A sustained release formulation of beta-hydroxybutyric acid or a salt thereof

Abstract

The application provides a sustained-release preparation of beta-hydroxybutyric acid or a salt thereof, which comprises the following components by weight percentage: 40-50% of beta-hydroxybutyric acid or a salt thereof, 40-60% of a sustained-release skeleton matrix material, and 1-3% of an auxiliary material. The product of the application has excellent water dispersion performance, and can realize slow release of beta-hydroxybutyric acid or a salt, maintain stable and effective blood drug concentration for a long time in the body, and has very important significance for the practical application of beta-hydroxybutyric acid and a salt.

Description

Technical Field

[0001] This invention belongs to the field of dietary supplements, specifically relating to a sustained-release formulation of β-hydroxybutyric acid or its salt. Background Technology

[0002] β-hydroxybutyrate, also known as 3-hydroxybutyric acid, with the chemical formula CH3CH(OH)CH2CO2H, is a hydroxy acid. β-hydroxybutyrate is chiral and has two enantiomers: D-3-hydroxybutyric acid and L-3-hydroxybutyric acid. This compound plays an important role in the physiological response to hypoglycemia during starvation in the human body.

[0003] The ketogenic diet (KD) is a diet high in fat, low in carbohydrates, and with adequate protein and other nutrients. It works by producing ketones through the body's metabolism. Initially used to treat epilepsy, it was later found to be effective for weight loss (ketones also suppress appetite) and improving athletic performance. Besides inducing the body to produce ketones through dietary changes, a more direct method is to ingest ketones directly. Ketones ingested from outside the body are exogenous ketones, which can replace carbohydrates to provide energy for muscles and the brain.

[0004] Besides β-hydroxybutyrate, common exogenous ketone forms include its salts such as sodium β-hydroxybutyrate, magnesium β-hydroxybutyrate, calcium β-hydroxybutyrate, and potassium β-hydroxybutyrate. However, exogenous ketones are easily metabolized by the body, and the ketone bodies in the body may return to their initial basal state within an hour at the earliest.

[0005] Currently, the most common forms of β-hydroxybutyric acid and its salts on the market are powders and capsules. Existing commercially available dosage forms only maintain a nutritional blood ketone concentration (0.5-3.0 mmol / L) for 30-40 minutes after a single dose, requiring 2-3 doses per day to maintain the blood ketone concentration. In addition, these preparations are highly susceptible to moisture absorption and caking during production, storage, transportation and use.

[0006] Therefore, there is an urgent need to develop sustained-release formulation technologies and products for β-hydroxybutyric acid and its salts to solve the aforementioned problems in the application of β-hydroxybutyric acid and its salt formulations. Such dietary supplements will have a very broad market prospect. Summary of the Invention

[0007] To address the aforementioned problems, this invention provides a sustained-release formulation containing β-hydroxybutyric acid (BHA) or its salts. This formulation effectively encapsulates BHA or its salts and slowly and continuously releases BHA and its salts for human absorption within 0–5 hours after administration. The sustained-release formulation has a simple preparation process, is stably dispersed in water, and exhibits good sustained-release effect. This sustained-release formulation maintains the optimal blood ketone concentration of BHA and its salts within 0–5 hours, effectively improving the defect of rapid metabolism of BHA after oral administration.

[0008] In a first aspect, the present invention provides a sustained-release formulation of β-hydroxybutyric acid or a salt thereof, comprising the following components in weight percentage: 40-50% β-hydroxybutyric acid or a salt thereof, 40-60% sustained-release matrix material, and 1-3% excipients.

[0009] In some embodiments, β-hydroxybutyric acid or a salt thereof is selected from any one or a mixture of any proportions of the following: β-hydroxybutyric acid, sodium β-hydroxybutyrate, potassium β-hydroxybutyrate, calcium β-hydroxybutyrate, and magnesium β-hydroxybutyrate.

