Pharmaceutical composition containing vitamin D and orally disintegrating tablet thereof

Abstract

The invention relates to a pharmaceutical composition containing vitamin D as well as a preparation method and application of the pharmaceutical composition. The pharmaceutical composition contains the following components: (A) 0.0001-0.5 wt% of vitamin D; (B) an emulsifier; (C) an oil solvent; and (D) 0.1-70 wt% of an adhesive, the emulsifier is selected from at least one of starch sodium octenylsuccinate or beta-cyclodextrin, and the pharmaceutical composition contains 0.001-80 wt% of the emulsifier; the ratio of the use amount of the oil solvent to the use amount of the vitamin D is (1.4-1000): 1. According to the invention, the vitamin D pharmaceutical composition with a wide concentration content range is prepared by selecting proper auxiliary materials and dosage thereof, and the vitamin D pharmaceutical composition has good drug dispersibility and stability and proper disintegration performance.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to a pharmaceutical composition containing vitamin D and an orally disintegrating tablet thereof. Background Art

[0002] Vitamin D has a wide range of complex effects on the human body. It can regulate the metabolism of calcium and phosphorus in the body and maintain the stability of plasma calcium and phosphorus levels. According to the definition of the International Unit (IU) of vitamin D, 1g of vitamin D contains 40 million international units. The Chinese Nutrition Society recommends that adults supplement 400 to 600 IU of vitamin D per day, that is, the daily intake of vitamin D is 10μg to 20μg.

[0003] Currently, there are many vitamin D preparations on the market worldwide, most of which are oral solid preparations or oral liquid preparations dissolved in oil. However, oral solid preparations are not suitable for people who cannot swallow, such as infants, the elderly or patients, and oral liquid preparations are less convenient to administer. Therefore, the preparation of vitamin D oral preparations that can melt in the mouth is an urgent problem to be solved. Summary of the invention

[0004] In view of this, the inventors conducted in-depth research on the orally disintegrating vitamin D tablets and found that the mass of the orally disintegrating tablets suitable for taking is usually 2-1500 mg. Based on the calculation of taking 1-2 tablets at a time, the content of vitamin D in the orally disintegrating tablets is about 10 μg, that is, the content of vitamin D in the orally disintegrating tablets is less than 0.5wt%. However, due to the presence of unsaturated double bonds in the chemical structure of vitamin D and the fact that it is a lipophilic substance, the conventional production and storage process deteriorates aggravatedly, and it is difficult to evenly disperse in the tablets. At low concentrations, the tablet stability and dispersibility are further deteriorated, thereby affecting the efficacy.

[0005] Therefore, the present invention provides a pharmaceutical composition containing vitamin D, an orally disintegrating tablet thereof and a preparation method thereof. By selecting appropriate excipients and their amounts, a pharmaceutical composition of vitamin D with a wide concentration range is prepared. The composition has good drug dispersibility and stability, as well as appropriate disintegration performance, and is particularly suitable for preparing vitamin D preparations with a low concentration range.

[0006] In a first aspect, the present invention provides a pharmaceutical composition containing vitamin D, comprising:

[0007] (A) Vitamin D 0.0001-0.5wt%;

[0008] (B) emulsifier;

[0009] (C) oil solvent; and,

[0010] (D) 0.1-70 wt % of binder;

[0011] The emulsifier is selected from at least one of sodium starch octenyl succinate or β-cyclodextrin, and the pharmaceutical composition contains 0.001-80wt% of the emulsifier;

[0012] In the pharmaceutical composition, the content ratio of the oil solvent to the vitamin D is 1.4-1000:1.

[0013] Preferably, in the pharmaceutical composition, the emulsifier is 0.24-73wt% sodium starch octenylsuccinate or 0.04-71wt% β-cyclodextrin.

[0014] Preferably, in the pharmaceutical composition, the oil solvent comprises esters of C3-C30 saturated or unsaturated fatty acids.

[0015] Preferably, in the pharmaceutical composition, the oil solvent comprises triglycerides of saturated or unsaturated fatty acids of C3-C30.

[0016] Preferably, in the pharmaceutical composition, the oil solvent includes at least one of short-chain saturated or unsaturated fatty acid triglycerides of C3-C5, medium-chain saturated or unsaturated fatty acid triglycerides of C6-C12, or long-chain saturated or unsaturated fatty acid triglycerides of C13-C22.

[0017] Preferably, in the pharmaceutical composition, the oil solvent includes at least one of olive oil, castor oil or C6-C12 medium-chain saturated or unsaturated fatty acid triglycerides (i.e., the medium-chain triglycerides used in the embodiments of the present invention).

[0018] Preferably, in the pharmaceutical composition, the vitamin D includes at least one of vitamin D2 or vitamin D3.

[0019] Preferably, in the pharmaceutical composition, the content of vitamin D is 0.001-0.1 wt %.

[0020] More preferably, in the pharmaceutical composition, the content of vitamin D is 0.001-0.05wt%.

[0021] Preferably, in the pharmaceutical composition, the oil solvent is C6-C12 medium-chain saturated or unsaturated fatty acid triglyceride.

[0022] Preferably, in the pharmaceutical composition, the content ratio of the oil solvent to the vitamin D is 1.4-60:1.

[0023] Preferably, in the pharmaceutical composition, the content of the oil solvent is 0.001-20wt%.

[0024] More preferably, in the pharmaceutical composition, the content of the oil solvent is 0.01-13 wt %.

[0025] Preferably, in the pharmaceutical composition, the binder comprises at least one of pullulan, xanthan gum, gelatin or dextran.

