Vitamin A inclusion powder as well as preparation method and application thereof

Abstract

The invention discloses vitamin A inclusion powder as well as a preparation method and application thereof, and belongs to the technical field of pharmaceutical preparations. The vitamin A inclusion powder comprises the following raw materials: a vitamin A active component, a capsule material, a filler, a stabilizer, a pellet core and water, the capsule material comprises Arabic gum and / or gelatin; the filling agent comprises cane sugar and maltodextrin; the preparation method of the vitamin A inclusion powder comprises the following steps: dissolving a capsule material in water to prepare a water phase; mixing the vitamin A active ingredient with the stabilizer to prepare an oil phase; mixing the water phase with the oil phase to prepare a primary emulsion; homogenizing the primary emulsion, adding a filling agent, and mixing to prepare a spray solution; performing fluidized bed spray drying on the spray solution to pellet cores to prepare the vitamin A inclusion powder; the atomization pressure of the spray drying of the fluidized bed is 2.0-4.0 bar. The vitamin A inclusion powder prepared by the invention is stable in quality, low in adhesion degree and good in long-term stability.

Description

Technical Field

[0001] The present application relates to the technical field of pharmaceutical preparations, and in particular to a vitamin A inclusion powder, a preparation method and application thereof. Background Art

[0002] Vitamin A is retinol. In a broad sense, vitamin A also includes retinol derivatives such as retinal, retinoic acid, vitamin A acetate and vitamin A palmitate. Causes of vitamin A deficiency include insufficient intake, fat malabsorption or liver disease. Vitamin A deficiency induces eye abnormalities, causing xerophthalmia and night blindness. In addition, other diseases that may be associated with vitamin A deficiency include neonatal sepsis, hospital-acquired sepsis, measles, meningitis, pneumonia, necrotizing enterocolitis and other viral or bacterial infections.

[0003] The structures of retinol, vitamin A acetate, and vitamin A palmitate are shown below:

[0004] .

[0005] Vitamin A contains 5 conjugated double bonds and hydroxyl groups. Vitamin A ester derivatives contain 1 ester group in addition to 5 conjugated double bonds. The chemical properties of conjugated double bonds are unstable and are prone to reactions such as addition, oxidation, polymerization, cleavage and dehydration; hydroxyl groups undergo oxidation and dehydration reactions; and ester groups are prone to decarboxylation reactions. Light, oxygen, heat and free radicals can trigger the above reactions or accelerate them. Since these factors are difficult to avoid during the production, storage and use of vitamin A, vitamin A products need to be stored in a dark, nitrogen-filled, and 4°C environment. Literature reports that the content of vitamin A decreased by 73.6% after being stored in a low-density polyethylene bag for 7 days. This results in poor operational feasibility of vitamin A preparation into tablets, capsules, suspensions and other dosage forms.

[0006] In order to improve the chemical stability of vitamin A and extend its shelf life, vitamin A is usually processed into microcapsule particles through a fluidized bed spray granulation process before use. However, microcapsule particles are greatly affected by processing conditions, and are prone to production fluctuations and unstable content. In addition, due to their small particle size, microcapsule particles are prone to agglomeration, which greatly affects their use effect.

[0007] Therefore, there is an urgent need to provide vitamin A inclusion powder with stable quality, low adhesion and good long-term stability.

[0008] Application Contents

[0009] Based on this, the main purpose of this application is to provide vitamin A inclusion powder with stable quality, low adhesion and good long-term stability, so as to provide the feasibility of application of vitamin A in the form of tablets, capsules, suspensions and other dosage forms.

[0010] In a first aspect of the present application, a method for preparing a vitamin A inclusion powder is provided, wherein the vitamin A inclusion powder comprises the following raw materials: a vitamin A active ingredient, a capsule material, a filler, a stabilizer, a pellet core, and water; the capsule material comprises gum arabic and / or gelatin; the filler comprises sucrose and maltodextrin;

[0011] The preparation method comprises the following steps:

[0012] Dissolving the capsule material in water to prepare an aqueous phase;

[0013] Mixing vitamin A active ingredient and a stabilizer to prepare an oil phase;

[0014] Mixing the water phase with the oil phase to prepare a primary emulsion;

[0015] After homogenizing the primary emulsion, the filler is added and mixed to prepare a spray solution;

[0016] Fluid-bed spray drying the spray solution onto the pellet cores to prepare the vitamin A inclusion powder;

[0017] The atomization pressure of the fluidized bed spray drying is 2.0-4.0 bar.

[0018] In some embodiments, the vitamin A inclusion powder comprises the following raw materials in parts by weight:

[0019] 30-80 parts of vitamin A active ingredient, 50-200 parts of capsule material, 40-120 parts of filler, 0.5-20 parts of stabilizer, 600-900 parts of pellet core and 150-400 parts of water.

[0020] In some embodiments, the vitamin A active ingredient includes vitamin A acetate and / or vitamin A palmitate.

[0021] In some embodiments, the stabilizer includes at least one of butylated p-hydroxyanisole (BHA), butylated hydroxytoluene (BHT), α-tocopherol, and tert-butylhydroquinone (TBHQ).

[0022] In some embodiments, the pellet core comprises a sucrose pellet core and / or a microcrystalline cellulose pellet core.

[0023] In some embodiments, the particle size of the pellet core is 100-500 μm.

[0024] In some embodiments, the mass ratio of sucrose to maltodextrin is 1:0.5-2.

[0025] In some embodiments, the homogenization includes shear homogenization and / or high-pressure homogenization; the conditions of shear homogenization include a rotation speed of 10000-20000 rpm and homogenization for 20-30 min; the conditions of high-pressure homogenization include a homogenization pressure of 600-1500 bar and homogenization for 3-8 times.

[0026] In some embodiments, the step of fluidizing the bed and spray-drying the spray solution onto the pellet cores is specifically as follows: adding the pellet cores into the fluidized bed, and spray-drying the spray solution onto the pellet cores.

[0027] In some embodiments, the fluidized bed spray drying conditions further include: bottom spray mode; air inlet temperature of 50-70°C; material temperature of 30-50°C; liquid inlet speed of 4-8rpm.