[0010] In some implementations, the sustained-release matrix material is selected from one or more of hydrophilic gel matrix materials, erodible matrix materials, and water-insoluble matrix materials.

[0011] In some implementations, the hydrophilic gel skeleton material is any one or a mixture of two or more of the following in any proportion: hydroxypropyl methylcellulose, sodium alginate, inulin, konjac glucomannan, carrageenan, locust bean gum, and astragalus gum.

[0012] In some embodiments, the erosive matrix material is any one or a mixture of two or more of hydrogenated vegetable oil, stearic acid, beeswax, carnauba wax, and glyceryl behenate in any proportion.

[0013] In some implementations, the water-insoluble skeleton material is any one or a mixture of two or more of ethyl cellulose, methyl cellulose, and corn gluten in any proportion.

[0014] In some implementations, the excipients include adhesives or suspending agents.

[0015] In some embodiments, the adhesive is any one or a mixture of two or more of guar gum, gum arabic, and pectin in any proportion; the suspending agent is any one or a mixture of two or more of xanthan gum, guar gum, pectin, and agar in any proportion.

[0016] In some implementations, the sustained-release formulation can be prepared by wet granulation, hot melt granulation, or dry granulation.

[0017] In some implementations, the sustained-release formulation can be used to prepare food, beverages, nutritional products, dietary supplements, and cosmetics.

[0018] This invention, through screening the sustained-release matrix materials and the ratios of various components in sustained-release formulations of β-hydroxybutyric acid (BHA) and its salts, identified the optimal formulation ratios in various preparation processes that ensure stable release of the active substance and reduce burst release. In vitro release experiments demonstrate that the sustained-release formulations of BHA or its salts of this invention can effectively control the stable release of the active substance, thereby enabling BHA to maintain a stable and effective blood concentration in vivo for a longer period. This is of great significance for the practical application of BHA and its salts. Furthermore, the preparation methods for the sustained-release formulations of BHA or its salts of this invention can be achieved using wet granulation, hot-melt granulation, and dry granulation. The preparation processes are simple, easily reproducible, and do not use organic solvents, involve chemical reactions, or cause environmental pollution, making them suitable for industrial production. Detailed Implementation

[0019] In the foregoing summary of the invention and the detailed description of the invention in this section, as well as in the claims below, specific features of the invention have been mentioned. It should be understood that the specification of this invention discloses all possible combinations including these specific features. For example, when a specific feature is disclosed in a particular aspect or embodiment of the invention or in a particular claim, that feature may also be used as much as possible and / or in combination with other specific aspects and embodiments of the invention.

[0020] As used herein, the term “or” is intended to include both “and” and “or”. In other words, the term “or” can also be replaced with “and / or”.

[0021] As used herein, unless the context clearly indicates otherwise, the singular forms “a / an” and “the” are intended to include the plural forms as well.

[0022] As used herein, the terms “comprising” or “including” or variations thereof refer to items that are included in the context of the term in their non-restrictive sense, but do not exclude items not specifically mentioned. It also includes the more restrictive verbs 'consistently composed of' and 'comprises of'.

[0023] "Water dispersibility" refers to the speed at which a product disperses from the surface of water into water, and also the speed at which particles sink and become wetted. It is determined using the following experimental method: Take a 150ml beaker and add 100ml of 25℃ water. Let it stand for 15–45 seconds until no air bubbles appear and the water surface is calm. Take 2g of the sample (accurate to 0.01g) and quickly pour it into the water from 50mm above the center of the beaker. Time the time it takes for the sample to be completely wetted and leave the water surface, recording the time T1min. A T1min exceeding 2min is considered poor water dispersibility, while a T1min less than 1min is considered good water dispersibility.

