CN113116830A

CN113116830A - Preparation of sustained-release granules

Info

Publication number: CN113116830A
Application number: CN201911422073.9A
Authority: CN
Inventors: 刘荣; 王代丰; 严米娜
Original assignee: Guangzhou Bosia Biomedical Technology Co ltd
Current assignee: Guangzhou Bositao Controlled Release Pharmaceutical Co ltd
Priority date: 2019-12-31
Filing date: 2019-12-31
Publication date: 2021-07-16
Anticipated expiration: 2039-12-31
Also published as: CN113116830B

Abstract

Disclosed is a method of preparing sustained release granules, 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 in a water-ethanol mixture and is capable of dissolving a biodegradable polymer; c) extruding the second mixture, thereby obtaining a first extrudate; and d) dividing the first extrudate to obtain the sustained release granules.

Description

Preparation of sustained-release granules

FIELD

The present disclosure relates generally to the field of medicine. More specifically, the present disclosure relates to the field of sustained release granules.

Background

The general procedure for preparing sustained release granules by hot melt extrusion is as follows: mixing the drug and 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 sustained-release granules.

SUMMARY

In one aspect, the present disclosure relates to a method of making 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 in a water-ethanol mixture and is capable of dissolving a biodegradable polymer; c) extruding the second mixture, thereby obtaining a first extrudate; and d) dividing the first extrudate to obtain the sustained release granules.

In another aspect, the present disclosure relates to 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) extruding the first mixture, thereby obtaining a first extrudate; c) segmenting the first extrudate to obtain a first segmentation; and d) subjecting the first partition to high temperature treatment, thereby obtaining the sustained-release granule.

In yet another aspect, the present disclosure relates to a method of making 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 in a water-ethanol mixture and is capable of dissolving a biodegradable polymer; c) extruding the second mixture, thereby obtaining a first extrudate; d) segmenting the first extrudate to obtain a first segmentation; and e) subjecting the first partition to high temperature treatment, thereby obtaining the sustained-release granule.

In yet another aspect, the present disclosure relates to a sustained release granule prepared by a method 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 in a water-ethanol mixture and is capable of dissolving a biodegradable polymer; c) extruding the second mixture, thereby obtaining a first extrudate; and d) dividing the first extrudate to obtain the sustained release granules.

In another aspect, the present disclosure relates to a sustained 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, thereby obtaining a first extrudate; c) segmenting the first extrudate to obtain a first segmentation; and d) subjecting the first partition to high temperature treatment, thereby obtaining the sustained-release granule.

In yet another aspect, the present disclosure relates to sustained release granules 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 in a water-ethanol mixture and is capable of dissolving a biodegradable polymer; c) extruding the second mixture, thereby obtaining a first extrudate; d) segmenting the first extrudate to obtain a first segmentation; and e) subjecting the first partition to high temperature treatment, thereby obtaining the sustained-release granule.

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 sustained release particle made by a method 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 in a water-ethanol mixture and is capable of dissolving a biodegradable polymer; c) extruding the second mixture, thereby obtaining a first extrudate; and d) dividing the first extrudate to obtain the sustained release granules.

In 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 sustained release particle made by a method 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, thereby obtaining a first extrudate; c) segmenting the first extrudate to obtain a first segmentation; and d) subjecting the first partition to high temperature treatment, thereby obtaining the sustained-release granule.

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 sustained release particle made by a method 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 in a water-ethanol mixture and is capable of dissolving a biodegradable polymer; c) extruding the second mixture, thereby obtaining a first extrudate; d) segmenting the first extrudate to obtain a first segmentation; and e) subjecting the first partition to high temperature treatment, thereby obtaining the sustained-release granule.

Brief description of the drawings

Fig. 1 shows the cumulative release profile of the drug (triamcinolone acetonide) with and without high temperature treatment of experiment 1 (No. 1) in example 3 of the present disclosure.

Fig. 2 shows the cumulative release profile of the drug (huperzine a) after high temperature treatment and without high temperature treatment of the drug (huperzine a) of experiment 2 (No. 2) in example 3 of the present disclosure.

Fig. 3 shows the cumulative release profile of the drug (triamcinolone acetonide) with and without high temperature treatment of experiment 3 (serial No. 3) of the present disclosure.

