performed at an extrusion temperature of about 0 to 50 ℃.
In certain embodiments, the extrusion is performed at an extrusion temperature of about 20 to 40 DEG C
In certain embodiments, illustrative examples of means for dividing the first extrudate that can be used in the present application include, but are not limited to, a pelletizer (chopper) of a hot melt extrusion apparatus, a hammer mill, a universal mill, a jet mill, a ball mill, a cone mill, and a cutter.
In certain embodiments, the first extrudate is cut.
In certain embodiments, the first extrudate is sheared.
In certain embodiments, the first extrudate is partitioned using an external force.
In another aspect, the present disclosure is directed to a method of preparing a slow release particle comprising:
a) Mixing an active pharmaceutical ingredient (active pharmaceutical ingredient) with a biodegradable polymer, thereby obtaining a first mixture;
b) Extruding the first mixture to obtain a first extrudate;
c) Dividing the first extrudate to obtain a first divided object; and
D) And carrying out high-temperature treatment on the first partition, thereby obtaining the slow-release particles.
In certain embodiments, the active pharmaceutical ingredient and the biodegradable polymer are separately milled and then mixed to provide a first mixture.
In certain embodiments, the active pharmaceutical ingredient is mixed with the biodegradable polymer and then ground to provide a first mixture.
In certain embodiments, the mass ratio of active pharmaceutical ingredient to biodegradable polymer is about 1:99 to about 10:90.
In certain embodiments, the mass ratio of active pharmaceutical ingredient to biodegradable polymer is about 5:95 to about 10:90.
In some embodiments of the present invention, in some embodiments, illustrative examples of pharmaceutically active ingredients that can be used in the methods of preparing the sustained release particles of the present disclosure include, but are not limited to, yu Teli Paraguesin, somatotropin, leuprorelin, goserelin, triptorelin, octreotide, lanreotide, pasireotide, cetirizine, ganirelix, oxytocin, vasopressin, corticotropin, epidermal growth factor, prolactin, luteinizing hormone, gonadotropin-releasing hormone, luteinizing hormone gonadotropin-releasing hormone agonist, gonadotropin-releasing hormone antagonist, auxin, ghrelin, insulin, erythropoietin, somatostatin, glucagon, interleukin, interferon-alpha, interferon-beta, interferon-gamma, gastrin, tetrapeptide gastrin, pentagastrin, urostatin, glucagon, calcitonin, enkephalin, endorphin, angiotensin, glucagon, peptide-binding agent, and peptide-binding agent thyrotropin releasing hormone, tumor necrosis factor, parathyroid hormone, nerve growth factor, granulocyte colony stimulating factor, granulocyte macrophage colony stimulating factor, heparinase, vascular endothelial growth factor, bone morphogenic protein, glucagon-like peptide, exenatide, liraglutide, cable Ma Lutai, dolraglutide, ghrelin, renin, bradykinin, bacitracin, polymyxin, gracilin, cyclosporin, follicle stimulating hormone, thymine, thymosin, serum thymus factor, motilin, neurotensin, urokinase, angiotensin II, melanogenesis hormone, thyroid hormone releasing hormone, parathyroid hormone, thyroid stimulating hormone, human chorionic gonadotropin, gastric inhibitory peptide, vasoactive intestinal peptide, hypothalamic release factor prolactin, bupivacaine, buprenorphine, paclitaxel, huperzine A, steroidal anti-inflammatory drugs, minocycline, doxycycline, meloxicam, carmustine, granisetron, naltrexone, risperidone and paliperidone.
In certain embodiments, illustrative examples of steroid anti-inflammatory drugs that can be used in the present disclosure include, but are not limited to, dexamethasone, triamcinolone acetonide, cortisone, fluocinolone acetonide, hydrocortisone, methylprednisone, prednisolone, prednisone, levonorgestrel, and triamcinolone.
In certain embodiments, illustrative examples of pharmaceutically active ingredients that can be used in the methods of preparing the sustained release particles of the present disclosure include, but are not limited to, non-heat sensitive drugs.
