Composition containing vitamin D3 and provitamin D3 and preparation method thereof

Abstract

The invention relates to the field of pharmacy, in particular to a composition containing vitamin D3 and provitamin D3 and a preparation method of the composition. The provitamin D3 and the vitamin D3 are simultaneously clathrated by cyclodextrin to form a water-soluble clathrate compound, and the provitamin D3 and the vitamin D3 are stabilized at a certain ratio to maintain the stability of the vitamin D3. The preparation method disclosed by the invention is simple, low in equipment requirement, simple in process and operation, suitable for large-scale production and capable of greatly reducing the production cost.

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, specifically to a composition containing vitamin D3 and previtamin D3 and a method for preparing the same. Background Technology

[0002] Calcium is an essential element for the human body, participating in all aspects of life, from bone formation, muscle contraction, heartbeat, nerve and brain activity, to growth and development, fatigue relief, brain health, and slowing down aging. Therefore, adequate daily calcium intake is necessary to maintain normal metabolism and enhance the body's adaptability to the environment.

[0003] Vitamin D3 plays a vital role in promoting calcium absorption, inducing calcium and phosphorus deposition, and preventing rickets. However, vitamin D3 deficiency is widespread in the population, requiring supplementation for a large number of people. To meet the body's need for vitamin D3, researchers have developed oral solid dosage forms of calcium carbonate-vitamin D3 (including granules, tablets, chewable tablets, etc.) and alendronate sodium vitamin D3 tablets. However, developing vitamin D3-containing formulations presents numerous technical challenges, including: vitamin D3 is sensitive to light, oxygen, and acid, and is easily degraded under these conditions, resulting in poor stability, reduced content, and increased impurities; the unit dose of vitamin D3 in formulations is extremely low, typically only 60-200 IU (1.5-5.0 μg), making it difficult to achieve uniform mixing with other active pharmaceutical ingredients and excipients, failing to meet the pharmaceutical standard of RSD < 6% for uniform mixing; and the pretreatment of vitamin D3 (such as preparation into inclusion complexes) is particularly important.

[0004] Therefore, the industry needs a vitamin D3-containing formulation that has good long-term stability, high uniformity, simple preparation, and low cost. Summary of the Invention Invention Overview To address the above problems, the present invention provides a vitamin D3 inclusion complex and a method for preparing the same, and also provides a formulation containing the vitamin D3 inclusion complex.

[0006] On one hand, the present invention provides a composition containing vitamin D3 and pre-vitamin D3 and a method for preparing the same. In the composition, pre-vitamin D3 and vitamin D3 can interconvert under heating conditions, with pre-vitamin D3 isomerizing to vitamin D3. The rate of this isomerization reaction increases with increasing temperature. Pre-vitamin D3 and vitamin D3 are simultaneously included by cyclodextrin to form a water-soluble inclusion complex. In the presence of cyclodextrin, the conversion of pre-vitamin D3 generated by heating to vitamin D3 is accelerated. Finally, pre-vitamin D3 and vitamin D3 are stabilized at a certain ratio, maintaining the stability of vitamin D3.

[0007] On the other hand, the present invention solves the problem of mixing uniformity by adding the vitamin D3-containing solution via wet granulation and atomization spray. The vitamin D3-containing and pre-vitamin D3-containing compositions and calcium-containing compositions prepared by the present invention have uniform content and good stability. The preparation method of the present invention is simple, requires low equipment, has simple process and operation, is suitable for large-scale production, and significantly reduces production costs. Invention Details This invention provides a composition containing vitamin D3 and previtamin D3 and a method for preparing the same.

[0009] In a first aspect, the present invention provides a composition comprising previtamin D3, vitamin D3, and cyclodextrin, wherein the cyclodextrin is β-cyclodextrin or γ-cyclodextrin, and optionally, the composition comprises at least one water-soluble polymer.

[0010] In some embodiments, the water-soluble polymer comprises at least one of HPMC (hydroxypropyl methylcellulose), PVP (povidone or polyvinylpyrrolidone), and HPC (hydroxypropyl cellulose).

[0011] In some implementations, the ratio of vitamin D3 to previtamin D3 is 1:1 to 8:1.

[0012] In some implementations, the ratio of vitamin D3 to previtamin D3 is 1:1 to 5:1.

[0013] In some implementations, the ratio of vitamin D3 to previtamin D3 is 1:1 to 3:1.

[0014] In some implementations, the ratio of vitamin D3 to previtamin D3 is 1:1 to 2:1.

[0015] In some embodiments, the composition wherein the mass ratio of the sum of the masses of previtamin D3 and vitamin D3 to the mass ratio of β-cyclodextrin or γ-cyclodextrin is 1:50 to 1:2500.

[0016] In some embodiments, the composition wherein the mass ratio of the sum of the masses of previtamin D3 and vitamin D3 to the mass of β-cyclodextrin or γ-cyclodextrin is 1:100 to 1:2000.

[0017] In some embodiments, the composition wherein the mass ratio of the sum of the masses of previtamin D3 and vitamin D3 to the mass of β-cyclodextrin or γ-cyclodextrin is 1:200 to 1:1000.

[0018] In some embodiments, the composition wherein the mass ratio of the sum of the masses of previtamin D3 and vitamin D3 to the mass ratio of β-cyclodextrin or γ-cyclodextrin is 1:100.

[0019] In some embodiments, the composition wherein the mass ratio of the sum of the masses of previtamin D3 and vitamin D3 to the mass ratio of β-cyclodextrin or γ-cyclodextrin is 1:200.

[0020] In some embodiments, the composition wherein the mass ratio of the sum of the masses of previtamin D3 and vitamin D3 to the mass of β-cyclodextrin or γ-cyclodextrin is 1:1000.

[0021] In some embodiments, the composition wherein the mass ratio of the sum of the masses of previtamin D3 and vitamin D3 to the mass of β-cyclodextrin or γ-cyclodextrin is 1:2000.