[0026] Preferably, in the pharmaceutical composition, the content of the binder is 1-40wt%.

[0027] Preferably, the pharmaceutical composition further contains at least one of the following components (E) to (F):

[0028] (E) lyophilization protectant 5-96wt%;

[0029] (F) Antioxidant 0.01-10 wt %.

[0030] Preferably, the lyoprotectant comprises mannitol.

[0031] Preferably, the antioxidant comprises a vitamin-based antioxidant.

[0032] Preferably, the antioxidant comprises at least one of vitamin E or vitamin C.

[0033] In a second aspect, the present invention provides an orally disintegrating tablet comprising any of the aforementioned pharmaceutical compositions.

[0034] In a third aspect, the present invention provides a unit dosage form, which is an orally disintegrating tablet, wherein the mass of the orally disintegrating tablet is 2-1500 mg, and the orally disintegrating tablet contains 0.001-1.5 mg of vitamin D.

[0035] Preferably, in the unit dosage form, the mass of the orally disintegrating tablet is 5-1000 mg, preferably 10-100 mg.

[0036] Preferably, in the unit dosage form, the vitamin D is the only active ingredient in the orally disintegrating tablet.

[0037] Preferably, in the unit dosage form, the content of vitamin D in the orally disintegrating tablet is 0.002-0.1 mg, more preferably 0.005-0.02 mg.

[0038] Preferably, the unit dosage orally disintegrating tablet contains any of the aforementioned pharmaceutical compositions.

[0039] In a fourth aspect, the present invention further provides a method for preparing any of the aforementioned orally disintegrating tablets, comprising the following steps:

[0040] (S1) dissolving vitamin D in an oil solvent to prepare an oil phase;

[0041] (S2) mixing an emulsifier and water to prepare an aqueous phase;

[0042] (S3) mixing the oil phase and the water phase to prepare an emulsion; and,

[0043] (S4) freeze-drying the emulsion to obtain the orally disintegrating tablet.

[0044] Preferably, the method for preparing the orally disintegrating tablet comprises the following steps:

[0045] (S1) dissolving vitamin D and vitamin E antioxidants in an oil solvent to prepare an oil phase;

[0046] (S2) mixing an emulsifier, a vitamin C antioxidant and water to prepare an aqueous phase 1;

[0047] (S3-1) mixing the oil phase and the water phase 1 to prepare an emulsion 1;

[0048] (S3-2) mixing a binder, a lyoprotectant and water to prepare an aqueous phase 2;

[0049] (S3-3) adding the aqueous phase 2 to the emulsion 1 to obtain an emulsion 2; and,

[0050] (S4) freeze-drying the emulsion 2 to obtain the orally disintegrating tablet.

[0051] Preferably, the method for preparing the orally disintegrating tablet comprises the following steps:

[0052] (S1) dissolving vitamin D and vitamin E antioxidants in an oil solvent to prepare an oil phase;

[0053] (S2) mixing an emulsifier, a vitamin C antioxidant, a binder, a lyophilization protectant and water to prepare an aqueous phase;

[0054] (S3) mixing the oil phase and the water phase 1 to prepare an emulsion; and,

[0055] (S4) freeze-drying the emulsion to obtain the orally disintegrating tablet.

[0056] The pharmaceutical composition and preparation product of the present invention is loose and porous, has good rehydration properties in the oral cavity, can be rapidly disintegrated in the oral cavity (e.g., tongue, oral cavity or sublingual area of ​​the oral cavity), has low brittleness and high degree of molding, is convenient for patients to take and has accurate dosage, and has good chemical stability. DETAILED DESCRIPTION

[0057] In the following description, a large number of specific details are provided to provide a more thorough understanding of the present invention. However, it is apparent to those skilled in the art that the present invention can be implemented without one or more of these details. In other examples, in order to avoid confusion with the present invention, some technical features well known in the art are not described.

[0058] The implementation of the present invention is described in detail below in conjunction with the definitions of terms:

[0059] Unless otherwise specified, the percentage content % of the preparation of the present invention refers to wt %.

[0060] I Pharmaceutical composition containing vitamin D

[0061] The pharmaceutical composition containing vitamin D of the present invention contains:

[0062] (A) Vitamin D 0.0001-0.5wt%;

[0063] (B) emulsifier;

[0064] (C) oil solvent; and,

[0065] (D) Binder 0.1-70 wt %.

[0066] Vitamin D

[0067] The vitamin D of the present invention includes at least one of vitamin D2 (9,10-secoergoster-5,7,10(19),22-tetraene-3β-ol), vitamin D3 (9,10-secocholester-5,7,10(19)-triene-3β-ol) and vitamin D3 active metabolites (calcifediol, calcitriol, etc.). Vitamin D3 is most preferred.

[0068] In some embodiments, other active ingredients may be included in the pharmaceutical composition of the present invention without affecting the pharmaceutical efficacy of vitamin D.

[0069] In some embodiments, vitamin D is the only active ingredient in the pharmaceutical composition or formulation of the present invention.

[0070] In some embodiments, in the pharmaceutical composition, the content of vitamin D is 0.0001-0.5wt%, 0.001-0.2wt% or 0.01-0.05wt%, for example, it can be 0.005wt%, 0.015wt%, 0.025wt%, 0.03wt%, 0.04wt%, 0.05wt%, 0.075wt%, 0.1wt%, 0.15wt%, 0.2wt%, 0.3wt% or 0.5wt%, etc.