[0028] In some embodiments, in the step of fluidizing the spraying solution and spray drying it onto the pellet cores, the weight gain of the pellet cores is ≥27%.

[0029] The second aspect of the present application provides vitamin A inclusion powder prepared by the aforementioned preparation method.

[0030] The third aspect of the present application provides the use of the aforementioned vitamin A inclusion powder in a single or compound dosage form of vitamin A.

[0031] In some embodiments, the dosage form product comprises at least one of a tablet, a capsule, and a suspension.

[0032] The fourth aspect of the present application provides a dosage product of single or compound vitamin A, including the aforementioned vitamin A inclusion powder.

[0033] Beneficial effects of this application:

[0034] 1. In the present application, a spray solution is prepared by combining vitamin A active ingredient, capsule material, filler, stabilizer and water, and then the solution is dried on a pellet core by high-pressure spray in a fluidized bed to prepare a vitamin A inclusion powder with stable quality, low adhesion and good long-term stability.

[0035] 2. The present application provides a method for preparing a stable vitamin A inclusion powder, which increases the stability of vitamin A exponentially.

[0036] 3. The present application creatively provides a method for preparing a stable vitamin A inclusion powder, which can solve the stringent requirements of vitamin A that it needs to be protected from light, filled with nitrogen, and refrigerated, and provides the feasibility of preparing vitamin A into tablets, capsules, suspensions and other dosage forms.

[0037] 4. This application creatively proposes to prepare stable vitamin A inclusion powder by coating blank pill cores with drugs.

[0038] 5. The present application creatively prepares a vitamin A microemulsion solution encapsulated by a high-pressure homogenizer, which significantly improves the stability of vitamin A.

[0039] 6. This application creatively proposes to control the particle size range (0.5μm -1.3μm) of the vitamin A microemulsion solution by controlling the high-pressure homogenization parameters (pressure 600-1500 bar, homogenization 3-8 times) through the Malvern laser particle size detector (model 3000, wet method). This achieves a stable preparation and detection process for the vitamin A microemulsion solution, improves the inclusion rate of vitamin A, improves stability, and greatly improves the drugability of vitamin A.

[0040] 7. This application creatively solves the problem of severe adhesion of pellet cores due to emulsion viscosity during the production process through unique formula design and process parameter design, especially the use of unconventional atomization pressure (2.0-4.0 bar pressure for spraying).

[0041] 8. This application creatively realizes the preparation process of such viscous emulsions with high concentrations of more than 40wt% of varieties such as gum arabic or gelatin, and the weight gain of micropills with more than 27%, which has a breakthrough significance and provides a good reference basis for technical personnel in the same field to solve similar technical problems.

[0042] 9. The present application provides a preparation process for vitamin A inclusion powder suitable for large-scale industrial production. It does not require special process equipment or special process operations, and the qualified rate of large-scale production batches is over 98%. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 This is a comparison diagram of the emulsions obtained after homogenization in Example 1 (left) and Comparative Example 1 (right) after standing for 4 hours;

[0044] Figure 2 This is a laser particle size test image of the emulsion obtained after homogenization in Example 1;

[0045] Figure 3 This is a low magnification microscope photograph of the vitamin A inclusion powder of Example 1;

[0046] Figure 4 This is a high magnification microscope photograph of the vitamin A inclusion powder of Example 1;

[0047] Figure 5 This is a laser particle size test chart of the emulsion obtained after homogenization in Example 1. DETAILED DESCRIPTION

[0048] In order to facilitate the understanding of the present application, the present application will be described more comprehensively below in conjunction with specific embodiments. Preferred embodiments of the present application are provided hereinafter. However, the present application can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the present application more thorough and comprehensive.

[0049] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this application belongs. The terms used herein in the specification of this application are only for the purpose of describing specific embodiments and are not intended to limit this application. The term "and / or" used herein includes any and all combinations of one or more of the related listed items.

[0050] In this article, the technical features described in an open manner include closed technical solutions composed of the listed features, and also include open technical solutions containing the listed features.

[0051] In this article, the terms "first" and "second" are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the quantity of the indicated technical features.

[0052] In the description herein, "at least one" means more than one, including one or more than two, for example, one, two, three, etc., unless otherwise clearly defined.

[0053] The temperature parameters herein, if not specifically limited, allow for both constant temperature treatment and treatment within a certain temperature range. The constant temperature treatment allows for temperature fluctuations within the precision range of instrument control.

[0054] Herein, when it comes to numerical ranges, unless otherwise specified, the numerical ranges are deemed to be continuous and include the minimum and maximum values ​​of the range, as well as every value between such minimum and maximum values. Further, when a range refers to an integer, every integer between the minimum and maximum values ​​of the range is included. In addition, when multiple ranges are provided to describe features or characteristics, the ranges can be merged. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges included therein.

[0055] In this article, when referring to the units of a data range, if there is a unit only after the right endpoint, it means that the units of the left and right endpoints are the same. For example, 1-5h means that the units of the left endpoint "1" and the right endpoint "5" are both h (hours).

[0056] In a first aspect of the present application, a method for preparing a vitamin A inclusion powder is provided, wherein the vitamin A inclusion powder comprises the following raw materials: a vitamin A active ingredient, a capsule material, a filler, a stabilizer, a pellet core, and water; the capsule material comprises gum arabic and / or gelatin; the filler comprises sucrose and maltodextrin;

[0057] The preparation method comprises the following steps:

[0058] Dissolving the capsule material in water to prepare an aqueous phase;

[0059] Mixing vitamin A active ingredient and a stabilizer to prepare an oil phase;

[0060] Mixing the water phase with the oil phase to prepare a primary emulsion;

[0061] After homogenizing the primary emulsion, the filler is added and mixed to prepare a spray solution;

[0062] Fluid-bed spray drying the spray solution onto the pellet cores to prepare the vitamin A inclusion powder;

[0063] The atomization pressure of the fluidized bed spray drying is 2.0-4.0 bar.