[0024] "Release rate" refers to the rate and extent of release of an oral formulation in a specified solvent. If an oral formulation releases slowly and at a non-constant rate in a specified solvent as required, it can be called a sustained-release formulation. Specifically, it is determined using the following experimental method: Weigh an appropriate amount of sample and place it in a hydrochloric acid solution medium with a pH of 1.0. The rotation speed is 100 r / min, and the water bath temperature is 37℃. Take 5 ml of the medium solution at six time points: 0 h, 0.5 h, 1 h, 2 h, 3 h, and 5 h, and replenish with the same volume of medium solution in a timely manner. Filter the collected medium solution through a (0.45 μm) aqueous filter membrane. Perform derivatization treatment on the filtrate and then perform liquid chromatography analysis. Calculate the cumulative release rate and evaluate the release effect.

[0025] Example

[0026] In this invention, unless otherwise stated, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Furthermore, the laboratory procedures used herein are standard procedures used in the relevant fields.

[0027] Unless otherwise specified, all raw materials and reagents used in this invention are commercially available. All reagents are of commercial grade.

[0028] This invention provides a sustained-release formulation of β-hydroxybutyric acid or its salt, comprising the following components by weight percentage: main active ingredient: β-hydroxybutyric acid or its salt 40-50%, sustained-release matrix material 40-60%, and 1-3% of excipients acceptable in the field of dietary supplements as binders and 1-3% of suspending agents to form the sustained-release formulation of this invention.

[0029] By adjusting the types and proportions of components in the formulation, in vitro dissolution and animal experiments have confirmed that the above components maintain a certain blood ketone concentration over a long period of 0-5 hours. If the formulation proportions are not within the above range, the slow release effect of β-hydroxybutyric acid or salt cannot be guaranteed.

[0030] The main active ingredient β-hydroxybutyric acid or its salt is any one or a mixture of two or more of β-hydroxybutyric acid, sodium β-hydroxybutyrate, potassium β-hydroxybutyrate, calcium β-hydroxybutyrate and magnesium β-hydroxybutyrate in any proportion.

[0031] The sustained-release matrix material includes hydrophilic gel matrix materials, erosive matrix materials, and water-insoluble matrix materials. The hydrophilic gel matrix material is any one or a mixture of two or more of the following in any proportion: hydroxypropyl methylcellulose, sodium alginate, inulin, konjac glucomannan, carrageenan, locust bean gum, and astragalus gum. The erosive matrix material is any one or a mixture of two or more of the following in any proportion: hydrogenated vegetable oil, stearic acid, beeswax, carnauba wax, and glyceryl behenate. The water-insoluble matrix material is any one or a mixture of two or more of the following in any proportion: ethyl cellulose, methyl cellulose, and zein.

[0032] The auxiliary materials include adhesives or suspending agents. The adhesive is any one or a mixture of two or more of guar gum, gum arabic, and pectin in any proportion; the suspending agent is any one or a mixture of two or more of xanthan gum, jaro gum, pectin, and agar in any proportion.

[0033] Since β-hydroxybutyric acid (β-hydroxybutyric acid) or its salts are highly soluble in water, the key factor affecting the sustained-release formulation of this invention is the selection of the sustained-release matrix material. The inventors have tried various sustained-release matrix materials, ratios, and dosages, some resulting in excessively rapid release and unstable drug release, while others resulted in excessively slow release and failure to reach effective blood ketone concentrations, leading to unstable blood ketone concentrations and an inability to maintain nutritional ketone levels for extended periods. By adjusting the sustained-release matrix material and its dosage ratio in the formulation, the product of this invention exhibits excellent dispersibility in water. Furthermore, in vitro and in vivo experimental data confirm that this formulation can achieve the slow release of β-hydroxybutyric acid (β-hydroxybutyric acid) or its salts. If the formulation composition and ratio are not within the above range, it will be impossible to ensure the maintenance of a long-term effective nutritional ketogenic state, and uniform dispersion in water cannot be guaranteed.