[0071] Emulsifier

[0072] After screening by the inventors, sodium starch octenylsuccinate and / or β-cyclodextrin are particularly suitable as emulsifiers for vitamin D, especially low-concentration vitamin D pharmaceutical compositions or preparations. Within a suitable content range, they can improve the dispersibility and stability of vitamin D.

[0073] Therefore, in an embodiment of the present invention, the emulsifier in the pharmaceutical composition is selected from at least one of sodium starch octenyl succinate or β-cyclodextrin, and the pharmaceutical composition contains 0.001-80 wt % of the emulsifier.

[0074] In some embodiments, the emulsifier in the pharmaceutical composition is sodium starch octenyl succinate, and the content of sodium starch octenyl succinate in the pharmaceutical composition is 0.01-80wt% or 0.24-73wt%, for example, 0.5wt%, 1wt%, 2wt%, 5wt%, 10wt%, 20wt%, 30wt%, 40wt%, 50wt%, 60wt%, 70wt% or 75wt%, etc.

[0075] In some embodiments, the emulsifier in the pharmaceutical composition is β-cyclodextrin, and the content of β-cyclodextrin in the pharmaceutical composition is 0.01-80wt% or 0.04-71wt%, for example, 0.05wt%, 0.1wt%, 0.2wt%, 0.5wt%, 1wt%, 2wt%, 5wt%, 10wt%, 20wt%, 30wt%, 40wt%, 50wt%, 60wt%, 70wt% or 75wt%, etc.

[0076] In some embodiments, the emulsifier in the pharmaceutical composition is a mixture of sodium starch octenyl succinate and β-cyclodextrin, the total content of the emulsifier is 0.1-80wt%, and the content of sodium starch octenyl succinate is 0.01-80wt% or 0.24-73wt%, and the content of β-cyclodextrin is 0.01-80wt% or 0.04-71wt%. For example, the content of sodium starch octenyl succinate in the pharmaceutical composition can be 0.01wt%, 0.1wt%, 0.2wt%, 0.5wt%, 1wt%, 5wt%, 10wt%, or 20wt%. %, 30wt%, 40wt%, 50wt%, 60wt%, 70wt% or 75wt%, etc., and the content of β-cyclodextrin in the pharmaceutical composition can be 0.01wt%, 0.1wt%, 0.2wt%, 0.5wt%, 1wt%, 2wt%, 5wt%, 10wt%, 20wt%. 30wt%, 40wt%, 50wt%, 60wt%, 70wt% or 75wt%, etc.

[0077] C oil solvent

[0078] The oil solvent of the present invention can dissolve vitamin D and improve its dispersibility and stability.

[0079] The oil solvent may be any oil solvent known in the art, such as an ester of a saturated or unsaturated fatty acid of C3-C30, wherein the ester may be a triglyceride of the aforementioned fatty acid.

[0080] In some embodiments, the oil solvent of the present invention may include at least one of short-chain saturated or unsaturated fatty acid triglycerides of C3-C5, medium-chain saturated or unsaturated fatty acid triglycerides of C6-C12, or long-chain saturated or unsaturated fatty acid triglycerides of C13-C22.

[0081] In some embodiments, the oil solvent of the present invention can be at least one of sesame oil, soybean oil, medium chain triglycerides, castor oil, peanut oil, cottonseed oil, olive oil, corn oil, tea oil, peach kernel oil or linseed oil. In some embodiments, the oil solvent of the present invention contains at least one of olive oil, castor oil or medium chain triglycerides, preferably medium chain triglycerides.

[0082] The inventors have found that appropriate oil solvent content combined with the selection of emulsifiers can make vitamin D, especially low-concentration vitamin D, dispersed evenly and stably in the pharmaceutical composition.

[0083] Therefore, in the pharmaceutical composition of the present invention, the content ratio of the oil solvent to the vitamin D is 1.4-1000:1.

[0084] In some embodiments, the content ratio of the oil solvent to the vitamin D is 1.4-60:1.

[0085] In some embodiments, the content ratio of the oil solvent and the vitamin D can be, for example, 2:1, 5:1, 10:1, 20:1, 30:1, 40:1, 50:1, 60:1, 100:1, 200:1, 500:1 or 800:1, etc.

[0086] In some embodiments, in the pharmaceutical composition of the present invention, the content of the oil solvent is 0.001-20wt%, 0.005-15wt%, 0.01-13wt% or 0.01-2wt%, for example, it can be 0.005wt%, 0.01wt%, 0.05wt%, 0.2wt%, 0.5wt%, 1wt%, 2wt%, 5wt%, 10wt%, 15wt%, or 20wt%, etc.

[0087] D Adhesive

[0088] The binder of the present invention helps to obtain a pharmaceutical composition with suitable disintegration properties.

[0089] Can use the adhesive conventional in this area, for example, in some embodiments, adhesive comprises at least one of pullulan, xanthan gum, gelatin, dextran, gum arabic, gellan gum, sodium carboxymethyl cellulose, carrageenan, guar gum.In some embodiments, preferably comprise at least one of pullulan, xanthan gum, gelatin or dextran in the adhesive of the present invention.Suitable adhesive type can prepare pharmaceutical composition and preparation with good disintegration time.

[0090] In some embodiments, in the pharmaceutical composition of the present invention, the content of the binder in the pharmaceutical composition is 0.1-70wt%, 1-50wt% or 2-40wt%, for example, it can be 2wt%, 5wt%, 10wt%, 20wt%, 30wt%, 40wt%, 50wt% or 60wt%, etc.

[0091] E Freeze-drying Protectant

[0092] The pharmaceutical composition of the present invention may further contain a lyoprotectant as required.