Fig. 4 shows the cumulative release profile of the drug (triamcinolone acetonide) with and without high temperature treatment of experiment 4 (No. 4) in example 3 of the present disclosure.

Fig. 5 shows the cumulative release profile of the drug (milrins) of experiment 5 (No. 5) of example 3 of the present disclosure with and without the high temperature treatment of the sustained release granules.

Fig. 6 shows the cumulative release profile of the drug (naltrexone) sustained release granules treated and not treated with high temperature for experiment 6 (No. 6) in example 3 of the present disclosure.

Fig. 7 shows the cumulative release profile of the drug (risperidone) sustained release granules with and without high temperature treatment of experiment 1 (No. 1) in example 4 of the present disclosure.

Fig. 8 shows the cumulative release profile of the drug (risperidone) sustained release granules with and without high temperature treatment of experiment 2 (No. 2) in example 4 of the present disclosure.

Fig. 9 shows the cumulative release profile of the drug (risperidone) sustained release granules with and without high temperature treatment of experiment 3 (No. 3) in example 4 of the present disclosure.

Fig. 10 shows the cumulative release profile of the drug (risperidone) sustained release granules with and without high temperature treatment of experiment 4 (No. 4) in example 4 of the present disclosure.

Fig. 11 shows the cumulative release profile of the drug (risperidone) sustained release granules with and without high temperature treatment of experiment 5 (No. 5) in example 4 of the present disclosure.

Fig. 12 shows the cumulative release profile of the drug (risperidone) sustained release granules with and without high temperature treatment of experiment 6 (serial No. 6) in example 4 of the present disclosure.

Fig. 13 shows the cumulative release profile of the drug (risperidone) sustained release granules with and without high temperature treatment of experiment 7 (No. 7) in example 4 of the present disclosure.

Detailed description of the invention

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 can be practiced without one or more of the specific details, or with other methods, components, materials, and so forth.

Throughout this specification and the claims which follow, unless the context requires otherwise, the words "comprise", "comprising", and "have" are to be construed in an open, inclusive sense, i.e., "including but not limited to".

Reference throughout the specification to "one embodiment," "an embodiment," "in another embodiment," or "in certain embodiments" means that a particular reference element, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" or "in another embodiment" or "in certain embodiments" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular elements, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

Definition of

In the present disclosure, the term "sustained release granule" is a dispersion of microparticles in which the active pharmaceutical ingredient is dispersed or adsorbed in a polymeric, polymeric matrix.

In the present disclosure, the term "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 kind of high molecular material that can be degraded or enzymatically decomposed in the living body, and the generated small molecular substances can be absorbed by the body and discharged out of the body.

In the present disclosure, the term "poly (lactic-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 poly-epsilon-caprolactone, which is a high molecular organic polymer prepared by ring-opening polymerization of epsilon-caprolactone monomer under the catalysis of metal anion complex catalyst.

In the present disclosure, the term "heat-sensitive drug" refers to a drug active ingredient that is stored in a solid or solution state under a light-tight seal at 60 ℃ and that has a drug active ingredient content reduced by more than 3% within 3 days.

Detailed Description

In one aspect, the present disclosure relates to a method of making 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 in a water-ethanol mixture and is capable of dissolving a biodegradable polymer;

c) extruding the second mixture, thereby obtaining a first extrudate; and

d) segmenting the first extrusion to obtain the sustained release granule.

In certain embodiments, the active pharmaceutical ingredient and the biodegradable polymer are separately ground and then mixed to provide a first mixture.

In certain embodiments, the active pharmaceutical ingredient is mixed with the biodegradable polymer and then milled to provide a first mixture.

In certain embodiments, the mass ratio of active pharmaceutical ingredient to biodegradable polymer is about 1:99 to 10: 90.

In certain embodiments, the mass ratio of active pharmaceutical ingredient to biodegradable polymer is about 5:95 to 10: 90.