[0022] On the other hand, the present invention provides a calcium-containing composition, wherein the calcium-containing composition comprises the composition described in the present invention, and at least one of calcium carbonate, calcium citrate and calcium gluconate.

[0023] In some embodiments, the calcium-containing composition comprises the composition of the present invention and calcium carbonate.

[0024] In some embodiments, the calcium-containing composition comprises pharmaceutically acceptable excipients or excipients.

[0025] In some embodiments, the pharmaceutically acceptable excipient or excipient comprises at least one of fillers, flavoring agents, binders, and flavorings.

[0026] In some embodiments, the calcium carbonate accounts for 30%-70% of the total weight of the calcium-containing composition.

[0027] In some embodiments, the calcium carbonate accounts for 40%-60% of the total weight of the calcium-containing composition.

[0028] In some embodiments, the filler comprises at least one of mannitol, sorbitol, sucrose, maltodextrin, and maltitol.

[0029] In some embodiments, the filler accounts for 20%-70% of the total weight of the calcium-containing composition.

[0030] In some embodiments, the filler accounts for 30%-60% of the total weight of the calcium-containing composition.

[0031] In some embodiments, the flavoring agent comprises at least one of sucralose, aspartame, and steviol glycosides.

[0032] In some embodiments, the flavoring agent accounts for 0.015%-2% of the total weight of the calcium-containing composition.

[0033] In some embodiments, the flavoring agent accounts for 0.05%-1% of the total weight of the calcium-containing composition.

[0034] In some embodiments, the adhesive comprises at least one of HPMC, PVP, and HPC.

[0035] In some embodiments, the adhesive is HPMCE5.

[0036] In some embodiments, the flavoring comprises at least one of pharmaceutically acceptable orange flavoring, strawberry flavoring, peppermint flavoring, milk flavoring, pineapple flavoring, and peach flavoring.

[0037] In some embodiments, the flavoring accounts for 0.2%-1.0% of the total weight of the calcium-containing composition.

[0038] In some embodiments, the flavoring comprises 0.4%-0.6% of the total weight of the calcium-containing composition.

[0039] On the other hand, the calcium-containing composition provided by the present invention can be prepared into granules, tablets or chewable tablets.

[0040] On the other hand, the present invention provides a method for preparing the composition of the present invention, comprising: (1) Preparation of anhydrous ethanol solution of vitamin D3 Weigh out the prescribed amount of vitamin D3, dissolve it in an appropriate amount of anhydrous ethanol, mix well, and prepare a 0.5-10 mg / ml vitamin D3 anhydrous ethanol solution. (2) Preparation of aqueous solutions of β-cyclodextrin or γ-cyclodextrin Weigh the prescribed amount of β-cyclodextrin or γ-cyclodextrin into an aqueous solution to prepare a solution with a solid content of 1%-10%, and stir to dissolve in a water bath at a temperature of 30℃-80℃; add a certain amount of water-soluble polymer to dissolve, so that the concentration of the water-soluble polymer in the β-cyclodextrin aqueous solution is in the range of 0.1%-8%; (3) In a water bath at 55°C, under stirring and in the dark, add the anhydrous ethanol solution of vitamin D3 from step (1) to the aqueous solution of β-cyclodextrin or γ-cyclodextrin for inclusion, with an inclusion time range of 0.5h-10h; to obtain a β-cyclodextrin or γ-cyclodextrin inclusion solution containing vitamin D3 and pre-vitamin D3.

[0041] In some implementations, the solid content is 3%-8%.

[0042] In some implementations, the solid content is 4%-6%.

[0043] In some embodiments, the solid content is 4%; In some implementations, the water bath temperature is 40°C-60°C.

[0044] In some implementations, the water bath temperature is 50°C-60°C.

[0045] In some implementations, the water bath temperature is 55°C.

[0046] In some embodiments, the water-soluble polymer comprises at least one of HPMC, PVP, and HPC.

[0047] In some embodiments, the water-soluble polymer is HPMCE5.

[0048] In some embodiments, the concentration of the water-soluble polymer in the β-cyclodextrin aqueous solution is in the range of 5%.

[0049] On the other hand, the present invention provides a method for preparing the calcium-containing composition of the present invention, comprising: (1) Use calcium carbonate, calcium citrate or calcium gluconate and pharmaceutically acceptable excipients as high-shear granulation substrates in a high-shear granulation pot. (2) The inclusion liquid prepared in this invention is atomized and sprayed into a high-shear granulation pot for mixing. An appropriate amount of 5% HPMCE5 is added for high-shear granulation, or further shake granulation is performed. Then, the mixture is dried and granulated. Flavoring is added and mixed evenly to obtain calcium-containing composition granules. After the obtained granules and lubricant are mixed, they can be further compressed into tablets or chewable tablets.

[0050] In some embodiments, the atomization pressure of the atomized injection is 0.1 MPa to 0.3 MPa.

[0051] In some embodiments, the atomization pressure of the atomized injection is 0.15 MPa to 0.2 MPa.

[0052] In some implementations, the drying air inlet temperature is 50°C-60°C.

[0053] In some implementations, the drying air inlet temperature is 55°C.

[0054] In some implementations, the moisture content of the dried material is controlled to be less than 0.5%.

[0055] In some implementations, the moisture content of the dried material is controlled to be less than 0.3%.

[0056] In some embodiments, the lubricant comprises at least one of magnesium stearate and sodium stearate fumarate; In some embodiments, the lubricant accounts for 0.5%-2.0% of the total weight of the calcium-containing composition.

[0057] In some embodiments, the lubricant accounts for 1% of the total weight of the calcium-containing composition.

[0058] Terminology Explanation As used in this invention, the following words and phrases are generally intended to have the meanings described below, unless the context otherwise requires.