[0093] In some embodiments, the lyoprotectants used in the present invention are substances such as polysaccharides, inorganic salts and amino acids.

[0094] For example, in some embodiments, freeze-drying protective agent of the present invention comprises at least one of mannitol, sorbitol, maltitol, xylitol, lactitol, erythritol, isomalt, kapokose, maltose, glucose, galactose, trehalose, dextrin, sodium phosphate, sodium chloride, aluminum silicate, glycine, alanine, aspartic acid, glutamic acid, hydroxyproline, isoleucine, leucine or phenylalanine. In some embodiments, freeze-drying protective agent of the present invention preferably comprises mannitol. Suitable freeze-drying protective agent helps to reduce the loss and performance change of medicine in the freeze drying process.

[0095] In some embodiments, the pharmaceutical composition contains 5-96wt% of the lyoprotectant, for example, 10wt%, 20wt%, 30wt%, 40wt%, 50wt%, 60wt%, 70wt%, 80wt% or 90wt%.

[0096] FAntioxidants

[0097] The composition of the present invention may further contain an antioxidant as needed to reduce the loss and performance change of vitamin D during the production process. In some embodiments, the antioxidant of the present invention comprises at least one of vitamin E or vitamin C, for example, the vitamin E antioxidant may be DL-α-tocopherol, DL-α-tocopherol acetate, etc., and the vitamin C antioxidant may be vitamin C or sodium vitamin C, etc.

[0098] In some embodiments, the antioxidant of the present invention preferably comprises at least one of DL-α-tocopherol and vitamin C sodium.

[0099] In some embodiments, the content of antioxidant in the pharmaceutical composition of the present invention is 0.1-10wt%, for example, it can be 0.2wt%, 0.5wt%, 1wt%, 2wt%, or 5wt%.

[0100] GOther auxiliary materials

[0101] On the basis of not affecting the efficacy of each component, the pharmaceutical composition of the present invention may also contain other conventional pharmaceutical excipients in the art, such as sweeteners (such as sucrose), preservatives, pigments or flavors.

[0102] II Orally disintegrating tablet

[0103] The pharmaceutical composition of the present invention is suitable for preparing orally disintegrating tablets and has good disintegration performance.

[0104] In some embodiments, the pharmaceutical composition of the present invention has a disintegration time of 5-60 seconds as measured by the method of the Chinese Pharmacopoeia 2020 edition (0921 Disintegration Time Test Method).

[0105] In some embodiments, the pharmaceutical composition of the present invention has a disintegration time of 10-60 seconds or 10-45 seconds as measured by the method of the Chinese Pharmacopoeia 2020 edition (0921 Disintegration Time Test Method).

[0106] In some embodiments, the pharmaceutical composition of the present invention has a disintegration time of 1-60 seconds, 1-30 seconds or 1-10 seconds in the human oral cavity.

[0107] The orally disintegrating tablet of the present invention can be prepared into a unit dosage form, namely, a unit orally disintegrating tablet.

[0108] In some embodiments, the mass of the unit orally disintegrating tablet of the present invention is 2-1500 mg, 5-1000 mg, 10-100 mg, or 100-900 mg. In some embodiments, the mass of the unit orally disintegrating tablet of the present invention is preferably 30-80 mg.

[0109] In some embodiments, the mass of the unit orally disintegrating tablet of the present invention can be, for example, 10 mg, 20 mg, 50 mg, 100 mg, 150 mg, 200 mg, 400 mg, 600 mg, 800 mg, 1000 mg or 1200 mg.

[0110] In some embodiments, the orally disintegrating tablet of the present invention contains 0.001-1.5 mg, 0.002-0.1 mg, or 0.005-0.02 mg of vitamin D.

[0111] In some embodiments, the content of vitamin D in the unit orally disintegrating tablet of the present invention can be, for example, 0.002 mg, 0.005 mg, 0.01 mg, 0.05 mg, 0.1 mg, 0.2 mg, 0.5 mg, 1 mg or 1.5 mg.

[0112] In some embodiments, the mass of the unit orally disintegrating tablet is 10-100 mg, and the orally disintegrating tablet contains 0.002-0.1 mg of vitamin D.

[0113] In some embodiments, the mass of the unit orally disintegrating tablet is 10-100 mg, and the orally disintegrating tablet contains 0.005-0.05 mg of vitamin D.

[0114] In some embodiments, the mass of the unit orally disintegrating tablet is 10-100 mg, and the content of vitamin D in the unit orally disintegrating tablet is 0.01-0.015 mg.

[0115] In some embodiments, the mass of the unit orally disintegrating tablet is 100-900 mg, and the orally disintegrating tablet contains 0.002-0.1 mg of vitamin D.

[0116] In some embodiments, the mass of the unit orally disintegrating tablet is 100-900 mg, and the orally disintegrating tablet contains 0.01-0.015 mg of vitamin D.

[0117] In some embodiments, the unit orally disintegrating tablet contains any of the aforementioned pharmaceutical compositions.

[0118] III. Preparation method

[0119] The preparation method of the pharmaceutical composition or preparation of the present invention comprises the following steps:

[0120] (S1) dissolving vitamin D in an oil solvent to prepare an oil phase;

[0121] (S2) mixing an emulsifier and water to prepare an aqueous phase;

[0122] (S3) mixing the oil phase and the water phase to prepare an emulsion; and,

[0123] (S4) freeze-drying the emulsion to obtain the orally disintegrating tablet.