In certain embodiments, illustrative examples of pharmaceutically active ingredients that can be used in the methods of making sustained release particles of the present disclosure include, but are not limited to, teriparatide, growth hormone, leuprolide, goserelin, triptorelin, octreotide, lanreotide, pasiretin, cetrorelix, ganirelix, oxytocin, vasopressin, corticotropin, epidermal growth factor, prolactin, luteinizing hormone, gonadotropin-releasing hormone agonists, gonadotropin-releasing hormone antagonists, ghrelin, insulin, erythropoietin, somatostatin, glucagon, interleukin, interferon- α, interferon- β, interferon- γ, gastrin, tetrapeptide gastrin, pentapeptide gastrin, urogastrin, secretin, calcitonin, enkephalin, ghrelin, Endorphin, angiotensin, 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 morphogenetic protein, glucagon-like peptide, exenatide, liraglutide, somaglutelin, dolarreptide, ghraglutide, ghrelin, renin, bradykinin, bacitracin, polymyxin, tyrocide, gramicidin, cyclosporine, follicle stimulating hormone, thymopoietin, thymosin, thymic hormone, thymic humoral factor, serum thymic factor, motilin, neurotensin, urokinase, angiotensin II, melanocyte, thyroid hormone releasing hormone, parathyroid hormone, thyroid stimulating hormone, human chorionic gonadotropin, chorionic hormone, chorionic, Gastric inhibitory peptides, vasoactive intestinal peptides, 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 steroidal anti-inflammatory drugs that can be used in the present disclosure include, but are not limited to, dexamethasone, triamcinolone acetonide, cortisone, fluocinolone, hydrocortisone, methylprednisolone, prednisolone, prednisone, levonorgestrel, and triamcinolone.

In certain embodiments, illustrative examples of pharmaceutically active ingredients that can be used in the methods of making sustained release particles of the present disclosure include, but are not limited to, heat-sensitive drugs.

In certain embodiments, illustrative examples of heat-sensitive drugs that can be used in the methods of making sustained release particles of the present disclosure include, but are not limited to, teriparatide, growth hormone, leuprolide, goserelin, triptorelin, octreotide, lanreotide, pasiretin, cetrorelix, ganirelix, oxytocin, vasopressin, corticotropin, epidermal growth factor, prolactin, luteinizing hormone, gonadotropin releasing hormone agonists, gonadotropin releasing hormone antagonists, ghrelin, insulin, erythropoietin, somatostatin, glucagon, interleukin, interferon- α, interferon- β, interferon- γ, gastrin, tetrapeptide gastrin, pentapeptide gastrin, urogastrin, secretin, calcitonin, enkephalin, ghrelin, gh, Endorphin, angiotensin, 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 morphogenetic protein, glucagon-like peptide, exenatide, liraglutide, somaglutelin, dolarreptide, ghraglutide, ghrelin, renin, bradykinin, bacitracin, polymyxin, tyrocide, gramicidin, cyclosporine, follicle stimulating hormone, thymopoietin, thymosin, thymic hormone, thymic humoral factor, serum thymic factor, motilin, neurotensin, urokinase, angiotensin II, melanocyte, thyroid hormone releasing hormone, parathyroid hormone, thyroid stimulating hormone, human chorionic gonadotropin, chorionic hormone, chorionic, Gastric inhibitory peptides, vasoactive intestinal peptides and the hypothalamic release factor prolactin.

In certain embodiments, illustrative examples of biodegradable polymers that can be used in the methods of making sustained release particles of the present disclosure include, but are not limited to, polyglycolic acid, polylactic-co-glycolic acid (PLGA), polycaprolactone, polyorthocarbonate, polyacetals, poly (lactic-caprolactone), polyorthoesters, poly (glycolic acid caprolactone), polyanhydrides, and hyaluronic acid.

In certain embodiments, the first solvent is sprayed onto the first mixture, thereby obtaining a second mixture.

In certain embodiments, the first solvent is added dropwise to the first mixture, thereby obtaining a second mixture.

In certain embodiments, the first solvent is added to the first mixture in other combinations to provide a second mixture.

In certain embodiments, after the first solvent is added to the first mixture, it may be brought into a homogeneous mixed system using suitable means to obtain a second mixture.

In certain embodiments, the second mixture is added to an extrusion device and extruded to provide 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 the extrusion apparatus followed by the addition of the first solvent, and the first mixture is mixed with the first solvent to provide a second mixture, which is extruded to provide the 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 carried out at an extrusion temperature of about-10 to 60 ℃.