[0064] Among them, the physical and chemical pressure can be specifically 2.0 bar, 2.2 bar, 2.4 bar, 2.6 bar, 2.8 bar, 3.0 bar, 3.2 bar, 3.4 bar, 3.6 bar, 3.8 bar, 4.0 bar, etc.

[0065] Understandably, the raw material composition and spray drying pressure of vitamin A inclusion powder will affect the quality of vitamin A inclusion powder, especially in the system of the present application, it is also necessary to realize the drug application to the pill core. The mass concentration of the emulsion used for spray drying is usually 10%-20%. If the emulsion concentration is too high, it will cause the emulsion to stick together, making it difficult to achieve a good embedding effect and the quality of the product cannot be guaranteed. However, simply increasing the atomization pressure cannot solve the problems existing when high-concentration emulsions are spray-dried, and the characteristics of the spray solution itself also have a great influence. Even at the same mass concentration, the difference in fillers and the different timing of adding fillers will lead to significant differences in the spray drying effect. Poor spray drying effect will cause pill core adhesion, low embedding rate, low drug loading and decreased uniformity, thereby deteriorating the long-term stability of the product.

[0066] The present application prepares vitamin A inclusion powder by coating blank pill cores with drugs, and through unique formula design and process parameter design, especially the use of unconventional high-pressure spray (2.0-4.0 bar, conventional spray pressure is ≤1.5 bar), spray drying of high-concentration spray solutions (more than 40wt%) can be achieved, and the effect of increasing the weight of pill cores by more than 27% can be achieved. The prepared vitamin A inclusion powder has stable quality, high drug loading, low adhesion, and good long-term stability.

[0067] Optionally, the concentration of the spray solution is 40-50wt%, for example, 40wt%, 41wt%, 42wt%, 43wt%, 44wt%, 45wt%, 46wt%, 47wt%, 48wt%, 49wt%, 50wt%, etc.

[0068] In some embodiments, the vitamin A inclusion powder comprises the following raw materials in parts by weight:

[0069] 30-80 parts of vitamin A active ingredient, 50-200 parts of capsule material, 40-120 parts of filler, 0.5-20 parts of stabilizer, 600-900 parts of pellet core and 150-400 parts of water.

[0070] In some embodiments, the vitamin A active ingredient includes vitamin A acetate and / or vitamin A palmitate.

[0071] In some embodiments, the stabilizer includes at least one of butylated p-hydroxyanisole (BHA), butylated hydroxytoluene (BHT), α-tocopherol, and tert-butylhydroquinone (TBHQ).

[0072] It is understandable that the stabilizer can be used alone or in combination, for example, butylated p-hydroxyanisole (BHA) can be used, or butylated p-hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) can be used in combination. Relatively speaking, the combination can achieve improved stability.

[0073] In some embodiments, the pellet core comprises a sucrose pellet core and / or a microcrystalline cellulose pellet core.

[0074] It is understandable that the particle size of the pellet core is usually a range, and the particle size of the pellet core is not specifically limited in the present application. In some embodiments, the particle size of the pellet core is 100-500 μm; specifically, it can be 100-250 μm, 100-400 μm, 150-450 μm, 200-350 μm, 200-400 μm, 300-500 μm, etc.; preferably, it is 200-350 μm.

[0075] In some embodiments, the mass ratio of sucrose to maltodextrin is 1:0.5-2, specifically 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.0.

[0076] In some embodiments, the homogenizing comprises shear homogenizing and / or high pressure homogenizing.

[0077] It is understandable that there is no special requirement for the shearing conditions, as long as good mixing and uniformity of the emulsion can be achieved. In some embodiments, the shearing homogenization conditions include a rotation speed of 10000-20000 rpm and homogenization for 20-30 minutes; the high-pressure homogenization conditions include a homogenization pressure of 600-1500 bar and homogenization for 3-8 times. Specifically, the speed of shear homogenization can be 10000rpm, 11000rpm, 12000rpm, 13000rpm, 14000rpm, 15000rpm, 16000rpm, 17000rpm, 18000rpm, 19000rpm, 20000rpm, etc., and the homogenization time can be 20min, 21min, 22min, 23min, 24min, 25min, 26min, 27min, 28min, 29min, 30min, etc.; the pressure of high-pressure homogenization can be 600bar, 700bar, 800bar, 900bar, 1000bar, 1100bar, 1200bar, 1300bar, 1400bar, 1500bar; the number of homogenization can be 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, etc.

[0078] Optionally, after the primary emulsion is homogenized, the D90 particle size of the emulsion is 0.5 μm-1.3 μm.

[0079] In some embodiments, the step of fluidizing the bed and spray-drying the spray solution onto the pellet cores is specifically as follows: adding the pellet cores into the fluidized bed, and spray-drying the spray solution onto the pellet cores.

[0080] In some embodiments, the conditions of fluidized bed spray drying also include: bottom spray mode; air inlet temperature of 50-70°C; material temperature of 30-50°C; liquid inlet speed of 4-8rpm; specifically, the air inlet temperature can be 50°C, 55°C, 60°C, 65°C, 70°C, etc., the material temperature can be 30°C, 35°C, 40°C, 45°C, 50°C, etc., and the liquid inlet speed can be 4rpm, 5rpm, 6rpm, 7rpm, 8rpm, etc.

[0081] It is understandable that in the fluidized bed spray drying process, after the emulsion is sprayed, the inlet air temperature can be maintained to continue drying for 5-20 minutes.

[0082] In some embodiments, in the step of fluidizing and spraying the spray solution onto the pill cores, the weight gain of the pill cores is ≥27%, and can be optionally 27.0-45%, for example, 27.1%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, etc.

[0083] It is understandable that in the steps of preparing the water phase, preparing the oil phase and preparing the primary emulsion, heating may be performed to improve the mixing effect, and the heating temperature may be 35-70°C.

[0084] The second aspect of the present application provides vitamin A inclusion powder prepared by the aforementioned preparation method.

[0085] The third aspect of the present application provides the use of the aforementioned vitamin A inclusion powder in a single or compound dosage form of vitamin A.

[0086] In some embodiments, the dosage form product comprises at least one of a tablet, a capsule, and a suspension.