[0059] The term "comprising" and its variations, such as "including" and "comprise," should be understood as open-ended, meaning "including but not limited to." When used to define compositions and methods, "consistently composed of" or its grammatical variations should indicate the exclusion of other elements that have any significant meaning to the composition and preparation method, but not the exclusion of factors that do not have a substantial impact on the composition and preparation method. "Constituted of" or its grammatical variations should indicate the exclusion of elements not expressly listed. Embodiments defined by these transitional terms are all within the scope of this invention. For example, when a formulation is described as comprising ingredients A, B, and C, the formulation being substantially composed of A, B, and C and the formulation being composed of A, B, and C are independently within the scope of this invention.

[0060] Unless the context clearly indicates otherwise, the singular forms “one,” “an,” and “the” include plural references. For example, the reference to “excipient” includes multiple excipients.

[0061] Unless the context clearly specifies otherwise, "multiple" or "various" includes plural references of two or more. For example, "various excipients" includes two or more excipients.

[0062] As used herein, in the context of quantitative measurement, the term “about” means ±10%, ±5%, or ±1% of the value. For example, “about 10” means 9–11, 9.5–10.5, or 9.9–10.1. The term “about X” also includes “X”.

[0063] The descriptions of numerical ranges in this document are intended as a shorthand for referring to each individual value falling within that range. Unless otherwise stated herein, each individual value is incorporated into this specification as if it were cited separately herein.

[0064] As used herein, the term "% w / w" refers to the percentage by weight of a component in a composition or mixture containing that component.

[0065] The term "pharmaceutically acceptable" refers to a material that is not biologically or otherwise undesirable; for example, the material can be incorporated into a pharmaceutical formulation given to a patient without causing any significant adverse biological effects or interacting with other components of the formulation in any harmful manner. Pharmaceutically acceptable carriers (e.g., carriers, adjuvants, and / or other excipients) preferably meet toxicological and manufacturing testing standards and / or contain inactive ingredients as defined in the guidelines issued by the U.S. Food and Drug Administration.

[0066] The terms “excipient” or “pharmaceuticalally acceptable excipient” or “pharmaceuticalally acceptable formulation” refer to fillers, diluents, disintegrants, precipitation inhibitors, surfactants, gliding agents, binders, lubricants, and other excipients and carriers that are administered with a compound. The excipients or formulations described in this article are described in EW Martin’s “Remington’s Pharmaceutical Sciences”.

[0067] The term "filler" refers to a compound that facilitates the shaping of a drug. Non-limiting examples of fillers include lactose, sucrose, fructose, fructooligosaccharides, glucose, maltose, powdered sugar, D-mannitol, erythritol, xylitol and other sugar alcohols, corn starch, potato starch, rice starch, some α-starch and other starches, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate and other inorganic salts.

[0068] The term "binder" refers to any pharmaceutically acceptable excipient used to bind active and inert ingredients together to maintain viscous and discrete portions. Non-limiting examples of binders include hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, copovidone, and ethyl cellulose.

[0069] The term "lubricant" refers to a substance added to a powder mixture to prevent compacted powder material from adhering to equipment during tableting or encapsulation. Lubricants can help tablets eject from the die and can improve powder flow. Non-limiting examples of lubricants include magnesium stearate, stearic acid, micronized silica, fats, calcium stearate, polyethylene glycol, sodium stearoyl fumarate, sucrose fatty acid esters, or talc; and solubilizers such as fatty acids, including lauric acid, oleic acid, and C8 / C10 fatty acids.

[0070] Cyclodextrins and their derivatives are compounds (cyclic oligosaccharides) in which sugar molecules (e.g., glucose) or their derivatives are linked together in a ring. Cyclodextrin derivatives include derivatives of α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin, wherein one or more hydrogen atoms of the hydroxyl group are substituted with substituents, such as alkyl or substituted alkyl (-R), acyl (-C(O)R), and sulfate (-S(O)2OH or a salt thereof), wherein R is an alkyl or substituted alkyl group. In some embodiments, R is an alkyl group (C1-C6 alkyl) having 1, 2, 3, 4, 5, or 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, etc. In some embodiments, R is an alkyl group substituted with one or more substituents independently selected from hydroxyl and sulfate groups, such as hydroxymethyl (-CH2OH) or sulfobutyl (-CH2CH2CH2CH2S(O)2OH or a salt thereof). Examples of cyclodextrins and their derivatives include, but are not limited to, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin (also known as hydroxypropyl cellulose beta-cyclodextrin, β-cyclodextrin hydroxypropyl ether, or HPBCD), 2-hydroxypropyl-β-cyclodextrin, sulfonyl-β-cyclodextrin, dihydro-β-cyclodextrin, methyl-β-cyclodextrin, dimethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, sodium β-cyclodextrin-sulfonyl ether (also known as sulfonyl ether-β-cyclodextrin, sulfonyl ether-β-cyclodextrin sodium salt, sulfonyl ether-β-cyclodextrin, sulfonyl ether-β-cyclodextrin sodium salt), glucose cyclodextrin, maltodextrin, carboxymethyl cyclodextrin, and sulfonyl alkyl cyclodextrin.

[0071] The structural formulas of vitamin D3 and pre-vitamin D3 are shown below: (Vitamin D3) (Previtamin D3).

[0072] Beneficial effects Compared with the prior art, the present invention provides a composition containing vitamin D3 and previtamin D3 and a method for preparing the same, which has at least the following technical advantages: 1. In this invention, pre-vitamin D3 and vitamin D3 are simultaneously included by cyclodextrin to form a water-soluble inclusion complex. In the presence of cyclodextrin, pre-vitamin D3 and vitamin D3 are stably maintained at a certain ratio, thus maintaining the stability of vitamin D3.

[0073] 2. This invention solves the problem of uniform mixing by adding a solution containing vitamin D3 through wet granulation and atomizing the solution.

