White hypromellose hollow capsule, method of preparation and use thereof

Abstract

The application discloses a white hypromellose hollow capsule, a preparation method and application thereof, and the composition of the hollow capsule comprises the following components in percentage by weight: 10-35 parts of hypromellose, 0.1-3 parts of a gelling agent, 0.2-3 parts of a complexing agent, 0.1-3 parts of a phosphate, 0.05-1 parts of an emulsifying agent, 0.05-1 parts of a coagulant, 0.01-1 parts of starch, 0-2 parts of a pigment, and the rest is water. The application discloses a white hypromellose hollow capsule with a whitening effect, which is obtained by adding the complexing agent and the phosphate and controlling the drying temperature and the drying time, and does not contain white pigment light-proof agents such as titanium dioxide, zinc oxide, calcium carbonate, barium sulfate and magnesium oxide. The hollow capsule has the advantages of uniform surface, good gloss, good uniformity, good light-proof property, small capsule weight difference, market demand satisfaction, and application in the fields of medicines and health products.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of pharmaceutical excipients, and particularly relates to a white hypromellose hollow capsule, a preparation method thereof and application thereof. BACKGROUND

[0002] The hollow capsule is a common dosage form in medicines and health products, and a light shielding agent needs to be added or the capsule shell is whitened to achieve the light shielding effect to ensure the stability of light-sensitive drugs. In the prior art, titanium dioxide is generally used as the light shielding agent, and a small amount of addition can achieve good light shielding effect. However, in recent years, titanium dioxide is listed as a carcinogen in European countries. On November 8, 2021, member states approved the proposal of the European Commission on banning the use of titanium dioxide (E171) as a food additive from 2022. On January 14, 2022, the European Commission officially passed the ban on the use of titanium dioxide as a food additive (E171), with a transition period of 6 months. On August 7, 2022, the EU's ban on titanium dioxide came into full effect. France is even more advanced than the European Commission, and has completely banned food containing titanium dioxide since the beginning of 2020.

[0003] With the implementation of the policy of banning titanium dioxide as a food additive, titanium dioxide substitutes have become the focus of the industry. In order to seek a product that can replace the light shielding effect of titanium dioxide and be applied to the production of hollow capsule shells, the application prepares a white hypromellose hollow capsule to meet the market demand.

[0004] Through retrieval, no patent disclosure related to the present patent application has been found. SUMMARY

[0005] The application aims to overcome the shortcomings of the prior art and provide a white hypromellose hollow capsule and a preparation method thereof.

[0006] The application adopts the technical scheme to solve the technical problem:

[0007] A white hypromellose hollow capsule, raw material components and weight fractions of which comprise:

[0008]

[0009]

[0010] Further, the hypromellose is hypromellose 2910 type, and the viscosity is 3-8 mpa.s.

[0011] Further, the gelling agent is one or several of carrageenan, welan gum, xanthan gum, gellan gum, locust bean gum, guar gum, gum arabic, konjac gum, pectin.

[0012] Further, the complexing agent is one or several of ethylenediaminetetraacetic acid, triethanolamine, citric acid, tartaric acid, oxalic acid.

[0013] Further, the phosphate is one or several of sodium tripolyphosphate, sodium hexametaphosphate, sodium pyrophosphate, trisodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium acid pyrophosphate, disodium dihydrogen pyrophosphate, potassium dihydrogen phosphate, potassium hydrogen phosphate.

[0014] Further, the emulsifying agent is one or several of sucrose oleate, sucrose laurate, sucrose fatty acid ester, triethanolamine, butanediol laurate, fatty acid glyceride, sodium caseinate.

[0015] Further, the coagulating agent is one or several of potassium carbonate, potassium chloride, potassium citrate, calcium chloride, magnesium chloride.

[0016] Further, the starch is one or several of water-soluble starch, soluble starch, corn starch, potato starch, or the pigment is a synthetic pigment or a natural pigment.

[0017] The preparation method of the white hypromellose hollow capsule as described above comprises the following steps:

[0018] (1) The complexing agent and the gelling agent are weighed and added to a container containing cold purified water, stirred uniformly, sealed, and heated in a water bath, with the water bath temperature set to 95-100°C. When the water bath temperature rises to 90-100°C and stabilizes for 30 minutes, the hypromellose, phosphate, coagulating agent, and starch are added, stirred uniformly, and stabilized for 30 minutes, and then the temperature is lowered to 60-65°C, the emulsifying agent is added, stirred uniformly, and the formed glue liquid is continuously stabilized at 60-65°C for 0.5-1h.