[0124] In some embodiments, the method for preparing the orally disintegrating tablet comprises the following steps:

[0125] (S1) dissolving vitamin D and vitamin E antioxidants in an oil solvent to prepare an oil phase;

[0126] (S2) mixing an emulsifier, a vitamin C antioxidant and water to prepare an aqueous phase 1;

[0127] (S3-1) mixing the oil phase and the water phase 1 to prepare an emulsion 1;

[0128] (S3-2) mixing a binder, a lyoprotectant and water to prepare an aqueous phase 2;

[0129] (S3-3) adding the aqueous phase 2 to the emulsion 1 to obtain an emulsion 2; and,

[0130] (S4) freeze-drying the emulsion 2 to obtain the orally disintegrating tablet.

[0131] In some embodiments, the method for preparing the orally disintegrating tablet comprises the following steps:

[0132] (S1) dissolving vitamin D and vitamin E antioxidants in an oil solvent to prepare an oil phase;

[0133] (S2) mixing an emulsifier, a vitamin C antioxidant, a binder, a lyophilization protectant and water to prepare an aqueous phase;

[0134] (S3) mixing the oil phase and the water phase 1 to prepare an emulsion; and,

[0135] (S4) freeze-drying the emulsion to obtain the orally disintegrating tablet.

[0136] In some embodiments, step (S4) comprises:

[0137] (S4-1) freezing the emulsion at -40°C to -90°C to form a solid drug solution;

[0138] (S4-2) Freezing the solid drug solution at -30°C to -50°C for 30-120 min, and then freeze-drying at a temperature range of -20°C to 40°C for 4-12 h to obtain the orally disintegrating tablet.

[0139] IV Application

[0140] The pharmaceutical composition or preparation containing vitamin D of the present invention can be used to prepare various medicines or health products for patients or people who need vitamin D supplementation, such as for the treatment of metabolic diseases, oral diseases or orthopedic diseases.

[0141] Hereinafter, the present invention will be described in more detail through specific examples.

[0142] Raw materials and auxiliary materials

[0143] Vitamin D3, gelatin, dextran: meet the standards of Part II of the Chinese Pharmacopoeia 2020 edition.

[0144] β-Cyclodextrin, Poloxamer 188, Tragacanth gum, Sodium starch glycolate: meet the standards of Part IV of the Chinese Pharmacopoeia 2020 edition.

[0145] Sodium starch octenylsuccinate: complies with the United States Pharmacopoeia NF standard or is registered with the Drug Evaluation Center of the State Food and Drug Administration.

[0146] The remaining reagents were purchased from qualified domestic auxiliary material manufacturers and used directly.

[0147] Detection Methods

[0148] 1. Detection of vitamin D3 content in liquid medicine or freeze-dried tablets

[0149] Detection instrument: High performance liquid chromatograph, manufacturer: Agilent, model: Agilent 1260.

[0150] Testing process (avoid light throughout the process):

[0151] Mobile phase: n-hexane-isopropanol (995:5, v / v);

[0152] Detection wavelength: 265nm;

[0153] Column temperature: 35°C.

[0154] Sample processing:

[0155] (1) Drug solution: Extract vitamin D3 from the drug solution using an organic solvent, then centrifuge and take the supernatant to obtain the sample to be tested.

[0156] (2) Freeze-dried tablets: Dissolve in aqueous solvent, add organic solvent to extract vitamin D3 in the freeze-dried tablets, and then centrifuge to obtain the supernatant to obtain the sample to be tested.

[0157] Examples 1-11 and Comparative Examples 1-2

[0158] Weigh the raw materials and auxiliary materials as shown in the prescription amount in Table 1-3: (1) Heat the oil solvent, DL-α-tocopherol and vitamin D3 in a water bath at 80°C to dissolve to obtain liquid 1; (2) Dissolve water, emulsifier, sucrose and sodium vitamin C in water accounting for about 2% of the prescription amount to obtain liquid 2; (3) Transfer liquid 2 to liquid 1 and emulsify by high-speed stirring to obtain liquid 3; (4) Dissolve the binder and lyophilization protective agent in purified water accounting for about 98% of the prescription amount, add liquid 3 and emulsify by high-speed stirring to obtain liquid 4; (5) Inject liquid 4 into a blister mold in a quantitative manner and place it in a freeze dryer, pre-freeze at -40°C for 60 minutes; then evacuate to a vacuum degree of 20 Pa; then heat to -10°C and hold for 3 hours; then heat to 20°C and hold for 6 hours; then heat to 30°C and hold for 4 hours; (6) Remove from the box after decompression, and then coat and punch in sequence to obtain orally disintegrating tablets.

[0159] Table 1 Emulsifier Selection Octenyl Succinate Starch Sodium

[0160]

[0161]

[0162] Table 2 Emulsifier selection β-cyclodextrin

[0163]

[0164] Table 3 Emulsifier selection other than the present invention

[0165]

[0166]

[0167] (1) Determination of the uniformity of vitamin D3 content in the drug solution

[0168] Detection: Use a dropper sampler to take the upper, middle and lower layers of the liquid 4 prepared in Example 1-11 and Comparative Example 1-2 to detect the content of vitamin D3 in the liquid. The test results are the relative content of the labeled amount, as shown in Table 4-5. The total height of the liquid is about 80 mm, the upper layer refers to the sampling position about 2 mm below the liquid surface, the middle layer refers to the sampling position about 40 mm below the liquid surface, and the lower layer refers to the sampling position about 80 mm below the liquid surface. Qualification standard: The content of the upper, middle and lower layers is 90.0% to 110.0%, and the relative standard deviation (RSD) of the content of the upper, middle and lower layers is less than 5.0%.