In certain embodiments, illustrative examples of non-heat sensitive drugs that can be used in the methods of making the sustained release particles of the present disclosure include, but are not limited to, bupivacaine, buprenorphine, paclitaxel, huperzine a, steroid anti-inflammatory drugs, minocycline, doxycycline, meloxicam, carmustine, granisetron, naltrexone, risperidone, and paliperidone.
In certain embodiments, illustrative examples of steroid anti-inflammatory drugs that can be used in the present disclosure include, but are not limited to, dexamethasone, triamcinolone acetonide, cortisone, fluocinolone acetonide, hydrocortisone, methylprednisone, prednisolone, prednisone, levonorgestrel, and triamcinolone.
In certain embodiments, illustrative examples of biodegradable polymers that can be used in the methods of making the sustained release particles of the present disclosure include, but are not limited to, polyglycolic acid, polylactic-co-glycolic acid (PLGA), polycaprolactone, polyorthocarbonate, polyacetal, poly (lactic-caprolactone), polyorthoester, poly (glycolic acid caprolactone), polyanhydrides, and hyaluronic acid.
In certain embodiments, the extrusion is performed at an extrusion temperature of about 40 to 280 ℃.
In certain embodiments, the extrusion is performed at an extrusion temperature of about 60 to 250 ℃.
In certain embodiments, illustrative examples of means for dividing the first extrudate that can be used in the present application include, but are not limited to, a pelletizer (chopper) of a hot melt extrusion apparatus, a hammer mill, a universal mill, a jet mill, a ball mill, a cone mill, and a cutter.
In certain embodiments, the first extrudate is cut.
In certain embodiments, the first extrudate is sheared.
In certain embodiments, the first extrudate is partitioned using an external force.
In certain embodiments, the temperature of the high temperature treatment is about 50 to 80 ℃.
In certain embodiments, the temperature of the high temperature treatment is about 55 to 75 ℃.
In certain embodiments, the temperature of the high temperature treatment is about 60 to 70 ℃.
In certain embodiments, the time of the high temperature treatment is about 4 hours to 14 days.
In certain embodiments, the time of the high temperature treatment is about 4 days to about 8 days.
In certain embodiments, the excipient is added during the high temperature treatment.
In certain embodiments, illustrative examples of excipients that can be used in the present disclosure that are added during high temperature processing include, but are not limited to, polyols, sugars, amino acids, inorganic salts, proteins, peptides, and mixtures thereof.
In certain embodiments, illustrative examples of polyols that can be used in the present disclosure include, but are not limited to, glycerin, sorbitol, mannitol, inositol, adonitol, ethylene glycol, and polyethylene glycol.
In certain embodiments, illustrative examples of sugars that can be used in the present disclosure include, but are not limited to, dextran (dextran), 13-cyclodextrin, maltodextrin, trehalose, sucrose, lactose, maltose, and glucose.
In certain embodiments, illustrative examples of amino acids that can be used in the present disclosure include, but are not limited to, sodium glutamate, proline, lysine, and alanine.
In certain embodiments, illustrative examples of inorganic salts that can be used in the present disclosure include, but are not limited to, phosphates, calcium carbonate, manganese sulfate, and sodium acetate.
In certain embodiments, illustrative examples of proteins and peptides that can be used in the present disclosure include, but are not limited to, glycosaminoglycan proteins, casein, and bovine serum albumin.
In certain embodiments, the resulting sustained release particles are further subjected to a high temperature treatment to avoid drug burst phenomena.
In certain embodiments, further high temperature treatment of the resulting slow release particles can cause the slow release particles to melt and resolidify at their surface, thereby allowing the slow release particles to have a reduced comparative area.