[0087] The fourth aspect of the present application provides a dosage product of single or compound vitamin A, including the aforementioned vitamin A inclusion powder.

[0088] It is worth noting that the raw materials used in the examples of the present application are all common commercially available products, and their sources are not specifically limited.

[0089] The following is an exemplary description of some of the raw materials in the examples:

[0090] Vitamin A palmitate: purchased from Hebei Guolong Pharmaceutical Co., Ltd.;

[0091] Vitamin A acetate: purchased from Zhejiang Xinhecheng Co., Ltd.;

[0092] Gum Arabic: purchased from Hubei Gedian Renfu Pharmaceutical Excipients Co., Ltd.;

[0093] Gelatin: purchased from Rousselot (Wenzhou) Gelatin Co., Ltd.

[0094] Maltodextrin: purchased from Hunan Jiudian Hongyang Pharmaceutical Co., Ltd.;

[0095] Sucrose pellets: 200-350 μm, purchased from Hangzhou Gaocheng Biological Nutrition Technology Co., Ltd.

[0096] Example 1

[0097] A preparation method of vitamin A inclusion powder

[0098] The recipe is as follows:

[0099]

[0100] *Vitamin A palmitate was added at 105%.

[0101] The preparation method is as follows:

[0102] S1. Preparation of aqueous phase: Add purified water to gum arabic, heat at 45°C, stir until dissolved, and keep warm at 45°C for later use;

[0103] S2. Preparation of oil phase: Heat vitamin A palmitate at 40°C, stir until it becomes a uniform liquid, then add butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA), continue stirring to dissolve, and keep warm at 40°C for later use.

[0104] S3. Preparation of primary emulsion: Place the oil phase at 45°C, slowly add the aqueous phase solution under stirring, and continue stirring until a uniform primary emulsion is formed.

[0105] S4, emulsion homogenization

[0106] ① Shear homogenization

[0107] The primary emulsion was placed in a water bath and sheared and homogenized using an IKA (model T25) high shear homogenizer. The speed of the homogenizer was set to 18,000 rpm and the homogenization was performed for 20 minutes.

[0108] ②High pressure homogenization

[0109] The primary emulsion after shear homogenization was subjected to high pressure homogenization using an ATS high pressure homogenizer (model AH-PILOT), with an average pressure of 1200 bar, and the emulsion was subjected to high pressure homogenization 4 times; the appearance of the emulsion after homogenization was placed at room temperature for 4 hours is shown in FIG. Figure 1 The laser particle size test diagram is shown in Figure 2 .

[0110] ③Particle size detection

[0111] The particle size of the emulsion was tested using Malvern 3000 (wet method), and the D90 of the emulsion was 1.17 μm.

[0112] S5. Preparation of spray solution

[0113] The homogenized emulsion was transferred to a stirrer, sucrose and maltodextrin were added, and stirred for 30 minutes until completely dissolved to obtain a spray solution with an emulsion concentration of 45.13 wt%.

[0114] S6, fluidized bed spray drying

[0115] The multifunctional fluidized bed (model WBF-5G) was set to bottom spray mode, the air inlet temperature was 65°C, the sucrose pellets were added to the fluidized bed, the material temperature was controlled at 40±5°C, the emulsion inlet speed was 6rpm, and the atomization pressure was 3.0bar. After the emulsion was sprayed, it was dried for 10 minutes at an air inlet temperature of 60°C. The moisture content was measured at 80°C using a fast halogen moisture meter and controlled to be no more than 1.0%; the theoretical weight gain of the pellets was 32.75%; the microscopic photo of the prepared vitamin A inclusion powder is shown in Figure 3-4 , it can be seen that the sphere is intact, without damage or adhesion.

[0116] Example 2

[0117] A preparation method of vitamin A inclusion powder

[0118] The recipe is as follows:

[0119]

[0120] *Vitamin A acetate is added at 105%.

[0121] The preparation method is as follows:

[0122] S1. Preparation of aqueous phase: Add purified water to gum arabic, heat at 40°C, stir until dissolved, and keep warm at 40°C for later use;

[0123] S2. Preparation of oil phase: Heat vitamin A acetate (crystal oil solution) and α-tocopherol at 60°C, stir until they become a uniform liquid, then add butylated hydroxytoluene (BHT), continue stirring to dissolve, and keep warm at 45°C for later use.

[0124] S3. Preparation of primary emulsion: Place the oil phase at 45°C, slowly add the aqueous phase solution under stirring, and continue stirring until a uniform primary emulsion is formed.

[0125] S4, emulsion homogenization

[0126] ① Shear homogenization

[0127] The primary emulsion was placed in a water bath and shear homogenized using an IKA (model T25) high shear homogenizer. The speed of the homogenizer was set to 15,000 rpm and the homogenization was performed for 25 minutes.

[0128] ②High pressure homogenization

[0129] The primary emulsion after shear homogenization was subjected to high-pressure homogenization using an ATS high-pressure homogenizer (model AH-PILOT), with an average pressure of 1000 bar, and the emulsion was high-pressure homogenized 6 times.

[0130] ③Particle size detection

[0131] The particle size of the emulsion was tested using Malvern 3000 (wet method), and the D90 of the emulsion was 0.93 μm.

[0132] S5. Preparation of spray solution

[0133] The homogenized emulsion was transferred to a stirrer, sucrose and maltodextrin were added, and stirred for 30 minutes until completely dissolved to obtain a spray solution with an emulsion concentration of 41.62 wt%.

[0134] S6, fluidized bed spray drying

[0135] The multifunctional fluidized bed (model WBF-5G) was set to bottom spray mode, the air inlet temperature was 60°C, the sucrose pellets were added to the fluidized bed, the material temperature was controlled at 40±5°C, the emulsion inlet speed was 8rpm, and the atomization pressure was 2.5bar. After the emulsion was sprayed, it was continued to dry for 15min at an air inlet temperature of 60°C, and the moisture was measured at 80°C using a fast halogen moisture meter to control the moisture content to not exceed 1.0%; the theoretical weight gain of the pills was 27.12%.