In certain embodiments, the extrusion is carried out at an extrusion temperature of about 0 to 50 ℃.

In certain embodiments, the extrusion is conducted at an extrusion temperature of about 20 to about 40 deg.C

In certain embodiments, illustrative examples of devices that can be used in the present application to divide the first extrudate include, but are not limited to, pelletizers (shredders) of hot melt extrusion equipment, hammer mills, universal mills, jet mills, ball mills, conical mills, and cutters.

In certain embodiments, the first extrudate is cut.

In certain embodiments, the first extrudate is subjected to shear cutting.

In certain embodiments, the first extrudate is divided using an external force.

In another aspect, the present disclosure relates to a method of preparing a sustained release granule comprising:

b) extruding the first mixture, thereby obtaining a first extrudate;

c) segmenting the first extrudate to obtain a first segmentation; and

d) and carrying out high-temperature treatment on the first segmentation object so as to obtain the slow-release particles.

In certain embodiments, illustrative examples of pharmaceutically active ingredients that can be used in the methods of making 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 sustained release particles of the present disclosure include, but are not limited to, bupivacaine, buprenorphine, paclitaxel, huperzine a, steroidal anti-inflammatory drugs, milnacin, doxycycline, meloxicam, carmustine, granisetron, naltrexone, risperidone, and paliperidone.

In certain embodiments, the extrusion is carried out at an extrusion temperature of about 40 to 280 ℃.

In certain embodiments, the extrusion is carried out at an extrusion temperature of about 60 to 250 ℃.

In certain embodiments, the first extrudate is cut.

In certain embodiments, the first extrudate is subjected to shear cutting.

In certain embodiments, the first extrudate is divided 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 period for the high temperature treatment is about 4 hours to 14 days.

In certain embodiments, the time period for the high temperature treatment is about 4 days to 8 days.

In certain embodiments, excipients are added during high temperature processing.

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, glycerol, sorbitol, mannitol, inositol, adonitol, ethylene glycol, and polyethylene glycol.

In certain embodiments, illustrative examples of saccharides 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, mucopolysaccharide protein, casein, and bovine serum albumin.

In certain embodiments, the resulting sustained release granules are further subjected to high temperature treatment to avoid a drug burst.

In certain embodiments, the sustained-release granules prepared by the method are further subjected to high temperature treatment, so that the surfaces of the sustained-release granules are melted and re-solidified, and the comparative area of the sustained-release granules is reduced.

In yet another aspect, the present disclosure relates to a method of making a sustained release granule comprising:

c) extruding the second mixture, thereby obtaining a first extrudate;

d) segmenting the first extrudate to obtain a first segmentation; and

e) and carrying out high-temperature treatment on the first segmentation object so as to obtain the slow-release particles.

In certain embodiments, illustrative examples of first solvents that can be dissolved in a water-ethanol mixture and that can dissolve the biodegradable polymer that can be used in the present disclosure include, but are not limited to, ethyl acetate, acetone, and acetic acid.

In certain embodiments, illustrative examples of pharmaceutically active ingredients that can be used in the methods of making 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 sustained release particles of the present disclosure include, but are not limited to, bupivacaine, buprenorphine, paclitaxel, huperzine a, steroidal anti-inflammatory drugs, milnacin, doxycycline, meloxicam, carmustine, granisetron, naltrexone, risperidone, and paliperidone.

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, in the water-ethanol mixture, the concentration of ethanol is from 5 to 99% based on the mass of the water-ethanol mixture.

In certain embodiments, in the water-ethanol mixture, the concentration of ethanol is from 25 to 60% based on the mass of the water-ethanol mixture.

In certain embodiments, the first extrudate is cut.

In certain embodiments, the first extrudate is subjected to shear cutting.

In certain embodiments, the first extrudate is divided using an external force.

In certain embodiments, the addition of a first solvent capable of dissolving a water-ethanol mixture and capable of dissolving a biodegradable polymer to a first mixture comprising an active pharmaceutical ingredient and a biodegradable polymer can lower the extrusion temperature, thereby enabling the methods of the present disclosure to be used in the preparation of biodegradable polymer sustained release particles of temperature sensitive active pharmaceutical ingredients.