[0019] (2) The stabilized glue liquid in step (1) is poured into a glue box, and the mold is dipped into the glue liquid to form when the temperature of the glue liquid drops to 55-60°C. The mold with the dipped glue liquid is placed in a sealed condition at 28-35°C for drying for 30 minutes, and then air-dried at 40-50°C for 30 minutes to obtain a capsule cap glue blank. The mold is demolded using a demolding device, manually cut, and fitted to produce white hypromellose hollow capsules that meet the standard requirements. If colored hollow capsules with light-shielding properties are to be produced, a pigment dye is added on this basis.

[0020] The white hypromellose hollow capsule as described above is applied in the preparation of capsules.

[0021] The advantages and positive effects obtained by the present application are as follows:

[0022] 1. The present application provides a white hypromellose hollow capsule without using opacifying agents, which meets the requirements of the European Union countries that prohibit the use of titanium dioxide, and can replace titanium dioxide in hollow capsules to achieve light-proof effect and ensure the stability of light-sensitive drugs.

[0023] 2. The method of the present application uses the addition amount of complexing agent and phosphate and controls the drying temperature and drying time to prepare hypromellose hollow capsules with whitening effect. If other colors are required, corresponding pigments can be added on this basis. The surface of the hollow capsule is uniform, has good gloss, good uniformity, good light-blocking property, and small capsule weight difference, which can meet the use requirements of hypromellose hollow capsules in the Chinese Pharmacopoeia.

[0024] 3. The white hypromellose hollow capsule of the present application does not contain titanium dioxide, zinc oxide, calcium carbonate, barium sulfate, magnesium oxide and other white pigment light-proof agents. By adding pharmaceutical excipients and using a special processing technology, white hypromellose hollow capsules are produced to meet market demand and can be applied to the fields of pharmaceuticals and health products.

[0025] 4. Because calcium carbonate, zinc oxide and other substances are relatively unstable in acidic conditions, they are prone to subtle chemical reactions with acidic contents, resulting in different degrees of discoloration of the capsule shell, and the capsule shell friability will also deteriorate with the chemical reaction between the content and the capsule shell. The white hypromellose hollow capsule of the present application has optimal whiteness and brightness, stable chemical properties, and is not prone to react with the content, which is particularly advantageous when filling acidic content such as pharmaceutical powders. BRIEF DESCRIPTION OF DRAWINGS

[0026] Figure 1 Figure for the influence of different complexing agent amounts on the whiteness of white hypromellose hollow capsules in the present application;

[0027] Figure 2 Figure for the influence of different phosphate amounts on the whiteness of white hypromellose hollow capsules in the present application;

[0028] Figure 3 Figure for the influence of different drying temperatures in the second stage (i.e. step (2) of the preparation method) on the whiteness of white hypromellose hollow capsules in the present application;

[0029] Figure 4 Figure for the influence of different drying times in the second stage (i.e. step (2) of the preparation method) on the whiteness of white hypromellose hollow capsules in the present application;

[0030] Figure 5Appearance, uniformity, color contrast chart of white hypromellose hollow capsules prepared by the method of the present application and capsules prepared by using titanium dioxide, zinc oxide, calcium carbonate as light shielding agents;

[0031] Figure 6 Appearance contrast chart of capsule shells after three types of capsules in the present application are filled with apple vinegar and placed for six months; wherein, the pictures from left to right are calcium carbonate capsules, zinc oxide capsules, capsules of the present application, respectively;

[0032] Figure 7 Appearance contrast chart of capsule shells after three types of capsules in the present application are filled with glucosamine hydrochloride and placed for six months; wherein, the pictures from left to right are calcium carbonate capsules, zinc oxide capsules, capsules of the present application, respectively;

[0033] Figure 8 Appearance contrast chart of three types of capsules in the present application when not filled with drug powder; wherein, the pictures from left to right are zinc oxide capsules, calcium carbonate capsules, capsules of the present application, respectively. DETAILED DESCRIPTION

[0034] The present application is further described below in conjunction with examples, which are descriptive rather than limiting, and cannot be used to limit the protection scope of the present application.

