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WO2022170677A1 - Granulés de sel de bêta-hydroxybutyrate et leurs procédés de production - Google Patents

Granulés de sel de bêta-hydroxybutyrate et leurs procédés de production Download PDF

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Publication number
WO2022170677A1
WO2022170677A1 PCT/CN2021/087134 CN2021087134W WO2022170677A1 WO 2022170677 A1 WO2022170677 A1 WO 2022170677A1 CN 2021087134 W CN2021087134 W CN 2021087134W WO 2022170677 A1 WO2022170677 A1 WO 2022170677A1
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Prior art keywords
bhb
salt
granules
spheronization
beta
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Ceased
Application number
PCT/CN2021/087134
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English (en)
Inventor
Long Jiang
Xuyang SUN
Qiru FAN
Ronghua YI
Kylin LIAO
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Nanjing Nutrabuilding Bio Tech Co Ltd
Original Assignee
Nanjing Nutrabuilding Bio Tech Co Ltd
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Publication date
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Priority to AU2021367386A priority Critical patent/AU2021367386A1/en
Priority to US17/768,409 priority patent/US20240156735A1/en
Priority to CA3159208A priority patent/CA3159208A1/fr
Priority to CN202180002492.6A priority patent/CN115210212B/zh
Publication of WO2022170677A1 publication Critical patent/WO2022170677A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient

Definitions

  • This invention generally relates to the field of pharmaceutics, and more specifically relates to formulations of beta-hydroxybutyrate (BHB) salt granules and methods for preparing or producing beta-hydroxybutyrate (BHB) salt granules.
  • BHB beta-hydroxybutyrate
  • ketosis is the physiological state of elevated blood ketone body levels resulting from ketogenic diets, calorie restriction, therapeutic fasting and/or supplementation with ketogenic precursors.
  • the body When in ketosis. the body is essentially burning fat for its primary fuel, and begins cleaving fats into fatty acids and glycerol and transforms the fatty acids into acetyl CoA molecules, which are then eventually transformed through ketogenisis into ketone bodies beta-hydroxybutyrate (beta-hydroxybutyrate or "BHB" ) , acetoacetate (acetylacetonate) , and acetone in the liver.
  • BHB and acetoacetate are the ketone bodies used by the body for energy while acetone is removed as a by-product of ketogenesis.
  • Ketone bodies represent alternative energy substrates for both peripheral tissues and the central nervous system.
  • Beta-hydroxybutyrate (BHB) salts are pharmaceutics or supplements that contain a ketone (BHB) bound to a mineral. When these BHB salts are consumed, the salt may dissociate into its individual ions and release BHB, which then raises circulating concentrations of BHB in the blood, thereby promoting or sustaining the ketosis state.
  • BHB salts are as small as dust, and causes many troubles and problems when being processed by downstream manufacturers.
  • the issues for conventional production methods of BHB salts include, e.g., problem of dust, repeated or prolonged inhalation of dust by workers, high material consumption, and industrial/environmental pollutions.
  • This invention generally relates to formulations of BHB salt granules, and methods for producing such BHB salt granules.
  • the BHB salt granules according to the present invention have uniform particle size and can effectively solves problem of dust, reduces material consumption, reduces industrial or environmental pollutions, and/or reduces the repeated or prolonged inhalation of dust in association with BHB salts.
  • BHB beta-hydroxybutyrate
  • the BHB salt granule is made of raw materials comprising (a) the BHB salt with a mass percentage ranging from 10%to 99%and (b) the filler with a mass percentage ranging from 1%to 90%.
  • the BHB salt granule is made of raw materials comprising (a) the BHB salt with a mass percentage ranging from 50%to 99%; and (b) the filler with a mass percentage ranging from 1%to 50%.
  • the BHB salt comprises a BHB metal salt.
  • the BHB metal salt may be formed from potassium, calcium, sodium, magnesium, or a mixture thereof (e.g., a mixture of any two or any three thereof, in any ratio) .
  • the filler comprises microcrystalline cellulose, lactose, mannitol, starch, pregelatinized starch, sodium carboxymethyl cellulose, resistance dextrin, xanthan gum, gum acacia, guar gum, sodium carboxymethyl starch, cross-linked sodium carboxymethyl starch, methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, ⁇ -cyclodextrin, or a mixture thereof (e.g., a mixture of any two or any three thereof, in any ratio) .
  • Another aspect ofthe present invention provides a composition for promoting and/or sustaining ketosis in a mammal (e.g., human) , comprising BHB salt granule (s) as described above.
  • a mammal e.g., human
  • BHB salt granule (s) as described above.
  • the prevent invention relates to a method for producing BHB salt granules, wherein the BHB salt granules are prepared by granulation process.
  • the production method comprises (a) wet granulation; (b) extrusion; (c) spheronization; and (d) drying.
  • the wet granulation comprises: mixing a BHB salt and a filler; and adding a binder solution for wet granulation to obtain a wet material.
  • the binder may be water.
  • the ratio of the filler and binder ranges from 1: 1 to 1: 1.5, rotating speed of the wet granulator is 100-500 rounds/minute ( “r/min” ) , and/or the feeding speed is 5-15 r/min.
  • the extrusion comprises: extruding the wet material obtained in step (a) by the extruder, to obtain strip material with the same diameter.
  • the extruder has sieve plate aperture of 0.8-1.2 mm, and/or the screw speed of the extruder is 100-300 r/min.
  • the spheronization comprises: sphering the strip materials obtained in step (b) at a high speed through the spheronization device to get granules with the same size and desired roundness.
  • the rotation speed of the spheronization device may be 400-800 r/min, and/or the time of spheronization may be 15-60 s.
  • the drying step comprising drying the granules prepared in step (c) to obtain the BHB salt granules.
  • the moisture content of final material is controlled below 3%.
  • the drying temperature may be 40-60°C, and/or the drying time may be 15-30 minutes.
  • the BHB salts have a uniform particle size. In some embodiments, the BHB salts have a particle size of 10-100 mesh.
  • the BHB salt is formed from potassium, calcium, sodium, magnesium, or a mixture thereof.
  • the filler comprises microcrystalline cellulose, lactose, mannitol, starch, pregelatinized starch, sodium carboxymethyl cellulose, resistance dextrin, xanthan gum, gum acacia, guar gum, sodium carboxymethyl starch, cross-linked sodium carboxymethyl starch, methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, ⁇ -cyclodextrin, or a mixture thereof.
  • the method effectively solves problem of dust, reduces material consumption, reduces industrial or environmental pollutions, and/or reduces the repeated or prolonged inhalation of dust in association with BHB salts.
  • the term “or” is meant to include both “and” and “or. ” In other words, the term “or” may also be replaced with “and/or. ”
  • Figure 1 (a) and Figure 1 (b) illustrate the particle size analysis of BHB sodium salts and BHB sodium salt granules according to one embodiment of the present invention.
  • Figure 2 (a) and Figure 2 (b) illustrate the particle size analysis of BHB calcium salts and BHB calcium salt granules according to one embodiment of the present invention.
  • Figure 3 (a) and Figure 3 (b) illustrate the particle size analysis of BHB magnesium salts and BHB magnesium salt granules according to one embodiment of the present invention.
  • various embodiments of the present invention provide forformulations of BHB salt granules, which include BHB salts and fillers, as well as methods for producing BHB salt granules, e.g., by granulation.