[0136] Example 3

[0137] A preparation method of vitamin A inclusion powder

[0138] The recipe is as follows:

[0139]

[0140] *Vitamin A palmitate was added at 105%.

[0141] The preparation method is as follows:

[0142] S1. Preparation of aqueous phase: Add purified water to gum arabic, heat at 45°C, stir until dissolved, and keep warm at 45°C for later use;

[0143] S2. Preparation of oil phase: Heat vitamin A palmitate (oil solution) at 40°C, stir until it becomes a uniform liquid, then add butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA), continue stirring to dissolve, and keep warm at 40°C for later use.

[0144] S3. Preparation of primary emulsion: Place the oil phase at 45°C, slowly add the aqueous phase solution under stirring, and continue stirring until a uniform primary emulsion is formed.

[0145] S4, emulsion homogenization

[0146] ① Shear homogenization

[0147] The primary emulsion was placed in a water bath and sheared and homogenized using an IKA (model T25) high shear homogenizer. The speed of the homogenizer was set to 15,000 rpm and the homogenization was performed for 20 minutes.

[0148] ②High pressure homogenization

[0149] The primary emulsion after shear homogenization was subjected to high-pressure homogenization using an ATS high-pressure homogenizer (model AH-PILOT), with an average pressure of 800 bar, and the emulsion was high-pressure homogenized 6 times.

[0150] ③Particle size detection

[0151] The particle size of the emulsion was tested using Malvern 3000 (wet method), and the D90 of the emulsion was 0.74 μm.

[0152] S5. Preparation of spray solution

[0153] The homogenized emulsion was transferred to a stirrer, sucrose and maltodextrin were added, and stirred for 30 minutes until completely dissolved to obtain a spray solution with an emulsion concentration of 48.53 wt%.

[0154] S6, fluidized bed spray drying

[0155] The multifunctional fluidized bed (small trial model WBF-5G) was set to bottom spray mode, the air inlet temperature was 65°C, the sucrose pellets were added to the fluidized bed, the material temperature was controlled at 45°C, the emulsion inlet speed was 7rpm, and the atomization pressure was 3.5bar. After the emulsion was sprayed, it was continued to dry for 10 minutes at an air inlet temperature of 65°C, and the moisture was measured at 80°C with a fast halogen moisture meter to control the moisture content to not exceed 1.0%; the theoretical weight gain of the pills was 30.84%.

[0156] Example 4

[0157] A preparation method of vitamin A inclusion powder

[0158] The recipe is as follows:

[0159]

[0160] *Vitamin A palmitate was added at 105%.

[0161] S1. Preparation of aqueous phase

[0162] Weigh the prescribed amount of gum arabic and gelatin, add the prescribed amount of purified water, heat at 45°C, stir until dissolved, and keep warm at 45°C for later use;

[0163] S2. Oil phase preparation

[0164] Weigh the prescribed amount of vitamin A palmitate, heat at 40°C, stir until it becomes a uniform liquid, then add the prescribed amount of butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA), continue stirring to dissolve, and keep warm at 40°C for later use.

[0165] S3. Preparation of primary emulsion

[0166] Place the oil phase at 45°C, slowly add the aqueous phase solution under stirring, and continue stirring until a uniform primary emulsion is formed.

[0167] S4, emulsion homogenization

[0168] ① Emulsion high shear

[0169] The primary emulsion was placed in a water bath and sheared and homogenized using an IKA (model T25) high shear homogenizer. The speed of the homogenizer was set to 16,000 rpm and the homogenization was performed for 25 minutes.

[0170] ②Emulsion high pressure homogenization

[0171] ③ Use ATS high-pressure homogenizer (model AH-PILOT) for high-pressure homogenization with a homogenization pressure of 1000 bar, and high-pressure homogenization of the emulsion for 5 times.

[0172] ④ The particle size of the emulsion was tested using Malvern 3000 (wet method), and the emulsion D90 was 0.91 μm.

[0173] S5. Emulsion preparation

[0174] The homogenized emulsion was transferred to a stirrer, and the prescribed amount of sucrose and maltodextrin was added, and stirred for 30 minutes until completely dissolved, and set aside. The emulsion concentration was 41.49wt%.

[0175] S6, Fluidized Bed Pellets Drug Application

[0176] The multifunctional fluidized bed (model WBF-5G) was set to bottom spray mode, the air inlet temperature was 60°C, the prescribed amount of sucrose pellets were weighed and added to the fluidized bed, the material temperature was controlled at 40±5°C, the emulsion inlet speed was 4rpm, and the atomization pressure was 2.5bar. After the emulsion was sprayed, it was continued to dry for 10 minutes at an air inlet temperature of 60°C, and the moisture was measured at 80°C using a fast halogen moisture meter to control the moisture content to not exceed 1.0%; the theoretical weight gain of the pills was 27.03%.

[0177] Example 5

[0178] A preparation method of vitamin A inclusion powder

[0179] The recipe is as follows:

[0180]

[0181] *Vitamin A palmitate was added at 105%.

[0182] S1. Preparation of aqueous phase

[0183] Weigh the prescribed amount of gum arabic, add the prescribed amount of purified water, heat at 45°C, stir until dissolved, and keep warm at 45°C for later use;

[0184] S2. Oil phase preparation

[0185] Weigh the prescribed amount of vitamin A palmitate, heat it at 40°C, stir it until it becomes a uniform liquid, then add the prescribed amount of butylated hydroxytoluene (BHT) and tert-butylhydroquinone (TBHQ), continue stirring to dissolve, and keep it warm at 40°C for later use.

[0186] S3. Preparation of primary emulsion

[0187] Place the oil phase at 45°C, slowly add the aqueous phase solution under stirring, and continue stirring until a uniform primary emulsion is formed.

[0188] S4, emulsion homogenization

[0189] ① Emulsion high shear

[0190] The primary emulsion was placed in a water bath and sheared and homogenized using an IKA (model T25) high shear homogenizer. The speed of the homogenizer was set to 20,000 rpm and the homogenization was performed for 25 minutes.

[0191] ②Emulsion high pressure homogenization

[0192] ③ Use ATS high-pressure homogenizer (model AH-PILOT) for high-pressure homogenization with a homogenization pressure of 1200 bar, and the emulsion is high-pressure homogenized 6 times.