[0035] The various experimental operations involved in the specific embodiments are all conventional techniques in the art, and the parts not specially noted in the text can be implemented by referring to various commonly used tool books, scientific and technical literature or related instructions, manuals, etc. before the application date of the present application.

[0036] A white hypromellose hollow capsule, the raw material composition and weight fraction thereof include:

[0037]

[0038] More preferably, the hypromellose is hypromellose type 2910, and the viscosity thereof is 3-8 mpa.s.

[0039] More preferably, the gelling agent is one or a mixture of several of carrageenan, welan gum, xanthan gum, gellan gum, locust bean gum, guar gum, gum arabic, konjac gum, and pectin.

[0040] More preferably, the complexing agent is one or several of ethylenediaminetetraacetic acid, triethanolamine, citric acid, tartaric acid, and oxalic acid.

[0041] More preferably, the phosphate is one or several of sodium tripolyphosphate, sodium hexametaphosphate, sodium pyrophosphate, trisodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium acid pyrophosphate, disodium dihydrogen pyrophosphate, potassium dihydrogen phosphate, and dipotassium hydrogen phosphate.

[0042] Preferably, the emulsifier is one or more of sucrose oleate, sucrose laurate, sucrose fatty acid ester, triethanolamine, butylene glycol laurate, glycerol fatty acid ester, sodium caseinate.

[0043] Preferably, the coagulant is one or more of potassium carbonate, potassium chloride, potassium citrate, calcium chloride, magnesium chloride.

[0044] Preferably, the starch is one or more of water-soluble starch, soluble starch, corn starch, potato starch, or the pigment is a synthetic pigment or a natural pigment.

[0045] The preparation method of the white hypromellose hollow capsule as described above comprises the following steps:

[0046] (1) The complexing agent and the gelling agent are weighed and added to a container containing cold purified water, stirred uniformly, sealed, and heated in a water bath, with the water bath temperature set to 95-100°C. When the water bath temperature rises to 90-100°C and stabilizes for 30 minutes, the hypromellose, phosphate, coagulant, and starch are added, stirred uniformly, and stabilized for 30 minutes, and then the temperature is lowered to 60-65°C. The emulsifier is added, stirred uniformly, and the formed glue liquid is continuously stabilized at 60-65°C for 0.5-1h.

[0047] (2) The stabilized glue liquid in step (1) is poured into a glue box, and the glue liquid is molded by dipping into a mold at a temperature of 55-60°C. The mold with the dipped glue liquid is placed in a sealed condition at 28-35°C for drying for 30 minutes, and then air-dried at 40-50°C for 30 minutes to obtain a capsule cap glue blank. The mold is demolded using a demolding device, manually cut, and fitted to produce white hypromellose hollow capsules that meet the standard requirements. If colored hollow capsules with light-shielding properties are to be produced, a pigment dye is added on this basis.

[0048] The application of the white hypromellose hollow capsule as described above in the preparation of capsules.

[0049] Specifically, the relevant preparation and detection are as follows:

[0050] Example 1

[0051] A preparation method of a white hypromellose hollow capsule comprises the following steps:

[0052] (1) Respectively take 100, 150, 200 parts of ethylenediaminetetraacetic acid, 120 parts of carrageenan into a beaker containing cold purified water, stir uniformly with a glass rod, seal the beaker mouth with plastic wrap, put into a water bath to start heating, set the water bath temperature to 95℃, when the water bath temperature rises to 90℃, stabilize for 30 minutes, then add 6000 parts of hydroxypropyl methyl cellulose, 100 parts of potassium dihydrogen phosphate, 50 parts of potassium chloride, 19 parts of soluble starch into the solution, stir uniformly, stabilize for 30 minutes, then cool to 60℃, add 45 parts of sucrose fatty acid ester into the glue solution, stir uniformly, and continue to stabilize the glue solution at 60℃ for 1 hour;

[0053] Wherein, the above parts are all weight parts;

[0054] (2) Pour the stabilized glue solution into the glue box, perform mold dipping forming at a glue solution temperature of 58℃, place the mold dipped with glue solution in a 30℃ closed condition for drying for 30 minutes, then perform air blowing drying at 40℃ for 30 minutes, to obtain a capsule cap body glue blank, use a demolding device to perform demolding, manual cutting and fitting, to produce white hydroxypropyl methyl cellulose hollow capsules meeting the standard requirements;

[0055] (3) The white hydroxypropyl methyl cellulose hollow capsules obtained in step (2) meet the standard requirements of the 2020 edition of Chinese Pharmacopoeia for hydroxypropyl methyl cellulose hollow capsules.