[0034] The sustained-release formulations of β-hydroxybutyric acid or its salts of the present invention depend on their formulation composition and can be prepared using conventional solid dosage form methods in the art. The preparation methods can be selected from, but are not limited to, the following:

[0035] Method 1, wet granulation: (1) Material pretreatment: β-hydroxybutyric acid or its salt and hydrophilic gel skeleton material are sieved separately, and 50-100 mesh can be selected. (2) Weigh the erosive skeleton material and heat and stir it to a molten state under conditions higher than its melting point. (3) Weigh β-hydroxybutyric acid or its salt and add it to the erosive skeleton material obtained in step (2) under stirring conditions. After being dispersed evenly, it is cooled, crushed and sieved. (4) Weigh the adhesive material and dissolve it in water to obtain an adhesive. (5) Weigh the hydrophilic gel skeleton material and the powder obtained in step (3) and place them in a high-efficiency wet mixing granulator for granulation. Add the adhesive obtained in step (4) and perform wet granulation under certain conditions. Sieve to obtain β-hydroxybutyric acid or its salt particles. (6) Weigh the suspending material and add it to the water-insoluble skeleton material that is evenly dispersed in water. After stirring evenly, a coating solution is obtained. (7) The wet particles obtained in step (5) are placed in a fluidized bed and the coating liquid obtained in step (6) is sprayed in under certain conditions. The particles are then subjected to low-temperature boiling and drying. The intermediate material is taken from a 24-50 mesh sieve to obtain a β-hydroxybutyric acid or salt sustained-release formulation.

[0036] Method 2, hot melt granulation: (1) Material pretreatment: β-hydroxybutyric acid or its salt and the slow-release matrix material are sieved and mixed evenly in a three-dimensional mixer. (2) Hot melt granulation: The temperatures of the conveying section, melting section, mixing section and metering section of the hot melt extruder are set according to the melting point of the raw materials. After preheating and balancing for a certain period of time, the material mixed evenly in step (1) is added to the feed port of the hot melt extruder and the extruded strips are naturally cooled. (3) The strips obtained in step (2) are crushed and granulated and then sieved to obtain particles within a certain particle size range. (4) The sieved hot melt extruded particles and the suspending material are mixed evenly to obtain the β-hydroxybutyric acid or salt slow-release preparation.

[0037] Method 3, dry granulation: (1) Material pretreatment: β-hydroxybutyric acid or its salt, slow-release matrix material, and excipients are sieved and mixed evenly in a three-dimensional mixer. (2) Dry granulation: The pretreated material is fed into the hopper of a dry granulator. The feeding screw speed is 10-30 rpm, the pressure roller speed is 5-10 rpm, the pressure roller pressure is 10-50 bar, the granulator speed is 70-120 rpm, and the granulator screen aperture is 10 mesh. (3) The granules obtained in step (2) are further sieved to obtain intermediate material through a 24-50 mesh sieve to obtain the slow-release formulation of β-hydroxybutyric acid or its salt.

[0038] Example 1: β-hydroxybutyric acid sustained-release formulation A

[0039] A β-hydroxybutyric acid sustained-release formulation A comprises the following components by weight percentage:

[0040]

[0041] The production method is as follows: (1) Material pretreatment: β-hydroxybutyric acid and hydroxypropyl methylcellulose are passed through a 50-mesh sieve. (2) The amount of behenicol glyceride in the formula is weighed and heated and stirred at 80°C until it melts. (3) The amount of β-hydroxybutyric acid in the formula is weighed and added to the soluble skeleton material obtained in step (2) under stirring. After being dispersed evenly, it is cooled to room temperature and then pulverized and passed through a 50-mesh sieve. (4) The amount of guar gum in the formula is weighed and dissolved in water to obtain an adhesive. (5) The amount of hydroxypropyl methylcellulose in the formula and the powder obtained in step (3) are weighed and placed in a high-efficiency wet mixing granulator for granulation. The adhesive obtained in step (4) is added and wet granulation is carried out under the conditions of a stirring paddle speed of 240 r / min, a shear blade speed of 1800 r / min, and a granulation time of 5 min. The β-hydroxybutyric acid wet granules are obtained by passing through a 30-mesh sieve. (6) The amount of xanthan gum in the formula is weighed and added to the ethyl cellulose aqueous dispersion. After being stirred evenly, a coating solution is obtained. (7) The wet granules obtained in step (5) are placed in a fluidized bed with an inlet air temperature of 60°C, a material temperature of 50°C, and an air volume of 20-30 m³ / h. 3 Under the condition of / h, the coating liquid obtained in step (6) is sprayed in and boiled and dried until complete. The intermediate material between the 24-mesh sieve and the 50-mesh sieve is taken to obtain β-hydroxybutyric acid sustained-release formulation A.