[0074] 3. The preparation method of the present invention is simple, has low equipment requirements, is simple in process and operation, is suitable for large-scale production, and significantly reduces production costs. Attached Figure Description

[0075] Figure 1 This is a flowchart illustrating the process for preparing the calcium-containing composition of the present invention. Detailed Implementation

[0076] Those skilled in the art will understand that the following embodiments are intended to illustrate the invention and not to limit it. Various modifications and variations of the invention will be apparent to those skilled in the art. Unless specifically stated otherwise, where specific techniques or conditions are not explicitly described in the following embodiments, those skilled in the art can follow commonly used techniques or conditions in the art or according to the product instructions. All pharmaceuticals, reagents, or instruments used, unless otherwise specified, are commercially available, conventional products.

[0077] Unless otherwise specified, the terms “Mean±SD” mean ± standard deviation; “min” means minutes; “M” means moles per liter; “V / V” means volume ratio; “pH” means acidity or alkalinity; “nm” means nanometer; “g” means gram; “ng” means nanogram; “mL” means milliliter; “h” means hour; “LC-MS-MS” means liquid chromatography-mass spectrometry; “90%CI” means 90% confidence interval; and “n” or “N” in pharmacokinetic studies means the number of subjects.

[0078] Process flow diagram for the preparation of calcium-containing compositions: see Figure 1 .

[0079] The preparation process of this invention is simple to operate, has low requirements for equipment and technology, and is suitable for large-scale production.

[0080] Comparative Example 1: The commercially available product, Dicalcium Phosphate Granules (calcium carbonate D3 granules), underwent stability testing at 50°C for 30 days. The vitamin D3 content significantly decreased. Previtamin D3 remained stable, while vitamin D3 gradually decreased at a greater rate than previtamin D3, resulting in a lower vitamin D3 / previtamin D3 ratio. The low previtamin D3 content was significantly affected by methodological biases. The vitamin D3 in Dicalcium Phosphate Granules is a pre-treated microencapsulated material, which is then directly mixed with other materials to obtain the granules (refer to patent CN111617042A). Previtamin D3 can be converted into vitamin D3 in vivo, and the vitamin D3 content includes both previtamin D3 and the total vitamin D3 content. In the following stability studies, accelerated conditions refer to (40°C, 75%RH), and long-term conditions refer to (25°C, 60%RH).

[0081] Table 1: Stability of Dicalcium Phosphate Content at 50℃ and Ratio of Vitamin D3 to Previtamin D3 in Dicalcium Phosphate

[0082] Table 2: Accelerated stability of Dicalcium Phosphate content and ratio of vitamin D3 to previtamin D3

[0083] Comparative Example 2: The stability of commercially available vitamin D3 products, namely D-Cal chewable tablets (calcium carbonate D3 chewable tablets) and D-Cal tablets (calcium carbonate D3 tablets), was investigated by sampling at 50℃ and under accelerated conditions.

[0084] Table 3: Stability of D-Cal Chewable Tablets at 50℃ and Ratio of Vitamin D3 to Previtamin D3

[0085] Table 4: Stability of Dicalcium Phosphate Content at 50℃ and Ratio of Vitamin D3 to Previtamin D3 in Dicalcium Phosphate Tablets

[0086] Table 5: Accelerated Conditional Stability of Dicalcium Phosphate Content and Ratio of Vitamin D3 to Previtamin D3 in Dicalcium Phosphate Chewable Tablets

[0087] Table 6: Accelerated stability of Dicalcium Phosphate content and ratio of vitamin D3 to previtamin D3 in Dicalcium Phosphate Tablets

[0088] The study found that among the three dosage forms developed by Dicalcium Carbonate—tablets, chewable tablets, and granules—the granules exhibited the worst vitamin D3 stability, with a 45.1% decrease in vitamin D3 content after 30 days at 50℃ and a 56.7% decrease after 6 months of accelerated testing. Tablets showed the best stability, with a 6.5% decrease in vitamin D3 content after 30 days at 50℃ and a 13.3% decrease after 6 months of accelerated testing. Considering the unstable nature of vitamin D3, and given the larger surface area of ​​granules, vitamin D3 stability is even worse in granules. The stability of vitamin D3 in calcium carbonate D3 granules remains an unsolved technical challenge.

[0089] Comparative Example 3: The commercially available product, Calcium Carbonate Granules (calcium carbonate D3 granules), exhibited stability at 50°C for 30 days, but the vitamin D3 content significantly decreased. Previtamin D3 levels remained stable, but the vitamin D3 / previtamin D3 ratio gradually decreased as vitamin D3 levels decreased. According to the preparation process described in the relevant patent (CN118319865A) applied for by the Calcium Carbonate Granules manufacturer, an ethanol solution containing vitamin D3, binder (PVPK30), and antioxidant (BHA) is added to calcium carbonate via spraying, followed by wet granulation, resulting in poor product stability.

[0090] Table 7: Stability of Calcium Granules at 50℃ and Ratio of Vitamin D3 to Previtamin D3

[0091] Table 8: Accelerated stability of calcium granules and ratio of vitamin D3 to previtamin D3

[0092] Commercially available calcium granules exhibit poor stability under accelerated and high-temperature conditions, resulting in a significant decrease in their content.

[0093] Comparative Example 4: The commercially available product, Lizhizhu Compound Calcium Carbonate Granules (Calcium Carbonate D3 Granules) (β-CD:Vitamin D3 molar ratio 6:1, i.e., mass ratio 17.7:1), showed stability at 50℃ for 30 days. The vitamin D3 content decreased significantly. Both vitamin D3 and pre-vitamin D3 decreased simultaneously, while the vitamin D3 / pre-vitamin D3 ratio remained relatively stable.

[0094] According to the cyclodextrin inclusion process described in the patent (ZL201110139889.8) related to Lizhizhu products, the stability of the obtained inclusion complex is not ideal. Vitamin D3 is easily degraded under high temperature and humidity conditions, and has high requirements for the environment during transportation, storage and use. It needs to be stored below 25°C, while the normal room temperature is often higher than 25°C, especially in the hot summer, which has a greater impact on the stability of the product.