[0056] The relevant detection is as follows:

[0057] According to the different amounts of complexing agent, the whiteness of the capsules is as follows: Figure 1 ;

[0058] Use CI7800 benchtop spectrophotometer to test the whiteness of the hollow capsules, take the batch number V2021-043602 of 00 # White titanium dioxide capsules are used as white body reference samples, and the whiteness of three kinds of white capsules with different amounts of complexing agent is tested, and the experimental results are as follows:

[0059] Sample information DL* DE* Sample 1 (complexing agent addition 100 parts) -8.42 darker 8.43 Sample 2 (complexing agent addition 150 parts) -3.49 darker 3.91 Sample 3 (complexing agent addition 200 parts) 1.50 lighter 1.79

[0060] Note: Dl* is the depth index, the worse the light shielding effect of the capsule, the deeper the display, the lighter; DE* is the total color difference;

[0061] From the above table data and pictures, it can be seen that the whiteness of the hollow capsule varies with the amount of complexing agent. Taking the commercially available white titanium dioxide capsule as the reference sample, the whiteness and light shielding effect of sample 1 are the worst, and the total color difference is the largest. The whiteness and light shielding effect of sample 3 are higher than those of the reference sample, and the total color difference is close to that of the reference sample. The hollow capsule can meet the requirements of different whiteness, and samples 1-3 can replace titanium dioxide capsules with different whiteness requirements.

[0062] From the above data, it can be seen that when the hydroxypropyl methyl cellulose hollow capsule contains a complexing agent and a phosphate, the whiteness of the hollow capsule can be adjusted by controlling the amount of the complexing agent. Without adding a light shielding agent such as titanium dioxide, the same light shielding effect and whiteness as adding different amounts of titanium dioxide can be achieved.

[0063] Example 2

[0064] A method for preparing a white hydroxypropyl methyl cellulose hollow capsule, comprising the following steps:

[0065] (1) Take 100 parts of ethylenediaminetetraacetic acid and 120 parts of carrageenan and add them to a beaker containing cold purified water. Stir uniformly with a glass rod, seal the beaker opening with plastic wrap, and place it in a water bath. Set the water bath temperature to 95°C. When the water bath temperature rises to 90°C, stabilize for 30 minutes. Then add 6000 parts of hydroxypropyl methyl cellulose, 100 parts, 150 parts, and 200 parts of potassium dihydrogen phosphate, 50 parts of potassium chloride, and 19 parts of soluble starch to the solution. Stir uniformly and stabilize for 30 minutes. Then reduce the temperature to 60°C and add 45 parts of sucrose fatty acid ester to the glue solution. Stir uniformly and continue to stabilize the glue solution at 60°C for 1 hour;

[0066] In the above, the parts are all weight parts;

[0067] (2) Pour the stabilized glue solution into the glue box. At a glue temperature of 58°C, perform mold dipping and molding. Place the mold dipped with glue in a 30°C sealed environment for drying for 30 minutes. Then dry at 40°C with air blowing for 30 minutes to obtain a capsule cap body blank. Use a demolding device for demolding, manual cutting, and assembly to produce white hydroxypropyl methyl cellulose hollow capsules that meet the standard requirements;

[0068] (3) The white hydroxypropyl methyl cellulose hollow capsules obtained in step (2) meet the standard requirements of the 2020 edition of the Chinese Pharmacopoeia for hydroxypropyl methyl cellulose hollow capsules.