[0193] ④ The particle size of the emulsion was tested using Malvern 3000 (wet method), and the emulsion D90 was 0.61 μm.

[0194] S5. Emulsion preparation

[0195] The homogenized emulsion was transferred to a stirrer, and the prescribed amount of sucrose and maltodextrin was added, and stirred for 30 minutes until completely dissolved, and set aside. The emulsion concentration was 43.58wt%.

[0196] S6, Fluidized Bed Pellets Drug Application

[0197] The multifunctional fluidized bed (model WBF-5G) was set to bottom spray mode, the air inlet temperature was 65°C, the prescribed amount of sucrose pellets were weighed and added to the fluidized bed, the material temperature was controlled at 40±5°C, the emulsion inlet speed was 7rpm, and the atomization pressure was 3.0bar. After the emulsion was sprayed, it was continued to dry for 15 minutes at an air inlet temperature of 60°C, and the moisture was measured at 80°C with a fast halogen moisture meter to control the moisture content to not exceed 1.0%; the theoretical weight gain of the pill core was 30.16%.

[0198] Example 6

[0199] A preparation method of vitamin A inclusion powder

[0200] The recipe is as follows:

[0201]

[0202] *Vitamin A palmitate was added at 105%.

[0203] S1. Preparation of aqueous phase

[0204] Weigh the prescribed amount of gum arabic, add the prescribed amount of purified water, heat at 45°C, stir until dissolved, and keep warm at 45°C for later use;

[0205] S2. Oil phase preparation

[0206] Weigh the prescribed amount of vitamin A palmitate (oil solution), heat it at 40°C, stir until it becomes a uniform liquid, then add the prescribed amount of butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA), continue stirring to dissolve, and keep warm at 40°C for later use.

[0207] S3. Preparation of primary emulsion

[0208] Place the oil phase at 45°C, slowly add the aqueous phase solution under stirring, and continue stirring until a uniform primary emulsion is formed.

[0209] S4, emulsion homogenization

[0210] ① Emulsion high shear

[0211] The primary emulsion was placed in a water bath and sheared and homogenized using an IKA (model T25) high shear homogenizer. The speed of the homogenizer was set to 18,000 rpm and the homogenization was performed for 20 minutes.

[0212] ②Emulsion high pressure homogenization

[0213] ATS high-pressure homogenizer (model AH-PILOT) was used for high-pressure homogenization with a homogenization pressure of 1000 bar, and the emulsion was high-pressure homogenized 6 times.

[0214] ③ Malvern 3000 (wet method) was used to detect the particle size of the emulsion, and the emulsion D90 was 0.86μm.

[0215] S5. Preparation of spray solution

[0216] The homogenized emulsion was transferred to a stirrer, and the prescribed amount of sucrose and maltodextrin was added, and stirred for 30 minutes until completely dissolved, and set aside. The emulsion concentration was 47.99wt%.

[0217] S6, fluidized bed spray drying

[0218] The multifunctional fluidized bed (small trial model WBF-5G) was set to bottom spray mode, the air inlet temperature was 70°C, the prescribed amount of pellets were weighed and added to the fluidized bed, the material temperature was controlled at 40±5°C, the emulsion inlet speed was 7rpm, and the atomization pressure was 4.0bar. After the emulsion was sprayed, it was continued to dry for 10 minutes at an air inlet temperature of 60°C, and the moisture was measured at 80°C with a fast halogen moisture meter to control the moisture content to not exceed 1.0%; the theoretical weight gain of the pills was 38.26%.

[0219] Comparative Example 1

[0220] The difference between Comparative Example 1 and Example 1 is that the vitamin A emulsion in Comparative Example 1 is not subjected to high pressure homogenization, and the rest is the same as Example 1. The specific process is as follows:

[0221] S1. Preparation of aqueous phase: Add purified water to gum arabic, heat at 45°C, stir until dissolved, and keep warm at 45°C for later use;

[0222] S2. Preparation of oil phase: Heat vitamin A palmitate at 40°C, stir until it becomes a uniform liquid, then add butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA), continue stirring to dissolve, and keep warm at 40°C for later use.

[0223] S3. Preparation of primary emulsion: Place the oil phase at 45°C, slowly add the aqueous phase solution under stirring, and continue stirring until a uniform primary emulsion is formed.

[0224] S4, emulsion high shear homogenization

[0225] The primary emulsion was placed in a water bath and sheared and homogenized using an IKA (model T25) high shear homogenizer. The speed of the homogenizer was set to 18,000 rpm and the homogenization was performed for 20 minutes. The appearance of the homogenized emulsion after being placed at room temperature for 4 hours is shown in the figure. Figure 1 The laser particle size test diagram is shown in Figure 5 .

[0226] S5. Preparation of spray solution

[0227] The homogenized emulsion was transferred to a stirrer, sucrose and maltodextrin were added, and stirred for 30 minutes until they were completely dissolved to obtain a spray solution.

[0228] S6, fluidized bed spray drying

[0229] The multifunctional fluidized bed (model WBF-5G) was set to bottom spray mode, the air inlet temperature was 65°C, the sucrose pellets were added to the fluidized bed, the material temperature was controlled at 40±5°C, the emulsion inlet speed was 6rpm, and the atomization pressure was 3.0bar. After the emulsion was sprayed, it was continued to dry for 10 minutes at an air inlet temperature of 60°C, and the moisture was measured at 80°C using a fast halogen moisture analyzer to control the moisture content to not exceed 1.0%.

[0230] Comparative Example 2

[0231] Except that the filler is all maltodextrin (i.e., the amount of sucrose is 0 g and the amount of maltodextrin is 60 g), the rest is the same as Example 1.

[0232] Comparative Example 3

[0233] Except that the atomization pressure is selected as the conventional 1.5 bar, the rest is the same as in Example 1.

[0234] Experimental results: There was no difference in the emulsion preparation process. During the fluidized bed micro-pellet loading operation, serious adhesion and pot collapse occurred and the operation could not continue.