[0169] Table 4 Vitamin D3 content in the medicinal solution of Examples 1-6

[0170] serial number Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 upper layer 98.66％ 90.42％ 104.83％ 103.25％ 94.66％ 99.93％ Middle level 99.12％ 90.41％ 105.68％ 103.48％ 97.49％ 108.37％ Lower level 99.47％ 90.07％ 105.56％ 104.45％ 97.12％ 103.82％ RSD 0.5％ 0.3％ 0.5％ 0.7％ 1.6％ 4.1％ evaluate qualified qualified qualified qualified qualified qualified

[0171] Table 5 Vitamin D3 content in the solutions of Examples 7-11 and Comparative Examples 1-2

[0172] serial number Example 7 Example 8 Example 9 Example 10 Embodiment 11 Comparative Example 1 Comparative Example 2 upper layer 94.14％ 99.85％ 99.76％ 98.22％ 97.78％ 60.48％ 56.28％ Middle level 98.41％ 100.75％ 99.94％ 96.93％ 101.00％ 60.50％ 61.65％ Lower level 96.79％ 101.33％ 98.91％ 97.58％ 102.10％ 60.51％ 59.67％ RSD 2.30％ 0.8％ 0.6％ 0.7％ 2.30％ 0.1％ 4.6％ evaluate qualified qualified qualified qualified qualified Failure Failure

[0173] Conclusion: The type and amount of emulsifier not only affect the emulsification effect, but may also affect the dispersion and stability of vitamin D3. Therefore, choosing the right type and amount of emulsifier is crucial to improving the stability and uniformity of vitamin D3 freeze-dried orodisintegrating tablets. The inventors found through experiments that when the emulsifier content is within the scope of the present invention, qualified orodisintegrating tablets can be obtained. If the emulsifier content exceeds the scope of the present invention, the content uniformity of the orodisintegrating tablets is unqualified.

[0174] (2) Investigation of stability and uniformity of vitamin D3 during freeze-drying

[0175] Take 10 freeze-dried tablets made from the qualified medicinal solution of Examples 1-11, detect the total content of vitamin D3 in the 10 freeze-dried tablets, and calculate the relative content relative to the labeled amount. The results are shown in Table 6. The content should be 90% to 110% of the labeled amount to be qualified.

[0176] Table 6 Vitamin D3 content in freeze-dried tablets

[0177] serial number Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 content 94.9％ 97.7％ 100.9％ 104.1％ 94.9％ 93.9％ evaluate qualified qualified qualified qualified qualified qualified

[0178] Table 7 Vitamin D3 content in freeze-dried tablets

[0179] serial number Example 7 Example 8 Example 9 Example 10 Embodiment 11 content 92.5％ 99.1％ 98.8％ 93.7％ 96.5％ evaluate qualified qualified qualified qualified qualified

[0180] It can be seen from the results in Tables 6-7 that the vitamin D3 freeze-dried orally disintegrating tablets prepared by the present invention have stable vitamin D3 during the freeze-drying process and the content meets the requirements.

[0181] Ten freeze-dried tablets made from the qualified medicinal solution in Examples 1-11 were taken as a group of samples, and the specific content of vitamin D3 in each tablet in each group was detected. The results are shown in Tables 8-9. The uniformity was judged based on A+2.2S≤15 (refer to "0941 Content Uniformity Test Method" in Part IV of the 2020 Edition of the Chinese Pharmacopoeia).

[0182] Table 8 Freeze-dried tablet content uniformity

[0183]

[0184]

[0185] Table 9 Content uniformity of freeze-dried tablets

[0186] Sample No. Example 7 Example 8 Example 9 Example 10 Embodiment 11 Sheet 1 93.39％ 97.02％ 99.74％ 96.96％ 97.10％ Sheet 2 94.39％ 94.21％ 96.37％ 97.33％ 96.02％ Slice 3 93.01％ 97.70％ 98.05％ 96.97％ 96.43％ Slice 4 93.31％ 97.58％ 98.23％ 95.73％ 95.29％ Slice 5 92.29％ 99.25％ 97.87％ 96.43％ 96.37％ Film 6 94.81％ 94.19％ 97.89％ 96.92％ 95.77％ Sheet 7 94.49％ 95.78％ 98.53％ 97.23％ 95.91％ Slice 8 85.57％ 93.22％ 98.77％ 97.07％ 95.94％ Film 9 97.14％ 96.21％ 96.04％ 97.38％ 96.03％ Tablet 10 95.35％ 93.49％ 96.25％ 97.55％ 97.59％ average value 93.37％ 95.86％ 97.77％ 96.96％ 96.25％ A+2.2S 13.4 8.6 4.9 4.2 5.2 evaluate qualified qualified qualified qualified qualified

[0187] Conclusion: It can be seen from Tables 8-9 that the freeze-dried orally disintegrating tablets prepared by the present invention have uniform content and meet the quality requirements.

[0188] Examples 12-14

[0189] According to the prescription in Table 10, orally disintegrating tablets of Examples 12 to 14 were prepared in the same manner as Examples 1 to 11, wherein no binder was added to Example 12.

[0190] Table 10 Adhesive formula adjustment

[0191]

[0192]

[0193] (1) Appearance inspection

[0194] The freeze-dried orally disintegrating tablets of Examples 1-14 were visually inspected for appearance. The inspection results are shown in Table 11. The tablets were intact and had uniform color and were considered qualified.

[0195] Table 11 Appearance test results of freeze-dried orally disintegrating tablets

[0196]

[0197]

[0198] As shown in Table 11, the binder of the present invention has a great influence on the appearance of the freeze-dried orally disintegrating tablets. The formulation composition without the binder has loose and incomplete tablets, which does not meet the requirements.