[0069] The relevant tests are as follows:

[0070] According to the different amounts of phosphate, the whiteness of the capsule is as follows: Figure 2 ​

[0071] The whiteness of the empty capsules was tested using a CI7800 benchtop spectrophotometer. Using our company's commercially available 00# white titanium dioxide capsules (batch number V2021-043602) as the whiteness reference sample, whiteness tests were conducted on three white capsules with different phosphate dosages. The experimental results are shown in the table below:

[0072] Sample information DL* DE* Sample 1 (phosphate addition 100 parts) -12.66 darker 12.58 Sample 2 (phosphate addition 150 parts) -4.10 darker 4.05 Sample 3 (phosphate addition 200 parts) -1.30 darker 1.46

[0073] Note: Dl* is the darkness index; the worse the capsule's light-blocking effect, the more transparent it appears, and the darker it appears. DE* is the total color difference.

[0074] The data and images above show that the whiteness of the empty capsules varies with the amount of phosphate added. Taking the company's commercially available white titanium dioxide capsules as the reference sample, sample 1 capsule has the worst whiteness and light-blocking effect, and the biggest difference from the reference sample. The whiteness, light-blocking effect, and total color difference of sample 3 are close to the reference sample, and it can meet the requirements of different whiteness of the empty capsules. Samples 1-3 can all replace titanium dioxide capsule samples with different whiteness requirements.

[0075] The data above shows that when hydroxypropyl methylcellulose (HPMC) empty capsules contain complexing agents and phosphates, the whiteness of the capsules can be adjusted by controlling the amount of phosphate added. This achieves the same light-blocking effect and whiteness as adding different amounts of titanium dioxide without adding light-blocking agents such as titanium dioxide. Furthermore, it can be seen that when the weight ratio of ethylenediaminetetraacetic acid (EDTA):carrageenan:phosphate is 100:120:200, EDTA, carrageenan, and phosphate have a synergistic effect, enhancing the properties of the prepared white HPMC empty capsules.

[0076] Example 3

[0077] A method for preparing white hydroxypropyl methylcellulose empty capsules includes the following steps:

[0078] (1) Weigh 100 parts of ethylenediaminetetraacetic acid and 120 parts of carrageenan and add them to a beaker containing cold purified water. Stir with a glass rod until homogeneous. Seal the mouth of the beaker with plastic wrap and place it in a water bath to start heating. Set the water bath temperature to 95℃. After the water bath temperature rises to 90℃ and stabilizes for 30 minutes, add 6000 parts of hydroxypropyl methylcellulose, 100 parts of potassium dihydrogen phosphate, 50 parts of potassium chloride, and 19 parts of soluble starch to the solution. Stir until homogeneous and stabilize for 30 minutes. Then cool down to 60℃. Add 45 parts of emulsifier to the glue solution and stir until homogeneous. Continue to stabilize the glue solution at 60℃ for 1 hour.

[0079] All of the above quantities are by weight.

[0080] (2) The stable glue solution is poured into the glue box, and the mold is dipped into the glue solution at a temperature of 58°C to form a mold. The mold with the dipped glue solution is placed in a closed condition at 30°C for drying for 30 minutes, and then air-dried at 40°C, 45°C and 50°C for 30 minutes respectively to obtain a capsule cap glue blank. The mold is removed using a demolding device, manually cut and fitted to produce white hypromellose hollow capsules that meet the standard requirements;

[0081] (3) The white hypromellose hollow capsules obtained in step (2) meet the standard requirements of the 2020 edition of Chinese Pharmacopoeia for hypromellose hollow capsules.

[0082] The relevant tests are as follows:

[0083] According to the different drying temperatures in the second stage (i.e. step (2)), the whiteness of the capsules is as follows: Figure 3 ;

[0084] The CI7800 spectrophotometer is used to test the whiteness of the hollow capsules. The 00# white titanium dioxide capsules produced by our company with batch number V2021-043602 are used as the white body reference sample. The whiteness of three kinds of white capsules with different two-stage drying temperatures is tested. The experimental results are as follows:

[0085] Sample information DL* DE* Sample 1 (drying temperature 40°C) -4.69 darker 4.54 Sample 2 (drying temperature 45°C) -4.53 darker 4.11 Sample 3 (drying temperature 50°C) 0.79 lighter 0.85

[0086] Note: Dl* is the depth index. The worse the light shielding effect of the capsule, the deeper the display; DE* is the total color difference;