[0042] Example 2: Preparation of sodium β-hydroxybutyrate sustained-release formulation B

[0043] Sodium β-hydroxybutyrate extended-release formulation B comprises the following components by weight percentage:

[0044]

[0045] The production method is as follows: (1) Material pretreatment: Sodium β-hydroxybutyrate and sodium alginate are passed through a 50-mesh sieve. (2) The amount of hydrogenated palm oil in the formula is heated and stirred at 40°C until it melts. (3) The amount of sodium β-hydroxybutyrate in the formula is added to the soluble skeleton material obtained in step (2) under stirring. After being dispersed evenly, it is cooled to 25°C and then crushed and passed through a 50-mesh sieve. (4) The amount of gum arabic in the formula is dissolved in water to obtain an adhesive. (5) The amount of sodium alginate in the formula and the powder obtained in step (3) are placed in a high-efficiency wet mixing granulator for granulation. The adhesive obtained in step (4) is added and wet granulation is carried out under the conditions of a stirring paddle speed of 240 r / min, a shear blade speed of 1800 r / min, and a granulation time of 5 min. The β-hydroxybutyrate wet granules are obtained by passing through a 30-mesh sieve. (6) The amount of xanthan gum in the formula is added to the coating material of ethyl cellulose dispersed in water. After stirring evenly, a coating solution is obtained. (7) The wet granules obtained in step (5) are placed in a fluidized bed with an inlet air temperature of 60°C, a material temperature of 50°C, and an air volume of 20-30 m³ / h. 3Under the condition of / h, the coating liquid obtained in step (6) is sprayed in and boiled and dried until complete. The intermediate material between the 24-mesh sieve and the 50-mesh sieve is taken to obtain sodium β-hydroxybutyrate sustained-release formulation B.

[0046] Example 3: Preparation of magnesium β-hydroxybutyrate sustained-release formulation C

[0047] Magnesium β-hydroxybutyrate sustained-release formulation C comprises the following components by weight percentage:

[0048]

[0049] The production method is as follows: (1) Material pretreatment: Magnesium β-hydroxybutyrate and sodium alginate are passed through a 50-mesh sieve. (2) Stearic acid of the formula amount is heated and stirred at 75°C until it melts. (3) Magnesium β-hydroxybutyrate of the formula amount is added to the soluble skeleton material obtained in step (2) under stirring. After being dispersed evenly, it is cooled to room temperature and then crushed and passed through a 50-mesh sieve. (4) Gum arabic of the formula amount is dissolved in water to obtain an adhesive. (5) Sodium alginate of the formula amount and the powder obtained in step (3) are placed in a high-efficiency wet mixing granulator for granulation. The adhesive obtained in step (4) is added and wet granulation is carried out under the conditions of stirring paddle speed of 140r / min, shear blade speed of 2100r / min, and granulation time of 5min. The β-hydroxybutyrate wet granules are obtained by passing through a 30-mesh sieve. (6) Guar gum of the formula amount is added to corn gluten that is dispersed in water and stirred evenly to obtain a coating solution. (7) The wet particles obtained in step (5) are placed in a fluidized bed and the coating liquid obtained in step (6) is sprayed in under the conditions of air inlet temperature of 60℃, material temperature of 50℃ and air volume of 20~30m3 / h. The mixture is boiled and dried until complete. The intermediate material between 24 mesh sieve and 50 mesh sieve is used to obtain β-hydroxybutyrate magnesium sustained-release formulation C.