In yet another aspect, the present disclosure is directed to a method of preparing a slow release granule comprising:
a) Mixing an active pharmaceutical ingredient (active pharmaceutical ingredient) with a biodegradable polymer, thereby obtaining a first mixture;
b) Mixing the first mixture with a first solvent, thereby obtaining a second mixture, wherein the first solvent is capable of dissolving the water-ethanol mixture and of dissolving the biodegradable polymer;
c) Extruding the second mixture to obtain a first extrudate;
d) Dividing the first extrudate to obtain a first divided object; and
E) And carrying out high-temperature treatment on the first partition, thereby obtaining the slow-release particles.
In certain embodiments, illustrative examples of first solvents that can be used in the present disclosure that are soluble in water-ethanol mixtures and that can dissolve the biodegradable polymer include, but are not limited to, ethyl acetate, acetone, and acetic acid.
In certain embodiments, the active pharmaceutical ingredient and the biodegradable polymer are separately milled and then mixed to provide a first mixture.
In certain embodiments, the active pharmaceutical ingredient is mixed with the biodegradable polymer and then ground to provide a first mixture.
In certain embodiments, the mass ratio of active pharmaceutical ingredient to biodegradable polymer is about 1:99 to about 10:90.
In certain embodiments, the mass ratio of active pharmaceutical ingredient to biodegradable polymer is about 5:95 to about 10:90.
In some embodiments of the present invention, in some embodiments, illustrative examples of pharmaceutically active ingredients that can be used in the methods of preparing the sustained release particles of the present disclosure include, but are not limited to, yu Teli Paraguesin, somatotropin, leuprorelin, goserelin, triptorelin, octreotide, lanreotide, pasireotide, cetirizine, ganirelix, oxytocin, vasopressin, corticotropin, epidermal growth factor, prolactin, luteinizing hormone, gonadotropin-releasing hormone, luteinizing hormone gonadotropin-releasing hormone agonist, gonadotropin-releasing hormone antagonist, auxin, ghrelin, insulin, erythropoietin, somatostatin, glucagon, interleukin, interferon-alpha, interferon-beta, interferon-gamma, gastrin, tetrapeptide gastrin, pentagastrin, urostatin, glucagon, calcitonin, enkephalin, endorphin, angiotensin, glucagon, peptide-binding agent, and peptide-binding agent thyrotropin releasing hormone, tumor necrosis factor, parathyroid hormone, nerve growth factor, granulocyte colony stimulating factor, granulocyte macrophage colony stimulating factor, heparinase, vascular endothelial growth factor, bone morphogenic protein, glucagon-like peptide, exenatide, liraglutide, cable Ma Lutai, dolraglutide, ghrelin, renin, bradykinin, bacitracin, polymyxin, gracilin, cyclosporin, follicle stimulating hormone, thymine, thymosin, serum thymus factor, motilin, neurotensin, urokinase, angiotensin II, melanogenesis hormone, thyroid hormone releasing hormone, parathyroid hormone, thyroid stimulating hormone, human chorionic gonadotropin, gastric inhibitory peptide, vasoactive intestinal peptide, hypothalamic release factor prolactin, bupivacaine, buprenorphine, paclitaxel, huperzine A, steroidal anti-inflammatory drugs, minocycline, doxycycline, meloxicam, carmustine, granisetron, naltrexone, risperidone and paliperidone.
In certain embodiments, illustrative examples of steroid anti-inflammatory drugs that can be used in the present disclosure include, but are not limited to, dexamethasone, triamcinolone acetonide, cortisone, fluocinolone acetonide, hydrocortisone, methylprednisone, prednisolone, prednisone, levonorgestrel, and triamcinolone.
In certain embodiments, illustrative examples of pharmaceutically active ingredients that can be used in the methods of preparing the sustained release particles of the present disclosure include, but are not limited to, non-heat sensitive drugs. In certain embodiments, illustrative examples of non-heat sensitive drugs that can be used in the methods of making the sustained release particles of the present disclosure include, but are not limited to, bupivacaine, buprenorphine, paclitaxel, huperzine a, steroid anti-inflammatory drugs, minocycline, doxycycline, meloxicam, carmustine, granisetron, naltrexone, risperidone, and paliperidone.