[0087] From the above table data and pictures, it can be seen that when the complexing agent and phosphate are contained, the whiteness of the hollow capsules has a certain range of whiteness change with the different two-stage drying temperatures. Taking the company's commercially available white titanium dioxide capsules as the reference sample, the light shielding effect of sample 1 and sample 2 capsules is not much different, and the whiteness and light shielding effect are slightly worse than the reference sample. The whiteness and light shielding effect of sample 3 are slightly better than the reference sample, which can meet the requirements of hollow capsules for different whiteness. Samples 1-3 can replace the titanium dioxide capsules with different whiteness requirements;

[0088] From the above data, it can be seen that when the hypromellose hollow capsules contain complexing agents and phosphates, the whiteness of the hollow capsules can be adjusted by controlling the two-stage drying temperature. In the absence of titanium dioxide and other light shielding agents, the same light shielding effect and whiteness as adding different amounts of titanium dioxide can be achieved. At the same time, it can also be seen that when the weight ratio of ethylenediaminetetraacetic acid to carrageenan is 100:120 and the drying temperature is 50°C, ethylenediaminetetraacetic acid, carrageenan and drying temperature of 50°C have a synergistic effect among them. The three can synergistically improve the related properties of the prepared white hypromellose hollow capsules.

[0089] Example 4

[0090] A method for preparing a white hypromellose hollow capsule, comprising the following steps:

[0091] (1) Take 100 parts of ethylenediaminetetraacetic acid, 120 parts of carrageenan into a beaker containing cold purified water, stir uniformly with a glass rod, seal the beaker opening with plastic wrap, and start heating in a water bath. Set the water bath temperature to 95℃. When the water bath temperature rises to 90℃, stabilize for 30 minutes. Then add 6000 parts of hypromellose, 100 parts of potassium dihydrogen phosphate, 50 parts of potassium chloride, and 19 parts of soluble starch into the solution and stir uniformly. After stabilizing for 30 minutes, cool to 60℃. Add 45 parts of sucrose fatty acid ester to the glue solution and stir uniformly. Continue to stabilize the glue solution at 60℃ for 1 hour;

[0092] Wherein, the above parts are all weight parts;

[0093] (2) Pour the stabilized glue solution into the glue box. At a glue solution temperature of 58℃, perform mold dipping to form the glue. Place the mold dipped with glue solution in a 30℃ sealed condition for drying for 30 minutes. Then dry by blowing air at 50℃ for 20 minutes, 30 minutes, and 40 minutes respectively to obtain a capsule cap glue blank. Use a demolding device for demolding, manual cutting, and fitting to produce white hypromellose hollow capsules that meet the standard requirements;

[0094] (3) The white hypromellose hollow capsules obtained in step (2) meet the standard requirements of the 2020 edition of Chinese Pharmacopoeia for hypromellose hollow capsules.

[0095] The relevant tests are as follows:

[0096] According to different two-stage drying times, the capsule whiteness is as follows: Figure 4 ;

[0097] Use CI7800 benchtop spectrophotometer to test the whiteness of the hollow capsules. Take the 00# white titanium dioxide capsule produced by our company with batch number V2021-043602 as the white body reference sample. Test the whiteness of three kinds of white capsules with different two-stage drying times. The experimental results are as follows:

[0098] Sample information DL* DE* Sample 1 (drying time 20 minutes) -4.51 darker 4.43 Sample 2 (drying time 30 minutes) -2.43 darker 2.35 Sample 3 (drying time 40 minutes) -0.51 darker 0.62

[0099] Note: Dl* is the depth index. The worse the light shielding effect of the capsule, the deeper it shows.

[0100] From the above table data and pictures, it can be seen that when the complexing agent and phosphate are contained, the whiteness of the hollow capsule has a certain range of whiteness change with different two-stage drying times. Taking the company's commercially available white titanium dioxide capsule as a reference sample, the whiteness and light shielding effect of samples 1-3 have little difference, and the difference range with the reference sample is small. Especially, the light shielding effect and total color difference of sample 3 are less than 1, which can meet the requirements of hollow capsules for different whiteness, and samples 1-3 can replace titanium dioxide capsules with different whiteness requirements;

[0101] From the above data, it can be seen that when the hollow capsule of hydroxypropyl methyl cellulose contains a complexing agent and a phosphate, the whiteness of the hollow capsule can be adjusted by controlling the two-stage drying time, and the same light shielding effect and whiteness as adding different amounts of titanium dioxide can be achieved without adding titanium dioxide and other light shielding agents. At the same time, it can also be seen that when the weight ratio of ethylenediaminetetraacetic acid to carrageenan is 100:120, the drying temperature is 50℃, and the drying time is 40 minutes, ethylenediaminetetraacetic acid, carrageenan, drying temperature is 50℃, and drying time is 40 minutes, the four have a synergistic effect, and the four can synergistically improve the performance of the prepared white hydroxypropyl methyl cellulose hollow capsule.