  • the production methods of BHB salt granules according to the present invention may include (a) wet granulation; (b) extrusion; (c) spheronization; and (d) drying.
  • the particle size of the BHB salt granules prepared according to the present invention can be 10-100 (e.g., 10-40) mesh.
  • the dust problem of BHB salts can be effectively solved; the materials consumption of BHB salts can be effective reduced; the environmental pollutions of BHB salts can be effectively reduced; and the repeated or prolonged inhalation of dust problem of BHB salts can be effectively reduced.
  • the BHB salt granules may maintain the uniform particle size.
  • Example 1 The formulation of BHB salt granules in Example 1 is made of the raw materials with the respective mass percentages, as shown in Table 1 below.
  • the preparation method of such BHB salt granulesin includes the followingsteps:
  • step (3) Dry the granules prepared in step (3) to get BHB salt granules with the moisture content of 2.8%and the particle size of 10-40 mesh.
  • the drying temperature is adjusted to 40°C and the drying time is 30 minutes.
  • Example 2 The formulation of BHB salt granules in Example 2 is made of the raw materials with the respective mass percentages, as shown in Table 2 below.
  • the preparation method of such BHB salt granules includes the following steps:
  • wet granulation Mix 5 kg of BHB calcium salt and 5 kg of lactose, and add 5 kg of water for wet granulation to obtain wet material.
  • the rotating speed of the wet granulator is adjusted to 300 r/min and the feeding speed is 10 r/min;
  • step (3) Dry the granules prepared in step (3) to get BHB salt granules with the moisture content of 2.7%and the particle size of 10-40 mesh.
  • the drying temperature is adjusted to 50°C and the drying time is 25 minutes.
  • Example 3 The formulation of BHB salt granules in Example 3 is made of the raw materials with the respective mass percentages, as shown in Table 3 below.
  • the above-mentioned preparation method of BHB salt granules includes the following steps:
  • wet granulation Mix 5 kg of BHB potassium salt and 5 kg of starch, and add 5 kg of water for wet granulation to obtain wet material.
  • the rotating speed of the wet granulator is adjusted to 500 r/min and the feeding speed is 15 r/min;
  • step (3) Dry the granules prepared in step (3) to get BHB salt granules with the moisture content of 2.5%and the particle size of 10-40 mesh.
  • the drying temperature is adjusted to 60°C and the drying time is 15 minutes.
  • Example 4 The formulation of BHB salt granules in Example 4 is made of the raw materials with the respective mass percentages, as shown in Table 4 below.
  • the above-mentioned preparation method of BHB salt granules includes the following steps:
  • wet granulation Mix 7 kg of BHB sodium salt and 3 kg of microcrystalline cellulose, and add 4 kg of water for wet granulation to obtain wet material.
  • the rotating speed of the wet granulator is adjusted to 300 r/min and the feeding speed is 10 r/min;
  • step (3) Dry the granules prepared in step (3) to get BHB salt granules with the moisture content of 2.6%and the particle size of 40-80 mesh.
  • the drying temperature is adjusted to 60°C and the drying time is 15 minutes.
  • Example 5 The formulation of BHB salt granules in Example 5 is made of the raw materials with the respective mass percentages, as shown in Table 5 below.
  • the above-mentioned preparation method of BHB salt granules includes the following steps:
  • wet granulation Mix 8 kg of BHB sodium salt and 2 kg of microcrystalline cellulose, and add 3 kg of water for wet granulation to obtain wet material.
  • the rotating speed of the wet granulator is adjusted to 300 r/min and the feeding speed is 10 r/min;
  • step (3) Dry the granules prepared in step (3) to get BHB salt granules with the moisture content of 2.5%and the particle size of 60-100 mesh.
  • the drying temperature is adjusted to 60°C and the drying time is 15 minutes.
  • Example 6 The formulation of BHB salt granules in Example 6 is made of the raw materials with the respective mass percentages, as shown in Table 6 below.
  • the above-mentioned preparation method of BHB salt granules includes the following steps:
  • wet granulation Mix 7 kg of BHB sodium salt, 1.5 kg of microcrystalline cellulose and 1.5 kg of lactose, and add 4 kg of water for wet granulation to obtain wet material.
  • the rotating speed of the wet granulator is adjusted to 300 r/min and the feeding speed is 10 r/min;
  • step (3) Dry the granules prepared in step (3) to get BHB salt granules with the moisture content of 2.6%and the particle size of 40-80 mesh.
  • the drying temperature is adjusted to 60°C and the drying time is 15 minutes.
  • Figure 1 (a) shows the particle size analysis of BHB sodium salts
  • Figure 1 (b) shows the particle size analysis of BHB sodium salt granules in Example 6.
  • Example 7 The formulation of BHB salt granules in Example 7 is made of the raw materials with the respective mass percentages, as show in Table 7.
  • the above-mentioned preparation method of BHB salt granules includes the following steps:
  • wet granulation Mix 7 kg of BHB sodium salt, 1.5 kg of microcrystalline cellulose and 1.5 kg of starch, and add 4 kg of water for wet granulation to obtain wet material.
  • the rotating speed of the wet granulator is adjusted to 300 r/min and the feeding speed is 10 r/min;
  • step (3) Dry the granules prepared in step (3) to get BHB salt granules with the moisture content of 2.5%and the particle size of 40-80 mesh.
  • the drying temperature is adjusted to 60°C and the drying time is 15 minutes.
  • Figure 2 (a) shows the particle size analysis of BHB calcium salts
  • Figure 2 (b) shows the particle size analysis of BHB calcium salt granules in Example 7.
  • Example 8 The formulation of BHB salt granules in Example 8 is made of the raw materials with the respective mass percentages as shown in Table 8 below.
  • the above-mentioned preparation method of BHB salt granules includes the following steps:
  • wet granulation Mix 7 kg of BHB sodium salt, 1.5 kg of lactose and 1.5 kg of starch, and add 4 kg of water for wet granulation to obtain wet material.
  • the rotating speed of the wet granulator is adjusted to 300 r/min and the feeding speed is 10 r/min;
  • step (3) Dry the granules prepared in step (3) to get BHB salt granules with the moisture content of 2.6%and the particle size of 40-80 mesh.
  • the drying temperature is adjusted to 60°C and the drying time is 15 minutes.
  • Figure3 (a) shows the particle size analysis of BHB magnesium salts
  • Figure 3 (b) shows the particle size analysis of BHB magnesium salt granules in Example 8.