In certain embodiments, illustrative examples of steroid anti-inflammatory drugs that can be used in the present disclosure include, but are not limited to, dexamethasone, triamcinolone acetonide, cortisone, fluocinolone acetonide, hydrocortisone, methylprednisone, prednisolone, prednisone, levonorgestrel, and triamcinolone.
In certain embodiments, the second mixture is obtained after spraying the first solvent onto the first mixture.
In certain embodiments, the first solvent is added dropwise to the first mixture to provide a second mixture.
In certain embodiments, the second mixture is obtained after the first solvent is added to the first mixture in other mixing manners.
In certain embodiments, after the first solvent is added to the first mixture, it may be formed into a uniform mixed system in a suitable manner, thereby obtaining a second mixture.
In certain embodiments, the second mixture is fed into an extrusion device and extruded to obtain a first extrudate.
In certain embodiments, illustrative examples of extrusion devices that can be used in the present disclosure include, but are not limited to, screw extrusion devices.
In certain embodiments, the first mixture is added to an extrusion device prior to the addition of the first solvent, and the first mixture is mixed with the first solvent to provide a second mixture, and the second mixture is extruded to provide a first extrudate.
In certain embodiments, the methods of the present disclosure further comprise immersing the first extrudate in a water-ethanol mixture.
In certain embodiments, the methods of the present disclosure further comprise immersing the first extrudate in a low temperature water-ethanol mixture.
In certain embodiments, the methods of the present disclosure further comprise immersing the first extrudate in a water-ethanol mixture having a temperature of-100 to 0 ℃.
In certain embodiments, the methods of the present disclosure further comprise immersing the first extrudate in a water-ethanol mixture having a temperature of-30 to-10 ℃.
In certain embodiments, the concentration of ethanol in the water-ethanol mixture is from 5 to 99% based on the mass of the water-ethanol mixture.
In certain embodiments, the concentration of ethanol in the water-ethanol mixture is from 25 to 60% based on the mass of the water-ethanol mixture.
In certain embodiments, the concentration of the first solvent is about 1 to 50% by mass based on the mass of the first mixture.
In certain embodiments, the concentration of the first solvent is about 1 to 20% by mass based on the mass of the first mixture.
In certain embodiments, the concentration of the first solvent is about 8 to 12% by mass based on the mass of the first mixture.
In certain embodiments, the extrusion is performed at an extrusion temperature of about 40 to 280 ℃.
In certain embodiments, the extrusion is performed at an extrusion temperature of about 60 to 250 ℃.
In certain embodiments, illustrative examples of means for dividing the first extrudate that can be used in the present application include, but are not limited to, a pelletizer (chopper) of a hot melt extrusion apparatus, a hammer mill, a universal mill, a jet mill, a ball mill, a cone mill, and a cutter.
In certain embodiments, the first extrudate is cut.
In certain embodiments, the first extrudate is sheared.
In certain embodiments, the first extrudate is partitioned using an external force.
In certain embodiments, the temperature of the high temperature treatment is about 50 to 80 ℃.
In certain embodiments, the temperature of the high temperature treatment is about 55 to 75 ℃.
In certain embodiments, the temperature of the high temperature treatment is about 60 to 70 ℃.
In certain embodiments, the time of the high temperature treatment is about 4 hours to 14 days.
In certain embodiments, the time of the high temperature treatment is about 4 days to about 8 days.
In certain embodiments, the excipient is added during the high temperature treatment.
In certain embodiments, illustrative examples of excipients that can be used in the present disclosure that are added during high temperature processing include, but are not limited to, polyols, sugars, amino acids, inorganic salts, proteins, peptides, and mixtures thereof.
In certain embodiments, illustrative examples of polyols that can be used in the present disclosure include, but are not limited to, glycerin, sorbitol, mannitol, inositol, adonitol, ethylene glycol, and polyethylene glycol.