In certain embodiments, the solvent is selected to dissolve the biodegradable polymer because it reduces the extrusion temperature, thereby avoiding high temperature damage to the drug during extrusion.

In the present disclosure, methanol and ethanol are not particularly suitable for the preparation method 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 granule prepared by a method comprising the steps of:

c) extruding the second mixture, thereby obtaining a first extrudate; and

d) segmenting the first extrudate to obtain the sustained release granules.

In certain embodiments, the active pharmaceutical ingredient (active pharmaceutical ingredient) in the sustained release particles produced by the methods of the present disclosure is free of burst release.

In another aspect, the present disclosure relates to a sustained release granule prepared by a process comprising the steps of:

b) extruding the first mixture, thereby obtaining a first extrudate;

c) segmenting the first extrudate to obtain a first segmentation; and

In yet another aspect, the present disclosure relates to sustained release granules prepared by a process comprising the steps of:

c) extruding the second mixture, thereby obtaining a first extrudate; d) segmenting the first extrudate to obtain a first segmentation; and

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 sustained release particle made by a method comprising the steps of:

c) extruding the second mixture, thereby obtaining a first extrudate;

d) segmenting the first extrudate to obtain the sustained release granules.

In 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 sustained release particle made by a method comprising the steps of:

b) extruding the first mixture, thereby obtaining a first extrudate;

c) segmenting the first extrudate to obtain a first segmentation; and

c) extruding the second mixture, thereby obtaining a first extrudate;

d) segmenting the first extrudate to obtain a first segmentation; and

Hereinafter, the present disclosure will be explained in detail by the following examples in order to better understand various aspects of the present application and advantages thereof. It should be understood, however, that the following examples are not limiting and are merely illustrative of certain embodiments of the present disclosure.

Examples

The reagents and equipment used in the examples of the present disclosure are conventional and commercially available.

For example:

acetic acid (manufacturer/lot): tianjin Damao chemical reagent factory/20180802-2

Oscillating water bath (manufacturer/model): Jumbo/SW 23

Example 1

Fully mixing the medicine and the biodegradable polymer according to a certain mass ratio, spraying ethyl acetate, acetone or acetic acid into the mixture, then adding the mixture into a hot-melt extruder, immersing an extrudate into a low-temperature water-ethanol mixed solution, then crushing and sieving to obtain sustained-release granules, and measuring and calculating the content change percentage of related substances in the raw material medicine and the sustained-release granules. The experimental conditions and the measurement results are shown in table 1 below.

TABLE 1

Example 2

The ethyl acetate content of the sustained-release granules obtained in experiment 4 (No. 4) of example 1 was measured. The sustained release particles were added to 5mL of dimethyl sulfoxide, and samples were taken after 10min of vortexing for GC assay with a detection result of 0.12%.

Example 3

Mixing the medicine and the biodegradable polymer in a certain proportion, adding into a hot-melting extruder, extruding at 90 ℃, cooling at room temperature for forming, pulverizing, and dividing the sieved sustained-release particles into two parts, wherein one part is treated at high temperature for a certain time.

Respectively measuring the release degree of the sustained-release particles subjected to high-temperature treatment and not subjected to high-temperature treatment by adopting a shaking flask method, wherein the water bath temperature is 37 +/-0.5 ℃, putting sustained-release particle samples into preheated shaking flasks, respectively sampling at specified time points, filtering by using a 0.45-micrometer microporous filter membrane, simultaneously supplementing release media at the same temperature, and taking the subsequent filtrate for HPLC measurement. The cumulative release degree of the sustained-release granules at different times was calculated, and a cumulative release curve was plotted, and the results are shown in fig. 1 to 6.

TABLE 2

Example 4

Fully mixing risperidone and a biodegradable polymer according to a certain proportion, optionally spraying ethyl acetate, acetone or acetic acid into the mixture, then adding the mixture into a hot-melt extruder, immersing an extrudate into a low-temperature water-ethanol mixed solution, then crushing and sieving the extrudate, measuring the content of related substances, and comparing the growth percentage of the total related substances before and after extrusion. The results of the specific experimental conditions and the determination of the percentage of total related substances increase are shown in the following table 3.