[0050] Example 4: Preparation of β-hydroxybutyrate mixed salt sustained-release formulation D

[0051] The β-hydroxybutyrate mixed salt sustained-release formulation D comprises the following components by weight percentage:

[0052]

[0053] The production method is as follows: (1) Material pretreatment: three types of β-hydroxybutyrate and sodium alginate are passed through a 50-mesh sieve. (2) The amount of beeswax in the formula is heated and stirred at 80°C until it melts. (3) The amount of β-hydroxybutyric acid mixed salt in the formula is added to the soluble skeleton material obtained in step (2) under stirring. After being dispersed evenly, it is cooled to room temperature and then crushed and passed through a 50-mesh sieve. (4) The amount of pectin in the formula is dissolved in water to obtain an adhesive. (5) The amount of sodium carboxymethyl cellulose in the formula and the powder obtained in step (3) are placed in a high-efficiency wet mixing granulator for granulation. The adhesive obtained in step (4) is added and wet granulation is carried out under the conditions of stirring paddle speed of 240 r / min, shear blade speed of 1800 r / min, and granulation time of 5 min. The β-hydroxybutyric acid mixed salt wet granules are obtained by passing through a 30-mesh sieve. (6) The amount of xanthan gum in the formula is added to the coating material dispersed in water and stirred evenly to obtain a coating solution. (7) The wet granules obtained in step (5) are placed in a fluidized bed with an inlet air temperature of 60°C, a material temperature of 50°C, and an air volume of 20-30 m³ / h. 3 Under the condition of / h, the coating liquid obtained in step (6) is sprayed in and boiled and dried until complete. The intermediate material between the 24-mesh sieve and the 50-mesh sieve is taken to obtain the β-hydroxybutyric acid mixed salt sustained-release formulation D.

[0054] Example 5: Preparation of Potassium β-hydroxybutyrate sustained-release formulation E

[0055] Potassium β-hydroxybutyrate sustained-release formulation comprises the following components by weight percentage:

[0056]

[0057] The production method is as follows: (1) Material pretreatment: The raw and auxiliary materials of the prescription amount are processed through a 50-mesh sieve and mixed evenly in a three-dimensional mixer. (2) Extrusion and granulation: The temperatures of the conveying section, melting section, mixing section and metering section of the hot melt extruder are set to 90℃-150℃-150℃-150℃-100℃ respectively. After preheating and balancing for 20 minutes, the material mixed evenly in step (1) is added evenly to the feed port of the hot melt extruder. The extruded strips are cooled naturally. (3) The strips obtained in step (2) are crushed, granulated and sieved to obtain particles with a certain particle size range. (4) The sieved hot melt extruded particles and the suspending agent xanthan gum are mixed evenly to obtain potassium β-hydroxybutyrate sustained-release preparation E.

[0058] Example 6: Preparation of sodium β-hydroxybutyrate sustained-release formulation F

[0059] The sustained-release formulation of sodium β-hydroxybutyrate comprises the following components by weight percentage:

[0060]

[0061] The production method is as follows: (1) Material pretreatment: The raw and auxiliary materials of the prescription amount are processed through a 50-mesh sieve and mixed evenly in a three-dimensional mixer. (2) Extrusion and granulation: The temperatures of the conveying section, melting section, mixing section and metering section of the hot melt extruder are set to 65℃-75℃-80℃-90℃-90℃ respectively. After preheating and balancing for 20 minutes, the material mixed evenly in step (1) is added evenly to the feed port of the hot melt extruder. The extruded strips are cooled naturally. (3) The strips obtained in step (2) are crushed, granulated and sieved to obtain particles with a certain particle size range. (4) The sieved hot melt extruded particles and the suspending material guar gum are mixed evenly to obtain β-hydroxybutyrate potassium sustained-release preparation F.