[0199] (2) Determination of disintegration time of freeze-dried orally disintegrating tablets

[0200] Take the freeze-dried orally disintegrating tablets of Examples 1-11 and 13-14, and measure them according to the method of the Chinese Pharmacopoeia 2020 edition (0921 Disintegration Time Limit Test Method): Use a disintegrator, fix the stainless steel tube on the bracket, immerse it in a 1000ml cup, and the cup contains about 900ml of water at a temperature of 37°C ± 1°C. Adjust the water level so that the sieve is 15mm ± 1mm ​​below the water surface when the stainless steel tube is at the lowest position. Start the instrument. Take 1 sample and place it in the above-mentioned stainless steel tube for inspection. A total of 6 pieces are measured. The average values ​​are listed in Tables 12-13. The qualified standard is that all disintegrated within 60 seconds.

[0201] Table 12 Disintegration time limit of freeze-dried tablets measured by disintegration instrument

[0202] Sample name Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Disintegration time 41.3 seconds 11.8 seconds 16.0 seconds 41 seconds 38.3 seconds 46.7 seconds Eligibility qualified qualified qualified qualified qualified qualified

[0203] Table 13 Disintegration time limit of freeze-dried tablets measured by disintegration instrument

[0204] Sample name Example 7 Example 8 Example 9 Example 10 Embodiment 11 Example 13 Embodiment 14 Disintegration time 35.5 seconds 11.8 seconds 18.2 seconds 24.3 seconds 16.5 seconds 37 seconds 51 seconds Eligibility qualified qualified qualified qualified qualified qualified qualified

[0205] Conclusion: It can be seen from Tables 12-13 that the disintegration time of the freeze-dried orally disintegrating tablets prepared by the present invention meets the requirements of the 2020 edition of the Chinese Pharmacopoeia.

[0206] (3) Determination of oral disintegration time

[0207] The freeze-dried orally disintegrating tablets of Examples 1-11 and 13-14 were used to measure the oral disintegration time of human body: one tablet was placed in the oral cavity of a healthy adult volunteer, and the time for the tablet to disintegrate and completely dissolve in the oral cavity was calculated as the disintegration time. The test was performed 3 times, and the average value was listed.

[0208] Table 14 Lyophilized tablets disintegration time in healthy people's oral cavity

[0209] Sample name Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Disintegration time 20 seconds 4 seconds 5 seconds 8 seconds 5 seconds 40 seconds

[0210] Table 15 Lyophilized tablets disintegration time in healthy people's oral cavity

[0211]

[0212] Conclusion: It can be seen from Tables 14-15 that the disintegration time of the freeze-dried orally disintegrating tablets prepared according to the present invention in the oral cavity of a healthy human body does not exceed 1 minute.

[0213] Examples 15-21

[0214] The amount of the oil solvent is adjusted to prepare a freeze-dried predrug solution intermediate.

[0215] The preparation methods of Examples 15-19 are the same as those of Example 1 to prepare liquid 4.

[0216] Preparation method of Examples 20-21: Weigh the raw and auxiliary materials as shown in the prescription amount in Table 16: (1) Heat the oil solvent, DL-α-tocopherol, and vitamin D3 in a water bath at 80°C to dissolve them to obtain liquid 1; (2) Dissolve water, emulsifier, sucrose, sodium vitamin C, gelatin, and mannitol in the prescribed amount of water to obtain liquid 2; (3) Transfer liquid 2 to liquid 1 and emulsify it by high-speed stirring to obtain liquid 3.

[0217] Table 16 Adjustment of oil solvent content in the prescription

[0218]

[0219] (1) Study on the uniformity of vitamin D3 content in liquid medicine

[0220] The content of vitamin D3 in the medicinal solutions of Examples 15-21 was determined by the same method as in Example 1. The results are shown in Table 17.

[0221] Table 17 Content of vitamin D3 in the medicinal solution of Examples 13-18

[0222]

[0223]

[0224] Conclusion: From the test results in Table 17, it can be seen that the dosage of the oil solvent in the freeze-dried orally disintegrating tablet formulation proposed in the present invention will affect the stability of the intermediate drug solution. The inventors have found through experiments that when the oil solvent content is within the range of the present invention, qualified orally disintegrating tablets can be obtained. If the oil solvent content exceeds this range, orally disintegrating tablets with good dispersion and uniform content cannot be obtained.

[0225] Example 22 Study on the long-term stability of vitamin D3 orally disintegrating tablets

[0226] Orally disintegrating tablet samples were prepared according to the prescription in Table 18 for long-term stability study. The preparation method was the same as in Example 1.

[0227] Table 18 Vitamin D3 Freeze-dried Orally Disintegrating Tablets Prescription

[0228]

[0229] The samples prepared in Example 19 were sealed and packaged, and subjected to accelerated tests (40°C ± 2°C / 75% RH ± 5% RH) and long-term tests (25°C ± 2°C / 60% RH ± 5% RH), and the index of investigation was the change in the content of vitamin D3 in the orally disintegrating tablets. The content of vitamin D3 in the orally disintegrating freeze-dried tablets was tested in 0 month, 1 month, 2 months and 3 months, respectively. The vitamin D3 content of the tablets was the relative content of the labeled amount of 0.01 mg. The results are shown in Table 19.