[0095] Table 9: Stability of Lizhizhu Compound Calcium Carbonate Granules at 50℃ and Ratio of Vitamin D3 to Previtamin D3

[0096] Table 10: Stability of Lizhizhu Compound Calcium Carbonate Granules under Accelerated and Long-Term Conditions and Ratio of Vitamin D3 to Previtamin D3

[0097] Comparative Example 5: After wet granulation of DSM vitamin D3 powder samples and exposure to 50°C for 30 days, the vitamin D3 content decreased by 18.6%. The pre-vitamin D3 content was low, and the vitamin D3 content gradually decreased, while the vitamin D3 / pre-vitamin D3 ratio remained relatively stable. The wet granulation process affects the stability of conventionally encapsulated vitamin D3, disrupting the structure of the vitamin D3 microcapsules and impacting stability. Furthermore, the relatively large particle size of DSM vitamin D3 powder increases the risk of poor mixing uniformity; the RSD of the sampled mixing uniformity was greater than 5%, indicating poor mixing uniformity.

[0098] Table 11: Prescription Table for Comparative Example 5

[0099] Table 12: Stability of Vitamin D3 and Ratio of Previtamin D3 in Comparative Example 5 at 50℃

[0100] Table 13: Mixing uniformity of Comparative Example 5

[0101] Comparative Example 6: Vitamin D3 was directly dissolved in anhydrous ethanol and granulated using a high-shear wet granulation process. After 30 days at 50°C, the vitamin D3 content decreased significantly. The initial vitamin D3 content was low, and during the stabilization process, the initial vitamin D3 content remained stable, gradually decreasing, as did the vitamin D3 / pre-vitamin D3 ratio. Using anhydrous ethanol spraying resulted in good content uniformity.

[0102] Table 14: Stability of Vitamin D3 and Ratio of Previtamin D3 at High Temperature of Comparative Example 6 at 50℃

[0103] Table 15: Comparative Example 6: Content Stability under Accelerated and Long-Term Conditions and Ratio of Vitamin D3 to Previtamin D3

[0104] Table 16: Mixing uniformity of Comparative Example 6

[0105] Example 1: Example 1 Prescription Table

[0106] The direct mixing stability of DSM vitamin D3 powder was tested at 50°C. The vitamin D3 content remained relatively stable initially, increasing slightly during the mixing process, but the increase was small before stabilizing. The ratio of vitamin D3 to unmixed vitamin D3 remained relatively stable. Ungranulated D3 powder showed a higher risk of mixing uniformity issues, with an RSD of 13.1%.

[0107] Table 17: Stability of Vitamin D3 and Ratio of Previtamin D3 at 50°C in Example 1

[0108] Table 18: Mixing uniformity in Example 1

[0109] Example 2: Example 2 Prescription Table

[0110] Based on the above-mentioned formulation, calcium carbonate, sucrose / sorbitol / mannitol / cyclodextrin, HPMCE5, and flavoring were used as substrates in a granulation pan to prepare a 5% HPMCE5 aqueous solution to disperse vitamin D3. The solution was then sprayed and subjected to high-shear wet granulation and shake granulation. After drying, samples were tested at 50°C for stability. A significant decrease in vitamin D3 content was observed after 30 days. Unexpectedly, it was found that stability tended to improve when the vitamin D3 / pre-vitamin D3 ratio was below 11.

[0111] Table 19: Stability of Prescription 2 at 50℃ and Ratio of Vitamin D3 to Previtamin D3

[0112] Table 20: Stability of Prescription 3 at 50℃ and Ratio of Vitamin D3 to Previtamin D3

[0113] Table 21: Stability of Prescription 4 at 50℃ and Ratio of Vitamin D3 to Previtamin D3

[0114] Table 22: Stability of Prescription 5 at 50℃ and Ratio of Vitamin D3 to Previtamin D3

[0115] Example 3: Example 3 Prescription Table (β-CD Inclusion Prescription)

[0116] Based on the above-mentioned formulation, calcium carbonate, mannitol, steviol glycosides, and flavoring ingredients were used as substrates in a granulation pan to prepare a 1 mg / mL vitamin D3 alcohol solution. The prescribed amount of vitamin D3 alcohol solution was transferred into the prescribed amount of β-CD solution. The aqueous solution was heated to 50-60°C, and then the solution was sprayed and subjected to high-shear wet granulation and shake granulation. After drying, the stability was tested at 50°C for 30 days. The decrease in vitamin D3 content was minimal. Unexpectedly, when the vitamin D3 / pre-vitamin D3 ratio was below 5, the stability of D3 was significantly improved.

[0117] Table 23: Stability of Prescription 6 at 50℃ and Ratio of Vitamin D3 to Previtamin D3

[0118] Table 24: Stability of Prescription 7 at 50℃ and Ratio of Vitamin D3 to Previtamin D3

[0119] Table 25: Stability of Prescription 8 at 50℃ and Ratio of Vitamin D3 to Previtamin D3

[0120] Table 26: Stability of Prescription 9 at 50℃ and Ratio of Vitamin D3 to Previtamin D3

[0121] Example 4 Example 4 Prescription Table

[0122] Based on the above-mentioned formulation, calcium carbonate, sucrose, HPMCE5, and flavoring ingredients were used as substrates in a granulation pan to prepare a 1 mg / mL vitamin D3 alcohol solution. The prescribed amount of this vitamin D3 alcohol solution was then transferred to a 5% HPMCE5 aqueous solution containing 4% solid β-CD (vitamin D3:β-CD = 1:1000) for inclusion in a 50-60°C water bath. The solution was then sprayed and subjected to high-shear wet granulation and shake granulation. After drying, the solution was tested for stability at 50°C, and the decrease in vitamin D3 content after 30 days was minimal. Simultaneously, the mixing uniformity data were good.

[0123] The content of pre-vitamin D3 was high and remained stable, the decline in vitamin D3 was low, and the ratio of vitamin D3 to pre-vitamin D3 did not change much.