[0235] Comparative Example 4

[0236] Except for adding the filler in step S1, the rest is the same as in Example 1. The specific process is as follows:

[0237] S1. Preparation of aqueous phase

[0238] Weigh the prescribed amount of gum arabic, add the prescribed amount of purified water, and add sucrose and maltodextrin, heat at 45°C, stir until dissolved, and keep warm at 45°C for later use;

[0239] S2. Oil phase preparation

[0240] Weigh the prescribed amount of vitamin A palmitate, heat at 40°C, stir until it becomes a uniform liquid, then add the prescribed amount of butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA), continue stirring to dissolve, and keep warm at 40°C for later use.

[0241] S3. Preparation of primary emulsion

[0242] Place the oil phase at 45°C, slowly add the aqueous phase solution under stirring, and continue stirring until a uniform primary emulsion is formed.

[0243] S4, emulsion homogenization

[0244] ① Emulsion high shear

[0245] The primary emulsion was placed in a water bath and shear homogenized using an IKA (model T25) high shear homogenizer. The speed of the homogenizer was set to 18,000 rpm and the homogenization was performed for 20 minutes.

[0246] ②Emulsion high pressure homogenization

[0247] ATS high-pressure homogenizer (model AH-PILOT) was used for high-pressure homogenization with an average pressure of 1200 bar, and the emulsion was high-pressure homogenized 4 times.

[0248] ③Particle size detection

[0249] The particle size of the emulsion was tested using Malvern 3000 (wet method), and the D90 of the emulsion was 1.17 μm.

[0250] S5. Preparation of spray solution

[0251] Transfer the homogenized emulsion to a stirrer and stir for 30 minutes until completely dissolved, and set aside.

[0252] S6, Fluidized Bed Pellets Drug Application

[0253] The multifunctional fluidized bed (model WBF-5G) was set to bottom spray mode, the air inlet temperature was 65°C, the pellet cores were weighed and added to the fluidized bed, the material temperature was controlled at 40±5°C, the emulsion inlet speed was 6rpm, and the atomization pressure was 3.0bar. After the emulsion was sprayed, it was dried for 10 minutes at an air inlet temperature of 60°C, and the moisture was measured at 80°C using a fast halogen moisture analyzer to control the moisture content to not exceed 1.0%.

[0254] Test 1: Inclusion rate test

[0255] Detection method:

[0256] 1) Total Vitamin A Content

[0257] Determine according to the high performance liquid chromatography method (General Rule 0512). Operate in a dark environment.

[0258] Test solution: Take about 200 mg of the product, place it in a 200 mL volumetric flask, add 10 mL of purified water, ultrasonicate in a 60°C water bath for 5 min, and shake from time to time. Cool rapidly, dilute to the mark with isopropanol, shake well, and filter.

[0259] Reference substance stock solution: Take about 75 mg of vitamin A reference substance, weigh accurately, place in a 50 mL volumetric flask, add isopropanol to dissolve and quantitatively dilute to the scale.

[0260] Reference solution: Take 5 mL of vitamin A reference stock solution, place it in a 50 mL volumetric flask, and dilute to the mark with isopropanol.

[0261] Chromatographic conditions: silica gel as filler (Tnature C18 4.6mm×150mm, 5μm or chromatographic column with equivalent performance); methanol as mobile phase; flow rate of 1.5mL per minute; column temperature of 35℃; detection wavelength of 325nm; injection volume of 20μl.

[0262] Determination method: Accurately measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, record the chromatogram, and calculate by peak area according to the external standard method.

[0263] 2) Free vitamin A content

[0264] Test solution: Take about 200 mg of the product, place it in a 200 mL volumetric flask, add about 150 mL of ether, shake vigorously at 25°C for 10 min, dilute to the mark with ether, shake well, and filter.

[0265] Determine free vitamin A by referring to the method for determining total vitamin A content.

[0266] Inclusion rate = (total vitamin A - free vitamin A) / total vitamin A × 100%. The results are shown in Table 1.

[0267] Table 1 Determination results of vitamin A inclusion rate of different samples

[0268]

[0269] Result analysis: The vitamin A inclusion rate of Examples 1-6 is relatively high (>95%), which shows that the vitamin A inclusion powder of the present application has a good vitamin A inclusion effect.

[0270] The emulsion of comparative example 1 after homogenization was clearly stratified after standing for 4 hours, while the emulsion of example 1 after homogenization was stable, and the vitamin A inclusion rate of comparative example 1 was significantly lower than that of example 1. It can be seen that the preparation process of high-pressure homogenization has a significant improvement in product quality.

[0271] In Comparative Example 2, the type of filler was adjusted, and the vitamin A inclusion rate decreased; in Comparative Example 3, after the atomization pressure was lowered, the micro-pills could not be smoothly loaded with the drug; in Comparative Example 4, the filler was added in step S1, and the vitamin A inclusion rate was significantly deteriorated. It can be seen that the type of filler, the timing of addition and the atomization pressure all have a significant impact.

[0272] Test 2 Stability test of vitamin A emulsion

[0273] Sample: the homogenized emulsions of Example 1 and Comparative Example 1.

[0274] Storage conditions: Keep still, away from light, at room temperature.

[0275] Detection method: Take about 210 mg of the product from the middle and lower layers of the emulsion, place it in a 200 mL volumetric flask, add 10 mL of purified water, ultrasonicate in a 60°C water bath for 5 min, and shake from time to time. Cool rapidly, dilute to the mark with isopropanol, shake well, and filter.

[0276] Reference solution: Preparation method is the same as that for total vitamin A content determination.

[0277] Chromatographic conditions: Same as the total vitamin A content determination method. The results are shown in Table 2.

[0278] Table 2 Stability test results of emulsion after homogenization

[0279]

[0280] Experimental results: After high-pressure homogenization, the emulsion of Example 1 was milky white in color, and remained a uniform milky white emulsion after standing for 24 hours. However, the color of Comparative Example 1 was light yellow after high-shear preparation, and after standing for 4 hours, significant stratification occurred, with the upper layer being yellow (mainly the yellow color of vitamin A palmitate oil) and the lower layer being light yellow (mainly the color of gum arabic). It can be seen that high-pressure homogenization is beneficial to improving the stability of the emulsion after homogenization.