In certain embodiments, illustrative examples of sugars that can be used in the present disclosure include, but are not limited to, dextran (dextran), 13-cyclodextrin, maltodextrin, trehalose, sucrose, lactose, maltose, and glucose.
In certain embodiments, illustrative examples of amino acids that can be used in the present disclosure include, but are not limited to, sodium glutamate, proline, lysine, and alanine.
In certain embodiments, illustrative examples of inorganic salts that can be used in the present disclosure include, but are not limited to, phosphates, calcium carbonate, manganese sulfate, and sodium acetate.
In certain embodiments, illustrative examples of proteins and peptides that can be used in the present disclosure include, but are not limited to, glycosaminoglycan proteins, casein, and bovine serum albumin.
In certain embodiments, adding a first solvent capable of dissolving the water-ethanol mixture and capable of dissolving the biodegradable polymer to a first mixture comprising the active pharmaceutical ingredient and the biodegradable polymer can reduce the extrusion temperature, thereby enabling the methods of the present disclosure to be used in the preparation of biodegradable polymer sustained release particles of the active pharmaceutical ingredient that are temperature sensitive.
In certain embodiments, a solvent capable of dissolving the biodegradable polymer is selected because the extrusion temperature can be reduced so as to avoid the drug from being damaged by high temperatures during extrusion.
In certain embodiments, the resulting sustained release particles are further subjected to a high temperature treatment to avoid drug burst phenomena.
In certain embodiments, further high temperature treatment of the resulting slow release particles can cause the slow release particles to melt and resolidify at their surface, thereby allowing the slow release particles to have a reduced comparative area.
In the present disclosure, methanol and ethanol are particularly unsuitable for use in the preparation methods of the present disclosure. The reason is that methanol and ethanol are not good solvents for biodegradable polymers.
In yet another aspect, the present disclosure relates to a sustained release particle prepared by a process comprising the steps of:
a) Mixing an active pharmaceutical ingredient (active pharmaceutical ingredient) with a biodegradable polymer, thereby obtaining a first mixture;
b) Mixing the first mixture with a first solvent, thereby obtaining a second mixture, wherein the first solvent is capable of dissolving the water-ethanol mixture and of dissolving the biodegradable polymer;
c) Extruding the second mixture to obtain a first extrudate; and
D) The first extrudate is divided to obtain the slow release particles.
In certain embodiments, the active pharmaceutical ingredient (active pharmaceutical ingredient) in the sustained-release particles prepared by the methods of the present disclosure is free of burst release.
In another aspect, the present disclosure relates to slow release particles prepared by a process comprising the steps of:
a) Mixing an active pharmaceutical ingredient (active pharmaceutical ingredient) with a biodegradable polymer, thereby obtaining a first mixture;
b) Extruding the first mixture to obtain a first extrudate;
c) Dividing the first extrudate to obtain a first divided object; and
D) And carrying out high-temperature treatment on the first partition, thereby obtaining the slow-release particles.
In certain embodiments, the active pharmaceutical ingredient (active pharmaceutical ingredient) in the sustained-release particles prepared by the methods of the present disclosure is free of burst release.
In yet another aspect, the present disclosure relates to a sustained release particle prepared by a process comprising the steps of:
a) Mixing an active pharmaceutical ingredient (active pharmaceutical ingredient) with a biodegradable polymer, thereby obtaining a first mixture;
b) Mixing the first mixture with a first solvent, thereby obtaining a second mixture, wherein the first solvent is capable of dissolving the water-ethanol mixture and of dissolving the biodegradable polymer;
c) Extruding the second mixture to obtain a first extrudate; d) Dividing the first extrudate to obtain a first divided object; and
E) And carrying out high-temperature treatment on the first partition, thereby obtaining the slow-release particles.
In certain embodiments, the active pharmaceutical ingredient (active pharmaceutical ingredient) in the sustained-release particles prepared by the methods of the present disclosure is free of burst release.