[0124] Table 27: Stability of Vitamin D3 and Ratio of Previtamin D3 at 50°C in Example 4

[0125] Table 28: Example 4 Accelerated Long-Term Content Stability and Ratio of Vitamin D3 to Previtamin D3

[0126] A: Acceleration condition; L: Long-term condition Table 29: Mixing Uniformity Data for Example 4

[0127] Example 5: Example 5 Prescription Table

[0128] According to the above-mentioned formulation, calcium carbonate, mannitol, HPMCE5, sucralose, and flavoring ingredients were used as substrates in a granulation pan to prepare a 1 mg / mL vitamin D3 alcohol solution. The prescribed amount of vitamin D3 alcohol solution was transferred to a 5% HPMCE5 aqueous solution containing 4% solid content γ-CD (vitamin D3:β-CD = 1:1000). The solution was then sprayed and subjected to high-shear wet granulation and shake granulation. After drying, the stability was tested at 50°C. After 30 days, the decrease in vitamin D3 content was small, the vitamin D3 / pre-vitamin D3 ratio was small, and the pre-vitamin D3 content was high. Table 30: Example 5: Stability of content at 50°C and ratio of vitamin D3 to pre-vitamin D3

[0129] Example 6: Example 6 Prescription Table

[0130] Based on the above-mentioned formulation, calcium carbonate, mannitol / β-cyclodextrin / maltodextrin, steviol glycosides, and flavoring were used as substrates in a granulation pan to prepare a 1 mg / mL vitamin D3 alcohol solution. The prescribed amount of vitamin D3 alcohol solution was transferred into the prescribed amount of β-CD solution, and the mixture was heated in a water bath at different inclusion temperatures. The solution was then sprayed and subjected to high-shear wet granulation and shake granulation. After drying, the stability was tested at 50°C. The decrease in vitamin D3 content after 30 days was minimal. Unexpectedly, when the vitamin D3 / pre-vitamin D3 ratio was below 5, the stability of vitamin D3 was significantly improved. However, when the inclusion temperature reached 70°C, the content had already decreased significantly by day 0.

[0131] Table 31: Stability of Prescription 8 at 50℃ and Ratio of Vitamin D3 to Previtamin D3

[0132] Table 32: Stability of Prescription 10 at 50℃ and Ratio of Vitamin D3 to Previtamin D3

[0133] Table 33: Stability of Prescription 11 at 50℃ and Ratio of Vitamin D3 to Previtamin D3

[0134] Table 34: Stability of Prescription 12 at 50℃ and Ratio of Vitamin D3 to Previtamin D3

[0135] Table 35: Stability of Prescription 13 at 50℃ and Ratio of Vitamin D3 to Prescription D3

[0136] Example 7: Example 7 Prescription Table

[0137] Based on the above-mentioned formulation ratios of calcium carbonate, mannitol, steviol glycosides / sucralose, and flavoring ingredients, a 2 mg / mL vitamin D3 alcohol solution was prepared in a granulation pan as a substrate. The mass ratio of vitamin D3 to β-CD was 1:1000. 1 mg / mL of the vitamin D3 alcohol solution was pipetted into aqueous solutions of β-CD with different ethanol concentrations. The mixture was then heated in a 50°C water bath for inclusion. The solution was then sprayed and subjected to high-shear wet granulation and shake granulation. After drying, samples were tested for stability at 50°C. With increasing ethanol concentration, the vitamin D3 / pre-vitamin D3 ratio also increased. The stability of vitamin D3 inclusion in a 50% ethanol aqueous solution decreased the most. Compared to the aqueous solution, the pre-vitamin D3 content was lower, and the vitamin D3 / pre-vitamin D3 ratio was higher. When the concentration of the vitamin D3 ethanol solution was too low, the ethanol concentration in the inclusion solution became too high during the inclusion process, leading to decreased stability.

[0138] Table 36: Stability of Prescription 8 at 50℃ and Ratio of Vitamin D3 to Previtamin D3

[0139] Table 37: Stability of Prescription 14 at 50℃ and Ratio of Vitamin D3 to Previtamin D3

[0140] Table 38: Stability of Prescription 15 at 50℃ and Ratio of Vitamin D3 to Previtamin D3

[0141] Table 39: Stability of Prescription 16 at 50℃ and Ratio of Vitamin D3 to Previtamin D3

[0142] Table 40: Stability of Prescription 17 at 50℃ and Ratio of Vitamin D3 to Previtamin D3

[0143] Example 8: Example 8 Prescription Table

[0144] Mannitol / sucrose, sucralose, and flavoring ingredients, according to the above-mentioned formulation ratio, were used as substrates in a granulation pan to prepare a 0.5 mg / mL vitamin D3 alcohol solution. The prescribed amount of vitamin D3 alcohol solution was transferred to the prescribed amount of β-CD in an HPMC solution, heated in a 50-60°C water bath, and then sprayed into the solution for high-shear wet granulation and shake granulation. After drying, the stability was tested at 50°C, and the vitamin D3 content showed a small decrease after 30 days. During the preparation of calcium carbonate vitamin D3 granules, it was unexpectedly discovered that adding a certain proportion of polymeric material could further reduce the vitamin D3 / pre-vitamin D3 ratio, thereby further improving the stability of vitamin D3.

[0145] Table 41: Stability of Prescription 18 at 50℃ and Ratio of Vitamin D3 to Previtamin D3

[0146] Table 42: Stability of Prescription 19 at 50℃ and Ratio of Vitamin D3 to Previtamin D3

[0147] Table 43: Stability of Prescription 20 at 50℃ and Ratio of Vitamin D3 to Previtamin D3

[0148] Table 44: Stability of Prescription 21 at 50℃ and Ratio of Vitamin D3 to Previtamin D3

[0149] Table 45: Stability of Prescription 22 at 50℃ and Ratio of Vitamin D3 to Previtamin D3

[0150] Example 9: Example 9 Prescription Table

[0151] Based on the above-mentioned formulation, calcium carbonate, mannitol, and flavoring were used as substrates in a granulation pan to prepare a 2 mg / mL vitamin D3 ethanol solution. The mass ratio of vitamin D3 to β-CD was 1:1000. 1 mg / mL of the vitamin D3 ethanol solution was pipetted into aqueous solutions of β-CD with different ethanol concentrations. Different proportions of HPMC, PVP, and HPC were added, and the mixture was heated in a 50°C water bath for encapsulation. The solution was then sprayed and subjected to high-shear wet granulation and shake granulation. After drying, the samples were tested for stability at 50°C. The effects of different polymer additions on stability varied. The vitamin D3 / pre-vitamin D3 ratio did not differ significantly. The addition of HPMC further increased the stability of vitamin D3.