[0062] Example 7: Preparation of β-hydroxybutyrate calcium sustained-release formulation G

[0063] The sustained-release formulation of calcium β-hydroxybutyrate comprises the following components by weight percentage:

[0064]

[0065] The production method is basically the same as that of sustained-release formulation F.

[0066] Example 8: Preparation of β-hydroxybutyric acid mixed salt release formulation H

[0067] The β-hydroxybutyrate mixed salt sustained-release formulation comprises the following components by weight percentage:

[0068]

[0069] The production method is basically the same as that of sustained-release formulation F, and the suspending material is xanthan gum.

[0070] Example 9: Preparation of β-hydroxybutyrate calcium sustained-release formulation I

[0071] The sustained-release formulation of calcium β-hydroxybutyrate comprises the following components by weight percentage:

[0072]

[0073] The production method is as follows: (1) Material pretreatment: The prescribed amounts of calcium β-hydroxybutyrate, hydroxypropyl methylcellulose, behenicol glyceride and pectin are sieved and mixed evenly in a three-dimensional mixer. (2) Dry granulation: The pretreated material is fed into the hopper of a dry granulator. The feeding screw speed is 10-30 rpm, the pressure roller speed is 5-10 rpm, the pressure roller pressure is 10-50 bar, the granulator speed is 70-120 rpm, and the granulator screen aperture is 10 mesh. (3) The collected particles are further sieved to obtain intermediate material through a 24-50 mesh sieve to obtain calcium β-hydroxybutyrate sustained-release formulation I.

[0074] Example 10: Preparation of potassium β-hydroxybutyrate sustained-release formulation J

[0075] Potassium β-hydroxybutyrate sustained-release formulation comprises the following components by weight percentage:

[0076]

[0077] The production method is basically the same as that of sustained-release formulation I. The material pretreatment in step (1) is as follows: the prescribed amount of potassium β-hydroxybutyrate, inulin, carnauba wax and xanthan gum are sieved and then mixed evenly in a three-dimensional mixer.

[0078] Example 11 Preparation of magnesium β-hydroxybutyrate sustained-release formulation K

[0079] Magnesium β-hydroxybutyrate sustained-release formulations comprise the following components by weight percentage:

[0080]

[0081] The production method is basically the same as that of sustained-release formulation I. The material pretreatment in step (1) is as follows: the prescribed amount of magnesium β-hydroxybutyrate, sodium alginate, stearic acid and xanthan gum are sieved and then mixed evenly in a three-dimensional mixer.

[0082] Example 12: Preparation of β-hydroxybutyrate mixed salt sustained-release formulation L

[0083] The β-hydroxybutyrate mixed salt sustained-release formulation comprises the following components by weight percentage:

[0084]

[0085] The production method is basically the same as that of sustained-release formulation I. The material pretreatment in step (1) is as follows: the prescribed amount of sodium β-hydroxybutyrate, calcium β-hydroxybutyrate, magnesium β-hydroxybutyrate, astragalus gum, carnauba wax and guar gum are sieved and then mixed evenly in a three-dimensional mixer.

[0086] Example 13 evaluates the water dispersibility of β-hydroxybutyric acid and its salt-release formulations prepared in the above examples.

[0087] Water dispersibility evaluation: Take a 150ml beaker and add 100ml of 25℃ water. Let it stand for 15-45s until there are no bubbles in the water and the water surface is calm. Take 2g each of β-hydroxybutyric acid oral sustained-release dry suspension A-L (accurate to 0.01g) and quickly pour them into the water from 50mm above the center of the beaker. Time the time required for the sample to be completely wetted and leave the water surface, and record the required time T1,min. The results are shown in Table 1 below.