[0102] Example 5

[0103] A method for preparing a white hydroxypropyl methyl cellulose hollow capsule, comprising the following steps:

[0104] (1) Take 150 parts of ethylenediaminetetraacetic acid, 120 parts of carrageenan, and add them to a beaker containing cold purified water. Stir uniformly with a glass rod, seal the beaker opening with plastic wrap, and start heating in a water bath. Set the water bath temperature to 95℃. When the water bath temperature rises to 90℃, stabilize for 30 minutes. Then add 6000 parts of hydroxypropyl methyl cellulose, 100 parts of potassium dihydrogen phosphate, 50 parts of potassium chloride, and 20 parts of soluble starch to the solution and stir uniformly. After stabilizing for 30 minutes, reduce the temperature to 60℃. Add 45 parts of sucrose fatty acid ester to the glue solution and stir uniformly. Continue to stabilize the glue solution at 60℃ for 1 hour;

[0105] Wherein, the above parts are all weight parts;

[0106] (2) Pour the stabilized glue solution into the glue box. At a glue temperature of 58℃, perform mold dipping to form the capsule. Place the mold dipped with glue in a 30℃ sealed environment for drying for 30 minutes. Then dry at 40℃ for 40 minutes with air blowing. The capsule cap body is obtained. Use a demolding device for demolding, manual cutting, and assembly to produce white hydroxypropyl methyl cellulose hollow capsules that meet the standard requirements;

[0107] (3) The white hypromellose hollow capsules obtained in step (2) meet the standard requirements of the 2020 edition of Chinese Pharmacopoeia for hypromellose hollow capsules.

[0108] The relevant tests are as follows:

[0109] The white hypromellose hollow capsules prepared in Example 5 were compared with the capsules containing titanium dioxide, zinc oxide, and calcium carbonate as opacifiers in terms of appearance, uniformity, and color, as shown in Figure 5 ;

[0110] The whiteness of the hollow capsules was tested using a CI7800 benchtop spectrophotometer. The commercially available product batch number V2021-043602 produced by our company was used as the 00 # The whiteness of the ZnO capsules, CaCO3 capsules, and Example 5 capsules was tested using the white TiO2 capsules as the white body reference sample (i.e., the TiO2 capsules in the above figure). The experimental results are shown in the following table:

[0111] Sample information DL* DE* ZnO capsule 4.51 lighter 4.38 CaCO3capsules -5.43 darker 5.23 Example 5 capsule 3.51 lighter 3.42

[0112] As shown by the test data in the table and the pictures, the whiteness and opacifying effect of the ZnO capsules and Example 5 capsules are slightly better than those of the TiO2 capsules (white body reference sample), and the opacifying effect of the CaCO3 capsules is slightly worse. The total color difference of the capsules made of the three different materials is within 6, which can achieve good opacifying effect for the drug powder.

[0113] As shown by the comparison of the pictures and the capsule whiteness test values, the capsules manufactured by the present technology can achieve the replacement of the hollow capsules containing titanium dioxide, zinc oxide, and calcium carbonate as opacifiers in terms of appearance, uniformity, and color. At the same time, it can be seen that when the weight ratio of ethylenediaminetetraacetic acid: carrageenan: phosphate is 150: 120: 100, the drying temperature is 40°C, and the drying time is 40 minutes, the ethylenediaminetetraacetic acid, carrageenan, phosphate, and drying temperature of 40°C and drying time of 40 minutes have a synergistic effect, and the five can synergistically improve the related properties of the white hypromellose hollow capsules prepared.

[0114] In May 2021, the European Food Safety Authority (EFSA) published its safety opinion on titanium dioxide, which cannot rule out the genetic toxicity of titanium dioxide particles, and no longer considers titanium dioxide as a food additive to be safe. On August 7, 2022, the European Union's ban on titanium dioxide officially came into full effect.