[0152] Table 46: Stability of Prescription 23 at 50℃ and Ratio of Vitamin D3 to Previtamin D3

[0153] Table 47: Stability of Prescription 24 at 50℃ and Ratio of Vitamin D3 to Previtamin D3

[0154] Table 48: Stability of Prescription 25 at 50℃ and Ratio of Vitamin D3 to Previtamin D3

[0155] Table 49: Stability of Prescription 26 at 50℃ and Ratio of Vitamin D3 to Previtamin D3

[0156] Table 50: Stability of Prescription 27 at 50℃ and Ratio of Vitamin D3 to Previtamin D3

[0157] The addition of different polymers has different effects on stability; the addition of HPMC can further increase the stability of D3.

[0158] Example 10 Example 10 Prescription Table

[0159] Based on the above-mentioned formulation, calcium carbonate, mannitol, hydroxypropyl methylcellulose E5, and flavoring ingredients were used as substrates in a granulation pan to prepare a 1 mg / mL vitamin D3 alcohol solution. The prescribed amount of vitamin D3 alcohol solution was then transferred to a 5% HPMCE5 aqueous solution containing 4% solids β-CD (vitamin D3:β-CD = 1:1000) for inclusion in a 50-60°C water bath. The solution was then sprayed and subjected to high-shear wet granulation. After drying, the stability was tested at 50°C, and the decrease in vitamin D3 content after 30 days was minimal. Simultaneously, the mixing uniformity data were good.

[0160] Data on the uniformity of vitamin D3 content in the total mixed granules show that the total mixed granules prepared using the formulation process of this invention have good uniformity of vitamin D3 content, with an RSD of only 1.0%.

[0161] Table 51: Mixing Uniformity Data for Example 10

[0162] Vitamin D3 uniformity data during granule filling: Due to the extremely low vitamin D3 content, there is still a risk of stratification during the filling process, resulting in large content differences. Using the formulation process of this invention, no stratification risk occurred during the granule filling process, and the process is feasible.

[0163] Table 52: Uniformity data during granule filling process in Example 10

[0164]

[0165] The content of pre-vitamin D3 was high and remained stable, the decline in vitamin D3 was low, and the ratio of vitamin D3 to pre-vitamin D3 did not change much.

[0166] Table 53: High-temperature stability of content and ratio of vitamin D3 to previtamin D3 in Example 10 at 50°C

[0167] Table 54: Example 10 Accelerated Conditional Content Stability and Ratio of Vitamin D3 to Previtamin D3

[0168] Example 11 Example 11 Prescription Table

[0169] According to the above-mentioned prescription ratio, calcium carbonate, sorbitol, hydroxypropyl methylcellulose E5, flavoring, and red iron oxide are used as substrates in a granulation pan to prepare a 1 mg / mL vitamin D3 alcohol solution. The prescribed amount of vitamin D3 alcohol solution is transferred to a 5% HPMCE5 aqueous solution containing 4% solid content β-CD (vitamin D3: β-CD = 1:1000) for inclusion in a 50-60℃ water bath. The solution is then sprayed and subjected to high-shear wet granulation. After drying, the granules are sizing, magnesium stearate is added and mixed, and then compressed into tablets to obtain calcium carbonate D3 chewable tablets.

[0170] The chewable tablets prepared using the formulation process of this invention exhibit good uniformity of vitamin D3 content in the total mixed granules, with an RSD of only 1.7%.

[0171] Table 55: Data on the uniformity of particle mixing in Example 11

[0172] Vitamin D3 uniformity data during the tableting process: Due to the extremely low vitamin D3 content, there is still a risk of stratification during the tableting process, resulting in large differences in content. Using the formulation process of this invention, the chewable tablets do not exhibit the risk of stratification during the tableting process, and the process is feasible.

[0173] Table 56: Content Uniformity Data During Tableting Process in Example 11

[0174] The chewable tablets contain a high and stable amount of pre-vitamin D3, with a low decrease in vitamin D3 content and little change in the vitamin D3 / pre-vitamin D3 ratio.

[0175] Table 57: Stability of Vitamin D3 and Ratio of Previtamin D3 at 50°C in Example 11

[0176] Table 58: Example 11 Accelerated Conditional Content Stability and Ratio of Vitamin D3 to Previtamin D3

[0177] In summary, vitamin D3 has poor chemical stability, which is even worse in granules with a larger specific surface area. It is sensitive to temperature and oxygen, and is prone to degradation during storage and transportation, thereby reducing efficacy. Using the technology of this invention, it was unexpectedly discovered that adjusting the relative ratio of vitamin D3 to pre-vitamin D3 within the range of 1:1 to 1:5 stabilizes the vitamin D3 content in granules and chewable tablets.

[0178] The method of this invention has been described through preferred embodiments. Those skilled in the art will readily be able to modify or appropriately alter and combine the methods and applications described herein within the scope, spirit, and context of this invention to implement and apply the technology of this invention. Those skilled in the art can refer to the content herein to appropriately improve process parameters. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the scope of this invention.

Claims

1. A composition comprising previtamin D3, vitamin D3, and cyclodextrin, wherein the cyclodextrin is β-cyclodextrin or γ-cyclodextrin; Optionally, the composition comprises at least one water-soluble polymer.

2. The composition according to claim 1, wherein, The water-soluble polymer comprises at least one of HPMC, PVP, and HPC.