[0230] Table 19 Vitamin D3 freeze-dried disintegrating tablet stability study results

[0231]

[0232] Conclusion: According to the "Technical Requirements for Pharmaceutical Research of Calcium Carbonate D3 Chewable Tablets" issued by the Drug Review Center of the State Drug Administration, vitamin D3 is extremely unstable, and vitamin D3 is allowed to be overdosed, and the overdosage amount generally shall not exceed 20%. From the above stability research data, it can be seen that the content of the long-term test (25℃±2℃ / 60%RH±5%RH) for 3 months did not show significant changes, indicating that the sample prepared according to the present invention has good storage stability at room temperature and is suitable for commercial large-scale production.

[0233] In the above embodiments, all technical solutions under the concept of the present invention belong to the protection scope of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications without departing from the principle of the present invention should also be regarded as the protection scope of the present invention.

Claims

1. A pharmaceutical composition containing vitamin D, comprising: (A) Vitamin D 0.0001-0.5wt%; (B) emulsifier; (C) oil solvent; and, (D) 0.1-70 wt % of binder; The emulsifier is selected from at least one of sodium starch octenyl succinate or β-cyclodextrin, and the pharmaceutical composition contains 0.001-80wt% of the emulsifier; The content ratio of the oil solvent to the vitamin D in the pharmaceutical composition is 1.4-1000:

1.

2. The pharmaceutical composition according to claim 1, wherein the emulsifier is 0.24-73wt% sodium starch octenylsuccinate or 0.04-71wt% β-cyclodextrin.

3. The pharmaceutical composition according to claim 1, wherein the oil solvent comprises an ester of a saturated or unsaturated fatty acid of C3-C30, preferably the ester is a triglyceride; Preferably, the oil solvent includes at least one of a C3-C5 short-chain saturated or unsaturated fatty acid triglyceride, a C6-C12 medium-chain saturated or unsaturated fatty acid triglyceride, or a C13-C22 long-chain saturated or unsaturated fatty acid triglyceride; Preferably, the oil solvent includes at least one of olive oil, castor oil or C6-C12 medium-chain saturated or unsaturated fatty acid triglycerides.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein: Preferably, in the pharmaceutical composition, the vitamin D comprises at least one of vitamin D2 or vitamin D3; Preferably, in the pharmaceutical composition, the content of vitamin D is 0.001-0.1wt%; More preferably, in the pharmaceutical composition, the content of vitamin D is 0.001-0.05wt%; Preferably, in the pharmaceutical composition, the oil solvent is C6-C12 medium-chain saturated or unsaturated fatty acid triglyceride; Preferably, in the pharmaceutical composition, the content ratio of the oil solvent to the vitamin D is 1.4-60:1; Preferably, in the pharmaceutical composition, the content of the oil solvent is 0.001-20wt%; More preferably, in the pharmaceutical composition, the content of the oil solvent is 0.01-13wt%; Preferably, in the pharmaceutical composition, the binder comprises at least one of pullulan, xanthan gum, gelatin or dextran; Preferably, in the pharmaceutical composition, the content of the binder is 1-40wt%.

5. The pharmaceutical composition according to any one of claims 1 to 3, wherein The pharmaceutical composition further comprises at least one of the following components (E) to (F): (E) lyophilization protectant 5-96wt%; (F) 0.01-10 wt % antioxidant; Preferably, the lyoprotectant comprises mannitol; Preferably, the antioxidant comprises a vitamin antioxidant, and more preferably, the antioxidant comprises at least one of vitamin E or vitamin C.

6. An orally disintegrating tablet comprising the pharmaceutical composition according to any one of claims 1 to 5.

7. A unit dosage form, which is an orally disintegrating tablet, wherein the mass of the orally disintegrating tablet is 2-1500 mg, and the orally disintegrating tablet contains 0.001-1.5 mg of vitamin D.

8. The unit dosage form according to claim 7, wherein the mass of the orally disintegrating tablet is 5-1000 mg, preferably 10-100 mg; Preferably, the vitamin D is the only active ingredient in the orally disintegrating tablet; Preferably, the content of vitamin D in the orally disintegrating tablet is 0.002-0.1 mg, more preferably 0.005-0.02 mg.

9. The unit dosage form according to any one of claims 7-8, wherein the orally disintegrating tablet contains the pharmaceutical composition according to any one of claims 1-5.

10. The method for preparing the orally disintegrating tablet according to claim 7, comprising the following steps: (S1) dissolving vitamin D in an oil solvent to prepare an oil phase; (S2) mixing an emulsifier and water to prepare an aqueous phase; (S3) mixing the oil phase and the water phase to prepare an emulsion; and, (S4) freeze-drying the emulsion to obtain the orally disintegrating tablet. Preferably, the preparation method comprises the following steps: (S1) dissolving vitamin D and vitamin E antioxidants in an oil solvent to prepare an oil phase; (S2) mixing an emulsifier, a vitamin C antioxidant and water to prepare an aqueous phase 1; (S3-1) mixing the oil phase and the water phase 1 to prepare an emulsion 1; (S3-2) mixing a binder, a lyoprotectant and water to prepare an aqueous phase 2; (S3-3) adding the aqueous phase 2 to the emulsion 1 to obtain an emulsion 2; and, (S4) freeze-drying the emulsion 2 to obtain the orally disintegrating tablet; Or, preferably, the preparation method comprises the following steps: (S1) dissolving vitamin D and vitamin E antioxidants in an oil solvent to prepare an oil phase; (S2) mixing an emulsifier, a vitamin C antioxidant, a binder, a lyophilization protectant and water to prepare an aqueous phase; (S3) mixing the oil phase and the water phase to prepare an emulsion; and, (S4) freeze-drying the emulsion to obtain the orally disintegrating tablet.

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