In yet another aspect, the present disclosure relates to a method of improving the release of an active pharmaceutical ingredient (active pharmaceutical ingredient) in an individual comprising administering to an individual in need thereof a slow release granule prepared by a process comprising the steps of:
a) Mixing an active pharmaceutical ingredient (active pharmaceutical ingredient) with a biodegradable polymer, thereby obtaining a first mixture;
b) Mixing the first mixture with a first solvent, thereby obtaining a second mixture, wherein the first solvent is capable of dissolving the water-ethanol mixture and of dissolving the biodegradable polymer;
c) Extruding the second mixture to obtain a first extrudate;
d) The first extrudate is divided to obtain the slow release particles.
In another aspect, the present disclosure relates to a method of improving the release of an active pharmaceutical ingredient (active pharmaceutical ingredient) in a subject, comprising administering to a subject in need thereof a slow-release granule prepared by a process comprising the steps of:
a) Mixing an active pharmaceutical ingredient (active pharmaceutical ingredient) with a biodegradable polymer, thereby obtaining a first mixture;
b) Extruding the first mixture to obtain a first extrudate;
c) Dividing the first extrudate to obtain a first divided object; and
D) And carrying out high-temperature treatment on the first partition, thereby obtaining the slow-release particles.
In yet another aspect, the present disclosure relates to a method of improving the release of an active pharmaceutical ingredient (active pharmaceutical ingredient) in an individual comprising administering to an individual in need thereof a slow release granule prepared by a process comprising the steps of:
a) Mixing an active pharmaceutical ingredient (active pharmaceutical ingredient) with a biodegradable polymer, thereby obtaining a first mixture;
b) Mixing the first mixture with a first solvent, thereby obtaining a second mixture, wherein the first solvent is capable of dissolving the water-ethanol mixture and of dissolving the biodegradable polymer;
c) Extruding the second mixture to obtain a first extrudate;
d) Dividing the first extrudate to obtain a first divided object; and
E) And carrying out high-temperature treatment on the first partition, thereby obtaining the slow-release particles.
Hereinafter, the present disclosure will be explained in detail by the following examples in order to better understand the aspects of the present application and the advantages thereof. However, it should be understood that the following examples are non-limiting and are merely illustrative of certain embodiments of the present disclosure.
Examples
Reagents and equipment used in the examples of the present disclosure were all conventional and commercially available.
For example:
acetic acid (manufacturer/lot): tianjin Meta chemical reagent plant/20180802-2
Oscillating water bath (manufacturer/model): julabo/SW23
Example 1
Fully mixing the medicine and the biodegradable polymer in a certain mass ratio, spraying ethyl acetate, acetone or acetic acid into the mixture, then adding the mixture into a hot melt extruder, immersing the extrudate into a low-temperature water-ethanol mixed solution, crushing and sieving the mixture to obtain slow-release particles, and measuring and calculating the content change percentage of related substances in the raw medicine and the slow-release particles. The experimental conditions and the measurement results are shown in the following table 1.
TABLE 1
Example 2
The ethyl acetate content of the slow-release particles in experiment 4 (No. 4) of example 1 was measured. The slow release particles were added to 5mL of dimethyl sulfoxide, vortexed for 10min, sampled and subjected to GC determination, and the detection result was 0.12%.
Example 3
Mixing the medicine and the biodegradable polymer in a certain proportion, adding the mixture into a hot melt extruder, extruding at 90 ℃, cooling at room temperature, forming, crushing, and dividing the sieved slow release particles into two parts, wherein one part is treated at a high temperature for a certain time.
And (3) respectively measuring the release degree of the slow release particles subjected to high temperature treatment and not subjected to high temperature treatment by adopting a shaking bottle method, putting a slow release particle sample into a preheated shaking bottle at the water bath temperature of 37+/-0.5 ℃, sampling at a specified time point respectively, filtering by using a 0.45 mu m microporous filter membrane, supplementing a release medium at the same temperature, and taking a subsequent filtrate for HPLC measurement. The cumulative release of the slow-release particles at various times was calculated and the cumulative release curves were plotted, the results being shown in fig. 1 to 6.