[0088] Table 1. Water dispersibility of β-hydroxybutyric acid and its sustained-release formulations

[0089] Example Sustained-release formulations T1(min) 1 Sustained-release formulation A 0.8 2 Sustained-release formulation B 0.4 3 Sustained-release formulation C 0.6 4 Sustained-release formulation D 0.8 5 Sustained-release formulation E 0.8 6 Sustained-release formulation F 0.9 7 Sustained-release formulation G 0.7 8 Sustained-release formulation H 0.5 9 Sustained-release formulation I 0.7 10 Sustained-release formulation J 0.8 11 Sustained-release formulation K 0.8 12 Sustained-release formulation L 0.9

[0090] According to the pharmacopoeia, a T1 exceeding 2 minutes is considered poor water dispersibility, while a T1 less than 1 minute is considered good water dispersibility. The β-hydroxybutyric acid sustained-release formulations prepared using the processes in Examples 1-12 all exhibit good water dispersibility.

[0091] Example 14 evaluates the water release rate of β-hydroxybutyric acid and its salt sustained-release formulations prepared in the above examples.

[0092] Appropriate amounts of β-hydroxybutyric acid sustained-release formulations A through L were weighed and placed in hydrochloric acid solution at pH 1.0. The solution was heated at 100 rpm in a water bath at 37°C. At six time points (0 h, 0.5 h, 1 h, 2 h, and 5 h), 5 ml of the solution was collected and replenished with the same volume of solution. The collected solutions were filtered through a 0.45 μm aqueous filter membrane. The filtrate was derivatized and then analyzed by liquid chromatography. The cumulative release rate was calculated, and the release effect was evaluated. The results are shown in Table 2 below.

[0093] Table 2 Evaluation of the release rate of β-hydroxybutyric acid and its sustained-release formulations

[0094]

[0095]

[0096] As can be seen from Table 2, compared with the raw material data, β-hydroxybutyric acid and its salt sustained-release formulations A to L all exhibit a slow and continuous release characteristic of 2 to 5 hours or more.

[0097] While specific embodiments and examples of the invention have been described herein, those skilled in the art will understand that any modifications and variations can be made without departing from the principles of the invention. The above embodiments and descriptions do not limit the scope of the invention. Any combination of embodiments of the invention, as well as any obvious extensions or analogies thereof, are within the scope of the invention. Furthermore, the invention covers any arrangement intended to achieve the same purpose, and all such variations and modifications falling within the scope of the appended claims.

Claims

1. A sustained-release formulation of β-hydroxybutyric acid or a salt thereof, characterized in that: It comprises the following components by weight percentage: 40-50% β-hydroxybutyric acid or its salt, 40-60% sustained-release matrix material, and 1-3% excipients. The sustained-release matrix material includes a soluble matrix material, which is any one or a mixture of two of hydrogenated vegetable oil and stearic acid in any proportion. The sustained-release matrix material also includes one or more of hydrophilic gel matrix materials and water-insoluble matrix materials. The hydrophilic gel matrix material is any one or a mixture of two or more of hydroxypropyl methylcellulose, sodium alginate, inulin, konjac glucomannan, carrageenan, locust bean gum, and astragalus gum in any proportion. The water-insoluble matrix material is any one or a mixture of two or more of ethyl cellulose, methylcellulose, and zein in any proportion.

2. The sustained-release formulation according to claim 1, characterized in that, The β-hydroxybutyric acid or its salts are selected from any one or more of the following in any proportion: β-hydroxybutyric acid, sodium β-hydroxybutyrate, potassium β-hydroxybutyrate, calcium β-hydroxybutyrate, and magnesium β-hydroxybutyrate.

3. The sustained-release formulation according to claim 1, characterized in that, The auxiliary materials include adhesives or suspending materials.

4. The sustained-release formulation according to claim 3, characterized in that, The adhesive material is any one or a mixture of two or more of guar gum, gum arabic, and pectin in any proportion; the suspending material is any one or a mixture of two or more of xanthan gum, guar gum, pectin, and agar in any proportion.

5. The method for preparing the sustained-release formulation according to any one of claims 1-4, characterized in that, It includes wet granulation, hot melt granulation, or dry granulation.

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