[0281] Test 3: Influencing factors test

[0282] Samples: Examples 1-6, Comparative Example 1, Comparative Example 2, Comparative Example 4.

[0283] Test conditions: high temperature 60°C, high humidity 75%RH and composite conditions (40°C+75%RH)

[0284] Each sample was placed in each test environment for 10 days to conduct the influencing factor experiment. The total vitamin A content was measured at 5 days and 10 days respectively to investigate the stability of different samples under different conditions. The results are shown in Table 3.

[0285] Detection method: Refer to test 1.

[0286] Table 3 Test results of influencing factors of various embodiments and comparative examples

[0287]

[0288] It can be seen from Table 3 that the stability of Examples 1-6 under different conditions is significantly better than that of Comparative Examples 1-2 and 4. It can be seen that high-pressure homogenization, the type of filler and the timing of addition have a significant impact on the stability of the vitamin A inclusion powder.

[0289] Test 4 Storage stability test

[0290] Samples: Examples 1-4 and Comparative Examples 1-2.

[0291] Packaging: composite film bag packaging, 10g / bag.

[0292] Test conditions: ① Refrigeration (2-8℃); ② Long-term test (25±2℃, 60%±10%RH); ③ Accelerated test (40℃±2℃, 75%RH±5%RH).

[0293] Inspection time points: January, February and March.

[0294] Detection method: Refer to Test 1 for the determination of total vitamin A content. The results are shown in Tables 4-6.

[0295] Table 4 Refrigerated (2-8°C) stability results

[0296]

[0297] Table 5 Stability results of long-term test (25±2℃, 60%±10%RH)

[0298]

[0299] Table 6 Accelerated test (40℃±2℃, 75%RH±5%RH) stability results

[0300]

[0301] Experimental results:

[0302] Under refrigerated conditions, Examples 1-4 had good stability and almost no decreasing trend in content. Comparative Example 1-2 had a faster decrease in content in the first month under refrigerated conditions, which may be due to the high free vitamin A content.

[0303] Under long-term test conditions, Examples 1-4 have better stability, while Comparative Examples 1-2 have poorer stability.

[0304] The stability changes of each sample in the examples and comparative examples under accelerated conditions (40°C±2°C, 75%RH±5%RH) are relatively greater, and the stability of examples 1-4 is significantly better than that of comparative examples 1-2.

[0305] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0306] The above-described embodiments only express several implementation methods of the present application, and the descriptions thereof are relatively specific and detailed, but they cannot be construed as limiting the scope of the patent application. It should be pointed out that, for a person of ordinary skill in the art, several variations and improvements can be made without departing from the concept of the present application, and these all belong to the protection scope of the present application. Therefore, the protection scope of the patent application shall be subject to the attached claims.

Claims

1. A method for preparing vitamin A inclusion powder, characterized in that: The vitamin A inclusion powder comprises the following raw materials: vitamin A active ingredient, capsule material, filler, stabilizer, pellet core and water; the capsule material comprises gum arabic and / or gelatin; the filler comprises sucrose and maltodextrin; The preparation method comprises the following steps: Dissolving the capsule material in water to prepare an aqueous phase; Mixing vitamin A active ingredient and a stabilizer to prepare an oil phase; Mixing the water phase with the oil phase to prepare a primary emulsion; After homogenizing the primary emulsion, the filler is added and mixed to prepare a spray solution; Fluid-bed spray drying the spray solution onto the pellet cores to prepare the vitamin A inclusion powder; The atomization pressure of the fluidized bed spray drying is 2.0-4.0 bar.

2. The preparation method according to claim 1, characterized in that The vitamin A inclusion powder comprises the following raw materials in parts by weight: 30-80 parts of vitamin A active ingredient, 50-200 parts of capsule material, 40-120 parts of filler, 0.5-20 parts of stabilizer, 600-900 parts of pellet core and 150-400 parts of water.

3. The preparation method according to claim 1 or 2, characterized in that: The vitamin A active ingredient includes vitamin A acetate and / or vitamin A palmitate; and / or the stabilizer comprises at least one of butylated p-hydroxyanisole, butylated hydroxytoluene, α-tocopherol and tert-butylhydroquinone; And / or the pellet core comprises a sucrose pellet core and / or a microcrystalline cellulose pellet core.

4. The preparation method according to claim 1 or 2, characterized in that: The particle size of the pellet core is 100-500 μm.

5. The preparation method according to claim 1 or 2, characterized in that: The mass ratio of the sucrose to maltodextrin is 1:0.5-2.

6. The preparation method according to claim 1 or 2, characterized in that: The homogenization includes shear homogenization and / or high pressure homogenization; And / or the shear homogenization conditions include a rotation speed of 10000-20000 rpm and homogenization for 20-30 min; And / or the conditions of the high-pressure homogenization include a homogenization pressure of 600-1500 bar and homogenization for 3-8 times.

7. The preparation method according to claim 1 or 2, characterized in that: The step of fluidizing the spray bed and spray drying the spray solution onto the pellet cores is specifically as follows: adding the pellet cores into the fluidized bed and spray drying the spray solution onto the pellet cores; And / or the fluidized bed spray drying conditions also include: bottom spray mode; air inlet temperature of 50-70°C; material temperature of 30-50°C; liquid inlet speed of 4-8rpm; And / or in the step of fluidizing the spraying solution and spraying it onto the pellet cores, the weight gain of the pellet cores is ≥27%.

8. Vitamin A inclusion powder prepared by the preparation method according to any one of claims 1 to 7.

9. Use of the vitamin A inclusion powder prepared by the preparation method according to any one of claims 1 to 7 or the vitamin A inclusion powder according to claim 8 in a single or compound dosage form of vitamin A; Optionally, the dosage form product includes at least one of a tablet, a capsule and a suspension.

10. A single or compound dosage form of vitamin A, characterized in that: The invention comprises the vitamin A inclusion powder prepared by the preparation method according to any one of claims 1 to 7 or the vitamin A inclusion powder according to claim 8.

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