TABLE 2
Example 4
Risperidone and biodegradable polymer are mixed thoroughly in a certain proportion, ethyl acetate, acetone or acetic acid are sprayed into the mixture optionally, then the mixture is added into a hot melt extruder, the extrudate is immersed into low-temperature water-ethanol mixed liquid, and then the mixture is crushed and sieved, the content of related substances is measured, and the total related substance increase percentage before and after extrusion is compared. The results of the specific experimental conditions and the percentage increase of the total related substances are shown in the following table 3.
Each set of sustained release particles was equally divided into two parts, one part was subjected to high temperature treatment and the other part was not subjected to high temperature treatment, wherein the time and temperature of the high temperature treatment are shown in table 3. And (3) respectively measuring the release degree of the two parts of slow release particles by adopting a shaking bottle method, putting a slow release particle sample into a preheated shaking bottle at the water bath temperature of 37+/-0.5 ℃, sampling on days 1, 15 and 30 respectively, filtering by using a 0.45 mu m microporous filter membrane, supplementing a release medium at the same temperature, and taking a subsequent filtrate for HPLC measurement. The cumulative release of the slow-release particles at various times was calculated and the cumulative release curves were plotted, the results being shown in fig. 7 to 13.
TABLE 3 Table 3
In this disclosure, relational terms such as first and second, and the like are used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions.
From the foregoing it will be appreciated that, although specific embodiments of the disclosure have been described herein for purposes of illustration, various modifications or improvements may be made by those skilled in the art without deviating from the spirit and scope of the disclosure. Such variations or modifications are intended to fall within the scope of the claims appended hereto.

Claims (9)

1. A method of preparing a slow release granule comprising:
a) Mixing an active pharmaceutical ingredient (active pharmaceutical ingredient) with a biodegradable polymer, thereby obtaining a first mixture;
b) Mixing the first mixture with a first solvent, thereby obtaining a second mixture, wherein the first solvent is capable of dissolving the water-ethanol mixture and of dissolving the biodegradable polymer;
c) Extruding the second mixture to obtain a first extrudate, and immersing the first extrudate in a water-ethanol mixture having a temperature of-100 to 0 ℃;
d) Dividing the first extrudate to obtain a first divided object; and
E) Performing high-temperature treatment on the first partition, thereby obtaining the slow-release particles,
Wherein the active pharmaceutical ingredient is risperidone, the biodegradable polymer is a polylactic acid-glycolic acid copolymer, the first solvent is ethyl acetate, the mass ratio of risperidone to polylactic acid-glycolic acid copolymer is 10:90, the concentration of the first solvent is 8% by mass based on the mass of the first mixture, the extrusion temperature at which the extrusion is performed is 40 ℃, and the temperature of the high temperature treatment is 75 ℃, and an excipient selected from mannitol, sucrose, or a mixture thereof is added during the high temperature treatment.
2. The method of claim 1, wherein the high temperature treatment is for a period of 4 hours to 14 days.
3. The method of claim 2, wherein the high temperature treatment is for a period of 4 days to 8 days.
4. The method of claim 1, wherein the concentration of ethanol in the water-ethanol mixture is from 1 to 99% based on the mass of the water-ethanol mixture.
5. The method of claim 4, wherein the concentration of ethanol in the water-ethanol mixture is 25 to 60% based on the mass of the water-ethanol mixture.
6. The method of any one of claims 1 to 5, wherein the first solvent is sprayed onto the first mixture, thereby obtaining a second mixture.
7. A slow release granule prepared by the method of any one of claims 1 to 6.
8. The sustained release granule of claim 7, wherein the active pharmaceutical ingredient (active pharmaceutical ingredient) is free of burst.
9. Use of the slow release particles of claim 7 or 8 for the manufacture of a medicament for improving the release of an active pharmaceutical ingredient (active pharmaceutical ingredient) in an individual.
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