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Abstract

L'invention concerne des granulés de sel de bêta-hydroxybutyrate (BHB), comprenant des sels BHB et des charges. L'invention concerne également des procédés de production de granulés de sel BHB, les granulés de sel BHB étant préparés par procédé de granulation. Les procédés de production peuvent comprendre (a) la granulation par voie humide ; (b) l'extrusion ; (c) la sphéronisation ; et (d) le séchage.
PCT/CN2021/087134 2021-02-09 2021-04-14 Granulés de sel de bêta-hydroxybutyrate et leurs procédés de production Ceased WO2022170677A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU2021367386A AU2021367386A1 (en) 2021-02-09 2021-04-14 Beta-hydroxybutyrate salt granule and methods for producing the same
US17/768,409 US20240156735A1 (en) 2021-02-09 2021-04-14 Beta-hydroxybutyrate Salt Granule and Methods for Producing the Same
CA3159208A CA3159208A1 (fr) 2021-02-09 2021-04-14 Granule de sel de beta-hydroxybutyrate et methodes de production
CN202180002492.6A CN115210212B (zh) 2021-02-09 2021-04-14 β-羟基丁酸盐颗粒及其制备方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CNPCT/CN2021/076213 2021-02-09
CN2021076213 2021-02-09

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WO2022170677A1 true WO2022170677A1 (fr) 2022-08-18

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5594030A (en) * 1993-07-22 1997-01-14 Laboratorio Farmaceutico C.T. S.R.L. Controlled release pharmaceutical compositions based on one or more pharmaceutically acceptable salts of gamma hydroxy-butyric acid
US20180008629A1 (en) * 2015-01-29 2018-01-11 Yale University Compositions and Methods for Treating NLRP3 Inflammasome-Related Diseases and Disorders
CN109394745A (zh) * 2017-08-17 2019-03-01 博瑞生物医药（苏州）股份有限公司 一种包含左旋肉碱和β-羟基丁酸化合物的组合物
CN109789096A (zh) * 2016-07-22 2019-05-21 弗拉梅尔爱尔兰有限公司 具有经改善药代动力学的γ-羟基丁酸盐改进释放制剂
CN109796326A (zh) * 2018-12-27 2019-05-24 宣城菁科生物科技有限公司 一种3-羟基丁酸盐的制备方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5594030A (en) * 1993-07-22 1997-01-14 Laboratorio Farmaceutico C.T. S.R.L. Controlled release pharmaceutical compositions based on one or more pharmaceutically acceptable salts of gamma hydroxy-butyric acid
US20180008629A1 (en) * 2015-01-29 2018-01-11 Yale University Compositions and Methods for Treating NLRP3 Inflammasome-Related Diseases and Disorders
CN109789096A (zh) * 2016-07-22 2019-05-21 弗拉梅尔爱尔兰有限公司 具有经改善药代动力学的γ-羟基丁酸盐改进释放制剂
CN109394745A (zh) * 2017-08-17 2019-03-01 博瑞生物医药（苏州）股份有限公司 一种包含左旋肉碱和β-羟基丁酸化合物的组合物
CN109796326A (zh) * 2018-12-27 2019-05-24 宣城菁科生物科技有限公司 一种3-羟基丁酸盐的制备方法

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