[0115] Since the implementation of the ban, more and more countries have begun to propose the ban on titanium dioxide for food additives, and the industry has begun to pay attention to the research on the replacement products of titanium dioxide. According to the substances reported at home and abroad that can replace titanium dioxide as an opacifier, there are zinc oxide, calcium carbonate; the present inventor found that the technology not only has the same light shielding effect as titanium dioxide, and the technology has better drug stability than the capsule shell using calcium carbonate and zinc oxide as the light shielding agent for some acidic drug powders such as apple vinegar, glucosamine hydrochloride and the like. After 6 months of capsule stability test of apple vinegar and glucosamine hydrochloride drug powder filled with calcium carbonate, zinc oxide and the hydroxypropyl methyl cellulose white capsule of example 5 respectively, the test data are as follows:

[0116] Fragility: If the consumer takes the medicine, the capsule shell will be broken, which will affect the use of the medicine. After filling the drug powder into the three types of capsules and placing them at room temperature, 6 months later, 50 capsules were detected according to the method of Chinese Pharmacopoeia, each capsule was repeatedly hit 10 times, and the capsule breakage rate was investigated.

[0117]

[0118] After filling the apple vinegar and glucosamine hydrochloride drug powder into the capsules prepared in the above example 5 and the calcium carbonate and zinc oxide capsules, placing them at room temperature, and investigating the change of the light shielding effect of the capsules after 6 months, see Figures 6 to 8 ;

[0119] Since calcium carbonate, zinc oxide and the like are relatively unstable in chemical properties under acidic conditions, they are easy to have subtle chemical reactions with acidic contents, resulting in different degrees of discoloration of the capsule shell. The capsule shell fragility will also be poor with the chemical reaction of the contents and the capsule shell, and the present technology has the best whiteness and brightness, the chemical properties are stable, and it is not easy to react with the contents. When filling the acidic contents such as drug powder, it has the advantages.

[0120] In addition, according to the product performance test of hydroxypropyl methyl cellulose hollow capsule detection index in the 2020 edition of Chinese Pharmacopoeia, the obtained data meets the use requirements specified in Chinese Pharmacopoeia.

[0121] Although the embodiments of the present application are disclosed for illustrative purposes, those skilled in the art can understand that various alternatives, changes and modifications are possible without departing from the spirit and scope of the present application and the appended claims, therefore, the scope of the present application is not limited to the disclosed content of the embodiments.

Claims

1. A white hydroxypropyl methylcellulose empty capsule, characterized in that: Its raw material composition and the weight ratio of each component are as follows: The weight ratio of hydroxypropyl methylcellulose: ethylenediaminetetraacetic acid: carrageenan: potassium dihydrogen phosphate: potassium chloride: soluble starch: sucrose fatty acid ester is 6000:100:120:100:50:19:45; The hydroxypropyl methylcellulose is hydroxypropyl methylcellulose type 2910, with a viscosity of 3-8 mPa·s; The method for preparing the white hydroxypropyl methylcellulose empty capsules includes the following steps: (1) Weigh out ethylenediaminetetraacetic acid and carrageenan and add them to a container filled with cold purified water. Stir well, seal and heat in a water bath. Set the water bath temperature to 95℃-100℃. After the water bath temperature rises to 90℃-100℃ and stabilizes for 30 minutes, add hydroxypropyl methylcellulose, potassium dihydrogen phosphate, potassium chloride and soluble starch. Stir well and stabilize for 30 minutes. Then cool down to 60℃-65℃, add sucrose fatty acid ester, stir well, and continue to stabilize the formed gel at 60℃-65℃ for 0.5-1h. (2) Pour the stabilized adhesive solution from step (1) into the adhesive box. Dip the mold into the adhesive solution when the temperature of the adhesive solution drops to 55-60℃. Place the mold dipped in the adhesive solution under a sealed condition at 28-35℃ for 30 minutes to dry. Then dry it in a forced air at 50℃ for 40 minutes to obtain the capsule cap body blank. Demold it using a demolding device, cut it manually and assemble it to produce white hydroxypropyl methylcellulose hollow capsules that meet the standard requirements.

2. The application of the white hydroxypropyl methylcellulose hollow capsule as described in claim 1 in capsule preparation.

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