Each group of sustained-release granules was divided into two portions, one portion was subjected to high-temperature treatment, and the other portion was not subjected to high-temperature treatment, wherein the time and temperature of the high-temperature treatment are shown in Table 3. Respectively measuring the release degree of the two sustained-release granules by adopting a shaking flask method, wherein the water bath temperature is 37 +/-0.5 ℃, putting a sustained-release granule sample into a preheated shaking flask, respectively sampling at 1 st, 15 th and 30 th days, filtering by using a 0.45 mu m microporous filter membrane, simultaneously supplementing a release medium with the same temperature, and taking a subsequent filtrate for HPLC measurement. Cumulative release degrees of the sustained-release granules at different times were calculated, and cumulative release curves were plotted, with the results shown in fig. 7 to 13.

TABLE 3

In the present disclosure, relational terms such as first and second, and the like may be 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 departing from the spirit and scope of the disclosure. Such variations and modifications are intended to fall within the scope of the appended claims of this disclosure.

Claims

1. A method of making a sustained release granule comprising:

c) extruding the second mixture, thereby obtaining a first extrudate; and

d) segmenting the first extrudate to obtain the sustained release granules.

2. A method of making a sustained release granule comprising:

c) extruding the second mixture, thereby obtaining a first extrudate;

d) segmenting the first extrudate to obtain a first segmentation; and

3. The process of any one of claims 1 or 2, wherein the first solvent is selected from the group consisting of ethyl acetate, acetone, acetic acid, and mixtures thereof.

4. A process according to claim 2 or 3, wherein the temperature of the high temperature treatment is from 50 to 80 ℃, preferably from 55 to 75 ℃, more preferably from 60 to 70 ℃.

5. A process according to any one of claims 2 to 4 wherein the high temperature treatment is for a period of from 4 hours to 14 days, preferably from 4 days to 8 days.

6. A process according to any one of claims 2 to 5, wherein excipients, preferably mannitol, sucrose and mixtures thereof, are added during the high temperature treatment.

7. A process according to claim 1 or 3, wherein the extrusion is carried out at an extrusion temperature of from-10 to 60 ℃, preferably from 0 to 50 ℃, more preferably from 20 to 40 ℃.

8. A process according to any one of claims 2, 4 to 6 wherein the extrusion is carried out at an extrusion temperature of from 40 to 280 ℃, preferably from 60 to 250 ℃.

9. The method of any one of claims 1 to 7, wherein the concentration of the first solvent is 1 to 50% by mass, preferably 1 to 20% by mass, more preferably 8 to 12% by mass, based on the mass of the first mixture.

10. The method according to any one of claims 1 to 9, wherein the mass ratio of active pharmaceutical ingredient to biodegradable polymer is from 1:99 to 10:90, preferably from 5:95 to 10: 90.

11. The method of any one of claims 1 to 10, further comprising immersing the first extrudate in a water-ethanol mixture.

12. The process according to claim 11, wherein in the water-ethanol mixture, the concentration of ethanol is from 1 to 99%, preferably from 25 to 60%, based on the mass of the water-ethanol mixture.

13. The process according to claim 11 or 12, wherein the temperature of the water-ethanol mixture is from-100 to 0 ℃, preferably from-30 to-10 ℃.

14. The method of any one of claims 1 to 13, wherein the first solvent is sprayed to the first mixture, thereby obtaining a second mixture.