3. The composition according to claim 1, wherein, Vitamin D3:Previtamin D3 = 1:1 to 8:1; or, Vitamin D3:Previtamin D3 = 1:1 to 5:1; or, Vitamin D3:Previtamin D3 = 1:1 to 3:1; or, Vitamin D3:Previtamin D3 = 1:1 to 2:

1.

4. The composition according to claim 1, wherein, The ratio of the mass of pre-vitamin D3 to the sum of the masses of vitamin D3 and β-cyclodextrin or γ-cyclodextrin is 1:50-1:2500; or, The mass ratio of the sum of pre-vitamin D3 and vitamin D3 to β-cyclodextrin or γ-cyclodextrin is 1:100-1:2000; or, The mass ratio of the sum of pre-vitamin D3 and vitamin D3 to β-cyclodextrin or γ-cyclodextrin is 1:200-1:1000; or, The mass ratio of the sum of previtamin D3 and vitamin D3 to β-cyclodextrin or γ-cyclodextrin is 1:100, 1:200, 1:1000 or 1:2000.

5. A calcium-containing composition, wherein, The calcium-containing composition comprises the composition according to any one of claims 1-4, and at least one of calcium carbonate, calcium citrate, and calcium gluconate; or, The calcium-containing composition comprises the composition according to any one of claims 1-4 and calcium carbonate; Optionally, the calcium-containing composition comprises pharmaceutically acceptable excipients or excipients.

6. The calcium-containing composition according to claim 5, wherein, The pharmaceutically acceptable excipients or excipients include at least one of fillers, flavoring agents, binders, and flavorings.

7. The calcium-containing composition according to claim 5, wherein, The calcium carbonate constitutes 30%-70% of the total weight of the calcium-containing composition; or, The calcium carbonate accounts for 40%-60% of the total weight of the calcium-containing composition.

8. The calcium-containing composition according to claim 6, wherein, The filler comprises at least one of mannitol, sorbitol, sucrose, maltodextrin, and maltitol; the filler accounts for 20%-70% of the total weight of the calcium-containing composition; or, The filler accounts for 30%-60% of the total weight of the calcium-containing composition.

9. The calcium-containing composition according to claim 6, wherein, The flavoring agent contains at least one of sucralose, aspartame, and steviol glycosides; The flavoring agent accounts for 0.015%-2% of the total weight of the calcium-containing composition; or, the flavoring agent accounts for 0.05%-1% of the total weight of the calcium-containing composition. The adhesive comprises at least one of HPMC, PVP and HPC; or, the adhesive is HPMCE5.

10. The calcium-containing composition according to claim 6, wherein, The flavoring comprises at least one of pharmaceutically acceptable orange flavoring, strawberry flavoring, peppermint flavoring, milk flavoring, pineapple flavoring, and peach flavoring, wherein the flavoring comprises 0.2%-1.0% of the total weight of the calcium-containing composition; or, wherein the flavoring comprises 0.4%-0.6% of the total weight of the calcium-containing composition.

11. The calcium-containing composition according to claim 5, wherein the calcium-containing composition can be prepared into granules, tablets or chewable tablets.

12. A method for preparing the composition according to any one of claims 1-4, comprising: (1) Preparation of anhydrous ethanol solution of vitamin D3 Dissolve vitamin D3 in anhydrous ethanol, mix well, and prepare a 0.5-10 mg / ml vitamin D3 anhydrous ethanol solution; (2) Preparation of aqueous solutions of β-cyclodextrin or γ-cyclodextrin β-Cyclodextrin or γ-Cyclodextrin is dissolved in water to prepare a solution with a solid content of 1%-10%, and stirred and dissolved in a water bath at a temperature of 30℃-80℃; a water-soluble polymer is added and dissolved to make the concentration of the water-soluble polymer in the β-Cyclodextrin aqueous solution or γ-Cyclodextrin aqueous solution range from 0.1% to 8%. (3) Under the conditions of water bath at 55℃, stirring and protected from light, add the vitamin D3 anhydrous ethanol solution from step (1) to the β-cyclodextrin or γ-cyclodextrin aqueous solution for inclusion, with an inclusion time range of 0.5h-10h; to obtain a β-cyclodextrin or γ-cyclodextrin inclusion solution containing vitamin D3 and pre-vitamin D3.

13. The method for preparing the composition according to claim 12, wherein, The solid content is 3%-8%; or, the solid content is 4%-6%; or, the solid content is 4%. The water bath temperature is 40℃-60℃; or, the water bath temperature is 50℃-60℃; or, the water bath temperature is 55℃. The water-soluble polymer comprises at least one of HPMC, PVP and HPC; or, the water-soluble polymer is HPMCE5. The concentration range of the water-soluble polymer in the β-cyclodextrin aqueous solution is 5%.

14. A method for preparing the calcium-containing composition according to any one of claims 5-10, comprising: (1) Use calcium carbonate, calcium citrate or calcium gluconate and pharmaceutically acceptable excipients as high-shear granulation substrates in a high-shear granulation pot. (2) The inclusion liquid prepared according to claim 12 or 13 is atomized and sprayed into a high-shear granulation pot for mixing. An appropriate amount of 5% HPMCE5 is added for high-shear granulation, or further shake granulation is performed. Then, the mixture is dried and granulated. Fragrance is added and mixed evenly to obtain calcium-containing composition granules. The obtained granules and lubricant are mixed and further compressed into tablets or chewable tablets.

15. The method for preparing the calcium-containing composition according to claim 14, wherein, The atomization pressure of the atomized injection is 0.1 MPa-0.3 MPa; or, the atomization pressure is 0.15 MPa-0.2 MPa. The drying air inlet temperature is 50℃-60℃; or, the drying air inlet temperature is 55℃. The moisture content of the dried product is controlled to be less than 0.5%; or, the moisture content is controlled to be less than 0.3%. The lubricant contains at least one of magnesium stearate and sodium stearate fumarate; The lubricant comprises 0.5%-2.0% of the total weight of the calcium-containing composition; or, 1% of the total weight of the calcium-containing composition.

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