15. A method according to any one of claims 1 to 14, wherein the active pharmaceutical ingredient is selected from teriparatide, growth hormone, leuprorelin, goserelin, triptorelin, octreotide, lanreotide, pasireotide, cetrorelix, ganirelix, oxytocin, vasopressin, corticotropin, epidermal growth factor, prolactin, luteinizing hormone, gonadotropin-releasing hormone agonists, gonadotropin-releasing hormone antagonists, ghrelin, insulin, erythropoietin, somatostatin, glucagon, interleukins, interferon- α, interferon- β, interferon- γ, gastrin, tetrapeptide gastrin, pentapeptide gastrin, urocortin, secretin, enkephalin, endopeptide, angiotensin, calcitonin, ghrelin, Thyrotropin releasing factor, tumor necrosis factor, parathyroid hormone, nerve growth factor, granulocyte colony stimulating factor, granulocyte macrophage colony stimulating factor, heparinase, vascular endothelial growth factor, bone morphogenetic protein, glucagon-like peptide, exenatide, liraglutide, somaglutelin, dolarreptide, ghrelin, renin, bradykinin, bacitracin, polymyxin, gramicin, brevibacillin, cyclosporine, follicle stimulating hormone, thymopoietin, thymosin, thymidysin, thymic humoral factor, serum thymic factor, motilin, neurotensin, urokinase, angiotensin II, melanocyte, thyroid hormone releasing hormone, parathyroid hormone, thyroid hormone, human chorionic gonadotropin, gastric inhibitory peptide, gastric inhibitory hormone, and the like, Vasoactive intestinal peptide, hypothalamic release factor prolactin, bupivacaine, buprenorphine, paclitaxel, huperzine A, steroidal anti-inflammatory drugs, milrins, doxycycline, meloxicam, carmustine, granisetron, naltrexone, risperidone and paliperidone, the steroidal anti-inflammatory drugs preferably being dexamethasone, triamcinolone acetonide, cortisone, fluocinolone, hydrocortisone, methylprednisolone, prednisolone, prednisone, levonorgestrel and triamcinolone.

16. The method according to any one of claims 1, 3, 7, 9 to 14, wherein the active pharmaceutical ingredient is selected from heat-sensitive drugs, preferably from teriparatide, growth hormone, leuprorelin, goserelin, triptorelin, octreotide, lanreotide, pasiretide, cetrorelix, ganirelix, oxytocin, vasopressin, corticotropin, epidermal growth factor, prolactin, luteinizing hormone, gonadotropin-releasing hormone agonists, gonadotropin-releasing hormone antagonists, ghrelin, insulin, erythropoietin, somatostatin, glucagon, interleukin, interferon- α, interferon- β, interferon- γ, gastrin, tetrapeptide gastrin, pentagastrin, urogastrin, secretin, calcitonin, tretinoin, leuprolin, ghrelin, leuprolin, ghrelin, glareotide, and glareo, Enkephalin, endorphin, angiotensin, 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 morphogenetic protein, glucagon-like peptide, exenatide, liraglutide, somaglutelin, dolabrlutide, ghrelin, renin, bradykinin, bacitracin, polymyxin, brevibacillin, gramicidin, cyclosporine, follicle stimulating hormone, thymopoietin, thymosin, thymic hormone, thymic fluid factor, serum thymic factor, motilin, neurotensin, urokinase, angiotensin II, melanocyte, thyroid hormone releasing hormone, parathyroid hormone, thyroid stimulating hormone, Human chorionic gonadotropin, gastric inhibitory peptide, vasoactive intestinal peptide, and hypothalamic releasing factor prolactin.

17. The method of any one of claims 2, 4-6, 8 and 10, wherein the active pharmaceutical ingredient is selected from non-heat sensitive drugs, preferably from bupivacaine, buprenorphine, paclitaxel, huperzine A, steroidal anti-inflammatory drugs, milrins, doxycycline, meloxicam, carmustine, granisetron, naltrexone, risperidone and paliperidone, said steroidal anti-inflammatory drugs preferably being dexamethasone, triamcinolone acetonide, cortisone, fluocinolone, hydrocortisone, methylprednisolone, prednisolone, prednisone, levonorgestrel and triamcinolone.

18. The method according to any one of claims 1 to 17, wherein the biodegradable polymer is selected from the group consisting of polyglycolic acid, polylactic acid-glycolic acid copolymer, polycaprolactone, polyorthocarbonate, polyacetals, poly (lactic acid-caprolactone), polyorthoesters, poly (glycolic acid-caprolactone), polyanhydrides, hyaluronic acid and mixtures thereof, preferably from polylactic acid-glycolic acid copolymer, polycaprolactone, polylactic acid and mixtures thereof.

19. Sustained release granules prepared by the process of any one of claims 1 to 18.

20. The sustained-release granule according to claim 19, wherein the active pharmaceutical ingredient (active pharmaceutical ingredient) is free from burst release.

21. 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 the extended release particle of claim 19 or 20.